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661 Cards in this Set

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What is pharmacokinetics?
Deals with what the body does to the drug: absorption, distribution, sites of action, tissue storage, metabolism and excretion.
What factors are involved in drug permeation/absorption?
Solubility, concentration gradient, surface area, vascularity, ionization.
In what form can drugs cross cell membranes?
Non-ionized form (lipid soluble).
In what form are drugs excreted?
Ionized form (water soluble) are better renally excreted
What factors affect renal clearance of drugs?
The drug must be in free form, ionized or nonionized. Only nonionized drug can be actively secreted or reabsorbed.
What effect does acidification of urine have on drugs?
Increases ionized fraction of weak bases and increases their renal elimination. NH4Cl, vitamin C, cranberry juice.
What effect does alkalinization of urine have on drugs?
Increases ionized fraction of weak acids and increases their renal elimination. NaHCO3, acetazolamide.
Urine alkalinization agents
NaHCO3, acetazolamide
Urine acidification agents
NH4Cl, vitamin C, cranberry juice
What is Cmax?
Maximal drug level obtained with the dose
What is Tmax?
Time at which Cmax occurs
What is the lag time?
Time from administration to appearance in blood
What is onset of activity?
Time from administration to blood level reaching minimal effective concentraion
What is duration of action?
Time that the plasma concentration remains above minimial effective concentration
What is time to peak?
Time from administration to Cmax.
What is bioavailability?
Is the fraction of a dose that reaches the systemic circulation after 1st pass metabolism
What is the first-pass effect?
Is the decrease in bioavailability of an oral drug after passing through intestines or from the portal blood through the liver. Portal blood will always have a higher concentration of the drug before passing for the first time through the liver.
What is bioequivalence and what factors are involved?
Bioequivalence is the similarity between two formulations of the same drug. To be bioequivalent they must have the same bioavailability and the same rate of absorption.
How are rate of absorption, Tmax and Cmax related?
The faster the rate of absorption the smaller Tmax and larger Cmax. Tmax and Cmax are rate dependant.
What is distribution?
Is the process by which a drug reaches the target tissues from systemic circulation.
What factors affect distribution of a drug?
Protein-binding capacity and competition between drugs for protein-binding sites, barriers such as placenta or brain.
What is volume of distribution?
Correlates dose given with the plasma level at time X. Vd=Dose/C0. C0=[plasma] at zero time.
What is the significance of the volume of distribution?
It's needed to calculate a loading dose; when Vd is low, a high fraction of the drug is bound to proteins; when Vd is high, a big fraction of the drug is being sequestered in tissues.
Relationship between plasma concentration and volume of distribution
Inversely proportional. The higher the plasma concetration, the lower the volume of distribution
Relationship between dose and plasma concentration
Directly proportional.
What is redistribution?
Is when a lipid-soluble drug gets temporarily stored in fat tissue before being eliminated.
What is the significance of the redistribution rate?
A second dose of a CNS drug redistributes to fat in lesser amount because fat is "saturated" therefore allowing more drug to enter the CNS and increasing the duration of action.
What is biotransformation?
Is the conversion of a drug to a more water-soluble form to be excreted. A metabolite may or may not have pharmacologic action.
What is phase I biotransformation?
Modification of the drug via oxidation, reduction or hydrolysis.
What is microsomal metabolism?
Cytochrome P450 isoenzymes in the SER require NADPH for oxidation and reduction of drugs.
General inducers of the P450 enzymes
Anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin), chronic alcohol, glucocorticoids.
General inhibitors of the P450 enzymes
Proton pump inhibitors (cimetidine, omeprazole), antibiotics (chloramphenicol, macrolides, ritonavir, ketoconazole), acute alcohol, grapefruit juice, isoniazid
What is nonmicrosomal metabolism?
Hydrolysis reactions by esterases and amidases; MAO; alcohol dehydrogenases.
What is phase II biotransformation?
Modification of the drug by transferases via glucoronidation, acetylation, sulfation, gluthathione conjugation.
What are the major modes of drug elimination?
Biotransformation to inactive metabolites, excretion via the kidney, bile ducts, lungs and sweat.
What is the elimination half-life (t1/2)?
t1/2 is the time to eliminate 50% of a given amount of drug.
What is zero-order elimination rate kinetics?
A constant amount is eliminated per unit time. Independent of plasma concentration, variable t1/2.
What is first-order elimination rate kinetics?
A constant percentage of the drug is eliminated per unit time. t1/2 is constant, directly porportional to plasma levels.
Rate of elimination
Equals to GFR + active secretion - reabsorption
Clearance
Equals to free fraction * GFR or 0.7 * Vd/half life
What is steady state and when is it achieved?
Its when the rate in = rate out. 50% of SS is achieved at 1 t1/2; 90% at 3.3 t1/2; 95% at 4-5 t1/2.
How does rate of infusion affect steady state and plasma levels at steady state?
It takes the same amout of time to reach steady state but if rate of infusion increases the plasma levels at steady state will increase.
Formula: volume of distribution
Vd = D/C0
Formula: half life
t1/2 = 0.7/k or t1/2 = 0.7 x Vd/Cl
Formula: clearance
Cl = k x Vd
Formula: infusion rate
k0 = Cl x Css
Formula: loading dose
LD = Vd x Css
Formula: Maintenance dose
MD = Cl x Css x t
Relationship between half-life and elimination
Inversely proportional
Relationship between half-life and clearance
Inversely proportional
Relationship between half-life and volume of distribution
Directly proportional.
Relationship between clearance and volume of distribution
Inversely proportional
Relationship between infusion rate and clearance
Directly proportional.
Relationship between infusion rate and steady state concentration
Directly proportional.
Relationship between steady state concentration and clearance
Inversely proportional.
What is pharmacodynamics?
The effects of drugs in the body and drug receptor binding.
Affinity
Ability of the drug to bind its receptor. The closer to the y axis, the more affinity.
Potency
The quanity of drug required to produce a desired effect. The closer to the y axis, the more potent.
Efficacy
The maximal effect an agonist can achieve at the highest practical concentration. The taller the curve, the more efficacy.
What is meant by the "duality" of partial agonists?
Partial agonists can compete with full agonists for its receptor, lowering the maximal response, therefore it acts as an antagonist in the presence of a full agonist.
Effect of a competitive antagonist
Parallel shift of the dose-response curve to the right; appears to increase potency; also increases Km; reversed by increasing agonist dose
Effect of a noncompetitive antagonist
Non-parallel shift to the right; appears to decrease efficacy of agonist; partially reversed by increasing agonist dose; decreases Vmax
Physiologic antagonism
Two agonists with opposing actions antagonize each other: vasoconstrictor Vs. vasodilator
Chemical antagonism
Agonist-chemical complex lowers effect of agonist
Potentiation
Parallel shift of the curve to the left; appears to increase potency of agonist.
TD50
Dose that causes toxicity in 50% of the population
ED50
Effective dose in 50% of the population
Therapeutic index
TD50/ED50; gives a measure of the relative safety of a drug
ANS receptors and their second messenger systems
"qiss qiq siq sqs". α1, α2, β1, β2, M1, M2, M3, D1, D2, H1, H2, V1, V2
Substances with intracellular receptors
Glucocorticoids, vitamin D, thyroid hormones, gonadal steroids
Substances with ion channel receptors
Nicotine, choline esters (ACh), ganglion blockers, skeletal muscle relaxants.
Substances that interact with Gs receptors
Catecholamines, dopamine, glucagon, histamine, prostacyclin. "qiss qiq siq sqs"
Substances that interact with Gi receptors
Epinephrine, norepinephrine, Ach, dopamine. "qiss qiq siq sqs"
Substances that interact with Gq receptors
Ach, norepinephrine, angiotensin II
Phase 1 clinical testing
Dose-response studies on small group of volunteers without disease. Includes pharmacokinetics characterization.
Phase 2 clinical testing
Dose-response studies on 100 patients in comparison with placebo and a positive control. Single or double blind.
Phase 3 clinical testing
Dose-response studies on 1000 patients in comparison to placebo and positive control. Usually double blind
Phase 4 clinical testing
New drug application, marketing approval and post-marketing surveillance.
Zero-order kinetics curve
Linear kinetics or exponential kinetics on log graph
First-order kinetics curve
Exponential kinetics or linear kinetics on log graph
Dose-response curve
Bell curve. Shows absoption phase, distribution, metabolism and elimination phases.
Neurotransmitter of preganglionic neurons
Acetylcholine
Neurotransmitters of postganglionic neurons
Acetylcholine, norepinephrine, epinephrine, dopamine
Mechanism of miosis
Sphincter muscle of the pupilla has M3 receptors. Muscarinic agonists causes contraction and miosis. Muscarinic antagonists cause relaxation and mydriasis with cycloplegia.
Mechanism of mydriasis
Dilator muscle of the pupilla has α1 receptors. α1 agonists cause contraction and mydriasis without cycloplegia. Also muscarinic blockers.
Mechanism of accomodation
Ciliary muscle has M3 receptors. Muscarinic agonists cause contraction and widening of the lens for close vision. Muscarinic antagonists cause cycloplegia and stretching of the lens for far vision.
Muscarinic receptors of the eye
Sphincter of the pupilla and cilliary muscles --> M3 --> miosis and accomodation
Muscarinic receptors of the heart
SA node and AV node --> M2 --> decrease heart rate, decrease conduction velocity
Muscarinic receptors of the lungs
Bronchioles and glands --> M3 --> bronchospasm and gland secretion
Muscarinic receptors in the GI tract
Stomach, intestines --> M3 --> increased motility, cramps, diarrhea; GI glands --> M1 --> gland secretion
Muscarinic receptors of the bladder
M3 --> contraction of detrusor, relaxation of the trigone/sphincter --> urination and urinary incontinence
Muscarinic receptors of sphincters (GI, GU)
M3 --> relaxation, excep LES which contracts
Muscarinic receptors of glands
M3 --> gland secretion --> sweat, salivation, lacrimation
Muscarinic receptors in endothelium
M3 --> cause vasodilation via release of NO
Location of M3 receptros
Eye (sphincter and cilliary), smooth muscle of bronchioles, GU and GI, glands except GI, sphicters, endothelium.
Net effects of M3 receptor activation
Miosis, accomodation, salivation, lacrimation, sweating, bronchoconstriction, increased GI motility, relaxation of sphincters (except LES), release of NO (indirect vasodilation).
Net effects of M2 receptor activation
Decreased heart rate, decreased conduction velocity of AV node.
Net effects of M1 receptor activation
Gland secretions of the GI tract.
Receptors in the adrenal medulla
Nn --> secretion of epinephrine and norepinephrine
Receptors at the neuromuscular junction
Nm --> muscle depolarization and contraction
Receptors in autonomic ganglia
Nn --> net effects depend on PANS/SANS dominance
Muscarinic receptor mechanisms and second messenger systems
M1, M3 --> Gq; M2 --> Gi; Nn, Nm --> Na/K channels
Hemicholinium
Inhibits reuptake of choline decreasing Ach synthesis (anticholinergic)
Botulinum toxin
Blocks release of ACh. Used in blepharospasm, strabismus, dystonia, cosmetics.
Direct muscarinic agonists
ACh, bethanecol, methacholine, pilocarpine
Properties and use of acethylcholine
Acts on muscarinic and nicotinic receptors. Strongly hydrolised by AChE. No clinical use.
Properties and use of bethanecol
Acts on muscarinic receptors. No AChE hydrolisis. Rx.: paralytic ileus, urinary retention
Properties and use of methacholine
More muscarinic than nicotinic actions. Weakly hydrolised by AChE. Used to Dx. Bronchial hyperreactivity.
Properties and use of pilocarpine
Acts on muscarinic receptors. Not hydrolyzed by AChE. Used for Rx. of glaucoma and xerostomia.
Rx. of paralytic ileus
Bethanecol, neostigmine, pyridostigmine
Rx. of urinary retention
Bethanecol, neostigmine, pyridostigmine
Dx of bronchial hyperreactivity
Methacholine
Rx of glaucoma and xerostomia
Pilocarpine, physostigmine
Acetylcholinesterase inhibitors
Edrophonium, physostigmine, neostigmine, pyridostigmine, donepezil, tacrine, organophosphates (irreversible)
Properties and use of edrophonium
Short acting AChE inhibitor. Dx myasthenia gravis
Properties and use of physostigmine
Tertiary amine AChE inhibitor. Rx glaucoma, antidote in atropine overdose
Properties and use of neostigmine and pyridostigmine
Cuaternary amines AChE inhibitors. Rx paralytic ileus, urinary retention, myasthenia, reversal of nondepolarizing NM blockers
Properties and use of donepezil and tacrine
Lipid-soluble AChE inhibitor enters CNS. Rx Alzheimer disease.
Properties and use of organophosphates
Lipid soluble irreversible AChE inhibitors. Rx glaucoma. Also insecticides parathion, malathion and nerve gas sarin.
Dx and Rx of myasthenia gravis
Edrophonium (Dx), neostigmine, pyridostigmine (Rx)
Rx Alzheimer disease
Donepezil, tacrine
Signs and symptoms of organophosphate intoxication
"Dumbbelss" Diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation, lacrimation, salivation, sweating.
Rx of organophosphate intoxication
Atropine + pralidoxime for regeneration of non-aged AChE.
MOA pralidoxime
Removes organophosphate group from AChE thus regenerating it. Aged AChE that have just a phosphate attached cannot be regenerated.
Muscarinic blockers
Atropine, tropicamide, ipratropium, scopolamine, benztropine
Effects of muscarinic blockers
Decreased salivary, bronchiolar and sweat secretions, mydriasis and cycloplegia, hyperthermia, tachychardia, sedation, urinary retention, constipation, hallucinations
Rx of muscarinic blocker intoxication
Physostigmine
Uses of atropine
Anesthesia, management of organophosphate toxicity
Uses of propicamide
Opthalmologic mydriasis
Uses of ipratropium
Inhaled in asthma and COPD. Doesn’t enter CNS.
Uses of scopolamine
Motion sickness, sedation, short-term memory block.
Uses of benztropine
Lipid-soluble, enters CNS. Used in parkinsonism and acute extrapyramidal symptoms of antipsychotics.
Effects of ganglion blockers
Reduce the predominant autonomic tone. PANS is dominant in heart, pupil, GI, GU and sphincters. SANS is dominant in blood vessels and sweat glands.
Synthesis of catecholamines
Tyrosine + tyrosine hydroxylase --> dopa + dopa decarboxylase --> dopamine + dopamine β hydroxylase --> norepinephrine + SAM + methyltransferase --> epinephrine
MAO
Located in outer mitochondrial membrane, degrades catecholamines by oxidative deamination. MAO-A: mainly in liver metabolizes NE, 5HT and tyramine. MAO-B mainly in brain, metabolizes DA.
COMT
Located in postsynaptic membrane, degrades catecholamines by methylations (requires SAM).
Distribution of α1 receptors
Pupil dilator muscle, arterioles of skin and viscera, veins, bladder trigone and sphincter, vas deferens, liver, kidney
Distribution of α2 receptors
Presynaptic terminal, platelets, pancreas
Distribution of β1 receptors
Heart SA node, AV node, atrial and ventricular muscle, His-Purkinje, kidney
Distribution of β2 receptors
All blood vessels, uterus, bronchioles, skeletal muscle, liver, pancreas
Distribution of D1 receptors
Renal, mesenteric, coronary vasculature
α1 effects
Mydriasis, increases TPR, diastolic pressure, afterload, venous return, preload, reflex bradycardia, urinary retention, ejaculation, glycogenolysis, decreases renin release
α2 effects
Decreases NE synthesis and release, promotes platelet aggregation, decreases insulin secretion
β1 effects
Increases HR, conduction velocity, contractility, CO, oxygen consumption and renin release
β2 effects
Vasodilation, decreases TPR, diastolic pressure and afterload, uterine relaxation, bronchodilation, increases glycogenolysis in liver and muscle, increases insulin secretion
D1 effects
Vasodilation of renal, mesenteric, coronary vasculatures, increases RBF, GFR
α1 agonists
Phenylephrine, methoxamine
Uses of phenylephrine
Nasal decongestant and opthalmologic mydriasis without cycloplegia
α2 agonists
Clonidine, methyldopa
Uses of clonidine
Mild to moderate hypertension
Uses of methyldopa
Mild to moderate hypertension
Effects of β agonists on CV system
β1: increase HR, CO, pulse pressure; β2: decrease TPR, BP.
β agonists
Isopreterenol, dobutamine
β2 selective agonists
Salmeterol, albuterol, terbutaline
Uses of β2 selective agonists
Asthma and ritodrine in premature labor
Uses of isoproterenol
β1=β2: used in bronchospasms, heart blocks and bradyarrhythmias. Side effects: flushing, angina, arrhythmias
Uses of dobutamine
β1 > β2: congestive heart failure
Effects of norepinephrine on CV system
Acts on α1 (increases TPR, BP), α2 and β1 (increases HR, CO, pulse pressure). Potential reflex bradycardia.
Effects of low dose of epinephrine on CV and respiratory systems
Acts on β1 (increases HR, SV, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation)
Effects of medium dose epinephrine on CV and respiratory systems
Acts on β1 (increases HR, SV, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation), α1 (increases TPR, BP)
Effects of high dose epinephrine on CV and respiratory systems
Acts on α1 (increases TPR, BP), β1 (increases HR, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation). Potential reflex bradycardia.
Effect of adding α1 blocker to epinephrine
Reverses hypertension to hypotension. Use this to differentiate from norepinephrine.
Uses of epinephrine
Cardiac arrest, adjunct to local anesthetic, hypotension, anaphylaxis, asthma
Uses of norepinephrine
Cardiac arrest, adjunct to local anesthetic, hypotension
Indirect acting adrenergic agonists
Releasers of catecolamines: Tyramine, amphetamines (methylphenidate), ephedrine. Reuptake inhibitors: cocaine, tricyclic antidepressants. MAO-A inhibitors interaction can cause hypertensive crisis.
Effects of α blockers
Decrease TPR and BP. May cause reflex tachychardia and salt/water retention.
Uses of α blockers
Hypertension, pheochromocytoma, BPH (selective α1 blocker)
Nonselective α blockers
Phentolamine (reversible), phenoxybenzamine (irreversible)
Selective α1 blockers
Prazosin, doxazosin, terazosin, tamsulosin
Selective α2 blockers
Yohimbe (used in hypotension and impotence), mirtazapine (depression)
Effects of β1 blockers
Decresed HR, SV, CO, renin, aqueous humor production
Side effects of β2 blockers
Bronchospasm in asthmatics, vasospasm, decreased glycogenolysis, gluneogenesis, increased LDLs, TGs
Selective β1 blockers
Acebutolol, atenolol, metroprolol
Nonselective β blockers
Pindolol, propranolol, timolol
β blockers that raise blood lipids
Atenolol (β1), metroprolol (β1), propranolol, timolol
β blockers that cause the most sedation
Propranolol, timolol
β blockers with intrinsic sympathomimetic activity
Act as partial agonists, less bradycardia, slight vasodilation, bronchodilation, minimal change in lipids: acebutolol, pindolol
General uses of β blockers
Angina, hypertension, post-MI
β blockers used as antiarrhythmics
Propranolol, acebutolol, esmolol
Specific uses of timolol
Glaucoma
Specific uses of propranolol
Migraine, thyrotoxicosis, performance anxiety, essential tremor
Combined α1 and β blockers
Labetalol, carvedilol. Used in CHF.
Combined K channel and β blockers
Sotalol. Class III antiarrhythmic.
Phase 0 of the cardiac action potential
Fast Na channels open causing depolarization. Class I antiarrhythmics slow or block phase 0.
Phase 1 of the cardiac action potential
Overshoot. Na channels inactivated, transient outward K currents.
Phase 2 of the cardiac action potential
Plateau phase. Slow influx of Ca and late-appearing outward K current.
Phase 3 of the cardiac action potential
Repolarization. Delayed rectifier K outward current. Class III antiarrhythmics slow repolarization.
Phase 4 of the cardiac action potential
Resting membrane potential. Maintained by the Na/K ATPase pump.
Phase 0 of the pacemaker action potential
Depolarization depends on Ca channels. Class IV antiarrhythmics slow or block this phase.
Phase 3 of the pacemaker action potential
Repolarization. Ca currents are opposed by outward delayed K currents.
Phase 4 of the pacemaker action potential
Spontaneous depolarization caused by Na funny current, Ca inward curents and K outward currents. Class II and IV antiarrhythmics slow this phase.
Effective refractory period
No stimulus can elicit a response. Lasts into phase 3 due to Na channel inactivation. K channel blockers prolong ERP.
Relative refractory period
Only a strong stimulus can elicit a response. Associated with arrhythmias.
Innervation of the SA and AV nodes
Parasympathetic via M2 receptors. Sympathetic via β1 receptors.
What effect does sympathetic stimulation have on SA and AV nodes
β1 activation increases cAMP, increasing upstroke velocity by increase of Ca conductance. Shortens action potential duration by increase of K conductance. Increases HR by increase of Na funny currents and increased phase 4 slope.
What effect does parasympathetic stimulation have on SA and AV nodes
M2 activation decreases cAMP. Decrease upstroke velocity by decreasing Ca conductance. Prolongs action potential duration by decrease of K conductance. Decreases HR by decrease of Na funny current and by increase K conductance.
Class 1A antiarrhythmics
Quinidine, procainamide
1A antiarrhythmics MOA
Block fast Na channels in the open state (decreases excitability and phase 0 slope) increasing APD and ERP. Block K channels which prolongs repolarization (decrease phase 3 slope).
Quinidine pharmacokinetics
Orally effective weak base enhanced absorption and toxicity by antacids. In atrial fibrilation needs intitial digitalization.
Quinidine pharmacodynamics
Class 1A effects plus muscarinic receptor blockade (increase HR and AV conduction); vasodilation via alpha block with reflex tachychardia.
Quinidine adverse effects
Cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), hypotension, QRS and QT prolongation associated with syncope torsades
Quinidine drug interactions
Hyperkalemia enhances effects and vice versa. Displaces digoxin from tissue binding sites, enhancing toxicity.
Procainamide pharmacokinetics
Phase 2 acetylation by N-acetyltransferase to N-acetylprocainamide (NAPA) active metabolite. Subject to genotypic variation/slow acetylators/drug-induced lupus.
Procainamide adverse effects
SLE-like syndrome (30%) in slow acetylators. Thrombocytopenia, agranulocytosis, torsades.
Class 1B antiarrhythmics
Lidocaine, mexiletine, tocainide
Class 1B antiarrhythmics MOA
Block fast Na channels in the inactive state, preferentially in hypoxic tissues results in increased threshold for excitation and less excitability of hypoxic heart muscle. Block of slow Na window currents with decreased APD (decreased phase 2 of AP). Increases dyastole and time for recovery (leads to asystolia)
Uses and side effects of lidocaine
Post MI, open heart surgery, digoxin toxicity. Seizures, least cardiotoxic antiarrhythmic. IV because of first-pass metabolism.
Class 1C antiarrhythmics MOA
Block fast Na channels specially in His-Purkinje fibers without altering the APD (decreases phase 0 slope at the expense of shortening phase 2 duration)
Flecainide
Class 1C antiarrhythmic. Limited use because of proarrhythmogenic effects. Increased risk of sudden death post-MI.
Effects of class 1A antiarrhythmics on action potential
Decrease slope of phase 0; increase APD and ERP.
Effects of class 1B antiarrhythmics on action potential
Decrease length of phase 2 (plateau) with no change in phase 0 or 3 which decreases APD.
Effects of class 1C antiarrhythmics on action potential
Decrease slope of phase 0 and decrease length of phase 2 which cancels out effect on APD.
Class II antiarrhythmics MOA
Block β1 receptors in the heart decreasing cAMP; Decrease upstroke velocity by decreasing Ca conductance (decreased phase 4). Prolongs action potential duration by decrease of K conductance (decreased phase 3 slope). Decreases HR by decrease of Na funny current and by increase K/ACh conductance (decreased phase 4)
Class II antiarrhythmics
Propranolol (nonselective), acebutolol, esmolol (β1 selective)
Uses of class II antiarrhythmics
Prophylaxis post MI, supraventricular tachyarrhythmias
Properties of propranolol
Nonselective β blocker, no sympathicomimetic activity, produces sedation and increases blood lipids.
Properties of acebutolol
Selective β1 blocker with intrinsic sympathicomimetic activity, no sedation, no increase in blood lipids.
Class III antiarrhythmics MOA
Decreased delayed rectifier K currents which slows phase 3 and increases APD and ERP.
Class III antiarrhythmics
Amiodarone, sotalol (combined K channel and β1 blocker)
Amiodarone pharmacokinetics
t1/2 > 80 days, large Vd.
Amiodarone pharmacodynamics
Blocks K channels in many tissues. Mimics class I, II and IV antiarrhythmics. Increases APD and ERP.
Amiodarone side effects
Large Vd affects many tissues: pulmonary fibrosis, blue pigmentation of skin, phototoxicity, corneal deposits, hepatic necrosis, thyroid dysfunction.
Sotalol MOA
Blocks K channels decreasing phase 3 of AP (increases APD); blocks β1 which decreases phase 4 and phase 3 slopes in pacemaker cells (which decreases HR and conduction)
Class IV antiarrhythmics MOA
Block slow Ca channels in pacemaker cells which decreases phase 4 and 0 slopes, which decreases HR.
Class IV antiarrhythmics
Verapamil, diltiazem
Uses of verapamil
Supraventricular tachyarhythmias
Verapamil side effects
Constipation, dizziness, flushing, hypotension, AV block
Verapamil drug interactions
Additive AV block with β-blockers and digoxin; displaces digoxin from tissue-binding sites.
Properties of adenosine
Activates adenosine receptors coupled to Gi, decreasing cAMP, decreasing SA and AV node activity. Used for paroxysmal supraventricular tachyarrhythmias. t1/2 < 10 seconds. Side effects: flushing, sedation, dyspnea. Antagonized by theophylline.
Drugs that cause torsades
Class IA (quinidine) and III (sotalol) antiarrhythmics, antipsychotics (ziprasidone), tricylic antidepressants.
Drugs that displace digoxin
Verapamil, quinidine
Drugs that cause drug-induced lupus
Hydralazine > procainamide > isoniazid (slow acetylators)
Effects of hyperkalemia on heart
Decreases K efflux reducing repolarization. Membrane is depolarized. Can cause heart stop on systole. Peaked T waves.
Effects of hypokalemia on heart
Increases K conductance and hyperpolarization. Heart stops of dyastole.
What is the strategy to treat hypertension
Decrease TPR (α2 agonists, α1 blockers), decrease CO (β-blockers), decrease body fluids (diuretics), vasodilation (hydralazine, nitirites, ACEIs, ARBs).
α2 agonists
Clonidine, methyldopa
Uses and side effects of clonidine
Uses: Mild to moderate hypertension, opiate withdrawal; Side effects: CNS depression, edema.
Uses and side effects of methyldopa
Uses: mild to moderate hypertension, hypertension management in pregnancy; Side effects: positive Coombs test, CNS depression, edema.
Reserpine MOA and side effects
Destroys catecolamine vesicles leading to decrease in CNS and peripheral levels. Side effects: depression, edema.
Guanethidine MOA and side effects
Accumulates into nerve endings by reuptake, binds catecolamine vesicles and inhibits release of NE; Side effects: diarrhea, edema. Tricyclics block reuptake and actions of guanethidine
α1 blockers
Prazosin, doxazosin, terazosin
α1 blockers MOA
Decrease arteriolar and venous resistance. Decrease prostate and urinary sphincter tone.
α1 blockers side effects
First dose syncope, orthostatic hypotension, urinary incontincence
β-blockers cautions in use
Asthma, vasospastic disorders (atherosclerosis, Raynauds), diabetics (hypoglycemia normally induces tachychardia which is perceived by patient, but β-blockers prevent tachychardia warning signs).
Properties of hydralazine
Direct vasodilator as nitric oxide donor. Decreases TPR. Use in moderate to severe hypertension. Side effects: Drug-induced lupus in slow acetylators, edema, reflex tachychardia.
Drugs metabolized by acetylation
Hydralazine > procainamide > isoniazid (slow acetylators)
Nitroprusside
Nitric oxide donor vasodilates arterioles and venules. Used for hypertensive emergencies. Releases cyanide thus coadminister thiosulfate to form nontoxic thiocyanate. In case of cyanide poisoning give nitrites.
Direct vasodilators
Hydralazine (NO), nitroprusside (NO), minoxidil (opens K channels --> hyperpolarization --> vasodilation)
Minoxidil
Opens K channels in smooth muscle --> hyperpolarization --> vasodilation. Use in severe hypertension and alopecia. Side effects: hypertrichosis, edema, reflex tachychardia.
Diazoxide
Opens K channels in smooth muscle --> hyperpolarization --> vasodilation. Use in hypertensive emergencies. Side effects: hyperglycemia (decreases insulin release)
Arteriolar vasodilators
Ca channel blockers (nifedipine), hydralazine, K channel openers (minoxidil)
Venular vasodilation
Nitrates (nitroprusside)
Orthostatic hypotension
Due to venular dilation not arteriolar. Usually from α1 blockers.
Calcium channel blockers MOA
Block L-type Ca channels in heart and blood vessels smooth muscle --> decrease intracellular Ca --> decreased CO and TPR.
Calcium channel blockers
Verapamil, diltiazem, nifedipines and derivatives.
Uses of calcium channel blockers
Hypertension, angina, antiarrhythmics (verapamil, diltiazem)
Side effects of calcium channel blockers
Reflex tachychardia (nifedipine and derivatives), gingival hyperplasia (nifedipine and derivatives), constipation (verapamil)
ACE inhibitors MOA
Block formation of angiotensin II --> no AT-1 receptor stimulation --> decreased aldosterone secretion and vasodilation; also prevent bradykinin degradation by ACE (dry cough). Captopril and other -prils
Angiotensin receptor blockers MOA
Block angiotensin receptors --> decreased aldosterone secretion and vasodilation. Losartan and other -sartans
Uses of ACEIs and ARBs
Mild to moderate hypertension, protective of diabetic neprhopathy, CHF
ACEIs side effects
Dry cough (no degradation of bradykinin), hyperkalemia (no aldosterone), acute renal failure in renal artery stenosis (angiotensin maintains RBF), angioedema, rash
ARBs side effects
Hyperkalemia (no aldosterone), acute renal failure in renal artery stenosis (angiotensin maintains RBF), angioedema
Treatment strategy for heart failure
Decrease preload (diuretics, ACEIs, ARBs, venodilators), decrease afterload (ACEIs, ARBs, arteriodilators), increase contractility (digoxin, beta agonists), decrease cardiac remodeling (ACEIs, ARBs, spironolactone)
What drugs are beneficial in CHF and why?
ACEIs, ARBs and spironolactone prevent cardiac remodeling
Digoxin MOA
Inhibits cardiac Na/K ATPase --> increase intracellular Na --> decrease Na/Ca exchange --> increase intracellular Ca --> increase Ca release on sarcoplasmic reticulum --> increase contractile force. It also inhibits neuronal Na/K ATPase which increases vagal and sympathetic stimulation.
Digoxin pharmacokinetics
Long t1/2 needs loading dose; renal clearance; large Vd and displacement by verapamil and quinidine
Uses of digoxin
CHF and supraventricular tachychardias except Wolff-Parkinson-White syndrome
Wolff-Parkinson-White syndrome
Prexcitation of the ventricles due to accesory conduction bundle of Kent. Block accessory path with class IA or III antiarrhythmics, avoid β-blockers, CCBs and adenosine
Digoxin side effects
Anorexia, nausea, ECG changes, disorientation, visual halos, cardiac arrhythmias
Digoxin toxicity
Can cause cardiac arrhythmias. Use Fab antibodies against digoxin and class IB antiarrhythmics.
Digoxin drug interactions
Quinidine, verapamil displace digoxin; sympathicomimetics; diuretics
Phosphodiesterase inhibitors MOA
Inamrinone, milrinone. Phosphodiesterase normally converts cAMP into AMP, inhibitors increase cAMP and inotropy in heart and relax smooth muscle cells which leads to decreased TPR
Antianginal drugs
Nitroglycerin, isosorbide, CCBs (nifedipine), β-blockers and carvedilol
Nitrates MOA
Pro drugs of nitric oxide; NO activates smooth muscle guanylyl cyclase --> increase cGMP --> relaxation --> venodilation --> decrease preload --> decrease cardiac work and oxygen requirements
Nitroglycerin side effects
flushing, headache, orthostatic hypotension, reflex tachychardia, methhemoglobinemia.
Nitroglycerin interactions
Cardiovascular toxicity with sildenafil
Sildenafil MOA
Inhibits PDE5 in blood vessels of corpora cavernosa --> increase cGMP --> vasodilation --> erection
Uses and side effects of manitol
Decreases IOP in glaucoma, decreases intracerebral pressure in cerebral edema. Side effects: hypovolemia
Carbonic anhydrase inhibitors drugs
Acetazolamide, dorzolamide
Azetazolamide MOA
Decreases H+ formation in PCT --> decrease Na/H+ antiport --> increases Na and HCO3 in lumen --> diuresis
Uses of azetazolamide and CA inhibitors
Glaucoma, acute moutain sickness (acidosis stimulates ventilation), metabolic alkalosis
Azetazolamide and CA inhibitors side effects
Bicarbonaturia/acidosis, hypokalemia (increases Na load dowstream), hyperchloremia, paresthesia, renal stones (alkalinizes urine), sulfa hypersensitivity
Loop diuretic drugs
Ethacrynic acid, furosemide
Loop diuretics MOA
Inhibit Na/K/2Cl cotransporter --> decrease intracell K+ --> decrease positive potential --> decrease reabsorption of Ca, Mg --> increased diuresis
Uses of loop diuretics
Acute pulmonary edema, CHF, hypertension, refractory edema, acute renal failure, anion overdose, hypercalcemia
Loop diuretic side effects
Sulfonamide hypersensitivity (except ethacrynic acid), hypokalemia, alkalosis, hypocalcemia, hypomagnasemia, hyperuricemia, ototoxicity (ethacrynic acid > furosemide)
Loop diuretics drug interactions
Enhanced ototoxicity with aminoglycosides; decrease clearance of lithium, increase digoxin toxicity
Thiazide drugs
Hydrochlorothiazide, indapamide
Thiazides MOA
Inhibit Na/Cl transporter in DCT --> increases Na and Cl in the lumen --> increase diuresis
Uses of thiazides
Hypertension, CHF, nephrolithiasis (calcium stones), nephrogenic diabetes insipidus
Thiazides side effects
Sulfonamide hypersensitivity, hypokalemia, alkalosis, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia
Thiazide drug interactions
Increase digoxin toxicity, avoid in diabetics
K+ sparing agents
Spironolactone, eplerenone, amiloride, triamterene
MOA spironolactone
Aldosterone receptor antagonist --> no sodium reabsorption --> no K+ secretion
Uses of spironolactone
Hyperaldosteronism, adjunct to K+ wasting diuretics, hirsutism, CHF
Spironolactone side effects
Hyperkalemia, acidosis, antiandrogenic (except eplerenone)
MOA amiloride/triamterene
Blocks Na+ channels in principal cells of collecting ducts --> decreased Na+ reabsorption and K+ secretion
Uses of K+ sparing agents
Adjunct to K+ wasting diuretics, lithium-induced nephrogenic diabetes insipidus (amiloride)
Side effects of K+ sparing agents
Hyperkalemia, acidosis, antiandrogenic (except epleronone)
Electrolytes excreted by acetazolamide
Na, K, HCO3
Electrolytes excreted by loop diuretics
Na, K, Ca, Mg, Cl
Electrolytes excreted by thiazides
Na, K, Cl; Ca is reabsorbed
Electrolytes excreted by K+ sparing agents
Na; K is not secreted
Statins MOA
Inhibition of HMG-CoA-Reductase --> decreased cholesterol --> increased LDL receptor expression --> decresed LDLs
Statins side effects
Myalgia, myopathy, rhabdomyolysis due to decrease in farnesyl ppi
Statins drug interactions
Gemfribozil increases rhabdomyolysis; P450 inhibitors enhance toxicity
Bile acid sequestrant drugs
Cholestyramine, colestipol
MOA of bile acid sequestrants
Decreased enterohepatic circulation --> increased new bile salts in liver --> decreased liver cholesterol --> increased LDL receptor expression --> decreased blood LDL
Side effects of bile acid sequestrants
Increased VLDL and triglycerides; gastrointestinal disturbances; malabsorption of lipid-soluble vitamins
Drug interactions of bile acid sequestrants
Interact with orally administered drugs
Contraindications of bile acid sequestrants
Hypertriglyceridemia
Niacin MOA
Inhibits VLDL synthesis --> decreased plasma VLDL --> decreases LDL --> increases HDL
Niacin side effects
Flushing, pruritus, rashes, hepatotoxicity
Gemfibozil MOA
Activates lipoprotein lipase --> decreases VLDL and IDL --> decreases LDL --> increases HDL
Uses of gemfibrozil
Hypertriglyceridemia
Ezetimibe MOA
Prevents intestinal reabsorption of cholesterol --> decreased LDL
Which antihyperlipidemic: increased cholesterol
Cholestyramine, colestipol, ezetimibe
Which antihyperlipidemic: increased triglycerides
Gemfibrozil
Which antihyperlipidemic: increased cholesterol and triglycerides
Statins, niacin, ezetimibe
Properties of benzodiazepines
Bind to gamma subunit of GABAa complex to increase frequency of Cl- channel opening; no GABAmimetic activity; BZ1 mediates sedation; BZ2 mediates antianxiety and impairment of cognitive functions
Benzodiazepine drugs
Alprazolam, diazepam, lorazepam, midazolam, temazepam, oxazepam
Uses of alprazolam
Anxiety, phobias, panic attacks
Uses of diazepam
Anxiety, preop sedation, muscle relaxation, withdrawal states
Uses of lorazepam
Anxiety, preop sedation, status epilepticus
Uses of midazolam
Preop sedation and anesthesia, anterograde amnesia
Uses of temazepam
Sleep disorders
Uses of oxazepam
Sleep disorder and anxiety
Pharmacokinetics of benzodiazepines
Liver metabolized to active compounds except oxazepam, temazepam, lorazepam; t1/2: diazepam > lorazepam > alprazolam > temazepam > oxazepam > midazolam
Uses of barbiturates
Phenobarbital for seizures; thiopental for induction of anesthesia
Properties of barbiturates
Prolong GABA activity; increase duration of Cl- channel opening; GABAmimetic activity at high doses; bind to beta subunit of GABA(a) complex; inhibit complex I of ETC, induces P450
Pharmacokinetics of barbiturates
General inducers of P450; contraindicated in porphyrias
Withdrawal signs of benzodiazepines
Rebound insomnia, anxiety, seizures
Withdrawal signs of barbiturates and ethanol
Anxiety, agitation, life threatening seizures
Drug interactions of GABA drugs
Life threatening respiratory depression if used with other CNS depressants (antihistaminics, opiates, beta blockers); Barbiturates induce metabolism of lipid-soluble drugs (oral contraceptives, carbamazepine, phenytoin, warfarin)
Flumazenil
Benzodiazepine receptor antagonist. Used as antidote for benzodiazepine overdose.
Zolpidem
BZ1 receptor agonist used in sleep disorders. No cognitive impairment (no BZ2 actions), overdose reversed by flumazenil, less tolerance and abuse liability
Buspirone
No effect on GABA, 5-HT1a partial agonist, used for generalized anxiety, nonsedative, 1-2 weeks for effects
Effects of alcohols
GABA mimetic activity causes CNS depression; metabolic acidosis; fetal alcohol syndrome
Metabolism of ethylene glycol
Ethylene glycol + alcohol DH --> glycoaldehyde + aldehyde DH --> glycolic acid --> oxalic acid
Effects of ethylene glycol
CNS depression, severe metabolic acidosis, nephrotoxicity
Metabolism of methanol
Methanol + alcohol DH --> formaldehyde + aldehyde DH --> formic acid
Effects of methanol
Respiratory failure, severe anion gap metabolic acidosis, ocular damage
Treatment of alcohol overdose
Fomepizole (alcohol DH inhibitor) and hemodialisis
Metabolism of ethanol
Ethanol + alcohol DH --> acetaldehyde + NADH + acetaldehyde DH --> acetic acid + NADH
Effects of ethanol
CNS depression, metabolic acidosis, acetaldehyde toxicity
Acetaldehyde toxicity
Nausea, vomit, headache, hypotension, inactivates folate, decreases availability of thiamine
Drugs that cause disulfram-like effects
Disulfram-like effects = acetaldehyde toxicity. Disulfram inhibits acetaldehyde DH. Metronidazole, cefamandole, cefoperazone, cefotetan, chlorpropamide
Anticonvulsant drugs
Phenytoin, carbamazepine, benzodiazepines, barbiturates, lamotrigine, topiramate, felbamate, ethosuximide, valproic acid
Drugs used for partial seizures
Valproic acid, phenytoin, carbamazepine
Drugs used for general tonic-clonic seizures
Valproic acid, phenytoin, carbamazepine
Drugs used for absence seizures
Ethosuximide
Drugs used for status epilepticus
Lorazepam, diazepam, phenytoin
Phenytoin MOA
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation
Pharmacokinetics of phenytoin
Variable absorption, nonlinear kinetics at low doses, zero-order kinetics at high doses, inducer of P450
Phenytoin side effects
CNS depression, gingival hyperplasia, hirsutism, osteomalacia (decreases vitamin D), megaloblastic anemia (decreases folate), aplastic anemia, teratogenic (cleft lip and palate).
Carbamazepine MOA
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation
Pharmacokinetics of carbamazepine
Induces P450
Carbamazepine side effects
CNS depression, osteomalacia, megaloblastic anemia, aplastic anemia, exfoliative dermatitis, increases ADH secretion (dilutional hyponatremia), teratogenic (cleft lip and palate, spina bifida)
Valproic acid MOA
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation; Inhibits GABA transaminase; Blocks presynaptic Ca+ channels
Uses of valproic acid
Seizures, bipolar mania, migraines
Pharmacokinetics of valproic acid
Inhibits P450
Valproic acid side effects
Hepatotoxic metabolite, thrombocytopenia, pancreatitis, alopecia, spina bifida
Ethosuxamide MOA
Blocks presynaptic T-type Ca+ channels in thalamic neurons
Lamotrigine MOA
Blocks Na+ channels and glutamate receptors. Side effect: Steven-Johnson
Inhaled anesthetic drugs
Nitrous oxide, halothane
Properties of halothane
High potency (0.8% MAC), high blood-gas ratio (2.3), sensitizes heart to catecholamines
Side effects of halothane
Malignant hyperthermia, hepatitis, cardiac arrhythmias
What is MAC?
Minimal alveolar concentration is the amount of anesthetic at which 50% of patients don't respond to surgical stimulus. Analogous to ED50, measures potency, the more lipid soluble the lower the MAC, lower in elderly
What is the blood-gas ratio?
Measure of the onset of recovery. The more soluble in the blood the slower the anesthesia and recovery.
Intravenous anesthetic drugs
Midazolam, thiopental, propofol, fentanyl, ketamine
General anesthesia protocol
Includes sedation and anterograde amnesia (midazolam), induction (propofol), analgesia (fentanyl), muscle relaxant for intubation (succinylcholine) and may or may not include atropine in case of CV depression due to propofol
Naloxone
Antidote for opiods
Neostigmine
AChE inhibitor reverses non-depolarizing muscle relaxants
What are the ester local anesthetics?
Procaine, cocaine, benzocaine. Metabolized by plasma esterases. All have only one "i"
What are the amide local anesthetics?
Lidocaine, bupivacaine, mepivacaine. Metabolized by liver amidases. All have two "i".
MOA of local anesthetics
Nonionized form crosses axonal membrane --> ionized form blocks inactivated Na+ channel --> prevent propagation of action potentials
Side effects of local anesthetics
Neurotoxicity, cardiovascular toxicity, allergies. Use alpha-1 agonists to prevent absorption.
Skeletal muscle relaxants MOA
Nicotinic antagonists (competitive, nondepolarizing); Nicotinic agonists (noncompetitive, depolarizing)
Non-depolarizing muscle relaxant drugs
Atracurium, mivacurium, tubocurarine
Non-depolarizing muscle relaxant properties
Nicotinic antagonists, reversible with AChE inhibitors, progressive paralysis, no effects on heart or CNS
Properties of succinylcholine
Depolarizing muscle relaxant, nicotinic agonist; Phase I: depolarization, fasciculation, flaccid paralysis; Phase II: desensitization. Caution in atypical pseudocholineeterase, hyperkalemia, malignant hyperthermia
Malignant hyperthermia
Succinylcholine side effect in genetically susceptible people. Muscle rigidity, hyperthermia, hypertension, acidosis, hyperkalemia. Rx.: dantrolene
Opiod analgesic drugs
Morphine, meperidine, methadone, codeine, fentanyl
Contraindications of opiod analgesics
Head injuries, pulmonary dysfunction, hepatic or renal dysfunction, adrenal or thyroid deficiencies, pregnancy
Effects of morphine
Analgesia, sedation, respiratory depression (decreased response to PCO2), miosis, cough supression, nausea, vomiting
Pharmacokinetics of morphine
Phase 2 metabolism by glucoronidation. Caution in renal dysfunction as morphine-6-glucoronide is highly active
Opiod toxicity
Pinpoint pupils, repiratory depression and coma. Rx. Naloxone
Meperidine
Opiod without miosis or spasms. Metabolized via P450 to normeperidine which can cause seizures
Methadone
Used for opiate withdrawal in addicts
Codeine
Cough suppressant, analgesia, use in combination with NSAIDs
Symptoms of opiod withdrawal
Yawning, lacrimation, rhinorrea, salivation, anxiety, muscle spasms and CNS-originating pain. Rx.: methadone
Drugs used in Parkinson disease
Levodopa, tolcapone, selegiline, bromocriptine, benztropine, amantadine
Levodopa
Crosses CNS barrier. Converted to dopamine in CNS and periphery, so use tolcapone, carbidopa and selegiline
Tolcapone
Inhibits COMT which blocks levodopa conversion to methyldopa which has no pharm actions
Carbidopa
Inhibits conversion of levodopa to dopamine in peripheral tissues, increasing CNS availability
Selegiline
MAOb selective inhibitor, adjunt to levodopa to decrease dopamine metabolism in CNS
Bromocriptine
Dopamine-receptor agonist used in hyperprolactinemia, acromegaly
Benztropine
Muscarinic blocker used to decrease Ach activity in Parkinson. Decreases tremor and rigidity but not bradykinesia
Atypical antipsychotics
Clozapine, olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone, paliperidone
Atypical antipsychotic MOA
Inhibition of dopamine and 5HT2 receptors
Side effects of antipsychotic drugs
Extrapyramidal symptoms, akathisia, tardive dyskinesia, dysphoria, endocrine dysfunction, weight gain, hypotension, muscarinic blockade tachychardia
Specific side effects of thioridazine
Torsades, retinal deposits
Typical antipsychotics
Chlorpromazine, thioridazine, fluphenazine, haloperidol
Specific side effects of haloperidol
Neuroleptic malignant syndrome, tardive diskynesia
Specific side effects of clozapine
Agranylocytosis, seizures, salivation
MAO inhibitor drugs
phenelzine, tranylcypromine
Drug interaction of MAO inhibitors
Tyramine, TCAs, alpha-1 agonists, levodopa: increase NE --> hypertensive crisis; Serotonin syndrome with SSRI, TCA, meperidine --> sweating, rigidity, myoclonus, hyperthermia
Tricyclic antidepressant drugs
Amitriptyline, imipramine, clomipramine
TCAs MOA
Nonspecific blockade of 5HT and NE reuptake
Side effects of TCAs
Muscarinic blockade, alpha blockade, serotonin syndrome, hypertensive crisis
SSRI drugs
Fluoxetine, sertraline, paroxetine, citalopram
Side effects of SSRI
Anxiety, agitation, bruxism, sexual dysfunction, weight loss, serotonin syndrome
Serotonin syndrome
Sweating, rigidity, myoclonus, hyperthermia. Interaction between MAOi, TCAs, SSRIs, meperidine, dextromethorphan
Drug-induced hypertensive crisis
Due to interaction between MAOi, TCAs, alpha-1 agonists
Venlafaxine
Selective reuptake inhibitor of NE and 5HT. Can cause hypertensive crisis and serotonin syndrome
Bupropion
Dopamine reuptake blocker. Used in smoking cessation
Lithium MOA
Prevents recycling of inositol (decreases PIP2), decreases cAMP
Lithium side effects
Narrow therapeutic index requires monitoring, tremor, hypothyroidism (decreases TSH effects and inhibits 5'-deiodinase), nephrogenic diabetes insipidus (manage with amiloride), teratogenic
Methylphenidate
inhibits reuptake of DA and NE. Side effects: agitation, restlessness, insomnia, CV toxicity. Treats ADHD.
Atomoxetine
Selective NE reuptake inhibitor. Treats ADHD.
MOA of penicillins
Bind PBPs to inhibit transpeptidation reactions in peptidoglycan cross-linking --> inhibit cell wall synthesis
Mechanism of resistance to penicillin
Beta-lactamases (staphylococci); structural change in PBPs (MRSA); change in porin structure (pseudomonas)
Narrow spectrum penicillins
Penicillin G and V. Strep, pneumococci, menigococci, treponema
Very narrow spectrum penicillins
Nafcillin, methcillin, oxacillin. Staph. If MRSA use vancomycin.
Broad spectrum penicillins
Ampicillin, amoxicillin. Gram+ cocci (except staph), Listeria, H. influenzae, E. coli., Borrelia and H. pylory: amoxi
Extended spectrum penicillins
Ticarcillin, piperacillin, azlocillin. Increased activity against gram- plus anti-pseudomonal
Beta-lactamase inhibitors
Clavulanic acid, sulbactam. Use in combination with broad and extended spectrum penicillins
Pharmacokinetics of penicillins
Most are eliminated via active tubular secretion. Nafcillin and oxacillin are eliminated in bile. Ampicillin undergoes enterohepatic circulation but is excreted by the kidney. Benzathine penicillin G repository form (t1/2: 2 weeks)
Side effects of penicillins
Hypersensitivity (5-7%). Urticarial skin rash to anaphylaxis. Interstitial nephritis (methicillin).
First generation cephalosporins
Cefazolin, cephalexin. Gram+ cocci (not MRSA), E. coli, Klebsiella pneumoniae, some proteus. Surgical prophylaxis
Second generation cephalosporins
Cefotetan, cefaclor, cefuroxime. Increased gram- coverage, including some anaerobes
Third generation cephalosporins
Ceftriaxone (IM), cefotaxime (IV), cefdinir, cefixime (oral). Gram+ and gram- cocci plus gram- rods. Enter CNS. Use in meningitis, sepsis
Fourth generation cephalosporins
Cefepime (IV). Enter CNS, resistant to betalactamases
Pharmacokinetics of cephalosporins
Active tubular secretion blocked by probenecid. Cefoperazone and ceftriaxone largely eliminated in bile.
Side effects of cephalosporins
Hypersensitivity (2%), rashes, fever, positive Coombs test, disulfram-like effect
Drugs to use in case of penicillin/cephalosporin allergy
Macrolides for gram+, aztreonam for gram- rods
Imipenem and meropenem
Resistant to betalactamases. Active against gram+ cocci, gram- rods and anaerobes. Use in life-threatening infections. Used IV. Imipenem is given with cilastatin to inhibit rapid renal metabolism by dehydropeptidase. Side effect: seizures
Aztreonam
Resistant to betalactamases. Used IV against gram- rods. No cross-allergenicity with penicillins or cephalosporins
Vancomycin MOA
Binds D-Ala-D-Ala pentapeptide to inhibit elongation of peptidoglycan chains. Does not bind PBPs.
Uses of vancomycin
MRSA, enterococci, C. difficile (backup drug)
Resistance to vancomycin
Terminal D-ala is replaced with D-lactate in muramyl pentapeptide
Pharmacokinetics of vancomycin
Used IV and orally (not absorbed) in colitis. Enters most tissues but not CNS. Eliminated by renal filtration. Long t1/2
Side effects of vancomycin
"Red man syndrome" (histamine release); permanent ototoxicity; nephrotoxicity
Antibiotics that act on 30S ribosomal subunit
Aminoglycosides, tetracyclines. "buy AT 30, CCEL at 50".
Antibiotics that act on 50S ribosomal subunit
Chloranphenicol, clindamycin, erythromycin (macrolides), linezolid. "buy AT 30, CCEL at 50"
Antibiotics that inhibit formation of initiation complex
Aminoglycosides (30S), linezolid (50S)
Antibiotics that block attachment of aminoacyl-tRNA to A site
Tetracyclines (30S), dalfopristin (50S)
Antibiotics that inhibit peptidyltransferase (peptide bond formation)
Chloranphenicol (50S)
Antibiotics that inhibit translocation
Macrolides (50S), clindamycin (50S)
Mecanisms of resistance to macrolides and clindamycin
Methyltransferases alter drug binding site on the 50S ribosome; active transport out of cell
Mechanism of resistance to tetracyclines
Tetracycline pumps transport drug out of the cell
Mechanism of resistance to aminoglycosides
Conjugation enzymes
Mechanism of resistance to sulfonamides
Change in target enzyme decreases drug sensitivity; formation of PABA; use of exogenous folic acid
Mechanism of resistance to fluoroquinolones
Change in target enzyme decreases drug sensitivity; pumps transport drugs out of the cell
Mechanism of resistance to chloranphenicol
Formation of inactivating acetyltransferases
Pharmacokinetics of aminoglycosides
Polar compounds not absorbed orally or widly distributed. Renal elimination. Modify in renal dysfunction
Aminoglycoside drugs
Gentamicin, tobramycin, amikacin: gram- aerobic rods; Streptomycin: TB, plague and tularemia; neomycin
Side effects of aminoglycosides
Nephrotoxicity (6-7%), ototoxicity enhanced by loop diuretics.
Tetracycline drugs
Tetracycline, doxycycline, minocycline, demeclocycline
Uses of tetracyclines
Chlamydia, mycoplasma, H. pylory, Rickettsia, Borrelia, Brucella, Vibrio
Phamacokinetics of tetracyclines
Metabolized by kidney (most), and liver (doxycycline). Decrease absorption of divalent cations by chelation.
Side effects of tetracyclines
Tooth enamel dysplasia, decreased bone growth (avoid in children), phototoxicity, contraindicated in pregnancy
Drugs that cause phototoxicity
amiodarone, tetracyclines, sulfonamides, quinolones
Drugs that are nephrotoxic
Vancomycin, aminoglycosides, amphotericin B, cisplatin, cyclosporine
Drugs that are ototoxic
Aminoglycosides, loop diuretics
Pharmacokinetics of chloranphenicol
Orally effective, enters CNS, metabolized by hepatic glucoronidation, inhibits P450
Side effects of chloranphenicol
Dose-dependant bone-marrow suppression, "gray baby" in neonates (decreased glucoronosyl transferase)
Macrolide drugs
Erythromycin, azithromycin, clarithromycin
Uses of Erythromycin
Gram+ cocci, atypicals (chlamydia, mycoplasma, ureaplasma), legionella, campylobacter
Uses of azithromycin
Gram+ cocci, atypicals (chlamydia, mycoplasma, ureaplasma), legionella, campylobacter, more activity in respiratory infections
Pharmacokinetics of macrolides
Erythromycin and clarithromycin: metabolized by liver, excreted in bile, inhibit P450, not safe in pregnancy. Azithromycin: excreted by kidney, doesn't inhibit P450, safer in pregnancy
Side effects of macrolides
Stimulate motilin receptors and cause GI distress, reversible deafness, cholestasis, jaundice
Drugs to avoid in pregnancy
Aminoglycosides, erythromycin, clarithromycin, fluoroquinolones, sulfonamides, tetracyclines
Uses of clindamycin
Gram+ cocci, anaerobes, toxoplasmosis. Use in gram+ osteomyelitis. Can cause pseudomembranous colitis
Linezolid
VRSA, VRE, drug-resistant pneumococci. Side effect: bone marrow suppression (platelets)
Streptogramin drugs
Quinupristin-dalfopristin
MOA of streptogramins
Bind 50S ribosomal subunit
Uses of streptogramins
Vancomycin resistant staph (VRSA), vancomycin resistant enterococci (VRE), drug-resistant gram+ cocci
Inhibitors of nucleic acid synthesis drugs
5-MP, 6-FU, hydroxyurea, methotrexate, sulfonamides, trimethoprim, pyrimethamine
MOA of sulfonamides
Inhibits dihydropteroate synthetase which inhibits folic acid synthesis
MOA of trimethoprim
Inhibits dihydrofolate reductase which inhibits folic acid synthesis
Uses of trimethoprim-sulfamethoxazole
DOC in Nocardiosis; mycobacteria; gram+ cocci, E. coli, Salmonella, Shigella, H. influenzae, P. carinii, toxoplasma
Pharmacokinetics of sulfonamides
Hepatically acetylated; renally excreted metabolites cause crystalluria; high protein binding
Side effects of sulfonamides
Hypersensitivity, Steven Johnson, phototoxicity, GI distress, hemolysis in G6PDH deficiency
Side effects of trimethoprim
Bone marrow suppression, enterocolitis
Quinolone drugs
Norfloxacin, ciprofloxacin, ofloxacin, levofloxacin
MOA of quinolones
Bactericidal. Inhibit topoisomerase II (DNA gyrase).
Uses of quinolones
UTIs resistant to cotrimoxazole, PID (chlamydia, gonococcus), skin and bone infections by gram-, diarrhea to shigella, salmonella, E. coli, campylobacter
Pharmacokinetics of quinolones
Iron and Ca+ limit their absorption, eliminated by kidney active secretion (inhibited by probenecid)
Side effects of quinolones
GI distress, phototoxicity, rashes, tendonitis, increases QT interval, contraindicated in pregnancy and children
Regimens used in H. pylori infections and ulcers
BMT: bismuth, metronidazole, tetracyclines or clarithromycin, amoxicillin, omeprazole
Uses of metronidazole
Giardia, trichomonas, entamoeba, gram- anaerobics, clostridium (DOC pseudomembranous colitis)
MOA and resistance to isoniazid
Inhibits mycolic acid synthesis; prodrug requires conversion by catalase; resistance: deletions if katG gene encodes catalase needed for activation; deletions in inhA gene encodes acyl carrier protein, the target
Side effects of isoniazid
Age-dependant hepatitis, peripheral neuritis (use B6), sideroblastic anemia (use B6), hemolysis in G6PDH deficiency, drug-induced lupus in slow acetylators
MOA and resistance to rifampin
Inhibits DNA-dependant RNA polymerase; resistance via change in enzyme
Side effects of rifampin
Hepatitis, induction of P450, red-orange metabolites
MOA of ethambutol
Inhibits synthesis of cell wall component arabingalactan
Side effects of ethambutol
Dose-dependant retrobulbar neuritis --> decreases visual acuity and red-green discrimination
Side effects of streptomycin
Deafness, vestibular dysfunction, nephrotoxicity
Polyene drugs
Amp B, nystatin
MOA of polyenes
Formation of artificial pores in the ergosterol membranes disrupts membrane permeability
Uses of amphotericin B
Severe infections by Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, Sporothrix
Uses of nystatin
Topical localized infections; too toxic for systemic use
Pharmacokinetics of amphotericin B
Given by slow IV infusion, does not enter CNS, slow t1/2 > 2 weeks, hepatic metabolism and renal elimination
Side effects of amphotericin B
Infusion-related: fever chills, muscle rigor, hypotension alleviated by NSAIDs, antihistamines, meperidine, steroids. Dose-dependant: nephrotoxicity, decreased GFR, tubular acidosis, anemia
Azole drugs
Ketoconazole, fluconazole, itraconazole, clotrimazole
MOA of azoles
Fungicidal by inhibiting 14-alpha-demethylase which converts lanosterol to ergosterol
Uses of ketoconazole
DOC for Paracoccidioides; backup for Blastomyces, Histoplasma; Oral use in mucocutaneous candidiasis or dermatophytoses
Uses of fluconazole
DOC for esophageal and invasive candidiasis and coccidioidomycoses. Prophylaxis and suppression of cryptococcal meningitis
Uses of itraconazole
DOC in blastomycoses and sporotrichoses
Uses of clotrimazole
Used topically for candidal and dermatophytic infections
Pharmacokinetics of ketoconazole
Orally effective; absorption decreased by antacids; metabolized by liver enzymes; inhibits P450
Pharmacokinetics of itraconazole
Orally effective; absorption increased by food; metabolized by liver enzymes; inhibits P450
Pharmacokinetics of fluconazole
Orally effective; enters CSF; eliminated in the urine in unchanged form
Side effects of azoles
Decreased synthesis of cortisol and testosterone --> decreased libido, gynecomastia, menstrual irregularities; Increased liver function tests and rare hepatotoxicity
Drugs that block viral penetration and uncoating
Amantadine, enfurvitide
Drugs that inhibit viral DNA polymerases
Acyclovir, foscarnet, ganciclovir
Drugs that inhibit viral RNA polymerases
Foscarnet, ribavirin
Drugs that inhibit viral reverse transcriptase
Zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz
Drugs that inhibt viral aspartate protease
Indinavir, ritonavir, saquinavir, nelfinavir
Drugs that inhibit viral neuraminidase
Zanamivir, oseltamivir
Drugs used to treat herpes
Acyclovir, ganciclovir, foscarnet
Acyclovir
Activated by viral thymidine kinase, inhibitor and chain terminator of DNA polymerase. Use for HSV ans VZV. Side effects: crystalluria, neurotoxicity
Ganciclovir
Activated by viral thymidine kinase, inhibitor and chain terminator of DNA polymerase. Use for HSV, VZV, CMV, AIDS retinitis and transplant patients. Side effects: hematotoxicity, crystalluria, rash
Foscarnet
Inhibits viral DNA and RNA polymerases. Use for HSV, VZV, CMV, AIDS retinitis, transplant patients. Side effects: nephrotoxic acute tubular necrosis, hypocalcemia (tremors, seizures)
Zidovudine (ZDV, AZT)
Converted to triphosphate that inhibits reverse transcriptase and causes chain termination. Resistance by mutations of RT gene.
Drug interaction of zidovudine (ZDV, AZT)
Increase levels of ZDV: azoles, cimetidine, indomethacin, probenecid, TMP-SMX. Decrease levels of ZDV: rifampin
Side effects of ZDV
Neutropenia, anemia, granulocytopenia, headache, myalgias, neuropathy, lactic acidosis
MOA enfuvirtide
Binds gp41 and inhibits fusion of HIV-1 to CD4 cells
Needle stick HIV prophylaxis
ZDV + 3TC + indinavir
Pregnancy HIV prophylaxis
ZDV trimester 2 and 3 plus 6 weeks to neonate reduces vertical transmission by 80%. Or ZDV intrapartum reduces transmission by 50-60%
Amantadine
Blocks attachment, penetration and uncoating of Influenza A. May decrease flu symptoms. Side effects: nervousness, insomnia, atropine-like effects
Uses of interferons
Antiviral: HBV, HCV; antiumor: Kaposi, CML, multiple myeloma, renal CA; Immunoregulatory: mutiple sclerosis
Effects of H1 receptor activation
Increased capillary dilation and permeability (hypotension, edema), bronchoconstriction, activation of nociceptive receptors (pain, pruritus)
Effects of H2 receptor activation
Increased gastric acid secretion (ulcers), positive inotropism
H1 antagonist drugs
Diphenhydramine, promethazine, chlorpheniramine, meclizine, hydroxyzine, loratadine, fexofenadine
Uses of H1 antagonists
Hay fever, rhinitis, urticaria, motion sickness and vertigo (meclizine), nausea in pregnancy
Adverse effects of H1 antagonists
M block and sedation, GI distress, allergic reactions.
Substances that increase proton pump activity
ACh, gastrin, histamine (H2 receptors)
H2 antagonist drugs
Cimetidine, ranitidine
MOA of H2 antagonists
Indirectly decrease proton pump activity (histamine increases proton pump activity)
Uses of H2 antagonists
Peptic ulcer disease, GERD, Zollinger-Ellison
Side effects of H2 antagonists
GI distress, dizziness, sommnolence; Cimetidine: inhibits P450 --> increases effects of quinidie, phenytoin, TCAs, warfarin; also decreases androgens --> gynecomastia
Omeprazole
Direct, irreversible proton pump inhibitor. Uses: PUD, GERD, Zollinger-Ellison, H. pylori. Side effects: decreases bioavailability of weak acids (fluoroquinolones, ketoconazole), inhibits P450
Misoprostol
PGE1 analog, increases mucus and bicarbonate, decreases HCL secretion. Use: NSAID-induced ulcers.
Sulcralfate
Polymerizes in stomach to coat ulcers. Increases healing and decreases ulcer recurrence.
Drugs that require acid stomach pH to be absorbed
Azoles, fluoroquinolones, warfarin
Drugs used as antiemetics
5HT3 antagonists (ondansetron), DA antagonists (metoclopramide), H1 blockers (diphenhydramine, meclizine), muscarinic blockers (scopolamine)
Metabolism of serotonin
5HT is metabolized by MAOa to 5-hydroxyinolacetic acid (marker for carcinoid)
Buspirone
Partial 5HT1a agonist used for generalized anxiety disorder
Sumatriptan
5HT1d agonist in cerebral vessels, used for migraine
Olanzapine
Atypical antipsychotic, 5HT2A and D2 receptor antagonist, decreases psychosis. Side effects: weight gain, tardive diskinesia, metabolic syndrome
Cyproheptadine
5HT2 antagonist used in carcinoid
Ondansetron
5HT3 antagonist, used as antiemetic in chemotherapy, radiation and post-op. 5HT3 receptors are found in area postrema
Ergonovine
Uterine muscle contraction after placental delivery
Ergotamine
Partial 5HT2 and alpha agonist causes vasoconstriction to decrease pulsation in migraine acute attack. Side effect is vasoconstriction (prinzmetal)
Prophylaxis of migraine headaches
Propranolol, verapamil, amitriptyline, valproic acid
PGE2
Vasodilation in kidneys, increases renal blood flow, increases gastric mucosal blood flow (mucoprotection), activates osteoclasts, fever, pain, maintains ductus arteriosus
Prostacyclin (PGI2)
Vasodilation and inhibits platelet aggregation
COX1
Constitutive enzyme synthesizes GI PGs and TxA2
COX2
Inducible enzyme synthesizes PGs involved in inflammation, fever and pain.
Zileuton
Lipoxygenase inhibtor used in asthma
Zafirlukast and -lukasts
Leukotriene receptor antagonist used in asthma
MOA of aspirin
Nonselective, irreversible COX inhibitor via acetylation of serine near active site
Actions of aspirin
Low dose: antiplatelet aggregation (post-MI); moderate dose: analgesia, antipiresis, hyperuricemia; High dose: antiinflammatory, uricosuria
Effects of aspirin on acid-base and electrolytes
Antiinflammatory doses: uncoupling of ETC --> increases respiration --> decreased pCO2 --> resp. alkalosis --> renal compensation via HCO3 excretion --> compensated respiratory alkalosis. Toxic doses: inhibits respiratory center --> decreases respiration --> resp. acidosis plus ETC uncoupling --> metabolic acidosis, decreases ATP, hyperthermia, hypokalemia
Side effects of aspirin
Gastritis, ulcers, bleeding, tinnitus, vertigo, decreased hearing, bronchoconstriction, hypersensitivity (asthma, nasal polyps, rhinitis), Reye syndrome, increased bleeding time, renal dysfunction at high doses
Aspirin overdose management
Gastric lavage, alkalinization of urine (zero-order kinetics at toxic doses)
Celecoxib
Selective COX-2 inhibitor. Antiinflammatory. Increases PT when used with warfarin, prothrombotic. Cross hypersensitivity with sulfonamides. Potential cardiotoxicity resulted in withdrawal of rofecoxib.
Acetaminophen
Inhibits COX in CNS only. No antiplatelet activity, not implicated in Reye syndrome, no effects on uric acid, no bronchoconstriction. Metabolized via P450. Hepatotoxic due to reactive metabolite N-acetylbenzoquinonemine, which is inactivated by GSH. Upon GSH depletion, metabolite damages hepatocytes, nausea, vomiting, abdominal pain, centrilobular necrosis. Inducers of P450 enhance toxicity. Management of hepatotoxicity: N-acetylcysteine.
Hydroxychloroquine
Used for rheumatoid arthritis. Stabilizes lysosomes and decreases chemotaxis. Side effects: GI distress, visual dysfunction, hemolysis in G6PDH deficiency
Methotrexate
Used for rheumatoid arthritis. Cytotoxic to lymphocytes. Side effects: hematotoxicity, mucositis, crystalluria
Sulfasalazine
Used for rheumatoid arthritis. Decreases B cell function, possibly inhibits COX. Side effects: GI distress, rash, hemolysis in G6PDH deficiency, drug-induced lupus
Glucocorticoids
Used in rheumatoid arthritis. Decrease LTs and platelet activating factor (PAF). Side effects: ACTH suppression, Cushingoid state, osteoporosis, GI distress, glaucoma
Gold salts
Used in rheumatoid arthritis. Decreases lysosomal and macrophage functions. Side effects: dermatitis, hematotoxicity, nephrotoxicity
Penicillamine
Used in rheumatoid arthritis. Suppresses T cells and circulating rheumatoid factor. Side effects: proteinuria, hematotoxicity, autoimmune disease.
Etanercept
Used in rheumatoid arthritis. Binds TNF. Side effects: hypersensitivity, injection site reactions, infections
Infliximab
Used in rheumatoid arthritis. Monoclonal antibody to TNF. Side effects: infusion reactions, infections
Anakinra
Used in rheumatoid arthritis. IL-1 receptor antagonist. Side effects: infections, injection site reactions
Colchicine
Used in acute gout. Binds tubulin --> decreases microtubular polymerization ; decreases LTB4 and leukocyte/granulocyte migration. Side effects: diarrhea, GI pain, hematuria, myelosuppression, neuropathy
Allopurinol
Prodrug converted by xanthine osidase into alloxanthine which inhibits the enzyme --> decreases purine metabolism --> decreases uric acid. Side effects: GI distress, neuropathy, rash, vasculitis, stones.
Probenecid
Inhibits tubular reabsorption of urate. Interactions: inhibits secretion of acidic drugs (cephalosporins, fluoroquinolones). Side effects: GI distress, rash, nephrotic syndrome, crystallization
Glucocorticoid drugs
Cortisol, prednisone, triamcinolone, betamethasone, dexamethasone
MOA of glucocorticoids
Inhibits leukocyte migration, phagocytosis and capillary permeability, decreases PGs, LTs, expression of COX2, PAF and interleukins
Uses of glucocorticoids
Antiinflammatory and immunosuppressive
Side effects of glucocorticoids
Suppression of ACTH --> cortical atrophy, shock if abruptly withdrawn, cushingoid syndrome, hyperglycemia (increased gluconeogenesis), osteoporosis with vertebral fractures, gastric acid secretion (ulcers), Na+ and H2O retention with edema and hypertension, hypokalemic alkalosis, hypocalcemia, inhibits bone growth in children, decreases wound healing (infections), increased sorbitol (glaucoma, cataracts), mental dysfunction.
Role of beta agonists in asthma
Slective β2 agonists: Relief of acute bronchoconstriction (albuterol, metaproterenol, terbutaline) and prophylaxis of nightime attacks (salmeterol). Side effects include anxiety, tremors and CV toxicity
Ipratropium
Muscarinic blocker causes bronchodilation in acute asthma. Safer than β1 agonists in patients with cardiovascular disease. DOC in bronchospasm induced by β-blockers.
Theophylline
Inhibits phosphodiesterase --> increases cAMP --> bronchodilation. Also antagonizes adenosine (bronchoconstrictor). Narrow therapeutic index. Side effects: nausea, diarrhea, increases HR, arrhythmias. Increased toxicity with erythromycin, cimetidine and fluoroquinolones.
Role of glucocorticoids in asthma
Decreases reactivity by decreasing PGs, LTs and Ils; May cause oropharyngeal candidiasis and retarded bone growth with chronic use; low doses prevent desensitization of β receptors.
Zafirlukast, mentelukast
LTD4 antagonists with slow onset. Used prophylactically for antigen, exercise or drug-induced asthma.
Zileuton
Selective inhibitor of lypoxygenases --> decreased ILs. Rapid onset, adjunct to steroids.
first generation sulfonylureas
tolbutamide, chlorpropamide; block K+ channels of β cells --> depolarization --> ↑Ca+ --> release of insulin
second generation sulfonylureas
glipizide, glyburide, glimepiride; block K+ channels of β cells --> depolarization --> ↑Ca+ --> release of insulin
side effects of sulfonylureas
hypoglycemia, weight gain, sulfa allergy, hypoglycemia with cimetidine (fisrt generation), disulfram-like (first generation)
hypoglycemia
paresthesia, lethargy, confusion, sweats, tremors, tachychardia, coma, seizures
metformin
↓ gluconeogenesis; can be used in patients with no islet function; side effect: lactic acidosis
glitazones
↑ target cell sensitivity to glucose via PPARs; side effects: weight gain, edema, hepatotoxicity, CV toxicity
α-glucosidase inhibitors
acarbose, miglitol; no hypoglycemia; inhibit brush border α-glucosidase; side effects: GI disturbance
xenatide
GLP-1 receptor full agonist --> augments insulin secretion; hypoglycemia when used with sulfonylureas
orlistat
inhibits pancreatic lipases; used in obesity; side effects: steatorrhea, fat malabsorption
sibutramine
serotonin/norepinephrine reuptake inhibitor; obesity management; side effects: tachychardia
propylthiouracil/methimazole
inhibits organification and coupling; side effects: agranulocytosis, aplastic anemia, skin rash
anastrozole
aromatase inhibitor --> ↓ estrogen synthesis; use: estrogen-dependant postmenopausal breast cancer
clomiphene
↓ feedback inhibition --> ↑FHS/LH --> ↑ovulation; fertility drugs; adverse effects: multiple births
tamoxifen/raloxifene
estrogen receptor agonist in bone; estrogen receptor antagonist in breast; partial agonist in endometrium
progestins/estrogens/oral contraceptives
medroxyprogesterone, norethindrone, desogestrel, estrogens; ↑progesterone --> ↓LH/FSH; side effects: ↑LDL ↓HDL, glucose intolerance, androgenic, antiestrogenic
mifepristone
progesterone antagonist --> abortifacient
methyltestosterone
ilicit in athletics, used in male hypogonadism; side effects: premature closure of epiphysis, jaundice, aggression
flutamide
androgen receptor blocker; used in prostate cancer
leuprolide
GnRH analog; prostate cancer
finasteride
5-α-reductase inhibitor --> ↓dihydrotestosterone; BPH, baldness; teratogenic
biphosphonates
use in Paget, osteoporosis; alendronate, etidronate, pamidronate
energy source of RBC
anaerobic glycolysis --> lactate (90%) and HMP shunt (10%)
antithrombin III
activated by heparin; inactivates thrombin, IXa, Xa, XIa
tPA
tissue plasminogen activator; fibrinolytic; generates plasmin from plasminogen; ↑PT and ↑PTT
protein C
inactivates factors Va and VIIIa --> anticoagulation
factor V leiden
mutation causes resistance to activated protein C --> hypercoagulable state
warm agglutinin
IgG; AIHA seen in SLE, CLL and methyldopa; "Warm weather is GGGreat, Cold ice cream MMM"
cold agglutinin
IgM; AIHA seen in mycoplasma or infectious mononucleosis infections; "Warm weather is GGGreat, Cold ice cream MMM"
heparin
activates antithrombin III; measure PTT; use: PE, DVT, AMI, DIC; side effects: bleeding, heparin-induced thrombocytopenia, hypersensitivity
protamine sulfate
rapid reversal of heparinization; binds negatively-charged heparin
antithrombin III
serine protease inhibitor binds to activated clotting factors (IXa, Xa, XIa) to inactivate them
warfarin antidote
vitamin K
warfarin
epoxide reductase inhibitor decreases vitamin K-dependant factors; slow onset; check PT; SE: skin necrosis; metabolized by P450
warfarin-induced skin necrosis
protein C and VIIa have the shortest half-lives --> transient inactivation of protein C and extrinsic pathway while intrinsic path is still active and unopposed due to longer half-lives of factors --> hypercoagulable state --> thrombosis
platelet activators
TxA2, ADP, 5HT --> ↑expression of GpIIb/IIIa receptors
platelet deactivators
prostacyclin, cAMP, clopidogrel, gpIIb/IIIa blockers (abciximab)
clopidogrel
blocks platelet ADP receptors --> ↓platelet activation; SE neutropenia
abciximab
gpIIb/IIIa antagonist --> ↓platelet aggregation
methotrexate
inhibits dihydrofolate reductase --> ↓dTMP --> ↓DNA synthesis; uses: leukemias, lymphomas, abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis
5-FU MOA
inhibits thymidylate synthase --> ↓dTMP --> ↓DNA synthesis; uses: colon cancer and solid tumors, basal cell carcinoma
6-MP
activated by HGPRTase --> blocks purine synthesis; uses: leukemias, lymphomas (except CLL or Hodgkin); metabolized by xanthine oxidase (↑toxicity with allopurinol); hepatotoxic
cytarabine (ara-C)
DNA polymerase inhibitor; use: AML
cyclophosphamide
alkylating agent ---> attacks guanine N7 --> denatures DNA; uses: non-Hodgkin lymphoma, ovarian and breast cancer, neuroblastoma
cisplatin
alkylating agent cross-links DNA strands; uses testicular, bladder, ovary and lung carcinomas; nephrotoxic
doxorubicin
intercalates DNA inhibits topoisomerase II; uses: Hodgkin's, myelomas, solid tumors; dilated cardiomyopathy
actinomycin D (dactinomycin)
intercalates DNA inhibits topoisomerase; uses: Wilm's tumor, Ewing's sarcoma. Rhabdomyosarcoma
bleomycin
formation of free radicals cause breaks in DNA strands; uses: testicular cancer, lymphomas; pulmonary fibrosis is side effect
hydroxyurea
inhibits ribonucleotidde reductase --> decreases DNA synthesis; uses: melanoma, CML, sickle cell disease
tamoxifen
estrogen receptor antagonist in breast, agonist in bone; use: breast cancer
vincristine
bind tubulin during M phase blocking polymerization of microtubules and formation of mitotic spindle; uses: lymphoma, Wilm's tumor, choriocarcinoma; neurotoxic
cyclosporine
binds cyclophillin --> ↓calcineurin --> ↓IL-2, IL-3, IFN-gamma; use in organ transplants
tacrolimus
inhibits calcineurin --> ↓IL-2, IL-3, IFN-gamma; use in organ transplants
infliximab
monoclonal Ig against TNF; use in rheumatoid arthritis and Crohn's
trastuzumab
erb-B2 antagonist; use in breast cancer
dacliximab
blocks IL-2 receptors; use in kidney transplants
etanercept
Recombinant TNF receptor binds TNF; uses: rheumatoid arthritis, psoriasis, ankylosing spondylitis
first generation H1 blockers
reversible; diphenhydramine, chlorpheniramine; uses: allergy, motion sickness, sleep aid; SE: sedation, antimuscarinic and anti-alpha adrenergic effect
2nd generation H1 blockers
loratadine, fexofenadine, desloratadine, cetirizine; use: allergy; less sedation
salmeterol
beta2 agonist; long-acting; tremor and arrhythmias
albuterol
beta2 agonist; use in acute asthma attack
theophylline
inhibits phosphodiesterase and increases cAMP --> bronchodilation; cardiotoxic, neurotoxic, narrow therapeutic index; metabolized by P450
ipratropium
antimuscarinic used in asthma and COPD
cromolyn
stabilizes mast cell membrane; not effective in acute asthma attack just prophylaxis
zileuton
5-lipoxygenase inhibitor --> decreases leukotrienes
lukasts
leukotriene receptor antagonists; aspirin-induced asthma
guainfenesin
expectorant; doesn’t suppress cough reflex
colchicine
use in acute gout; depolymerizes tubulin microtubules, prevents leukocyte chemotaxis and degranulation; SE: GI disturbances
probenecid
use in chronic gout; inhibits reabsorption of uric acid in PCT
allopurinol
use in chronic gout and leukemia; inhibits xanthine oxidase and decreases uric acid.