книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Chapter 4 λ Antiarrhythmic Drugs

−Uses: DOC for paroxysmal supraventricular tachycardias and AV nodal arrhythmias

−Administered IV: t1/2 <10 seconds

−Side effects: flushing, sedation, dyspnea

−Adenosine is antagonized by methylxanthines (theophylline and caffeine)

λMagnesium

−Use: torsades

−Drugs causing torsades include:

ºPotassium-channel blockers (class 1A and class III)

ºAntipsychotics (thioridazine)

ºTricyclic antidepressants

Chapter Summary

λThe sequences of ionic events in the action potential of cardiac cells are described.

λDepolarization (phase 0) is due to Na+ influx in fast fibers and due to Ca2+ influx in SA and AV nodal cells. Class I antiarrhythmic drugs block Na+ influx and class IV antiarrhythmics block Ca2+ influx.

λRepolarization (phase 3) in all cardiac cells is due to K+ efflux (delayed rectifier current) and this is blocked by class IA and class III antiarrhythmic drugs. Pacemaker currents (phase 4) are blocked by class II and class IV drugs.

λResponsivity, capacity of a cell for depolarization, depends on resting membrane potential; con-ductance is the rate of potential spread; refractoriness is the inability to respond to excitation.

λFigure III-4-4 depicts the M and h gates of cardiac Na+ channels. Three conformations exist—resting (ready), active (open), and inactive (refractory). Class I drugs are least active when Na+ channels are in the resting state (state-dependent actions).

λActions of class II antiarrhythmics (beta blockers) involve antagonism of

SANS-mediated increases in cAMP, especially at SA and AV nodal cells to slow phase 0 and 4 of the action potential.

λThe class I antiarrhythmic drugs block Na+ channels. Class IA drugs are state-dependent blockers of fast Na+ channels, and they increase the action potential duration (APD). Quinidine, in addition, is an M blocker and can increase the heart rate and AV conduction. Procainamide has less M block than quinidine and no alpha block. The uses and contraindications of quinidine and procainamide are provided.

λClass IB drugs are less state-dependent blockers of fast Na+ channels, and they decrease the APD. The uses for lidocaine, mexiletine, and tocainide are discussed, as are the metabolism and adverse effects of lidocaine.

λThe class IC drug flecainide blocks fast Na+ channels, especially of HisPurkinje cells, and has no effect on the APD and no ANS effects.

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Section III λ Cardiac and Renal Pharmacology

Chapter Summary (cont’d )

λClass II antiarrhythmic drugs are beta-blockers that decrease SA and AV

nodal activity, decrease the phase 4 slope, and prevent β1 adrenoceptor activation, thereby circumventing the normal increase in cAMP. Propranolol is nonselective; acebutolol and esmolol are selective. Their antiarrhythmic use is discussed.

λClass III antiarrhythmic drugs are K+-channel blockers that increase the APD and effective refractory period (ERP), especially in Purkinje and ventricular tissues. Amiodarone and sotalol are the examples discussed.

λClass IV antiarrhythmic drugs are Ca2+-channel blockers that decrease the SA and AV nodal activity and the slope of phase 4 of the action potential in pacemakers. The uses and adverse effects of verapamil are indicated.

λAdenosine and magnesium are two unclassified antiarrhythmic drugs. Adenosine decreases SA and AV node activity and increases the AV node refractory period. Magnesium has possible use in torsades. Drugs (other than classes Ia and III antiarrhythmics) associated with torsades include thioridazine and tricyclic antidepressants.

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Learning Objectives

Solve problems concerning the rationale for the use of nitrates, beta blockers, and carvedilol for angina

Use knowledge of calcium channel blockers

Demonstrate understanding of ranolazine

RATIONALE FOR USE

Angina pectoris is the principal syndrome of ischemic heart disease, anginal pain occurring when oxygen delivery to the heart is inadequate for myocardial requirement.

λStable/classic angina (angina of effort or exercise) is due to coronary atherosclerotic occlusion

λVasospastic or variant angina (Prinzmetal) is due to a reversible decrease in coronary blood flow

Drug Strategies in Stable and Vasospastic Angina

Drug strategies in stable and vasospastic angina involve:

↓ oxygen requirement by ↓ TPR, CO, or both (nitrates, CCBs, and beta blockers).

↑ oxygen delivery by ↓ vasospasm (nitrates and CCBs).

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Chapter 5 λ Antianginal Drugs

Chapter Summary

λAngina is the principal syndrome caused by ischemic heart disease. The forms are classic, stable and vasospastic.

λThe drug strategies are to increase oxygen supply by decreasing vasospasm (nitrates and calcium channel antagonists [CCBs]) and to decrease cardiac oxygen requirements by decreasing peripheral vascular resistance and/or cardiac output (nitrates, CCBs, and beta blockers).

λNitrates increase NO concentrations. Increased NO activates guanylyl cyclase; this increases cGMP levels, which dephosphorylates myosin light chains, decreasing their association with actin and thereby promoting smooth muscle relaxation. These mechanisms are summarized in Figure III-5-1.

λNO-enhancing drugs used to treat angina include nitroglycerin and isosorbide.

λThe adverse effects of the nitrates are also considered.

λCCBs decrease contractility and increase vasodilation by preventing the influx of Ca2+ required for muscle contraction. The sequence of reactions involved is summarized in Figure III-5-2. The CCBs considered are the dihydropyridines (e.g., nifedipine), verapamil, and diltiazem.

λBeta blockers act directly on the heart by decreasing the heart rate, the force of contraction, and cardiac output, thereby decreasing the work performed.

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