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126 Cards in this Set
- Front
- Back
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Triamterene
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Like Amiloride: potassium sparing diuretic, inhibit the Na/K exchange mechanism in the distal renal tubule independently of aldosterone
• weak diuretic effect • oral administration • absorption from G.I. tract is rapid • excreted in the urine • action is not significantly affected by either acidosis or alkalosis • they do not cause retention of urates (no hyperuricemia) Toxicity • hyperkalemia is the only serious toxicity (on chronic use or in combination with other potassium sparing agents) • nausea, vomiting, leg cramps, dizziness, etc. • mild azotemia, increased blood urea nitrogen, etc. • megaloblastic anemia in cirrhotic patients is presumably due to an adverse action on folic acid metabolism • triamterene presumably inhibits dihydrofolate reductase • triamterene and spironolactone should not be administered simultaneously (may cause severe hyperkalemia) Use • main use is in combination with potassium losing diuretics • amiloride is the DOC for lithium induced DI Pharm-27-pdf-16 |
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Amiloride
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Like Triamterene: potassium sparing diuretic, inhibit the Na/K exchange mechanism in the distal renal tubule independently of aldosterone
• weak diuretic effect • oral administration • absorption from G.I. tract is rapid • excreted in the urine • action is not significantly affected by either acidosis or alkalosis • they do not cause retention of urates (no hyperuricemia) Toxicity • hyperkalemia is the only serious toxicity (on chronic use or in combination with other potassium sparing agents) • nausea, vomiting, leg cramps, dizziness, etc. • mild azotemia, increased blood urea nitrogen, etc. • megaloblastic anemia in cirrhotic patients is presumably due to an adverse action on folic acid metabolism • triamterene presumably inhibits dihydrofolate reductase • triamterene and spironolactone should not be administered simultaneously (may cause severe hyperkalemia) Use • main use is in combination with potassium losing diuretics • amiloride is the DOC for lithium induced DI Pharm-27-pdf-16 |
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Osmotic Diuretics
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Osmotic diuretics:
• Freely filtrable at the glomerulus • Undergo very limited absorption from the renal tubules • Pharmacologically inactive or inert Mechanism of Action • increase the osmolality of the and tubular fluid when administered in sufficiently large quantity • produce diuresis by inhibiting water reabsorption in the proximal tubules and in the loop of Henle Uses • for the prophylaxis of acute renal failure • to reduce intraocular pressure and volume prior to eye surgery • to reduce intracranial pressure in patients with brain edema • to reduce the pressure and volume of the cerebrospinal fluid • to protect the kidney against nephrotoxic substances that may reach high concentration DOC: Mannitol • most effective, less irritating, less likely to cause thrombophlebitis, does not cause tissue necrosis following extravasation and safer in patients with renal failure • works even when the filtration rate is low • IV w/administered intravenously, usually with furosemide to produce diuresis in the early phase of acute oliguria, renal failure • not absorbed orally, not metabolized, filtered in the glomeruli but not reabsorbed Toxicity • headache, nausea, vomiting, chills, dizziness, polydipsia, lethargy, confusion, chest pain • excessive administration may cause over expansion of intravascular space (pulmonary edema, congestive heart failure), or excessive cellular dehydration • may cause increased cerebral blood flow and risks of cerebral bleeding in neurosurgical patients Pharm-27-pdf-17 |
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Diuretic combinations
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• loop agents & thiazides may produce diuresis when none of them is effective alone
• potassium sparing diuretics & loop agents or thiazides may balance out potassium losses Pharm-27-pdf-18 |
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Changes in Urinary electrolyte patterns in response to diuretic drugs:
Carbonic Anhydrase inhibitors, Loop Diuretics, Thiazides, Loop Agents + thiazides, K+ sparing agents |
Pharm-27-pdf-18
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Order of the expected maximum diuretic effect
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loop >> thiazides >> CA inhibitors > K+ sparing
CA inhibitors work only for a few days! Pharm-27-pdf-18 |
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Clinical applications of diuretics
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Edematous states
• CHF • kidney disease • hepatic cirrhosis Nonedematous states • hypertension • nephrolithiasis • hypercalcemia • diabetes insipidus |
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Vasopressin
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• parenteral form of ADH used central diabetes insipidus (polyuria, polydipsia, dehydration)
• intravenous vasopressin is included in the Advanced Cardiac Life Support (ACLS) algorithm as an alternative to epinephrine for the treatment of cardiac arrest associated with asystole or pulseless electrical activity Pharm-27-pdf-19 |
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Desmopressin
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• a synthetic analog of ADH
• it is more potent and much longer acting than vasopressin • strong V2 agonist, inert on V1 receptors increases plasma factor VIII (FVIII) and von Willebrand factor (vWF) more than vasopressin no effect in V2 receptor KO mutants effective in Hemophilia A and von Willebrand disease Pharm-27-pdf-19 |
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ADH antagonists
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[• a variety of medical conditions, including congestive heart failure and syndrome of inappropriate ADH secretion (SIADH), cause water retention as the result of ADH excess
• dangerous hyponatremia can result.] |
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Conivaptan
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• non-peptide dual V1A and V2 vasopressin receptor antagonists
• increase urine output and decreases reabsorption of free water by antagonizing ADH • very new drugs, little experience [As an ADH antagonist: • a variety of medical conditions, including congestive heart failure and syndrome of inappropriate ADH secretion (SIADH), cause water retention as the result of ADH excess • dangerous hyponatremia can result.] |
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Demeclocycline
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• a tetracycline antibiotic
• uncouples the V2 receptor from adenylyl cyclase enzyme-->nephrogenic diabetes insipidus • less toxic than lithium (same mech) • see tetracyclines too Pharm-27-pdf-20 |
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Lithium
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• uncouples the V2 receptor from adenylyl cyclase enzyme-->nephrogenic diabetes insipidus
• more toxic than demeclocycline (same mech) • see lithium in CNS pharmacology too Pharm-27-pdf-20 |
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CHF
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This is not an objective
• heart cannot oxygenate periphery • > 2% Americans, 900,000 hospitalizations that cost $9 billion/year • CHF prevalence increases with age from < 1% at 50-59 years and then doubling with every decade to reach almost 10% by age 80-89 • it is the most common cause of hospitalization in patients over 65 years old • quality of life is adversely affected by progressive fatigue, shortness of breath, and functional disability • the long-term prognosis of CHF is poor • 30-50% of CHF patients with severe symptoms die within one year • 5-year survival is about 38% in men and 57% in women without treatment • mortality can be reduced significantly by drug treatment Pharm-29-4 |
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High Output CHF
Main causes, heart work conditions, CO, resposne to inotropic agents |
Causes: Hyperthyroidism, Anemia, AV shunts, Thiamine deficiency (beriberi)
Heart is healthy but exhausted by working too hard CO: High as the heart works hard to keep up with the greatly increased body demands poor or no response to inotropic agents Pharm-29-pdf-5 |
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Low Output CHF
Main causes, heart work conditions, CO, resposne to inotropic agents |
Causes: CAD, htn, MI, Persistent arrhythmias, Rheumatic heart disease, General cardiomyopathy
Heart fails to pump enough blood to meet tissue needs CO: Low because the heart is unable to keep up with the tissue metabolic demands improve with inotropic agents Pharm-29-pdf-5 |
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Major hemodynamic characteristics of CHF
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• subnormal cardiac output, causing decreased exercise tolerance with rapid muscular fatigue, tachycardia, pulmonary edema, and cardiomegaly
• myocardial hypertrophy develops to maintain cardiac performance • increased myocardial muscle mass and muscle wall thickness • SNS/RAAS mediated compensation Pharm-29-pdf-5 |
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Main Determinants of CO in CHF
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increased preload due to blood volume and venous tone
increased averload due to aortic impedance and arterial constriction decreased contraftility due to ventricular increased HR due to SNS tachycardia Pharm-29-pdf-8 |
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Eletrolyte determinants of contractility
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• sensitivity of the contractile proteins to Ca++
• the amount of Ca++ released from the sarcoplasmic reticulum (SR) • the amount of Ca++ stored in the SR • the amount of trigger Ca++ • activity of the Na+ - Ca++ exchanger • intracellular Na+ concentration and activity of the Na+/K+ATPase Pharm-29-pdf-6 |
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diuretic venodilator in CHF
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used to reduce preload in CHF
Pharm-29-pdf-8 |
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ateriodilator in CHF
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used to reduce afterload in CHF
Pharm-29-pdf-8 |
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inotropic drug in CHF
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used to increase contractility in CHF
Pharm-29-pdf-8 |
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Beta adrenergic agonist in CHF
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used to reduce energy expenditure
Pharm-29-pdf-8 |
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Digitalis
Efficts |
Cardiac Glycosides, DOC: Digoxin
inhibition of membrane sodium pump Na+,K+-ATPase (aka digitalis receptor) Inotropy is increased o increased intracellular [Na+] o decreased expulsion of [Ca2+] --->increased actin-myosin--> contractility --->also decreased intracellular [K+] from [Ca2+] HR slowed o in normal hearts via baro-vagal response, increased SA sensitivity to ACh o in failing hearts: high SNS tone reduced (no need to maintain contractility) normal heart, baro-vagal vasoconstrx NO CO increase failing heart: baro-vagal casodilation CO increased Electrical effects • electrical effects:direct action on myocardial cells + PSNS stimulation • digitalis pretreatment will slow the ventricular rate and prevent paradoxical ventricular tachycardia before Class IA antiarrhythmic drugs are used (cause PVT alone) kidneys: diuresis of CHF edema 2ndry to cardiovascular effects GI: dirrect irritation + chemoreceptor triggered vomitting, pain from mesenteric arteriolar constrxn Pharm-29-pdf-18 |
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Digitoxin
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Digitalis not avialable in US
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ouabain
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Digitalis used for experimental purpose
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Chemical strx of Digoxin
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Chemical Strx are not Objectives
• see page 205 of Katzung for the chemical structure of digoxin • aglycone or genin, consisting of: o steroid nucleus which has unsaturated 5-member lactone ring at 17 position o series of sugars at carbon 3 of the nucleus o the genin is responsible for all biological activity o 3 molecules of sugar (digitoxose) influence pharmacokinetics including absorption, half-life, and metabolism Pharm-29-pdf-10 |
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Treating Digitalis Toxicity with Electrolytes
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K+ & digitalis, compete for Na+, K+-ATPase
K+ blocks digitalis toxicity reduces abnormal cardiac automaticity Ca2+ increases digitalis toxicity therefore digitalis toxicity is treated with potassium, but never with calcium |
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Digitalis Pharmacokientics
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Lipid solubility: Medium
Oral availability: 75% (inactivated by enteric bacteria in 10% of pts) Half-life 40h Plasma protein binding ~30% Renal elimination >80% Volume of distribution 6.3 L/Kg steady state after 1 week of of constant dosing OR 3x over 36 h, followed by regular maintenance doses Pharm-29-pdf-12 |
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Adverse effects of Digitalis
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there are no “non-toxic” digitalis glycosides
all digitalis glycosides produce the same toxic effects narrow margin of safety: Tx dose = ~60% Toxic dose, toxicity common, always side effects Ealiest: myriad of intense GI Sx + salivation Most Common: various arrhythmias including sinus bradycardia, ectopic ventricular beats, AV block, and bigeminy [Bolded] o ventricular fibrillation, most common cause of death o requies routine ECG, + serum [digitalis] & [K+] measurements • CNS side effects (include...weird stuff) • skin rashes, eosinophilia, and gynecomastia are rare Tx: discontinue, K+, Digitalis Fab, lidocaine, phenytoin, or propranolol; and Do not Tx arrhythmias w/ cardioversion (except V for fib) Pharm-29-pdf-13 |
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Drug Interactions of Digitalis
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many drugs influence toxicity
Pharmacokinetic toxocity enhancement by: • decreasing digoxin renal clearance or volume of distribution (quinidine, amiodarone, captopril, verapamil, diltiazem, cyclosporine) • increasing digoxin GI absorption (erythromycin, omeprazole, etc.) • Quinidine displaces digoxin from renal clearance and increases plasma [digoxin] Pharmacokinetic toxicity reduction by decreasing digoxin GI absorption (cholestyramine, bran, etc.) Pharmacodynamic toxicity enhancement via o diuretics which decrease K+, hypokalemia often occurs with thiazide or loop diuretics o β-adrenergic antagonists which decrease SA or AV node activity o calcium-channel antagonists which decrease myocardial contractility o catecholamines which may sensitize the myocardium to digoxin Elderly patients: hypochlorhydria or reduced renal clearance--> more susceptible Infants: require 50% more than body weight calculation Hypothyroidism: reduced renal clearance-->more toxic Pharm-29-pdf-14 |
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How many people need to discontinue Digitalis Therapy
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Not an objective
• toxicity leads to discontinuing digitalis in 5-25% of patients |
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Phosphodiesterase inhibitors
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bipyridines: Inamrinone, milrinone
inodilators: ubitriot + vasodilation inhibit cAMP phosphodiesterase isozyme in cardiac and vascular muscle maintains high cAMP levels: improve diastolic function and inotropy Pharmacokinetics o IV or oral o liver metabolism and urinary excretion Uses: • should be used only in patients who can be closely monitored and who have not responded adequately to conventional therapy (digitalis, diuretics, and/or vasodilators). • not proven safe or effective in the long-term treatment of heart failure. • did not consistently alleviate symptoms, but did increase the risk of mortality and hospitalization. • NYHA Class IV patients had the highest risk of adverse events. ... • in patients with ischemic heart disease, improvement in left ventricular function has been reported • administration to patients with congestive heart failure has resulted in dose-related effects including increased cardiac output, decreased pulmonary capillary wedge pressure and decreased vascular resistance. These changes are accompanied by mild-to-moderate increases in heart rate, but without an increase in myocardial oxygen consumption Pharm-29-pdf-15 |
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Dopamine for CHF
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A sympatheticomimetic
Dopamine is indicated in severe refractory congestive heart failure and acute heart failure following cardiovascular surgery • Exerts positive inotropic effect due to a direct action on the heart • In low doses, it increases cardiac output. and renal blood flow • Lowers peripheral resistance • Enhances sodium excretion • Not useful in treating shock • IV administration Pharm-27-pdf-15 |
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Dobutamine
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A sympatheticomimetic
• selective beta-1 agonist • positive inotropic effect, somewhat less tachycardia • reduced filling pressure and increased oxygen consumption • IV administration Pharm-29-pdf-15 |
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Calcium sensitizers
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• experimental drugs
• inhibit phosphodiesterase III and sensitizes troponin-C myofilaments to intracellular calcium ions: increase cardiac tissue sensitivity to calcium without increasing tissue concentrations of calcium; • Uses: under review for the management of acute and chronic congestive heart failure (ongoing clinical studies: SURVIVE, REVIVE) Pharm-29-pdf-15 |
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B type natriuretic peptide (hBNP)
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• produced by the ventricular muscle
• endogenous [hBNP] are elevated in patients with heart failure Pharm-29-pdf17 |
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Nesiritide
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• IV recombinant purified human B-type natriuretic peptide (hBNP),
• indicated for the acute Tx of decompensated CHF, primarily in patients with elevated pulmonary capillary wedge pressure (i.e., PCWP > 20 mmHg). • in decompensated heart failure, the use of nesiritide reduces PCWP and improves the symptoms of heart failure, including global clinical status, dyspnea, and fatigue • no tolerance dvlp (better than Nitroglycerin) • dose dependent hypotension: monitor pt Pharm-29-pdf-17 |
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3 major effects of Angiotensin II
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1. Rapid Pressor Response
2. Slow Pressor Response 3. Cadiovascular Remodelling/Hypertrophy There's way more intermediate steps on teh chart Pharm-29-pdf-17 |
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Factors that increase RAAS activity in CHF
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o reduced renal perfusion, activating renal renin secretion
o increased sympathetic activity, causing ß-adrenergic stimulation of the juxtaglomerular apparatus o antihypertensive drugs that stimulate renin secretion o diuretics which reduce sodium at the macula densa o vasodilators which reduce renal perfusion pressure Pharm-29-pdf-18 |
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How does RAAS impair cardiac fnx in CHF
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o increased afterload: vasoconstriction
o increased preload - aldosterone expands fluid volume o increased cardiac tissue remodeling Pharm-29-pdf-18 |
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ACE inhibitor therapy
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diminish cardiac workload by
decreasing afterload by blocking angiotensin mediated vasoconstriction decreasing preload by blocking aldosterone release effective in the treatment of CHF • dry cough may occur with ACE inhibitors • chronic ACE inhibitor and angiotensin receptor inhibitor therapy can reduce CHF mortality by ~1/3 Pharm-29-pdf-18 |
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angiotensin (AT1) receptor antagonist
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odd stuff here
to be effective in the treatment of CHF • dry cough may occur with ACE inhibitors but not with losartan • chronic ACE inhibitor and angiotensin receptor inhibitor therapy can reduce CHF mortality by ~1/3 % Pharm-29-pdf-18 |
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Beta blockers & CHF
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the -olols
dangerous: negative inotropic effect reduction of mortality in stable class II and III CHF, probably because of o attenuation of the effects of high concentration of catecholamines o up-regulation of beta receptors o decreased heart rate o reduced remodeling o antiarrhythmic effect >>many of the other antiarrhythmic agents don’t have similar beneficial effects!!!<< Pharm-29-pdf-19 |
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diastolic dysfunction or cardiomyopathies
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respond favorably to beta blockers (decreased heart rate, improved ejection)
Pharm-29-pdf-19 |
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sodium nitroprusside
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IV infusion for acutely decompensated CHF as long as cerebral and renal perfusion can be maintained
o dilates both veins and arteries to reduce both preload and afterload o the most common adverse effect is excessive hypotension Pharm-29-pdf-19 |
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organic nitrates
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nitroglycerin or isosorbide dinitrate
given orally in CHF to dilate veins: lowers preload long term use = tolerance long term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart Pharm-29-pdf-10 |
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hydralazine
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peripheral vasodilator
o direct relaxn arteriols: decreases afterload: increases heart rate, cardiac output, and left ventricular ejection fraction Sodium and fluid retention increases plasma volume increases: tolerance long term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart Pharm-29-pdf-19 |
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Pts at risk for arrythmias
[not an objective] |
• 25% of patients treated with digitalis
• 50% of anesthetized patients • 80% of AMI patients • some arrhythmias can precipitate lethal arrhythmias (e.g. ventricular fibrillation) Pharm-31-pdf-3 |
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Fast Response Fibers
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Atria
• Ventricles • Bundle of His • Purkinje cells Pharm-31-pdf-3 |
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Slow Response Fibers
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S-A Node
• A-V Node Pharm-31-pdf-3 |
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Excitability
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How close a cell lives to its threshold potential
Pharm-31-pdf-3 |
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Effective Refractory Period
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shortest interval at which a premature stimulus results in a propagated response. The ERP usually includes phase 0, 1, 2 and most of 3. ERP can be either increased or decreased by several types of drugs
Pharm-31-pdf-4 |
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Action Potential Duration
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time interval between the point of depolarization and repolarization
Pharm-31-pdf-4 |
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Phases of the cardiac action potential
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Phase 0 -- Na channels open, rapid depolarization, inactivation of the sodium channels; (Ca2+ dependent slow response in SA and AV)
Phase 1 -- rapid partial repolarization due to the inactivation of fast sodium channels Phase 2 -- plateau phase, calcium channels are open Phase 3 -- repolarization, Ca++ channels inactivated, K+ channels open, Na+ channels turning to rested state Phase 4 -- resting membrane potential, spontaneous depolarization Pharm-31-pdf-4 |
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Electrical Parameters which influence condxn velocity of the cardiac cell
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• maximum rate of depolarization, ie Vmax of phase 0, proportional to |membrane potential|
• threshold potential • resting membrane potential (mV) – determines Vmax Pharm-31-pdf-6 |
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Precipitating factors for arrhythmias
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• ischemia, hypoxia,
• alkalosis, electrolyte abnormalities, • excessive catecholamine exposure, • drug toxicities (digitalis, antiarrhythmic agents etc.), • overstretching of cardiac fibers, • presence of scarred or otherwise diseased tissues Pharm-31-pdf-6 |
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Determining factors of the rate of pacemaker cells
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o duration of the action potential
o duration of the diastolic interval o maximum diastolic potential o slope of phase 4 depolarization o threshold potential Pharm-31-pdf-6 |
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Disturbances of impulse conduction
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Simple blocks:
o AV nodal block o bundle branch block Reentry mechanism o obstacle to homogenous conduction o unidirectional block at some point o conduction time along the circuit is long enough to find excitable tissues Pharm-31-pdf-7 |
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Aim of therapy for the arrhythmias
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• reduce ectopic pacemaker activity
• modify conduction or refractoriness to disable reentry Pharm-31-pdf-7 |
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Main features of antiarrhythmic drugs
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• decrease automaticity of ectopic pacemakers more than that of the SA node
• reduce conduction and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissues • accomplished by selectively blocking the sodium and calcium channels of depolarized cells • have high affinity for activated or inactivated but low affinity for rested channels (use-dependent or state dependent action) • in cells with abnormal automaticity these drugs reduce phase 4 depolarization • beta blockers remove the chronotropic action of norepinephrine (NE) Pharm-31-pdf-7 |
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Dose dependent fnx of Antiarrhythmic agents
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Regular doses suppress ectopic automaticity &/abnormal conduction with minimal effect on normal cells
Higher doses depress conduction in normal tissues &/ produce drug induced arrhythmia Antiarrhythmic agents can precipitate lethal arrhythmias! Pharm-31-pdf-7 |
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Quinidine
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Quinidine is a prototype of Class 1 antiarrhythmic Drugs
d-isomer of quinine Quinidine is a myocardial depressant and produces antiarrhythmic effects by: o binding to open and activated sodium channels (“state dependent” blockade) o decreasing the myocardial automaticity and membrane responsiveness o increasing the diastolic threshold o slowing maximal rate of rise of the cellular action potential (Vmax of 0 phase) o prolonging the Action Potential Duration (APD) Prolonging the Effective Refractory Period (ERP) o increasing the ratio of ERP/ADP and preventing the closely coupled "re-entry circuit" in the Purkinje fibers o blocking K+ channels (prolongs depolarization) Other Cardiac Effects o Quinidine causes muscarinic receptor blockade, which can increase HR and AV conduction o Quinidine causes certain EKG changes - such as widening of QRS and QT intervals, etc. These are the manifestations of toxicity o Quinidine causes S-A block, A-V block, ventricular, arrhythmia, and severe hypotension at toxic doses. Other effects o blocks alpha receptors (hypotension), may cause reflex tachycardia o G.I. irritation, nausea, vomiting and diarrhea o CNS stimulation, convulsions at very high doses o "Cinchonism", tinnitus, headache, vertigo, allergy. o Quinidine has a curare-like effect (membrane stabilizing effect) on the skeletal muscle o Quinidine potentiates the action of neuromuscular blocking agents Pharmacokinetics • oral administration is most common, relatively safe and rapid in onset • absorption is essentially complete • bioavailability is variable due to "first pass" effect • I.V. administration is hazardous (causes severe hypotension), I.M. injection is painful • maximal blood levels are reached in 90 minutes • about 80% of the drug is metabolized by the liver, 20% is excreted through the kidney • t1/2 is about 6 hours. The t1/2 is prolonged in congestive heart failure or in renal insufficiency • 70%-80% quinidine is plasma protein bound • a major metabolite of quinidine is also active Toxicity: • low therapeutic index. • cardiac toxicity is the most significant, often life threatening. • quinidine causes severe hypotension and shock-like effect by virtue of its alpha-adrenergic receptor blocking action. • paradoxical tachycardia ("anticholinergic" effect) • quinidine + digitalis-->syncope and death: esp pts with long QT interval • torsade de pointes • diarrhea, nausea and vomiting is the most often seen extracardiac toxicity • Cinchonism: Loss of hearing, angioedema, vertigo, tinnitus, visual disturbances, thrombocytopenic purpura, vascular collapse. Contraindications to quinidine therapy • Pre-existing complete A-V block (ventricular arrest may take place). • Thrombocytopenia associated with previous quinidine therapy (allergic response). Therapeutic Use: • Quinidine is a "broad spectrum" antiarrhythmic drug effective for acute or chronic treatment of varieties of supraventricular and ventricular arrhythmias. Drug Interactions: • Drugs like phenytoin and phenobarbital which induce hepatic microsomal enzymes are likely to shorten the duration of action • quinidine may increase prothrombin time in patients receiving oral anticoagulant warfarin therapy • quinidine and nitroglycerin will produce a significant vasodilation and fall in blood pressure • increased plasma K+ may enhance the toxic effect of quinidine • quinidine may exaggerate skeletal muscle weakness, or increase the paralyzing effect of curare and curare-like drugs, aminoglycosides |
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Procainamide
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Class 1A antiarrhythmic agent
• electrophysiological and pharmacological actions similar to those of quinidine • short duration of action • chronic use = probable negative reactions • can be administered safely I.V. • procainamide may be useful in patients with severe ventricular arrhythmias who are unresponsive to lidocaine Mechanism of action • similar to that of quinidine Therapeutic uses of Procainamide: To treat a wide variety of cardiac arrhythmias such as: o Ventricular arrhythmias -except those resulting from digitalis intoxication o Supraventricular arrhythmias - atrial flutter and atrial fibrillation, etc. Pharmacokinetics • well absorbed after oral administration • bioavailability 75% • peak plasma levels: 15-60 minutes • protein binding: 20% • half-life: 3-5 hours • t1/2 is prolonged in renal insufficiency, hepatic disease and congestive heart failure • metabolism: acetylated to active n-acetyl procainamide (NAPA) in the liver • the rate of acetylation is under genetic control and shows bimodal distribution into "slow" and "fast" acetylators; fast acetylators have higher plasma ratio of NAPA/ procainamide • about 40-60% is excreted in the urine Toxicity • in general, adverse effects of procainamide are almost similar to those of quinidine, including precipitation of new arrhythmias, torsade de pointes • anorexia, nausea, and vomiting (but procainamide is better tolerated than quinidine in some patients) • Systemic Lupus Erythematosus-like Syndrome (SLE) in about 30% of patients during prolonged use • procainamide causes an increased titer in antinuclear antibodies (ANA) in about 30% of patients • occasional hypersensitivity (rash, urticaria, fever, agranulocytosis, pancytopenia) may be seen • rarely, mental disturbances (depression, hallucination, psychosis) Precautions and Contraindications • Do not use procainamide in complete A-V block • Use it with great caution in partial A-V block Pharm-31-pdf-12 |
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Disopyramide
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Class 1A antiarrhythmic agent
• structurally unique • Disopyramide is likely to reduce cardiac index. • Disopyramide is effective in the management of unifocal, multifocal and paired premature ventricular contractions as well as the episodes of ventricular tachycardia Therapeutic Uses: • indicated for ventricular tachycardia Mechanism: • Na+ channel blockade (like quinidine) • prolongs the Effective Refractory Period (ERP), increases the electric threshold, depresses the conduction velocity • high doses of disopyramide may depress myocardial contractility Pharmacokinetics: • administered orally, no significant adverse hemodynamic effects following oral administration • about 16% is metabolized on the "first pass" through the liver • peak effect ~3 hours • plasma half-life ~7 hours, markedly increased in patients with renal insufficiency • 80% is excreted in the kidney in 72 hours (45% as unchanged drug) • 40% protein binding Toxicity: • prolongation of QT-interval and prominent U waves • widening of QRS complex, increased P-wave duration • do not use disopyramide in sick sinus syndrome • ventricular arrhythmias, including torsade de pointes and syncope • increases His-Purkinje conduction time but does not affect A-V conduction time • significant negative inotropic effect, aggravates heart failure • anticholinergic effects: dry mouth, urinary hesitancy, constipation, blurred vision, contraindicated in glaucoma • nausea, vomiting, abdominal pain, headache, edema, weight gain, dizziness and fatigue Pharm-31-pdf-13 |
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Lidocaine
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• local anesthetic antiarrhythmic agent, prototype for IB
Mechanism of action: • binds to the inactivated sodium channels, fast binding and dissociation • decreases APD, shortens ERP due to block of the slow Na+ “window” currents Therapeutic Uses For the treatment of VENTRICULAR arrhythmias Effects: • lidocaine has no significant effects on QRS, QT intervals • it causes less hypotension than procainamide • It has little or no depressant action on myocardial contractility • it has no vagal blocking action like that of quinidine, procainamide or disopyramide • antiarrhythmic action develops immediately after I.V. loading dose and declines rapidly upon discontinuation of infusion. • lidocaine is relatively free of hemodynamic and cardiac complications • cannot be used orally (first pass metabolism), therefore, is not suitable for maintenance or in an outpatient setting • lidocaine is not effective for supraventricular arrhythmias Pharmacokinetics: • I.V. only • I.V. - loading dose (bolus) is 50 mg - 100 mg (1 mg/kg) at a rate of 25-30 mg/minute. Boluses of above strength may be given every 3-5 minutes until the desired effect is achieved or side effects appear. To maintain anti-arrhythmic effect, I.V. infusion must be maintained at a rate of 1-4 mg/minute • onset of action – 1-2 minute • duration of anti-arrhythmic effect – 0-20 minutes • serum t½ - 8-9 minutes (initial active phase of distribution). To maintain serum levels achieved by the bolus, start I.V. infusion within 10 minutes • t½ of second phase - 1.5 - 2 hours • metabolism - primarily in the liver. (90-95%) • excretion - Less than 5% unchanged drug in the urine • therapeutic level – 1-5 mg/ml, toxic level – 6-10 mg/mg Toxicity: • minor side effects are lightheadedness, tinnitus, muscle twitches, blurred double vision • CNS depression, stupor, restlessness, euphoria, hypotension, and convulsion • infrequently bradycardia and aggravation of arrhythmia may occur • very large doses may depress myocardial contractility and A-V conduction (least negative inotropic among the antiarrhythmics) • Untoward effects are seen mostly in patients with hepatic disease and congestive heart failure, etc. Pharm-31-pdf-15 |
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Phenytoin
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1B antiarrhythmic
• phenytoin is a classical antiepileptic drug (anti-grand mal drug) and may also be useful in the treatment of ventricular arrhythmias induced by digitalis toxicity • since the introduction of digitalis immune fab, its use has declined • short term administration as an antiarrhythmic agent Mechanism of action: • binding to active and inactivated sodium channels • shortens ERP • depression of myocardial automaticity • does not depress conduction at A-V system or in the ventricles • little or no depressant effect on myocardial contractility at therapeutic doses • hypotension occurs only on rapid I.V. injection Pharmacokinetics: • oral and parenteral administration • complex pharmacokinetics: lower doses first order, higher doses saturation (zero order) kinetics • onset: within one hour following I.V. loading dose (20 mg/kg); 2-24 hours following oral loading dose of 1 gram • protein binding: 95% (source of interactions) • serum t1/2: 18-24 hours • metabolism: in the liver to inactive metabolites, induces P-450 system • excretion: 75% in urine as metabolites; 1% unchanged in urine • therapeutic level: 20 μg/mL Toxicity and side effects (short term use): • dose related toxic effects are nystagmus, ataxia, slurred speech, mental confusion. • dizziness and transient nervousness which will disappear at reduced dose or on slow administration • phenytoin elevates blood glucose level at higher doses • patients with renal insufficiency and diabetes are more susceptible • dermatological manifestations, fever, rash, blood dyscrasia, toxic hepatitis, liver damage Drug Interactions: • warfarin, disulfiram, phenylbutazone, INH, etc. inhibit the metabolism of phenytoin and enhance its toxicity • Induces the P450 system, enhances the metabolism of many drugs (amiodarone, carbamazepine, clozapine, dihydropyridine Ca++ channel blockers, fluvoxamine, imipramine, etc.) • phenytoin may induce folic acid deficiency Pharm-31-pdf-15 |
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Tocainide
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1B antiarrhythmic
• blockade of the fast sodium channels • orally active antiarrhythmic agent similar in action to lidocaine and primarily useful in ventricular arrhythmias. • well absorbed: 90% bioavailability; no significant "first pass", hepatic metabolism Toxicity: • mostly on CNS and G.I. - not serious • leukopenia, thrombocytopenia and agranulocytosis, etc. are drug related • may increase ventricular rate in patients with atrial flutter or atrial fibrillation • may aggravate congestive heart failure and conduction disturbances • allergy to lidocaine like drugs; and second or third degree heart block are contraindications Therapeutic Uses: • for all kinds of symptomatic ventricular ectopia and ventricular arrhythmias, however, it does not prevent sudden death • may be useful in patients refractory to quinidine, procainamide, disopyramide, propranolol, etc. Mexiletine (Mexitil) • oral, local anesthetic-type antiarrhythmic agent similar to lidocaine and tocainide • used to treat life-threatening ventricular arrhythmias • it also has been used successfully in the treatment of pain associated with diabetic neuropathy • no extensive first pass metabolism upon oral use • t½ about 12 hours Toxicity: Minor CNS effects; tremor, dizziness, blurred vision, hypotension, bradycardia, etc. Therapeutic Uses: • For acute or chronic ventricular arrhythmias. Useful in patients resistant to lidocaine |
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Flecainide
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• local anesthetic antiarrhythmic agent
• prototype for IC Mechanism of action: • binds to all sodium channels, no effect on APD, no ANS effects • slow dissociation from binding • significantly slow His-Purkinje conduction and cause QRS widening • shorten the action potential of Purkinje fibers without affecting the surrounding myocardial tissue Pharmacokinetics: • oral absorption is good • no extensive plasma protein binding • t½ is about 13 hrs. for single dose; 16 hrs. for multiple doses • no "first pass" metabolism • excreted by the kidney - partly metabolized Toxicity: • most common - blurred vision • dizziness, nausea, palpitation, tremors, paresthesia, metallic taste occurs • worsening of heart failure, prolongation of PR interval and QRS complex • risks of proarrhythmic effects in some patients (4-12%) particularly those with ventricular dysfunction (increased ventricular ectopia, ventricular tachycardia, and V. fibrillation, etc.) see Cardiac Arrhythmia Suppression Trial (CAST) Therapeutic Uses: • life-threatening ventricular arrhythmias • for conversion to and/or maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter associated with disabling symptoms and without structural heart disease • prevention of various forms of paroxysmal supraventricular tachycardia (PSVT) caused by both reentrant and non-reentrant mechanisms. Contraindications: • pre-existing A-V block (II or III degree) • patients with cardiogenic shock • congestive heart failure Pharm-31-pdf-17 |
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Propafenone
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1C Antiarrythmic
• oral antiarrhythmic agent mechanistically similar to flecainide • used for the suppression of life-threatening ventricular arrhythmias • structurally similar to beta-blockers and possesses beta-blocking activity • propafenone therapy should be initiated in the hospital to allow for appropriate electrocardiographic monitoring • high “first pass” metabolism • slow and fast metabolizing phenotypes Use of propafenone should be reserved for refractory patients with severe, life-threatening arrhythmias because the Ic agents have been shown to possess proarrhythmic characteristics! Pharm-31-pdf-18 |
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Moricizine
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• oral class IC antiarrhythmic agent.
• chemically unrelated to any other antiarrhythmic • although sometimes referred to as a class IC agent, classification of moricizine within the class I antiarrhythmics is difficult since the drug has electrophysiologic features of all three subclasses, class IA, IB, and IC • indicated for the treatment of life-threatening ventricular arrhythmias Pharm-31-pdf-19 |
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Beta Blockers
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class II antiarrhytmic drugs
see handouts |
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Amiodarone
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• class III antiarrhythmic agent approved for the treatment of refractory life threatening ventricular arrhythmias;
• the drug's roles are expanding to include the treatment of atrial and/or ventricular arrhythmias in various patient types and healthcare settings Mechanism of action • blocks potassium channels (Class III) • binds to inactivated sodium channels (Class I) • some calcium channel blocking effect (Class IV) • powerful inhibitor of abnormal automaticity • slows sinus rate, conduction and prolongs QT and QRS • causes peripheral vasodilatation (alpha blocking effect) Pharmacokinetics: • oral or I.V. administration • extensive distribution (Vd = 70 L/kg) • half-life: 13-103 days!!! • loading takes 15-30 days • liver metabolism Toxicity: • bradycardia, heart block, heart failure • pulmonary fibrosis (5-15%) at higher doses • deposited in tissues, cornea (yellowish-brown), skin (grayish-blue), photodermatitis • thyroid disfunction • liver toxicity • constipation Uses: • effective against both supraventricular and ventricular arrhythmias • considered for expanded use, prior to administration of lidocaine, in patients receiving ACLS for ventricular fibrillation/pulseless ventricular tachycardia; o this recommendation is based on the ARREST trial of amiodarone pre-hospital use for resuscitation of cardiac arrest due to ventricular fibrillation. • ACLS algorithms also include amiodarone as a recommended antiarrhythmic for the treatment of stable ventricular tachycardia during cardiopulmonary resuscitation • although amiodarone possesses many adverse effects, some of which are severe and potentially fatal, it has not been associated with proarrhythmic effects as frequently as other antiarrhythmics have |
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Sotalol
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• racemic mixture of isomers
o l-isomer: nonselective beta blocker (Class II) o d-isomer: prolongs action potential duration (Class III) • has no intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity (Class I) • used in ventricular and supraventricular arrhythmias • orally effective, excreted by the kidney Toxicity: • adverse effects of beta receptor blockade • torsade de pointes |
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Bretylium
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• parenteral Class III antiarrhythmic agent
• increases the action potential duration without affecting 0 phase depolarization or resting membrane potential of ventricular tissue • it was originally investigated for use as an antihypertensive • it is indicated for the treatment of ventricular fibrillation and unstable ventricular tachycardia, although it is not considered a first-line agent. • the ECC/AHA 2000 guidelines have removed bretylium from all ACLS algorithms due to its high incidence of adverse effects • clinically, bretylium causes an initial increase in blood pressure and heart rate; these effects are short-lived and are followed by adrenergic blockade resulting in vasodilation and, commonly, hypotension. Tolerance to the hypotension develops after several days of therapy, although increased sensitivity to circulating catecholamines ensues Pharmacokinetics • administered via IV or IM injection • duration of action 6-24 hours, • antifibrillatory effects beginning within minutes following IV injection, and suppression of ventricular tachycardia beginning within 20 minutes-6 hours following IM or IV injection. • 70-80% is excreted unchanged in the urine • half-life in patients with normal renal function is 4-17 hours, while the half-life in patients with impaired renal function is 31-105 hours. Bretylium clearance is directly correlated with creatinine clearance. Adverse effects • hypotension and orthostatic hypotension are the most common adverse cardiovascular • increased arrhythmias (e.g., premature ventricular contractions (PVCs), ventricular tachycardia) • sinus bradycardia, sensation of substernal pressure, and precipitation of angina |
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Ibutilide
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• intravenous Class III antiarrhythmic agent
• indicated for rapid conversion of atrial fibrillation or atrial flutter to normal sinus rhythm • ibutilide exerts its actions by promoting the influx of sodium through slow inward sodium channels and prolongs the action potential duration • causes a mild slowing of the sinus rate and AV conduction. • converts atrial fibrillation or flutter to normal sinus rhythm without altering blood pressure, heart rate, QRS duration, or PR interval. Pharm-31-pdf-21 |
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Dofetilide
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• class III antiarrhythmic used for the conversion and maintenance of normal sinus rhythm in atrial fibrillation/flutter
• primarily effective for supraventricular arrhythmias • selective and potent blocker of potassium channels and prolongs ventricular refractoriness • lacks negative inotropic properties • administered orally, bioavailability is greater than 90% • maximal plasma concentrations occurring in about 2—3 hours in fasted patients • half life of dofetilide is approximately 10 hours; • 80% of a single dose of dofetilide is excreted in urine Adverse effects • serious arrhythmias and cardiac conduction disturbances may occur with dofetilide • torsade de pointes and QT prolongation • ventricular fibrillation • headache, chest pain, dizziness, respiratory tract infection, dyspnea, influenza syndrome, insomnia Pharm-31-pdf-21 |
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Verapamil
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Mechanism and effects:
• blocks slow cardiac Ca++ channels • slows AV nodal conduction, decreases heart rate • the atrial arrhythmias that depend upon A-V-Nodal Re-entry are interrupted • most pronounced effects are on the heart, less on the periphery • effective in supraventricular tachyarrhythmias • causes peripheral vasodilation, and relaxes smooth muscle • also an effective antihypertensive and antianginal agent Pharmacokinetics: • administered I.V. or orally • up to 70% of administered dose is excreted by the kidneys • undergoes "first pass" hepatic metabolism after oral use Toxicity: • minimal after oral use • G.I. intolerance, constipation are more common • bradycardia, negative inotropic effect, A-V block, etc. may be encountered upon I.V. use • contraindicated in the presence of CHF and A-V conduction defects • avoid combined use of Verapamil and beta-blockers, since both drugs will markedly reduce ventricular contractility, and enhance A-V transmission failureTherapeutic uses: • reentrant supraventricular tachycardia is the major indication for Verapamil (adenosine is the drug of choice). • reduces ventricular rate in atrial flutter and atrial fibrillation • it is rarely effective in ventricular arrhythmias Caution: Proper differentiation between ventricular tachycardia and supraventricular tachycardia (SVT) is crucial when administering verapamil. Although verapamil may be effective in treating supraventricular tachycardia, administration to patients with ventricular tachycardia can cause ventricular fibrillation, severe hemodynamic deterioration, or death. Pharm-31-pdf-22 |
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Diltiazem
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• calcium-channel blocking agent most similar to verapamil
• inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes • reduces heart rate • increases exercise capacity and improves multiple markers of myocardial ischemia • may increase cardiac output (decreased peripheral resistance), reduces left ventricular workload • improves myocardial perfusion Pharmacokinetics: • oral absorption, I.V. available • dose-dependent kinetics, predisposing patients to accumulation with repeated dosing • half-life of diltiazem ranges from 3.5—9 hours and is usually 4—6 hours Uses: • in the treatment of paroxysmal supraventricular tachycardia and to control of ventricular rate in atrial fibrillation and flutter • for the management of Prinzmetal's variant angina, stable angina pectoris, hypertension • prevention of injury following angioplasty. Adverse effects: • similar to those of verapamil Pharm-31-pdf-23 |
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Bepridil
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• rarely used, primarily to control refractive angina
• prolongs action potential and QT (danger of torsade de pointes) Pharm-31-pdf-24 |
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Adenosine as an antiarrhythmic
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• adenosine is a nucleoside that occur naturally throughout the body
• very effective in suppressing Paroxysmal Supra Ventricular Tachycardia (PSVT) and WPW Syndrome • effective against only those arrhythmias that depend on "reentry” mechanism • does not convert ordinary atrial flutter, or atrial fibrillation to normal sinus rhythm. Mechanism of action • adenosine slows conduction in the A-V node and thereby interrupts "Reentry Pathways" through A-V node. • the ventricular slowing is not blocked by atropine but may be blocked by caffeine • its mechanism of action involves enhanced K+ conductance and inhibition of cAMP-induced Ca++ influx. Pharmacokinetics • Route - I.V. injection • duration is very short, 10-12 seconds, t½ is less than 10 seconds • Metabolism - Adenosine → Inosine → AMP (inactive) Toxicities • very low at recommended dose • flushing • shortness of breath • chest burning • bronchospasms • headache • hypotension • nausea • paresthesia Contraindications • A-V Block • Sick Sinus Syndrome Therapeutic Uses • PSVP (dependent upon reentry pathways) • Wolff-Parkinson-White Syndrome • Adenosine is currently the drug of choice for prompt management of paroxysmal supraventricular tachycardia (PSVT) because of very high efficiency (90-95%) and very short duration of action. Pharm-31-pdf-24 |
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Magnesium as an antiarrhythmic
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• originally used for patients with digitalis induced arrhythmias who were hypomagnesemic
• has antiarrhythmic effect in patients with normal magnesium levels • may affect potassium, sodium, calcium channels, Na+/K+ATPase, mechanism unknown • intravenous administration of magnesium sulfate produces an immediate effect that lasts for about 30 minutes Uses • digitalis induced arrhythmias • torsade de pointes • the management of seizures and/or hypertension seizures associated with severe toxemia of pregnancy (e.g., eclampsia) Pharm-31-pdf-25 |
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Potassium as an antiarrhythmic
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• both insufficient and excess potassium are arrhythmogenic
• potassium therapy is directed toward normalizing potassium gradients and pools in the body • increasing serum K+ decreases (depolarizes) resting potential • increasing serum K+ has membrane potential stabilizing action by increased potassium permeability Pharm-31-pdf-25 |
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All of the anticoagulant lecture before page 6
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yep
probably the rest wont make sense without it anyway |
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Heparin sodium
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Anticoagulant
Regular heparin is injected exclusively i.v. (NOT IM – hematoma) • It is mainly cleared by heparinase in the liver • Endogenous heparin is found in mast cells, in the plasma, and in the endothelial layer of mast cells • Heparin is a heterogeneous mix of sulfated mucopolysacharides • Mechanism o Activity is dependent on AT III o Accelerates 1000-fold the inactivation of factors IXa, Xa, and IIa (thrombin) by AT III (Affects factors XIIa and XIIIa as well). • Heparin is a catalyst – stays active after releasing from the inactivated clotting factor • Heparin inhibits blood clotting both in vivo and in vitro • Increases activated partial thromboplastin time (aPTT) • Onset of action is immediate, half-life is 50-150 minutes, depending on dose • Therapeutic target is aPTT 2-2.5 times normal for a patient with venous thrombi to prevent pulmonary emboli • Duration of action is greatly increased by low body temperature (e.g. in cardiac bypass surgery) • Action is prolonged in patients with renal or hepatic dysfunction • Heparin is a catalyst – stays active after releasing from the inactivated clotting factor • Heparin inhibits blood clotting both in vivo and in vitro • Increases activated partial thromboplastin time (aPTT) • Onset of action is immediate, half-life is 50-150 minutes, depending on dose • Therapeutic target is aPTT 2-2.5 times normal for a patient with venous thrombi to prevent pulmonary emboli • Duration of action is greatly increased by low body temperature (e.g. in cardiac bypass surgery) • Action is prolonged in patients with renal or hepatic dysfunction Pharm-39 |
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Protamine sulfate
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• Specific antagonist to heparin
• Note that in the absence of heparin, protamine interacts with platelets and fibrinogen, producing anticoagulant effect • Adverse cardiovascular responses include hypotension due to histamine release, pulmonary hypertension, and allergic reactions Lepirudin (Refludan) • Recombinant form of hirudin, a natural anticoagulant from leeches • Highly specific direct inhibitor of thrombin, does not require antithrombin III • Given intravenously as alternative in heparin-induced thrombocytopenia • Cleared by kidney, so in patients with poor renal function, use argatroban Pharm-39 |
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Warfarin (Coumadin)
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• Given orally
• Long plasma half-life (36h) • Prevents reduction of vitamin K and interfere with processing of clotting factors II, VII, IX and X • Acts only in vivo • Effect can take from 12-16 hours to develop, because the drugs inhibit production of new factors, and there is no effect until the old factors have decayed • Effect lasts 4-5 days • Therapy is complicated because the peak effect of the drug occurs after 48 hours, numerous conditions affect the actions of the drug, and numerous drugs interact with it • Administration o Initiation of therapy is begun slowly over about a week o The therapeutic range is defined in terms of an international normalized ratio (INR), which is a function of the prothrombin time o The target INR should be 2 to 3 for most indications (INR=3 is equivalent to a prothrombin time ration of about 1.6) • Drug Interactions (What doesn’t interact with warfarin?) Please READ the section in Katzung on warfarin’s drug interactions (P. 596) o Drugs which decrease availability of vitamin K or alter the level of clotting factors will interact with anticoagulants o Agents that impair platelet aggregation and platelet function, such as aspirin, can cause serious bleeding if given to a patient on anticoagulants. o Warfarin is 98% bound to plasma albumin. Agents that displace oral anticoagulants from binding sites on plasma albumin will increase free levels of warfarin. These include phenylbutazone, and ethacrynic acid. o Agents that inhibit microsomal liver enzymes, such as cimetidine, chloramphenicol, imipramine, and metronidazole increase concentration o Drugs that induce liver microsomal enzymes (barbiturates) decrease warfarin effect o Pregnancy and oral contraceptives decrease the effects of warfarin o Antibiotics may alter effects, as Vitamin K is synthesized by intestinal flora • Toxicity o Hemorrhage, especially into the bowel, which can be dangerous because it may not be noticed quickly o Bleeding into spaces where compression damage may occur (intracranial, pericardial, nerve sheath, spinal cord) is also very serious o Contraindicated in pregnancy – warfarin crosses the placenta and causes birth defects o Warfarin quickly reduces levels of protein C which has a short half-life. Warfarin-induced thrombosis causing cutaneous necrosis and infarction can occur during early therapy • Reversal of action o Vitamin K1 (Mephyton) with discontinuation of warfarin o Fresh frozen plasma o Factor IX concentrates (Konyne 80, Proplex T) • Therapeutic Uses o The oral anticoagulants are used clinically to prevent development of emboli o They have no effect on already formed thrombi o Uses include: Prevention of deep vein thrombosis resulting from bed rest, cardiac failure, pelvic, abdominal, or hip replacement surgery Reduce the incidence of thromboembolism associated with prosthetic heart valves and atrial fibrillation in the presence of rheumatic heart disease Pharm-39 |
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Dabigatran
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• Administered orally
• Therapeutic uses: o Approved October 2010 o Prevention of stroke in patients with non-valvular atrial fibrillation • Toxicity o Bleeding o Do not use: Severe renal failure (GFR < 15mL/min) Advanced liver disease • Short shelf life (30 days) Pharm-39 |
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Rivaroxaban
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• Administered orally
• Inhibitor of factor Xa • Therapeutic uses: o Approved July 2011 o Prevention of deep vein thrombosis (DVT) that may lead to pulmonary embolism (PE) after hip replacement or knee replacement surgery • Toxicity o Bleeding o Avoid use in patients with: Renal failure (GFR < 30mL/min) Liver disease Pharm-39 |
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Streptokinase
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• Forms a complex with plasminogen, increasing fibrinolytic activity
• Administered intravenously or by intravascular catheter, slowly • Can cause allergic responses, anaphylaxis, and pyrexia • Not fibrin specific, causes generalized systemic fibrinolysis • With aspirin, is as effective as other fibrinolytics • May lose efficacy after first course of treatment due to antibody formation Pharm-39 |
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Urokinase
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• Acts directly as a plasminogen activator
• Not fibrin specific • Given intravenously Pharm-39 |
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Anistreplase
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• Mixture of plasminogen and streptokinase that has been protected and rendered inert by acylation
• The acyl group hydrolyzes in the blood, and the compound then becomes fibrinolytic • Has a long duration of action • More clot selective than streptokinase and can be administered more rapidly • Causes considerable fibrinogenolysis and is antigenic Toxicity • The main hazard with these drugs is potentially serious bleeding • Bleeding is treated with tranexamic acid, and if necessary, whole blood • Streptokinase may cause allergic reactions and often causes fever Pharm-39 |
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Aminocaproic acid
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• Chemically similar to lysine
• Completely inhibits plasminogen activation o Inhibits streptokinase and urokinase activity and prevents formation of plasmin • Used for bleeding disorders o Adjunct in hemophilia o Reversal of fibrinolytic therapy o Prophylaxis against re-bleeding in intracranial aneurysms Pharm-39 |
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Tranexamic acid
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• Similar to aminocaproic acid
• Inhibits plasminogen activation and thus prevents fibrinolysis • Used to treat bleeding or when there is a risk of bleeding • Very useful in upper gastrointestinal hemorrhage Toxicity • These two drugs can cause intravascular thrombosis • Other adverse effects include: hypotension, myopathy, GI discomfort, and nasal stuffiness Pharm-39 |
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Aspirin
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• Inhibits thromboxane A2 synthesis in platelets and thus decreases platelet aggregation
• Effects on the platelet are irreversible and last the life of the platelet (7-10 days) • A single dose may prolong bleeding time for days • May be useful in patients at risk for embolisms • 325 mg/d FDA approved for primary prevention of MI • Should not be taken before dental procedures or surgery • When combined with warfarin, dose of warfarin should be adjusted appropriately Pharm-39 |
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Clopidogrel
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• Inhibit platelet aggregation
• Inhibits the ADP pathway in the platelet • Does not affect prostaglandin metabolism like aspirin does • Given orally • Used in patients who are allergic to aspirin; less GI bleeding than aspirin • Ticlopidine may cause rare but severe bone marrow toxicity; clopidogrel does not • Both can cause bleeding, nausea and diarrhea in many patients • Used to reduce thrombotic events following myocardial infarction and stroke • Used to prevent thrombosis in patients undergoing placement of coronary stents Pharm-39 |
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Abciximab
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• Inhibit platelet aggregation by inhibiting GP IIb/IIIa receptors
o Prevent binding of fibrinogen and von Willebrand factor to the GP IIb/IIIa integrin receptor • Combined with heparin in patients undergoing percutaneous coronary intervention • Used in patients undergoing angioplasty, atherectomy, and stent placement • Used in unstable angina not responding to conventional therapy • Given intravenously • Abciximab is an antibody (humanized Fab fragment); eptifibatide is a cyclic peptide; tirofiban is not a peptide, so lasts longer in the circulation • Toxicity o bleeding o thrombocytopenia • These drugs are very expensive (Abciximab ~$1500/dose) Pharm-39 |
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Cilostazol
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• Oral
• Phosphodiesterase III inhibitor • Promotes vasodilation and inhibits platelet aggregation • Used to treat intermittent claudication • Contraindicated with CHF Pharm-39 |
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Fondaparinux
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• Similar to Enoxaparin (LMWH)
• Binds factor Xa Pharm-39 |
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Bivalirudin
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• Similar to lepirudin
• Direct inhibitor of thrombin • Inhibits platlet activation • 20% renal, 80% metabolic clearance • Approved for use in percutaneous coronary angioplasty Pharm-39 |
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Argatroban
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• Direct inhibitor of thrombin
• FDA approved for use in patients with heparin-induced thrombocytopenia • Cleared by liver, avoid use in patients with hepatic insufficiency • Administered by continuous IV infusion Pharm-39 |
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Arnica
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• An herbal product purported to relieve bruising and help reduce pain and inflammation associated with skin wounds and infections
• A 1998 scientific review of eight controlled studies revealed no scientific evidence to support these claims (Ernst E, Pittler MH. Efficacy of homeopathic arnica: a systematic review of placebo-controlled clinical trials. Arch Surg. 1998;133:1187-1190) • Arnica is not safe for internal use • Repeated external application can lead to inflammation and allergic reactions Pharm-39 |
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Niacin
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Effects and mechanism
• a water-soluble vitamin that is excreted in the urine • lowers plasma VLDL and LDL by inhibiting VLDL secretion also inhibits hepatic cholesterologenesis • increased clearance in the lipoprotein lipase pathway • increases levels of HDL (most effective agent) Pharmacokinetics • oral absorption, renal excretion Uses • most effective in heterozygous familial hypercholesterolemia especially when combined with bile acid-binding resin • also effective in familial combined hyperlipoproteinemia, familial dysbetalipoproteinemia, and hypercholesterolemia\ Adverse effects • toxic effects are generally mild • cutaneous vasodilation, warm sensation, pruritus, dry skin o prostaglandin dependent o small dose of aspirin prevents it • nausea and abdominal discomfort • may elevate aminotransferases or alkaline phosphatase, impair glucose tolerance, • hyperuricemia • rarely may cause severe hepatotoxicity Pharm-37 |
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Fibric acid derivatives:
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Gemfibrozil, Clofibrate, fenofibrate
Effects and mechanism • function primarily as a ligand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-alpha (PPAR-α) • they produce ↑ lipoprotein lipase activity to promote catabolism of VLDL ↓ triglycerides by lowering VLDL concentration ↓ cholesterol by inhibiting hepatic cholesterologenesis Pharmacokinetics • oral absorption, high plasma protein binding, renal excretion is about 70% • enterohepatic circulation, half-life = 1.5 hr Uses • effective in o familial dysbetalipoproteinemia and o hypertriglyceridemia • ineffective in o primary chylomicronemia and o familial hypercholesterolemia Adverse effects • skin rashes, GI symptoms, arrhythmias, hypokalemia, myopathy • ↑ blood aminotransferases and alkaline phosphokinase • ↑ incidence of cholelithiasis or gallstones • potentiate anticoagulant action of indanedione and coumadin • inhibits the metabolism of statins • clofibrate is seldom used because it increases risks for gastrointestinal and hepatobiliary neoplasms Pharm-37 |
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Bile Acid-Binding Resins
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colestipol, cholestyramine and colesevelam
Effects and mechanism • large cationic exchange resins that are insoluble in water • have an unpleasant sandy or gritty quality • act by binding bile acids and prevent their intestinal reabsorption o reduction in bile acids increases the expression of hepatic LDL receptors to increase uptake of plasma LDL o the reduced LDL levels will lower plasma cholesterol Pharmacokinetics • they are not absorbed • should be taken with meals (bile production is needed for effect) Uses • effective whenever LDL is elevated as in o heterozygous familial hypercholesterolemia, and o combined hyperlipoproteinemia • no effect in homozygous familial hypercholesterolemia - no functional receptors • not effective in hypertriglyceridemia Adverse effects • the safest hypolipidemics because they are not absorbed • most common toxic effects are constipation and bloating • steatorrhea may occur in patients with cholestasis • gallstone formation may be enhanced in obese patients • may cause hypoprothrombinemia due to vitamin K malabsorption • may impair absorption of certain drugs like digitalis, thiazides, tetracycline, thyroxine, or aspirin Pharm-37 |
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HMG-CoA Reductase Inhibitors
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lovastatin
Effects and mechanism • lovastatin and simvastatin are inactive and have to be hydrolyzed to form the active beta-hydroxyl derivatives • atorvastatin, fluvastatin, and pravastatin are already active • active forms are structural analogs of HMG-CoA reductase intermediate in mevalonate synthesis • reduce plasma LDL by inhibiting the reductase to increase high-affinity LDL receptors • decrease plasma triglycerides and increase HDL cholesterol • although the statins exert their main therapeutic effect on CHD by lowering LDL they may exert other beneficial effects as well, they o decrease C-Reactive Protein (CRP) in patients with CHD o enhance the endothelial production of NO o increase plaque stability o reduce lipoprotein oxidation o decrease platelet aggregation Pharmacokinetics • high first pass, liver metabolism, GI excretion • given in the evening (diurnal pattern of cholesterol synthesis) Uses • most effective when plasma LDL is elevated as in o heterozygous familial hypercholesterolemia or o combined hyperlipoproteinemia Adverse effects • elevation of serum aminotransferase • may produce liver damage in alcoholics or patients with preexisting liver problems • increased serum creatine kinase activity - associated with physical activity • rhabdomyolysis - myoglobinuria → renal shutdown • all statins are contraindicated in pregnancy (category X) Drug interactions • macrolides, cyclosporine, ketoconazole, verapamil and ritonavir increase the plasma concentrations of statins • phenytoin, griseofulvin, barbiturates, rifampin decrease the plasma concentrations of statins • grapefruit juice enhances bioavailability • gemfibrozil inhibits their metabolism Pharm-37 |
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Inhibitor of cholesterol absorption
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Ezetimibe (Zetia)
• selectively blocks the intestinal absorption of cholesterol and related phytosterols • when used as monotherapy, ezetimibe reduces LDL-cholesterol by about 18%, compared with more potent reductions (25—40%) typically achieved with statin monotherapy • combining ezetimibe with a statin results in synergistic cholesterol-lowering effects o when used in combination with 10—80 mg of either simvastatin or atorvastatin, combined use with ezetimibe achieves LDL reductions of approximately 51 or 56%, respectively, compared to LDL reductions of 36% with simvastatin or 44% with atorvastatin monotherapy • metabolized by glucuronidation, no important interactions are known • enterohepatically recirculated • discontinuation rate due to adverse events during ezetimibe therapy was similar to placebo Pharm-37 |
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Orlistat
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• Therapeutic use: weight loss
• Mechanism: inhibits pancreatic lipase → ↓ triglyceride breakdown in the intestine • Side effects: oily stools (steatorrhea), diarrhea; ↓ absorption of lipid-soluble vitamins Pharm-37 |
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Charts and Stuff in lecture 37, plus you've got to review monrmal lipid metabolism
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yep
Pharm-37 |
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Classic or atherosclerotic
"angina of effort" |
atheromatous obstruction of large coronary vessels
especially with exercise if uncontrolled by drugs may require coronary bypass or angioplasty Pharm-36 |
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Variant or angiospastic or Prinzmetal’s
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spasm or constriction in atherosclerotic coronary vessels
reversed by nitrates or calcium channel blockers Pharm-36 |
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Pathophysiology of myocardial ischemia
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• myocardial ischemia results from an imbalance between oxygen (O2) supply versus O2 demand
• O2 demand depends on cardiac workload which is determined by: heart rate, myocardial contractility, and ventricular wall tension • wall tension representing the force developed during contraction is increased by ↑ pressure and/or ↑ volume, any ↑ in heart rate or contractility will ↑ the need for O2 • O2 supply depends on myocardial delivery and extraction; even at rest O2 extraction is already almost maximal; the heart normally extracts 75% of the O2 in arterial blood • consequently, additional O2 can be made available only by increasing O2 delivery through coronary blood flow • coronary blood flow (CBF) is directly related or proportional to: o perfusion pressure, and o duration of diastole Pharm-36 |
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Nitrates and nitrites
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Actions and effects
• nitrates cause vasodilation by releasing nitrite ion → metabolized to nitric oxide → activates guanylyl cyclase → increases cGMP → relaxes vascular smooth muscles • all vascular smooth muscle cells are relaxed but vasodilation is uneven (1) large veins are markedly dilated to ↑ venous capacitance and decrease preload (2) arterioles and precapillary sphincters are dilated less and arteriolar dilation will decrease afterload • cardiac workload is reduced by the decrease of both preload and afterload • on the other hand, nitrates can also increase cardiac workload by lowering BP → reflexively increases sympathetic activity → increases heart rate and myocardial contractility; reflex tachycardia will shorten the time for diastolic perfusion • thus, nitrates can exert both beneficial and harmful effects • two mechanisms for anginal relief during nitrate therapy are: o predominant relief mechanism: ↓ myocardial O2 requirement due to marked dilation of large veins, decreasing preload and cardiac work, and o secondary relief mechanism: redistribution of regional coronary blood flow from normal to ischemic areas even though total flow remains unchanged • nitrates also relax other smooth muscles in bronchi, and in gastrointestinal and genito-urinary tracts Other effects • decreased platelet aggregation and production of methemoglobin from reaction of nitrite ion with hemoglobin • sodium nitrite is used to induce methemoglobin formation for treatment of cyanide poisoning because methemoglobin has a very high affinity for cyanide ion • nitrates have been used as sex-enhancing drugs to enhance erection by relaxing smooth muscles in the corpora cavernosa Absorption and Metabolism • composition varies widely from volatile liquids such as amyl nitrite or nitroglycerin to a solid like isosorbide dinitrate • oral organic nitrates are metabolized rapidly by a hepatic reductase (high first pass) • routes of administration: inhalation, sublingual, oral, or transdermal • the sublingual route avoids hepatic destruction and is preferred for rapid absorption especially of nitroglycerin and isosorbide dinitrate • the fastest acting preparations are: o inhaled amyl nitrite o intravenous nitroprusside • sublingual nitroglycerin is used for immediate anginal relief because its action is rapid onset (1-3 min) and of short duration (10-30 min) Adverse Effects • acute toxicity may cause pronounced vasodilation leading to orthostatic hypotension, tachycardia, throbbing headaches (overextension of pharmacological actions) • frequent repeated exposure to nitrates results in tolerance or a marked reduction in the magnitude of most effects • people who manufacture explosives are chronically exposed to high nitrate levels. This may cause tolerance leading to "Monday disease". Headache and dizziness on Mondays because of the tolerance to the nitrates diminishes on weekends; symptoms gradually disappear during weekdays as tolerance develops again with continuous exposure The combination of sildenafil and nitrites is contraindicated. Pharm-36 |
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Calcium Channel Antagonists
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Actions and Effects
• intracellular calcium has two important functions: o triggers muscular contraction in both the myocardium and vascular smooth muscles o required for pacemaker activity of the SA node and for conduction through the AV node • two major types of calcium channels in the cardiovascular system are the L- (long-lasting) and T- (transient) channels. Calcium ions flow thru open pores in the calcium channels. • in heart and vascular smooth muscle calcium channels are: o opened by β-adrenergic stimulation to enhance calcium entry and o closed by CCAs to inhibit calcium entry • CCAs are orally active drugs that bind to L-type channels in the myocardium and vascular smooth muscles • binding with CCAs will close pores on the calcium channel to cause o ↓ transmembrane calcium current o long-lasting relaxation of vascular smooth muscles, and o ↓ cardiac contractility, automaticity, and conduction • CCAs will relax all smooth muscles that depend on calcium for normal resting tone and contraction • vascular smooth muscle is the most sensitive, but bronchiolar, gastrointestinal, and uterine muscles are also relaxed • among blood vessels, arterioles are more sensitive than veins • major cardiac effects are: o negative inotropic effect due to decreased contractility, o reduced impulse generation in the SA node, and o slowed AV node conduction • of the 3 prototypes, o nifedipine is the strongest vasodilator, o verapamil has the strongest cardiac effects, and o diltiazem is in-between nifedipine and verapamil • differences in tissue selectivity can result in opposite effects on heart rate, as heart rate would be increased by nifedipine but slowed by verapamil • nifedipine is most likely to produce reflex tachycardia because it causes the most pronounced vasodilation → marked hypotension → reflex sympathetic hyperactivity with little or no inhibition of SA or AV nodal function • verapamil and diltiazem are not as likely to elicit reflex tachycardia because o they have weaker vasodilator effects and o they slow the heart by directly depressing SA and AV node function • as with nitrates, CCAs for treatment of angina can have beneficial as well as harmful effects • nifedipine and other dihydropyridines: o beneficial effects or anginal relief are due to: coronary vasodilation → ↑ myocardial O2 supply coronary vasodilation → ↓ afterload o the harmful effect is enhanced development of myocardial infarction because rapid hypotension → reflex sympathetic activation which will ↑ cardiac workload • verapamil and diltiazem: o beneficial effects or anginal relief are due to ↓ cardiac workload resulting from: ↓ myocardial contractility bradycardia caused by ↓ SA node automaticity and AV node conduction o the harmful effect is the potential to cause serious cardiac depression that could end in cardiac arrest, A-V block, or CHF • other CCA effects include: inhibition of insulin secretion and interference with platelet aggregation Pharmacokinetics • oral administration with considerable first pass effect (bioavailability varies from 25 – 75%) • liver metabolism is minimal (1-10 %), renal excretion accounts for the majority of elimination • half life: 3 – 5 hours. Slow release formulations allow once a day dosing (except amlodipine and bepridil with half-lives of 40 and 25 hours, respectively, so there is no need for slow release formulation). Adverse effects • CCAs in general may cause minor side-effects of flushing, edema, dizziness, nausea, and constipation • some may increase plasma digoxin and enhance digoxin toxicity • verapamil and diltiazem should not be used in patients with ventricular dysfunction or SA-AV node disturbances Pharm-36 |
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ß-adrenergic blockers used for treatment of angina
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atenolol, metoprolol, propranolol, nadolol
Actions and Effects • cardiovascular effects are due to ß-adrenergic blockade at 3 organs: • heart to reduce cardiac output • kidneys to reduce renin secretion • CNS to reduce sympathetic vasomotor tone • the major effects are both cardiac and vascular • beneficial effects: anginal relief from ß-adrenergic blockade due to: • ↓ sympathetic activation → ↓ cardiac activity and ↓ vasoconstriction → hypotension and bradycardia → ↓ cardiac workload = ↓ myocardial O2 demand • bradycardia would also increase myocardial perfusion time ß-adrenergic blockade is ineffective in producing coronary vasodilation! harmful effect: ß-adrenergic blockade may induce or worsen CHF whenever sympathetic activity provides critical support for cardiac performance, as in patients with acute myocardial infarction, cardiomegaly, or compensated heart failure Adverse effects • bronchoconstriction can be life-threatening in asthmatic patients • plasma triglycerides may increase • recovery from insulin-induced hypoglycemia is delayed • may produce CNS side-effects of fatigue, depression, and sleep disturbances• can be potentially harmful in variant angina because by slowing heart rate and prolonging ejection time → left ventricular end-diastolic volume increases → increase myocardial O2 requirement Pharm-36 |
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Ranolazine
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Mechanism of action:
• it is a partial fatty-acid oxidation (PFox) inhibitor • also inhibits late inward sodium current • decreases left ventricular wall stiffness, improves coronary circulation Pharmacokinetics: • administered orally 73% of the dose is systemically available • rapidly and extensively metabolized within the liver and intestine by CYP3A isoenzymes and to a lesser extent by CYP2D6 isoenzymes, it is also a substrate of P-glycoprotein • approximately 75% of an oral dose of ranolazine is excreted in urine; 25% is excreted in feces Uses: • for the treatment of chronic stable angina in patients who have failed to respond optimally to, or are intolerant of, other anti-anginal medications • reserve for treatment of adult patients who have not achieved a satisfactory response to other antianginal drugs Adverse effects: • dizziness • headache • constipation • nausea/vomiting Contraindications: • hypokalemia • QT prolongation • renal failure • torsade de pointes • ventricular arrhythmias • ventricular tachycardia Pharm-36 |
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Treatment of Angina Pectoris
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• effective therapy will:
o increase exercise tolerance, and o decrease frequency and duration of myocardial ischemia • for variant or angiospastic angina, nitrates and CCAs are more effective than ß-adrenergic blockers (because ß-blockers will not dilate spastic coronary blood vessels) • various combinations of the 3 major drug classes can be used • among the most effective drug combinations are: • ß-adrenergic blockers and CCAs, or • 2 CCAs (e.g. nifedipine and verapamil) • potentially harmful effects of CCAs or ß-adrenergic blockade can be prevented by combined treatment with nitrates and vice versa • reflex tachycardia can be minimized by combining nitrates with CCAs or ß-adrenergic blockers Pharm-36 |
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Sildenafil (Viagra)
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• an oral drug for the treatment of male erectile dysfunction
• selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) • originally developed as an antianginal agent, was found to be more effective in the treatment of impotence • administered orally, as opposed to other therapies for impotence which require direct injection into the penis or insertion of a urethral suppository • also shown efficacy in treating pulmonary hypertension • an oral drug for the treatment of male erectile dysfunction • selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) • originally developed as an antianginal agent, was found to be more effective in the treatment of impotence • administered orally, as opposed to other therapies for impotence which require direct injection into the penis or insertion of a urethral suppository • also shown efficacy in treating pulmonary hypertension • Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug Pharmacokinetics • rapidly absorbed after oral administration, with absolute bioavailability of about 40%. • its pharmacokinetics are dose-proportional over the recommended dose range • maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state • half-life: 4 hours • sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes Adverse effects • generally transient and mild to moderate in nature • adverse events reported by >= 2% of patients treated with sildenafil and which were more frequent on drug than placebo in as needed flexible-dose phase II/III studies include o headache (16% vs. 4%), o flushing (10% vs. 1%), o dyspepsia (7% vs. 2%), o nasal congestion (4% vs. 2%), o urinary tract infection (3% vs. 2%), o visual impairment including mild and transient color tinge to vision, photophobia or blurred vision Contraindications • Sildenafil is not indicated for use in pregnant or lactating women or in infants or children Interactions • administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated • Concurrent dosing with sildenafil and alpha blockers may lead to symptomatic hypotension in some patients • inhibitors of CYP 3A4 and 2C9 isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects • the manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as... Pharm-36 |
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Vardenafil
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• similar to sildenafil
• vardenafil is more selective for PDE5 than PDE6, which is present in the retina • this leads to fewer visual adverse effects such as those reported in sildenafil-treated patients • the advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil or tadalafil, which may result in a faster onset of action Pharm-36 |
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endothelins
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• a family of peptides, termed endothelins, is stored in vascular endothelial cells
• their release produces contraction of vascular smooth muscle • endothelins probably counterbalance the effects of NO Pharm-39 |
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Bosentan
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• belongs to a group of compounds known as endothelin-receptor antagonists
• it is only indicated for use in severe pulmonary hypertension. • itt is a specific and competitive antagonist at both type A and B endothelin-1 receptors • it is associated with a high frequency of elevated hepatic enzymes, potential teratogenic effects, and multiple drug interactions • administered orally • bosentan is extensively metabolized by, and a significant inducer of, CYP2C9 and CYP3A4 isoenzymes Pharm-39 |
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blew through a bunch of stuff in htn lecture up until Ganglion blockers, and then all the stuff after adrenergic neuron blockers until K+ channel regulators
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sorry
and also everything after fendolapam Pharm-33 |
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Adrenergic Neuron Blockers
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guanethidine (Ismelin)
reserpine (Serpasil) Mechanism of Action • act by binding to secretory vesicles that normally store and release norepinephrine in peripheral adrenergic nerve endings • reserpine o inhibits the active transport of NE into the vesicle o released NE is metabolized by MAO enzyme o serious interaction with MAOIs • guanethidine o taken up by the nerve ending o replaces NE in the vesicles o inhibits exocytosis o interaction with TCAs, cocaine, indirect sympathomimetics • the final effect is the reduction sympathetic activity by preventing norepinephrine release • reduced sympathetic activity causes vasodilation to lower BP • usually given orally • I.V. guanethidine may elevate blood pressure by sudden release of endogenous norepinephrine, may produce hypertensive crisis in pheochromocytoma Common Adverse Effects: • rarely used for monotherapy because of unpleasant side effects • guanethidine: postural hypotension, fluid retention, diarrhea, and retrograde ejaculation for; • reserpine: sedation, psychic depression, stuffy nose, dry mouth, and gastrointestinal disturbances for Pharm-33 |
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Minoxidil (
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• opens the potassium channels and stabilizes the membrane
• dilates arterioles but not veins • oral absorption, liver metabolism, active metabolite • half-life 4 hours, effect persist for 24 hours Toxicity • tachycardia, palpitations, angina, edema • headache sweating, hypertrichosis • topical minoxidil (Rogaine) stimulates hair growth |
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Diazoxide
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• exerts its effects by hyperpolarizing (and effectively relaxing) arterial smooth muscle cells by activating ATP-sensitive potassium channels (see also insulin release)
• non-diuretic thiazide, vasodilator and hyperglycemic • produces dose related hyperglycemia by directly inhibiting insulin secretion • oral administration • fairly long duration of action (t½ = 24-36 hours) • patients should be closely watched for possible overdose; effects, such as hyperglycemia with ketoacidosis or non-ketotic hyperosmolar coma, etc. • used in patients with insulinoma • Adverse reactions o sodium and water retention, hypotension o GI irritation o hyperuricemia o thrombocytopenia, neutropenia, etc.. o excessive hair growth (most frequently in children). Pharm-33 |
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D1 receptor agonist
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Fenoldopam (Corlopam)
• specific agonist on D1 receptors • postsynaptic D1 receptor stimulation relaxes arteriolar smooth muscle • IV administration, liver metabolism, half-life: 5 minutes Toxicity: • reflex tachycardia, headache, flushing Pharm-33 |
