ACE inhibitors reduce blood pressure and provide mortality benefit in heart failure and proteinuric kidney disease but produce a recognizable cluster of side effects: dry cough, angioedema (more common in black patients), hyperkalemia, a small creatinine rise, and teratogenicity. The cough and angioedema stem from bradykinin accumulation, since ACE normally degrades bradykinin. In bilateral renal artery stenosis, ACE inhibitors can cause an acute GFR drop because the kidneys depend on angiotensin II to maintain efferent arteriolar tone. ARBs block the AT1 receptor instead, avoiding bradykinin-related effects while retaining the same potassium and creatinine risks. Aliskiren directly inhibits renin, and sacubitril/valsartan combines a neprilysin inhibitor (raising natriuretic peptides) with an ARB for HFrEF but requires a 36-hour washout from ACE inhibitors to prevent angioedema. Statins inhibit HMG-CoA reductase to lower cholesterol synthesis, with major adverse effects of myopathy and rhabdomyolysis (especially combined with fibrates) and hepatotoxicity.
Beta-blockers are stratified by selectivity: metoprolol, atenolol, esmolol, and bisoprolol are β1-selective (preferred in asthma/COPD and diabetes, although selectivity is lost at high doses), while propranolol is non-selective and also blocks β2 receptors. They are contraindicated in severe bradycardia, AV block, decompensated heart failure, and severe asthma. Carvedilol, metoprolol succinate, and bisoprolol specifically reduce mortality in HFrEF by blunting sympathetic-driven remodeling. Non-selective beta-blockers tend to increase triglycerides and decrease HDL. Prazosin is a selective α1 antagonist used for hypertension and PTSD-related nightmares, with a first-dose orthostatic hypotension warning. Phenoxybenzamine is an irreversible non-selective alpha antagonist used preoperatively for pheochromocytoma (a beta-blocker is added only after adequate alpha blockade to avoid unopposed alpha vasoconstriction), and phentolamine is a reversible non-selective alpha antagonist for MAOI-tyramine crisis and norepinephrine extravasation. Central α2 agonists clonidine and methyldopa reduce sympathetic outflow; clonidine is used for ADHD and opioid withdrawal with rebound hypertension on abrupt discontinuation, while methyldopa is a mainstay for hypertension in pregnancy despite risk of Coombs-positive hemolytic anemia.
Direct vasodilators include hydralazine, an arteriolar vasodilator that can cause a lupus-like syndrome and reflex tachycardia and is often combined with a beta-blocker and diuretic; it is safe in pregnancy. Nitroprusside is an NO donor metabolized to cyanide, with toxicity risk during prolonged high-dose infusion or in renal failure, treated with hydroxocobalamin or sodium thiosulfate. Nitrates also release NO, primarily causing venodilation at low doses and reducing preload, with reflex tachycardia and headache; tolerance develops with continuous exposure and is prevented by a daily nitrate-free interval. Isosorbide dinitrate requires hepatic first-pass activation and is shorter acting with more tolerance issues, while isosorbide mononitrate is the active metabolite with longer duration. Calcium channel blockers split into dihydropyridines (amlodipine, nifedipine) that are vascular-selective and cause reflex tachycardia, and non-dihydropyridines (verapamil, diltiazem) with cardiac effects; verapamil causes more constipation and cardiac depression while diltiazem is intermediate and often used for rate control in atrial fibrillation. Diuretics include loop agents (furosemide blocks Na-K-2Cl in the thick ascending limb, causing hypokalemia, hypocalcemia, ototoxicity at high IV doses, and hyperuricemia), thiazides (hyperGLUC: hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia, plus hyponatremia, hypokalemia, hypomagnesemia), and potassium-sparing aldosterone antagonists (spironolactone causes gynecomastia via anti-androgen effect while eplerenone does not).
Class IA antiarrhythmics (quinidine, procainamide) slow phase 0 and prolong the action potential. Class IB agents like lidocaine have a fast off-rate and shorten the action potential, useful for ventricular arrhythmias but with CNS toxicity at high plasma levels. Class IC (flecainide) is the strongest sodium blocker and is avoided post-MI. Amiodarone is a Class III agent with properties of all four classes and characteristic toxicities including pulmonary fibrosis, hypo- and hyperthyroidism (it contains iodine and inhibits 5'-deiodinase), corneal microdeposits, blue-gray skin discoloration, and hepatotoxicity; it inhibits CYP3A4 and P-glycoprotein, raising warfarin and digoxin levels and displacing digoxin from tissues. Sotalol combines Class III activity with non-selective beta-blockade, predisposing to torsades. Ibutilide is a Class III agent used for pharmacologic cardioversion of atrial flutter and fibrillation with the same torsades risk. Cardiac inotropes include digoxin, which inhibits Na/K-ATPase to increase intracellular Na and via the Na/Ca exchanger raise intracellular Ca and inotropy, producing scooped ST depression on ECG, with toxicity including yellow-green vision (xanthopsia), AV block, and arrhythmias worsened by hypokalemia, treated with digoxin immune Fab for severe toxicity; loop and thiazide diuretics worsen digoxin toxicity through hypokalemia, so potassium supplementation or potassium-sparing diuretics are often co-administered. Milrinone is a PDE3 inhibitor producing inotropy and vasodilation but increasing mortality with long-term use; dobutamine is a β1 agonist useful in acute decompensated heart failure and stress testing but causing tachyarrhythmias; and nesiritide is recombinant BNP causing vasodilation and natriuresis with limited mortality benefit. Adenosine activates A1 receptors to hyperpolarize the AV node for transient block in SVT, with effects lasting only about 10 seconds, but is contraindicated in WPW with atrial fibrillation because blocking the AV node can drive conduction down the accessory pathway and precipitate ventricular fibrillation.