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452 Cards in this Set
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"enalapril
(captopril, lisinopril, and the other “-prils”) |
<b>Mechanism of Action</b>: <u>ACE Inhibitors</u>: <u>reversibly</u> inhibit <u>angiotensin converting enzyme (ACE)</u> by binding Zn moiety. ACE catalyzes the conversion of angiotensin-I to <u>angiotensin-II;</u> AT-II acts on the angiotensin type 1 receptor (<u>AT-1</u>) via PLC, IP3, and DAG to produce a variety of effects. ACE also catalyzes the <u>breakdown of bradykinin</u>.
<b>Effects</b>: ACE-I effects come from <u>inhibition</u> of AT-II effects and an <u>increase</u> in bradykinin effects. <b>AT-II's effects</b>: increase <u>aldosterone </u>(more Na/H2O reabsorption & K secretion), acts directly on tubules to <u>increase Na reabsorption</u>, triggers <u>L-type calcium channels</u> for vascular smooth muscle contraction, stimulates <u>central & peipheral sympathetic</u> responses by increasing catecholamine relase, and acts as a <u>mitogen</u> (smooth muscle hyperplasia, hypertrophy, and migration - remodeling). <b><u>ACE-inhibitors</u> </b>therefore <u>reduce vasoconstriction</u> (A&V), <u>reduce myocardial remodeling</u>, <u>reduce plasma aldosterone</u>, and <u>reduce intraglomerular pressure</u>. <b>Selective Toxicity</b>: <b> Indications</b>: <b><u>Hypertension</u></b> (decrease Na/H2O retention and increase K reabsorption, decrease vasoconstriction, dropping blood pressure). <b><u>Heart failure</u></b> (block AT-II so drop resistance / afterload, decrease cardiac remodeling; also reduce preload by decreasing sodium retention via aldosterone, resulting in <u>increased cardiac output </u>and <u>reduced filling pressures</u>). Also <u>asymptomatic LV dysfunction & diabetic nephropathy</u> (decreases intraglomerular pressure)<b> Toxicity</b>: <b><u>Cough</u> </b>(10-15%, non-productive, often nocturnal / post-URI, not related to cardiopulmonary problems, reversible in 1wk, probably related to <u>bradykinin</u> effects). <b><u>Angioedema</u></b> (abrupt non-pitting swelling of a specific area; often one side of face / extremity/etc, 6-24 hrs). Also <u>dysguesia</u> (loss of taste), <u>hypotension</u> (via volume depletion in setting of low EF), <u>hyperkalemia</u> (increasing K reabsorption). |
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losartan (and the other -sartans)
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<b>Mechanism of Action</b>: <u>Angiotensin receptor blockers</u>: bind to <u>AT-1 receptor</u> (not AT-2), inhibiting the known physiological effects of angiotensin II (all AT-1 mediated).
<b>Effects</b>: ACE-I effects come from <u>inhibition</u> of AT-II effects at AT-1 receptor. <u>Bradykinin is unaffected</u>, and <u>circulating AT-II actually increases</u> (upregulated via feedback from unstimulated AT-1 receptors). Similar effects to ACE-I: <b><u>inhibit </u><u>AT-II's effects</u></b><i><b> </b>(vascular smooth mm contraction, aldosterone secretion, release of adrenal catecholamines, increased sympathetic tone, change in renal function, cellular hypertrophy/hyperplasia)</i> <b>Selective Toxicity</b>: <b> Indications</b>: <b><u>Hypertension</u>, </b>hypertension with <u>LV dysfunction</u>, <u>diabetic nephropathy</u><b> Toxicity</b>: <b>NO <u>Cough</u> </b>(not changing bradykinin breakdown). <b><u>Angioedema</u></b> is <b>more rare.</b> Still see <u>renal failure / hyperkalemia</u> in some cases. |
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quinidine (procainamide, disopyramide)
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<b>Mechanism of Action</b>: <u>Class Ia </u>antiarrhythmic drug; blocks <u>Na </u>channel (<u>prolongs AP</u> and <u>increases QT</u> interval)
<b>Effects</b>: <u>moderate</u> potency and <u>intermediate</u> kinetics. <u>Local anesthetic</u>. <b>Other:</b> Class I = <u>use- and voltage-dependent block</u> (more effective at <u>fast</u> HR and in <u>depolarized</u> tissues). <u>Raises DFTs </u>(have to give more juice to defibrillate) |
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lidocaine (tocainide, mexiletine)
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<b>Mechanism of Action</b>: <u>Class Ib </u>antiarrhythmic drug; blocks <u>Na </u>channel (<u>prolongs AP</u> and <u>increases QT</u> interval)
<b>Effects</b>: <u>lowest</u> potency and <u>fastest</u> kinetics of class. <u>Local anesthetic</u>. <b>Other:</b> Class I = <u>use- and voltage-dependent block</u> (more effective at <u>fast</u> HR and in <u>depolarized</u> tissues) <u>Raises DFTs </u>(have to give more juice to defibrillate) |
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flecainide (propafenone)
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<b>Mechanism of Action</b>: <u>Class Ic</u> antiarrhythmic drug; blocks <u>Na </u>channel (<u>prolongs AP</u> and <u>increases QT</u> interval)
<b>Effects</b>: <u>highest</u> potency and <u>slowest</u> kinetics of class. <u>Local anesthetic</u>. <b>Other:</b> Class I = <u>use- and voltage-dependent block</u> (more effective at <u>fast</u> HR and in <u>depolarized</u> tissues). <u>Raises DFTs </u>(have to give more juice to defibrillate) |
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sotalol
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<b>Mechanism of Action</b>: <u>Class III</u> <u>antiarrythmic drug</u>. Blocks <u>IKf</u> (K channel); <u>prolongs AP</u> and causes <u>longer refractoriness to activation (longer repolarization)</u>
<b>Effects</b>: <u>Prolongs</u> <u>QT interval.</u> <b>Other</b>: Class III = <u>reverse use dependence</u> (more effective at <u>slow</u> HR). <u>Lowers DFTs </u>(have to give <u>less</u> juice to defibrillate) |
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ibutilide
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<b>Mechanism of Action</b>: <u>Class III</u> <u>antiarrythmic drug</u>. Blocks <u>IKf</u> (K channel); <u>prolongs AP</u> and causes <u>longer refractoriness to activation (longer repolarization)</u>. <b>special for ibutilide: </b><u>also prevents Na channels from closing</u><b> (double effect</b>)
<b>Effects</b>: <u>Prolongs</u> <u>QT interval</u> |
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amiodarone
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<b>Mechanism of Action</b>: <u>Class III</u> <u>antiarrythmic drug</u> but has <u>ALL FOUR V-W classes of action</u>.
<b>Effects</b>: <u>Prolongs</u> <u>QT interval</u>, <u>decreases HR</u>, <u>increases PR</u>. Also <u>alpha-adrenergic-receptor</u> and <u>muscarinic recptor</u> blockade<b> Administration</b>: <u>VERY LONG HALF LIFE</u> (20-60d) and <u>very large volume of distribution</u> (>50L/kg)<b> Toxicity</b>: <u>LOTS</u> (“dirty drug for a dirty job”). Contains lots of iodine and <u>looks like thyroxine</u> so it <u>induces thyroid hormone resistance state</u>. Also pulmonary fibrosis, ARDS, hepatitis, neuropathy, thyroid abnormalities, skin discoloration, photosensitivity, drug-drug interactions. <u>CYP3A4 AND CYP2C9 INHIBITOR</u> (metabolized by 3A4). <u>Raises DFTs </u>(have to give more juice to defibrillate)<b> Other</b>: Others being developed (non iodinated) but don't work nearly as well. Class III = <u>reverse use dependence</u> (more effective at <u>slow</u> HR). |
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adenosine
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<b>Mechanism of Action</b>: <u>antiarrythmic agent</u>. Activates <u>GCPR</u>, opens a <u>K channel</u> (direct effect) and <u>inhibits adenylyl cyclase </u>(indirect effect)
<b>Effects</b>: <u>Hyperpolarizes</u> atrial myocytes (<u>shortens APD</u>)<b> Indications</b>:<u> Rapid termination of SVT</u><b> Administration</b>: Short half-life (seconds/minutes)<b> </b> |
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verapamil (phenylalkylamines)
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<b>Mechanism of Action</b>: <u>Calcium channel blocker</u>: directly blinds extracellular domains of <u>alpha subunit </u> of <u>L-type calcium channel</u>, blocks <u>smooth muscle contraction</u> (vascular relaxation) & <u>slowing</u> of AV-node conduction.
<b>Effects</b>: <u>Blocks ability of L-type Ca channel to transport extracellular Ca to intracellular space</u>, blocking cascade of intracelular-Ca-induced Ca release from SR & blocking <u>smooth muscle contraction</u>. Effects localized to <u>vascular / visceral smooth muscle</u>, <u>cardiac muscle</u>, <u>SA/AV nodes</u> (where L-type Ca channels found). At AV node, <u>prolongs refractory period</u> (slower AV node conduction) <b>Selective Toxicity</b>: <b> Indications</b>: <u>Hypertension</u>; <u>supraventricular</u> <u>arrhythmias</u> ( block av node); <u>myocardial</u> <u>ischemic</u> <u>syndromes</u> (but <u>not acute MI / unstable angina!</u>) - drugs of choice for <u>variant</u> (<u>prinzmetal</u>) <u>angina</u> (coronary spasm); also used for <u>stable angina</u> (Beta blockers are first choice). Also used in hypertrophic cardiomyopathy, Raynaud's phenomenon. <b><u>Verapamil only: </u></b><u>migraine prophylaxis</u> (decreases frequence / severity) <b>Administration</b>:Original formulations rapidly metabolized; newer agents have longer half-lives<b> Toxicity</b>: Moderate <u>inhibitor of CYP3A4</u>. <u>Heart block / heart failure</u>, especially with <u>beta blockers</u>, pts with conduction system disease (verapamil >> diltiazem > nefedipine). <u>Aggrevate gastroesophageal reflux</u> (confound chest pain assesment!). <u>Urinary frequency / incontinence</u>. <b><u>Constipation</u></b> (specific to verapamil) <b>Metabolism</b>: Inactivated by <u>CYP3A4</u> metabolism<b> Other</b>:<b> </b>Three classes of Ca channel blockers bind to different parts of L-subunit & <u>don't compete</u> with each other. <u>Verapamil-type</u> drugs have <u>greater ionotropic effect</u> & more marked <u>SA/AV node inhibition </u>(verapamil > diltiazem; nefedipine has none) |
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nefedipine, nimodipine (dihydropyridines)
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<b>Mechanism of Action</b>: <u>Calcium channel blocker</u>: directly blinds extracellular domains of <u>alpha subunit </u> of <u>L-type calcium channel</u>, blocks <u>smooth muscle contraction</u> & <u>slowing</u> of AV-node conduction.
<b>Effects</b>: <u>Blocks ability of L-type Ca channel to transport extracellular Ca to intracellular space</u>, blocking cascade of intracelular-Ca-induced Ca release from SR & blocking <u>smooth muscle contraction</u>. Effects localized to <u>vascular / visceral smooth muscle</u>, <u>cardiac muscle</u>, <u>SA/AV nodes</u> (where L-type Ca channels found). At AV node, <u>prolongs refractory period</u> (slower AV node conduction) <b>Selective Toxicity</b>: <b> Indications</b>: <u>Hypertension</u>; <u>supraventricular</u> <u>arrhythmias</u> ( block av node); <u>myocardial</u> <u>ischemic</u> <u>syndromes</u> (but <u>not acute MI / unstable angina!</u>) - drugs of choice for <u>variant</u> (<u>prinzmetal</u>) <u>angina</u> (coronary spasm); also used for <u>stable angina</u> (Beta blockers are first choice). Also used in hypertrophic cardiomyopathy, Raynaud's phenomenon, <b><u>Nimodipine</u></b><u> </u>(a different dihydropyridine) can be uesd for <u>subarachnoid hemmorhage</u><b> Administration</b>: Original formulations rapidly metabolized; newer agents have longer half-lives<b> Toxicity</b>: Don't inhibit CYP3A4 (others do). <u>Heart block / heart failure</u>, especially with <u>beta blockers</u>, pts with conduction system disease (verapamil >> diltiazem > nefedipine). <u>Aggrevate gastroesophageal reflux</u> (confound chest pain assesment!). <u>Urinary frequency / incontinence</u>. <b><u>Tachycardia, edema</u></b> (specific to dihydropyridines). <b>Metabolism</b>: Inactivated by <u>CYP3A4</u> metabolism<b> Other</b>: also other drugs that end in “-ipine”. Dihydropyridine drugs have <u>no ionotropic effect</u> & <u>no SA/AV node inhibition </u>(verapamil > diltiazem; nefedipine has none) |
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diltiazem (benzothiazepines)
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<b>Mechanism of Action</b>: <u>Calcium channel blocker</u>: directly blinds extracellular domains of <u>alpha subunit </u> of <u>L-type calcium channel</u>, blocks <u>smooth muscle contraction</u> & <u>slowing</u> of AV-node conduction.
<b>Effects</b>: <u>Blocks ability of L-type Ca channel to transport extracellular Ca to intracellular space</u>, blocking cascade of intracelular-Ca-induced Ca release from SR & blocking <u>smooth muscle contraction</u>. Effects localized to <u>vascular / visceral smooth muscle</u>, <u>cardiac muscle</u>, <u>SA/AV nodes</u> (where L-type Ca channels found). At AV node, <u>prolongs refractory period</u> (slower AV node conduction) <b>Selective Toxicity</b>: <b> Indications</b>: <u>Hypertension</u>; <u>supraventricular</u> <u>arrhythmias</u> ( block av node); <u>myocardial</u> <u>ischemic</u> <u>syndromes</u> (but <u>not acute MI / unstable angina!</u>) - drugs of choice for <u>variant</u> (<u>prinzmetal</u>) <u>angina</u> (coronary spasm); also used for <u>stable angina</u> (Beta blockers are first choice). Also used in hypertrophic cardiomyopathy, Raynaud's phenomenon<b> Administration</b>: Original formulations rapidly metabolized; newer agents have longer half-lives<b> Toxicity</b>: Moderate <u>inhibitor of CYP3A4</u>. Don't inhibit CYP3A4 (others do). <u>Heart block / heart failure</u>, especially with <u>beta blockers</u>, pts with conduction system disease (verapamil >> diltiazem > nefedipine). <u>Aggrevate gastroesophageal reflux</u> (confound chest pain assesment!). <u>Urinary frequency / incontinence</u>. <b>Metabolism</b>: Inactivated by <u>CYP3A4</u> metabolism<b> Other</b>: <u>Diltiazem-type</u> drugs have <u>some ionotropic effect</u> & <u>some SA/AV node inhibition</u> (verapamil > diltiazem; nefedipine has none) |
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digoxin
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<b>Mechanism of Action</b>: cardiac glycoside <u>inotropic agent</u>. <u>Inhibits Na/K ATPase</u>
<b>Effects</b>: less <u>Na extrusion</u>, less <u>Ca extrusion</u> (needs gradient), more <u>Ca sequestration</u> in SR, more available for next contraction. Also <u>vagal stimulation</u> & <u>decrease in sympathetic activity</u> <b>Indications</b>: <u>ADJUNCT</u> for treatment of <u>CHF</u> & <u>sinus cardiac rhythm</u>; can control <u>ventricular HR</u> in <u>A-fib.</u> <b><u>AAD effects</u></b>: increase sodium inside; parasympathomimetic, little effect on conduction but used in rate control.<b> Administration</b>:<u>VERY NARROW THERAPEUTIC INDEX (must monitor levels)</u><b> Toxicity</b>: <u>Complete heart block</u>, <u>any </u>other <u>arrhythmia</u>, <u>nausea/vomiting</u>, visual disturbance (classic: <u>yellow vision:</u> Van Gough xanthopsia - yellow paintings). In high doses: intracellular calcium overload, SNS activation.<b> Other</b>: also digitoxin, ouabain (not used as much). <u>PROTOTYPE FOR MIXED CLEARANCE</u> (60-70% renal, 30-40% non-renal) <u>Digitalis</u>: Almost all eliminated by <u>P-glycoprotein</u> (potential for drug-drug interactions) |
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dobutamine
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<b>Mechanism of Action</b>: <u>beta-adrenergic agonist</u> (beta-1, beta-2, also alpha-1 partial agonist)
<b>Effects</b>: <u>enhances cardiac output</u> (increased <b><u>contractility</u></b>), <b><u>little</u></b> change in <u>SVR</u> <b>Indications</b>:<u>short-term </u>tx of <u>cardiac decompensation</u><b> Toxicity</b>: <u>tachycardia, hypotension, ventricular ectopic activit</u>y. Dobutamine-specific: <u>hypertension</u> too |
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isoproteronol
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<b>Mechanism of Action</b>: <u>beta-adrenergic agonist</u> (beta-1, beta-2, also alpha-1 partial agonist)
<b>Effects</b>: <u>enhances cardiac output</u> (increased <b><u>heart rate</u></b>), <b><u>drop</u></b> in <u>SVR</u> <b>Indications</b>:<u>short-term </u>tx of <u>cardiac decompensation</u><b> Toxicity</b>: <u>tachycardia, hypotension, ventricular ectopic activit</u>y. |
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dopamine
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<b>Mechanism of Action</b>: <u>Dopamine agonist</u>: three drugs in one. <u>Low dose</u>: agonist at <u>DA1 receptor</u>, <u>renal vasodilation</u> (increased renal blood flow, diuresis). <u>Intermediate dose</u>: stimulates <u>beta-1</u> receptor; increases <u>HR & contractility</u>. <u>Higher doses</u>: stimulates <u>alpha-1 receptor</u>; <u>vasoconstriction</u>
<b>Indications</b>: <u>Refractory edema with low renal blood flow</u> (<b>low </b>dose- want<b> </b>renal vasodilatory effects). <u>Low CO & shock</u> <b>(intermediate</b> dose - want HR & contractility increased). <u>Shock</u> (<b>high</b> dose: want vasoconstriction)<b> Toxicity</b>: <u>ventricular arrythmia, angina, hypertension,</u> <u>impairment</u> of <u>blood perfusion</u> (high doses) |
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milrone
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<b>Mechanism of Action</b>: <u>Phosphodiesterase inhibitor</u>. <b>increase cGMP</b>, increasing <u>inhibition</u> of <u>cGMP-inhibited cAMP phosphodiesterase</u>, resulting in <u>rise</u> in <u>cAMP</u>, stimulating <u>contractility</u>, <u>accelerating diastolic relaxation</u>, <u>dilation</u>(arterial & venous)
<b>Tried to use</b> in <u>CHF</u> but <u>MORTALITY WORSE</u> <b>Adverse effects</b>: <u>arrythmia, hypotensin</u> |
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statins
(rosuva-, pitava-, atorva-, simva-*, prava-*, fluva-) *=off patent |
<b>Mechanism of Action</b>: <u>HMG-CoA reductase inhibitor</u> (competitive); inhibits cholesterol <u>synthesis</u>.
<b>Effects</b>: <u>Lowers LDL cholesterol </u>up to 60%; reduces MI/angioplasty/bypass/stroke/all-cause mortality in those with CHD. Also <u>raises HDL</u> (8-10%), <u>lowers TGs</u> (10-30%). Also <u>decrease thrombosis</u>, have <u>anti-inflammatory effects</u>, and <u>improve endothelial function</u>. <b> Indications</b>: Lowering cholesterol. All patients with CAD should be on a statin<b> Toxicity</b>: Contrindicated in liver disease but pretty well tolerated. No side effects vs placebo in trials but <u>yes</u> in clinic: <u>muscle pain, reversible liver enzyme abnormalities, myositis</u> (can lead to <u>rhabdomyolysis</u>, myoglobin released after muscle cells lysed, can cause <u>renal failure, </u>rare but serious, can happen when other drugs block CYP3A4 metabolism). No cancer risk increase<b> Other</b>: <u>CYP3A4</u> metabolism. Rosuvastatin = Crestor, atorvastatin = Lipitor, simvistatin = Zocor. |
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ezetimibe
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<b>Mechanism of Action</b>: inhibits absorption of cholesterol. Blocks the Niemann Pick C-1-like-1 protein (<u>NPC1L1 protein</u>), needed to absorb cholesterol from intestine.<b>
Indications</b>: adjunct to dietary measures: hypercholesterolemia <b>Resistance</b>: <u>Genetic differences</u> in NPC1L1 protein: genetic difference in response to drug<b> </b> |
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(cholestyramine, cholestipol, cholesevelam*)
*=pill, others powder |
<b>Mechanism of Action</b>: bile acid sequestrants. Bind bile acids so that they can't be re-absorbed
<b>Effects</b>: Long-chain positively-charged polymer, binds <i>anything</i> that's negatively charged (including bile acids but also negatively charged drugs) <b>Selective Toxicity</b>: <b> Indications</b>: <u>lowers</u> <u>LDL</u> cholesterol (10-25%), also <u>raises</u> <u>HDL</u> a little (1-3%), <u>no change in TGs</u> (can actually increase!)<b> Toxicity</b>: <u>GI sx</u> (including <u>constipation</u>), <u>decreased absorption </u>of some <u>drugs</u>, <u>elevated liver transaminases</u> (rare)<b> Other</b>: <u>Don't use </u>with <u>elevated TGs</u> |
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fenofibrate, gemfibrozil
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<b>Mechanism of Action</b>: Act on <u>PPAR alpha</u> to <u>inhibit synthesis of apo C-III</u>, which <u>inhibits lipoprotein lipase</u>
<b>Effects</b>: <u>Increases lipoprotein lipase activity</u>, speeding <u>removal of TGs from VLDL</u><b> Indications</b>: <u>Lower TGs (</u>20-60%). Also <u>raise HDL-ch</u> (8-10%), may raise <u>LDL</u> cholesterol (BAD!). Both fenofibrate & gemfibrozil have equal effectiveness.<b> Toxicity</b>: <u>GI Sx</u>, elevated <u>liver transaminases.</u> For <u>gemfibrozil</u> (not fenofibrate) <u>myositis</u> (and rhabdmyolysis = myoglobin release with kidney problems) when given with statins |
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lovasa
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<b>Mechanism of Action</b>: Purified fish oils (omega 3 FAs); Lowers TGs by <u>inhibiting diglyceride to triglyceride</u> conversion in liver & intestine<b>
Indications</b>: Very effective at <u>lowering TG</u>s (up to 60% reduction), doesn't affect LDL/HDL<b> Other</b>: Purified ethyl esters of omega-3 FAs (active), 4x more potent than OTC fish oil pills |
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niacin
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<b>Mechanism of Action</b>: Raises HDL cholesterol. <u>Blocks release </u>of <u>fatty acids</u> from adipose tissue
<b>Effects</b>: Activates <u>GPCR</u> that <u>inhibits cAMP</u> formation; cAMP normally activates <u>hormone-sensitive lipase </u>in <u>adipose tissu</u>e (breaks down TGs to release FA to bloodstream). So niacin blocks this release.<b> Indications</b>: <u>Across-the-board </u>activity. <u>Lower LDL-cholesterol</u>(10-25%), <u>raise HDL-cholesterol</u> (15-35%), <u>lower TGs</u> (20-30%)<b> Administration</b>: Crystalline, <u>extended release</u> is most common (1 pill every night); sustained/slow release gives liver damage!<b> Toxicity</b>: <u>Flushing</u>, <u>upper GI</u> sx, <u>hepatotoxicity</u>, increased <u>uric acid / gout</u>, mild <u>hyperglycemia</u> (PROBLEMATIC)<b> Other</b>: A vitamin! Need 1000x vitamin levels to increase HDL though. Nicatinomides (“no flush” niacins) are big on the internet, but they don't work |
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nitroglycerin (NTG)
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<b>Mechanism of Action</b>: <u>Organic nitrate</u>; causes v<u>ascular smooth muscle relaxation</u> Two mechanisms. <u>High</u> <u>doses</u>: <u>direct NO donor</u> (local formation of NO from NTG maybe via a CYP450, activates guanlylyl cyclase by binding to ferrous Fe in hemeprotine; cGMP activates protein kinases / ion channels, leading to smooth muscle relaxation). <u>Low doses</u>: bioactivated by <u>mitochondrial aldehyde dehydrogenase (ALDH-2)</u>, forming bioactive NOx intermediate, activating guanlylyl cyclase as well).
<b>Effects</b>: <u>Smooth muscle relaxation</u>. Graded hemodynamic effects: <u>venous </u>dilation at <u>lower</u> doses than <u>arteriolar</u> (decreased <u>preload</u> / RA/LA pressure; c<u>oronary vessels</u> dilated; redistribution of blood to ischemic areas of heart in CAD pts). <u>Higher doses</u>: <u>arteriolar dilation</u> too (<u>decrease afterload / systemic vascular resistance)</u><b> Indications</b>: Prevent / relieveof <u>MI</u> & associated <u>pain</u>, prevent / relieve <u>CHF Sx & hemodynamic disturbances; CN poisoning;</u> <u>biliary/esophageal </u>pain <b> Administration</b>: <u>Intermittent dosing</u> (during the day, not at night) to desensitize / avoid <u>tolerance</u>. Various forms (sublingual, oral, topical, IV, etc). <u>Dose to effect</u> (wide therapeutic index)<b> Toxicity</b>: Extension of benefits. <u>Headache</u>, <u>hypotension</u>, <u>facial flushing</u>, <u>reflex tachycardia</u>, tolerance/<u>withdrawal</u>, methemoglobinemia <b>Tolerance</b>: <u>Early</u> tolerance (“pseudotolerance”) from <u>baroreceptor reflex</u> to vasodilatory effects; also NO is oxidant, causes some <u>endothelilal dysfunction</u>. <u>Late tolerance</u> (iatrogenic; hours/days) from <u>inactivation of ALDH-2</u> from circulating NOx; can get <u>withdrawal</u> sx (coronary/peripheral arterial spasm - vasoconstriction!) |
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sodium nitroprusside
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<b>Mechanism of Action</b>: <u>Inorganic nitrate</u>; causes v<u>ascular smooth muscle relaxation</u> <u>NO donor</u> (NO formed via local reduction @ vascular smooth muscle: <u>different pathway</u> than NTG).
<b>Effects</b>: <u>Smooth muscle relaxation / vasodilation</u><b> Indications</b>: <u>Hypertensive</u> <u>crisis</u>; <u>Acute heart failure </u>with <u>severe HTN</u>; <u>precise BP reduction </u>( e.g.vascular & neuro<u>surgery</u>); <u>aortic dissection</u>; <u>Ergot </u>poisoning<b> Administration</b>: <u>IV only</u><b> Toxicity</b>: <u>Thiocyanate toxicity:</u> <u>cyanide</u> is part of molecule; released with local metabolism, converted to <u>thiocyanate</u> in liver & excreted by <u>kidney</u>; can have <u>adverse effects of CN poisoning</u> (e.g. <u>seizures</u>) if pt has <u>renal dysfunction</u> & CN builds up. <u>Hypotension</u> too. <b>Tolerance</b>:NO TOLERANCE with prolonged exposure |
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clonidine
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<b>Mechanism of Action</b>: <u>alpha-2</u> adrenergic receptor <u>agonist</u>
<b>Effects</b>:<u>Decreases sympathetic outflow</u> pre-synaptically (takes advantage of feedback mechanism to <u>inhibit AC</u>). <u>Decreases SVR, venous return, and CO</u><b> Indications</b>: Class-wide: <u>Hypertension</u>. Clonidine-specific: analgesia with <u>cancer pain,</u> suppresion of <u>opioid/opiate withdrawal</u><b> Administration</b>: Oral, predictable onset & duration but multiple daily doses needed. Also <u>topical patch</u> (1 wk duration)<b> Toxicity</b>: Class-wide: <u>sedation, orthostatic hypotension, erectile dysfunction</u>. Clonidine-specific: <u>bradycardia</u>, can get <u>rebound hypertension</u> on abupt discontinuation |
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alpha methyldopa
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<b>Mechanism of Action</b>: <u>alpha-2</u> adrenergic receptor <u>agonist</u>
<b>Effects</b>:<u>Decreases sympathetic outflow</u> pre-synaptically (takes advantage of feedback mechanism to <u>inhibit AC</u>). <u>Decreases SVR, venous return, and CO</u><b> Indications</b>: Class-wide: <u>Hypertension</u>. Methyldopa-specific: <u>pregnancy-associated hypertension</u> (safe)<b> Administration</b>: Oral, predictable onset & duration but multiple daily doses needed. Also <u>topical patch</u> (1 wk duration)<b> Toxicity</b>: Class-wide: <u>sedation, orthostatic hypotension, erectile dysfunction</u>. Methyldopa-specific:<u>chronic hepatitis</u> (cirrhosis), <u>positive Coomb's test</u> (rare hemolysis) |
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trimethaphan
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<u>Sympathetic Inhibitor: Ganglionic Blockade</u>
Formerly used for <u>HTN </u>(especially emergent – very potent), now mostly historical & mechanical interest <u>Adverse effects</u> limit use (postural hypotension, constipation, urinary retention, serious impairment of sexual function, lots more) |
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riserpine
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<u>Sympathetic inhibitor: presynaptic catecholamine depletion</u>
Still available for HTN but not widely used (side effects) Adverse effects limit use (severe depression, especially at higher doses, sedation, nasal stuffiness) |
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phenoxybenzamine
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<b>Mechanism of Action</b>: <b><u>Irreversible</u> </b><u>postsynaptic</u> <u>inhibitor</u> of <u>alpha1</u>- and <u>alph</u>a2- <u>adrenergic</u> <u>receptors</u> (binds covalently)<b>
Indications</b>: <u>Hypertension</u> in <b><u>pheochromocytoma</u> Toxicity</b>: <u>Postural hypertension, sexual dysfunction</u><b> Other</b>:Pheochromocytoma: huge sympathetic overflow; can't use beta-blockers or others (won't affect outflow issues, BP could actually go UP!) |
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phentolamine
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<b>Mechanism of Action</b>: <b><u>R</u><u>eversible</u> </b><u>postsynaptic</u> <u>inhibitor</u> of <u>alpha1</u>- and <u>alph</u>a2- <u>adrenergic</u> <u>receptors</u> (binds covalently)<b>
Indications</b>: <u>Hypertension</u> in <b><u>pheochromocytoma</u> Toxicity</b>: <u>Postural hypertension, sexual dysfunction</u><b> Other</b>:Pheochromocytoma: huge sympathetic overflow; can't use beta-blockers or others (won't affect outflow issues, BP could actually go UP!) |
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tolazoline
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<b>Mechanism of Action</b>: <b><u>Reversible</u> </b><u>postsynaptic</u> <u>inhibitor</u> of <u>alpha1</u>- and <u>alph</u>a2- <u>adrenergic</u> <u>receptors</u> (binds covalently)<b>
Indications</b>: <u>Hypertension</u> in <b><u>pheochromocytoma</u> Toxicity</b>: <u>Postural hypertension, sexual dysfunction</u><b> Other</b>:Pheochromocytoma: huge sympathetic overflow; can't use beta-blockers or others (won't affect outflow issues, BP could actually go UP!) |
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prazosin (terazosin, doxazosin)
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<b>Mechanism of Action</b>: Selective post-synaptic inhibitor of <u>alpha-1 adrenergic receptors</u>
<b>Effects</b>:blocks smooth muscle constriction (relaxes ureters); arterial & venous dilation (can help with hypertension) <b>Indications</b>: <u>Hypertension</u> (but <u>questionable mortality benefit </u>in ALL-HAT!), especially with <u>BPH-induced urinary obstruction</u> (especially terazosin) - helps <u>relax ureters </u>(kill two birds with one stone). Also <u>decreases LDL & total cholesterol</u>. <b> Administration</b>: terazosin, doxazosin have longer duration of action than prazosin<b> Toxicity</b>:<u>Postural hypotension</u> & syncope (especially with <u>first dose!</u>); nasal congestion, impotence |
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propranolol, nadolol
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<b>Mechanism of Action</b>: <b><u>Non-selective beta-blocker</u></b> (blocks beta-1 and beta-2 adrenergic receptors post-synaptically; <u>reversible</u>)
<b>Effects</b>: decreased <u>cardiac output</u> (decrease <u>heart rate</u>, <u>contractility</u>, <u>automaticity</u>, <u>AV conduction</u>, <u>myocardial oxygen demand</u>), <u>bronchial smooth mm constriction</u> (don't use in asthma)<b> Indications</b>: Class-wide: <u>hypertension</u>, <u>ischemic heart syndromes (MI/angina</u>), <u>heart failure</u>, <u>arrythmias</u>, <u>tremor</u> (reduce neuromuscular excitability), <u>migraine prophylaxis</u>. Special: <b>timolol</b> (similar agent) treats <u>open angle glaucoma</u> <b>Adverse effects</b>: <u>Heart failure</u>, <u>heart block</u>, <u>asthma</u>, <u>depression / sleep disturbance</u>, <u>hypoglycemia</u>, <u>claudication</u> (exacerbates Raynaud's phenomenon), <u>erectile dysfunction</u>, <u>ischemic syndromes on withdrawal</u>.<b> Other</b>: <b><u>First-pass</u> </b>effects (<u>oral and parenteral</u> doses are <u>very different</u>). <u>Genetic polymorphisms</u> affect responsiveness. |
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metoprolol
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<b>Mechanism of Action</b>:”<b><u>Selective” beta-blocker</u></b> (blocks beta-1 > beta-2 adrenergic receptors post-synaptically; <u>reversible</u>)
<b>Effects</b>: decreased <u>cardiac output</u> (decrease <u>heart rate</u>, <u>contractility</u>, <u>automaticity</u>, <u>AV conduction</u>, <u>myocardial oxygen demand</u>), <u>bronchial smooth mm constriction</u> (don't use in asthma). <b><u>AAD effects:</u> slow </b><u>sinus node discharge</u> (phase 4) and <u>AV conduction</u>; block <u>sympathetic-dependent LV function</u><b> Indications</b>: Class-wide: <u>hypertension</u>, <u>ischemic heart syndromes (MI/angina</u>), <u>heart failure</u>, <u>arrythmias</u>, <u>tremor</u> (reduce neuromuscular excitability), <u>migraine prophylaxis</u>. Special: <b>timolol</b> (similar agent) treats <u>open angle glaucoma</u> <b>Adverse effects</b>: <u>Heart failure</u>, <u>heart block</u>, <u>asthma</u>, <u>depression / sleep disturbance</u>, <u>hypoglycemia</u>, <u>claudication</u> (exacerbates Raynaud's phenomenon), <u>erectile dysfunction</u>, <u>ischemic syndromes on withdrawal</u>.<b> Other</b>: <b><u>First-pass</u> </b>effects (<u>oral and parenteral</u> doses are <u>very different</u>). <u>Genetic polymorphisms</u> affect responsiveness. <b>Selectivity decreases with increasing dose.</b> |
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carevediolol
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<b>Mechanism of action</b>: <u>beta and alpha blocker (alpha-1, beta-1, beta-2)
</u><b>Used in</b>: <u>Congestive Heart Failure</u> <b>Adverse effects</b>: <u>hyptension, bradycardia, heart block, heart failure, asthma</u> |
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labetalol
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<b>Mechanism of action</b>: <u>beta and alpha blocker (alpha-1, beta-1, beta-2)
</u><b>Used in</b>: <u>Hypertension</u> <b>Adverse effects</b>: <u>hyptension, bradycardia, heart block, heart failure, asthma</u> |
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fenoldopam
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<b>Mechanism of Action</b>:post-synaptic dopamine receptor agonist (<u>selective DA1 peripheral agonist)</u>
<b>Effects</b>:Binds <u>DA1</u> receptors on <u>renal, splanchnic</u> arterioles; results in <u>vasodilation & diuresis</u> <b>Indications</b>: <u>hypertensive emergencies</u>, esp. with <u>renal insufficiency</u> & <u>post-op settings</u><b> Toxicity</b>: can <u>increase intraocular pressure</u> |
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erythropoietin (EPO)
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<b>Mechanism of Action</b>: <u>promotes erythropoiesis</u> (hormone)<u>
</u><b>Effects:</b> binds <u>EPO receptor</u> on erythroid precursor cells, causes <u>conformational change</u> & activates <u>Jak-STAT</u> pathway (Jak-2 TK p-lates receptor, recruits STAT-5, which gets p-lated & goes to nucleus as transcription factor) to induce <u>red cell maturation gene expression.</u> Actually primarily <u>BLOCKS APOPTOSIS</u><b> </b>of erythroid precursor cells.<b> Indications</b>: <u>anemia</u> (chronic renal failure, cancer, AIDS); <u>perioperatively</u> (reduce transfusion); <u>illicit</u> (blood doping by athletes)<b> Administration</b>: <u>IV/sub-q,</u> usually start at 80-120 U/kg 3x/wk; sustained effect after its disappearance<b> Toxicity</b>: <u>aggrivates hypertension</u>; potential increase in <u>thrombosis</u> risk, theoretical <u>neoplasm risk</u> (cell growth factor - now a black box warming)<b> Other</b>: 193-AA <u>protein</u>, 1st 23 AA cleaved off, then heavily glycosylated (<u>recombinant</u> form used) |
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zoledronic acid
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<b><u>zoledronic-acid-specific:
</u>Administration: <u>yearly IV</u></b> <b><u>Acute-phase reaction</u></b> (25% after <b>first dose!</b>) <u>In </u><b><u>osteoporosis</u></b>: works on <b><u>spine, non-spine, and hip</u></b> fractures. <b><u>prevents second hip fracture</u></b> after <u>hip fx</u> <b><u>Bisphos in general:</u></b> <b>Mechanism of Action</b>: <u>nitrogen-containing bisophosphonate anti-resorptive agents</u>. Inhibit <u>farnesyl-PP synthase</u>, in osteoclast <u>mevalonate pathway</u>, so <u>osteoclasts can't prenylate proteins</u> <b>Effects:</b> <u>prenylation </u>needed for <u>membrane ruffling, vesicular trafficking, actin ring formation, osteoclast survival</u>. Inhibition leads to <u>loss of osteoclast function</u> and <u>apoptosis!</u><b> Selective Toxicity</b>: Binds <u>hydroxyapatite</u> (targeted to osteoclasts, which eat it up!)<b> Administration: <u>alendronate</u> can be given <u>once a year IV</u> for osteoporosis Indications</b>: <u>osteoporosis, Paget's disease </u><b>Metabolism: </b>biggest problem is that they're <u>really hard to absorb</u>: for <u>oral administration</u> have to give <u>1st thing in morning</u> with <u>lots of water</u> and <u>wait 30 min to eat</u> (60m with ibandorate). <u>Remain upright until after breakfast!</u> Fast / complete uptake into bone; slow release. Excretion mainly <u>renal - no metabolites</u>. New agents: <u>q7d or q1mo</u> <b> Toxicity</b>: <u>upper GI disturbances</u> with oral formulations. <u>flu-like symptoms</u> (fever / myaligia) with <u>1st IV dose</u>. <u>Musculoskeletal pain</u> (can be diffuse; rarely systemic or severe. Can happen at <u>any point in treatment!</u>). <u>Osteonecrosis of jaw</u> (very rare; 1/50k) <b>Contraindications</b>: <u>Hypocalcemia</u> (esp. if pt depending on bone supply for Ca - vit D deficiency, hypoparathyroidism, etc - bisphosphonates would block!). <u>swallowing disorders</u> (pill just sits there) or <u>inability to remain upright</u> after <u>oral dosing</u> (to protect esophagus - don't go back to bed!). <u>Significant renal insufficiency</u> (CrCl < 30 mL/min) |
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spironolactone (immunology use)
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<b>Mechanism of Action</b>: “<u>anti-corticosteroid”</u>. Steroid analog that <u>selectively blocks</u> the <u>mineralocorticoid receptor</u><b>
Indications</b>: <u>hyperaldosteronism</u> (low K, hypertension); also has a <u>diuretic effect</u><b> Toxicity</b>: <u>gynecomastia</u> in men (anti-androgen action) |
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mycophenolate mofetil
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<b>Mechanism of Action</b>: (selective) <u>inhibitor</u> of <u>T-cell proliferation.</u> <u>Prodrug</u> for <u>mycophenolic acid</u> (ester cleaved), which <u>inhibits inosine monophosphate dehydrogenase</u>, required for <u>de novo purine biosynthesis</u>
<b>Effects</b>: Leads to <u>cell cycle arrest</u> of proliferating <u>T/B cells</u> in <u>G1</u> <b>Selective Toxicity</b>: <u>T/B cells </u>rely on <u>de novo purine biosynthesis</u> (don't have hypoxanthine-guanine phosphoribosyl transferase <u>salvage pathway</u>), so <u>selectively sensitive</u> to <i>de novo</i> pathway inhibition<b> Indications</b>: Used primarily in <u>renal transplant</u>. Has <u>anti-angiogenic activity too</u> (endothelial cells rely on <i>de novo</i> pathway exclusively too!) |
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golimumab
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<b>Mechanism of Action</b>: <u>human anti-TNF-alpha antibody</u> (made from <u>transgenic mice</u>, all human!)
<b>Effects</b>: binds <b><u>TNF-alpha</u></b>, inhibits production of other <u>pro-inflammatory cytokines.</u> Less <u>swelling, subjective Sx, granulocyte migration</u> into <u>joints.</u> <b>Indications</b>: <u>Rheumatoid arthritis</u>. <b>Administration:</b> has <u>longer half-life</u> (fully human) - <u>2 wks!</u> can give <u>q1m</u> as <u>self-injection</u> (big advantage!) |
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buprenorphine
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<b>Mechanism of Action</b>: <u>Partial mu agonist</u> and <u>kappa antagonist</u> opioid at <u>high doses</u>
<b>Metabolism</b>: <u>semisynthetic, highly lipophilic</u> opioid; has <u>very tight binding</u> & is <u>slow to disperse</u> (degree of analgesia not related to plasma concentrations!)<b> Indications</b>: Can cause “<u>blockade effect”</u> to other opioids that can last <u>>24h</u>; FDA approved for <u>induction of withdrawal</u> (but can be legally prescribed for pain)<b> Administration</b>: For pain: TID/QID. <u>low oral bioavailability </u>(1st pass effect), so give <u>sublingually</u>. <u>Suboxone</u> when given with <u>naloxone</u> |
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fentanyl
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<b>Mechanism of Action</b>: opioid, mainly a <u>mu agonist</u> with <u>minimal kappa effects</u>
<b>Administration</b>: Most often as <u>transdermal patch</u> (difficult to abuse) because it's <u>very lipophilic</u> . Can also give <u>IV</u> (<u>really potent - 50-100x morphine!</u>, <u>rapid onset - lipophilic!</u>)<b> Toxicity</b>: <u>Drug interactions</u> (meatbolized by <u>CYP3A4</u>). May cause <u>less constipation</u> than morphine for equivalent doses.<b> Other</b>: Delivery affected by <u>body fat, temperature, edema, placement</u> - but absorption doesn't really vary between <u>chest / abdomen / thigh</u> |
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tramadol
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<b><u>Mechanism of Action</u></b><u>:</u> <b><u>Weak mu-opioid receptor agonist</u></b> (6000x less than morphine), Also <b>inhibits NE / serotonin uptake.</b>
<b><u>Metabolism</u>: Short-acting </b>(onset < 1h, peak 2-4h, duration 6h), <b>ok oral bioavailability </b>(70%: 100% absorbed; 20-30% 1st pass). <b>Chief metabolite</b> is <b>also an analgesic </b>(2-4x activity of tramadol)<b> <u>Indications</u></b><u>:</u><b>Better analgesic</b> than <b>codeine</b>, hydrocodone, propoxyphene) <b> </b> |
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hydrocodone
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<b><u>Mechanism</u><u> of Action</u></b>: <b>Classic</b> opioid, <b>widely prescribed</b>.
<b><u>Kinetics</u><u>:</u> Rapid</b> absorption & <b>short duration</b> (onset 30-60m, duration 3-8h), so <b>significant abuse potential</b> (sched III)<b> <u>Indications</u></b>:<b>Administration</b>: dosed <b>q3-6h</b>. Often combined with <b>acetaminophen </b>(as <b><u>Vicodin</u></b>) or ibuprofen - <b>better analgesic effect</b>, but <b>hepatic / renal </b>toxicity.<b> <u>Toxicity</u></b>: <b>High doses</b> may lead to <b>deafness</b> |
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hydromorphone
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<b>Mechanism of Action</b>: <u>Mu agonist</u>, derived from <u>morphine</u>
<b>Selective Toxicity</b>: <b> Indications</b>: <b><u>Efficacy</u></b> <u>comparable to morphine</u> although <u>more </u><b><u>potent</u></b> than morphine!<b> Metabolism:</b> <u>H-3-G</u> (metabolite) has <u>neuroexcitatory effects</u>. <b>Administration</b>: <u>Oral</u> (IR; 30-60m onset, 4-6h duration) or <u>parenteral</u> (5m onset/ < 20m peak)<b> Toxicity</b>: H-3-G <u>accumulates</u> in <u>renal impairment</u> |
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oxycodone
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<b>Mechanism of Action</b>: Semi-synthetic <u>opioid analgesic</u> - mostly a <u>kappa opioid receptor agonist</u> via an <u>active metabolite</u> (<u>oxymorphone</u>)
<b>Effects</b>: <u>decreases neurotransmission</u> (less Ca-mediated release of neurotransmitters) - see lecture for details<b> Administration</b>: Available in <u>lots of oral formulations</u>: Immediate release (onset 15-60m, duration 4-6h) or controlled-release (onset < 1h, duration 8-12h). <u>Lower dose</u> in <u>females</u> (25% higher plasma concentration). Can be given with <b><u>acetaminophen</u></b> as <b><u>Percocet</u> Metabolism</b>: 60-80% lower bioavailability (<u>first-pass metabolism</u>)<b> Toxicity</b>: <u>High abuse potential</u>. <u>Serotonin syndrome</u> with coadministration of oxycodone / <u>sertraline</u> <b>Resistance</b>: <u>Tolerance & hyperalgesia</u> (all opioids) <b>Other</b>: metabolites play <u>less of a role</u> therapeutically<b> </b> |
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pentazocine (Talwin)
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First widely employed <b>mixed agonist - antagonist: less addicting</b> and <b>effective analgesic
</b>Downside<b>: psychotomimetic effects</b> (probably from <b>kappa </b>receptors) <b>See lecture for more details on opioids</b> |
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tramadol (Ultram)
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<b>Weak agonist</b> at <b>mu opiate receptors</b>; may have other actions too (only partially blocked by naloxone)
<b>Inhibits NE/serotonin uptake</b> (maybe relevant) Side effects like other opiates but <b>less respiratory depression</b> Introduced <b>recently, widely used; </b>same spectrum as <b>codeine-acetaminophen</b> (for <b>moderate pain)</b> <b>See lecture for more details on opioids</b> |
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chlorpropamide
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<b>Mechanism of Action</b>: <u>sulfonylurea</u> <u>oral antidiabetic agent</u>. <u>Stimulates insulin secretion</u>
<b>Effects</b>: Activates <u>sulfonylurea receptor</u>, in pancreatic beta cells, which <u>inactivates ATP/ADP-dependent potassium channel</u>, leading to <u>membrane depolarization</u> & <u>Ca-mediated exocytosis of insulin</u> <b> Indications</b>: <u>type 2 diabetes</u> (as first or second choice - metformin usually first - either alone or in combo with other therapy)<b> Toxicity</b>: <u>hypoglycemia</u> (overdose causes excess insulin secretion). Unusual: <u>hepatotoxicity</u> (tranaminasemia) and <u>allergic responses</u> (can cross react with other sulfa allergies). <u>modest weight gain</u>. <u>Black box warning:</u> <u>death</u> by <u>CVD</u> (but not yet confirmed). <b><u>AVOID IN RENAL DISEASE</u></b> <b><u>Metabolism</u></b>: Excreted <u>unchanged in the urine</u> - so the <b><u>LONGEST-ACTING SULFONYLUREA</u></b> (>24h duration). <b> <u>The bottom line</u></b>: <b>Good option for type 2 DM treatment </b>(but old - has <b>short, polar side chain = less potent). Another SU (e.g. </b>glipizide) could<b> be 1st or 2nd choice </b>(metformin usually first) <b>oral hypoglycemic agent, alone or in combo with other oral agents, or combined with insulin therapy</b> |
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recombinant GLP-1 analogue (Byetta)
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<b>Mechanism of Action</b>: <u>incretin mimetic</u> oral antidiabetic agent. <u>Mimics endogenous incretin function</u> - incretins <u>“prime” the beta cells</u><b> </b>in response to <u>oral CHO load</u> (released from K-cells in small bowel) - why <u>more insulin secreted</u> after <u>oral vs IV glc.</u>
<b>Effects</b>: <u>Incretins</u> have <u>multiple effects</u>: <u>prime beta cells</u> (more insulin secreted), <u>slow gastric emptying</u> (so hyperglycemic load is not too abrupt), <u>suppress pancreatic glucagon secretion</u> (so liver doesn't keep making glucose), and <u>cause satiety</u> at CNS level - all beneficial.<b> Indications</b>: <u>Type 2 DM</u>. <u>Weight reduction</u> is a <u>really popular feature</u>.<b> Administration</b>: <u>injections</u> (like insulin, but causes weight loss - not weight gain)<b> Toxicity</b>: can cause <u>nausea</u> (may require discontinuation) |
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iodine
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<b>Mechanism of Action</b>: in pharmacological doses, activates “<u>protective mechanisms”</u> of thyroid (used for <u>hyperthyroidism</u>)
<b>Effects</b>: Blocks <u>iodine trapping, organification, thyroid hormone release</u>. Also <u>decreases thyroidal blood flow</u> <b>Indications</b>: <u>emergent hyperthyroidism</u><b> </b>(<u>quick lowering</u> while waiting more definitive therapy - while waiting for <u>radioactive iodine</u> to work, or while awaiting <u>thyroidectomy</u>), <u>thyroid storm</u>. Also <u>decreases blood loss</u> during <u>surgery </u>for hyperthyroidism (decreases thyroidal blood flow)<b> Toxicity</b>: potential <u>longer-term exacerbation</u> of hyperthyroidism <b>Resistance</b>: <u>Thyroid escape </u>from inhibitory effects after 10-14d (why you don't use for more chronic hyperthyroidism |
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omeprazole
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<b>Mechanism of Action</b>: proton pump inhibitors (acid reduction - antisecretory therapy)
<b>Effects</b>: sufinyl group <u>protonated</u> in <u>parietal cells (need acid</u>), sulfenamide interacts <u>covalently</u> (irreversibly) with parietal cell H/K ATPase, reducing daily acid production by <u>95%</u>. <b>Selective Toxicity</b>: Only acts where activated by <u>acid</u> (also, not on inactive proton pumps)<b> Indications</b>: <u>Peptic ulcers</u> (esophagus, duodenum, stomach, esp. if H2RA unresponsive); <u>erosive esophagitis</u> from <u>GERD</u>, <u>Zollinger-Ellison syndrome</u><b> Toxicity</b>: Potential <u>bacterial overgrowth</u> of <u>small bowel</u>, <u>CYP450 inhibitor</u> (watch out for phenytoin, diazepam, warfarin), increased risk of <u>community acquired pneumonia</u> (more bacteria; more chance of pneumonia on aspiration) and <u>osteoporosis / fractures</u> <b>Pharmacokinetics: </b><u>Covalent </u>bonding; <u>long effects - days</u> after drug disappears from plasma; <i>de novo</i> synthesis of proton pumps required to increase acid production. <u>Degraded</u> by <u>stomach acid</u> (give enteric coating); metabolized by <u>liver </u>(need to adjust in liver failure)<b> Other</b>:<b> </b>omeprazole (prilosec, zegerid), lansoprazole (prevacid), esomeprazole (nexium). No real increase in risk of carcinoid tumors (thought that chronic elevation of gastrin would increase ECL populations) |
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ranitidine, cimetidine, famotidine
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<b>Mechanism of Action</b>: <u>H2 receptor antagonist</u> (antisecretory acid reduction agent)
<b>Effects</b>: <u>Competitive inhibition</u> of histamine at H2 receptors (parietal cell); dose-dependent inhibition of <u>gastric acid secretion</u> by histamine & other secretagogues (H2 agonists). <b>Selective Toxicity</b>: <b> Indications</b>: <u>Duodenal / gastric ulcers</u> (treatment, recurrence of duodenal), <u>acute & chronic GERD</u> treatment. Inhibits <u>basal acid secretion</u> best (<u>night / fasting</u>), also physiologic acid secretion (<u>feeding</u>)<b> Administration</b>: <u>1-2x/day</u> <b>Pharmacokinetics: </b>plasma peak 1-2h, mostly <u>renal</u> elimination, short half-life<b> Toxicity</b>: <u>CYP450 INHIBITION</u> (warfarin, theophylline, phenytoin). <u>CNS confusion / somnolence</u>. <u>Anti-androgen effects</u> (esp. cimetidine) - <u>gynecomastia, impotence</u> (males), <u>alactorrhea</u> (females)<b> Other: </b>cimetidine = Tagamet, ranitidine = Zantac, famotidine = Pepcid |
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scopolamine
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<b>Mechanism of action</b>: <u>Anticholinergic antiemetic/antinauseant agent</u>. Block ACh activity.
<b>Indications: </b>Nausea / vomiting from <u>motion sickness</u> |
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coumarins (warfarin sodium / coumadin, dicumarol, etc.)
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<b>Mechanism of Action</b>: <u>Anticoagulant</u> agent. Blocks <u>reduction of Vit K</u> by <u>vitamin K reductases</u>
<b>Effects</b>: Vitamin K required for factor <u>II, VII, IX, X</u> (and proteins C&S) to have gamma-carboxylated glutamic acid residues, which help bind Ca++ and PLs on platelets to enhance clotting. <u>1)</u> <u>decreases synthesis </u>of vitamin K-dependent factors (30-50%); <u>2)</u> <u>factors produced</u> only have 10-40% of <u>normal biologic activity</u><b> Indications</b>: <u>Prevention </u>& <u>treatment </u>(chronic) of thrombosis, but <u>don't dissolve clots</u> (prevent new ones from forming)<b> Administration</b>: <u>therapeutic monitoring</u> with <u>PT</u> (1.2-1.5x normal); <u>INR</u> widely used now. <u>LONG HALF LIFE + INVOLVEMENT OF CLOTTING FACTORS = LONG TIME TO STEADY STATE</u>. Adjust dose only <u>q48-72h</u> and <u>escalate conservatively</u> <b>Resistance</b>: occurs but is rare<b> Toxicity & Reversal</b>: <u>less toxicity</u> with lower levels of anticoagulation (and equal efficacy). <u>Bleeding: </u>reverse with <u>FFP </u>to replace coagulation factors (<u>first line</u> for acute bleeding) or <u>Vitamin K</u> in high doses (some reductases can bypass if enough vit K around; takes longer - 24h, have to wait for synthesis of new factors; effect lasts for days so use only if serious, might have to substitute <u>heparin</u> for 7-10d after high-dose vitamin K) <u>Skin necrosis</u>: from <u>Protein C inhibition </u>--> <u>necrotic infarction</u>, watch out for protein C-deficient pts. <u>Alopecia TERATOGENICITY</u>: esp 1st trimester, nasal hypoplasia / stippled epiphyseal calcifications / abortion / neonatal hemmorrhage. <u>STRICTLY CONTRAINDICATED IN PREGNANCY</u> (use heparin; safer). <b>Drug interactions</b>: key. Can <u>enhance</u> oral anticoagulant activity (decreased vitamin K absorption like <u>antibiotics</u>, displacement from plasma proteins, inhibition of biotransformation, inhibition of platelet aggregation like <u>aspirin</u>, decreased clotting factor production) or <u>depress</u> activity (induce metabolizing enzymes, <u>increase clotting factor production</u> as with <u>vitamin K </u>or <u>oral contraceptives</u>) <b>Pharmacokinetics:</b> <u>Nearly complete absorption</u>, <u>99% bound</u> to plasma protein (albumin), <u>metabolism</u> to inactive metabolites by hydroxylation (hepatic)<u> is variable</u> in population, genetically determined; half-life of ~40h. <u>Time course of antithrombotic effect</u> is <u>different</u> than plasma concentration (circulating half-lives of factors, which have to be re-synthesized: II>IX/X>VII for half-life, so VII recovered first and thrombin last)<b> Other</b>: Has an <u>asymmetric carbon</u> (<u>racemic mixture</u>, the enantiomers have <u>different potency/metabolism</u>) |
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low molecular weight heparins (enoxaparin, dalteparin, ardeparin) & hepanoid (danaproid)
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<b>Mechanism of Action</b>: <u>Anticoagulant</u> agent. inhibit <u>Factor Xa</u> but <i><u>not</u></i><u> thrombin</u>; still bind to <u>antithrombin III</u>; do <u>not</u> prolong APTT but work as well clinically. <b>
Indications</b>: <u>Prevention </u>& <u>treatment </u>(acute) of thrombosis, but <u>don't dissolve clots</u> (prevent new ones from forming). At least as good as preventing <u>DVT</u> as heparin; probably equivalent in treating DVT<b> Administration</b>: Dosed in <u>mg instead of units;</u> give <u>sub-q.</u> <b> Toxicity</b>: <u>Bleeding</u> (same as heparin); <u>thrombocytopenia</u> (maybe less frequently) <b>Pharmacokinetics:</b> <u>less frequent dosing</u> than heparin (reduced binding to plasma proteins / platelets / cells; increased bioavailability, longer half-life, dose-proportional / more normal PK instead of non-linear like heparin)<b> Other</b>: Preparation: depolymerization & size fractionation of HMW heparins; mixed species. <u>Way more expensive</u> but <u>popular</u> (no therapeutic monitoring, given sub-q, a little easier to manage). |
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heparin
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<b>Mechanism of Action</b>: <u>Anticoagulant</u> agent. Several mechanisms of action: <u>Boosts antithrombin activity;</u> inhibits <u>intrinsic >>> extrinsic</u> pathways (<u>APTT</u> primarily prolonged). <u>Low molecular weight heparins </u>inhibit <u>Factor Xa</u> but <i>not</i> thrombin; do <u>not</u> prolong APTT but work as well. At <u>high concentrations:</u> Interfere with <u>platelet aggregation</u> & activate <u>heparin cofactor II</u> (antithrombin homolog, thrombin-specific) <b>
Indications</b>: <u>Prevention </u>& <u>treatment </u>(acute) of thrombosis, but <u>don't dissolve clots</u> (prevent new ones from forming)<b> Administration</b>: <u>1 unit</u> = amt heparin needed to prevent<u> 1.0 mL plasma</u> from clotting<u> 1 hour</u> after adding calcium chloride (variable MW/size; only 30% of molecules have antithrombin-binding-site, so dose by activity). <u>Continuous / intermittent</u> infusions & <u>sub-q </u>injections<b> Toxicity</b>: <u>Bleeding</u> (often inadequte therapeutic monitoring, more common in elderly, worry about <u>intercranial</u> bleeding. Others: <u>thrombocytopenia</u> (mild is common; severe less frequently & 7-14d post tx initiation, always <u>reversible</u> with discontinuation); <u>paradoxial thrombosis / white clot syndrome</u> (uncommon), reversible <u>alopecia</u>, <u>OSTEOPOROSIS</u> (very important, lots of elderly pts) <b>Reversal of toxicity</b>: <u>STOP THERAPY</u>; can give <u>protamine</u> (positively charged low molecular weight proteins from fish sperm; give equimolar amount to titrate out heparin, only if life-threatening b/c can induce hypotension/anaphylaxis/hypercoagulation. Diabetics who take insulin with protamine are more prone to anaphylaxis b/c may already have anti-protamine Ab) <b>Pharmacokinetics:</b> complex & unusual. <u>Vd</u>: confined to <u>plasma</u> (high MW, neg charge); <u>not orally bioavailable</u>, <u>clearance</u> is <u>NON-LINEAR</u> (dose-dependent), cleared via <u>RES</u>, longer infusions can diminish clearance, <u>therapeutic monitoring</u> needed to reach <u>target APTT (1.5-2x)</u><b> Other</b>: naturally occuring, polymer of D-glucosamine/D-glucoronic acid. Found in <u>mast cell secretory granules</u> but natural function unknown; sulfation/molecular weight variable; prepared from bovine lung/porcine intestinal mucosa |
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small molecule IIb/IIIa antagonist (tirofiban)
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<b>Mechanism of Action</b>: <u>antiplatelet agent</u>. Blocks<u> GPIIb/IIIa-mediated platelet aggregation</u> by inhibiting <u>fibrinogen binding</u> to GPIIb/IIIa<u>
</u><b>Effects:</b> binds <u>reversibly</u> to IIb/IIIa receptor<b> Indications</b>: only anti-platelet mAB shown to have anti-thrombotic activity in humans<b> Administration</b>: Give as <u>large bolus</u> then <u>slow infusion</u> (up to 108h). <b> Toxicity</b>: <u>bleeding</u> (2x vs heparin+aspirin alone) <b>Other</b>: <u>Renal clearance</u> (2h half-life); effects <u>rapidly reversible</u> (mediated by plasma clearance) |
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mAb IIb/IIIa antagonist (abciximab)
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<b>Mechanism of Action</b>: <u>antiplatelet agent</u>. Blocks GPIIb/IIIa-mediated platelet aggregation<b>
Indications</b>: only anti-platelet mAB shown to have anti-thrombotic activity in humans<b> Administration</b>: <u>Always given with heparin & aspirin.</u> <u>Rapidly cleared</u> (10m half life); give as <u>large bolus</u> then <u>slow infusion</u> (18-24h). Half-life of recovery of aggregation is <u>24h</u> (Fabs remain on platelets & can <u>redistribute</u> to GPIIb/IIIa on new platelets). <b> Toxicity</b>: <u>bleeding</u> (2x vs heparin+aspirin alone), <u>pseudothrombocytopenia</u> (Ab-mediated platelet clumping) <b>Resistance</b>: <u>anti-murine antibodies</u> (6.5% after 1 dose, very important - avoid giving a second time!)<b> Other</b>: <u>chimeric</u> (mouse variable, human constant regions); only <u>Fab </u>portion used. Could use <u>platelet transfusion</u> to reverse side-effects if needed. |
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aspirin (acetyl salicylic acid)
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<b>Mechanism of Action</b>:<b> </b><u>antiplatelet agent</u> (and anti-inflammatory too). <u>Covalently</u> inhibits <u>cyclooxygenase</u> (which produces <u>thromboxane A2</u> in platelets)
<b>Effects</b>: <u>inhibits</u> thromboxane-A2-mediated <u>platelet aggregation </u>& <u>vasoconstriction</u> (aspirin --> vasodilation). Inhibition is <u>long-lived</u> (platelets don't synthesize new protein; have to wait for new platelets to be made)<b> Indications</b>:<b> Administration</b>: Dose to <u>inhibit platelet cyclooxygenase </u>(160mg) is <u>less than</u> dose for anti-inflammatory or antipyretic effects. <u>More </u>than 320mg is <u>counterproductive</u> (can block formation of <u>PGI2</u> / prostacyclin, a natural inhibitor of platelet aggregation)<b> Other</b>: Safe, effective, and <u>really cost-effective</u> (cheap!) |
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small peptide IIb/IIIa antagonist (eptifibatide)
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<b>Mechanism of Action</b>: <u>antiplatelet agent</u>. Blocks <u>GPIIb/IIIa-mediated platelet aggregation</u> by blocking <u>fibrinogen, vWF, vitronectin</u> binding to IIb/IIIa
<b>Effects</b>: mimics AA sequences important for GPIIb/IIIa binding: (KGD mediates <u>fibrinogen</u> binding; RGD mediates <u>vWF</u> binding)<b> Indications</b>: only anti-platelet mAB shown to have anti-thrombotic activity in humans<b> Administration</b>: Given with <u>aspirin + heparin</u>. <u>More slowly cleared</u> than abciximab; still given as <u>rapid large bolus</u> + <u>slow infusion</u> for up to 72 hrs. <u>Rapidly reversible</u> effects (mediated by drug clearance from plasma).<b> Toxicity</b>: <u>bleeding</u> (marginally increased vs heparin+aspirin alone), <u>not immunogenic</u><b> Other</b>: Elimitated via <u>proteolysis</u> to AA & <u>urinary elimination</u> of unchanged drug |
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dipyridamole
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<b>Mechanism of Action</b>: <u>antiplatelet agent</u> with dual mechanisms, both leading to <u>increased cAMP</u>: <u>inhibits</u> cyclic nucleotide <u>phosphodiesterase</u> and <u>inhibits nucleoside transport/uptake</u> (stimulates adenylate cyclase)
<b>Effects</b>: increased intracellular cAMP <u>inhibits platelet aggregation</u>. (also has vasodilator properties) <b>Indications</b>: combination treatment for prophylaxis of thrombosis / embolization<b> Administration</b>: <u>only</u> proven effective in <u>combination</u> (warfarin or aspirin); does <u>not</u> prevent embolization / thrombus by itself<b> Toxicity</b>: headache & hypotension (esp. in high doses) |
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ticlopidine & clopidogrel
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<b>Mechanism of Action</b>: <u>antiplatelet agents; </u>inhibit ADP-induced <u>platelet aggregation</u>
<b>Effects</b>: Bind <u>irreversibly</u> to <u>low-affinity ADP</u> receptors (<u>non-competitive</u>); block ADP-mediated <u>release of platelet alpha granules / dense granules</u>, inhibit <u>fibrinogen</u> binding to activated platelets; <u>indirectly </u>block activation of <u>platelet glycoprotein IIb/IIIa receptor</u> <b>Selective Toxicity</b>: <b> Indications</b>: Slightly better at preventing stroke in pts with TIAs than aspirin; can help prevent coronary thrombosis<b> Administration</b>: <u>long-lived</u> effects (ADP receptor blocked for life span of platelet; need to synthesize new ones: 7-10d)<b> Toxicity</b>: <u>neutropenia</u> (severe but reversible, ticlopidine 1%, clopidogrel 0.1%) <u>bleeding, diarrhea, thrombocytopenia</u> (TTP)<b> Other</b>: <b><u>CYP450</u> </b>substrates - <u>activity </u><b><u>requires conversion to active metabolite</u></b> (complicates treatment, as activity varies from pt to pt); <b><u>inhibit </u></b><u>CYP 2C9</u>. Clopidogrel = Plavix; thought to be less toxic than ticlopidine. <u>Much more expensive</u> than aspirin |
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recombinant tissue plasminogen activator (rtPA)
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<b>Mechanism of Action</b>: <u>Thrombolytic agent</u>. <u>Recombinant serine protease;</u>
<b>Effects</b>: Much tighter binding to <u>fibrin-bound plasminogen</u> than circulating free plasminogen (tPA has lysine binding sites at amino terminus) so <u>more active against bound</u> plasminogen (less systemic activity, more localized); can <u>overwhelm control mechanism</u> (serum concentrations 30-300x higher than physiologic [tPA])<b> Indications</b>: clot buster (helps digest pre-existing thrombi)<b> Administration</b>: <u>IV bolus</u> + <u>short infusion</u> (short half life, bleeding complications) <b>Resistance</b>:<b> Toxicity: </b>despite localization, can <u>induce lytic state</u>. <u>Bleeding</u> (more in elderly, intercranial is serious). Unique to rtPA: 1) <u>Damages endothelial cell membranes</u> \ <u>increases circulating vWF</u>; 2) <u>mid-moderate thrombocytopenia</u> (10% cases) <b>Drug interactions</b>: <b>Pharmacokinetics:</b> Metabolized by <u>liver</u>, identical halflife to tPA (3m)<b> Other</b>: <u>Most common </u>thrombolytic agent in clinical use |
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streptokinase
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<b>Mechanism of Action</b>: <u>Thrombolytic agent</u>. Not a kinase / protease but <u>binds to plasminogen</u>, induces conformational change, results in <u>cleavage</u> of arg-val bond & <u>activation</u> of enzyme (plasmin)
<b>Indications:</b> clot buster (helps digest pre-existing thrombi)<b> Administration</b>: Need <u>large loading dose</u> to absorb pre-existing Abs; used to give intracoronary but probably not much better. <u>Get it in FAST</u>!<b> Toxicity</b>: <u>Bleeding, allergic reactions, anaphylaxis, fever.</u> <u>VERY ANTIGENIC</u> (don't give more than q6-12m) <b>Pharmacokinetics:</b> Half life of about 80m after Abs absorbed<b> Other</b>: All adults have pre-existing <u>anti-SK</u> antibodies (exposure to strep) |
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urokinase
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<b>Mechanism of Action</b>: <u>Thrombolytic agent</u>. <u>Cleaves plasminogen </u>to plasmin directly at arg-val bond (like TPA)
<b>Effects</b>: activity <u>not localized</u> at clot (can cause <u>systemic fibrinolysis</u>)<b> Indications</b>: clot buster (helps digest pre-existing thrombi)<b> Toxicity: </b><u>Bleeding, allergic reactions</u> (less frequent than with streptokinase: skin rash, fever, bronchospasm) <b>Pharmacokinetics:</b> Metabolized by <u>liver</u>, half life 15m<b> Other</b>: Kind of like an early version of TPA |
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(epsilon)-Aminocaproic acid
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<b>Mechanism of Action</b>: <u>Procoagulant agent</u>. <u>Competitive inhibitor</u> of <u>plasmin/plasminogen</u> binding to <u>fibrin</u>
<b>Effects</b>: Interferes with <u>fibrinolysis</u>, maintaines <u>hemostasis</u><b> Indications</b>: <u>Hematuria</u> (excreted rapidly w/o change in urine). Has been hard to demonstrate clear-cut benefit except in some settings (minor surgery in hemophiliacs)<b> Toxicity: </b><u>Pathogenic thrombi</u> (by inhibiting physiologic thrombolysis); rare myopathy & muscle necrosis <b>Pharmacokinetics:</b> Excreted <u>rapidly</u> & <u>unchanged</u> in urine<b> </b> |
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desmopressin
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<b>Mechanism of Action</b>: <u>Procoagulant agent</u>. Promotes <u>release of endogenous pools </u>of <u>clotting </u>factors (<u>factor VIII, vWF</u>) into circulation<b>
Indications</b>: <u>vWD</u>, mild <u>hemophilia</u> (VIII > 5-10% normal); severe hemophiliacs don't respond (not enough endogenous factor VIII)<b> Toxicity</b>: <u>electrolyte imbalances; fluid overload</u> (ADH-type activity)<b> Other</b>: analog of <u>vasopressin</u> (<u>ADH)</u> |
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rifampin
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<b>Mechanism of Action</b>: antituberculosis agent. <u>macrocyclic antibiotic</u>, broad-spectrum inhibitor of bacterial <u>DNA-dependent RNApol</u>
<b>Effects</b>: <u>'Cidal</u> <b>Selective Toxicity</b>: <b> Indications</b>: 1st line anti-TB agent, part of multi-drug scheme for <u>active disease.</u><b> Administration</b>: if normal TB: 4 drugs x 2 months, then 2 active drugs x 4 months. <b> Toxicity</b>: <u>Orange discoloration</u> (urine, sweat, tears, soft contact lenses). <u>Hepatitis</u> (can be more common in children; opposite of INH hepatitis). <u>Hypersensitivity reactions</u> (flu-like syndrome; more common in healthy patients). <u>Light-chain proteinuria</u> in > 50% pts (“unexplained” proteinuria in labs). Note: <u>pharmacokinetics</u> are <b><u>non-linear!</u></b> drug can accumulate if high doses (saturating clearance mechanisms). Potent <b><u>inducer</u></b> of cyt P450s, including CYP3A4 (oral contraceptives, cyclosporin, coumarin, etc!) <b>Resistance</b>: Via RNApol gene mutations. Emerges quickly if used as single agent. MDR-TB is by definition resistant to rifampin and isoniazid; XDR resistant to all 1st line agents.<b> Other</b>: Also highly bactericidal against most <u>Gram (+)</u> and some <u>Gram (-)</u> bacteria (<i>H. influenzae, S. aureus, Neisseria</i> - commonly used as PEP for <i>N. meningitidis</i> exposure or to eradicate nasal carriage). Metabolized by <u>deacetylation</u> (<u>biliary excretion</u>, <u>enterohepatic recirculation</u>, makes elimination half-life longer than would be expected & unpredictible). |
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dapsone
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<b>Mechanism of Action</b>: Anti-leprosy agent (sulfone; sulfonilamide analog); <u>inhibits folate synthesis</u>
<b>Effects</b>: Inhibits folate synthesis; bacteria can't produce nucleotides for DNA synthesis<b> Indications</b>: Leprosy<b> Toxicity</b>: <u>Hemolytic anemia</u> (esp. pts with severe G6PD deficiency - southern Mediterranean); <u>Methemoglobinemia</u> and <u>subclinical hemolysis</u> common; <u>Hypersensitivity reactions</u> (rash/fever) like sulfonamides; <u>Agranulosis & fatal infectious mononucleosis-like syndrome</u> (rarely); <u>Reversal reactions</u> and <u>erythema nodosum leprosum</u> can occur during initiation of therapy (kills bacteria <i>so fast</i> that all bacteria lyse & cause reaction: severe fevers, big thick skin lesions, etc.). <b>Resistance</b>: Increasingly common (previous extensive use as “monotherapy for life” for leprosy)<b> Other</b>: Also active against <u>Pneumocystis carinii/jiroveci </u>(used as prophy in HIV pts); broad spectrum activity. Pharmacokinetics: <u>n-acetylation</u> (like INH, slow & fast acetylators genetic polymorphism). Half life 10-50 hrs. |
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ethambutol
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<b>Mechanism of Action</b>: antituberculosis agent; mechanism of action unknown
<b>Effects</b>: inhibits both RNA synthesis & mycolic acid metabolism<b> Indications</b>: Tuberculosis<b> Administration</b>:<b> Toxicity</b>: Affects optic nerve: <u>peripheral neuropathy</u> (esp. <i>retrobulbar optic neuritis</i>) with <u>color blindness</u> & eventual <u>loss of peripheral vision.</u> PERMANENT! Need to screen at baseline / every few months via opthalmologist; stop as soon as color blindness occurs (esp important in children) <b>Resistance</b>:<b> Other</b>: |
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rifabutin
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<b>Similar to rifampin; </b>more <b>potent</b> in vitro &<b> longer half-life
Mechanism of Action</b>: antituberculosis agent. <u>macrocyclic antibiotic</u>, broad-spectrum inhibitor of bacterial <u>DNA-dependent RNApol</u> <b>Effects</b>: <u>'Cidal</u><b> Indications</b>: <u>prophylaxis of MAI</u> in AIDS patients with CD4 < 100 (only FDA use); also used for <i>M. avium </i>treatment and active against M. TB (but more expensive)<b> Toxicity</b>: <u>Orange discoloration</u> (urine, sweat, tears, soft contact lenses). <u>Uveitis</u> (inflammation of anterior chamber of eye: dose-dependent; rare with regular doses, more common if pts. on Rx slowing hepatic clearance - clarithromycin, fluconazole, etc.) Rare: <u>granulocytopenia, rash.</u> Potent <b><u>inducer</u></b> of cyt P450s, including CYP3A4 (oral contraceptives, cyclosporin, coumarin, etc!) <b>Resistance</b>: Via RNApol gene mutations. Cross-resistance with rifampin. |
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isoniazid (INH)
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<b>Mechanism of Action</b>: antituberculosis agent; inhibits synthesis of mycolic acids
<b>Effects</b>: <b>'</b><u>Cidal.</u> blocks cell wall component (mycolic acid) production; accumulates inside mycobacteria & forms oxygen free radicals, killing the cell. <b>Selective Toxicity</b>: just passes in and out of human cells (doesn't accumulate, no free radicals)<b> Indications</b>: tuberculosis (as single therapy for <u>PPD converters</u> or part of multi-drug scheme for <u>active disease</u>). Can be used for post-exposure <u>prophylaxis</u> in pts under 35 (>35yo = risk of hepatotoxicity outweighs benefit)<b> Administration</b>: if normal TB: 4 drugs x 2 months, then 2 active drugs x 4 months. Coadminister with vitamin B6 to prevent neurotoxicity<b> Toxicity</b>: <u>hepatitis</u> (old age, slow acetylators, esp. in combo with rifampin; need to <u>monitor monthly</u> and stop drug as soon as hepatic transaminases increase significantly). <u>neurotoxicity</u> (peripheral neuropathy; INH competes with nicatinomide & leads to relative vitamin B6 deficiency; <u>coadminister vitamin B6</u> to prevent) <b>Resistance</b>: <u>katG</u>: catalase-peroxidase enzyme that probably “activates” drug through oxygen free radical formation; mutation in katG means the drug doesn't accumulate inside the cell and INH isn't toxic. <u>inhA</u>: encodes mycolic acid synthesis enzyme; contains binding pocket for nicotinamide, confers cross-resistance to ethionamide (INH analog), probably INH target; mutation is less common cause of resistance thatn katG. MDR-TB is by definition resistant to rifampin and isoniazid; XDR resistant to all 1st line agents.<b> Other</b>: metabolized by <u>hepatic N-acetyltransferase</u> (classic example of variable halflife because of gene polymorphisms). Slow acetylators (83% egyptians, 50% caucasian americans) half-life = 6hrs, fast acetylators half-life = 1 hr |
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pyrazinamide
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<b>Mechanism of Action</b>: antituberculosis agent.
<b>Effects</b>: '<u>Cidal</u>. Structural analog of nicatinomide, like INH <b>Selective Toxicity</b>: <b> Indications</b>: Tuberculosis<b> Toxicity</b>: <u>Hepatotoxicity</u> (now rare; common with previous higher doses). <u>Hyperuricemia</u> (gout-like Sx possible); <u>Photosensitivity dermatitis</u> (rare, give at <u>night</u> to prevent). <b> Other</b>: active at acidic pH; may be especially useful for killing intracellular mycobacteria. Not effective against dormant organisms. Metabolized to <u>pyrazinoic acid</u> (<u>renally excreted)</u>; half-life 12-24 hrs. |
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penicillin V
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<b>Pharmacokinetically improved penicillin </b>(all penicillin info applies)<b>
Longer peak </b>(few hours of action) + <b>PAE</b> makes for acceptible <b>po dosing</b> <b>Acid stable </b>so orally available (unlike penicillin G) |
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sulbactam,B-lactamase inhibitor; commonly paired with ampicillin (given IV as Unasyn)
vancomycin |
<b>Mechanism of Action</b>: H-bonds to D-Ala-D-Ala so transpeptidase can't access (<i>not</i> B-lactam)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: Great against S. aureus (e.g. MRSA); <i>C. difficile colitis</i>, <i>Enterococci </i>if susceptible<b> Administration</b>: No absorption (good for C. diff). Enters CSF poorly without inflammation. Usually dose IV a few times per day.<b> Toxicity</b>: <u>Allergenicity</u>: skin rash, eosinophilia, drug fever. <u>Phlebitis</u>, <u>“Red Man”</u> (flushing if dose IV too fast), ototoxicity & nephrotoxicity are <i>doubtful</i> <b>Resistance</b>:<u> NOT B-LACTAM</u> so <i>not</i> affected by B-lactamase. Vancomycin resistance emerging (e.g. in <i>E. faecium - <b>VRE</b>)</i>. Mechanism: changing D-ala-D-ala to D-ala-D-lac (9 genes required) <b>Other:</b> Renally excreted. Half life 6 hrs; <i>9 days</i> if anuric. Time-dependent killing (continuous dose best) |
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cefotetan
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<b>Mechanism of Action</b>: 2nd generation cephalosporin (B-lactam; suicide inhibitor of transpeptidase)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: Anaerobes! <i><b>B. fragilis</b> </i>plus normal 2nd gen: <i>E. coli, Klebsiella, Proteus, H. influenzae, M. catarrhalis. </i>Less anti-GPC (<i>Strep, S. aureus</i>) spectrum than 1st gen<b> Administration</b>: q8h<b> Toxicity</b>: 1/3 cross reactivity with PCNs for anaphylaxis (desensitize or avoid if PCN skin test +!) <b>Resistance</b>: B-lactamase, etc.<b> Other</b>: <b>PAE </b>against Gram (+). |
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benzathine penicillin
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<b>Pharmacokinetically improved penicillin </b>(all penicillin info applies)<b>
</b>2:1 <b>salt</b>: penicillin G and dibenzylethylene diamine Given <b>IM</b>, very <b>very</b> slow <b>absorption</b> Half life of penicillin is the <b>same</b> (absorption is the difference) |
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tazobactam
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<b>Mechanism of Action</b>: B-lactamase inhibitor (<b>suicide substrate)</b>
<b>Effects</b>: Blocks B-lactamase activity to potentiate coadministered B-lactam drug <b>Selective Toxicity</b>: Humans don't have B-lactamase <b>Resistance</b>: some inhibitor-resistant enzymes have emerged<b> Other</b>: If resistance isn't from B-lactamase production, THIS DOESN'T HELP. Unlike others, has action against Class C&D lactamases. Limitations: degraded after binding, multiple classes of enzyme from one organism or multi-organism infection |
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clavulanate
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<b>Mechanism of Action</b>: B-lactamase inhibitor (<b>suicide substrate)</b>
<b>Effects</b>: Blocks B-lactamase activity to potentiate coadministered B-lactam drug <b>Selective Toxicity</b>: No B-lactamase in humans<b> Administration</b>: with Amoxicillin as Augmentin <b>Resistance</b>: some inhibitor-resistant enzymes have emerged<b> Other</b>: If resistance isn't from B-lactamase production, THIS DOESN'T HELP. Limitations: Clavulanate induces B-lactamase expression, only works on Class A serine proteases, degraded after binding, multiple classes of enzyme from one organism or multi-organism infection |
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Augmentin
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Amoxicillin + Clavulanate
(B-lactam, suicide substrate for transpeptidase by mimicking D-ala-D-ala) + (B-lactamase inhibitor) Much more active than just Amoxicillin (lower MIC) for B-lactamase producing bugs (NOT PBP mutation or other resistance) <i> </i>Penicillin's spectrum + enterococcus and “dumb gram negatives”. <b>GPC</b>: <i>pneumococcus</i>, <i>streptococcus</i>, <i>enterococcus</i> (<i>faecalis</i>, not faecium); <b>GNR</b>: <i>H. influenzae</i>, <i>E. coli, P. mirabilis, Salmonella. </i> Addition of clavulanate adds b-lactamase producing <i>S. aureus, H. influenzae, M. catarrhalis, </i>many GNR |
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cilistatin
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<b>Inhibits renal dehydropeptidase I.
Coadministered with imipenem.</b> Imipenem: renal clearance; urinary carbopenem hydrolyzed by <i>proximal tubular dehydropeptidase I; </i>results in metabolite: <b>renal tubular toxin</b>. Co-administration with <i>cilastatin</i> (inhibits renal dehydropeptidase I) both 1) increases efficiency for UTI tx and 2) decreases renal tubular toxicity |
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amoxicillin
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<b>Like penicillin but with improved Gram (-) spectrum; like ampicillin but with 100% bioavailability
Mechanism of action</b>: B-lactam; inhibits bacterial transpeptidase <b>Effect</b>: <b>'cidal </b>(blocks cross-linking of cell wall) <b>Indications</b>: Penicillin's spectrum + enterococcus and “dumb gram negatives”. <b>GPC</b>: <i>pneumococcus</i>, <i>streptococcus</i>, <i>enterococcus</i> (<i>faecalis</i>, not faecium); <b>GNR</b>: <i>H. influenzae</i>, <i>E. coli, P. mirabilis, Salmonella. </i> <b>Administration</b>: often PO, can give <b>3 times a day (q8h)</b>; can be paired with B-lactamase inhibitor (amoxicillin + <b>clavulanate </b>= Augmentin, given po) to improve spectrum to include b-lactamase producing <i>S. aureus, H. influenzae, M. catarrhalis, </i>many GNR <b>Resistance: </b>B-lactamase, PBP mutations, etc. <b>Toxicity</b>: Diarrhea, skin rash (macular, evanescent). <b>Not allergy</b>.<b> Other</b>: 100% orally bioavailable. Just ampicillin with one OH group added. <b>PAE</b> against GPC, <i>not</i> GNR. |
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imipenem
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<b>Mechanism of Action</b>: Carbapenem (B-lactam; suicide substrate for transpeptidase
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: Very broad spectum: Gram (+) incl. <i>enterococcus</i>, Gram (-) incl. <i>pseudomonas</i>, anaerobes including <i>bacteroides</i><b> Administration</b>: q8h (half life short but PAE for all)<b> Toxicity</b>: Seizures (incidence not defined). Renal clearance; urinary carbopenem hydrolyzed by <i>proximal tubular dehydropeptidase I; </i>results in metabolite: <b>renal tubular toxin</b>. Co-administration with <i><b>cilastatin</b></i> (inhibits renal dehydropeptidase I) both 1) increases efficiency for UTI tx and 2) decreases renal tubular toxicity <b>Resistance</b>: Rare (so far). Imipenem + cilistatin = Primaxin<b> Other</b>: <b>PAE </b>against Gram (+) <b>AND GRAM (-)! </b>Renal metabolism. |
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cephalexin
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<b>Mechanism of Action</b>: 1st generation cephalosporin (B-lactam; suicide inhibitor of transpeptidase)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: <b>GPC: </b><i>Strep, S. aureus</i><b> Administration</b>: q8h<b> Toxicity</b>: 1/3 cross reactivity with PCNs for anaphylaxis (desensitize or avoid if PCN skin test +!) <b>Resistance</b>: B-lactamase, etc.<b> Other</b>: a.k.a. Keflex. <b>PAE </b>against Gram (+). No activity against enterococci or listeria |
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procaine penicillin
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<b>Pharmacokinetically improved penicillin </b>(all penicillin info applies)<b>
</b>1:1 <b>salt</b>: penicillin G and procaine Given <b>IM</b>, very slow <b>absorption</b> (near painless) Half life of penicillin is the <b>same</b> (absorption is the difference) |
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piperacillin
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<b>Like ampicillin but with coverage of more serious GNRs </b>(e.g. pseudomonas)<b>
Mechanism of action</b>: B-lactam; inhibits bacterial transpeptidase <b>Effect</b>: <b>'cidal </b>(blocks cross-linking of cell wall) <b>Indications</b>: Ampicillin's spectrum + <b>more nosocomial GNRs</b> (“more serious GNR”). Adds <i><b>pseudomonas aeruginosa</b> </i>& <i><b>bacteroides</b> <b>fragilis</b></i> <b>Administration</b>: Can pair with tazobactam to increase coverage (B-lactamase producing <i>staphylococci</i> and many <i>GNR</i>). Doesn't help against pseudomonas! In combination for <b>serious Gram (-) infections</b> (e.g. nosocomial / empirical) <b>Resistance: </b>B-lactamase, PBP mutations, etc.<b> Other</b>: <b>PAE</b> against GPC, <i>not</i> GNR. (Ampicillin coverage = GPC: <i>pneumococcus</i>, <i>streptococcus</i>, <i>enterococcus</i> (<i>faecalis</i>, not faecium); GNR: <i>H. influenzae</i>, <i>E. coli, P. mirabilis, Salmonella.</i>) |
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ceftriaxone
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<b>Mechanism of Action</b>: 3rd generation cephalosporin (B-lactam; suicide inhibitor of transpeptidase)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: <i>Enterobacteriae, Serratia, N. gonarrhea; Same </i>anti-GPC (<i>Strep, S. aureus</i>) spectrum as 1st gen<b> Administration</b>: <b><u>daily</u></b> (others q8h)<b> Toxicity</b>: 1/3 cross reactivity with PCNs for anaphylaxis (desensitize or avoid if PCN skin test +!) <b>Resistance</b>: B-lactamase, etc.<b> Other</b>: A.k.a. Rocephin. <b>PAE </b>against Gram (+). |
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ampicillin
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<b>Like penicillin but with improved Gram (-) spectrum
Mechanism of action</b>: B-lactam; inhibits bacterial transpeptidase <b>Effect</b>: <b>'cidal </b>(blocks cross-linking of cell wall) <b>Indications</b>: Penicillin's spectrum + enterococcus and “dumb gram negatives”. <b>GPC</b>: <i>pneumococcus</i>, <i>streptococcus</i>, <i>enterococcus</i> (<i>faecalis</i>, not faecium); <b>GNR</b>: <i>H. influenzae</i>, <i>E. coli, P. mirabilis, Salmonella. </i> <b>Administration</b>: often IV; can be paired with B-lactamase inhibitor (amp + <b>sulbactam</b> = Unasyn, given IV) to improve spectrum to include b-lactamase producing <i>S. aureus, H. influenzae, M. catarrhalis, </i>many GNR <b>Resistance: </b>B-lactamase, PBP mutations, etc. <b>Toxicity</b>: Diarrhea, skin rash (macular, evanescent). <b>Not allergy</b>.<b> Other</b>: 50% orally bioavailable. <b>PAE</b> against GPC, <i>not</i> GNR.<b> </b> <b> </b> |
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sulbactam
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<b>Mechanism of Action</b>: B-lactamase inhibitor (<b>suicide substrate)</b>
<b>Effects</b>: Blocks B-lactamase activity to potentiate coadministered B-lactam drug <b>Selective Toxicity</b>: No B-lactamase in humans <b>Resistance</b>: some inhibitor-resistant enzymes have emerged<b> Other</b>: If resistance isn't from B-lactamase production, THIS DOESN'T HELP. Limitations: only works on Class A serine proteases, degraded after binding, multiple classes of enzyme from one organism or multi-organism infection |
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oxacillin
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<b>Like penicillin but pencillinase resistant
Mechanism of action</b>: B-lactam; inhibits bacterial transpeptidase <b>Effect</b>: <b>'cidal </b>(blocks cross-linking of cell wall) <b>Indications</b>: Penicillin's spectrum + penicillinase-producing <i>staph</i>, <i>pneumococcus</i>, <i>Group A</i> <i>streptococci</i> <b>Resistance: </b>PBP mutations, like MRSA or MRSE. (resistance to one of these extends to ALL B-lactams)<b> Other</b>: <b>PAE</b> against GPC, <i>not</i> GNR. |
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aztreonam
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<b>Mechanism of Action</b>: Monobactam (B-lactam; suicide substrate for transpeptidase
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: “Non-aminoglycoside aminoglycoside”. <b>Gram (-)</b> coverage<b> Toxicity</b>: No cross-allergenicity with penicillins <b>Resistance</b>: B-lactamase, etc. |
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penicillin G
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<b>Mechanism of Action</b>:<b> </b>Suicide substrate for bacterial transpeptidase (B-lactam ring mimics D-ala-D-ala peptide bond)
<b>Effects</b>: <b>'Cidal</b>. Blocks formation of peptide cross-links during synthesis of new bacterial cell wall <b>Selective Toxicity</b>: Humans don't have D-ala or transpeptidase (no cell walls)<b> Indications</b>: GPC: Strep; oral / “above the belt” anaerobes<b> Administration</b>:<b> Toxicity</b>: Rare to common hypersensitivity; non-allergenic toxicity common (GI Sx for oral drugs; sodium overload; other rare ones (bone marrow depression, hepatitis, platelet aggregation, seizures)). Oral history + positive skin test = avoid or desensitize! (30% crossover with cephalosporin allergic reactions = avoid those too) <b>Resistance</b>: Altered PBP site (penicillin doesn't fit as well), reduced permeability, B-lactamase (plasma mediated, excreted, <i>consituitive</i> & periplasmic in many Gram-, can use B-lactamase inhibitors to counter)<b> Other</b>: Normally pumped out of CSF via organic anion transport (OAT) pump. Inflammation inhibits pump. Renal excretion (crystallized from urine during war!). Short half life (45m) but has <b>PAE</b> against <b>Gram (+)</b> |
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cefepime
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<b>Mechanism of Action</b>: 4th generation cephalosporin (B-lactam; suicide inhibitor of transpeptidase)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: Like third gen but more B-lactamase resistant. <i>Enterobacteriae, </i><b><u><i>P. aeruginosa</i></u></b><i>, Serratia, N. gonarrhea; Same </i>anti-GPC (<i>Strep, S. aureus</i>) spectrum as 1st gen<b> Administration</b>: q8h<b> Toxicity</b>: 1/3 cross reactivity with PCNs for anaphylaxis (desensitize or avoid if PCN skin test +!) <b>Resistance</b>: More B-lactamase resistant (doesn't help against pseudomona but use for p.aerug anyway)<b> Other</b>: <b>PAE </b>against Gram (+). |
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cefuroxime
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<b>Mechanism of Action</b>: 2nd generation cephalosporin (B-lactam; suicide inhibitor of transpeptidase)
<b>Effects</b>: Inhibits cross-linking of peptidoglycan layer of bacterial cell wall <b>Selective Toxicity</b>: Humans don't have bacterial cell wall<b> Indications</b>: <i>E. coli, Klebsiella, Proteus, H. influenzae, M. catarrhalis. </i>Less anti-GPC (<i>Strep, S. aureus</i>) spectrum than 1st gen<b> Administration</b>: q8h<b> Toxicity</b>: 1/3 cross reactivity with PCNs for anaphylaxis (desensitize or avoid if PCN skin test +!) <b>Resistance</b>: B-lactamase, etc.<b> Other:</b> <b>PAE </b>against Gram (+). |
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gatifloxacin
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Third generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and gram pos) |
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ciprofloxacin
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<b>Mechanism of Action</b>: second generation <u>fluroquinolone</u> antimicrobial agent. Inhibits <u>prokaryotic type II topoisomerases </u>(primarily <u>gyrase</u> in gram neg; <u>topo IV</u> in gram pos). Forms a tetramer and base pairs with “four base stagger” of cleaved DNA strand while bound to enzyme, stabilizing the transient DNA-enzyme covalent intermediate & forming a “<u>cleavable complex”</u>.
<b>Effects</b>: <u>'Cidal</u>: replication fork collides with cleavable complex; double strand break results <b>Selective Toxicity</b>: FQs bind more tightly to prokaryotic topo II than human counterparts<b> Indications</b>: Tissue infections & UTIs; good <u>Gram (-)</u> coverage; some Gram (+) too<b> Administration</b>: Mg, Al, Fe (e.g. antacids!) can reduce absorption<b> Toxicity</b>: <u>GI</u> (2-11% nausea, vomiting, diarrhea); <u>CNS</u> (1-7% H/A, dizziness, fatigue, sleep probls; <0.5% <u>hallucinations, depression, seizures</u> - rare but serious); <u>Skin</u> (20% phototoxicity, 0.4-2% hypersensitivity - rash, pururitis); arthropathy in juvenile animals (<u>not approved for <18yo</u>); <u>tendon rupture</u> (rare but black box warning) <b>Resistance</b>: <u>mutations in gyrase</u> (first in gram neg) or <u>topo IV</u> (first in gram pos) most common. Less common: mutations in <u>membrane protein transporters</u>; <u>plasmid</u> that encodes protein mimic of DNA substrate for FQs to bind to. <u>increasing resistance = big worry!</u><b> Other</b>: great bioavailability; wide intracellular distribution (up to 24x serum conc.); CSF 10-25% serum (w/o inflammation). Metabolized mostly by <u>PHASE I ENZYMES</u> (oxidation); predominantly <u>renal</u> elimination (adjust if renal failure; no adjustment for hepatic failure). |
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norfloxacin
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Second generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and some gram pos) |
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moxifloxacin
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<b>Mechanism of Action</b>: fourth generation <u>fluroquinolone</u> antimicrobial agent. Inhibits <u>prokaryotic type II topoisomerases </u>(primarily <u>gyrase</u> in gram neg; <u>topo IV</u> in gram pos). Forms a tetramer and base pairs with “four base stagger” of cleaved DNA strand while bound to enzyme, stabilizing the transient DNA-enzyme covalent intermediate & forming a “<u>cleavable complex”</u>.
<b>Effects</b>: <u>'Cidal</u>: replication fork collides with cleavable complex; double strand break results <b>Selective Toxicity</b>: FQs bind more tightly to prokaryotic topo II than human counterparts<b> Indications</b>: Tissue infections & UTIs; good <u>Gram (-)</u> and <u>Gram (+)</u> coverage, also <u>ANAEROBES</u><b> Administration</b>: Mg, Al, Fe (e.g. antacids!) can reduce absorption<b> Toxicity</b>: <u>GI</u> (2-11% nausea, vomiting, diarrhea); <u>CNS</u> (1-7% H/A, dizziness, fatigue, sleep probls; <0.5% <u>hallucinations, depression, seizures</u> - rare but serious); <u>Skin</u> (20% phototoxicity, 0.4-2% hypersensitivity - rash, pururitis); arthropathy in juvenile animals (<u>not approved for <18yo</u>); <u>tendon rupture</u> (rare but black box warning) <b>Resistance</b>: <u>mutations in gyrase</u> (first in gram neg) or <u>topo IV</u> (first in gram pos) most common. Less common: mutations in <u>membrane protein transporters</u>; <u>plasmid</u> that encodes protein mimic of DNA substrate for FQs to bind to. <u>increasing resistance = big worry!</u><b> Other</b>: great bioavailability; wide intracellular distribution (up to 24x serum conc.); CSF 10-25% serum (w/o inflammation). Metabolized mostly by <u>PHASE II ENZYMES</u> (conjugation/glucoronidation); 1/3 <u>renal, </u>2/3 <u>biliary </u>elimination (DON'T adjust if renal failure - only FQ that you don't have to adjust for; no adjustment for hepatic failure b/c phase II enzymes still active enough). |
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ofloxacin
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Second generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and some gram pos) |
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levofloxacin
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Second generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and some gram pos) |
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gemifloxacin
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Fourth generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and gram pos), anaerobes |
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naladixic acid
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First generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, gram negs only (concentrated in urine; only place it reaches therapeutic values) |
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besifloxacin
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Fourth generation fluoroquinolone antimicrobial agent. Inhibits prokaryotic topo II.
Spectrum: UTI, tissues (gram negs and gram pos), anaerobes |
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tetracycline
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 30S subunit at A site
<b>Effects</b>: Blocks A/T > A/A alignment (aminoacyl-tRNA can't “stand up”) <b>Selective Toxicity</b>: Will inhibit eukaryotic protein synthesis, but <u>actively transported</u> into bacteria & accumulates. <u>Doesn't accumulate</u> in eukaryotic cells<b> Indications</b>: <b><u>Atypicals</u></b>: <i><u>Chlamyidial infections</u></i> (e.g. <i>Chlamydia pneumonia</i>, most common young adult CAP, STIs, PID, etc.). <i><u>Borrelia burgdorferi</u> </i>(Lyme dz). <i><u>H. pylori</u></i> (along with other abx & bismuth subsalicylate). <b> Administration</b>: q3-4h (less half-life, bioavailability than doxy or mino). Can't administer with <u>antacids</u>, <u>Maalox</u>, <u>milk </u>(Ca & Mg, see below)<b> Toxicity</b>: <u>Chelates</u> with <u>calcium</u> (teeth/bones; darkened bands on teeth with sunlight exposure, important from <u>few days before birth</u> to <u>6yo</u>) <b>Resistance</b>: Genetically altered <u>active transport system</u> (shared by all tetracyclines)<b> Other</b>:Originally broad spectrum, now lots of resistance |
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tobramycin
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<b>Mechanism of Action</b>: <u>Aminoglycoside</u> antimicrobial agent. Binds 30S ribosomal A site rRNA
<b>Like gentamicin</b> but not worth the extra cost |
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neomycin
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<b>Mechanism of Action</b>: <u>Aminoglycoside</u> antimicrobial agent. Binds 30S ribosomal A site rRNA
<b>Used topically</b> (triple antibiotic cream, etc.) |
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clindamycin
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 50S peptidyl transferase (A & P site)
<b>Effects</b>: Peptide bond formation blocked <b>Selective Toxicity</b>: Doesn't bind human ribosomal subunit or inhibit eukaryotic peptidyl transferase<b> Indications</b>: <u>GPC</u> (<i>S. pneumoniae, </i>Group A<i> Strep</i>, <i>Staph aureus</i>), <b>most anaerobes</b> (important)<b> Administration</b>: q6-8h, orally absorbed<b> Toxicity</b>: <u>Pseudomembranous colitis</u> (alters gut flora, <i>C. diff, </i>nursing homes, etc. Use <u>metronidazole</u> and <u>vancomycin</u> if failure for C.diff tx. Associated with clindamycin most commonly but also other broad abx) <b>Resistance</b>: Seldom a clinical problem<b> </b> |
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minocycline
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 30S subunit at A site
<b>Effects</b>: Blocks A/T > A/A alignment (aminoacyl-tRNA can't “stand up”) <b>Selective Toxicity</b>: Will inhibit eukaryotic protein synthesis, but <u>actively transported</u> into bacteria & accumulates. <u>Doesn't accumulate</u> in eukaryotic cells<b> Indications</b>: <b><u>Atypicals</u></b>: <i><u>Chlamyidial infections</u></i> (e.g. <i>Chlamydia pneumonia</i>, most common young adult CAP, STIs, PID, etc.). <i><u>Borrelia burgdorferi</u> </i>(Lyme dz). <i><u>H. pylori</u></i> (along with other abx & bismuth subsalicylate). <b> Administration</b>: q1-2h (longer half life than tetracycline, better oral bioavailability). Can't administer with <u>antacids</u>, <u>Maalox</u>, <u>milk </u>(Ca & Mg, see below)<b> Toxicity</b>: <u>Chelates</u> with <u>calcium</u> (teeth/bones; darkened bands on teeth with sunlight exposure, important from <u>few days before birth</u> to <u>6yo</u>). <b>Resistance</b>: Genetically altered <u>active transport system</u> (shared by all tetracyclines)<b> Other</b>:Originally broad spectrum, now lots of resistance |
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clarithromycin
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Binds in bacterial ribosomal peptidyl transferase cavity (50S), blocks <u>peptide exit tunnel</u> via H-bonding.
<b>Effects</b>: Occupies only exit tunnel; allows up to 6-8 peptide bond formation, then termination <b>Selective Toxicity</b>: Don't bind to human larger subunit; don't inhibit human protein synthesis<b> Indications</b>: <u>Atypical organisms/pneumonias</u> (<i>Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila)</i>. Can use instead of <b>PCN</b> if <b>allergic</b> (<i>S. pneumoniae</i>, Group A <i>Streptococcus</i>)<b> Administration</b>: <u>q24h</u><b> Toxicity</b>: <u>Safest </u>of all antimicrobials, some nausea & vomiting <b>Resistance</b>: Becoming a problem (<i>very</i> frequently used)<b> Other</b>:<i> </i>Great <u>cellular uptake</u> (AZI > ERY for <u>macrophage penetration</u>). EXPENSIVE (probably not worth it vs AZI or even ERY). |
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linezolid
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Blocks formation of 70S initiation complex (blocks movement of fMet-tRNA into bacterial ribosomal 50S P site)
<b>Effects</b>: No formation of 70S ribosome, no protein synthesis in bacteria <b>Selective Toxicity</b>: Doesn't bind human 80S ribosomal subunit<b> Indications</b>: <b>WORST OF THE WORST </b>(<u>VRE</u>, <u>MRSA</u>, <u>PCN-resistant</u> <i><u>S</u><u>.</u> <u>pneumoniae</u>). </i><b>'Static</b> except against <i>S. pneumoniae. </i><b> Other</b>: <b>PAE</b> of 1-2 hrs; <u>time-dependent</u> killing |
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streptomycin
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<b>Mechanism of Action</b>: <u>Aminoglycoside</u> antimicrobial agent. Binds 30S ribosomal A site rRNA
<b>Like other AGs</b> but used for <b><u>TB</u></b> |
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erythromycin
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Binds in bacterial ribosomal peptidyl transferase cavity (50S), blocks <u>peptide exit tunnel</u> via H-bonding.
<b>Effects</b>: Occupies only exit tunnel; allows up to 6-8 peptide bond formation, then termination <b>Selective Toxicity</b>: Don't bind to human larger subunit; don't inhibit human protein synthesis<b> Indications</b>: <u>Atypical organisms/pneumonias</u> (<i>Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila)</i>. Can use instead of <b>PCN</b> if <b>allergic</b> (<i>S. pneumoniae</i>, Group A <i>Streptococcus</i>)<b> Administration</b>: <u>q6h</u> (more frequent than AZI)<b> Toxicity</b>: <u>Safest </u>of all antimicrobials, some nausea & vomiting <b>Resistance</b>: Becoming a problem (<i>very</i> frequently used)<b> Other</b>:<i> </i>Great <u>cellular uptake</u> (AZI > ERY for <u>macrophage penetration</u>) |
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amikacin
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<b>Mechanism of Action</b>: <u>Aminoglycoside</u> antimicrobial agent. Binds 30S ribosomal A site rRNA
<b>Effects</b>: Inhibit protein synthesis, <u>misreading</u>, <u>freezing initiation complex</u><b>. </b>Actively imported into bacteria via <u>polyamine transporter</u> (inhibited by chloramphenicol, calcium, anaerobic or acidic environment, mutations). Causes lysis & death of bacteria <b>Selective Toxicity</b>: human 80S ribosomes don't bind aminoglycosides well (exception: cells with <u>megalin membrane transporter</u>: PCT, inner ear, pigmented retina epithelia; mitochondrial rRNA)<b> Indications</b>: <u>Gram negative rods </u>(good against <i>E. coli</i>, Klebsiella, proteus, even some “bad” gram negatives. Great coverage even for <i>Pseudomonas</i> - save for important uses! Use for severe gram(-) infections & for synergy (<i>S. aureus, enterococci, </i>PCN-resistant S<i>. pneumoniae!</i>) with PCNs. <b> Administration</b>: IV, <u>once-daily dosing</u> (high peak for <u>concentration-dep killing</u>, drug-free interval to reverse <u>adaptive post-exposure resistance</u> by bacteria & <u>minimize toxicity</u>). Takes advantage of PAE. <u>Therapeutic drug monitoring</u> useful too<b> Toxicity</b>: <u>Nephrotoxicity</u> (10-20%, PCT changes in <i>all</i>, glomerular changes in <i>few</i>, rarely severe, <i>reversible</i>). <u>Ototoxicity</u> (uncommon, cochlear & vestibular single digit %s, <i>irreversible</i>); <u>Neuromuscular paralysis</u> (exceedingly rare, inc. with fast infusion, myasthenia, succinyl choline anesthesia) <b>Resistance</b>: very slow development of resistance (ribosomal & transport mutations rare). <u>Enzymatic modifications</u> most common (acetylation, phosphorylation, adenylation). One enzyme may inactivate all AGs; but <u>very few</u> generate resistance to AMI<b> Other</b>: <u>Synergistic</u> with beta-lactams. <u>Antagonistic</u> with chloramphenicol. Has activity against GPC but not used clinically except in synergistic combinations. <u>PAE </u>against Gram (-) <u>and</u> (+) |
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gentamicin
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<b>Mechanism of Action</b>: <u>Aminoglycoside</u> antimicrobial agent. Binds 30S ribosomal A site rRNA
<b>Effects</b>: Inhibit protein synthesis, <u>misreading</u>, <u>freezing initiation complex</u><b>. </b>Actively imported into bacteria via <u>polyamine transporter</u> (inhibited by chloramphenicol, calcium, anaerobic or acidic environment, mutations). Causes lysis & death of bacteria <b>Selective Toxicity</b>: human 80S ribosomes don't bind aminoglycosides well (exception: cells with <u>megalin membrane transporter</u>: PCT, inner ear, pigmented retina epithelia; mitochondrial rRNA)<b> Indications</b>: <u>Gram negative rods </u>(good against <i>E. coli</i>, Klebsiella, proteus, even some “bad” gram negatives. Not great against <i>Pseudomonas</i> or <i>Acinetobacter </i>- TOB or AMI better). Use for severe gram(-) infections & for synergy (<i>S. aureus, enterococci, </i>PCN-resistant S<i>. pneumoniae!</i>) with PCNs. <b> Administration</b>: IV, <u>once-daily dosing</u> (high peak for <u>concentration-dep killing</u>, drug-free interval to reverse <u>adaptive post-exposure resistance</u> by bacteria & <u>minimize toxicity</u>). Takes advantage of PAE. <u>Therapeutic drug monitoring</u> useful too<b> Toxicity</b>: <u>Nephrotoxicity</u> (10-20%, PCT changes in <i>all</i>, glomerular changes in <i>few</i>, rarely severe, <i>reversible</i>). <u>Ototoxicity</u> (uncommon, cochlear & vestibular single digit %s, <i>irreversible</i>); <u>Neuromuscular paralysis</u> (exceedingly rare, inc. with fast infusion, myasthenia, succinyl choline anesthesia). <u>Ethacrynic acid</u> (loop diuretic) potentiates nephro/ototoxicity! <b>Resistance</b>: very slow development of resistance (ribosomal & transport mutations rare). <u>Enzymatic modifications</u> most common (acetylation, phosphorylation, adenylation). One enzyme may inactivate all AGs; most that inactivate GEN also inactivate TOB<b> Other</b>: <u>Synergistic</u> with beta-lactams. <u>Antagonistic</u> with chloramphenicol. Has activity against GPC but not used clinically except in synergistic combinations. <u>PAE </u>against Gram (-) <u>and</u> (+) |
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tigecycline
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 30S subunit at A site. New “class”- glycylcycline - minocycline with a large sterically limiting side chain
<b>Effects</b>: Blocks A/T > A/A alignment (aminoacyl-tRNA can't “stand up”) <b> Overcomes 2 resistance mechanisms: </b>(1)<b> </b><u>active efflux</u> from bacteria; (2) <u>protection of ribosomes</u> <b>Spectrum: broad; '<u>Static.</u> </b><u>GPC</u> (incl. MRSA & VRE!)<u> GNR </u>(incl. <i>Acinetobacter</i>, NOT<i> pseudomonas), </i><u>AnO2 </u>(incl. <i>Bacteroides) </i>Good efficacy: intra-abdominal, skin/skinstructure, pneumonia Good <u>tissue penetration</u>, <u>36h half life!</u> no drug-drug interactions or food effect |
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doxycycline
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 30S subunit at A site
<b>Effects</b>: Blocks A/T > A/A alignment (aminoacyl-tRNA can't “stand up”) <b>Selective Toxicity</b>: Will inhibit eukaryotic protein synthesis, but <u>actively transported</u> into bacteria & accumulates. <u>Doesn't accumulate</u> in eukaryotic cells<b> Indications</b>: <b><u>Atypicals</u></b>: <i><u>Chlamyidial infections</u></i> (e.g. <i>Chlamydia pneumonia</i>, most common young adult CAP, STIs, PID, etc.). <i><u>Borrelia burgdorferi</u> </i>(Lyme dz). <i><u>H. pylori</u></i> (along with other abx & bismuth subsalicylate). <b> Administration</b>: q1-2h (100% bioavailability, longer half life than tetracycline). Can't administer with <u>antacids</u>, <u>Maalox</u>, <u>milk </u>(Ca & Mg, see below)<b> Toxicity</b>: <u>Chelates</u> with <u>calcium</u> (teeth/bones; darkened bands on teeth with sunlight exposure, important from <u>few days before birth</u> to <u>6yo</u>). <u>Least GI </u>side effects of class <b>Resistance</b>: Genetically altered <u>active transport system</u> (shared by all tetracyclines)<b> Other</b>:Originally broad spectrum, now lots of resistance |
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azithromycin
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Binds in bacterial ribosomal peptidyl transferase cavity (50S), blocks <u>peptide exit tunnel</u> via H-bonding.
<b>Effects</b>: Occupies only exit tunnel; allows up to 6-8 peptide bond formation, then termination <b>Selective Toxicity</b>: Don't bind to human larger subunit; don't inhibit human protein synthesis<b> Indications</b>: <u>Atypical organisms/pneumonias</u> (<i>Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila)</i>. Can use instead of <b>PCN</b> if <b>allergic</b> (<i>S. pneumoniae</i>, Group A <i>Streptococcus</i>)<b> Administration</b>: <u>q24h</u><b> Toxicity</b>: <u>Safest </u>of all antimicrobials, some nausea & vomiting <b>Resistance</b>: Becoming a problem (<i>very</i> frequently used)<b> Other</b>:<i> </i>Great <u>cellular uptake</u> (AZI > ERY for <u>macrophage penetration</u>) |
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chloramphenicol
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<b>Mechanism of Action</b>: Ribosomal inhibitor, antimicrobial agent. Inhibits bacterial ribosomal 50S peptidyl transferase at A site.
<b>Effects</b>: Blocks peptide elongation by blocking peptidyl transferase step <b>Selective Toxicity</b>: Doesn't bind human large ribosomal subunit, <i>does</i> bind <u><i>mitochondrial</i></u> peptidyl transferase<b> Indications</b>: <b>'Cidal</b> against <u><i>S. pneumoniae</i></u><i>, </i><u><i>N. meningitidis</i></u><i>, </i><u><i>H. influenzae</i></u><i>. '</i><b>Static</b> against many <u>Gram (-)</u> & <u>anaerobes.</u> Used for <b>CNS infections</b> of these.<b> Administration</b>: insoluble. <u>palmitate ester</u> used for PO (children syrup, hydrolized by <u>gut</u>). <u>succinate ester</u> used for IV (hydrolyzed by <u>liver</u>). <b> Toxicity</b>: <b><u>Bone marrow suppression:</u> transient</b>, <b>reversible (</b>dose-related, plasma-level related, marrow vacuolated; dec. reticulocytes, serum iron incr. with RBC decrease, from <u>inhibition of mito protein synth</u>). <b><u>Aplastic anemia: irreversible</u></b> > 50% (not dose/plasma/time related; often fatal, 1:40,000, just takes 1 dose). <b><u>Gray baby syndrome</u></b>: don't glucuronidate well, blood levels > 50mcg/mL, e- transport inhibited (ashen gray color, vomiting, refusal to suck, rapid/irreg breathing, abd distension, cyanosis, diarrhea, flacidity, hypothermia, death). <b>Resistance</b>: Enzymatic modification (<u>acetylation</u>)<b> Other</b>: Metabolism: <u>glucuronidated</u> by liver; mostly glucuronidated product cleared by <u>kidney</u>. Distribution<b>: </b><u>wide</u>, <u>intracellular</u>, <b><u>excellent CSF penetration</u></b> (>50% plasma concentrations). Not often used in US (afraid of aplastic anemia) although risk ~ PCNs, <NSAID/yr. |
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sulfamethoxazole
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<b>Mechanism of Action</b>:<b> </b>inhibits DHP synthase, blocking folate synthesis in bacteria. Structural analog of PABA, one of DHP synthase's substrates.
<b>Effects</b>: Folate is required 1C unit carrier for TMP & purine synthesis; no folate = no DNA synthesis & cell death. <b>Selective toxicity:</b><i> </i>Humans don't synthesize folate (no DHP synthase)<b> Indications</b>: Prophylaxis of simple UTI from Gram (-) bacteria. Drug of choice for Nocardia. <b>Administration:</b> Rarely used as monotherapy. TMP+SMX = cotrimoxazole (Bactrim).<b> Toxicity</b>: Hypersensitivity or idiopathic (flu-like, drug fever, skin rashes, joint pain, lymphadenopathy). <b>Kernicterus</b> in newborns (bumps bilirubin from albumin, increasing free bilirubin, which can cross cell membranes & deposit in basal ganglia) - never give to nursing mother or newborn (high mortality) <b>Resistance</b>: decreased bacterial permeability to sulfonamides, mutations in DHP synthase, increased DHP synthase activity, increased production of PABA<b> Other</b>:<b> </b>Longer half life, more soluble than sulfanilamide. A.k.a. <b>Gantanol</b> |
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sulfisoxazole
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<b>Mechanism of Action</b>:<b> </b>inhibits DHP synthase, blocking folate synthesis in bacteria. Structural analog of PABA, one of DHP synthase's substrates.
<b>Effects</b>: Folate is required 1C unit carrier for TMP & purine synthesis; no folate = no DNA synthesis & cell death. <b>Selective toxicity:</b><i> </i>Humans don't synthesize folate (no DHP synthase)<b> Indications</b>: Prophylaxis of simple UTI from Gram (-) bacteria. Drug of choice for Nocardia. <b>Administration:</b> Rarely used as monotherapy, but this one is the most common monotherapy. Often coadministered with erythromycin<b> Toxicity</b>: Hypersensitivity or idiopathic (flu-like, drug fever, skin rashes, joint pain, lymphadenopathy). <b>Kernicterus</b> in newborns (bumps bilirubin from albumin, increasing free bilirubin, which can cross cell membranes & deposit in basal ganglia) - never give to nursing mother or newborn (high mortality) <b>Resistance</b>: decreased bacterial permeability to sulfonamides, mutations in DHP synthase, increased DHP synthase activity, increased production of PABA<b> Other</b>:<b> </b>Longer half life, more soluble than sulfanilamide. A.k.a. <b>Gantrisin</b> |
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trimethoprim
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<b>Mechanism of Action</b>:<b> </b>Inhibits bacterial dihydrofolate reductase (conversion of FH2 to THF), blocking folate synthesis
<b>Effects</b>: Folate is required 1C unit carrier for TMP & purine synthesis; no folate = no DNA synthesis & cell death. <b>Selective toxicity:</b><i> </i>Doesn't fit into human DHFR (extremely selective for bacterial) <b>Administration:</b>TMP+SMX = cotrimoxazole (Bactrim).<b> Toxicity</b>: Rare: rash, nausea, vomiting in 3-5%. In nutritionally deprived (pregnant, malnourished, alcoholic, etc.) pts, can exacerbate folate deficiency (neutropenia, thrombocytopenia, megaloblastic anemia) <b>Resistance</b>: Mutation in DHFR; increase in DHFR<b> Other:</b> inhibits DHFR like methotrexate but bacterial-specific |
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sulfanilamide
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<b>Mechanism of Action</b>:<b> </b>inhibits DHP synthase, blocking folate synthesis in bacteria. Structural analog of PABA, one of DHP synthase's substrates.
<b>Effects</b>: Folate is required 1C unit carrier for TMP & purine synthesis; no folate = no DNA synthesis & cell death. <b>Selective toxicity:</b><i> </i>Humans don't synthesize folate (no DHP synthase)<b> Indications</b>: Now rarely used.<b> Toxicity</b>: Hypersensitivity or idiopathic (flu-like, drug fever, skin rashes, joint pain, lymphadenopathy). <b>Kernicterus</b> in newborns (bumps bilirubin from albumin, increasing free bilirubin, which can cross cell membranes & deposit in basal ganglia) - never give to nursing mother or newborn (high mortality) <b>Resistance</b>: decreased bacterial permeability to sulfonamides, mutations in DHP synthase, increased DHP synthase activity, increased production of PABA<b> Other</b>:<b> </b>Active part of prontosil, first big-time antibacterial agent. Crystallizes in urine, so replaced with newer versions (sulfamethoxazole, sulfisoxazole) |
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Fansidar (pyrimethamine + sulfadoxine),Combination drug for malaria (sort of like TMP+SMX - DHFR & DHP synthase inhibitors)
Cotrimoxazole (TMP+SMX) |
<b>Mechanism of Action</b>: Blocks folate synthesis (TMP blocks DHFR, SMX blocks DHP synthase)
<b>Effects</b>: Folate is required 1C unit carrier for TMP & purine synthesis; no folate = no DNA synthesis & cell death. <b>Selective Toxicity</b>: TMP: selective for bacterial DHFR; SMX: humans don't have DHP synthase (don't synthesize folate)<b> Indications</b>: Listeria monocytogenes, Nocarrdia, various others; prophylaxis of toxoplasmosis & PCP in HIV pts<b> Resistance</b>: less common because of combo effect<b> Advantages of combo: </b>Synergistic, broader spectrum, less resistance, lower dosage=less toxicity, '<b>cidal</b> instead of <b>'static</b> |
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naftifine
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<b>Mechanism of Action</b>: Allylamine antifungal drug. Inhibits <u>ergosterol biosynthesis.</u>
<b>Effects</b>: Inhibit <u>squaline-2-3-epoxidase</u> (earlier step in ergosterol biosynthesis than azoles); lead to membrane disruption and leakage of small molecules. <b>Selective Toxicity</b>: Highly selective for <u>fungal squalene epoxidase</u> over human (no effect <i>in vivo</i> on cholesterol biosynthesis<b> Indications</b>:Candida, etc.<b> Administration</b>: Topical<b> </b> |
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terbinafine
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<b>Mechanism of Action</b>: Allylamine antifungal drug. Inhibits <u>ergosterol biosynthesis.</u>
<b>Effects</b>: Inhibit <u>squaline-2-3-epoxidase</u> (earlier step in ergosterol biosynthesis than azoles); lead to membrane disruption and leakage of small molecules. <b>Selective Toxicity</b>: Highly selective for <u>fungal squalene epoxidase</u> over human (no effect <i>in vivo</i> on cholesterol biosynthesis<b> Indications</b>:Candida, etc.<b> Administration</b>: Topical and oral<b> Other:</b> Active ingredient in Lamisil |
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fluconazole
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<b>Mechanism of Action</b>: azole antifungal agent. <u>Low doses</u>: inhibits <u>ergestol biosynthesis</u>. <u>High doses</u>: may directly damage fungal cell membrane
<b>Effects</b>: <u>Low</u> dose: blocks <u>14-alpha-demethylase</u>, a CYP450 (lanosterol to ergosterol) <u>High</u> dose: direct damage <b>Selective Toxicity</b>: Binds fungal demethylase more than human (although both have this enzyme)<b> Indications</b>: Fungi<u>static</u>, no post-antifungal-effect. Maintenence of <u>cryptococcal meningitis</u>; prevention of <u>candidal infection</u> (transplants, etc)<b> Administration</b>: Good oral absorption; <u>independent</u> of gastric acidity; good into <u>CSF and eye</u><b> Toxicity</b>: <u>GI distress</u>, r<u>ash</u>, <u>hepatotoxicity</u>, drug <u>interactions</u> <u>(CYP3A4</u> inhibitor) <b>Other</b>: Elimination mostly <u>renal</u>; >80% dose excreted unchanged in urine. Long half-life |
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voriconazole
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<b>Mechanism of Action</b>: azole antifungal agent. <u>Low doses</u>: inhibits <u>ergestol biosynthesis</u>. <u>High doses</u>: may directly damage fungal cell membrane
<b>Effects</b>: <u>Low</u> dose: blocks <u>14-alpha-demethylase</u>, a CYP450 (lanosterol to ergosterol) <u>High</u> dose: direct damage <b>Selective Toxicity</b>: Binds fungal demethylase more than human (although both have this enzyme)<b> Indications</b>: <u>invasive aspergillosis</u> & <u>candidemia</u><b> Administration</b>: <u>good bioavailability, BETTER on EMPTY stomach</u><b> Toxicity</b>: <u>GI distress</u>, r<u>ash</u>, <u>hepatotoxicity</u>, drug <u>interactions</u> <u>(CYP3A4</u> inhibitor) <b>Resistance</b>:<b> Other</b>: exclusively <u>hepatic</u> metabolism; urine/bile excretion |
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ketoconazole
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<b>Mechanism of Action</b>: azole antifungal agent. <u>Low doses</u>: inhibits <u>ergestol biosynthesis</u>. <u>High doses</u>: may directly damage fungal cell membrane
<b>Effects</b>: <u>Low</u> dose: blocks <u>14-alpha-demethylase</u>, a CYP450 (lanosterol to ergosterol) <u>High</u> dose: direct damage <b>Selective Toxicity</b>: Binds fungal demethylase more than human (although both have this enzyme)<b> Indications</b>:<u>Alternative to ampho B</u> (systemic/mucocutaneous fungal infections)<b> Administration</b>: orally effective; long half life<b> Toxicity</b>: <u>GI distress</u>, r<u>ash</u>, <u>hepatotoxicity</u>, drug <u>interactions</u> <u>(CYP3A4</u> inhibitor)<b> Other</b>: Metabolized in <u>liver</u>, excreted in <u>rine</u> |
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itraconazole
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<b>Mechanism of Action</b>: azole antifungal agent. <u>Low doses</u>: inhibits <u>ergestol biosynthesis</u>. <u>High doses</u>: may directly damage fungal cell membrane
<b>Effects</b>: <u>Low</u> dose: blocks <u>14-alpha-demethylase</u>, a CYP450 (lanosterol to ergosterol) <u>High</u> dose: direct damage <b>Selective Toxicity</b>: Binds fungal demethylase more than human (although both have this enzyme)<b> Indications</b>: <u>systemic</u> (fewer side effects than ketoconazole but still liver-toxic)<b> Administration</b>: Oral absorption erratic; <u>improved by acid/food</u><b> Toxicity</b>: <u>GI distress</u>, r<u>ash</u>, <u>hepatotoxicity</u>, drug <u>interactions</u> <u>(CYP3A4</u> inhibitor)<b> Other</b>: Metabolism: exclusively <u>hepatic;</u> urine/bile for elimination, long half-life |
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nystatin
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<b>Very similar to amphotericin, but in topical preparation
Indications</b>: treatment of <u>oral, vulvovaginal, cutaneous</u> candidiasis<b> Administration</b>: Topical (below from amphotericin)<b> Mechanism of Action</b>:polyene antifungal agent. Big macrolide ring; <u>half hydropohbic</u>, <u>half hydrophilic</u>, forms a <u>channel</u> or pore in fungal membranes <b>Effects</b>: forms cylindrical <u>channel</u> (hydrophobic sides outside, against cell membrane) when bound to sterols & allows <u>leakage</u> of small molecules resulting in fungal death <b>Selective Toxicity</b>: Binds more avidly to <u>ergosterol</u> (fungi) than cholesterol; selective toxicity <u>not great</u><b> </b> |
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amphotericin B
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<b>Mechanism of Action</b>:polyene antifungal agent. Big macrolide ring; <u>half hydrophobic</u>, <u>half hydrophilic</u>, forms a <u>channel</u> or pore in fungal membranes
<b>Effects</b>: forms cylindrical <u>channel</u> (hydrophobic sides outside, against cell membrane) when bound to sterols & allows <u>leakage</u> of small molecules resulting in fungal death <b>Selective Toxicity</b>: Binds more avidly to <u>ergosterol</u> (fungi) than cholesterol; selective toxicity <u>not great</u><b> Indications</b>: potentially <u>fatal</u> fungal infections: <u>invasive aspergillosis, disseminated candidiasis</u> (think of toxicity)<b> Administration</b>: IV<b> Toxicity</b>: A lot. <b><u>NEPHROTOXICITY</u></b> is dose limiting. <u>Fever, chills, hypotension</u> (“shake 'n bake”) <b>Other: <u>deoxycholate</u></b> is usual form; also <b><u> lipid formulations</u></b> available: same efficacy, less toxicity, 30-40x more $$ |
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caspofungin
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<b>Mechanism of Action</b>: Antifungal agent. <u>Inhibits cell wall biosynthesis</u>
<b>Effects</b>: irreversible inhibitor of <u>1,3-beta-D-glucan synthase</u> (makes glucan polymers for fungal cell wall); <u>fungicidal</u> <b>Selective Toxicity</b>: Humans <u>don't have cell walls</u>; fungi need glucan polymers for structure & viability<b> Indications</b>:<u>Salvage</u> therapy for <u>invasive aspergillosis</u>; <u>esophogeal</u> <u>candidiasis</u>, <u>candidemia</u>. Used when <u>ampho B, others</u> don't work.<b> Toxicity</b>: Important (limits usage, 14% of recipients). <u>fever, nausea, vomiting, infusion site complications</u> <b>Resistance</b>: No cross-resistance with other classes<b> </b> |
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anidulafungin
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<b>Mechanism of Action</b>: Antifungal agent. <u>Inhibits cell wall biosynthesis</u>
<b>Effects</b>: irreversible inhibitor of <u>1,3-beta-D-glucan synthase</u> (makes glucan polymers for fungal cell wall); <u>fungicidal</u> <b>Selective Toxicity</b>: Humans <u>don't have cell walls</u>; fungi need glucan polymers for structure & viability<b> Indications</b>: <b><u>candidiemia</u> Toxicity</b>: Important (limits usage, 14% of recipients). <u>fever, nausea, vomiting, infusion site complications</u> <b>Resistance</b>: No cross-resistance with other classes |
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micafungin
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<b>Mechanism of Action</b>: Antifungal agent. <u>Inhibits cell wall biosynthesis</u>
<b>Effects</b>: irreversible inhibitor of <u>1,3-beta-D-glucan synthase</u> (makes glucan polymers for fungal cell wall); <u>fungicidal</u> <b>Selective Toxicity</b>: Humans <u>don't have cell walls</u>; fungi need glucan polymers for structure & viability<b> Indications</b>: <b><u>prophylaxis of candidiasis in BMT recipients; Tx of esophogeal candidiasis</u></b> <b> Toxicity</b>: Important (limits usage, 14% of recipients). <u>fever, nausea, vomiting, infusion site complications</u> <b>Resistance</b>: No cross-resistance with other classes |
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griseofulvin
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<b>Mechanism of Action</b>: Antifungal agent; Interferes with <u>microtubule formation</u>
<b>Effects</b>: <u>actively transported</u> into fungal cells; <u>disrupts microtubules</u> (mitotic & cytoplasmic), <u>cell cycle arrest</u> at mitosis, formation of <u>multinucleate cells.</u><b> Selective Toxicity</b>: Humans <u>don't actively transport</u> into our cells<b> Indications</b>: Severe infection of <u>hair, nails, palm, soles</u> (concentrates highly in <u>keratin layers</u>)<b> Administration</b>: Almost complete distribution; goes to <u>keratin layers</u><b> Toxicity</b>: Relatively safe (GI distress, temporary headache) |
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flucytosine (5FC)
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<b>Mechanism of Action</b>: Pyrimidine analog antifungal agent. Active form <u>interferes with nucleotide metabolism</u>
<b>Effects</b>: Converted to <u>5-FU</u> in fungi by <u>cytosine deaminase</u>. 5-FU has two roles: (1) metabolized to <u>5-FUMP</u>, <u>incorporated </u>into <u>fungal mRNA</u>, interferes with <u>protein synthesis</u>; (2) <u>5-FUMP</u> --> <u>5-dUMP</u> via ribonucleotide reductase; inhibits <u>thymidylate synthase</u> <b>Selective Toxicity</b>: Human <u>cytosine deaminase</u> can't deaminate <u>5-FC</u> (note that <u>fungi</u> and <u>GI FLORA</u> can!)<b> Indications</b>: <u>systemic Candida/Cryptococcus</u> infections<b> Administration</b>: co-administered with <u>amphotericin B</u> to combat resistance<b> Toxicity</b>: generally well tolerated but: <u>bone marrow depression</u>, <u>GI</u> distress (gut flora killed); reversible <u>hepatotoxicity</u> <b>Resistance</b>: MAJOR PROBLEM - develops very quickly with monotherapy<b> </b> |
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chloroquine
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<b>Mechanism of Action</b>: Antimalarial drug. Inhibits <u>heme detoxification</u> in plasmodia
<b>Effects</b>: Inhibits formation of heme polymers in plasmodia, leading to buildup of toxic <u>heme</u> <b>Selective Toxicity</b>: Humans use heme deoxygenase to make bilirubin & excrete (different pathway). <u>Concentrated</u> 100-200fold in infected RBC<b> Indications</b>: First line for <u>ovale & malariae</u><b> Toxicity</b>: <u>Retinopathy</u> (>100g cumulative dose, permanent) <b>Resistance</b>: Widespread (more common than not: Sub-saharan Africa, South America, SE Asia). <u>Mutations in transporter proteins (enhance efflux)</u><b> Other</b>: Cheap & available |
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artemether + lumefantrine (Coartem)
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<b>Antimalarial agent; non-synergistic fixed combination</b>
irrational mechanism: artemether forms free radicals; alkylates macromolecules; lumefantrine prevents heme polymerization) |
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metronidazole
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<b>Mechanism of Action</b>:<b> </b>Anti-protozoal & anti-anaerobe antibiotic. When two <u>nitro-radical anion</u> forms collide, they create a reactive complex that causes <u>alkylation & strand breakage</u> of DNA
<b>Selective Toxicity</b>: Only works against anaerobes: has aromatic NO2 group that accepts an electron from <u>reductive metabolism</u> process (production of ferredoxin), generating <u>nitro-radical anion</u> only in anaerobes<b> Indications</b>: <b><u>Protozoa </u></b><u>+ </u><b><u>anaerobes</u>.</b> <i>Trichomonas vaginalis Entamoeba histolytica, </i>anaerobic bacteria; of-label for <i>Giardia & H. pylori</i>.<b> Toxicity</b>: Genetic toxicity (? - controversial). <u>GI</u> common (<u>nausea</u>, <u>metallic taste</u>, disulfiram-like rxn with <u>alcohol</u>), <u>Neuro</u> (headache, ataxia, peripheral neuropathy, seizures - can be irreversible but <u>rare</u>). Avoid in <u>pregnant/lactating women</u><b> Other</b>: Prefers organisms with <u>high A/T content</u> in their genomes. Penetrates well into <u>abscess cavities, CSF,</u> bile, <u>bone, </u>placenta, milk. Excreted by <u>kidneys</u> (modify for renal failure) |
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mebendazole
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<b>Mechanism of Action</b>: Antihelminthic agent. <u>Block glucose transport</u> and <u>inhibit succinate dehydrogenase</u> activity; an enzyme used in parasite's respiratory chain. (also disrupt microtubules selectively)
<b>Effects</b>: No energy for parasites; die & get swept out <b>Selective Toxicity</b>:Helminths have <u>different metabolism</u> because they're anaerobic; <u>parasitic isoforms</u> are <u>different</u> for these enzymes than humans'. <b>POOR GI ABSORPTION (LUMINAL AGENT</b>, unlike albendazole)<b> Indications</b>:<u>Broad spectrum</u>. Gut organisms (<u>enterobius, ascaris, trichuris, hookworm</u>), NOT TISSUE <b>Toxicity</b>: Potent teratogen in animals. <u>Careful in pregnant women</u>. Minimal otherwise<b> Administration</b>:<b> </b>PO |
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primaquine
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Antimalarial agent; works against exoerythrocytic parasites; mechanism of action unknown
Can elicit <b>hemolytic anemia</b> in <b>G6PD-deficient patients</b> |
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pyrimethamine + sulfadoxine (Fansidar)
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<b>Synergistic</b> <b>antifolate+sulfonamide combination</b> for <b>malaria</b> use
Widespread resistance; Stevens-Johnson (rare) limits use |
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albendazole
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<b>Mechanism of Action</b>: Antihelminthic agent. <u>Block glucose transport</u> and <u>inhibit succinate dehydrogenase</u> activity; an enzyme used in parasite's respiratory chain. (also disrupt microtubules selectively)
<b>Effects</b>: No energy for parasites; die & get swept out <b>Selective Toxicity</b>:Helminths have <u>different metabolism</u> because they're anaerobic; <u>parasitic isoforms</u> are <u>different</u> for these enzymes than humans'. <u>Variable absorption</u> (good to get more coverage; bad because of human interactions - <u>not a luminal agent)</u><b> Indications</b>:<u>Broad spectrum</u>. Gut organisms (<u>enterobius, ascaris, trichuris, hookworm</u>) and tissue too (<u>strongyloides</u>, <u>tapeworm</u> which have tissue parts of life cycle) <b>Toxicity</b>: Potent teratogen in animals. <u>Don't give to pregnant women</u>. Minimal otherwise<b> Administration</b>:<b> </b>PO |
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pyrantel
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<b>Mechanism of Action</b>: Antihelminthic agent. Ach analog; <u>neuromuscular blocking agent</u> & <u>Ach inhibitor</u> (causes <u>spastic paralysis </u>& constant <u>muscle contraction</u> of worm)
<b>Effects</b>:Worms can't resist bowel peristalsis; get swept out <b>Selective Toxicity</b>: <u>Luminal agent</u> (poorly absorbed) - only affects parasites<b> Indications</b>:<u>Ascaris</u> infection (helminths)<b> Administration</b>:<b> </b>PO |
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praziquantel
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<b>Mechanism of Action</b>: Antihelminthic agent. Causes <u>tetanic contraction</u> of <u>schistotomes</u> (alters Ca transport) & alters <u>membrane integrity</u>
<b>Effects</b>:Worms can't resist bowel peristalsis; get swept out to <u>liver/lungs </u>(portal circulation from gut or systemic from bladder area). <u>Surface of worm disrupted</u> then, leading to death. <b>Selective Toxicity</b>: unknown (NOT LUMINAL) <b>Toxicity</b>: frequent <u>GI/CNS</u> butmild<b> Indications</b>:Cestodes / trematodes (<u>schistosomiasis & tapeworms</u> - taenia solium, etc.) |
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mefloquine
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<b>Similar to chloroquine</b> (inhibits heme detoxification)
<b>Drug of choice for</b>: <u>prophylaxis</u> against <u>chloroquine resistant falciparum malaria</u> Expensive; CNS toxicity means can't use to treat established infection |
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quinine
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Antimalarial agent; <b>similar to chloroquine</b> (inhibits heme detoxification)
<b>Drug of choice:</b> treatment of <u>chloroquine-resistant falciparum </u>malaria; can give <b><u>IV</u></b> in emergency 300+ years old <b>Toxicity</b> including “cinchonism” (tinnitus + H/A, nausea, vomiting) <b>quinidine </b>is stereoisomer, active & available in US (unlike quinine) |
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atovaquone + proguanil (Malarone)
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<b>Mechanism of action</b>: fixed, synergistic antimalarial combination. <b>Atovaquone </b>binds <u>cytochrome b</u> in plasmodium; both <u>inhibits pyrimidine biosynthesis</u> and <u>collapses mito membrane potential</u>. <b>Proguanil</b> is converted to <u>cycloguanil</u>, which selectively inhibits <u>dihydrofolate reductase</u>
<b>Selective toxicity</b>: enzyme isoforms different in plasmodia <b>Synergy</b>: probably based on <u>collapse of mito membrane potential</u> (not fully known; expts show not pyrimidine synthesis based) <b>Indications</b>: drug of choice for <u>MDR falciparum malaria</u> <b>Resistance</b>: arises fast with atovaquone alone; not with combination. |
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pentamadine
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<b>Mechanism of action</b>: <u>Active transport </u>& <u>accumulation</u> in parasites. Activity is <u>multifactorial</u>: disorganize mitoDNA, inhibit mito Topo, bind ribosomes, inhibit phospholipid synth, etc.
<b>Indications</b>: <i>T. brucei, Leishmania, Blastomycosis, Babesia, P. jiroveci</i>. <b>Aerosolized</b> form recommended for <u>PCP prophylaxis</u> in HIV patients (second line because of toxicity for Tx behind TMP+SMX) <b>Toxicity</b>: severe in 55% AIDS pts with PCP. leukopenia, azotemia, <u>hepatitis</u>, <b><u>unpredictable hypoglycemia</u></b> (insulin similarities), others. <b>Other:</b> Structural analog of <b>synthalin </b>(synthetic insulin) |
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Atripla
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1 pill qd for HIV!
efavirenz (NNRTI), emtricitabine (NRTI), tenofovir (NRTI) |
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nevirapine (NVP)
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<b>Mechanism of Action</b>:NNRTI Anti-HIV antiretroviral. <u>Non-competitive reverse transcriptase inhibitor</u>
<b>Effects</b>: Binds to HIV RT <u>distant</u> from active site, causes conf. change to make RT less efficient <b>Selective Toxicity</b>: No effect on human DNApols (incl. mitochondrial)<b> Indications</b>: HIV<b> Administration</b>:bid but could be qd (long half life)<b> Toxicity</b>:Rash, hypersensitivity (common), hepatitis, Stevens-Johnson syndrome (rare, systemic attack of immune system against epithelium: full body burn, slough off mucosa/epithelium): all <u>immune-mediated</u>. IMPORTANT: <u>CYP450 3A4 INDUCER</u> (drug interactions - like rifampin). <b>Resistance</b>: <u>FAST</u> (very poor monotherapy) - needs <u>single AA</u> change (1000x resistance), days to weeks, <u>Cross-resistance</u> to other NNRTIs (exception = etravirine)<b> Other:</b> <u>no </u>intracellular activation required. Doesn't work against <u>HIV-2</u> (doesn't bind RT). Well-absorbed, eliminated by CYP450 3A4 |
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efavirenz
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NNRTI like nevirapine
<u>Less toxicity</u>, longer half life part of Atripla (1 pill qd) Most common NNRTI in use in USA |
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zidovudine (azidothymidine, AZT)
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<b>Mechanism of Action</b>: NRTI, Anti-HIV antiretroviral agent. Thymidine analog. Triphosphate form inhibits HIV <u>reverse transcriptase</u>, acts like <u>chain terminator</u>
<b>Effects</b>: Incorporated but not substrate for elongation in RNA-dep-DNA-pol activity of HIV RT <b>Selective Toxicity</b>: poor, also inhibits <u>mitochondrial</u> DNApol<b> Indications</b>: HIV<b> Administration</b>: Short plasma half-life (1h) but much <u>longer</u> intracellular AZT-TP half-life (allows more infrequent dosing, <u>q12h</u>).<b> Toxicity</b>: <u>Bone marrow </u>suppression (common, mostly <u>anemia</u>, less commonly granulocytopenia). Rare: <u>Myopathy</u>, <u>lactic acidosis/steatosis</u> (steatosis = accumulation of fat in liver cells, <u>fatal</u> and <u>class-wide</u> for NRTIs albeit rare) <b>Resistance</b>: Need <u>5+</u> AA changes. <u>Slow</u> to develop (only 1/3 on monotherapy resistant in 1 year), <u>limited cross-resistance</u> with other NRTIs<b> Other</b>: <u>Phosphorylated</u> by <u><i>cellular</i></u> enzymes to triphosphate (active form). Rapidly converted to AZT-MP, accumulates in cell (-DP, -TP formation more slow) Well absorbed, eliminated by <u>glucuronidation (Phase II)</u>. Commonly used in other countries (cheap generic) and sometimes for needle-stick prophy here, although others probably work as well (only one studied) |
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tenofovir (TDF)
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NRTI antiretroviral
unlike AZT is a <u>broad-spectrum antiviral</u> (anti-HBV too), more commonly used than AZT in USA |
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Ritonavir (r)
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<b>Mechanism of Action</b>: PI, anti-HIV antiretroviral. <u>Competitive inhibitor of HIV protease</u> (mimics transition state)
<b>Effects</b>:Inhibits HIV protease; <u>prevents viral maturation</u> (can make immature virus, but can't make it infectious). 2-3 log reduction in VL (can't keep replicating + fast turnover of HIV = quick drop!), partially restores CD4 count even on own <b>Selective Toxicity</b>: No known human aspartyl proteases inhibited<b> Indications</b>: HIV: PI but mostly used now as <u>booster</u> (increase concentrations of other HIV drugs)<b> Administration</b>: bid (3-5h half life)<b> Toxicity</b>: <u>Inhibits CYP450 3A4</u> (also induces hepatic enzymes but net block). <u>Drug interactions </u>(but also used for boosting). <u>GI intolerance</u> (nausea, vomiting, diarrhea), <u>hyperlipidemia</u> (elevated cholesterol & TGs, reversing metabolic disturbance created by virus), rare <u>glucose intolerance</u>, <u>hepatic transaminitis</u> (inc AST/ALT). <u>First few weeks</u>: common <u>circumoral & extremity parasthesias</u> (important for adherence) <b>Resistance</b>: Weeks to months. Not necessarily in all subjects (unlike NRTIs)<u>Primary resistance</u> mutation: 1AA, 3-5x resistance. <u>Secondary resistance</u> changes <u>accumulate</u>, resistance keeps increasing, <u>cross-resistance</u> increases. If you can keep at high levels (e.g. boosting, drugs with high therapeutic index), 1st mutation will still be suppressed (dose-response curve). <b> Other</b>: no intracellular activation required. <u>99% protein bound</u>. Variable bioavailability (<u>first-pass metabolism</u>, <u>autoinduction</u>). Eliminated by <u>CYP450 3A4</u> (oxidative) |
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fomivirsen
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<b>Mechanism of Action</b>: anti-CMV agent. <u>Anti-sense RNA</u> complementary to a viral mRNA
<b>Effects</b>: Binds, inhibits translation of a CMV mRNA encoding a protein essential for viral replication <b>Selective Toxicity</b>: Doesn't bind human mRNAs<b> Indications</b>: ganciclovir-resistant or -contraindicated CMV retinitis<b> Administration</b>: <u>injected into eye</u> (completely unstable)<b> Toxicity</b>: to your wallet <b>Resistance</b>: has been reported<b> Other</b>: VERY EXPENSIVE, only FDA-approved antisense drug |
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lamivudine (3TC)
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<b>Mechanism of Action</b>: <u>nucleoside analog</u> (NRTI), inhibits both <u>HIV</u> and <u>HBV</u> <u>reverse transcriptase</u> (similarities in enzymes)
<b>Effects</b>: converted to <u>triphosphate</u> by <i>cellular</i> enzymes; <u>competitive inhibitors / chain terminator</u> of HBV DNApol (no 3' OH) <b>Selective Toxicity</b>: humans don't have RT<b> Indications</b>: HIV, HBV<b> Administration</b>: po (good oral bioavailability)<b> Toxicity</b>: <u>negligible</u> <b>Resistance</b>: mutations in <u>viral RT</u>, some mutants less fit in vitro, others 3TC-dependent. Discontinuing leads to rebound of viremia. <b> </b> |
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ganciclovir
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<b>Similar to ACV but active against CMV
<u>Similarities</u>: </b>converted to <u>monophosphate</u> by viral kinase, then -2P, -3P by cellular enzymes; competitive inhibitor of viral DNApol <b><u>Differences</u></b>: - single hydroxymethyl group on sugar side chain - <u>no viral TK</u><b> </b>(p-lated by UL97, a protein kinase) - <b><u>not an absolute chain terminator</u></b> (competitive inhibitor) - accumulates to <u>higher concentrations</u> in CMV-infected cells (although ACV is better viral DNApol substrate) <b> Toxicity</b>:<b> SERIOUS. </b><u>affects bone marrow progenitor cells</u> (low therapeutic index); inhibits lymphocyte blastogenic responses <b>Resistance</b>: mostly <u>kinase</u> mutations (like ACV) |
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rimantidine
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<b>Methylated derivative of amantadine</b>: more orally bioavailable, can't cross <u>blood-brain barrier</u> so less CNS side effects<b>
Mechanism of Action</b>: Anti-influenza agent. Inhibits <u>M2 protein</u> <b>Effects</b>: M2 protein = <u>ion channel</u> used to pump protons into virion compartment & <u>reduce pH</u>, which is required for uncoating. <u>Primary effect</u>: Drug binds inside M2 channel & blocks. <u>Secondary effect:</u> also d<u>ecreases pH in Golgi</u>, causing premature <u>HA conf change</u>, decreasing release. <b>Selective Toxicity</b>: Humans don't have M2 protein<b> Indications</b>: Influenza; not used as much anymore<b> Administration</b>: Oral (higher than amantadine)<b> Toxicity</b>: rimantadine <u>can't cross BBB </u>as well; less CNS side effects <b>Resistance</b>: <u>Rapid </u>(30% in 5 days) via mutations in <u>M2</u> AA's lining channel. Same mutations overcome early & late effects. Mutants retain fitness. |
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alpha-interferon
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<b>Mechanism of Action</b>: Anti-HBV agent. Stimulates Jak/STAT pathways leading to transcription of genes with “<u>interferon-specific response element (ISRE)</u>"<b>Effects</b>: ISRE genes interfere with pretty much all aspects of viral life cycle (especially <u>protein synthesis</u>)
<b>Selective Toxicity</b>: IFN is part of normal human antiviral response<b> Indications</b>: HBV (<u>chronic active HBV)</u><b> Administration</b>: Subcutaneous or IM (poor oral bioavailability)<b> Toxicity</b>: <u>flu-like symptoms</u> and sometimes <u>neuropsychiatric problems</u> <b>Resistance</b>: <u>tolerance</u> develops in most patients; HBV <u>terminal protein</u> blocks signal transduction<b> Other</b>: very <u>short-lived</u> effects |
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zanamivir
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<b>Mechanism of Action</b>: Anti-influenza agent. <u>Competitive, reversible inhibitor of</u> <u>viral neuraminindase (NA)</u>
<b>Effects</b>: <u>NA</u> cleaves terminal <u>sialic acids</u> from glycoproteins, glycolipids, proteoglycans, promoting <u>effective spread</u> of virus throughout respiratory epithelium. Drug is <u>sialic acid analog</u> with larger, <u>positively-charged</u> guanadine to interact more strongly with negative AA in active-site cleft <b>Selective Toxicity</b>: humans don't have NA<b> Indications</b>: <u>prophylaxis</u> and <u>treatment</u> of influenza<b> Administration</b>: poor oral bioavailability (<u>IV </u>or <u>aerosol spray</u>) - <u>CAN'T USE IN PTS WITH RESP PROBS</u><b> Toxicity</b>: Minimal (some nausea) <b>Resistance</b>: <u>inefficient</u> in vitro; <u>no cross-reactivity </u>with oseltamivir, mutants have <u>reduced fitness</u><b> </b> |
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foscarnet
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<b>Mechanism of Action</b>: antiviral (anti-herpes) agent. <u>Pyrophosphate analog</u> (inhibits all herpesviruses)
<b>Effects</b>: reversibly blocks <u>pyrophosphate binding site </u> on <u>DNApol</u>, inhibiting cleavage of pyrophosphate from nucleoside-3P during elongation (pushing reaction backwards) <b>Selective Toxicity</b>: <u>viral DNApol</u> is 100x more sensitive than cellular DNApol<b> Indications</b>: only for <u>life-threatening</u> infections with <u>no other treatment available</u> (mechanism of action different, so often works against ACV/GCV -resistant mutants of HSV/HZV/CMV)<b> Administration</b>: Oral<b> Toxicity</b>: <b>SERIOUS.</b> accumulates in <u>bone</u>, causes <u>kidney toxicity</u> <b>Resistance</b>: Mutations in viral <u>DNApol</u><b> </b> |
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valacyclovir
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<b>Like acyclovir</b> but <b>prodrug</b> with more <b>bioavailability</b> (substrate for intestinal/renal peptide transporters; rapidly converted to ACV by intestinal/hepatic enzymes after oral administration)<b>
Mechanism of Action</b>: Nucleoside analog antiviral agent. <u>Inhibits DNA synthesis</u> <b>Effects</b>: <u>Chain terminator</u> (no 3' OH) and <u>competitive inhibitor</u> of viral <u>DNApol</u> <b>Selective Toxicity</b>: Two mechanisms. For <u>initial phosphorylation</u> (ACV to ACV-MP) <u>viral TK</u> >> cellular TK in affinity, so drug <u>accumulates </u>in <u>infected</u> cells. (Next two P-lations via <u>cellular</u> TKs.) Also ACV-3P inhibits <u>viral DNApol</u> much more than cellular DNApol.<b> Indications</b>: HSV-1 (facial), half as active against HSV-2 (genital), not useful against CMV or HHV6<b> Administration</b>: Oral.<b> Toxicity</b>: Well tolerated: some nausea, diarrhea, rash, headache; rare renal/neural toxicity <b>Resistance</b>: Mutation in <u>viral TK </u>(can't P-late ACV); causes cross-resistance to analog. Less frequent: mutations in <u>viral DNApol</u> (less incorporation) <b>Other</b>: <u>prodrug</u> with more <u>bioavailability</u><b> </b>than ACV (substrate for intestinal/renal <u>peptide</u> <u>transporters</u>; rapidly converted to <u>ACV</u> by intestinal/hepatic enzymes after oral administration) |
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oseltamivir (Tamiflu)
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<b>Like zanamivir </b>but<b> more orally bioavailable (prodrug)</b> and has <b>increased binding</b> to hydrophobic pocket in active site cleft of NA<b>
Mechanism of Action</b>: Anti-influenza agent. <u>Competitive, reversible inhibitor of</u> <u>viral neuraminindase (NA)</u> <b>Effects</b>: <u>NA</u> cleaves terminal <u>sialic acids</u> from glycoproteins, glycolipids, proteoglycans, promoting <u>effective spread</u> of virus throughout respiratory epithelium. Drug is <u>sialic acid analog</u> with larger, <u>positively-charged</u> guanadine to interact more strongly with negative AA in active-site cleft. Also has hydrophobic binding region. <b>Selective Toxicity</b>: humans don't have NA<b> Indications</b>: <u>prophylaxis</u> and <u>treatment</u> of influenza<b> Administration</b>: Good oral bioavailability (given <u>PO</u>)<b> Toxicity</b>: Minimal (some nausea) <b>Resistance</b>: <u>inefficient</u> in vitro; <u>no cross-reactivity </u>with zanamivir, mutants have <u>reduced fitness</u><b> </b> |
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amantadine
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<b>Mechanism of Action</b>: Anti-influenza agent. Inhibits <u>M2 protein</u>
<b>Effects</b>: M2 protein = <u>ion channel</u> used to pump protons into virion compartment & <u>reduce pH</u>, which is required for uncoating. <u>Primary effect</u>: Drug binds inside M2 channel & blocks. <u>Secondary effect:</u> also d<u>ecreases pH in Golgi</u>, causing premature <u>HA conf change</u>, decreasing release. <b>Selective Toxicity</b>: Humans don't have M2 protein<b> Indications</b>: Influenza; not used as much anymore<b> Administration</b>: Oral <b> Toxicity</b>: <u>CNS side effects </u>(rimantadine can't cross BBB as well; less side effects) <b>Resistance</b>: <u>Rapid </u>(30% in 5 days) via mutations in <u>M2</u> AA's lining channel. Same mutations overcome early & late effects. Mutants retain fitness.<b> </b> |
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acyclovir
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<b>Mechanism of Action</b>: Nucleoside analog antiviral agent. <u>Inhibits DNA synthesis</u>
<b>Effects</b>: <u>Chain terminator</u> (no 3' OH) and <u>competitive inhibitor</u> of viral <u>DNApol</u> <b>Selective Toxicity</b>: Two mechanisms. For <u>initial phosphorylation</u> (ACV to ACV-MP) <u>viral TK</u> >> cellular TK in affinity, so drug <u>accumulates </u>in <u>infected</u> cells. (Next two P-lations via <u>cellular</u> TKs.) Also ACV-3P inhibits <u>viral DNApol</u> much more than cellular DNApol.<b> Indications</b>: HSV-1 (facial), half as active against HSV-2 (genital), not useful against CMV or HHV6<b> Administration</b>: 10-30% orally<b> Toxicity</b>: Well tolerated: some nausea, diarrhea, rash, headache; rare renal/neural toxicity <b>Resistance</b>: Mutation in <u>viral TK </u>(can't P-late ACV); causes cross-resistance to analog. Less frequent: mutations in <u>viral DNApol</u> (less incorporation) |
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irinotecan (CPT-11)
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<b>Mechanism of Action</b>: Topoisomerase I-targeted drug (antineoplastic agent)
<b>Effects</b>: Intercalates into & stabilizes topo-I / DNA covalent complex (sterically blocks DNA-DNA nucleophilic attack & reversal of enzyme-DNA complex formation). <b> Indications</b>: Solid tumors (first line for <b>colorectal</b> cancer in US/europe), also <b>ovarian</b> & other adult maligancies<b> Toxicity</b>: myelosuppression, nausea, hair loss, fatigue. <b>liver toxicity</b> in patients with gluconconjugation deficiencies. Early and late onset <b>diarrhea.</b> <b>Resistance:</b> MDR drug efflux pumps (ABC-type) <b>Other:</b> Like camptothecin, but more common in clinical use today. Lactone ring is not stable at neutral or basic pH (converts to inactive form). Administered as a <b>prodrug</b>; more bioavailable but gives diarrhea / liver toxicities from cleaved off prodrug part. Must be activated by carboxyesterase |
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teniposide
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<b>Mechanism of Action</b>: Topoisomerase II-targeted antineoplastic agent. Epipodophylotoxin.
<b>Effects</b>: Nonintercalative; increases covalent DNA-enzyme complex by unknown structural mechanism<b> Indications</b>: Many types of cancers<b> Toxicity</b>: Usual (myelosuppression, mucositis, nausea, anaphylaxis) <b>Resistance</b>: MDR drug efflux pumps (ABC-type) |
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ifosfamide
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<b>Mechanism of Action</b>: Bifunctional alkylating agent
<b>Effects</b>: Must first undergo metabolic activation (P450). Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of modified base.<b> Indications</b>: Sarcomas, many other cancers<b> Administration</b>: Administering with 2-mecaptoethane sulfonate and vigorous hydration can help prevent cystitis<b> Toxicity</b>: bone marrow suppression, alopecia, gonadal toxicity, and <b>hemorrhagic cystitis (</b>diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage) resulting from excretion of a reactive metabolite (acrolein). More hemorrhagic cystitis, less bone marrow suppression than cyclophosphamide<b> Other</b>: Similar to cyclophosphamide. |
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melphalan
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<b>Mechanism of Action</b>: Bifunctional alkylating agent; antineoplastic agent.
<b>Effects</b>: Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of modified base<b> Indications</b>: multiple myeloma<b> Administration:</b> can give PO<b> Toxicity</b>: bone marrow suppression, amenorrhea, sterility <b>Other</b>: substituted nitrogen mustard; less reactive than mechlorethamine. |
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metoprolol
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<b>Mechanism of Action</b>: selective antagonist of ß1 adrenergic receptor (beta-blocker)
<b>Effects</b>: reduces cardiac output, reducing demand on heart <b> Indications</b>: hypertension & angina<b> Other: </b>also may promote better filling of coronary arteries by increasing length of diastolic phase |
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albuterol
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<b>Mechanism of Action</b>: selective agonist of ß2 adrenergic receptor
<b>Effects</b>: dilates bronchial smooth muscle & uterine smooth muscle<b> Indications</b>: asthma; stopping premature labor<b> Other</b>: very few cardiac side effects because of ß2 selectivity. Also promotes glycogenolysis in liver (be careful not to precipitate diabetic state) |
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phenoxybenzamine
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<b>Mechanism of Action</b>: nonselective antagonist of α adrenergic receptors
<b>Effects</b>: Reduces NE effect via inhibition<b> Indications</b>: pheochromocytoma: adrenal tumor producing large amounts of catecholamines (tumor usually benign; reverse effects) |
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propranolol
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<b>Mechanism of Action</b>: nonselective antagonist of ß adrenergic receptors (general ß blocker)
<b>Effects</b>: decreased cardiac output, bronchial smooth mm constriction<b> Indications</b>: used to treat hypertension, angina, anxiety, <i>vasovagal syncope </i>(when heart rate rises, blood vessels dilate too much, decreased brain perfusion, patient faints), arrythmias<b> </b> |
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isoproterenol
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<b>Mechanism of Action</b>: nonselective agonist of the ß adrenergic receptors
<b>Effects</b>: stimulates cardiac output, dilates bronchial smooth muscle, dilates vascular smooth muscle<b> Indications</b>: bradychardia or heart block; rarely used to treat asthma<b> </b> |
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dexmedetomidine
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<b>Mechanism of Action</b>: <u>central alpha-2 adrenergic agonist</u>
<b>Effects</b>:stimulates alpha-2 receptors (pre-synaptic feedback receptors, decreases adrenergic response) <b>Indications & Administration</b>: <u>Long-term ICU sedation</u> (little or no withdrawal after prolonged infusion), combined with <u>opioids</u> for <u>surgery</u><b> Other effects: </b>keeps <u>resps</u> <u>stable</u> <b>Toxicity</b>: <u>Drops BP, very expensive</u> |
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thiopental
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<b>Mechanism of Action</b>: <u>GABA agonist IV anesthetic</u>.
<b>Effects</b>: Binds <u>separate site </u>on <u>GABA</u> <u>receptor</u> subunit; <u>increases</u> <u>sensitivity</u> of GABA receptor to GABA, increasing <u>chloride</u> flow & causing <u>more hyperpolarization</u> (inhibitory) in response to GABA. “Group 1” (acts via specific GABA-A receptor)<b> Administration & Indications</b>: <u>Rapid sequence induction</u> (emergency surgery); <u>Continuous infusion</u> (seizures, brain edema)<b> Toxicity</b>: <u>Lowers BP, hypovolemia, apnea, tissue necrosis</u> with <u>extravasation</u>: |
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phenytoin
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<b>Mechanism of Action</b>: Anticonvulsant, blocks <u>rapidly opening Na channels</u>
<b>Effects</b>: bind <u>open channels </u>selectively, limiting sustained repetitive transmission<b> Indications</b>:use for <u>common </u>seizure types (generalized / focal motor seizures, partial seizures with behavioral manifestations)<b> Metabolism</b>: <u>Saturable </u>hepatic metabolism (low levels = 1st order, <u>high levels = zero order</u> like alcohol – saturate enzymes - can have <u>sudden unexpected toxicity</u>)<b> Toxicity</b>: <u>High levels</u>: <u>ataxia, nystagmus</u>, also gum hypertrophy, increased hair; <u>Bradycardia</u> & <u>cardiac arrhythmias</u> if administration too rapid; <u>Purple glove syndrome</u> with IV phenytoin (skin / venous damage; can use <u>pro-drug</u> “Fosphenytoin” - water soluble with extra PO4 group - to avoid); <u>Induces </u>metabolism of <u>carmazepine</u>; <u>Teratogen</u> <b>Other</b>: less sedating than barbituates |
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entacapone
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<b>Mechanism of Action: </b><u>COMT inhibitor</u>.
<b>Effects</b>: helps <u>block hepatic metabolism of L-DOPA</u> (increases half-life in brain, L-DOPA to brain) <b>Administration</b>: with <u>sinemet</u> (L-DOPA + carbidopa, an <u>AADC inhibitor</u>). Need to give <u>3-4x daily</u> (like L-DOPA <b>Metabolism</b>: <u>don't cross BBB</u>: increase <u>peripheral L-DOPA</u>, helps stabilize concentrations over time <b>Toxicity</b>: generally <u>well tolerated</u> with <u>occasional GI complaints</u>, can cause <u>urine </u>to turn <u>reddish brown</u> |
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amantadine (Symmetrel)
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<b>Mechanism of Action</b>: anti-Parkinson Disease agent, multiple effects (poorly understood)
<b>Effects</b>: weak <u>anti-cholinergic</u>, weak <u>DA-releaser</u>, weak <u>glutamate antagonist </u><b>Toxicity:</b> <u>hallucinations, insomnia</u>, effects common to other anticholinergics (impaired cognition, dry mouth, constipation, urinary retention) |
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benztropine (Cogentin), trihexyphenidyl (Artane)
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<b>Mechanism of Action: </b><u>Anti-cholinergic</u> agents (anti-PD)
<b>Effects: </b>Restores “Ach/DA balance” in theory (less DA, so cut down on ACh<b> Indications</b>: <u>Parkinson Disease</u>, especially in <u>younger patients</u> with <u>tremor</u> as predominant complaint. Generally <u>contraindicated in elderly</u> (cognitive problems)<b> Toxicity</b>: <u>impaired cognition, constipation, urinary retention, dry mouth</u> <b>Other</b>: Use in PD largely supplanted by MAO-i and direct DA agonists<b> </b> |
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disulfiram
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<b>Mechanism of Action</b>: <u>Aldehyde dehydrogenase inhibitor</u>, used as “<u>aversive” medication</u> to “<u>punish” alcohol drinking</u>. Aldehyde dehydrogenase normally oxidizes <u>acetaldehyde</u> to <u>acetic acid</u> in the liver (alcohol dehydrogenase converts ethanol to acetaldehyde), so <u>acetaldehyde builds up</u> when ethanol ingested.
<b>Effects</b>: <u>Punishing agent</u>; works through <u>avoidance</u> of future episodes of drinking. Effects from <u>buildup of acetaldehyde</u> (toxic substance). Leads to <u>facial flushing, nausea, vomiting, hypotension, headache</u> within <u>10-15m</u> of <u>alcohol consumption</u> (<i>intended</i> effects, <i><b>not</b> side effects!</i>). <u>Rapid onset</u> is good for punishment (<u>closely linked</u> to drinking!)<b> Indications</b>: FDA-approved for <u>maintenance</u> of <u>alcohol abstinence</u>. <u>Effective</u>, as long as you get pts to keep using it.<b> Administration</b>: Compliance usually <u>poor</u> unless <u>special strategies used</u>. Onset of effects <u>1-2h</u>, peak ~ 12h, effective for <u>4-6d</u>, dosed at <u>250-500 mg</u> daily. <b> Toxicity</b>: <u>side-effects</u> (different from intended effects). <b><u>Mild</u></b>: <u>sedation, drowsiness, headache, garlic-like / metallic taste, dermatitis, skin rash</u>. <b><u>Moderate</u></b><u>/</u><b><u>severe</u></b> (more rare): <u>hepatotoxicity, peripheral neuropathy, psychosis, confusional states</u>. <u>CAN'T USE IN SEVERE LIVER DAMAGE</u> (works in liver!)<b> Strategies to improve compliance</b>:<b> </b><u>Incentives</u> (probation instead of incarceration, continued methadone program enrollment, cash, continued employment). <u>Medication depot implants</u>. <u>Contracts</u> (observed medication - involve family member). |
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topiramate
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<b>Mechanism of Action</b>: <u>facilitates GABA receptors</u> while <u>blocking glutamate receptors</u>, leading to <u>reduced dopamine release</u> (corticomesolimbic dopamine - reward).
<b>Effects</b>: <u>Decreases reinforcement</u> from alcohol ingestion. In RCTs, <u>reduces heavy drinking days</u> and <u>increases likelihood</u> of pts having at least <u>1 mo w/o heavy drinking episode</u><b> Indications</b>: Not FDA approved - for alcohol abstinence maintenance<b> Toxicity</b>: <u>Common</u> side effects include <u>paresthesia</u> (prickling / itching), <u>taste perversion, anorexia, nervousness, difficulty concentrating, pruritis</u> |
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acamprosate
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<b>Mechanism of Action</b>: <u>NMDA-receptor antagonist</u>.
<b>Effects</b>: <u>reduces long-term withdrawal</u> symptoms. Glutamate actions at NMDA receptor contributes to <u>alcohol intoxication, cognitive impairment</u>, some <u>withdrawal symptoms</u> (incl. seizures, etc). Most research in <u>Europe</u>: support acamprosate for <u>abstinence maintenance</u> vs placebo. Has <u>small-medium effect size</u> in <u>Europe</u>, but <u>really no effectiveness in US pts vs placebo</u> in a few large trials! <b>Selective Toxicity</b>: <b> Indications</b>: FDA-approved for <u>maintenance</u> of <u>alcohol abstinence</u>, but not really used in USA (not effective in USA pts?)<b> Administration</b>: 1.3-2g/day<b> Toxicity</b>: <u>Mild-moderate</u>: <u>diarrhea</u> (~1/3, 20% have to discontinue), <u>nausea / vomiting, H/A</u>. No evidence of CNS side effects, drug interactions, abuse liability. <u>ONLY FDA-APPROVED DRUG</u> for alcohol abstinence maintenance <u>that can be used in pts with LIVER DAMAGE!</u> But <u>contraindicated </u>in <u>renal dysfunction</u><b> Other</b>: aka <u>Campral</u> in USA |
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mirtazapine
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<b>Mechanism of Action</b>: <u>Dual action antidepressant</u> - act on <u>more than one</u> neurotransmitter system
<b>Effects</b>:generaly <u>block reuptake</u> of <u>norepi & serotonin +/- dopamine</u>. No tricyclic structure. May have superior efficacy, maybe faster onset of action? <b>Indications</b>: For <u>patients who don't respond to SSRIs</u><b> Toxicity</b>: <b><u>very sedating</u></b> (use for sleep), <b><u>increased appetite</u></b> with <b><u>significant weight gain</u> Other</b>: a.k.a. <b><u>R</u><u>emeron</u></b> |
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bupropion
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<b>Mechanism of Action</b>: <u>Dual action antidepressant</u> - act on <u>more than one</u> neurotransmitter system
<b>Effects</b>:generaly <u>block reuptake</u> of <u>norepi & serotonin +/- dopamine</u>. No tricyclic structure. May have superior efficacy, maybe faster onset of action? <b>Indications</b>: For <u>patients who don't respond to SSRIs.</u> <b><u>HAS LITTLE SEXUAL DYSFUNCTION</u></b> (UNIQUE!) - use if sexual dysfunction with SSRIs<b> Toxicity</b>: often <b><u>stimulating</u>, <u>lowers seizure threshold</u>, <u>tachycardia / higher BP</u> Other</b>: a.k.a. <b><u>Wellbutrin</u></b> |
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duloxetine
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<b>Mechanism of Action</b>: <u>Dual action antidepressant</u> - act on <u>more than one</u> neurotransmitter system
<b>Effects</b>:generaly <u>block reuptake</u> of <u>norepi & serotonin +/- dopamine</u>. No tricyclic structure. May have superior efficacy, maybe faster onset of action? <b>Indications</b>: For <u>patients who don't respond to SSRIs</u><b> Toxicity</b>: <b><u>GI distress, sedation, dizziness</u> Other</b>:<b> a.k.a. <u>Cymbalta</u></b> |
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venlafaxine
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<b>Mechanism of Action</b>: <u>Dual action antidepressant</u> - act on <u>more than one</u> neurotransmitter system
<b>Effects</b>:generaly <u>block reuptake</u> of <u>norepi & serotonin +/- dopamine</u>. No tricyclic structure. May have superior efficacy, maybe faster onset of action? <b>Indications</b>: For <u>patients who don't respond to SSRIs</u><b> Toxicity</b>: <b><u>increased diastolic blood pressure</u></b>, <b><u>GI distress</u>, <u>stimulating</u>, <u>withdrawal syndrome</u> </b>(can be very rapid-onset after missing one dose - actually improves compliance)<b> Other</b>: a.k.a. <b><u>effexor</u></b> |
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imipramine, amitriptyline, nortriptyline
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<b>Mechanism of Action</b>: <u>tricyclic antidepressants</u> - block <u>reuptake</u> of both <u>norepinephrine</u> & <u>serotonin</u>, so increased levels
<b>Indications</b>: <u>major depression</u>, BPD with mood stabilizer 1st. Can be uniquely effective in certain patients (<u>elderly</u> or <u>pts with chronic pain</u>)<b> Toxicity</b>: <u>Lethal in overdose</u>. <u>High</u> side effect profile: <u>sedation, orthostatic hypotension, EKG changes, dry mouth, constipation</u> (start on metamucil) <b>Other</b>: imipramine = Tofranil, amitryptyline = Elavil, nortryptyline = Pamelor |
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chlorpromazine
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<b>Mechanism of Action</b>: a <u>phenothiazine</u> <u>antipsychotic</u> agent.
<b>Effects</b>: Blockade in <u>limbic system</u> (ventral tegmental area of midbrain to nucleus accumbens, amygdala, prefrontal cerebral cortex, etc.), which modulates <u>emotional behavior</u> probably leads to antipsychotic effects<b> Indications</b>: <u>schizophrenia</u>; helps reduce <u>positive symptoms</u> primarily<b> Toxicity</b>: <b><u>Extrapyramidal</u></b><u> motor side effects</u>:can be <u>parkinsonian</u> (rigidity / tremor) or <u>akathisia</u> (motor restlessness - can't sit still). More frequent in <u>priprazine side chain</u> phenothiazines. <b><u>Tardive</u></b><u> </u><b><u>dyskinesia</u></b> possible (can be <u>irreversible</u>, with <u>long, high dosing</u>; from <u>supersensitivity</u> of <u>dopamine receptors</u>). All neuroleptics: <u>increased </u><b><u>serum prolactin</u></b> (can cause <b><u>amenorrhea</u></b> & <b><u>sexual </u></b><u>dysfunction</u>; from <u>hypothalamic blockade</u> - dopamine inhibits PRL secretion). <u>Less common</u>: Orthostatic hypotension & sedation (more common in <u>aliphatic side chain</u> phenothiazines, though) and weight gain<b> Other</b>: Similar chemical structure to <u>dopamine / norepinephrine</u> |
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olanzapine
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<b>Mechanism of Action</b>: “<b><u>atypical” antipsychotic agent</u></b>, similar to <b><u>clozapine</u></b> but newer
<b>Indications</b>: <u>schizophrenia</u>; affects <u>postitive</u> and <u>negative</u> symptoms. Appears to be <b><u>best of new atypical neuroleptics</u></b>, but still <u>not as effective as clozapine</u>. Also being used <u>more broadly</u>, even in <u>non-psychotic pts</u> (calm <u>manic / anxious pts</u>)<b> Toxicity</b>: Like clozapine (<u>sedation, hypotension,</u> with <u>lots of weight gain</u>) but <b><u>NO AGRANULOCYTOSIS</u></b>. Extrapyramidal effects <u>very rare</u> (lots of anticholinergic activity) All neuroleptics: <u>increased serum prolactin</u> (can cause <u>amenorrhea</u> & <u>sexual dysfunction</u>; from <u>hypothalamic blockade</u> - dopamine inhibits PRL secretion)<b> Other</b>: aka <b><u>Zyprexa</u></b> |
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zisperadone
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“<b><u>atypical” antipsychotic agent</u></b>, similar to <b><u>clozapine</u></b> but newer.
Distinguishing feature: <b><u>may have greater tendency to prolong QT</u></b> (could lead to <b>TdP!) Other</b>: aka <b><u>Geodon</u></b> |
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clopazine
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<b>Mechanism of Action</b>: an <b><u>“atypical”</u> <u>antipsychotic </u></b>agent. <u>Blocks dopamine receptors</u>, especially <u>D2</u> type (2,3,4).
<b>Effects</b>: Blockade in <u>limbic system</u> (ventral tegmental area of midbrain to nucleus accumbens, amygdala, prefrontal cerebral cortex, etc.), which modulates <u>emotional behavior</u> probably leads to antipsychotic effects<b> Indications</b>: <u>schizophrenia</u>; helps reduce <u>positive </u><b><u>and negative </u></b><u>symptoms</u><b>. <u>Effective in majority of pts resistant to typical neuroleptics</u></b>. <u>most effective!</u> but not 1st line (side effects)<b> Toxicity</b>: Specific to clopazine: <b><u>AGRANULOCYTOSIS</u></b> (can be fatal - do frequent bloodwork!). <b><u>Drooling, anticholinergic</u></b> side effects too (urinary retention, dry mouth, delirium, etc). Atypicals: <b><u>orthostatic </u></b><u>hypotension, </u><b><u>sedation</u></b><u>, </u>and <b><u>weight gain</u></b> (from blockade of H1 receptors in hypothalamic nuclei; activation of AMPK). <b><u>NO TARDIVE DYSKINESIA</u></b>; fewer extrapyramidal side effects. All neuroleptics: <u>increased serum </u><b><u>prolactin</u></b> (can cause <b><u>amenorrhea</u></b> & <b><u>sexual</u></b><u> </u><b><u>dysfunction</u></b>; from <u>hypothalalmic blockade</u> - dopamine inhibits PRL secretion). |
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lithium
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<b>Mechanism of Action</b>: <u>Mood stabilizer</u>. Mechanism not completely understood: <u>calcium signaling / inisitol phosphate pathway</u> is one possibility (popular in 80s); <u>GSK-3beta</u> / <u>Wnt signaling</u> (cell growth, embryogenesis, brain development) is more current model.<b>
Indications</b>: For <u>acute mania </u>(12 controlled trials - 70% pts improved, often given in conjunction with <u>antipsychotic</u> (e.g. <u>olanzapine</u>), but takes <u>10-30 days</u> for <u>effect</u>). For <u>prophylaxis of mania & depression</u> (<u>3x </u>less likely to relapse vs placebo; BP II less studied but probably similar benefit, <u>8x reduction</u> in <u>suicide risk!</u>) For <u>unipolar major depression</u> to <u>augment antidepressant</u> (those with Li added >2x more likely to improve).<b> Administration</b>: Pretty <u>narrow therapeutic window</u> (0.7-1.2 mEq/L). Measure 12h after dosing.<b><u> </u><u>Toxicity</u></b><u>: Increased thirst, polyuria. Tremor (dose-dependent). Weight gain (ver</u>y bothersome). <u>Hypothyroidism</u>. <u>Interstitial nephritis</u> (kidney problems with long-term use). If <u>blood levels too high</u>: <u>dysarthria, ataxia, seizures, delerium, renal failure.</u> <u>Thiazide diuretics</u> will <u>increase blood levels!</u> |
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carbamazepine
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<b>Mechanism of Action</b>: <u>Mood stabilizer</u> (& anticonvulsant). Mechanism not completely understood: <u>calcium signaling / inisitol phosphate pathway</u> is one possibility (popular in 80s); <u>GSK-3beta</u> / <u>Wnt signaling</u> (cell growth, embryogenesis, brain development) is more current model<b>
Indications</b>: <u>bipolar disorder</u>. <u>Acute mania</u> (good studies) & <u>maintenance</u> (protection against relapse, more evidence than divalproex sodium). <b> Administration</b>: Get <u>blood levels</u> (4-12 mg/L)<b> Toxicity</b>: <b>Common</b>: <u>vertigo, nystagmus, ataxia</u>. Very <b>rare</b>, but potentially <b>fatal</b>: <u>blood dyscrasias (agranulocytosis, aplastic anemia</u>), <u>hepatic failure</u>, <u>pancreatitis</u>. Can be <u>lethal in overdose</u>. <b>Metabolism:</b> <u>absorption</u> is <u>slow, erratic, unpredictable.</u> <u>Autoinduction</u> of <u>liver enzymes</u> can <u>lower blood levels</u>. May need to <u>increase dose with time </u><b>Other:</b> has a <u>tricyclic structure </u> |
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atomoxetine
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<b>Mechanism of Action</b>: <u>stimulant</u>. <u>blocks norepinephrine release </u><i><u>only</u></i>
<b>Effects</b>: <u>No buzz</u> (no dopamine effects)<b> Indications</b>: <u>ADHD</u><b> Other</b>:<b> </b>aka <b><u>Strattera</u></b> |
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PTH (1-34) (teriparatide)
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<b>Mechanism of Action</b>: <u>1st 34 AA</u> of <u>parathyroid hormone</u> (recombinant). PTH stimulates <u>osteoblasts and osteoclasts</u>, but given intermittently <u>OB > OC</u> (continuously, OC > OB).
<b>Effects</b>: <u>increases osteoblast number and function</u>, while <u>decreasing osteoblast apoptosis</u>, leading to <u>net bone formation</u>. Thickens <u>trabecular bone</u> and <u>cortical bone</u>.<b> Indications</b>: Only for <u>severe recalcitrant cases of osteoporosis</u>. Only approved for <u>two years use</u> in <u>whole life</u> (trial stopped for osteosarcoma in rats).<b> Administration</b>: <u>once daily subcutaneous injection</u>. <b> Toxicity</b>: <u>Expensive</u> and Sub-Q! <u>Hypercalcemia</u>(11% - some need to stop drug - from <u>increased reclamation from urine</u>). <u>uric acid</u> increased in <u>13%</u>. Minor side-effects: <u>nausea, headache, dizziness</u> (8-9%), <u>leg cramps</u>(3%). <b>Contraindications</b>: Any <u>high bone turnover states</u>: Hx of <u>skeletal malignancies</u> or <u>prior radiation to skeleton</u>. <u>Pre-existing hypercalcemia</u>, unexplained <u>alkaline phosphatase elevation</u>, or <u>Paget's disease</u>. Worry - PTH could cause malignancy? Osteosarcoma in rats - probably just a rat problem, but still... |
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ketoconazole (immunology use)
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<b>Mechanism of Action</b>: “<u>anti-corticosteroid”</u>. Imidazole antifungal agent, can block <u>CYP450 enzymes</u> involved in <u>corticosteroid production, androgen/estrogen biosynthesis</u><b>
Indications</b>: <u>short-term Cushing's syndrome</u> (e.g. prior to surgery), treatment of <u>paraneoplastic Cushing's</u><b> Administration</b>: Need to use <u>10-20 fold higher doses</u> than for antifungal use |
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cortisone
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<u>Short-acting corticosteroid.
</u><b>synthetic </b>form of <b>hydroxycortisone</b> (11-keto instead of 11-OH) Has glucocorticoid & some mineralocorticoid activity 11-keto group has to be <b>reduced in the liver</b> to 11-OH for activity, so <b>avoid in liver disease</b> Good for things like <b>replacement therapy</b> (mineralocorticoid activity is desired) Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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fludrocortisone
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<u>Intermediate-acting corticosteroid.
</u><b>MC >>> GC activity</b> Synthetic analogue to natural cortisol, but with <u>9-fluoro group</u> (<b>greatly increased mineralocorticoid activity)</b> Good for <b>hypoaldosteronism</b> / other types of <b>replacement therapy </b>to replace mineralocorticoid activity. Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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hydrocortisone
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<u>Short-acting corticosteroid.
</u><b>Natural compound. </b> The <b>standard of reference</b>; has glucocorticoid & some mineralocorticoid activity Good for things like <b>replacement therapy</b> (mineralocorticoid activity is desired) Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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triamcinolone
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<u>Intermediate-acting corticosteroid.
</u><b>GC >>>MC</b> activity Has<u> glucocorticoid activity</u> similar to <u>prednisone / prednisolone</u>, but <b>greatly reduced mineralocorticoid activity</b> (16OH group outweighs MC-inducing 9-fluoro) Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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dexamethasone
betamethasone |
<u>Long-acting corticosteroids
</u><b>GC >>>MC</b> activity, <b>really potent</b> Stereoisomers at 16-methyl group with <b>long-acting, hyper-glucocorticoid activity</b> Good for <b>emergency use </b>in <b>large doses </b>(minimal toxicity with single big dose) Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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prednisone
prednisolone |
<u>Short-acting corticosteroid.
</u>Have <b>1,2 double bonds</b> that <b>increase glucocorticoid activity. (GC>MC) Prednisone</b> has an 11-keto group that must be converted to 11-OH in the liver, so <b>avoid in liver dz</b> If you have to use a GC for <b>chronic disease</b>, this might be a good choice (less Na retention, short-acting) - give every-other-day to prevent HPA suppression & use long taper Way more information on corticosteroids can be found in the steroids lecture (too much for cards) |
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antithymocyte globulin
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<b>Mechanism of Action</b>: <u>Ab</u> against <u>TCR</u>: made from <u>animals</u> (horse, rabbit, sheep, goat) with <u>human thymocytes</u> as <u>antigens</u>
<b>Effects</b>: blocks <u>TCR / MHC-peptide</u> interaction (can't activate T-cells!) <b>Indications</b>: used to prevent <u>acute rejections</u><b> Toxicity</b>: <u>MAJOR</u> - <u>serum sickness, nephritis</u> (from immune response to animal Ab) |
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anti-CD3 antibodies (Orthoclone OKT3)
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<b>Mechanism of Action</b>: <u>anti-CD3 Ab</u> - prevents <u>T-cell activation</u> by <u>MHC-peptide complex</u> & <u>rapidly depletes circulating T-cells
</u><b>Indications:</b> help prevent transplant <u>rejection</u> <b>Selective Toxicity</b>: Can be <u>humanized</u> (prevent immune response to antibodies themselves)<b> Toxicity</b>: Also can bind <u>bivalently</u> & act as <u>agonists of TCR!</u> Leads to <u>secretion of cytokines & side effects:</u> <u>“</u><b><u>cytokine release syndrome”</u></b> (mild <u>flu-like illness</u> or <u>more severe shock-like reaction</u> that can be <u>lethal!</u>) |
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cyclosporine A (CsA, Sandimmune)
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<b>Mechanism of Action</b>: <u>Inhibitor</u> of the <u>TCR-mediated intracellular signaling pathway</u>.
<i>more in depth: </i><u>cyclosporine A</u> recruits <u>cyclophilin</u> (an immunophilin protein receptor); the complex inhibits <u>calcineurin</u>, which can't deP-late <u>NFAT</u>, so p-lated NFAT is stuck in the cytosol (needs to be de-p-lated to translocate to the nucleus & bind enhancer reginos of cytokine genes). <b>Effects</b>: Blocks <u>calcium-mediated signaling</u>, which would normally leads to <u>gene transcription modulation</u> & <u>cytokine production</u> by CD4+ T-cells. No <u>IL-2</u> / other cytokine secretion means <u>no T-cell activation!</u><b> Indications</b>: <u>frontline therapy</u> to <u>prevent rejection</u> - has <u>changed the game</u> for organ transplantation (can give long-term)<b> Administration</b>: IV and oral; oral now more popular (new formulations)<b> Pharmacokinetics</b>: <u>peak [plasma]</u> within <u>a few hours</u>. <b><u>over 50% sequestered in RBC</u></b> (serve as <u>reservoir</u> for drug)<b> Metabolism:</b> <u>extensively</u> metabolized in the <u>liver</u> (<u>CYP450 A3</u>) to over 30 metabolites. Excreted mostly <u>bile to feces</u>, small fraction to urine<b> Toxicity</b>: Mainly <u>nephrotoxicity</u> (same molecular mechanism as immunosuppression) - <u>don't use in kidney transplants</u><b> Other</b>: <u>fungal metabolite</u>; a <u>hydrophobic cyclic peptide </u> |
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FK506
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<b>Mechanism of Action</b>: <u>Inhibitor</u> of the <u>TCR-mediated intracellular signaling pathway</u>.
<i>more in depth: </i><u>FK506</u> recruits <u>FKBP</u> (an immunophilin protein receptor); the complex inhibits <u>calcineurin</u>, which can't deP-late <u>NFAT</u>, so p-lated NFAT is stuck in the cytosol (needs to be de-p-lated to translocate to the nucleus & bind enhancer reginos of cytokine genes). <b>Effects</b>: Blocks <u>calcium-mediated signaling</u>, which would normally leads to <u>gene transcription modulation</u> & <u>cytokine production</u> by CD4+ T-cells. No <u>IL-2</u> / other cytokine secretion means <u>no T-cell activation!</u> <b><u>Specific to FK506:</u></b> Actually <b><u>stimulates hepatocyte growth</u>. <u>10x more potent</u> than <u>CsA.</u> Indications</b>: <u>Alternative</u> & sometiems <u>complementary option</u> to <u>CsA</u> for <u>organ transplant patients</u>. Widely used in <b><u>liver transplants</u></b> (actually <u>stimulate hepatocyte growth</u>)<b> Administration</b>: <u>IV, oral</u><b> Pharmacokinetics</b>: <u>peak [plasma]</u> in a <u>few hours </u>(like CsA)<b> Metabolism</b>: Also <u>extensively metabolized</u> in the liver<b> Toxicity</b>: Mainly <u>nephrotoxicity</u> (like CsA) - <u>don't use in kidney transplants</u><b> Other</b>: Polyketide of bacterial orgiin - discovered by bioassay (offspring of CsA) |
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mAb against IL-2 receptor
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<b>IL-2 </b>is one of the <b>most important signals </b>to stimulate <b>T-cell proliferation</b>
<b>mAb </b>against the IL-2 receptor <b>blocks T-cell proliferation </b>- used in clinic to <b>prevent organ rejection</b> |
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rapamycin / sirolimus
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<b>Mechanism of Action</b>: Inhibits <u>cytokine receptor mediated signal transduction</u>, preventing <u>T-cell proliferation</u>
<b>Effects</b>: Binds <u>FKBP</u> (structurally similar to FK506); complex <u>inhibits mTOR.</u> mTOR is a <u>phospholipid kinase</u> which is involved in regulating both <u>transcription & translation</u> of genes required for <u>T-cell proliferation</u> - so <u>rapamycin blocks T-cell proliferation</u>. It also <b><u>ALLOWS FOR INDUCTION OF TOLERANCE</u></b> (an extra advantage - blocking proliferation, not activation pathway, so TCR-MHC pathway intact; can induce anergic / Treg pathway differentiation if strong TCR binding but no costimulatory molecules!) <b>Indications</b>: <u>immunosuppression</u>, <u>synergistic</u> with <u>CsA</u> & <u>FK506</u>. <b>Toxicity: </b>Reduces <u>dose of CsA</u> or <u>FK506 needed</u>, so <u>less toxicity</u> |
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infliximab (Remicade)
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<b>Mechanism of Action</b>: <u>Chimeric anti-TNF-alpha antibody </u>(mouse mAb Fv fused to human IgG1 Fc)
<b>Effects</b>: binds <b><u>TNF-alpha</u></b>, inhibits production of other <u>pro-inflammatory cytokines.</u> Less <u>swelling, subjective Sx, granulocyte migration</u> into <u>joints.</u> <b>Indications</b>: <u>Rheumatoid arthritis</u>. |
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recombinant <b>GM-CSF</b>
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<u>Mechanism of Action:</u><b> Cytokine</b>, stimulates<b> production</b> of <b>mature, functional PMNs
</b><u>Effects:</u> Binds receptor (4 TKs, p-lated, downstream effects) on <b>PMNs, precursors</b>, also <b>endothelial cells, CNS neurons / progenitors, cardiac myocytes, </b>others Benefits: <b>1. Higher PMN count </b>at <b>nadir </b>of leukopenia <b>2. Shortened nadir duration 3. </b>fewer <b>serious infections, treatment delays </b>(e.g. chemo), and <b>days of hospitalization </b><u>Indications:</u><b> </b>used for treatment of <b>neutropenia</b> in <b>BMT.</b> Also used for <b>congenital neutropenia. </b><i> </i><u>Pharmacokinetics:</u><b> give subcutaneously (or IM)</b> - results in <b>sustained concentration </b>(more effective) vs rapid peak, rapid offset IV dosing.<i> </i><b> </b>aka <b>sargramostim</b> |
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entanercept (Enbrel)
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<b>Mechanism of Action</b>: <u>“designer” antibody (chimeric:</u> TNF-alpha <u>receptor</u> fused to human IgG1 Fc)
<b>Effects</b>: binds <b><u>TNF-alpha</u></b>, inhibits production of other <u>pro-inflammatory cytokines.</u> Less <u>swelling, subjective Sx, granulocyte migration</u> into <u>joints.</u> <b>Indications</b>: <u>Rheumatoid arthritis</u>. |
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Raptiva (anti-LFA-1) and Tysabri (anti-VLA4),<b>mAb that block T-cell function </b>(migration into CNS) - associated with <b>PML</b>!
recombinant G-CSF |
<u>Mechanism of Action:</u><b> Cytokine</b>, stimulates<b> production</b> of <b>mature, functional PMNs
</b><u>Effects:</u> Binds receptor (4 TKs, p-lated, downstream effects) on <b>PMNs, precursors</b>, also <b>endothelial cells, CNS neurons / progenitors, cardiac myocytes, </b>others. Benefits: <b>1. Higher PMN count </b>at <b>nadir </b>of leukopenia <b>2. Shortened nadir duration 3. </b>fewer <b>serious infections, treatment delays </b>(e.g. chemo), and <b>days of hospitalization </b><u>Indications:</u><b> </b>used for treatment of <b>neutropenia</b> following <b>standard dose chemo</b>. Also for <b>congenital neutropenia. </b><i>May also have use in <b>MI</b> (promotes survival of heart muscle in animal models) </i><u>Pharmacokinetics:</u><b> give subcutaneously (or IM)</b> - results in <b>sustained concentration </b>(more effective) vs rapid peak, rapid offset IV dosing.<i> </i><b> </b>aka <b>filgrastim</b> |
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ribavirin
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<b>Purine nucleoside analog</b>, broad-spectrum <b>anti-viral drug</b>. Used with <b>IFN-alpha </b>for <b>hepatitis C (</b>3x weekly)
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interferon alpha
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<b>Type I interferon</b>; produced by <b>all nucleated cells</b>. <b>Various effects </b>(MHC-I expression, cytokine receptor expression, inhibition of viral attachment / uncoating / etc; reduces tumor cell growth).
<u>Pharmacokinetics:</u> give <b>sub-Q </b>or <b>IM </b>(longer sustained concentrations); can <b>pegylate </b>(add polyethylene glycol to lysine residues) to change <b>half-life </b>from <b>a few hours to days </b>(less <b>clearance</b> - protected from RES receptor-mediated uptake). Used for <b><u>chronic hepatitis </u>C </b>(with <b>ribavirin, 3x weekly)</b>. Pegaylated IFNs = pegasys, PEG intron. |
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celecoxib, rofecoxib, valdecoxib
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<b>Mechanism of Action</b>: <u>cyclooxygenase-2 (COX-2) inhibitors</u>, <b><u>reversible </u></b><u>& </u><b><u>selective</u></b> for COX-2 vs COX-1. <u>Big side groups</u> (methyl groups) can fit into <u>COX-2 side pocket</u>; COX-1 doesn't have a side pocket - so less inhibition.
<b>Indications</b>: Same effectiveness as traditional NSAIDs.<b> Toxicity</b>: <u>Less GI side effects</u> (nuisance, mucosal lesions on endoscopy, bleeding/ulcers/strictures) than traditional NSAIDs, but <u>more cardiovascular side effects</u>. Minimal inhibition of <u>COX-1 platelet function,</u> but <u>blocks prostacyclin effects</u> (COX-2 in macrovascular endothelium), leading to <u>prothrombotic states</u><b> Other</b>: celecoxib = Celebrex; rofecoxib = Vioxx. Vioxx pulled from market; Celebrex used only rarely. |
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aspirin
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<b>Mechanism of Action:</b>: <u>cyclooxygenase (COX) inhibitor</u>, <b><u>irreversible </u></b><u>& </u><b><u>non-selective</u></b> for COX-1 vs COX-2.
Steric block of arachadonic acid binding after acetylating COX-1; COX-2 retains activity after acetylation but produces novel product. <b>Indications</b>: <u>Pain</u> (low-moderate intensity), <u>Fever</u> (anti-pyretic in febrile states, not in excercise); <u>Anti-inflammatory</u> (symptomatic relief) <b>Pharmacokinetics: <u>Dose-dependent “half-life”</u></b> (longer with higher doses) - has <u>two saturable major pathways</u> & at least 3 <u>first-order minor pathways</u> for elimination, so <b><u>complex!</u>. <u>small dose increases</u></b> can result in <b><u>disproportionately high </u></b>changes in serum [salicylate]. <b> Administration</b>: Oral <b>Toxicity</b>: <b>GI, renal cardiovascular effects <u>Aspirin:</u></b> irreversibly inhibits COX in platelets (inhbiits platelet COX / TxA2 production for life of platelets); less effect on COX-2 in endothelial cells (synthetically capable), so <b><u>antithrombotic</u> Other</b>: See “NSAIDs in General” for more information. For anti-inflammatory effects: Acetaminophen « NSAIDs < Immunomodulators |
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NSAIDs in general
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<b>Mechanism of Action:</b> <u>cyclooxygenase inhibitors
</u><b>Effects</b>: COX mediates conversion of <u>arachadonic acid</u> to <u> prostanoids</u>, the precursors for <u>prostacyclins, prostaglandins</u>, & <u>thromboxanes</u>. <b><u>COX-1</u></b> is <u>ubiquitous, constituitively </u>expressed, and involved in <u>homeostasis</u> & <u>hemostasis</u> (“housekeeping”) <b><u>COX-2</u></b> is expressed in a <u>limited fashion</u>, <u>inducible</u> by cytokines, mitogens, and growth factors, and involved in <u>inflammation, immune reactions</u>, and <u>mitogenesis</u>. <b><u>Anti-pyretic</u></b>: inhibition of <u>PGE2</u> (tells hypothalamus to increase body temperature) <b><u>Analgesic</u></b>: inhibition of <u>PGE2 & PGI2</u> (both hyperalgesic) <b><u>Anti-inflammatory</u></b>: decreases <u>erythema</u> (from vasodilation; <u>PGE2 </u>& <u>prostacyclin </u>(PGI2) increase local blood flow) decreases <u>edema</u> (from vascular permeability, <u>PGE2</u> and local bradykinin/histamine effects responsible decreases <u>WBC migration</u> (increased with increased local blood flow) <b>Indications</b>: <u>Pain</u> (low-moderate intensity), <u>Fever</u> (anti-pyretic in febrile states, not in excercise); <u>Anti-inflammatory</u> (symptomatic relief) <b> Pharmacokinetics: Traditional NSAIDs:</b> <u>excellent absorption</u>; <u>highly protein bound</u>. Mostly <u>renal & hepatic</u> metabolism <b>Aspirin</b>: <u>dose-dependent half-life</u> (small dose increases can cause disproportionately large changes in serum concentration) <b> Administration</b>: Oral <b><u> </u><u>GI effects</u></b>: From inhibition of <u>gastric mucosal protection</u> (less COX activity in GI mucosa). <u>Nuisance symptoms</u> (heartburn / dyspepsia / N/V / abd pain), <u>mucosal lesions</u>, or <u>serious complications</u> (bleeding, perforation, strictures) <b><u>Cardiovascular effects</u></b>: inhibiting <u>TxA2 </u>is <u>antithrombotic</u> (released by activated platelets, platelet agonist, vasoconstrictor) inhibiting <u>prostacyclin</u> is <u>prothrombotic</u> (produced by COX in macrovascular endothelium; inhibits platelet aggregation, vascular tone <b> <u>Renal effects</u>: don't use</b> if <b>renally compromised</b> - can cause <u>acute renal failure</u>. Prostaglandins usually not involved in maintaining GFR, but may play important role in CHF, cirrhosis, renal insufficiency, etc. Blocking prostaglandins can rapidly decrease GFR, precipitate ARF!<b> Other</b>: For anti-inflammatory effects: Acetaminophen « NSAIDs < Immunomodulators |
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Naproxen, ibuprofen, indomethacin, diclofenac, ketorolac, etc.
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<b>Mechanism of Action: <u>Traditional NSAIDs:</u></b> <u>cyclooxygenase (COX) inhibitors</u>, <b><u>reversible </u></b><u>& </u><b><u>non-selective</u></b> for COX-1 vs COX-2.
<b>Indications</b>: <u>Pain</u> (low-moderate intensity), <u>Fever</u> (anti-pyretic in febrile states, not in excercise); <u>Anti-inflammatory</u> (symptomatic relief) <b>Pharmacokinetics: </b><u>excellent absorption</u>; <u>highly protein bound</u>. Mostly <u>renal & hepatic</u> metabolism <b>Short </b>t1/2 (<5h): <b>ibuprofen</b>, <b>indomethacin</b>, <b>diclofenac</b>, fenoprofen, ketoprofen, tolmetin <b>Long </b>t1/2 (> 5h): <b>naproxen</b>, diflunisal, piroxicam, sulindac <b> Administration</b>: Oral <b>Toxicity</b>: <b>GI, renal, cardiovascular effects. </b>CV effects vary with NSAID<b> Other</b>: See “NSAIDs in General” for more information. For anti-inflammatory effects: Acetaminophen « NSAIDs < Immunomodulators |
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methadone
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<b>Mechanism of Action</b>: <u>synthetic mu-agonist opioid.</u> <u>Racemic mix</u> of R/S-methadone in USA. <u>R</u> form (a.k.a. “l-form”) accounts for analgesic effects.
<b>Effects</b>: <u>decreases neurotransmission</u> (less Ca-mediated release of neurotransmitters) - see lecture for details. <u>Non-competitive NMDA receptor blockade</u><b> Indications</b>: Generally used for <u>MMT</u> / treatment of opiate addiction.<b> Administration</b>: <u>oral</u><b> Pharmacokinetics</b>: Important! <u>Long, variable half-life</u> (~40h), <u>good, variable bioavailability</u> (~75%), highly <u>protein-bound</u><b> Toxicity</b>: <b><u>associated with torsades</u></b>, but only a problem with really <u>high doses</u> or drugs that <u>prolong QT / induce torsades</u> (lots). <u>Lots of </u><b><u>drug interactions</u></b><u> (CYP450 3A4, 2D6 metabolism</u>). Inhibiting 3A4/2D6 <u>increases [methadone]</u> with <u>increased risk</u> of <u>respiratory depression, etc</u> (3A4 inhibitors: amitryptiline, cipro, fluconazole, sertraline; 2D6: fluoxetine, paroxetine, sertraline). <u>Inducing</u> 3A4/2D6 <u>decreases [methadone</u>], risk of <u>withdrawal</u> (e.g. <u>HIV meds</u> induce 3A4, also <u>rifampin</u>, <u>spironolactone</u>). careful with <u>textbook methadone conversions</u>! <b>Resistance</b>: <u>Tolerance & hyperalgesia</u> (all opioids)<b> Other</b>: Not necessarily any “stronger” or “weaker” than other opioids in the “strong” class. “Cheap” to buy compared to pharmaceuticaly-designed long-acting opioids; not perceived to be associated with abuse stigma. |
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levorphanol
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<b>Mechanism of Action</b>: <u>mu and kappa agonist</u> opioid; also <u>NMDA receptor antagonist</u><b>
Indications</b>: <u>Very potent</u> (5x greater than IV morphine)<b> Kinetics</b>: has <u>very long half-life </u>(12-16h), so <u>long duration</u> of <u>analgesic effect</u> (6-8h)<b> Toxicity</b>: Can <u>accumulate</u> (2-3d of continuous administration)! |
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morphine
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<b>Mechanism of Action</b>: <u>opioid</u>, classic <u>mu agonist</u>
<b>Effects</b>: <u>decreases neurotransmission</u> (less Ca-mediated release of neurotransmitters) - see lecture for details<b> Indications</b>: Most widely used <u>opioid analgesic</u>; but stigmatized (“addiction”, for “cancer/dying”) for chronic use<b> Administration</b>: <u>IM:oral</u> potency around <u>1:6</u>; 1:2-3 with <u>repeat administration, round-the-clock dosing</u>. PO has <u>onset 15-60m</u>, available in <u>extended release</u> (duration up to 24h). Also <u>SC/IM</u> (30-60m onset); <u>IV</u> (peak 20 min)<b> Toxicity</b>: <u>constipation</u> is #1 - maybe a greater incidence with morphine? Also <u>transient nausea, dizziness, sedation</u>. <b><u>Metabolites</u></b> can be a problem too: <b><u>M-3-G</u></b> (morphine-3-glucuronide) is major metabolite; n<u>ot an analgesic</u> (may be <u>anti-analgesic</u>, may have hyperalgesic or allodynic effect, maybe <u>stimulant for N/V</u>,<u> CNS excitatory agent</u> - <u>myoclonus, hyperalgesia, behavioral excitation</u>?) <b><u>M-6-G</u></b> too (morphone-6-glucuronide), <u>potent analgesic</u> (maybe the main component of morphine's analgesic effect?) and may be powerful respiratory depressant<u>.</u> <b> Resistance</b>: <u>Tolerance & hyperalgesia</u> (all opioids) |
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oxymorphone
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<b>Mechanism of Action</b>: <u>mu</u> and <u>delta agonist opioid</u><b>
Administration</b>: Poor oral bioavaility, but <u>better with food</u>. Can give PO, immediate release or extended release. <b> Toxicity</b>:<u>No clinically significant CYP-based drug interactions</u>. Has <u>much better absorption</u> when taken with <b><u>alcohol</u></b> (so be careful!) |
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dextromethorphan
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<b>“Inactive” D-isomer </b>opiate; used to treat <b>coughing
Vagus</b> afferents mediate coughing (trasmit bronchial irritation); DM blocks (probably non-opiate-receptor effect) <b>OTC</b>, main ingredient in <b>cough syrups</b> |
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codeine
paregoric (tincture of opium) |
Also used for <b>antidiarrheal effects</b> - have low abuse potential, cause “side effect” of constipation
Cheap & effective |
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morphine
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<b>Gold standard</b>, drug of choice for <b>severe pain</b> (esp. in <b>post-op patients)</b>
Poor <b>oral bioavailability - </b>generally given by <b>injection “Patient-controlled analgesia” (PCA) </b>- pt controls the pump <b> See lecture for more details on opioids</b> |
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heroin
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<b>Diacetyl morphine</b>; needs <b>deacetylation</b> from phenol ring for activity
Acetyl group can <b>readily dissociate</b> in <b>brain or other tissue </b>even without enzyme activity! So <b>opposite PK from codeine</b>: <u>easy access </u>to brain (acetyl groups) and <u>fast metabolism</u> = <b>euphoriant rush</b> <b>High abuse potential </b>(rush); <b>short-acting </b>(2-3h high) with <b>rapid offset </b>(withdrawal; need constant injections) Introduced by Bayer, 1898 <b>See lecture for more details on opioids</b> |
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naloxone (Narcan)
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First widely used <b>opiate antagonist</b>
Used to treat <b>opiate overdose </b>(IV injection can reverse coma in minutes!) <b> Not active orally, short-acting</b> - limited to OD treatment Give <b>repeated administrations </b>(short half-life) <i>Experimental use: are various phenomena mediated by endogenous opioid systems? Acupuncture, anesthesia, placebo-induced anesthesia blocked by naloxone </i><b>See lecture for more details on opioids</b> |
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<b>loperamide</b>
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<b>Hydrophobic opiate</b> that stays in the gut (extremely little absorption)
Takes advantage of <b>constipation</b> as opiate side effect (<b>antidiarrheal</b>) |
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methadone
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Principal treatment for <b>heroin addiction
Full agonist</b>, just as intrinsically addicting as <b>morphine</b> <b>Orally available</b> & <b>long-acting</b> (daily dosing); <b>gradual entry </b>into brain<b> </b>so less euphoria Can help pt <b>get rehabilitated, quit drug culture, stop criminal activity, function normally / hold job </b> LAM (L-acetyl-methadol) = longer-acting form (q3d) <b>See lecture for more details on opioids</b> |
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codeine
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<b>Structurally, </b>morphine with a <b>methyl group</b> instead of a <b>hydroxyl; </b>needs to be <b>demethylated </b>by <b>CYP450s</b> in liver to restore the <b>enkephalin-tyrosine-like </b>motif. Morphine (from this demethylation) <b>enters bloodstream slowly</b> (<b>less euphoria</b>, which needs rapid effect, so <b>less abuse liability</b>)
<b>Good oral bioavailability</b> (2/3 as potent by mouth as by injection) Used for <b>moderate pain, bad coughs </b> <b>Oxycodone, hydrocodone</b> are derivatives All frequently formulated with <b>acetaminophen </b>(potentiate each other, but watch out for <b>toxicity!</b>)<b> See lecture for more details on opioids</b> |
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naltrexone (Trean)
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<b>Orally active pure antagonist</b>; related to naloxone in structure
Theory: use for <b>treatment for opioid addicts </b>(but they have to take it, and they don't - <b>no euphoria</b>) <b>Implantable naltrexone </b>can last for a <b>month </b> Also effective in <b>alcoholism </b>(mechanism unknown) <b>See lecture for more details on opioids</b> |
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buprenorphine
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<b>Mixed agonist-antagonist of Mu receptors</b>, <i>not</i> psychotomimetic (not Kappa agonist)
<b> Less addicting</b> then methadone and <b>longer-acting, </b>but <b>not totally nonaddicting Schedule III (moderate </b>potential for abuse<b>), where </b>methadone = schedule II (high potential) Works by <b>mouth </b>(conventional <b>pills </b>or <b>sublingual, </b>e.g. as suboxone<b>); </b>can dispense at <b>retail pharmacies See lecture for more details on opioids </b> |
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phenylephrine
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<b>Big alpha effects</b> (good pressor)
<b>No beta effects</b> (not a chronotrope / inotrope) - like the <b>opposite </b>of <b>dobutamine</b> <b>Good </b>for, say, a <b>young patient </b>with a <b>good heart rate</b> - want to <b>increase BP</b> w/o affecting HR But <b>bad</b> if the cardiac output is down (would just increase afterload & knock down CO even more!) |
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epinephrine
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Catecholamine; <b>really potent</b> in high doses (both <b>alpha & beta</b> effects)
Used for <b>anaphylaxis</b> mostly |
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isoproterenol
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<b>Beta</b> effects: powerful <b>inotrope & chronotrope</b>
<b>No alpha effects - not </b>a <b>pressor</b>, so you <b>can't use it alone</b> for shock Rarely used in general |
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dobutamine
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<b>Beta effects</b>: <b>inotrope & chronotrope</b> (a lttle less powerful than isoproterenol)
<b>No alpha </b>effects (can't use alone for shock - not a pressor) |
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norepinephrine
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Works on <b>alpha > beta receptors</b>, but both
Has <b>less chronotropy</b> than <b>dopamine</b> but more <b>alpha-adrenergic </b>activity (<i>better</i> at maintaining BP) Maybe better than dopamine for patients with <b>higher heart rates</b> |
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dopamine
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<b>Low</b> doses: works on <b>splanchnic circulation</b> only (just <b>dopaminergic receptors</b>)
<b>High</b> doses: works on <b>alpha</b> (vasoconstrict)<b>, beta</b> receptors (ionotropic & chronotropic effects) <b>more</b> End result: <b>increased HR & BP </b>Limitation: <b>increases HR </b>(not great for patients with already highish HRs) |
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sitagliptin, saxagliptin
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<b>Mechanism of Action</b>: <u>DPP-IV inhibitors</u>, oral antidiabetic agents. <u>Prolongs action</u> & <u>enhances effect </u>of <u>endogenous incretins</u>
<b>Effects</b>: <u>dipeptidyl peptidase-IV (DPP-IV)</u> mediates <u>rapid metabolism of endogenous incretins</u>. So blocking DPP-IV will <u>prolong action</u> of <u>normal, endogenous incretins</u>. <u>Increases insulin secretion, slows gastric emptying, inhibits glucagon secretion</u>, but does <b><u>NOT</u></b> cause notable <u>satiety</u> (disadvantage vs. GLP-1 - <b><u>WEIGHT-NEUTRAL</u></b>)<b> Indications</b>: type 2 DM<b> Administration</b>: <u>oral</u> administration (advantage vs. GLP-1)<b> Other</b>: sitagliptin = Januvia, saxagliptin = Onglyza |
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rosiglitazone, pioglitazone
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<b>Mechanism of Action</b>: <u>thiazolidinedinone</u> (TZD) <u>oral hypoglycemic agents</u>. <u>Reduce peripheral insulin resistance</u> (“insulin sensitizers”)
<b>Effects</b>: Activate <u>nuclear recteptors in PPAR-gamma</u> family of genes to <u>reduce peripheral insulin resistance</u>. Do <u>NOT</u> cause hypoglycemia; can act <u>synergistically</u> with <u>metformin & sulfonylureas</u> (potentiate insulin)<b> Indications</b>: Moderately effective as <u>monotherapy</u> but <u>not first line</u> (cost, weight gain / fluid retention). Usualyl considered <u>3rd line</u>. Act <u>synergistically</u> with <u>sulfonylurea & metformin</u><b> Toxicity</b>: Cause <u>weight gain</u> in many people with <u>increased adipocyte mass</u>. Can cause <u>fluid retention</u> and even <u>CHF</u>. Very <u>expensive</u>. Increased risk of <u>forearm fractures</u>, especially in women. Earlier TZD: rare but fatal fulminant hepatic necrosis (not current TZDs). <u>Rosi</u> was associated with <u>increased MI</u> in one study (not confirmed subsequently); took a big hit.<b> Other</b>: Rosiglitazone = Avandia, pioglitazone = Actos. <b><u>The bottom line</u>: Established, effective, act to improve insulin sensitivity in type 2 DM. <u>PIOGLITAZONE > ROSIGLITAZONE</u></b> right now (MI history, etc) - will FDA / practicioners / pharma pull plug on rosi? |
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clomifen
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<u>anti-estrogen</u>, used to <u>induce ovulation</u> in infertility
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desmopressin (dDAVP)
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<b>Mechanism of Action</b>: <u>vasopressin analogue</u>
<b>Effects</b>: Vasopressin binding to <u>V2 receptors</u> triggers <u>increased cAMP</u>, leading to <u>aquaporin insertion</u> and <u>increased aquaporin synthesis</u> in renal tubular cells, leading to <u>more water retention</u> and a more concentrated urine. <b><u>Desmopressin</u></b> is <u>V2 selective</u> (avoids vascular side-effects of vasopressin) and has a <u>longer half-life</u> <b>Indications</b>: <u>Central DI</u><b> Administration</b>: <u>Intranasal</u> (rapid onset, lasts 6-20h) or <u>oral</u> (poor absorption, doses 10x higher than nasal) <b>Toxicity</b>: be <b><u>very careful</u></b> (don't want to go hyponatremic!)<b> Other</b>:Patients should experience a <u>POLYURIC PHASE EVERY DAY</u> to avoid <u>HYPONATREMIA</u> |
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CRH (Ovine),occasionally used to <u>diagnose Cushing’s syndrome</u> or <u>adrenal insufficiency. </u>Very <u>expensive</u> ($300 / vial)
prochlorperazine |
<b>Mechanism of Action</b>: phenothiazine <u>antiemetic / antinauseant</u>; block <u>dopamine</u> at <u>chemoreceptor trigger zone (CTZ)</u>
<b>Effects</b>: Also have <u>antihistamine, anticholinergic effects</u> <b>Indications</b>:Nausea / vomiting; better than odansetron for <u>motion sickness</u> (antihistamine, anti-Ach action) |
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lubiprostone
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<b>Mechanism of Action</b>: <u>promotility agent; </u>prostaglandin derivative; <u>Cl channel agonist</u>
<b>Effects</b>: Binds to <u>ClC-2 channel</u> on epithelial cell; <u>increased Cl</u> & <u>fluid secretion</u> into gut lument, <u>softens stool</u> and <u>stimulates motility</u> <b>Selective Toxicity</b>: Acts at <u>gut epithelium</u> & works <u>locally</u> (rapidly metabolized; binds channels; doesn't get into blood)<b> Indications</b>: <u>Idiopathic chronic constipation</u>, <u>constipation-dominant IBS</u> <b>Pharmacokinetics: </b>Negligibile bioavailability; rapidly metabolized in gut epithelium (no hepatic or CYP450 involvement)<b> Toxicity</b>: <u>Nausea, diarrhea</u> (too much of what you want), <u>headache, abdominal distension</u> (more fluid into gut lumen), <u>flatulence</u> |
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docetaxel
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<b>Mechanism of Action</b>: Mitotic spindle poison. Taxane.
<b>Effects</b>:Binds to beta-tubulin, maybe stabilizing lateral contacts & freezing protofilament in place. Slows down microtubule dynamics, hurting ability to undergo mitosis.<b> Indications</b>: metastatic breast cancer<b> Toxicity</b>: dose-limiting myelosuppression. Peripheral neuropathy (less effects than paclitaxel) <b>Resistance</b>: MDR drug efflux pumps (ABC-type) |
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camptothecin
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<b>Mechanism of Action</b>: Topoisomerase I-targeted drug (antineoplastic agent)
<b>Effects</b>: Intercalates into & stabilizes topo-I / DNA covalent complex (sterically blocks DNA-DNA nucleophilic attack & reversal of enzyme-DNA complex formation). <b> Indications</b>: Solid tumors (first line for <b>colorectal</b> cancer in US/europe), also <b>ovarian</b> & other adult maligancies<b> Toxicity</b>: myelosuppression, nausea, hair loss, fatigue <b>Resistance:</b> MDR drug efflux pumps (ABC-type) <b>Other:</b> lactone ring is not stable at neutral or basic pH (converts to inactive form) |
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doxorubicin
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<b>Mechanism of Action</b>: Topoisomerase-II-targeted antineoplastic agent. Anthracycline.
<b>Effects</b>: Intercalates into & stabilizes DNA-topo II covalent complex by direct or indirect interaction<b> Indications</b>: solid tumors<b> Toxicity</b>: Dose-limiting acute & chronic <b>cardiotoxicity. Liver toxicity</b> (where metabolism occurs - hydrophobic, so bile excretion). <b>Resistance</b>: MDR drug efflux pumps (ABC-type). Cardiotoxicity from quinone groups (generates hydroxyl radicals)<b> </b> |
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actinomycin D
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<b>Mechanism of Action</b>: “hybrid” minor groove binding antineoplastic agent
<b>Effects</b>: Precise target not known. Probably induces DNA bending / structural pertubations (may target RNA polymerase instead of topoisomerase I)<b> Indications</b>: <b>Childhood malignancies</b> (Wilm's tumor, Ewing's sarcoma, embryonal rhabdosarcoma)<b> Toxicity</b>: Usual (myelosupression, hair loss, oral / GI ulceration) <b>Resistance</b>: MDR drug efflux pumps (ABC-type)<b> </b> |
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etoposide
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<b>Mechanism of Action</b>: Topoisomerase II-targeted antineoplastic agent. Epipodophylotoxin.
<b>Effects</b>: Nonintercalative; increases covalent DNA-enzyme complex by unknown structural mechanism<b> Indications</b>: Many types of cancers<b> Toxicity</b>: Usual (myelosuppression, mucositis, nausea, anaphylaxis) <b>Resistance</b>: MDR drug efflux pumps (ABC-type)<b> </b> |
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paclitaxel
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<b>Mechanism of Action</b>: Mitotic spindle poison. Taxane.
<b>Effects</b>:Binds to beta-tubulin, maybe stabilizing lateral contacts & freezing protofilament in place. Slows down microtubule dynamics, hurting ability to undergo mitosis.<b> Indications</b>: ovarian, breast cancers<b> Toxicity</b>: dose-limiting myelosuppression. Peripheral neuropathy (more effects than docetaxel) <b>Resistance</b>: MDR drug efflux pumps (ABC-type) |
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vinorelbine
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<b>Mechanism of Action</b>: Mitotic spindle poison (antineoplastic agent). Vinca alkaloid
<b>Effects</b>: binds to beta-tubulin (distorts protofilament structure / polymerization, slows dynamics, affecting ability to undergo mitosis)<b> Indications</b>:lung, breast cancer<b> Toxicity</b>: <b>liver toxicity</b>, myelosuppression (dose-limiting) <b>Resistance</b>:MDR drug efflux pumps (ABC-type) |
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vincristine
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<b>Mechanism of Action</b>: Mitotic spindle poison (antineoplastic agent). Vinca alkaloid
<b>Effects</b>: binds to beta-tubulin (distorts protofilament structure / polymerization, slows dynamics, affecting ability to undergo mitosis)<b> Indications</b>: ALL, lymphoma, hodgkin's, childhood malignancies<b> Toxicity</b>: <b>Neurotoxicity</b> (limits dosage); <b>liver toxicity</b>, myelosuppression <b>Resistance</b>:MDR drug efflux pumps (ABC-type)<b> </b> |
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topotecan
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<b>Mechanism of Action</b>: Topoisomerase I-targeted drug (antineoplastic agent)
<b>Effects</b>: Intercalates into & stabilizes topo-I / DNA covalent complex (sterically blocks DNA-DNA nucleophilic attack & reversal of enzyme-DNA complex formation). <b> Indications</b>: Solid tumors (first line for <b>colorectal</b> cancer in US/europe), also <b>ovarian</b> & other adult maligancies<b> Toxicity</b>: myelosuppression, nausea, hair loss, fatigue <b>Resistance:</b> MDR drug efflux pumps (ABC-type) <b>Other:</b> Like camptothecin, but more common in clinical use. lactone ring is not stable at neutral or basic pH (converts to inactive form) |
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daunorubicin
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<b>Mechanism of Action</b>: Topoisomerase-II-targeted antineoplastic agent. Anthracycline.
<b>Effects</b>: Intercalates into & stabilizes DNA-topo II covalent complex by direct or indirect interaction<b> Indications</b>: ALL, AML (acute leukemias)<b> Toxicity</b>: Dose-limiting acute & chronic <b>cardiotoxicity. Liver toxicity</b> (where metabolism occurs - hydrophobic, so bile excretion). <b>Resistance</b>: MDR drug efflux pumps (ABC-type). Cardiotoxicity from quinone groups (generates hydroxyl radicals)<b> </b> |
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vinblastine
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<b>Mechanism of Action</b>: Mitotic spindle poison (antineoplastic agent). Vinca alkaloid
<b>Effects</b>: binds to beta-tubulin (distorts protofilament structure / polymerization, slows dynamics, affecting ability to undergo mitosis)<b> Indications</b>: germ cell tumors, Hodgkin's disease<b> Toxicity</b>:<b>liver toxicity</b>, myelosuppression (dose-limiting) <b>Resistance</b>:MDR drug efflux pumps (ABC-type) |
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cisplatin
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<b>Mechanism of Action</b>: DNA cross-linking agent (antineoplastic platinum compound)
<b>Effects</b>: Intra- and inter-strand crosslinking of DNA; crosslinking of DNA to other molecules. <b> Indications</b>: Wide variety of cancers, esp. epithelial (carcinomas of lung, bladder, stomach, ovary) & testis cancer.<b> Toxicity</b>: <b>nephrotoxicity</b>, ototoxicity, peripheral neuropathy <b>Resistance</b>: chemical detoxification, DNA repair<b> Other</b>:<b> </b>more side effects (shorter half-life) than carboplatin, oxaliplatin (which have bone marrow toxicity as dose limiting side effect rather than nephrotoxicity) |
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carboplatin
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<b>Mechanism of Action</b>: DNA cross-linking agent (antineoplastic platinum compound)
<b>Effects</b>: Intra- and inter-strand crosslinking of DNA; crosslinking of DNA to other molecules. <b> Indications</b>: Wide variety of cancers, esp. epithelial (carcinomas of lung, bladder, stomach, ovary) & testis cancer.<b> Toxicity</b>: <b>bone marrow suppression</b> <b>Resistance</b>: chemical detoxification, DNA repair<b> Other</b>:<b> </b>shorter half life than cisplatin (less nephrotoxicity) |
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oxaliplatin
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<b>Mechanism of Action</b>: DNA cross-linking agent (antineoplastic platinum compound)
<b>Effects</b>: Intra- and inter-strand crosslinking of DNA; crosslinking of DNA to other molecules. <b> Indications</b>: Wide variety of cancers, esp. epithelial (carcinomas of lung, bladder, stomach, ovary) & testis cancer.<b> Toxicity</b>: <b>bone marrow suppression</b>, neurotoxicity, diarrhea <b>Resistance</b>: chemical detoxification, DNA repair<b> Other</b>:<b> </b>shorter half life than cisplatin (less nephrotoxicity) |
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mechlorethamine
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<b>Mechanism of Action</b>: Bifunctional alkylating agent; antineoplastic agent.
<b>Effects</b>: Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of modified base.<b> Indications</b>: Hodgkin's disease, mycosis fungoides (cutaneous lymphoma)<b> Administration:</b> IV, very short half-life<b> Toxicity</b>: nausea, vomiting, phlebitis, bone marrow suppression <b>Other</b>: nitrogen mustard. Very reactive (reacts with everything even in blood, so have to give IV) |
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chlorambucil
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<b>Mechanism of Action</b>: Bifunctional alkylating agent; antineoplastic agent
<b>Effects</b>: Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of modified base.<b> Indications</b>: chronic lymphocytic leukemia (CLL), indolent lymphomas, Waldenstrom's macroglobulinemia.<b> Administration:</b> can give PO<b> Toxicity</b>: bone marrow suppression, amenorrhea, sterility <b>Other</b>: substituted nitrogen mustard; less reactive than mechlorethamine. |
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cyclophosphamide
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<b>Mechanism of Action</b>: Bifunctional alkylating agent
<b>Effects</b>: Must first undergo metabolic activation (P450). Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of modified base.<b> Indications</b>: Many human cancers (non-Hodgkin's lymphoma, breast cancer). Can also be used with bone marrow or peripheral hematopoietic stem cell transplantation therapy (high-dose). Used to treat auto-immune diseases as well.<b> Administration</b>: Administering with 2-mecaptoethane sulfonate and vigorous hydration can help prevent cystitis<b> Toxicity</b>: bone marrow suppression, alopecia, gonadal toxicity, and <b>hemorrhagic cystitis (</b>diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage) resulting from excretion of a reactive metabolite (acrolein)<b> Other</b>: Most commonly used alkylating agent. Stem cells have aldehyde dehydrogenase, which protects from the active form of cyclophosphamide (which means they won't get killed) |
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Velcade
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<b>Mechanism of Action</b>: Proteosome inhibitor. Antineoplastic agent
<b>Effects</b>: Inhibits the chymotrypsin-like active site of proteosome. NF-kappa-B controls expression of stress response genes & others that promote cell survival. I-kappa-B inhibits NF-kappa-B, degraded in proteosome after ubiquination to activate NF-kappa-B. Less proteosome activity = more NF-kappa-B inhibition<b> Indications</b>: myeloma<b> Other</b>: Boronic acid dipeptide; mimics tetrahedral peptidase reaction site. |
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6-mercaptopurine
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<b>Mechanism of Action</b>: Competitive inhibitor of several enzymes in purine synthesis pathways (looks like guanine); also gets incorporated into DNA
<b>Effects</b>: Purine biosynthesis antagonist; antimetabolite antineoplastic agent.<b> Indications</b>: leukemias<b> Administration</b>: oral<b> Toxicity</b>: Bone marrow suppression <b>Resistance</b>: inactivated by xanthine oxidase (XO). Decrease in HGPRTase activity is common resistance mechanism. <b> Other</b>: Must undergo activation to form mononucleotide (add sugar) via HGPRTase. Also inactivation, elimination in urine pathways competing. |
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gemcitabine (2', 2' difluorodeoxycitidine)
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<b>Mechanism of Action</b>: Inhibits DNA polymerase by blocking DNA strand elongation (substrate but can't elongage afterwards)
<b>Effects</b>: Antimetabolite antineoplastic agent<b> Indications</b>: pancreatic cancer<b> Toxicity</b>: myelosuppression <b>Resistance</b>: decreased activity of activating enzymes; decreased nucleoside transport across cell membrane<b> Other</b>: Must be activated by deoxycytidylate kinase and nucleoside diphosphate kinase |
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azathioprine
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<b>Mechanism of Action</b>: Competitive inhibitor of several enzymes in purine synthesis pathways (looks like guanine); also gets incorporated into DNA
<b>Effects</b>: Purine biosynthesis antagonist; antimetabolite antineoplastic agent.<b> Indications</b>: leukemias<b> Administration</b>: oral<b> Toxicity</b>: Bone marrow suppression <b>Resistance</b>: inactivated by xanthine oxidase (XO). Decrease in HGPRTase activity is common resistance mechanism. <b> Other</b>: Must undergo activation to form mononucleotide (add sugar) via HGPRTase. Also inactivation, elimination in urine pathways competing. |
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trastuzumab
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<b>Mechanism of Action</b>: monoclonal antibody that binds to extracellular region of HER2, a transmembrane receptor tyrosine kinase from epidermal growth factor receptor family
<b>Indications</b>: Antineoplastic agent. Breast cancer (25% invasive primary breast cancers have HER2 overexpression)<b> Resistance</b>: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)<b> Other</b>:<b> </b>a.k.a. Herceptin |
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gefitinib
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<b>Mechanism of Action</b>: Tyrosine kinase inhibitor (inhibits epithelial growth factor receptor kinase)<b>
Indications</b>: Non-small-cell lung cancer (NSCLC)<b> Resistance</b>:amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)<b> Other</b>: Higher response if EGFR mutated or overexpressed. |
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imatinib
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<b>Mechanism of Action</b>:<b> </b>inhibits tyrosine kinases (BCR-ABL, c-KIT, PGDF receptor kinase)
<b>Effects</b>: Tyrosine kinase inhibitor; antineoplastic agent. BCR-ABL is a hyperactive fusion kinase implicated in CML (philadelphia chromosome). PGDF RK = platelet-derived growth factor receptor kinase<b> Indications</b>:CML, gastrointestinal stromal cancer. <b>Resistance</b>: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)<b> Other</b>:<b> </b>aka Gleevec. BCR-ABL + cells are resistant to apoptosis, proliferate more, and have altered adhesion properties. |
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5-azacytidine
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<b>Mechanism of Action</b>: Inhibits DNA polymerase by blocking DNA strand elongation (substrate but can't elongage afterwards)
<b>Effects</b>: Antimetabolite antineoplastic agent<b> Toxicity</b>: myelosuppression <b>Resistance</b>: decreased activity of activating enzymes; decreased nucleoside transport across cell membrane<b> Other</b>: Must be activated by deoxycytidylate kinase and nucleoside diphosphate kinase. a.k.a. 5-aza-C |
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6-thioguanine
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<b>Mechanism of Action</b>: Competitive inhibitor of several enzymes in purine synthesis pathways (looks like guanine); also gets incorporated into DNA
<b>Effects</b>: Purine biosynthesis antagonist; antimetabolite antineoplastic agent.<b> Indications</b>: leukemias<b> Administration</b>: oral<b> Toxicity</b>: Bone marrow suppression <b>Resistance</b>: inactivated by xanthine oxidase (XO). Decrease in HGPRTase activity is common resistance mechanism. <b> Other</b>: Must undergo activation to form mononucleotide (add sugar) via HGPRTase. Also inactivation, elimination in urine pathways competing. |
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2-chlorodeoxyadenosine
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<b>Mechanism of Action</b>: Inhibits DNA polymerase by blocking DNA strand elongation (substrate but can't elongage afterwards)
<b>Effects</b>: Antimetabolite antineoplastic agent<b> Toxicity</b>: myelosuppression <b>Resistance</b>: decreased activity of activating enzymes; decreased nucleoside transport across cell membrane<b> Other</b>: Must be activated by deoxycytidylate kinase and nucleoside diphosphate kinase. aka cladribine, 2-CdA |
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cetuximab
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<b>Mechanism of Action</b>: monoclonal antibody against epidermal growth factor receptor (EGFR).
<b>Indications</b>: Antineoplastic agent. Epithelial tumors (colorectal cancer, head and neck tumors)<b> Resistance</b>: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)<b> </b> |
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5-fluorouracil
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<b>Mechanism of Action</b>: Covalently modifies thymidylate synthase, the enzyme which converts dUMP to TMP. Triphosphate form can also be incorporated into DNA and cause strand breaks
<b>Effects</b>: Antimetabolite antineoplastic agent. <b> Indications</b>: Colorectal and breast cancer<b> Administration</b>: IV and oral. Often co-administered with leucovorin. TS uses folate as a cofactor (also when 5-FU binding), so adding a folate analog like leucovorin pushese the inhibitory equilibrium through (LeChatlier's). Also often co-administered with 5-ethynyluracil, which inhibits dihydropyrimidine dehydrogenase in intestine.<b> Toxicity</b>: Bone marrow suppression <b>Resistance</b>: Decreased activity of activating enzyme. Intestinal enzyme dihydropyrimidine dehydrogenase can inactivate by converting it to dihydroform and preventing absorption.<b> Other</b>: Transported in via nucleoside transporter, then P-lated and trapped in cell (needs to fit in kinase) |
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fludarabine (arabinosyl-2-fluoroadenine)
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<b>Mechanism of Action</b>: Inhibits DNA polymerase by blocking DNA strand elongation (substrate but can't elongage afterwards)
<b>Effects</b>: Antimetabolite antineoplastic agent<b> Indications</b>: chronic lymphocitic leukemia (CLL)<b> Toxicity</b>: myelosuppression <b>Resistance</b>: decreased activity of activating enzymes; decreased nucleoside transport across cell membrane<b> Other</b>: Must be activated by deoxycytidylate kinase and nucleoside diphosphate kinase |
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leucovorin
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Folate analog / source. Co-administered with methotrexate for “leucovorin rescue” (administer after MTX treatment to replentish folate supply), or with 5-fluorouracil (5-FU). 5-FU covalently modifies thymidylate synthase and requires a THF cofactor, so adding leucovorin pushes the reaction through via equilibrium principles
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methotrexate
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<b>Mechanism of Action</b>: Folic antagonist (antimetabolite). Inhibits dihydrofolate reductase (DHFR).
<b>Effects</b>: Inhibits DHFR which is involved in synthesis of THF from folic acid. THF is the methyl/methelyne carrier for purine and thymidine synthesis. <b> Indications</b>: wide variety of cancer breast cancer, colorectal cancer, lymphoma<b> Administration</b>: often paired with leucovorin shortly after MTX given (“leucovorin rescue”) - replentishes folate stores<b> Toxicity</b>: mucositis, kidney damage, hepatotoxicity <b>Resistance</b>: Reduced uptake; reduction in enzymes that add polyglutamate; DHFR gene amplification<b> Other</b>: Actively transported into cells. Requires activation by addition of several glutamates (traps in cell; enhances inhibition). Aka MTX |
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cytosine arabinoside
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<b>Mechanism of Action</b>: Inhibits DNA polymerase by blocking DNA strand elongation (substrate but can't elongage afterwards)
<b>Effects</b>: Antimetabolite antineoplastic agent<b> Indications</b>: Acute myelogenous leukemia (AML)<b> Toxicity</b>: myelosuppression <b>Resistance</b>: decreased activity of activating enzymes; decreased nucleoside transport across cell membrane<b> Other</b>: a.k.a cytarabine, Ara-C. Must be activated by deoxycytidylate kinase and nucleoside diphosphate kinase |
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hydroxyurea
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<b>Mechanism of Action</b>: Inhibits ribonucleotide reductase. Antimetabolite antineoplastic agent.
<b>Effects</b>:Ribonucleotide reductase reduces NDPs to dNDPs for DNA synthesis<b> Indications</b>: Leukemias; head and neck cancers<b> Toxicity</b>: Standard (bone marrow, etc.) <b>Resistance</b>: Overexpression of reductase<b> </b> |
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atropine
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<b>Mechanism of Action</b>: competitive antagonist of muscarinic Ach receptors
<b>Effects</b>:<b> </b>dry mouth, constipation, urinary retention, dry skin, flush, bronchodilation, mydriasis (=pupil dilation), delirium. <i><b>Mad as a hatter, red as a beet, dry as a bone</b></i><b> Indications</b>: Stop asystole (code blue), diarrhea, antidote to AchE toxins, pupil dilation <b> Administration</b>: po, opthalmic, or by injection<b> </b> |
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ipratropium bromide
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<b>Mechanism of Action</b>: muscarinic Ach receptor antagonist
<b>Effects</b>:<b> </b>bronchodilation<b> Indications</b>: asthma, COPD<b> Administration</b>: metered dose inhaler<b> Other</b>:<b> </b>a.k.a. atrovent |
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metoclopramide
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<b>Mechanism of Action</b>: Muscarinic AcH receptor agonist
<b>Effects</b>:<b> </b>increases gastric emptying; anti-emetic (dopamine receptor agonist), also enhances cholinergic effects<b> Indications</b>: First-line gastroparesis & anti-emetic agent<b> Administration</b>: oral<b> Other</b>:<b> </b>a.k.a. “Reglan” |
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neostigmine
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<b>Mechanism of Action</b>: reversible covalent inhibitor of AchE<b>
Indications</b>: can be used for prophylactic protection to AchE inhibitor nerve gases (fills up site, then wears off unlike sarin, etc.) |
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sarin
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<b>Mechanism of Action</b>: “irreversible” covalent inhibitor of AchE
<b>Effects</b>: signs of AchE poisoning: bronchial spasm, salivation, lacrimation, defecation, urination, bradycardia, hypotension, muscle weakness, death in minutes to hours<b> Administration</b>: nerve gas / chemical warfare agent<b> Other</b>: can be reversed with pralidoxime rescue if “aging” doesn't occur first (irreversible complex formed with AchE over time, preventing palidoxime's nucleophilic attack). Treatment also includes large quantities of atropine |
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scopolamine
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<b>Mechanism of Action</b>: muscarinic Ach receptor antagonist
<b>Effects: Indications</b>: motion sickness<b> Administration</b>: oral or transdermal<b> Toxicity</b>:<b> Other</b>: |
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pralidoxime
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<b>Mechanism of Action</b>:<b> </b>nucleophilic attack on AchE-sarin covalent complex
<b>Effects</b>: Reversal of sarin AchE poisoning<b> Indications</b>: sarin AchE poisoning<b> Other</b>: used along with atropine for sarin & other similar AchE poisons |
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pilocarpine
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<b>Mechanism of Action</b>: muscarinic AcH receptor agonist
<b>Effects</b>:<b> </b>generalized muscarinic (incl. ocular-pupillary constriction, fall in intraocular pressure after sudden rise, <i>miosis</i> = constriction of pupil lasts several hours)<b> Indications</b>: glaucoma (esp. open angle)<b> Administration</b>: aqueous opthalmic solution (prevent cardiac effects)<b> </b> |
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prazosin
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<b>Mechanism of Action</b>: selective antagonist of the α1 adrenergic receptor
<b>Effects</b>: blocks smooth muscle constriction (relaxes ureters); vasodilation (can help with hypertension)<b> Indications</b>: enhances urine flow in benign prostatic hyperplasia, especially with hypertension<b> </b> |
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clonidine
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<b>Mechanism of Action</b>: selective agonist of the α2 adrenergic receptor.
<b>Effects</b>: decreases NE release pre-synaptically (α2 is on <i>pre-synaptic</i> side, for feedback inhibition). <b> Indications</b>: hypertension (reduces blood pressure), used for withdrawal in substance abuse<b> Administration</b>: orally (both indications) or patch (substance abuse)<b> </b> |
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phenylephrine
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<b>Mechanism of Action</b>: selective agonist of the α1 adrenergic receptor
<b>Effects</b>: induces vasoconstriction<b> Indications</b>: hypotension, nasal congestion<b> Administration</b>: po or nasal spray as decongestant<b> </b> |
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epinephrine
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<b>Mechanism of Action</b>: predominantly an agonist of ß adrenergic receptors (over α)
<b>Effects</b>: increases cardiac output & systolic arterial blood pressure; large metabolic effect (increases O2 consumption & blood glucose)<b> Indications</b>: stopping anaphylactic response, used in code blue settings |
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dobutamine
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<b>Mechanism of Action</b>: selective agonist of ß1 adrenergic receptor
<b>Effects</b>: increases cardiac rate & force of contraction (increased cardiac output); dilates coronary arteries to reduce afterload<b> Indications</b>: cardiomyopathy with CHF, especially in anginal states<b> Administration</b>: IV<b> Other</b>:<b> </b>doesn't work indefinitely |
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dopamine
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<b>Mechanism of Action</b>: Acts on D1 receptor in vasculature; also α and ß in high doses
<b>Effects</b>: Pressor (increases blood pressure), used in cardiac situations. <b> Indications</b>: Low dose (renal dose) can be used to impact D1 receptor only if patient has low renal perfusion; higher doses impact D, α, and ß receptors and is first pressor in most instances of shock (low BP) |
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norepinephrine
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<b>Mechanism of Action</b>: Primarily an agonist of α adrenergic receptors
<b>Effects</b>: Increases systolic and diastolic blood pressure; less effect on cardiac output & metabolism<b> Indications</b>: Hypotensive shock (largely replaced by phenylephrine now) |
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lapatinib
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<b>Mechanism of Action</b>: binds to HER-2 receptor on breast cancer tumor cells.
<b>Effects: </b>blocks downstream signalling through both homo and heterodimers <b>Indications</b>: HER-2 positive breast cancer (15-20%)<b> Other</b>: HER-2 is an epidermal growth factor receptor that is constituitively activated & overexpressed on some breast cancers |
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trastuzumab
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<b>Mechanism of Action</b>: Binds to HER-2 receptor on breast cancer tumor cells. Monoclonal antibody.
<b>Effects: </b>cytotoxicity, potentiates other therapies, triggers host immune response, anti-angiogenic <b>Indications</b>: HER-2 positive breast cancer (15-20%)<b> Other</b>: HER-2 is an epidermal growth factor receptor that is constituitively activated & overexpressed on some breast cancers |
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rofecoxib
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<b>Mechanism of Action</b>: Inhibits cycloogenase 2 (Cox-2 specific NSAID )
<b>Effects</b>: Depresses prostaglandin synthesis<b> Indications</b>: Arthritis. Tried for colorectal cancer chemoprevention (decreased # polyps), but increased risk of blood clot / stroke. Pulled from market.<b> Other</b>:<b> </b>a.k.a. Vioxx |
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dutasteride
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<b>Mechanism of Action</b>: 5-alpha-reductase inhibitor
<b>Effects</b>: depresses androgen synthesis<b> Indications</b>: male pattern baldness, BPH (shrinks prostate), prostate cancer prevention (?) |
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celecoxib
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<b>Mechanism of Action</b>: Inhibits cycloogenase 2 (Cox-2 specific NSAID )
<b>Effects</b>: Depresses prostaglandin synthesis<b> Indications</b>: Arthritis. Tried for colorectal cancer chemoprevention (decreased # polyps), but increased risk of blood clot / stroke<b> Other</b>:<b> </b>a.k.a. Celebrex |
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finasteride
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<b>Mechanism of Action</b>: 5-alpha-reductase inhibitor
<b>Effects</b>: depresses androgen synthesis<b> Indications</b>: male pattern baldness, BPH (shrinks prostate), prostate cancer prevention (?)<b> Other</b>:<b> </b>One study showed increase in high-grade cancer, but that might have been artifact of biopsying smaller prostates for non-placebo group. |
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raloxifene
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<b>Mechanism of Action</b>:Selective estrogen receptor modifier (SERM)
<b>Effects</b>: Different effects (pro-e or anti-e) in different tissues<b> Indications</b>: Prevention of breast cancer <b>Toxicity</b>: increased risk of blood clots, maybe endometrial cancers? <b>Other</b>:<b> </b>use is controversial (benefits vs risks). Fewer blood clots, endometrial cancers than tamoxifen in trials |
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tamoxifen
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<b>Mechanism of Action</b>:Selective estrogen receptor modifier (SERM)
<b>Effects</b>: Different effects (pro-e or anti-e) in different tissues<b> Indications</b>: Prevention of breast cancer <b>Toxicity</b>: increased risk of endometrial cancer, blood clots, storke <b>Other</b>:<b> </b>use is controversial (benefits vs risks). More blood clots, endometrial cancers than raloxifen |
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rituximab
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<b>Mechanism of Action</b>: Binds CD20, cell surface marker on B cells (but not stem cells or plasma cells), triggering apoptosis in B-cell, antibody-dependent cell-mediated cytotoxicity (NK cells, etc.) and/or fixation of complement
<b>Effects</b>: Induces rapid drop in B cell numbers<b> Indications</b>: B cell lymphoma (e.g. follicular lymphoma)<b> Toxicity</b>: Sickness (fever, etc.) more common during first infusion (B cell numbers dropping most rapidly) <b>Resistance</b>: Variation in apoptotic pathway (most common) or failure to activate ADCC). Ab still binds but doesn't kill (CD20 not downregulated, escape mutations rare)<b> Other</b>: |
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chromoglycate (Cromolyn)
neocromil |
<b>Mechanism of Action</b>: <u>“Mast cell stabilizers”</u> - antiasthma agents
<b>Effects</b>: NOT bronchodilators. <u>Inhibit mediator release</u> (histamine, leukotrine, platelet activating factor) from pulmonary inflammatory cells; <u>prevent degranulation</u>. Low concentration: <u>suppresses chemotactic factors' effects</u> (on PMNs, eos, monos). May prevent bronchoconstriction <u>neurally</u> (bradykinin / SO2-mediated bronchoconstriction; maybe C-fiber sensory nerve involved). <b> Indications</b>: prevention of <u>cold</u>- and <u>exercise-induced asthma</u>. chromoglycate especially effective against <u>cough</u>. Can work against both <u>acute</u> & <u>delayed effects</u> (single dose). |
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salmeterol
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<b>Mechanism of Action</b>: <b><u>Long-acting</u></b><u> beta-2 agonists </u>(anti-asthma)
<b>Effects</b>: Relaxes smooth muscle (<u>bronchodilation</u>) by stimulating <u>adenyl cyclase</u>, increasing <u>cAMP</u>. Other distant effects too (see other). <b>Long-acting</b> (has long-lipophilic side chain). Also <b><u>inhibits inflammatory mediator release</u> </b>from lung. <b>Selective Toxicity</b>: Selective for beta-2 over beta-1<b> Indications</b>: <b>Long-acting</b> maintenance / prevention for asthma. 12h protection against <u>bronchoconstricting stimuli</u>; especially <b><u>nocturnal / exercise-induced</u> </b>asthma<b> Administration</b>: MDI/neb. <b><u>Does not fully occupy beta-2 receptors</u></b> so can <u>use short-acting drugs</u> as needed as rescue meds (can still use albuterol).<b> Toxicity</b>: <b><u>Black box warning</u></b>: make sure to counsel on how to use (not for rescue!). side effects due to <u>excessive stimulation of beta receptors</u>. CVS (<u>tachycardia</u>, <u>palpitations</u>, <u>exacerbastes CAD</u>, <u>arrhythmias</u>). CNS (<u>anxiety, apprehension, tremor, anxiety</u>). Metabolic (<b><u>hypoK</u>, <u>hyper</u></b><u>glycemia</u>). <b>Resistance</b>: <u>Tolerance</u> has ben documented at high doses with chronic treatment. <b> Other</b>: Secondary effects (importance less than bronchodilation in asthma): suppresses histamine / leukotrine release from pulmonary inflammatory cells, enhances mucociliary clearance, decreases microvascular permeability. |
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propofol
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<b>Mechanism of Action</b>: <u>GABA agonist IV anesthetic</u>.
<b>Effects</b>: Binds <u>separate site </u>on <u>GABA</u> <u>receptor</u> subunit; <u>increases</u> <u>sensitivity</u> of GABA receptor to GABA, increasing <u>chloride</u> flow & causing <u>more hyperpolarization</u> (inhibitory) in response to GABA. “Group 1” (acts via specific GABA-A receptor)<b> Indications & Administration</b>: <u>Induction agent</u>, <u>Continuous infusion</u> (alone for <u>diagnostic </u>procedures, + <u>opioid</u> for <u>surgery</u>)<b> Toxicity</b>: Mild <u>drop </u>in <u>BP</u>, <u>decr. respiration</u>s, <u>anaphylaxis</u> with <u>egg</u> or <u>soy</u> allergies, <u>burning sensation</u> with injection<b> Other</b>: Hypnosis, amnesia, slowing of cortical EEG (GABA effects) |
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etomidate
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<b>Mechanism of Action</b>: <u>GABA agonist IV anesthetic</u>.
<b>Effects</b>: Binds <u>separate site </u>on <u>GABA</u> <u>receptor</u> subunit; <u>increases</u> <u>sensitivity</u> of GABA receptor to GABA, increasing <u>chloride</u> flow & causing <u>more hyperpolarization</u> (inhibitory) in response to GABA. “Group 1” (acts via specific GABA-A receptor) <b>Indications & Administration</b>: <u>Rapid sequence induction</u> (emergency surgery, esp. in <u>unstable pts</u>)<b> Toxicity</b>: <u>Apnea</u>, <u>inhibits 11-beta hydroxylase</u>, causing <u>drop in cortisol</u> (<u>CONTINUOUS INFUSION CONTRAINDICATED</u><b><u>)</u> Other</b>:Hypnosis, amnesia, slowing of cortical EEG (GABA effects) |
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remifentanil
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<b>Mechanism of Action</b>: opioid receptor agonist
<b>Indications & Administration</b>: Combined with <u>sedative</u> or <u>inhaled anesthetic</u> in surgery, used when <u>very rapid offset desired</u> (metaboilzed by <u>plasma cholinesterase</u>) <b>Toxicity</b>: <u>Apnea, BP drops, chest wall rigidity</u> (need neuromuscular block & endotracheal intubation before ventilating pt). |
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lorazepam, diazepam
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<b>Mechanism of Action</b>: <u>benzodiazepine anticonvulsants</u>
<b>Effects</b>: <u>Enhance GABA activity</u> (bind benzo receptor), increasing inhibitory signalling (hyperpolarizes by increasing Cl influx postsynaptically)<b> Indications</b>: used for <u>rare seizure types</u>, 1st line IV in <u>status epilepticus</u><b> Toxicity</b>: <u>powerful</u> but <u>sedative, cognitive side effects</u> |
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topiramate
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<b>Mechanism of Action</b>: <u>Anticonvulsant</u>, blocks <u>AMPA glutamate receptors</u>
<b>Effects</b>: decreases <u>excitatory glutamate signaling</u><b> Toxicity</b>: <u>Memory</u> & <u>speech problems</u> (AMPA receptors involved in memory formation) |
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pramipexole (Mirapex); ropinirole (Requip)
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<b>Mechanism of Action</b>:<u>Non-ergot</u> <u>DA receptor agonists</u> (directly stimulate DA receptors). For <u>Parkinson Disease</u><b>
Indications</b>: <u>Parkinson Disease</u><b> Adminstration: </b><u>multiple daily doses</u> (like L-DOPA)<b> Toxicity</b>: Generally well tolerated (alone / in combo). N<u>ausea, somnolence, hallucinations, orthostatic hypertension</u>. Can see <u>mental status changes</u> in elderly, <u>daytime sleepiness</u>, <u>compulsive gambling</u> (unusual side effect) <b>Other</b>: Above info for pramipexole; riponerole is very similar<b> </b> |
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selegiline (edepryl)
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<b>Mechanism of Action</b>: <u>MAO-inhibitor</u>, for <u>Parkinson Disease</u>
<b>Effects</b>: Probably related to <u>irreversible MAO inhibition</u> (increases DA by decreasing breakdown) - <u>symptomatic</u>, not neuroprotective<b> Indications</b>: Parkinson Disease (complements other anti-PD meds)<b> Adminstration: </b>twice daily, generic available<b> Metabolism</b>: Complex pharmacokinetics; <u>L-amphetamine, L-methamphetamine </u>are metabolites; parent compound has MAO-B inhibiting activity too, need to follow <u>MAO-B inhibition</u> as kinetic parameter (not serum levels of drug / dose)<b> Toxicity</b>: well tolerated; rare weight loss <b>Other</b>: shown to prolong time until L-DOPA is needed.<b> </b> |
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L-DOPA
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<b>Mechanism of Action</b>: <u>Dopamine receptor agonist </u>(via DA, active <u>metabolite</u>)
<b>Effects</b>: <u>L-DOPA</u> converted to <u>DA</u> via <u>AADC</u> (both peripheral and in nervous tissue), augments <u>DA signalling</u> (decreased in PD)<b> Indications</b>: Parkinson Disease<b> Adminstration:</b> <u>Short half life</u> (1-2 hrs); must give several times throughout day; can result in <u>large swings in serum [L-DOPA</u>]<b> Metabolism</b>: Can <u>cross BB</u>B (DA can't). <u>Less than 2% reaches CNS</u> (rapidly metabolized by AADC in liver, other tissues). <b> Toxicity</b>: <u>big swings </u>are bad: <u>involuntary movements</u> (excessive peak doses); <u>recurrence</u> of symptoms (low trough doses). <u>chronic spiking blood levels</u> may play role in development of delayed dyskinesias. <u>Acute</u> side effects: <u>nausea, orthostatic hypotension, hallucinations</u> <u>Chronic</u> side effects (50% of pts after 5 yrs): <u>wearing-off, on-off phenomenon,</u> disabling <u>dyskinesias</u><b> </b> |
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sinemet (L-DOPA + carbidopa)
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<b>Mechanism of Action</b>: L-DOPA: <u>Dopamine receptor agonist </u>(via DA, active <u>metabolite</u>); <u>carbidopa</u> is a <u>peripheral AADC inhibitor</u>
<b>Effects</b>: <u>L-DOPA</u> converted to <u>DA</u> via <u>AADC</u>, augments <u>DA signalling</u> (decreased in PD). . <u>Carbidopa blocks AADC peripherally</u>, <u>increasing delivery </u>to CNS. Effectively reduces <u>rest tremor, rigidity </u>and <u>bradykinesia;</u> <u>less</u> effective in reversing <u>postural instability</u><b> Indications</b>: Parkinson Disease<b> Adminstration:</b> <u>Short half life</u> (1-2 hrs); must give several times throughout day; can result in <u>large swings in serum [L-DOPA</u>]. <b>Controlled-release</b> preparations help, but <u>slower onset</u> of action, <u>reduced peak blood levels</u>, and <u>longer duration of action</u><b> Metabolism</b>: Can <u>cross BB</u>B (DA can't). Much still metabolized in liver (<u>COMT</u>)<b> Toxicity</b>: <u>big swings </u>are bad: <u>involuntary movements</u> (excessive peak doses); <u>recurrence</u> of symptoms (low trough doses). <u>chronic spiking blood levels</u> may play role in development of delayed dyskinesias<b> </b> |
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rasagaline (Azilect)
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MAO-B inhibitor: like selegiline, but <u>once-daily</u> (longer duration of action)<u>
</u>No L-amphetamine / L-methamphetamine metabolites (probably not clinically relevant) |
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Ketorolac
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<u>Topical non-steroidal</u>, used for <u>mild anterior segment irritation</u>
Only known effective treatment for <u>cystoid macular edema</u> (important cause of vision loss after cataract surgery) |
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cyclosporin A topical (Restasis)
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<b>Mechanism of Action</b>: <u>Anti-inflammatory agent</u> for <u>topical use</u> in <u>severe dry eye</u>
<b>Effects</b>: Suppresses inflammatory response (<u>cytokines</u> / <u>receptor-mediated inflammation</u> of <u>lacrimal gland,</u> <u>ocul</u>ar <u>surface</u> involved in pathogenesis of dry eye). <b>Indications</b>: <u>Dry eye</u> (improves <u>ocular discomfort</u> & <u>blurred vision)</u><b> Administration</b>: 0.05% emulsion |
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pilocarpine
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<b>Mechanism of Action</b>: <u>muscarinic agonist</u> used to <u>lower IOP</u> by <u>increasing aqueous humor outflow</u>
<b>Effects</b>: <u>Directly stimulates</u> muscarinic receptors on the <u>ciliary muscles</u>, causing them to <u>contract</u>, opening the <u>trabecular meshwork</u> and leading to <u>better outflow</u> of aqueous humor, lowering IPO <b>Indications</b>: <u>Glaucoma</u><b> Administration</b>: Needs to be given 4x/day<b> Toxicity</b>: Also constricts pupil; not used much anymore |
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brimonidine
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<b>Mechanism of Action</b>: <u>alpha-2 adrenergic agonist</u>, used to <u>decrease aqueous humor production</u>
<b>Effects</b>: bind <u>alpha-2 adrenergic receptors</u> in <u>ciliary processes</u>, <u>decreasing aqueous humor production</u> (and <u>lowering IOP</u>) as a result. May also <u>increase uveoscleral outflow</u> of aqueous humor <b>Indications</b>: <u>Glaucoma</u><b> Toxicity</b>: <u>Local allergy</u> |
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bimatoprost
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<b>Mechanism of Action</b>: <u>prostaglandin analogue</u>, used to <u>reduce intraocular pressure</u>
<b>Effects</b>: <u>Increase extracellular space</u> in <u>ciliary muscle</u> (increase rate that aqueous humor leaves eye) - makes ciliary muscle “spongier”<b> Indications</b>: <u>Glaucoma</u><b> Administration</b>: <u>eye drop</u><b> Toxicity</b>: <u>darken light irides</u>, cause <u>longer / bushier eyelashes</u> <b>Other</b>: Also approved by FDA as <u>Latisse</u> to promote growth of upper lashes (and make $$$ for pharma). Not causing an increase in number of melanocytes (not predisposing to melanoma) - just more melanosomes per cell (darken irides) |
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“-olol” eyedrops
(timolol, levobunolol, carteolol, metopranolol, betaxolol) |
<b>Mechanism of Action</b>: <u>beta-adrenergic antagonists</u> (beta-blockers), used to <u>decrease IOP</u>
<b>Effects</b>:bind <u>beta-2 adrenergic receptors</u> in <u>ciliary epithelium</u>, thereby <u>reducing production</u> of <u>aqueous humor</u>. <b>Indications</b>: <u>Glaucoma</u><b> Administration</b>: <u>eyedrops</u><b> Toxicity </b>:Can be the <u>same</u> as <u>oral beta-blockers</u> (can get into bloodstream via canalicular membrane to nasopharynx). Watch out for <u>asthma</u>, <u>chronic pulmonary disease</u>, <u>heart block</u>. Some <u>lower HDLs</u> too <b>Other</b>: cAMP theory of aqueous humor production: Binding to <u>beta-2 adrenergic receptors</u> leads to <u>Gs</u>-mediated <u>increase in cAMP</u> within epithelial cells, which <u>increases ion transport / fluid flow</u> out of epithelial cell, into posterior chamber. <u>Process blocked</u> by these drugs. |
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acetazolamide
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<b>Mechanism of Action</b>: <u>Carbonic anhydrase inhibitor</u>, used to <u>lower intraocular pressure</u>
<b>Effects</b>: <u>inhibit CA activity</u><i> </i>in <u>ciliary epithelium</u> (<u>lowers aqueous humor production</u>) <b>Administration</b>: Now available <u>topically</u> (previously only orally; more systemic side effects)<b> Indications</b>: <u>Glaucoma</u> |
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phospholine iodide
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<b>Mechanism of Action</b>: <u>Anticholinesterase agent</u> used to <u>lower IOP</u> by <u>increasing aqueous humor outflow</u>
<b>Effects</b>: <u>Inhibits AchE,</u> causing <u>more Ach</u> to be available for <u>muscarinic receptors </u>on the <u>ciliary muscles</u>, causing them to <u>contract</u>, opening the <u>trabecular meshwork</u> and leading to <u>better outflow</u> of aqueous humor, lowering IPO <b>Indications</b>: <u>Glaucoma </u><b>Toxicity</b>: can lead to <u>low levels</u> of <u>plasma pseudocholinesterase</u>; if such pts get <u>succinylcholine</u> during <u>general anesthesia</u>, can experience <u>prolonged neuromuscular blockade</u> |
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ranibizumab (Lucentis)
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<b>Mechanism of Action</b>: <u>anti-VEGF monoclonal antibody</u>
<b>Effects</b>: mAb against <u>all VEGF isoforms</u> <b>Indications</b>: Actually <u>improves vision</u> in some eyes with <u>“wet” age-related macular degeneration</u><b> Administration</b>: <u>intravitreal injection</u> |
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pegaptanib (Macugen)
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<b>Mechanism of Action</b>: <u>anti-VEGF aptamer</u>, used for “<u>wet AMD”</u>
<b>Effects</b>: used to reduce neovascularization <b>Indications</b>: Reduces <u>rate of vision loss</u> in <u>“wet” age-related macular degeneration</u><b> Administration</b>: <u>intravitreal injection</u><b> Toxicity</b>:<u>Repeated injections, not pleasant, could develop infection</u> |
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scopolamine
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<b>Mechanism of Action</b>: <u>Muscarinic antagonist mydriatic</u>. <u>Dilates pupil</u> by <u>antagonizing muscarinic ACh receptor</u> of <u>pupillary sphincter muscle</u>
<b>Effects</b>: Normally Ach binds muscarinic receptor on pupillary sphincter muscle, resulting in <u>constriction</u>, so antagonizing this receptor leads to <u>pupillary dilation</u> <b>Indications</b>: <u>pupillary dilation</u> (used to visualize <u>ocular structures posterior to iris</u>)<b> Administration</b>: often with <u>alpha-1 adrenergic agonist</u> for maximal dilation |
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tropicamide
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<b>Mechanism of Action</b>: <u>Muscarinic antagonist mydriatic</u>. <u>Dilates pupil</u> by <u>antagonizing muscarinic ACh receptor</u> of <u>pupillary sphincter muscle</u>
<b>Effects</b>: Normally Ach binds muscarinic receptor on pupillary sphincter muscle, resulting in <u>constriction</u>, so antagonizing this receptor leads to <u>pupillary dilation</u> <b>Indications</b>: <u>pupillary dilation</u> (used to visualize <u>ocular structures posterior to iris</u>)<b> Administration</b>: often with <u>alpha-1 adrenergic agonist</u> for maximal dilation |
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homatropine
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<b>Mechanism of Action</b>: <u>Muscarinic antagonist mydriatic</u>. <u>Dilates pupil</u> by <u>antagonizing muscarinic ACh receptor</u> of <u>pupillary sphincter muscle</u>
<b>Effects</b>: Normally Ach binds muscarinic receptor on pupillary sphincter muscle, resulting in <u>constriction</u>, so antagonizing this receptor leads to <u>pupillary dilation</u> <b>Indications</b>: <u>pupillary dilation</u> (used to visualize <u>ocular structures posterior to iris</u>)<b> Administration</b>: often with <u>alpha-1 adrenergic agonist</u> for maximal dilation |
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phenylephrine
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<b>Mechanism of Action</b>: <u>alpha-1 adrenergic agonist mydriatic</u>.
<b>Effects</b>: <u>Dilates pupil</u> by stimulating <u>alpha-1 adrenergic receptors</u> on <u>pupillary dilator muscle</u> <b>Indications</b>: <u>pupillary dilation</u> (used to visualize <u>ocular structures posterior to iris</u>)<b> Administration</b>: often with <u>muscarinic antagonist</u> for maximal dilation <b>Toxicity:</b> 1 drop of phenylephrine can contain 3.5-6 mg of the drug - can cause <u>serious systemic side effects</u> |
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atropine
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<b>Mechanism of Action</b>: <u>Muscarinic antagonist mydriatic</u>. <u>Dilates pupil</u> by <u>antagonizing muscarinic ACh receptor</u> of <u>pupillary sphincter muscle.</u> Also causes <u>ciliary body relaxation</u>
<b>Effects</b>: Normally Ach binds muscarinic receptor on pupillary sphincter muscle, resulting in <u>constriction</u>, so antagonizing this receptor leads to <u>pupillary dilation</u>. Ach on muscarinic receptors also <u>contract ciliary body</u>, so antagonism <u>relaxes</u> <b>Indications</b>: <u>pupillary dilation</u> (used to visualize <u>ocular structures posterior to iris</u>). <u>cycloplegia</u> (paralysis of ciliary muscle). Relaxing ciliary muscle also useful for <u>inflamed eyes</u> (more comfortable, helps prevent <u>posterior synechiae</u>), determining <u>refractive status</u> of <u>children</u>, and treating <u>amblyopia & strabismus</u>. <b> Administration</b>: often with <u>alpha-1 adrenergic agonist</u> for maximal dilation <b>Toxicity</b>: can lead to <u>fever, tachycardia, confusional psychosis</u> (“belladonna agents”) <b>Other</b>: a “parasympatholytic” |
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cyclopentolate
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<b>Mechanism of Action</b>: <u>Parasympatholytic</u> agents (<u>muscarinic antagonists</u>), causing <u>pupillary dilation</u> and <u>ciliary body relaxation</u>
<b>Effects</b>: <u>Block </u>normal effects of <u>Ach</u> on <u>muscarinic receptors</u> (constrict pupil, contract ciliary body) <b>Indications</b>: <u>Dilate pupil</u>, <u>cycloplegia</u> (paralysis of ciliary muscle). Relaxing ciliary muscle also useful for <u>inflamed eyes</u> (more comfortable, helps prevent <u>posterior synechiae</u>), determining <u>refractive status</u> of <u>children</u>, and treating <u>amblyopia & strabismus</u> (“penalyze” good eye - like patching) |
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ganciclovir,Used as <u>intraocular implant + oral</u> as an alternative to cidofovir for <u>CMV retinitis</u>
famciclovir (oral),for <u>early stages</u> of <u>herpes zoster keratitis</u> cidofovir |
Used <u>IV</u> once every two weeks for <u>CMV retinitis</u> (1st line)
Could use ganciclovir (implant + oral) instead |
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trifluorothymidine,<u>topical</u> agent used commonly for <u>cornea / anterior segment herpes simplex</u> infection
acyclovir (oral) |
<u>reduces recurrence</u> of <u>ocular herpes simplex virus</u> infection
Also used for <u>early stages</u> of <u>herpes zoster keratitis</u> |
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phenelzine, tranylcypromaine
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<b>Mechanism of Action</b>:<u>MAOI antidepressants</u>. Inhibit <u>monamine oxidase</u>, (A+B), increasing <u>norepi</u>, <u>dopamine</u>, <u>serotonin</u> levels
<b>Effects</b>: Can be a <u>miracle drug</u> for some patients (although risky) <b>Indications</b>: <u>Major depression</u>, BPD (with mood stabilizer 1st)<b> Administration</b>: <u>Dietary restrictions</u> (<u>low tyramine diet</u> - no cheese, aged meats, wine)<b> Toxicity</b>: <u>Lethal</u> in <u>OD</u> or <u>combined with other meds</u>. <u>Orthostatic hypotension</u> is most common (can limit use). Also <u>hypertension reaction</u> to <u>food with tyramine</u>, <u>sexual dysfunction</u>, <u>GI disturbance</u>, <u>peripheral edema</u> <b>Interactions: </b>can't use <u>OTC cold meds</u>, must be off of <u>all other antidepressants</u> for <u>1-2 wks</u> before starting<b> Other</b>: phenelzine = Nardil, tranylcypromaine = Parnate |
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risperidone
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<b>Mechanism of Action</b>: “<b><u>atypical” antipsychotic agent</u></b>, similar to <b><u>clozapine</u></b> but newer
<b>Indications</b>: <u>schizophrenia</u>; affects <u>postitive</u> and <u>negative</u> symptoms, but <u>not as effective as clozapine</u>. Also being used <u>more broadly</u>, even in <u>non-psychotic pts</u> (calm <u>manic / anxious pts</u>)<b> Toxicity</b>: Like clozapine (<u>sedation, hypotension,</u> with a little less weight gain) but <b><u>NO AGRANULOCYTOSIS</u></b>. <u>More </u>likely than other new atypicals to cause <b><u>extrapyramidal motor effects! </u></b>All neuroleptics: <u>increased serum prolactin</u> (can cause <u>amenorrhea</u> & <u>sexual dysfunction</u>; from <u>hypothalamic blockade</u> - dopamine inhibits PRL secretion)<b> Other</b>: aka <b><u>Risperdal</u></b> |
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lamotrigine
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<b>Mechanism of Action</b>: <u>Mood stabilizer</u> (& anticonvulsant). Mechanism not completely understood: <u>calcium signaling / inisitol phosphate pathway</u> is one possibility (popular in 80s); <u>GSK-3beta</u> / <u>Wnt signaling</u> (cell growth, embryogenesis, brain development) is more current model<b>
Indications</b>: <u>bipolar disorder</u> (prevents mood episodes - <u>depression > mania</u> for prevention). <b> Toxicity</b>: <u>rash</u> (10-15%), can progress to <u>Stevens-Johnson syndrome</u>(0.1%). Minimize with <u>slow upward dose titration</u> (over 2 mo)<b> Other</b>: First FDA-approved medication (2003) for maintenance tx of BP since Li in 1970s. <u>Lithium</u> best for controlling mania, <u>lamotrigine</u> maybe a little better for depression |
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triazolam (Halicon)
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<b>Mechanism of Action</b>: <b><u>SHORT-ACTING </u></b>b<u>enzodiazepine </u>- binds <u>benzoR</u>, potentiating <u>GABA's actions</u> (increases <u>frequency </u>of chloride channel opening)
<b>Effects</b>: <u>Sleepiness (hypnotic) & sedation</u> <b>Metabolism</b>: both parent & metabolite compounds active. <u>CYP3A4</u> metabolism; glucuronide conjugates excreted in urine.<b> </b> |
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calcium carbonate (CaCO3) antacids
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<b>Mechanism of Action</b>: <u>antacid</u>, basic compound which neutralizes HCl
<b>Effects</b>: <u>neutralizes HCl</u>, <u>increases gastric intraluminal pH</u>, inactivates <u>pepsin,</u> binds <u>bile salts</u> <b>Indications</b>: <u>duodenal ulcers, GERD, stress ulcer</u> prophylaxis (replaced generally by PPis for many of these)<b> Administration</b>: <u>Frequent administration needed</u> <b>Pharmacokinetics: <u>rapid neutralization</u> Toxicity</b>: <b><u>abdominal distension, belching</u></b>. <u>cation absorption</u> (renal pts: all antacids) <b>Other</b>: Maalox quick dissolve, Tums-EX are CaCO3 only |
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magnesium / aluminum combo antacids
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<b>Mechanism of Action</b>: <u>antacid</u>, basic compound which neutralizes HCl
<b>Effects</b>: <u>neutralizes HCl</u>, <u>increases gastric intraluminal pH</u>, inactivates <u>pepsin,</u> binds <u>bile salts</u> <b>Indications</b>: <u>duodenal ulcers, GERD, stress ulcer</u> prophylaxis (replaced generally by PPis for many of these)<b> Administration</b>: <u>Frequent administration needed</u> <b>Pharmacokinetics: <u>slower absorption (longer neutralizing ability)</u> Toxicity</b>: <b><u>Mg is laxative</u></b> (combo with Al, which decreases gut motility). <u>cation absorption</u> (renal pts: all antacids) <b>Other</b>: eg Maalox |
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sodium bicarbonate (NaHCO3) antacids
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<b>Mechanism of Action</b>: <u>antacid</u>, basic compound which neutralizes HCl
<b>Effects</b>: <u>neutralizes HCl</u>, <u>increases gastric intraluminal pH</u>, inactivates <u>pepsin,</u> binds <u>bile salts</u> <b>Indications</b>: <u>duodenal ulcers, GERD, stress ulcer</u> prophylaxis (replaced generally by PPis for many of these)<b> Administration</b>: <u>Frequent administration needed</u> <b>Pharmacokinetics: <u>rapidly cleared</u> </b>(very water soluble)<b> Toxicity</b>: <b><u>Alkali & sodium load</u></b> (CHF pts); <u>cation absorption</u> (renal pts: all antacids) |
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misoprostol
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<b>Mechanism of Action</b>: synthetic <u>prostaglandin E1 analogue</u>, increases <u>protective functions</u> of mucosal barrier (for acid protection)
<b>Effects</b>: <u>Antisecretory:</u> inhibits <u>basal</u>, & <u>nocturnal</u> gastric acid secretion by <u>direct action</u> on <u>parietal cells</u>. <u>Cytoprotective</u>: increases production of <u>gastric mucus</u> and secretion of <u>bicarbonate</u> (epithelial cells) <b>Indications</b>: prevention of <u>gastric ulcers</u> in patients requiring <u>long term NSAIDs</u> (inhibiting COX so normal prostaglandins decreased!) Can use to treat <u>constipation too</u>!<b> Toxicity</b>: <u>uterine contractions</u> (abortifacent - <u>DON'T USE in young women of reproductive age</u>). <u>Diarrhea, abdominal cramping</u> |
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sucralfate
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<b>Mechanism of Action</b>: improves <u>protective mucosal barrier</u> (protective to acid)
<b>Effects</b>: activated by <u>acid</u>, forms a viscous adherent <u>gel</u> that binds electrostatically to <u>positive protein molecules</u> in <u>ulcer craters</u>. Also <u>inhibits pepsin</u> and <u>absorbs bile salts</u> <b>Selective Toxicity</b>: Acivated by <u>acid</u>, works <u>locally</u> (not absorbed throughout body)<b> Indications</b>: <u>stress ulcers </u>(prophylaxis), <u>peptic ulcers</u>, <u>bile reflux</u> (chemical gastritis - from duodenum to stomach)<b> Administration</b>: Technically: should take on <u>empty stomach</u> (avoid binding to dietary protein / aluminum; also pH increases after meal - less activation). In practice: usually take when you eat & at bedtime. <b>Pharmacokinetics:</b> most of dose excreted <u>unchanged</u> in <u>stool</u> (works locally), <u>aluminum</u> accumulates with <u>renal failure</u><b> Toxicity: </b><u>Constipation</u>, as an anion resin; also binds <u>other drugs</u> (phenytoin, digoxin, theophyllin bioavailability reduced if given at same time) |
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loperamide
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<b>Mechanism of Action</b>: <u>opioid</u> <u>antimotility/antisecretory agent</u>
<b>Effects</b>: <u>increases fluid absorption, decreases fluid secretion, decreases motility</u> (increases transit time). <u>decreases longitudinal</u> muscle activity (propulsion), <u>increases segmentation activity</u> (non-propulsive)<b> Indications</b>: <u>diarrhea</u> (but not treating underlying cause) <b>Pharmacokinetics: </b><u>doesn't penetrate CNS</u> in normal doses. loperamide is <u>40-50x</u> more potent as anti-diarrheal than morphine; quick onset affter oral dosing, peak 3-5h, half life 11h, <u>hepatic metabolism</u><b> Toxicity</b>: <u>sedation</u> and <u>paralytic ileus</u> with overdose<b> Other</b>: aka Imodium |
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cholestyramine
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<b>Mechanism of Action</b>: <u>bile salt binding antidiarrheal agent</u>
<b>Effects</b>: Intraluminal; <u>binds excess bile salts</u> (reduce passage to colon & osmotic colon secretion of water) <b>Selective Toxicity</b>: <u>intraluminal</u> (not absorbed!)<b> Indications</b>: <u>diarrhea (if bile salt in excess)</u> |
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bismuth subsalicylate
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<b>Mechanism of Action</b>:<u>antidiarrheal agent</u>. Exact mechanism unknown
<b>Effects</b>: Bismuth has <u>antisecretory, antiinflammatory</u>, and <u>antimicrobial</u> effects <b>Selective Toxicity</b>: <u>intraluminal</u> (not absorbed!)<b> Indications</b>: <u>diarrhea</u><b> Other</b>: Pepto-Bismol |
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psyllium
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<b>Mechanism of Action</b>: <u>hydroscopic antidiarrheal agent</u>
<b>Effects</b>: Intraluminal; <u>absorbs excess water</u> from stool. Less fluid = less diarrhea. <b>Selective Toxicity</b>: <u>intraluminal</u> (not absorbed!)<b> Indications</b>: <u>diarrhea</u><b> Other</b>: aka metamucil |
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dronabinol
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<b>Mechanism of action</b>: <u>cannabinoid antiemetic/antinauseant</u>. Stimulates “cannabinoid receptors” in vomiting center?
<b>Effects:</b> also <u>stimulates appetite</u><b> Indications: </b>nausea, vomiting, <u>appetite</u> in <u>AIDS pts </u><b>Toxicity: $$$</b> |
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odansetron (zofran)
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<b>Mechanism of Action</b>: <u>antiemetic</u> (serotonin receptor blocker)
<b>Effects</b>: blocks <u>serotonin effect receptors</u> in CNS (chemo-receptor trigger zone, nucleus tractus solitarius of vagus nerve); may block vagal afferents in GI tract<b> Indications</b>: <u>Chemotherapy-induced </u>nausea, nausea from <u>upper GI irradiation</u>, <u>hyperemesis</u> of <u>pregnancy</u>, <u>postoperative nausea</u>, NOT MOTION SICKNESS (no serotonin in that pathway)<b> Administration</b>: <u>once/day</u> (antiemetic effect lasts long after drug cleared) <b>Pharmacokinetics:</b> well absorbed from gut, <u>CYP450</u> metabolism in liver (decrease dose in liver dysfunction)<b> Toxicity</b>: Generally well tolerated: constipation, diarrhea, headache, light-headedness, minor EKG changes (not clnically significant); <u>financial toxicity</u> (expensive!) |
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diphenhydramine, promethazine
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<b>Mechanism of Action</b>: antihistamines; <u>antiemetic / antinauseants</u>; block <u>histamine</u> at <u>chemoreceptor trigger zone (CTZ)</u>
<b>Effects</b>: H1 receptor antagonists<b> Indications</b>:Nausea / vomiting: <u>motion sickness, post-op emesis</u> |
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bisacodyl
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<b>Mechanism of action: </b><u>“stimulant” cathartic (laxative)</u><b>
Effects: </b>induce <u>low grade inflammation </u>in <u>small bowel & colon</u>! Inflammation ↑ fluid, electrolytes ↑ intestinal motility <b>Other</b> (feen-a-mint, correctol, dulcolax) |
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magnesium salts
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<b>Mechanism of action: </b><u>anti-constipation drugs;
</u><b>Effects</b>: Mg <u>poorly absorbed </u> <u>↑ intraluminal osmolarity </u> ↑ <u>water retention </u>by stool (Maybe ↑ CCK secretion (↑ bowel motility, secretion) too) <b>Other</b>: Most commonly used agents; hypertonic > isotonic for efficacy |
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bulk-forming laxatives
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Mechanism of Action: <u>Hydrophilic</u> compounds that <u>hold water in stool</u>; might <u>inhibit absorption of bile acids</u> (stimulate H2O secretion by colon) too
<b>Indications</b>: used more for <u>irritable bowel syndrome</u> than for constipation |
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senna
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<b>Mechanism of action: </b>Anthraquinone laxatives; <u>“stimulant” cathartic (laxative)</u><b>
Effects: </b>induce <u>low grade inflammation </u>in <u>small bowel & colon</u>! Inflammation ↑ fluid, electrolytes ↑ intestinal motility <b>Administration</b>: <u>not for daily use</u> (see below)<b> Toxicity</b>: <u>melanosis coli</u> (dark colon - <u>reversible</u>). <u>“CATHARTIC COLON</u>“ (years of laxative abuse; becomes dilated & ahaustral; <u>neurons lost</u> & <u>muscularis propria atrophies</u> - bowel function lost!) <b>Other</b>:aloe, cascara are also anthraquinone laxatives |
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docusate sodium (colace)
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<b>Mechanism of Action</b>: <u>emollient</u> (<u>stool softener)</u> - <u>anionic detergent</u>
<b>Effects</b>:<u> lowers surface tensio</u>n of stool (permits penetration of <u>water, fats</u>) <b>Indications</b>: used more for <u>hard stools</u> than constipation<b> </b> |
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domperidone
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<b>Mechanism of Action</b>: <u>promotility agent</u>: <u>antagonizes</u> <u>dopamine receptor</u>
<b>Effects</b>: <u>Dopamine</u> receptor usually <u>inhibits</u> <u>primary</u> <u>motor</u> <u>neur</u>on in gut wall, <u>slowing</u> gastric motility. <u>Inhibiting</u> dopamine receptor leads to <u>more</u> <u>contractility</u>. <b>Indications</b>: like metaclopromide (gastroparesis, GERD, <u>nausea / vomiting)</u> <b>Selective Toxicity</b>: <u>does not cross BBB</u> (no somnolence/extrapyramidal motor effects!) |
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metaclopramide
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<b>Mechanism of Action</b>: <u>5-HT4 receptor activation </u>(also <u>dopamine antagonist</u> and <u>cholinergic agonist</u>)
<b>Effects</b>: enhances smooth muscle propulsive contractionsof <u>upper</u> gut, <u>accelerates gastric emptying</u> (dopamine normally slows things down; blocking it speeds things up). Also <u>increases LES tone</u>, has <u>antiemetic effect</u> (CNS <u>dopamine</u> antagonism)<b> Indications</b>: <u>gastroparesis</u>(diabetic / idiopathic), <u>GERD</u> (increased LES tone, better gastric emptying), <u>nausea / vomiting</u> <b>Pharmacokinetics: </b>Half life increases in renal failure<b> Toxicity</b>: <u>somnolence, nervousness</u>; also can have <u>reversible extrapyramidal motor effects</u> (Parkinson-like), and <u>irreversible tarditive dyskinesia</u><b> </b>(inability to sit still / goes away with sleep) <b>Other</b>:<b> </b>a.k.a. Reglan |
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erythromycin
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<b>Mechanism of action</b>:Promotility agent; <u>macrolide; stimulates GI motility </u>by <u>agonizing motilin receptor
</u> |
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amiloride, triamterene
(K-sparing diuretics) |
<b>Mechanism of Action</b>: K-sparing diuretic, <u>sodium channel blocker</u>. Inhibit <u>sodium channel</u> in <u>principal cells</u> of <u>collecting duct</u> (apical side)
<b>Effects</b>: Less Na reabsorption, more Na secretion, water follows, diuresis. <u>Low potency</u> (because only 3% Na reabsorption in collecting duct)<b> Indications</b>: <u>Amiloride</u>: helps in <u>lithium toxicity</u> (Li enters via Na channel that amiloride blocks). All K-sparing diuretics: <u>useful in K wasting disorders.</u><b> Toxicity</b>: All K-sparing diuretics: <u>Hyperkalemia</u> (esp in pts with <u>renal failure)</u>, can be <u>fatal</u>, can have met <u>acidosis</u> too (K and H retention). |
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hydrochlorothiazide (HCTZ), chlorthalidone, indapamide, metolazone
(thiazide diuretics) |
<b>Mechanism of Action</b>: Thiazide diuretics. Inhibit <u>Na/Cl cotransporter</u> in <u>DCT</u> (apical side)
<b>Effects</b>: 5-10% of Na reabsorbed in DCT, so <u>block Na reabsorption</u>, more Na secretion, water follows, diuresis. <u>Low ceiling</u> (lower potency) because less Na reabsorption in DCT<b> Indications</b>: #1 diuretic for <u>HTN</u> (independent effects, synergistic with ACEi). Also: <u>nephrolithiasis</u> (decreases urine Ca / Ca excretion)<b> Administration</b>: <u>longer half life</u> than loops, <u>no rebound Na retention</u> so dose <u>once daily</u><b> Toxicity</b>: <u>Hypokalemic metabolic acidosis (contraction alkalosis</u>) - can be really bad! <u>more common than loops</u> (counterintuitive); give <u>K supplements</u> or <u>K sparing diuretic</u> <u>Hyperuricemia</u> (less uric acid clearance, can lead to <u>gout</u>) <u>Hyponatremia, hyperglycemia, hyperlipidemia</u> (except indapamide) <b> Other</b>: <i>Why hypokalemic metabolic acidosis? Multiple mechanisms (from K loss in blocking Na/K/2Cl transporter, increased distal Na delivery leads to increased Na absorption distally, increased K and H secretion, increased renin from low volume leads to more AT II, more aldo, more K/H loss)</i> |
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spironolactone
(K-sparing diuretic) |
<b>Mechanism of Action</b>: K-sparing diuretic, <u>aldosterone antagonist</u>. Inhibit <u>aldosterone's effect on 3Na/2K/ ATPase</u> in <u>principal cells</u> of <u>collecting duct</u> (basolateral side)
<b>Effects</b>: Inhibit <u>aldosterone-sensitive Na/K exchange</u>, more Na secretion, water follows, diuresis. <u>Low potency</u> (because only 3% Na reabsorption in collecting duct)<b> Indications</b>: <u>decreases mortality</u> in <u>CHF pts</u> (along with an ACEi and/or ARB). All K-sparing diuretics: <u>useful in K wasting disorders</u><b> Toxicity</b>: All K-sparing diuretics: <u>Hyperkalemia</u> (esp in pts with <u>renal failure)</u>, can be <u>fatal</u>, can have met <u>acidosis</u> too (K and H retention). <u>Spironolactone only</u>: <u>gynecomastia</u> & <u>impotence</u> |
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carbonic anhydrase inhibitors
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<b>Mechanism of Action</b>: Diuretics. Inhibit <u>carbonic anhydrase</u> in <u>proximal tubule</u> (important for bicarb reclamation)
<b>Effects</b>: H+ produced by CA intracellularly is exchanged for Na at apical membrane as part of bicarb reclamation pathway. <u>Less</u> <u>Na/H exchange</u> if less H+, so more Na secretion, water follows, diuresis. <u>Low potency</u> (because only blocking one way to get Na into PT, also distal nephron can compensate)<b> Indications</b>: <u>acute mountain sickness</u> (effects in brain), <u>open angle glaucoma, Meniere's disease</u>, patients with <u>met alkalosis</u> (if you can't give saline)<b> Toxicity</b>: <u>Hypokalemia, acidosis</u> (losing bicarb), <u>TERATOGENIC</u> |
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furosemide, bumetanide, torsemide, ethacrynic acid
(loop diuretics) |
<b>Mechanism of Action</b>: Loop diuretics. Inhibit<u> Na/K/2Cl transporter</u><b> </b>in <u>TALH</u><b> </b>(apical side)
<b>Effects</b>: 25% of Na reabsorbed in TALH, so <u>block Na reabsorption</u>, more Na secretion, water follows, diuresis. <u>High ceiling</u> (high potency) because high Na reabsorption in TALH<b> Indications</b>: #1 diuretic for <u>edematous states </u>(CHF, cirrhosis, nephrotic syndrome, renal failure). Also: <u>Hypercalemia</u> (increases Ca excretion), <u>acute pulmonary edema</u> (post-IV administration, venous capacitance increases)<b> Administration</b>: <u>short half-life </u>with <u>steep response curve</u>; rebound Na retention drops efficacy, so <u>twice daily</u><b> Toxicity</b>: <u>Hypokalemic metabolic acidosis (contraction alkalosis</u>) - can be really bad! <u>Hyperuricemia</u> (less uric acid clearance, can lead to <u>gout</u>) <u>Ototoxicity</u> (especially <u>ethacrynic acid</u> and <u>aminoglycoside</u>) <b> Other</b>: Furosemide = Lasix. <i>Why hypokalemic metabolic acidosis? Multiple mechanisms (from K loss in blocking Na/K/2Cl transporter, increased distal Na delivery leads to increased Na absorption distally, increased K and H secretion, increased renin from low volume leads to more AT II, more aldo, more K/H loss)</i> |
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theophylline
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<b>Mechanism of Action</b>: <u>methylxanthine</u> anti-asthma agent. Tons of possible mechanisms of action (see other section)
<b>Effects</b>: <u>relaxes smooth muscle</u>. CNS: <u>decreases drowsiness</u>, clearer flow of thought, less fatigue. Stimulates medullary respiratory center. CVS: <u>increases cardiac contractility</u>, may increase catecholamine sensitivity. Skeletal muscle: <u>reduces fatigue</u>. <u>Diuretic</u> effects. Increases secretion of <u>gastric acid</u> & <u>pepsin</u>. Increases <u>BMR</u> and <u>free plasma fatty acids</u>.<b> Administration</b>: with basic compound to enhance solubility. <u>aminophylline</u> = 80% theophylline, 20% ethylene diamine<b> Toxicity</b>: Similar to positive actions; <b><u>related to dose</u></b> (more toxic episodes with increased [serum]). <u>CNS</u>: <u>nausea, anxiety, tremor, insomnia, seizures.</u> CVS: <u>ventricular instability</u> increases, <u>reduces PVR</u> & <u>venodilates</u> in patients with CHF. <b> Other</b>: methylxanthine potency: theophylline > caffeine > theobromine. Possible mechanisms of action: <u>inhibit PDE</u> so more cAMP and cGMP, more smooth muscle relaxation. <u>Adenosine antagonists</u> so bind to <u>A2 receptors </u>(stimulate membrane bound adenyl cyclase). Short-term: may <u>increase catecholamine levels</u> & enhance effect on adrenergic receptors) |
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albuterol
metaproterenol terbutaline levalbuterol isoetharine |
<b>Mechanism of Action</b>: <u>Short-acting beta-2 agonists </u>(anti-asthma)
<b>Effects</b>: Relaxes smooth muscle (<u>bronchodilation</u>) by stimulating <u>adenyl cyclase</u>, increasing <u>cAMP</u>. Other distant effects too (see other) <b>Selective Toxicity</b>: Selective for beta-2 over beta-1<b> Indications</b>: Quick-acting symptom relief for asthma<b> Administration</b>: Metered-dose inhaler (better targeted delivery; less systemic exposure; requires more compliance) or nebulizer (increased risk systemic effects, more expensive)<b> Toxicity</b>: due to <u>excessive stimulation of beta receptors</u>. CVS (<u>tachycardia</u>, <u>palpitations</u>, <u>exacerbastes CAD</u>, <u>arrhythmias</u>). CNS (<u>anxiety, apprehension, tremor, anxiety</u>). Metabolic (<b><u>hypoK</u>, <u>hyper</u></b><u>glycemia</u>). <b>Resistance</b>: <u>Tolerance</u> has ben documented at high doses with chronic treatment. <b>Special Members of Class</b>: <b><u>Levalbuterol</u></b>: R-isomer of albuterol; 100x more affinity than S-isomer, more expensive but probably equally effective; occasionally use in kids<b> Other</b>: Secondary effects (importance less than bronchodilation in asthma): suppresses histamine / leukotrine release from pulmonary inflammatory cells, enhances mucociliary clearance, decreases microvascular permeability. |
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formoterol
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<b>Mechanism of Action</b>: <b><u>Long-acting</u></b><u> beta-2 agonist </u>(anti-asthma)
<b>Effects</b>: Relaxes smooth muscle (<u>bronchodilation</u>) by stimulating <u>adenyl cyclase</u>, increasing <u>cAMP</u>. Other distant effects too (see other). <b>Long-acting</b> (has long-lipophilic side chain). Also <b><u>inhibits inflammatory mediator release</u> </b>from lung. <b>Selective Toxicity</b>: Selective for beta-2 over beta-1<b> Indications</b>: <u>Maintenance treatment</u><b> </b>and <u>prevention of exercise-induced asthma</u><b> Administration</b>: <b><u>Dry powder aerolizer</u></b>. <b><u>q12h</u></b> (10h plasma halflife). <u>Faster onset</u> than salmeterol (1-3 min vs 10-20 min)<b> Toxicity</b>: <b><u>Black box warning</u></b>: make sure to counsel on how to use (not for rescue!). due to <u>excessive stimulation of beta receptors</u>. CVS (<u>tachycardia</u>, <u>palpitations</u>, <u>exacerbastes CAD</u>, <u>arrhythmias</u>). CNS (<u>anxiety, apprehension, tremor, anxiety</u>). Metabolic (<b><u>hypoK</u>, <u>hyper</u></b><u>glycemia</u>). <b>Metabolism</b>:<b> multiple <u>CYP </u>enzymes Resistance</b>: <u>Tolerance</u> has ben documented at high doses with chronic treatment. <b> Other</b>: Secondary effects (importance less than bronchodilation in asthma): suppresses histamine / leukotrine release from pulmonary inflammatory cells, enhances mucociliary clearance, decreases microvascular permeability. |
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inhaled glucocorticosteroids
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<b>Mechanism of Action</b>: <u>anti-inflammatory agents</u>. Suppress release of <u>leukotrine & prostaglandin</u> mediators from inflammatory cells (inhibit <u>phospholipase A2, ? phospholipase C</u>).<b>
Indications</b>: in asthma, <u>prophylaxis only</u> (NOT rescue). <u>MAINSTAY</u> of controller treatment.<b> Administration</b>: inhaled <b> Toxicity</b>: <u>Candida</u> infections (mouth/throat). <u>dysphonia</u> (laryngeal myopathy) - less with slow inhalation, using a spacer, gargling. <u>systemic</u> side effects possible with large doses (<u>inhibit hypothal-pituitary-adrenal axis</u>). <u>bruising </u>& <u>purpura</u> at high doses. May <u>inhibit growth in children</u> (but outweighed by benefits) |
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ipratropium bromide
tiotropium |
<b>Mechanism of Action</b>: <u>anticholinergic agent</u> (for asthma)
<b>Effects</b>: block <u>muscarinic receptors</u> in airway <u>smooth muscle</u> (inhibit resting cholinergic bronchoconstror tone by <u>reducing cGMP levels</u>). Also <u>block vagus reflex bronchoconstriction</u> (block sensory afferent input) - augments <u>parasympathetics</u> so more bronchodilation.<b> Indications</b>: <u>short-acting asthma rescue</u><b> Administration</b>: more robust response when <u>combined</u> with <u>albuterol</u><b> Other</b>:<b> </b><u>tiotropium</u>'s use in asthma is <u>off-label</u> |
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montelukast
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<b>Mechanism of Action</b>: <u>leukotriene antagonist</u> anti-asthma agent.
<b>Effects</b>: Inhibits <u>cysteinyl-LT</u> (enzyme involved in downstream conversion of leukotrines to effectors). <b> Indications</b>: Prophy/maintenance of asthma sx. Increases FEV1% and reduces asthma symptoms. At least as effective as zafirlukast. <b> Metabolism</b>: Rapid GI absorption; plasma [] peak in 3-4 hrs; half-life 2.75-5.5 hrs. Metabolized by <u>CYP</u><b><u>3A4</u></b> and <b><u>2C9</u></b>. <b>Toxicity</b>: fewer drug interactions than zafirlukast; doesn't inhibit P450 enzymes. Less hepatic toxicity / Churg-strauss vasculitis than zafirlukast |
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omalizumab (Xolair)
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<b>Mechanism of Action</b>: <u>anti-IgE mAB</u>(anti-asthma)
<b>Effects</b>: <u>binds free IgE </u>(released from mast cells & basophils in pts with allergic component to asthma); <u>down-regulation</u> of IgE receptors results (<u>long-lasting effect: 100-fold reduction</u> in IgE)<b> Indications</b>: > 12 years old with <u>moderate/severe persistent asthma</u> & reactivity to <u>allergen</u> with <u>symptoms inadequtely controlled </u>by inhaled corticosteroid (e.g. tons of hosp visits or severe symptoms).<b> Administration</b>: IV or SQ q 4 wks<b> Other</b>: <u>EXPENSIVE</u> (annual cost $6-12k) - cost-effective if preventing many hospital visits in allergic patients. |
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zafirlukast
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<b>Mechanism of Action</b>: <u>leukotriene antagonist</u> anti-asthma agent.
<b>Effects</b>: Inhibits <u>cysteinyl-LT</u> (enzyme involved in downstream conversion of leukotrines to effectors). <b> Indications</b>: Prophy/maintenance of asthma sx. Increases FEV1% and reduces asthma symptoms <b>Toxicity</b>: <u>inhibits CYP450 enzymes </u>(drug interactions with theophylline, warfarin, prednisone); <u>Churg-Strauss vasculitis</u> & <u>hepatic toxicity</u> too.<b> </b> |
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Zileuton
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<b>Mechanism of Action</b>: <u>leukotrine antagonist</u> antiasthma agent. Inhibits <u>5-lipoxygenas</u>
<b>Effects</b>: 5-lipoxygenase mediates conversion of <u>arachidonate</u> to <u>LTA4</u> in the leukotrine metabolite pathway. <b> Indications</b>: Not first line; may use as alternative to corticosteroids if contraindicated.<b> Administration</b>: 600 mg QID <b>Metabolism:</b> rapidly absorbed, Tmax = 2hrs, T1/2 = 2.5 hrs. <u>Hepatic glucuronidation</u>. |
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ketamine
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<b>Mechanism of Action</b>: <u>NMDA receptor blocker</u>
<b>Effects</b>:Blocks <u>excitatory glutamate </u>signaling (NMDA) “Group 2” (targets NMDA/AMPA/kainate glutamate receptors, K<sup>+</sup> channels). Produces <b><u>dissociative anesthesia</u></b> (eyes open but unresponsive) with <u>profound </u><b><u>cutaneous analgesia</u></b> <b>Indications & Administration</b>: <u>Rapid sequence induction</u> (emergency surgery, esp. <u>unstable pts</u>). <u>Burn dressing changes</u> (cutaneous analgesia). <u>Bronchodilator</u> (used for <b><u>severe asthma</u></b> in ICU). <b> Other effects: </b><u>Stimulates HR</u>, keeps <u>BP & resps</u> <u>stable</u>, stimulates <u>SNS</u> <b>Toxicity</b>: <u>Decreased seizure threshold</u> (contraindicated in <i>epilepsy</i>), <u>increased ICP</u> (contraindicated in <i>head trauma</i>), increased <u>oral secretions</u><b> </b> |
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sevoflurane
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<b>Mechanism of Action</b>: <u>Potent, volatile inhaled anesthetic</u>. Ether.
<b>Effects</b>: “Group 3”: <u>multiple</u> molecular <u>effects</u> (increases inhibitory ion channel flow, depresses excitatory ion channel flow)<b> Special Features</b>: <u>Rapid</u> onset / recovery<b> Toxicity</b>: <u>Emergence delerium</u> <b> Other</b>: Hypnosis, amnesia, slowing of cortical EEG (GABA effects). Blood/Gas solubility coefficient: 0.69 |
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nitrous oxide (N2O)
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<b>Mechanism of Action</b>: <u>Potent, volatile inhaled anesthetic</u>. Gas.
<b>Effects</b>: “Group 2”: targets <u>glutamate receptors</u>(NMDA, AMPA, kainate) and <u>two pore K+ channels</u><b> Toxicity</b>: Need to give with <u>O2</u> and <u>other anesthetics</u> (high MAC; would need to give lethal dose to achieve total anesthesia)<b> Other</b>: <u>Analgesia </u>(NMDA effect). Blood/Gas solubility coefficient: 0.47 |
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halothane
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<b>Mechanism of Action</b>: <u>Potent, volatile inhaled anesthetic</u>. Alkane.
<b>Effects</b>: “Group 3”: <u>multiple</u> molecular <u>effects</u> (increases inhibitory ion channel flow, depresses excitatory ion channel flow)<b> Special Features</b>: <u>Slow</u> onset / recovery, <u>metabolized</u> (40% elimination - unique among inhaled anesthetics). <b> Toxicity</b>: <u>Myocardial depressant</u><b> Other</b>: Hypnosis, amnesia, slowing of cortical EEG (GABA effects). Standard to measure solubility, Blood/Gas solubility coefficient: 2.3 |
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isoflurane
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<b>Mechanism of Action</b>: <u>Potent, volatile inhaled anesthetic</u>. Ether.
<b>Effects</b>: “Group 3”: <u>multiple</u> molecular <u>effects</u> (increases inhibitory ion channel flow, depresses excitatory ion channel flow)<b> Special Features</b>: <u>Medium</u> onset / recovery, slightly pungent odor<b> Toxicity</b>: <u>Airway irritant</u> (coughing)<b> Other</b>: Hypnosis, amnesia, slowing of cortical EEG (GABA effects). Blood/Gas solubility coefficient: 1.4 |
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desflurane
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<b>Mechanism of Action</b>: <u>Potent, volatile inhaled anesthetic</u>. Ether.
<b>Effects</b>: “Group 3”: <u>multiple</u> molecular <u>effects</u> (increases inhibitory ion channel flow, depresses excitatory ion channel flow)<b> Special Features</b>: <u>Rapid</u> onset / recovery<b> Toxicity</b>: <u>Laryngospasm</u> (<u>severe airway irritant</u>). Need to use another <u>inducing agent first</u> (to suppress laryngospasm)<b> Other</b>: Hypnosis, amnesia, slowing of cortical EEG (GABA effects). Blood/Gas solubility coefficient: 0.42 |
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phenobarbital, primidone
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<b>Mechanism of Action</b>: <u>barbituate</u> anticonvulsants
<b>Effects</b>: Enhance <u>GABA / benzodiazepine</u> receptor function, increasing <u>chloride</u> influx and causing <u>hyperpolarization / inhibition</u> of synaptic transmission<b> Indications</b>:<u>powerful</u>, use for <u>common </u>seizure types (generalized / focal motor seizures, partial seizures with behavioral manifestations)<b> Metabolism</b>: in <u>liver</u>, <u>long half lives</u>, 1st order kinetics over broad range. Primidone converted to phenobarbital & PEMA (both anticonvulsants) via in vivo metabolism.<b> Toxicity</b>: <u>Cognitive </u>and <u>behavioral</u> side effects, <u>depression</u>. <u>Teratogen</u> |
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valproic acid
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<b>Mechanism of Action</b>: Anticonvulsant, blocks <u>rapidly opening Na channels</u>, <u>enhances GABA / BZ receptors</u>, may have other mechanisms?
<b>Effects</b>: bind <u>open channels </u>selectively, limiting sustained repetitive transmission; other mechanisms too<b> Indications</b>: useful for <u>all seizure types</u><b> Metabolism</b>: <u>Hepatic</u> metabolism (as fatty acid)<b> Toxicity</b>: <u>Fatal hepatic necrosis</u> in children < 2 yo, especially if on <u>second anticonvulsant</u> (incidence 2/1000). <u>Slows</u> metabolism of <u>phenobarbital, lamotrigine</u>. <u>Teratogen</u> (strongly associated with <u>spina bifida</u>, can reduce risk with <u>folic acid</u>) |
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lamotrigine
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<b>Mechanism of Action</b>: Anticonvulsant, blocks <u>Na channels associated with pre-synaptic glutamate release</u>
<b>Effects</b>: limits sustained repetitive transmission<b> Indications</b>:use for <u>common </u>seizure types (generalized / focal motor seizures, partial seizures with behavioral manifestations). also used for <u>less common </u>seizure types (e.g. <u>generalized absence</u>)<b> Metabolism</b>: <u>Hepatic</u> metabolism via <u>glucuronidation</u>; half life <u>prolonged</u> by other drugs (e.g. <u>valproic acid</u>). <u>Teratogen</u><b> Toxicity</b>: <u>Severe skin rashes</u> in 1% children, 0.3% adults |
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carbamazepine
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<b>Mechanism of Action</b>: Anticonvulsant, blocks <u>rapidly opening Na channels</u>
<b>Effects</b>: bind <u>open channels </u>selectively, limiting sustained repetitive transmission<b> Indications</b>:use for <u>common </u>seizure types (generalized / focal motor seizures, partial seizures with behavioral manifestations). One of <u>most prescribed</u> anticonvulsants<b> Metabolism</b>: <u>Hepatic</u> metabolism to <u>epoxide metabolite</u> - <u>induces own metabolism</u>; short half-life with sustained release preparation available<b> Toxicity</b>: <u>Few cognitive side effects</u>. <u>Don't use in absence seizures</u> (can make them WORSE!). <u>Teratogen</u> |
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ethosuxamide
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<b>Mechanism of Action</b>: <u>anticonvulsant</u>, blocks <u>voltage-dependent Ca channels</u>
<b>Effects</b>: Decreases excitatory signaling (blocks Ca <u>reuptake </u>into <u>presynaptic neuron </u>and Ca <u>influx </u>into <u>post-synaptic neuron</u>)<b> Indications</b>:<u>Generalized absence seizures</u><b> Toxicity</b>: <u>Teratogen</u> |
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levetiracetam
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<b>Mechanism of Action</b>: <u>Anticonvulsant</u>, binds <u>SV2A vesicle protein</u> on synaptic vesicles
<b>Effects</b>: <u>inhibits Ca-mediated glutamate exocytosis</u> from pre-synaptic neuron<b> Toxicity</b>: teratogen |
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recombinant calcitonin
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<b>Mechanism of Action</b>: <u>recombinant calcitonin</u>. Natural peptide (thyroid C cells), but physiologic function unknown. At <u>pharm doses</u>: <u>inhibits bone resorption</u> by binding to <u>osteoclast GPCR</u>
<b>Effects</b>: <u>decreases bone absorption</u> (slower effect) and <u>increases calcium excretion</u> from <u>kidney</u> (both <u>lower calcium</u>)<b> Indications</b>: For <u>initial treatment of hypercalcemia</u> (rapid <u>calcium-lowering effect</u>; increased urinary excretion of Ca reduces <u>serum Ca</u> ~ 2mg/dL). Often give <u>calcitonin</u> while waiting for <u>bisphosphonate</u>to kick in!. Widely used for treatment of post-menopausal osteoporosis, but <u>efficacy in question</u> (no dose-response effect). <u>Weak anti-resorptive agent</u>, possible <u>analgesic effect</u> (bone and fracture pain). <b> Administration</b>: <u>nasal or subcutaneous</u>, nasal gives <u>less flushing</u>, is primary way it's used today. <b> Toxicity</b>: For <u>nasal calcitonin</u>: local effects (<u>nasal congestion, irritation, sores</u>. <u>Epistaxis</u>. <u>Headache</u>. <u>Sore throat)</u>. For osteoporosis, is <u>best tolerated</u> but <u>least potent</u>. <b> Other</b>: <u>Salmon calcitonin used</u> (more potent!) |
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etidronate
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<b>Mechanism of Action</b>: <u>non-nitrogen-containing bisophosphonate anti-resorptive agent</u>. Eaten by <u>osteoclasts</u>, then incorporated into <u>ATP</u>, produces <u>cytotoxic analog</u> & subsequent <u>cell death</u>
<b>Selective Toxicity</b>: Binds <u>hydroxyapatite</u> (targeted to osteoclasts, which eat it up!)<b> Indications</b>: older, not used much anymore<b> Toxicity</b>: Causes <u>osteomalacia!</u> |
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ibandronate
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<b><u>ibandronate-specific
</u>Administration: can be given as a <u>quarterly IV</u> or <u>monthly oral</u> formulation</b> <b><u>Acute-phase reaction</u></b>: fever, aches/pains <u>In </u><b><u>osteoporosis</u></b>: works on <b><u>spine</u> </b>fractures, others not so much (used a little less often) <b><u>Bisphos in general:</u></b> <b>Mechanism of Action</b>: <u>nitrogen-containing bisophosphonate anti-resorptive agents</u>. Inhibit <u>farnesyl-PP synthase</u>, in osteoclast <u>mevalonate pathway</u>, so <u>osteoclasts can't prenylate proteins</u> <b>Effects:</b> <u>prenylation </u>needed for <u>membrane ruffling, vesicular trafficking, actin ring formation, osteoclast survival</u>. Inhibition leads to <u>loss of osteoclast function</u> and <u>apoptosis!</u><b> Selective Toxicity</b>: Binds <u>hydroxyapatite</u> (targeted to osteoclasts, which eat it up!)<b> Administration: <u>alendronate</u> can be given <u>once a year IV</u> for osteoporosis Indications</b>: <u>osteoporosis, Paget's disease </u><b>Metabolism: </b>biggest problem is that they're <u>really hard to absorb</u>: for <u>oral administration</u> have to give <u>1st thing in morning</u> with <u>lots of water</u> and <u>wait 30 min to eat</u> (60m with ibandorate). <u>Remain upright until after breakfast!</u> Fast / complete uptake into bone; slow release. Excretion mainly <u>renal - no metabolites</u>. New agents: <u>q7d or q1mo</u> <b> Toxicity</b>: <u>upper GI disturbances</u> with oral formulations. <u>flu-like symptoms</u> (fever / myaligia) with <u>1st IV dose</u>. <u>Musculoskeletal pain</u> (can be diffuse; rarely systemic or severe. Can happen at <u>any point in treatment!</u>). <u>Osteonecrosis of jaw</u> (very rare; 1/50k) <b>Contraindications</b>: <u>Hypocalcemia</u> (esp. if pt depending on bone supply for Ca - vit D deficiency, hypoparathyroidism, etc - bisphosphonates would block!). <u>swallowing disorders</u> (pill just sits there) or <u>inability to remain upright</u> after <u>oral dosing</u> (to protect esophagus - don't go back to bed!). <u>Significant renal insufficiency</u> (CrCl < 30 mL/min) |
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risedronate
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<b><u>risedronate-specific:
</u>Administration: </b>available in <b>daily / weekly / monthly oral formulations</b> Has <b><u>upper GI side effects</u></b> <u>In </u><b><u>osteoporosis</u></b>: works on <b><u>spine, non-spine, and hip</u></b> fractures. <b><u>Bisphos in general:</u> Mechanism of Action</b>: <u>nitrogen-containing bisophosphonate anti-resorptive agents</u>. Inhibit <u>farnesyl-PP synthase</u>, in osteoclast <u>mevalonate pathway</u>, so <u>osteoclasts can't prenylate proteins</u> <b>Effects:</b> <u>prenylation </u>needed for <u>membrane ruffling, vesicular trafficking, actin ring formation, osteoclast survival</u>. Inhibition leads to <u>loss of osteoclast function</u> and <u>apoptosis!</u><b> Selective Toxicity</b>: Binds <u>hydroxyapatite</u> (targeted to osteoclasts, which eat it up!)<b> Indications</b>: <u>osteoporosis, Paget's disease </u><b>Metabolism: </b>biggest problem is that they're <u>really hard to absorb</u>: for <u>oral administration</u> have to give <u>1st thing in morning</u> with <u>lots of water</u> and <u>wait 30 min to eat</u> (60m with ibandorate). <u>Remain upright until after breakfast!</u> Fast / complete uptake into bone; slow release. Excretion mainly <u>renal - no metabolites</u>. New agents: <u>q7d or q1mo</u> <b> Toxicity</b>: <u>upper GI disturbances</u> with oral formulations. <u>flu-like symptoms</u> (fever / myaligia) with <u>1st IV dose</u>. <u>Musculoskeletal pain</u> (can be diffuse; rarely systemic or severe. Can happen at <u>any point in treatment!</u>). <u>Osteonecrosis of jaw</u> (very rare; 1/50k) <b>Contraindications</b>: <u>Hypocalcemia</u> (esp. if pt depending on bone supply for Ca - vit D deficiency, hypoparathyroidism, etc - bisphosphonates would block!). <u>swallowing disorders</u> (pill just sits there) or <u>inability to remain upright</u> after <u>oral dosing</u> (to protect esophagus - don't go back to bed!). <u>Significant renal insufficiency</u> (CrCl < 30 mL/min) |
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aledronate
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<b><u>alendronate-specific:
</u>Administration: <u>alendronate</u> can be given <u>once a year IV</u> for osteoporosis.</b> available in <b>daily / weekly oral formulations </b>too. Has <b><u>upper GI side effects</u></b> <u>In </u><b><u>osteoporosis</u></b>: works on <b><u>spine, non-spine, and hip</u></b> fractures. <b><u>Bisphos in general:</u> Mechanism of Action</b>: <u>nitrogen-containing bisophosphonate anti-resorptive agents</u>. Inhibit <u>farnesyl-PP synthase</u>, in osteoclast <u>mevalonate pathway</u>, so <u>osteoclasts can't prenylate proteins</u> <b>Effects:</b> <u>prenylation </u>needed for <u>membrane ruffling, vesicular trafficking, actin ring formation, osteoclast survival</u>. Inhibition leads to <u>loss of osteoclast function</u> and <u>apoptosis!</u><b> Selective Toxicity</b>: Binds <u>hydroxyapatite</u> (targeted to osteoclasts, which eat it up!)<b> Indications</b>: <u>osteoporosis, Paget's disease </u><b>Metabolism: </b>biggest problem is that they're <u>really hard to absorb</u>: for <u>oral administration</u> have to give <u>1st thing in morning</u> with <u>lots of water</u> and <u>wait 30 min to eat</u> (60m with ibandorate). <u>Remain upright until after breakfast!</u> Fast / complete uptake into bone; slow release. Excretion mainly <u>renal - no metabolites</u>. New agents: <u>q7d or q1mo</u> <b> Toxicity</b>: <u>upper GI disturbances</u> with oral formulations. <u>flu-like symptoms</u> (fever / myaligia) with <u>1st IV dose</u>. <u>Musculoskeletal pain</u> (can be diffuse; rarely systemic or severe. Can happen at <u>any point in treatment!</u>). <u>Osteonecrosis of jaw</u> (very rare; 1/50k) <b>Contraindications</b>: <u>Hypocalcemia</u> (esp. if pt depending on bone supply for Ca - vit D deficiency, hypoparathyroidism, etc - bisphosphonates would block!). <u>swallowing disorders</u> (pill just sits there) or <u>inability to remain upright</u> after <u>oral dosing</u> (to protect esophagus - don't go back to bed!). <u>Significant renal insufficiency</u> (CrCl < 30 mL/min) |
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raloxifene
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<b>Mechanism of Action</b>: <u>selective estrogen receptor modifier</u>, approved for use as an <u>antiresorptive agent</u> (bone effects). <u>Estrogen agonist</u> in <u>bone</u>, but <u>antagonist</u> in <u>uterus / breast</u> (good for cancer)
<b>Effects</b>: In bone: <u>INCREASES OPG PRODUCTION</u> (OPG binds to RANK-ligand on osteoblasts / stromal cells as a decoy receptor, covering it up so that the pre-osteoclasts' RANK receptor can't bind and trigger differentiation into active osteoclasts). Therefore <u>decreases bone resorption</u>.<b> Administration</b>: <u>daily oral dosing</u>, no time restrictions.<b> Toxicity</b>: <u>thromboembolic events</u>(1/2000 pt-yrs - an <u>estrogen agonist</u> effect!) <u>Hot flashes & leg cramps</u>(exacerbation in early post-menopausal women). <u>CONTRAINDICATED</u> IN <u>THROMBOEMBOLIC DISEASE</u> (PMH or even strong FHx). Careful in <u>liver disease</u>, no dosage change with age or renal insufficiency. |
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tamoxifen
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SERM; used for breast cancer but not bone loss (although is an estrogen agonist in bone and has bone effects).
estrogen antagonist in breast, but agonist in bone / uterus. |
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cholecalciferol
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Vitamin <u>D3</u>, oral preparation. Human / animal D3.
4-8 wks until peak activity; lasts 4-16 wks |
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calcidiol
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<u>25-OH-vitamin-D</u>
2-4wks until peak activity, 4-12 wks duration <b><u>really only use in severe liver failure</u></b> (can't do the 25-hydroxylation) |
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ergocalciferol
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Vitamin <u>D2</u>, oral preparation. <u>Plant</u> vitamin D
4-8 wks until peak activity; lasts 4-16 wks <b><u>only version available in prescription form</u></b> |
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calcitriol
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<u>1,25-OH2-vitamin-D</u>
1-3d peak activity, lasts 1-3 days. <b><u>Use for renal insufficiency</u></b> (can't do the 1-alpha hydroxylation)<b><u>; also the only IV version available</u></b> |
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insulin detemer (Levemir)
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<b><u>Long-acting</u></b> insulin analog, <b><u>complexed </u></b>to <b><u>fatty acid</u></b>, which binds to <b><u>albumin</u> </b>in <b><u>subcutaneous tissue</u></b>
Absorption <b>slowed </b>until <b><u>gradually released from albumin</u></b> Often called “<b>relatively flat peak</b>“ ; duration somewhat more predictable than glargine Has a <b>smoother action</b> over <b>24h </b>than <b>NPH</b> - use to mimic basal insulin secretion Onset 2h, peak ?, duration <b>16-20h</b> |
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regular insulin (Novolin-R; Humulin R)
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<b><u>Short-acting</u> human insulin - </b>unmodified human insulin
Take about <b>30-45m</b> before <b>meal</b> - need to <b>anticipate</b> Can mix with other insulins Used to be fastest befoer ultra-fast analogs came along Onset 30-45m, peak 2-4h, duration 3-6h |
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insulin glargine (Lantus)
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<b><u>Long-acting</u></b> insulin analog, AA sequence modified to give <b><u>acid pK</u></b>
Stored as liquid at <b>acid pH</b> but <b>precipitates</b> on injection <b>(tissue physiologic pH</b>), slowing absorption; requires <b>gradual dilution</b> to dissolve Often called “<b>peakless</b>“ but actually has an unpredictable peak over 24h Has a <b>smoother action</b> over <b>24h </b>than <b>NPH</b> - use to mimic basal insulin secretion Onset 24-h, peak 24h, duration <b>20-24h</b> |
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insulin lispro (humalog), insulin aspart (Novolog), glulisine insulin (Apidra)
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<b><u>Ultra-fast-acting</u> insulin analogs</b>: more rapid acting than unmodified, “regular” human insulin
Have <b>less</b> tendency to <b>hexamerize</b> / <b>dimerize</b> = more in <b>monomer</b> form, absorbed <b>more</b> <b>quickly </b>(modified AA sequence) Take <b>immediately before meal</b>; can mix with other insulins Onset ~ 15m, peak 1-2h, duration 3-4h |
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NPH (humulin-N, Novolin-N)
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<b><u>Intermediate-acting</u> human insulin. </b>Regular human insulin <b><u>crystallized with protamine</u></b> in cloudy, insuluble suspension.
<b>Crystallization </b>slows <b>solubilization</b>; then slowly broken down to <b>monomers</b> in <b>skin</b> Can mix with <b>short-acting</b>, give <b>q12h</b> to provide basal insulin levels Onset 2-4h, peak 4-10h, duration <b>10-16h</b> <b>“Netural protamine Hagedorn”</b> |
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glipizide
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<b>Mechanism of Action</b>: <u>sulfonylurea</u> <u>oral antidiabetic agent</u>. <u>Stimulates insulin secretion
</u><b>Specific for glipizide: <u>Newer agent (long, less polar side chains) so MORE POTENT</u></b>. <b><u>Metabolism:</u> </b> <b>virtually <u>entirely</u> metabolized to <u>inactive products</u> in the <u>liver</u></b> - so it's the <b><u>SHORTEST-ACTING SULFONYLUREA</u></b> (6-12H). Does have a <u>long-acting form</u>, though (given qd) <b><u>Toxicity</u></b>: <b><u>AVOID IN LIVER DISEASE</u> </b><i>glipizide = Glucotrol</i> <i><b>Below info for all sulfonylureas</b></i> <b>Effects</b>: Activates <u>sulfonylurea receptor</u>, in pancreatic beta cells, which <u>inactivates ATP/ADP-dependent potassium channel</u>, leading to <u>membrane depolarization</u> & <u>Ca-mediated exocytosis of insulin.</u><b> </b> <b> Indications</b>: <u>type 2 diabetes</u> (as first or second choice - metformin usually first - either alone or in combo with other therapy)<b> Toxicity</b>: <u>hypoglycemia</u> (overdose causes excess insulin secretion). Unusual: <u>hepatotoxicity</u> (tranaminasemia) and <u>allergic responses</u> (can cross react with other sulfa allergies). <u>modest weight gain</u>. <u>Black box warning:</u> <u>death</u> by <u>CVD</u> (but not yet confirmed) <b> <u>The bottom line</u></b>: <b>Good option for type 2 DM treatment. Can be 1st or 2nd choice </b>(metformin usually first) <b>oral hypoglycemic agent, alone or in combo with other oral agents, or combined with insulin therapy</b> |
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acarbose, miglatol
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<b>Mechanism of Action</b>: <u>alpha-glucosidase inhibitors</u>; oral antidiabetic agents. <u>inhibit pancreatic alpha-amylase</u> & <u>membrane-bound intestinal alpha-glucosidase hydrolase enzymes</u>.
<b>Effects</b>: <u>Delay digestion</u> of <u>ingested CHO</u>, slowing rise in blood glucose. Only <u>modestly effective</u>. <b>Selective Toxicity</b>: Act <u>entirely</u> on <u>intestinal brush border</u><b> Indications</b>: Use mainly for <u>post-prandial glycemia</u> (although limited by GI side effects)<b> Toxicity</b>: Major side effect is <u>flatulence & diarrhea</u> (changing GI flora) <b>Metabolism</b>: <2% of oral dose absorbed, excreted <u>unchanged in the feces</u><b> <u>The bottom line</u></b>: <b>limited by their <u>GI side effects</u></b>, but <b>may have some use in <u>post-prandial glycemic control</u></b>. |
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repaglinide, nateglinide
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<b>Mechanism of Action</b>: <u>short-acting non-sulfonylurea insulin secretagogues</u>
<b>Effects</b>: Structurally <u>distinct </u>from <u>sulfonylureas </u>& <u>don't act </u>at <u>SUR</u>, but <u>same insulin secretory effect</u><b> Indications</b>: <u>not major players</u> in managing diabetes - occasionally if <u>post-meal glucose</u> is <u>shooting up</u><b> Administration</b>: used <u>pre-meal</u> <b>Metabolism</b>: <u>rapidly metabolized</u> to inactive metabolites by the <u>liver</u> |
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pramlintide
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<b>Mechanism of Action</b>: <u>amylin analog</u> antidiabetic agent.
<b>Effects</b>: Sort of like an <u>incretin mimetic</u>, but not technically (analog of pancreatic, not intestinal hormone)<b> Indications</b>: type I or type II DM |
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metformin
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<b>Mechanism of Action</b>: A <u>biguinide oral antidiabetic </u>agent. <u>decreases hepatic glucose output</u>; sensitizing liver to insulin. Does <i><u>not</u></i> increase insulin secretion.
<b>Effects</b>: In DM, uncontrolled HGO; metformin helps suppress (best in controlling <u>fasting blood glucose</u>, which is most dependent on HGO). Does <u>NOT</u> cause <u>hypoglycemia</u> (doesn't stimulate insulin secretion). Can cause <u>mild weight loss</u> too. <b> Indications</b>: <u>type II diabetes</u> (a good 1st line drug)<b> Administration</b>: give <u>2-3x daily</u> (3h half life); does have <u>XL form</u> (doubles half life, but still usually dose bid)<b> Toxicity</b>: <u>GI side effects</u> are <u>common</u> (15%: GI intolerance - <u>diarrhea, bloating</u>, somewhat dose-related). <u>Lactic acidosis</u> less frequent but more complicated (inhibits <u>mitochondrial ox-phos</u>; can rarely lead to accumulatino of lactate. Life threatening acidosis <i>if</i> lactate over-produced / under-cleared due to <u>co-morbidities</u>). So <u>contraindicated in</u> settings of <u>increased lactate production</u> (<u>CHF</u>, <u>surgery</u> with <u>hypotension</u>, active <u>ischemia</u>, binge <u>alcohol</u> drinking) or <u>decreased lactate clearance</u> (e.g. <u>renal insufficiency</u>). <b>Metabolism</b>: excreted unchanged in the urine<b> The Bottom Line: A good option for type II DM; usually <u>1st choice oral agent </u>unless contraindicated / not tolerated.</b> |
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glyburide, glimepride
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<b>Mechanism of Action</b>: <u>sulfonylurea</u> <u>oral antidiabetic agent</u>. <u>Stimulates insulin secretion
</u><b>Specific for these two: <u>Newer agent (long, less polar side chains) so MORE POTENT</u></b>. <b><u>Metabolism:</u> </b> like most sulfonylureas, <b>mostly metabolized in <u>liver</u>, excred in <u>kidneys</u> (duration of action ~ <u>12 h</u>) </b><i>glyburide = Micronase, Diabeta; glimepride = Amaryl</i> <i><b>Below info for all sulfonylureas</b></i> <b>Effects</b>: Activates <u>sulfonylurea receptor</u>, in pancreatic beta cells, which <u>inactivates ATP/ADP-dependent potassium channel</u>, leading to <u>membrane depolarization</u> & <u>Ca-mediated exocytosis of insulin.</u><b> </b> <b> Indications</b>: <u>type 2 diabetes</u> (as first or second choice - metformin usually first - either alone or in combo with other therapy)<b> Toxicity</b>: <u>hypoglycemia</u> (overdose causes excess insulin secretion). Unusual: <u>hepatotoxicity</u> (tranaminasemia) and <u>allergic responses</u> (can cross react with other sulfa allergies). <u>modest weight gain</u>. <u>Black box warning:</u> <u>death</u> by <u>CVD</u> (but not yet confirmed) <b> <u>The bottom line</u></b><u>: </u><b>Good option for type 2 DM treatment. Can be 1st or 2nd choice </b>(metformin usually first) <b>oral hypoglycemic agent, alone or in combo with other oral agents, or combined with insulin therapy</b> |
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tolazamide, acetohexamide, tolbutamide
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<u>Older</u> sulfonylurea oral antidiabetic agents; <u>less</u> <u>potent</u> (smaller, polar side chains)
tolazamide (Tolinase), acetohexamide (Dymelor), tolbutamide (Orinase) |
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cabergoline
bromocriptine |
<b>Mechanism of Action</b>: <u>Ergot derivative</u> <u>dopaminergic</u> drugs (for <u>hyperprolactinemia)</u>
<b>Effects</b>: <u>Dopamine agonists</u> - <u>dopamine reduces prolactin secretion</u> (normal tonic suppression from hypothalamus; binds <u>D2 receptor</u> and triggers <u>Gi protein</u> which <u>inactivates AC </u>leading to <u>less cAMP</u> and <u>less PRL secretion</u>). Can also <u>shrink tumors</u> (helps with <u>visual field symptoms</u>). <b>Indications</b>: <u>Prolactinomas, other hyperprolactinemias</u>. <b><u>cabergoline</u></b> slightly <b>better</b> to <b><u>normalize PRL</u></b> (70-80 vs 80-90%)<b><u>, shrink tumor</u></b> (50-60 vs 60-70%). Occasionally used for <u>acromegaly</u> too (some tumors respond to dopamine)<b> Administration</b>: <b><u>bromocriptine</u></b>: 2.5-5mg <u>qd</u> or <u>bid</u>; <b><u>cabergoline</u></b>: 0.5-1mg <u>once or twice <i>per week</i></u> (better compliance?). <b> Toxicity</b>: <u>GI side effects</u> (dopamine agonists). <u>Nausea, reduction in BP.</u> Take with <u>snack</u> & <u>before going to bed</u> (less dizziness). <b><u>cabergoline</u></b> better tolerated (2-4% vs 5-10% can't tolerate side effects). <b><u>cabergoline</u> </b>may cause <b><u>heart valve abnormalities</u></b> in large doses (for Parkinson's disease) <b>Metabolism: </b>different half lives:<b> </b> <b><u>cabergoline</u></b> (63-109h) >> <b><u>bromocriptine</u></b> (3-7 h) <b> Other</b>:<b><u>Long-term efficacy</u>: </b>after 2 yrs therapy, if tumor has shrunken & PRL normal on 0.5mg/wk cabergoline,<u> 40% chance </u>of being <u>permanently cured / not recurring </u>after stopping meds |
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tolvaptan
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<b>Mechanism of Action</b>: <u>ADH receptor antagonists</u><b><u> (V2 selective</u></b><u>)</u>
<b>Effects</b>: Block ADH receptor. <b>Indications</b>: <u>SIADH</u><b> Administration</b>: <b><u>oral</u></b> |
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octreotide
octreotide LAR lanrotide autogel |
<b>Mechanism of Action</b>: <u>somatostatin analogue</u>, used to <u>inhibit growth hormone release</u> from <u>pituitary</u>
<b>Effects</b>:Somatostatin usually inhibits GH release, but somatostatin itself has a too-short half-life. Acts best on <u>type 2 and 5</u> (+/- type 3) somatostatin receptors (most tumors express these). <b>Indications</b>: <u>Acromegaly</u> (too much GH). Normalize IGF-1 in around 50% pts (full response) depending on <u>pre-therapy IGF-1, GH level</u>, whether or not you express the right receptors. Can also <u>shrink tumors</u> (micro > macro-adenomas for shrinkage). Often used to <u>shrink tumor before surgery</u> (not as dramatic as PRLomas)<b> Administration</b>: sub-Q or IM (half-life <u>1.7 h</u> for normal octreotide; give 3x/day) * <b><u>Octreotide LAR</u></b>: contained in <u>small spherules, injected; </u>drug released <u>slowly</u> - administer <b><u>once per month!</u> </b>Big spike, then drop in octreotide levels (1st week), then slow release after that.<b><u> </u>* <u>Lanrotide autogel</u></b>: gel injected (proprietary formula), slowly released over time. No big spike like octreotide LAR |
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GHRH,Used to test GH reserve in hypopituitaric patients (alone or with arginine;<u> no longer in production</u>)
pegvisomant (B-2306) |
<b>Mechanism of Action</b>: <u>Growth hormone receptor antagonist</u>. <u>Prevents receptor dimerization.</u>
<b>Effects</b>:<u>GH receptor</u> is a <u>dimer</u> (when growth hormone binds, dimerizes). pegvisomant has <u>two changes</u>: <u>binds tighter</u> to receptor and <u>prevents dimerization</u> <b>Selective Toxicity</b>: <b> Indications</b>: <u>Acromegaly</u> (for 20-30% pts that fail other meds & surgery). Just about everybody responds (normalizes IGF) - doesn't matter what tumor is expressing (working in periphery). <b><u>DOESN'T SHRINK TUMOR SIZE</u></b> (can keep growing, too). Don't use for whole life - use radiation therapy too.<b> Administration</b>: sub-Q |
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conivaptan
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<b>Mechanism of Action</b>: <u>ADH receptor antagonists</u><b><u> (non-selective</u></b><u>)</u>
<b>Effects</b>: Block ADH receptor. <b>Indications</b>: <u>SIADH</u><b> Administration</b>: <b><u>intravenous</u></b> |
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MMI (1-methyl, 2-mercaptoimidazole)
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<b>Mechanism of Action</b>: <u>antithyroid drugs; multiple mechanisms</u>
<b>Effects</b>: Inhibit <u>iodine utilization</u> by thyroid (inhibit <u>organification, </u>iodine binding to Tyr residues in Tg, by being substrates for iodinating TPO-Iox species and using it all up). Inhibit <u>coupling</u> of iodotyrosines. Possible <u>immunosuppressive effects</u>. <b>PTU: also inhibits <u>T3 to T4 conversion</u></b> <b>Selective Toxicity</b>: thiourea derivative, trying to <b><u>avoid goitrogenic effects</u> Indications</b>: <u>Graves' disease</u> (esp. popular for <u>younger pts</u> to avoid radioactive iodine). Not good for <u>amiodarone toxicity</u> (too much iodine around, so you can't use it all up). <b><u>More effective</u> </b>at <b><u>lowering T3/T4</u></b> than <b>PTU </b>(used more often)<b> Administration</b>: 10-30 mg/day as <b><u>single dose</u> </b>(longer half life than PTU). Give for <u>about a year, then taper</u> (no increase in remission rate for longer therapy)<b> Pharmacokinetics</b>: <b><u>methimazole</u></b> has a <b><u>longer half-life</u></b> than <b>PTU</b>; is also <u>not bound to serum proteins</u> (75% for PTU). <b><u>Methimazole</u></b> appears in <u>breast milk</u><b>; PTU </b>doesn't (but both drugs safe for baby) <b>Toxicity: </b>Tends to be <b><u>dose-related, less serious</u></b><u>.</u><b> </b><u>Minor reactions</u> (fever, rash), <u>agranulocytosis</u> (both dose-related). <u>Cholestatic toxicity</u> (very few deaths). ANCA / vasculitis rare! <b>Other</b>: takes <b><u>4-12 weeks</u></b> to achieve <u>euthyroid state </u>(just blocking synthesis of new hormone) , depending on <u>baseline severity, thyroid gland size, drug dose</u>. |
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thiourea
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<b>Mechanism of Action</b>: <u>antithyroid drugs; multiple mechanisms</u>
<b>Effects</b>: Inhibit <u>iodine utilization</u> by thyroid (inhibit <u>organification, </u>iodine binding to Tyr residues in Tg, by being substrates for iodinating TPO-Iox species and using it all up). Inhibit <u>coupling</u> of iodotyrosines. Possible <u>immunosuppressive effects</u>.<b> Indications</b>: <u>Graves' disease</u> (esp. popular for <u>younger pts</u> to avoid radioactive iodine). Not good for <u>amiodarone toxicity</u> (too much iodine around, so you can't use it all up). <b><u>PTU / MMI</u></b> (derivatives) used now<b> </b> |
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PTU (6-propyl, 2-thiouracil)
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<b>Mechanism of Action</b>: <u>antithyroid drugs; multiple mechanisms</u>
<b>Effects</b>: Inhibit <u>iodine utilization</u> by thyroid (inhibit <u>organification, </u>iodine binding to Tyr residues in Tg, by being substrates for iodinating TPO-Iox species and using it all up). Inhibit <u>coupling</u> of iodotyrosines. Possible <u>immunosuppressive effects</u>. <b>PTU: also inhibits <u>T3 to T4 conversion</u></b> <b>Selective Toxicity</b>: thiourea derivative, trying to <b><u>avoid goitrogenic effects</u> Indications</b>: <u>Graves' disease</u> (esp. popular for <u>younger pts</u> to avoid radioactive iodine). Remission in <u>30% pts</u> overall (10-70% depending on other factors). Not good for <u>amiodarone toxicity</u> (too much iodine around, so you can't use it all up). <b><u>Less effective</u> </b>at <u>lowering T3/T4</u> than methimazole and <b><u>more toxicity</u></b>. <b><u>NOT FIRST LINE</u></b> ANYMORE!<b> Administration</b>: 100 mg <b><u>tid</u></b> to start (shorter half life than MMI). Give for <u>about a year, then taper</u> (no increase in remission rate for longer therapy)<b> Pharmacokinetics</b>: <b><u>PTU</u></b> has a <b><u>shorter half-life</u></b> than <b>methimazole</b>; is also <u>75% bound to serum proteins</u> (none for methimazole). <b><u>Methimazole</u></b> appears in <u>breast milk</u><b>; PTU </b>doesn't (but both drugs safe for baby) <b>Toxicity: </b>Tends to be <b><u>non-dose-related</u></b> and <b><u>more serious</u>. </b><u>Minor reactions</u> (fever / rash), <u>agranulocytosis</u> (both <i>not</i> dose-related). <u>Hepatitis</u> (potentially fatal - <b><u>black box warning</u></b>), <u>ANCA & vasculitis</u> <b>Other</b>: takes <b><u>4-12 weeks</u></b> to achieve <u>euthyroid state </u>(just blocking synthesis of new hormone) , depending on <u>baseline severity, thyroid gland size, drug dose</u>. <b><u>MMI > PTU</u></b> for use except in <u>1st trimester</u> (MMI = teratogen?) |
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levothyroxine / thyroxine (T4)
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<b>Mechanism of Action</b>: Replaces T4; converted to T3<b>
Indications</b>: <u>hypothyroidism</u><b> Dosing:</b> * use <u>TSH</u> to guide (to goal serum TSH <u>0.5-2.5 to 3</u> mU/l; want to get them in <u>lower half of normal range</u> (0.5-6ish)) * Often <u>free T4</u> is <u>slightly elevated</u> to keep serum T3 / TSH normal - <u>thyroid not making its normal 20% of available T3</u> * <u>Individualized</u> (<u>severity, etiology</u> of hypothyroidism; <u>patient characteristics</u>: older needs less - slower metabolism, pregnant woman needs more: thyroid makes more during pregnancy). * For <u>outpatients < 60yo, no heart disease</u> use <u>full replacement dose</u> (1.5-1.8 ug/kg/day). * For <u>older patients</u> or <u>heart disease</u>, start with <u>25-50 ug/day</u> & increase 25-50 / month with TSH monitoring. * Dose on <u>lean body mass</u>, esp. for <u>very obese pts </u><b>* </b>in <u>thyroid cancer</u>, don't want <u>too much TSH around </u>(lower TSH goals)<b> Administration</b>: * <u>Single daily dose</u> (lots protein bound, long half-life). * Don't take with <u>calcium or iron</u>. * Can adjust <u>time of day</u> to maximize compliance (weekly dosing or catch-up is suboptimal but acceptable). * <u>Fasting</u> advisable, but not essential; foods / <u>coffee</u> can interfere with absorption. <b> Metabolism:</b> * <u>50-80% absorption</u> along <u>small bowel </u>* <u>long half life</u> <u>7 days</u> (can miss dose) * <u>converted to T3</u> in peripheral tissues (like endogenous T4). * <u>Faster</u> clearance in <u>children</u> (may need up to 2x dose), <u>slower</u> clearance in <u>elderly </u><b>* </b><u>Pregnancy</u>: need higher dose (<u>estrogen</u> effects on <u>TBG</u>? trans-placental passage of thyroid hormone?). 75% reaure increased dose (50-75% increase); especially in <u>1st and 2nd trimesters</u> (up to 20 wks)<b> Monitoring</b>: Need to monitor! 20% are <u>undertreated</u>, 18% <u>overtreated.</u> * clinical status <u>important</u> but often <u>inaccurate</u>. * Use <u>serum TSH</u> as principal guide (0.5-2.5 mU/l), but: can <u>lag</u> 1-2wks behind free T4, generally takes <u>6 wks (6 half-lives</u>) to <u>fully equilibrate</u>, can't use if pt has <u>central hypothyroidism</u> (TSH abnormal to begin with)<b> Toxicity</b>: No <u>“side-effects”</u> - allergy to dye maybe? * Could cause <u>increased oxygen consumption, exacerbate angina</u> in heart disease / older pts (taper up). * Restoring euthyroidism can <u>exacerbate ischemic heart disease</u>, can provoke <u>acute adrenal insufficiency</u> if previously borderline adrenal function (Schmidt's syndrome, central hypoadrenalism), can <u>increase ICP</u> in <u>children</u> (pseudotumor cerebri). * <u>Too much thyroxine</u> can lead to <u>iatrogenic thyrotoxicosis</u> (<u>bone mineral loss</u> in <u>postmenopausal women</u>; <u>A-fib</u> in <u>older pts</u>, <u>hyperthyroid symptoms</u>) <b>Drug interactions</b>: <u>separate</u> T4 from <u>drugs and supplements</u> by at least <u>four hours</u>. Bile acid sequestrants, Ca, Fe supplements, AlOH antacids, sucralfate, maybe raloxifene block T4 absorption; antiseizure drugs & rifampin <u>speed up</u> T4 metabolism, Estrogen <u>increases TBG</u>. All these <u>increase dose requirements!</u>. <u>Discontinuing</u> an <u>interfering substance</u> can lead to <u>iatrogenic hyperthyroidism</u>.<b> Other</b>: Normal T4 production is 80-100 ug/day; given 80% absorption, predicted average requirement is 100-125 ug/day. <u>Full replacment dose: </u> <u>1.5-1.8 ug/kg/day.</u> |
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radioactive iodine
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<b>Mechanism of Action</b>: <u>radioablation</u> of thyroid
<b>Selective Toxicity</b>: Targeted to thyroid (where uptake happens)<b> Indications</b>: Treatment of choice for most adults with <u>Graves' disease</u><b> Administration</b>: One pill (80% cure rate; takes 2-6 months)<b> Toxicity</b>: <u>Absolutely contraindicated in pregancy</u>! Can cause <u>transient worsening</u> of thyroid function (pretreat with ATD, but may be radioprotective!) Can <u>worsen Graves' eye disease</u> (worse with severe hyperthyroid, high TSAb titers, smoking, untreated postablative hypothyroidism; steroids can help). <u>INEVITABLE HYPOTHYROIDISM</u> (not a side effect). <u>Neonatal Graves' disease</u>: TSH receptor Ab titers rise in first six months after treatment; if pt becomes pregnant, Ab can cross placenta & stimulate baby's thyroid.<b> Other</b>: No evidence for infertility, birth defects, or cancer |
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naltrexone
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<b>Mechanism of Action</b>: <b><u>nonselective</u></b><u> opioid receptor antagonist</u>, works by <u>blocking activation of the opioid system</u> by alcohol.
<b>Effects</b>: <u>reduces craving</u> & <u>positive reinforcement</u> of drinking. <u>Decreases:</u> # of <u>drinking days</u>; <u>number of drinks / occasion</u>, <u>craving / desire to drink</u>, likelihood that a <u>“slip”</u> will lead to a <u>full-blown relapse</u>, self-reported alcohol “<u>high”</u> during a slip. Effect size is <u>small to medium</u> (only hitting one neurotransmitter system). Considerable <u>variability</u> between pts in response (combine psychosocial / pharm Tx; maybe <u>pharmacogenetic effect</u> with <u>mu-opioid-receptor polymorphism</u>?)<b> Indications</b>: FDA-approved for <u>maintenance</u> of <u>alcohol abstinence</u>. <b> Administration</b>: Both <u>oral</u> & <u>long-acting, injectable</u> formulations. Current standard dose 50mg qd po; maybe also 100mg? PRN? long-day injectable (30d)?<b> Toxicity</b>: <u>not addictive</u>. Common: <u>mild/moderate</u> side effects (<u>GI upset, nausea, H/A, dizziness, fatigue, insomnia</u>). Few serious side effects. <u>Monitor liver enzyme levels</u>. Not recommened if <u>acute hepatitis / liver failure</u>, on <u>narcotic analgesia</u> (<u>surgery </u>or <u>long-term</u>) or <u>opioid substitution therapy</u> (you're <i>blocking</i> opioid receptor really well!), <u> pregnant / nursing</u>.<b> Other</b>: Has <u>no psychoactive effects</u> of its own (<u>pure antagonist!</u>); <u>no known adverse interactions</u> (alcohol or most commonly prescribed meds) - <u>good!</u> |
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odansetron (for alcoholism)
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<b>Mechanism of Action</b>:<u> serotonin receptor antagonist</u> (works on <u>5-HT3</u> receptor, which mediates <u>alcohol reinforcement</u> in the brain)
<b>Effects</b>: reduces alcohol consumption in <u>animal models, across species</u>; reduces <u>preference / craving</u> for alcohol in <u>human lab studies</u>, and <u>decreases drinking</u> in large <u>RPCCTs</u><b> Indications</b>: FDA approved for nausea but not for alcoholism abstinence maintenance yet. Seems to work better in <u>younger-onset alcoholism</u> (maybe more prevalent serotonin defects?) |
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fluoxetine, sertraline, paroxetine, citalopram, escitalopram
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<b>Mechanism of Action</b>: <u>SSRI antidepressants.</u> Selectively block serotonin reuptake (hence the name).
<b>Indications</b>: Generally <u>first line of treatment</u> (mild side effect profile) for <u>depression</u>, also for <u>anxiety</u><b> Administration</b>: <u>once-a-day</u><b> Toxicity</b>: Few drug interactions; <u>not lethal in overdose</u> (good for suicidal pts!). <u>Headaches, GI upset, sexual dysfunction</u>. Can cause <u>sedation</u> (give at night) or <u>activation (decreased sleep, increased anxiety</u>) - no way to tell which patients ahead of time. <b>Other</b>:fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro) |
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aripiprazole
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<b>Mechanism of Action</b>: “<b><u>atypical” antipsychotic agent</u></b>, similar to <b><u>clozapine</u></b> but newer
Distinguishing feature: causes <b><u>less weight gain</u></b> than others!<b> Other</b>: aka <b><u>Abilify</u></b> |
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haloperidol
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<b>Mechanism of Action</b>: a <b><u>butyrophenone</u> <u>antipsychotic </u></b>agent. <u>Blocks dopamine receptors</u>, especially <u>D2</u> type (2,3,4).
<b>Effects</b>: Blockade in <u>limbic system</u> (ventral tegmental area of midbrain to nucleus accumbens, amygdala, prefrontal cerebral cortex, etc.), which modulates <u>emotional behavior</u> probably leads to antipsychotic effects<b> Indications</b>: <u>schizophrenia</u>; helps reduce <u>positive symptoms</u> primarily<b> Toxicity</b>: <b><u>Extrapyramidal</u></b><u> motor side effects</u>:can be <u>parkinsonian</u> (rigidity / tremor) or <u>akathisia</u> (motor restlessness - can't sit still). <b><u>Tardive</u></b><u> </u><b><u>dyskinesia</u></b> possible (can be <u>irreversible</u>, with <u>long, high dosing</u>; from <u>supersensitivity</u> of <u>dopamine receptors</u>). All neuroleptics: <u>increased serum </u><b><u>prolactin</u></b> (can cause <b><u>amenorrhea</u></b> & <b><u>sexual</u></b><u> </u><b><u>dysfunction</u></b>; from <u>hypothalalmic blockade</u> - dopamine inhibits PRL secretion). Orthostatic hypotension, sedation, weight gain less common.<b> Other</b>:aka <b><u>Haldol</u>. </b>very different structure from phenothiazines but same pharm effects. |
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quetiapine
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yet another “<b><u>atypical” antipsychotic agent</u></b>, similar to <b><u>clozapine</u></b> but newer<b>
Other</b>: aka <b><u>Seroquel</u></b> |
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divalproex sodium (Depakote)
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<b>Mechanism of Action</b>: <u>Mood stabilizer</u> (& anticonvulsant). Mechanism not completely understood: <u>calcium signaling / inisitol phosphate pathway</u> is one possibility (popular in 80s); <u>GSK-3beta</u> / <u>Wnt signaling</u> (cell growth, embryogenesis, brain development) is more current model<b>
Indications</b>: <u>acute mania</u> (as good as lithium - but antipsychotics might be better than both). <u>Prophylaxis</u>: only one good study, showed <u>no effect</u> (but Li didn't work either) - so <u>no good evidence in favor</u> for maintenance tx.<b> Administration</b>: Get <u>blood levels</u> (50-120 mg/L) - check compliance & adjust dosing<b> Toxicity</b>: <u>Nausea, diarrhea, tremor, sedation, ataxia, alopecia, weight gain</u>.<b> Other</b>: Very similar to <u>valproic acid</u>. Great marketing in 90s led to it replacing Li as prophylaxis, although evidence only good for acute mania. |
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methadone
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<b>Mechanism of Action</b>: <u>full</u><b><u> mu agonist opioid</u>.</b>
<b>Effects</b>: <b><u>suppresses</u></b> spontaneous opioid <b><u>withdrawal</u></b> & <u>blocks effects</u> of <u>other opioids</u> (<b><u>cross-tolerance</u></b>)<b> Indications</b>: for<b> <u>maintenance treatment</u></b><u> of opioid dependence</u>. Efficacy <u>dose-related</u>; increases <u>retention</u> (time in treatment), decreases <u>opioid use </u>(and other pro-social changes - less illegal income, less money spent on drugs, etc.) For <b><u>opioid withdrawal</u></b> (detox) too - but <u>can't give for more than 3 days</u> in outpatient basis if not an <u>approved OTP</u>! <b> Administration</b>: <u>Good </u><b><u>oral</u></b><u> </u>bioavailability with <u>long duration of action</u> - so <b><u>once daily </u></b><u>dosing</u>. “<b><u>Methadone maintenance treatment” (MMT)</u></b> is a <u>combination</u> of <u>medication</u> <i>and</i> <u>non-pharm treatments</u> (counseling, group therapy, urine monitoring, contingency interventions); MMT is more effective than placebo. Administered from special clinic system - <b><u>Opioid Treatment Programs (OTPs)</u></b> - rare for physicians to be allowed to prescribe outside this system. Usually dose in <u>oral solution</u> supervised by <u>nurse</u>, once a day. Attend clinic for dose (6-7d/wk), supervised urine collection, random testing, counseling. Usually start at <u>30mg qd</u>, <u>titrate up</u> as <u>clinically indicated</u> (10mg every few days; decrease illicit opioid use, craving, withdrawal). Avg dose ~ 80-90mg/day, up to 200mg. For <b><u>withdrawal (detox) in an OTP</u></b>: generally lasts<b> </b><u>7-182 days</u> (getting <u>longer, more gradual</u> over time). 3%/wk decrease (<u>30 wk detox</u>) more effective than 10%/wk (10wk) - but <u>withdrawal is </u><b><u>less effective</u></b> than<b> <u>indefinite maintenance</u></b> for <u>most patients</u> <b> Toxicity</b>: Generally <u>safe</u> & <u>well-tolerated</u>. Side effects <u>typical</u> for <u>mu-agonist opioids</u> (<b><u>constipation</u></b>, increased <b><u>sweating</u></b>). Rare case reports of <u>torsades</u> (with very high doses / other QTc prolongation risk factors). Risk of <b><u>respiratory depression</u></b> if <u>overdose</u> (esp. take-home doses, or if dose diverted / taken by person with lower tolerance level). <b> Other</b>: About 225-250k pts treated with methadone in USA; used since 1960s. Pts doing well can “earn”<b><u> take-home doses</u></b> - desired by pts (lessens burden of attendance); used as contingency for treatment goals. In past, some OTPs run poorly (punitive rules, inadequate doses); also often <u>community resistance</u> to opening new OTPs - part of motivation for having buprenorphine be office-based. |
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naltrexone
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<b>Mechanism of Action</b>: <u>opioid antagonist</u> (occupies receptor but <u>doesn't activate</u>)
<b>Effects</b>: <u>Blocks effects</u> of other opioids (don't get high from opioid when taking naltrexone), But <b><u>not</u></b><u> </u><b><u>reinforcing</u></b> (fundamentally <u>different </u>from buprenorphine, LAAM, methadone) <b>Indications</b>: for <u>maintenance treatment of opioid dependence</u>. Generally <u>limited use</u> (special situations, like when mandated to use as part of licensing).<b> Administration</b>: <u>daily</u> (50 mg po qd) or <u>3x weekly</u> (MWF, 100/100/150 mg). Effective if pt takes it - <u>but often stop taking it</u><b> Toxicity</b>: Will <u>precipitate withdrawal</u> in an opioid-dependent person, so <u>don't start</u> until pt <u>completely withdrawn </u>off opioids. Generally <u>safe, minimal side effects</u> (label warns to watch LFTs, but this was using high doses). <b>Other</b>: Current interest - approval of <u>extended relase form</u> (once/month by injection), currently available for alcohol dependence. Would increase compliance! |
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clonidine
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<b>Mechanism of Action</b>: <u>alpha-2 adrenergic agonist</u> (used for treatment of high blood pressure).
<b>Effects</b>: Useful in treatings <u>signs</u> of withdrawal, but <u>not symptoms</u> (<u>look good</u>, but <i>don't</i> <u>feel good</u>)<b> Indications</b>: <u>treatment of opioid withdrawal</u> (<u>not an approved use</u> - but <u>dosing protocols well-established)</u>. Now decreased use with buprenorphine availability. <b> Toxicity</b>: <u>hypotension, sedation</u><b> Other</b>: Current interest in <u>lofexidine</u> (another alpha-2 adrenergic agonist - markeded in UK, not available in US, less hypotension vs. clonidine) |
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buprenorphine
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<b>Mechanism of Action</b>: <u>thebaine derivative</u> (classified in law as a <u>narcotic</u>). <b><u>Opioid mixed agonist-antagonis</u></b><u>t</u> (partial mu agonist, ORL-1 agonist, kappa antagonist).
<b>Effects</b>: Has a <u>bell-shaped dose-response curve</u> - maximal effect with certain doses. <u>High affinity</u> for <u>mu opiiod receptor</u> - competes with other opioids, blocks their effects. Has <u>slow dissociation</u> (long therapeutic effect, contrasting to relatively <u>short analgesic effects</u>) <b>Indications</b>: for <b><u>maintenance </u></b><u>treatment of </u><b><u>opioid dependence</u></b>. In outpatient trials: superior to placebo, about the same as moderate methadone doses. Similar retention of pts, % opioid urine results. Also for medically supervised <b><u>opioid withdrawal</u></b> (detox) - use sublingual tablets. Better than <u>clonidine</u> for <b><u>RAPID (<1wk) withdrawals</u></b>. Use similar doses as for maintenance; withdrawal should be <b><u>gradual</u></b> (esp. if outpatient), decrase dose in <u>2 mg increments</u>; anecdotally withdrawal symptoms minimal with buprenorphine taper). <b> Administration</b>: <u>Poor oral bioavailability</u> - but <u>sublingual absorption</u> is good. IV or sublingual. Can combine with <b><u>naloxone</u></b> (4:1 dose ratio) to <b><u>reduce abuse potentia</u></b><u>l</u> (naloxone = opioid antagonist; has <u>poor sublingual absorption</u>, but good parenteral bioavailability - so if <u>injected</u> (abuse) instead of sublingual, will <u>precipitate withdrawal</u>). Two dose sizes: small (2 or 2/0.5 mg), and large (8 or 8/2 mg). Taken <u>once daily</u> or increase dose and take less than once daily. Daily doses generally between 8-32 mg; possible to prescribe from <b><u>primary care setting</u> </b>but need to be qualified, get special DEA number, limit on # pts treated. <b> Toxicity</b>: Similar profile to other mu agonist opioids: <b><u>constipation</u></b><u>, increased </u><b><u>sweating</u></b>. No evidence of CV concerns like QTc prolongation. <u>Can be </u><b><u>abused</u></b> (dissolve, inject tablets) - add NX to help avoid. Low risk of <u>respiratory depression</u> with overdose (partial agonist - reports from France when combined with benzo OD). Label notes to check <u>LFTs</u> in pts with liver disease. <b>Metabolism</b>: Highly bound to <b><u>plasma protein</u>;</b> metabolized in <u>liver</u> by <b><u>CYP450 3A4</u></b> into norbuprenorphine, other metabolites; <u>excreted in </u><b><u>urine</u></b>. <b>Other</b>: marketed as <u>sublingual tablets</u>(Suboxone with naloxone, or Subutex - buprenorphine alone). Used by about <u>200k pts</u> in USA |
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LAAM (l-alpha-acetylmethadyl)
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<b>Mechanism of Action</b>: Structurally related to <u>methadone</u>, but <u>longer duration than methadone</u> (can dose MWF).
<b>Indications</b>: for <u>maintenance treatment of opioid dependence</u>. <b> Administration</b>: Prescribed through <u>opioid treatment programs</u> (methadone clinics) for opioid dependence treatment.<b> Toxicity</b>: Small # of reports of torsades de points<b> Other</b>: No longer markeded in USA - low sales; could be picked up by another company. Didn't really seem to make an impact (still have to go to methadone clinic) |
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eszopiclone (Lunesta)
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<b>Mechanism of Action</b>: <u>Benzodiazepine receptor</u> agonist (although <u>chemicaly unrelated to benzos</u>)
<b>Effects</b>: Potentiates GABA (increased frequency of chloride channel opening) <b>Metabolism: </b><u>longer half-life than other z-drugs</u><b> Other</b>: Really essentially similar to other Z-drugs; <u>expensive but great marketing in USA (really popular)</u> |
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zaleplon (Sonata)
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<b>Mechanism of Action</b>: <u>Benzodiazepine receptor</u> agonist (although <u>chemicaly unrelated to benzos</u>)
<b>Effects</b>: Potentiates GABA (increased frequency of chloride channel opening) <b>Toxicity</b>: potential for <u>abuse/dependence</u>; <u>next-day somnolence / antegrade amnesia</u>, <u>rebound insomnia </u>@ high doses. <b>Metabolism: </b>CYP3A4 metabolism, short duration of effect, rapid onset.<b> Other</b>: Really essentially similar to other Z-drugs; <u>expensive!</u> |
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diphenhydramine (and other antihistamines)
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<b>Mechanism of Action</b>: <u>antihistamines</u>, can cause <u>sedative effects</u>
<b>Effects</b>: Think of them as mild, OTC <u>sedatives</u> <b>Indications</b>: Often give as sedatives <b> Toxicity</b>: Can cause <u>next-day sedation</u>, <u>impairment </u>of <u>performance skills</u> (like <u>driving</u>), and <u>troublesome anticholinergic effects - dry mouth, urinary retention</u>.<b> Other</b>:<b> </b>diphenhydramine = benadryl |
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diazepam (Valium), chlordiazepoxide (Librium), prazepam / flurazepam / chlorazepale
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<b>Mechanism of Action</b>: <b><u>LONG-acting </u></b>b<u>enzodiazepine </u>- binds <u>benzoR</u>, potentiating <u>GABA's actions</u> (increases <u>frequency </u>of chloride channel opening)
<b>Effects</b>: <u>Sleepiness (hypnotic) & sedation</u> <b>Metabolism</b>: both parent & metabolite compounds active. <u>CYP3A4</u> metabolism; glucuronide conjugates excreted in urine.<b> </b> |
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alprazolam (Xanax), halazepam (panipam)
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<b>Mechanism of Action</b>: <b><u>INTERMEDIATE-acting </u></b>b<u>enzodiazepine </u>- binds <u>benzoR</u>, potentiating <u>GABA's actions</u> (increases <u>frequency </u>of chloride channel opening)
<b>Effects</b>: <u>Sleepiness (hypnotic) & sedation</u> <b>Metabolism</b>: both parent & metabolite compounds active. <u>CYP3A4</u> metabolism; glucuronide conjugates excreted in urine.<b> </b> |
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zolpidem (Ambien)
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<b>Mechanism of Action</b>: <u>Benzodiazepine receptor</u> agonist (although <u>chemicaly unrelated to benzos</u>)
<b>Effects</b>: Potentiates GABA (increased frequency of chloride channel opening) <b>Indications</b>: sleep aid; has little effect on stages of sleep; EEG changes similar to benzos. Few / no anxiolytic / antconvulsant / muscle relaxant effects.<b> Other</b>: Really essentially similar to other Z-drugs. Now available in <b><u>generic!</u></b> |
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buspirone
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<b>Mechanism of Action</b>: The only FDA-approved <u>pure anxiolytic</u>; mechanism of action unknown (maybe serotonin receptor stimulation, dopamine effects?)
<b>Effects</b>: <u>no significant affinity</u> for <u>benzo receptor</u> or <u>effects on GABA</u> binding. Produces <u>anti-anxiety effects</u> without sedation or hypnosis. Just as effective as a benzo. <b>Indications</b>: Alternative to benzos for someone with <u>just anxiety</u><b> Administration</b>: 2-3x/day dosing (a little bit of a nuisance) |
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ramelteon
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<b>Mechanism of Action</b>: <u>melatonin receptor agonist</u> (selective for MT1/MT2 receptors - mediate circadian rhythm in mammals). MT1 = sleepiness, MT2 = biological clock
<b>Effects</b>: <u>reduces sleep latency</u> (7.5-16m) but <u>not really sleep maintenance</u>. <b> Toxicity</b>: No rebound insomnia & withdrawal effects; <u>teratogenic in ra</u>t<u>s</u> (avoid in pregnancy?). <u>Increases serum prolactin</u> - infertility & osteoporosis? <b>Metabolism</b>: 1-2.6h T(1/2), metabolized by <u>CYP1A2</u>, but also <u>CYP3A4/2C9</u> - look out for <u>inhibitors</u> (could lead to toxic concentrations); <u>inducers</u> (rifampin) can decrease effects. <u>High fat meals</u> impair absorption. <b> Other</b>:<b><u> not</u></b> a <u>controlled substance!</u> |
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oxazepam (Serax)
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<b>Mechanism of Action</b>: <b><u>SHORT-ACTING </u></b>b<u>enzodiazepine </u>- binds <u>benzoR</u>, potentiating <u>GABA's actions</u> (increases <u>frequency </u>of chloride channel opening)
<b>Effects</b>: <u>Sleepiness (hypnotic) & sedation</u> <b>Metabolism</b>: both parent & metabolite compounds active. <b>NO <u>CYP3A4</u> metabolism </b> |
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flumazenil
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<b>Mechanism of Action</b>: imidazobenzodiazepine, a <u>specific antagonist</u> acting <u>only at CNS benzo receptor</u>, not at other benzodiazepine binding sites (e.g. kidney)
<b>Effects</b>: <u>actively displaces</u> <u>benzos</u> from receptor but has <u>little or no facilitating action</u> on <u>GABA transmission</u><b> Indications</b>: <u>undo benzo effects</u> (overdose, bring people out of benzo treatment)<b> Toxicity</b>: If you give after <u>long-acting benzos, </u><b><u>RE-SEDATION</u> </b>can occur (flumazenil - half life 40-80m - wears off before long-acting benzos - 24h half-life). Short-acting benzos have about the same half-life (don't see the problem) <b>Metabolism:</b> eliminated by <u>liver</u>, half life is <u>40-80m</u> |
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lorazepam (Ativan), temazepam (Restoril)
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<b>Mechanism of Action</b>: <b><u>INTERMEDIATE-acting </u></b>b<u>enzodiazepines </u>- binds <u>benzoR</u>, potentiating <u>GABA's actions</u> (increases <u>frequency </u>of chloride channel opening)
<b>Effects</b>: <u>Sleepiness (hypnotic) & sedation</u> <b>Metabolism</b>: both parent & metabolite compounds active. <b><u>NO CYP3A4</u> metabolism</b> |
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pseudoephederine
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<b>Mechanism of Action</b>: <u>stimulant</u> (see stimulants in general).<b>
Indications</b>: <u>nasal congestion</u><b> Other</b>: aka <b><u>Sudafed</u></b> |
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d-amphetamine
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<b>Mechanism of Action</b>: <u>stimulant.</u> <u>increases norepi </u>& <u>dopamine release</u> & <u>blocks </u>their <u>reuptake</u>
<b>Other</b>: aka<b><u> Dexedrine, Dextrostat</u></b> |
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modafinil
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<b>Mechanism of Action</b>: <u>stimulant</u>. mechanism somewhat unclear: <u>blocks dopamine reuptake?</u><b>
Indications</b>: <u>narcolepsy</u><b> Other</b>: aka <b><u>Provigil, Sparlon</u>. </b>maybe a little longer action than others? |
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bupropion
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<b>Mechanism of Action</b>: <u>stimulant</u> (see stimulants in general). <b>
Indications</b>: mostly <u>depression</u> but <u>ADHD too</u><b> Other</b>:aka <b><u>Wellbutrin / Zyban</u></b> |
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d-methylphenylate
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<b>Mechanism of Action</b>: <u>stimulant</u> (see stimulants in general).<b>
Other</b>: aka <b><u>Focalin</u></b>, just a <u>single-enantiomer version of ritalin</u> |
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methamphetamine
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<b>Mechanism of Action</b>: <u>stimulant</u> (see stimulants in general).<b>
Other</b>: aka <b><u>desoxyn</u>; </b><u>amphetamine</u> with an <u>extra methyl group</u>. Illicit use big problem in <u>rural areas</u> (basement labs, etc) |
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dl-methylphenidate
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<b>Mechanism:</b> <u>stimulant</u>. Like amphetamine, <u>increases norepi </u>& <u>dopamine release</u> & <u>blocks </u>their <u>reuptake</u> (releases chronic vs recently stored NE/DA; minor difference)<b>
Other</b>: aka <b><u>Ritalin</u></b> |
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stimulants in general
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<b>Effects</b>: Increase <u>attention, vigilance</u>. Increase <u>activity</u> (but <u>decrease</u> in <u>hyperactive</u>). Increase <u>confidence</u> / <u>euphoria</u>. <u>Decrease appetite</u>. Increase <u>BP / HR / RR.</u> <u>Decongestants, bronchodilators</u>. <b>
Indications</b>: <u>ADHD, narcolepsy</u>. Also used for <u>obesity, activation/appetite stimulation in elderly, depression, hypotension</u>.<b> Administration</b>: For ADHD, start with <u>short-acting at home</u> (is it working?), then move to <u>longer-acting</u><b> Toxicity</b>: <b>more common</b> / even with good dosing: <u>decreased appetite, maybe growth, insomnia</u>. <b>Toxicity</b> (at high doses): progression from feeling <u>spacey / like a zombie</u> to <u>dysphoria / irritability / depression / anxiety</u> to <u>paranoia / confusion / psychosis</u> to <u>agitation / aggression</u> <b>Kinetics: <u>short-acting drugs!</u> </b>Half lives 5-10 hrs, 15 for <u>modafinil</u> |
