L3 - Ischemic Heart Disease (L2)

What is the physiologic goal of antianginal therapy, and what are the long-term treatment goals?

Reduce cardiac workload and myocardial O2 demand; decrease anginal attacks, prevent ACS/MI, prolong survival, and address risk factors such as smoking, cholesterol, and BP.

What are the major antianginal drug classes?

Organic nitrates, beta-blockers, calcium channel blockers (CCBs), and ranolazine.

What is the key pathophysiologic problem in angina, and how can drugs correct it?

Myocardial O2 demand exceeds O2 supply; therapy decreases O2 demand and/or increases O2 supply.

What factors determine myocardial O2 demand?

Heart rate, contractility, and ventricular wall stress.

How does decreasing preload help angina?

↓ venous return/filling → ↓ ventricular wall stress → ↓ myocardial O2 demand.

How does decreasing afterload help angina?

↓ resistance to ventricular ejection → ↓ cardiac workload → ↓ myocardial O2 demand.

How do organic nitrates work?

Enzyme-mediated NO release → guanylyl cyclase activation → ↑ cGMP → smooth muscle relaxation and venodilation.

How do nitrates affect preload, afterload, and contractility?

Primarily ↓ PRELOAD through venodilation; afterload is not the primary effect; no major direct effect on contractility.

How do nitrates improve the myocardial O2 supply-demand balance?

↓ preload/wall stress → ↓ O2 demand; coronary vasodilation and ↓ vasospasm help O2 supply.

What additional effect does NO have on platelets?

Inhibits platelet aggregation.

According to the lecture, how do nitrates affect overall coronary blood flow?

There is no net change in coronary blood flow.

Which forms of angina can nitrates treat?

Exertional angina, vasospastic (Prinzmetal) angina, and unstable angina.

What are the important pharmacokinetic features of nitrates?

Rapid onset, short half-life, significant nitroglycerin first-pass metabolism; SL avoids first-pass; patches prolong action.

What happens to oral isosorbide dinitrate?

It is biotransformed into two active mononitrate metabolites.

What are the major adverse effects of nitrates?

Headache, postural hypotension, facial flushing, reflex tachycardia, and tolerance.

How is nitrate tolerance reduced?

Use a daily nitrate-free period.

Why are nitrates contraindicated with PDE-5 inhibitors?

Both enhance cGMP-mediated vasodilation → potentially life-threatening hypotension.

What nitrate waiting periods are required after PDE-5 inhibitors?

Sildenafil or vardenafil: 24 hours; tadalafil: 48 hours.

What is the main antianginal mechanism of beta-blockers?

↓ HR + ↓ contractility → ↓ cardiac workload and myocardial O2 demand.

How do beta-blockers affect preload, afterload, and contractility?

Preload: little direct effect; afterload: can ↓ through ↓ BP/peripheral resistance; contractility: ↓.

How do beta-blockers lower blood pressure?

Primarily by ↓ cardiac output/contractility and peripheral resistance.

Why are beta-blockers useful for exertional angina?

They blunt exertional increases in HR and contractility, limiting the increase in myocardial O2 demand.

What are the major adverse effects of beta-blockers?

Excessive bradycardia, ↓ LV contractility, bronchoconstriction, fatigue, and masking hypoglycemic symptoms.

What is the mechanism of action of calcium channel blockers?

Block Ca2+ influx into cardiac and vascular smooth muscle → ↓ myocardial inotropy and vascular smooth muscle relaxation.

How do CCBs improve the myocardial O2 supply-demand balance?

↓ BP/afterload, contractility, and sometimes HR → ↓ O2 demand; coronary vasodilation/↓ vasospasm → ↑ O2 supply.

How do CCBs affect preload, afterload, and contractility?

Can ↓ preload; ↓ afterload via vasodilation; verapamil/diltiazem ↓ contractility, while DHPs have little cardiac depression.

How do verapamil, diltiazem, and DHP CCBs differ in selectivity?

Verapamil = primarily heart; diltiazem = heart + vessels; DHPs such as nifedipine = primarily vasculature.

How do verapamil, diltiazem, and DHPs compare pharmacologically?

Verapamil: strong ↓ contractility/AV conduction, mild vasodilation; diltiazem: intermediate effects on both; DHPs: strong vasodilation with little/no AV-node suppression.

Which CCBs decrease heart rate and AV-node conduction?

Verapamil and diltiazem.

Which DHP CCBs are listed in the lecture?

Amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine.

What are the major adverse effects of verapamil, diltiazem, and DHPs?

Verapamil: hypotension, bradycardia/AV block, constipation, edema; diltiazem: hypotension, bradycardia/AV block, edema; DHPs: hypotension, headache, flushing, edema.

Why are CCBs useful for coronary vasospasm?

They directly vasodilate coronary arteries and increase myocardial O2 supply.

What is ranolazine's mechanism and antianginal effect?

Inhibits late inward Na+ current → ↓ intracellular Na+ and Ca2+ overload → improved diastolic function and O2 supply-demand balance.

How does ranolazine affect preload, afterload, contractility, HR, and BP?

It has minimal major effects on preload, afterload, contractility, HR, or BP.

What are the key pharmacokinetic properties of ranolazine (Ranexa)?

Oral; 35–50% bioavailability; 7–9 hr half-life; primarily CYP3A4 metabolism with CYP2D6 involvement.

How is ranolazine eliminated?

~75% renal and 25% fecal; <5% is excreted unchanged in urine.

What are the major adverse effects of ranolazine?

Dizziness, headache, constipation, and nausea.

What is the high-yield hemodynamic comparison of antianginal drugs?

Nitrates = ↓ PRELOAD; beta-blockers = ↓ HR + contractility; DHP CCBs = ↓ AFTERLOAD; verapamil/diltiazem = ↓ HR + contractility + afterload; ranolazine = minimal hemodynamic effects.

Which antianginal drugs are especially useful for coronary vasospasm?

Nitrates and calcium channel blockers.