Cardiovascular Pharmacology — USMLE Step 2 CK Notes

Hypertension: what to target, and why

• Primary (essential) hypertension: the problem is raised total peripheral resistance and sodium/volume retention (MAP = CO × TPR). First-line agents are a thiazide diuretic, ACE inhibitor/ARB, or dihydropyridine calcium channel blocker — each attacks one arm (volume, RAAS, or vascular tone). Beta-blockers are no longer first line without another indication.
• Hypertension + heart failure (reduced EF): use the agents that also improve survival — ACE inhibitor/ARB or ARNI, beta-blocker, mineralocorticoid antagonist, SGLT2 inhibitor, with loop diuretics for congestion. Avoid non-dihydropyridine calcium channel blockers (verapamil, diltiazem) — their negative inotropy worsens systolic failure.
• Hypertension + diabetes: prefer an ACE inhibitor or ARB, which reduce intraglomerular pressure (efferent arteriolar dilatation) and slow diabetic nephropathy/proteinuria.
• Hypertension + asthma/COPD: avoid non-selective beta-blockers (bronchospasm). Use a calcium channel blocker, ACE inhibitor/ARB or thiazide; if a beta-blocker is essential, choose a cardioselective one (bisoprolol, metoprolol).
• Hypertension in pregnancy: use labetalol, nifedipine, methyldopa or hydralazine. ACE inhibitors, ARBs and renin inhibitors are contraindicated (fetal renal damage, oligohydramnios); avoid nitroprusside (cyanide).
• Hypertension + gout: avoid thiazide and loop diuretics (they reduce urate excretion and precipitate attacks). Losartan is useful because it is mildly uricosuric; calcium channel blockers are also safe.
• Hypertension + osteoporosis: thiazides are preferred — they reduce urinary calcium loss and preserve bone density (loop diuretics do the opposite).
• Hypertension + phaeochromocytoma: give alpha-blockade FIRST (phenoxybenzamine), then a beta-blocker. Giving a beta-blocker first leaves alpha-mediated vasoconstriction unopposed and precipitates a hypertensive crisis.
• Hypertension + benign prostatic hyperplasia: an alpha-1 blocker (doxazosin) treats both. Hypertension + migraine: a beta-blocker (propranolol) or verapamil.

Molecular targets of the major cardiac drug classes

• Calcium channel blockers: block L-type voltage-gated calcium channels. Dihydropyridines (amlodipine, nifedipine) act mainly on vascular smooth muscle → arteriolar dilatation; non-dihydropyridines (verapamil > diltiazem) act on the heart → reduced rate, conduction and contractility.
• Beta-blockers: block beta-1 (Gs-coupled) receptors → less adenylyl cyclase → less cAMP → less protein kinase A → reduced calcium entry, rate and contractility (and reduced renin release).
• Gi agonists (adenosine at A1, acetylcholine at M2, alpha-2 agonists such as clonidine): inhibit adenylyl cyclase → less cAMP → slower rate/conduction and reduced sympathetic outflow. Gs antagonists are effectively the beta-blockers — same end point, different receptor.
• PDE-3 inhibitors (milrinone): prevent cAMP breakdown in cardiac and vascular muscle → inodilation (increased contractility plus vasodilatation) — used in acute decompensated heart failure.
• PDE-5 inhibitors (sildenafil, tadalafil): prevent cGMP breakdown → prolonged vasodilatation — erectile dysfunction and pulmonary arterial hypertension. Never combine with nitrates (profound hypotension).
• Natriuretic peptide potentiation (sacubitril): inhibits neprilysin, the enzyme that degrades ANP/BNP → more natriuresis and vasodilatation. Always paired with valsartan (ARNI); do not combine with an ACE inhibitor (angioedema risk).
• Nitrates: release nitric oxide → activate guanylate cyclase → raise cGMP → smooth muscle relaxation, predominantly venous.
• Gq agonists (alpha-1 receptors, angiotensin II AT1, endothelin): activate phospholipase C → IP3/DAG → increased intracellular calcium → vasoconstriction. Blocking them (alpha-blockers, ARBs, bosentan) lowers blood pressure.

Antianginal & vasodilator drugs

• Nitrates (glyceryl trinitrate, isosorbide): NO → cGMP → mainly venodilatation → reduced preload and end-diastolic volume, lowering wall tension and myocardial oxygen demand. Adverse: throbbing headache, flushing, reflex tachycardia (blunt with a beta-blocker), tolerance (needs a nitrate-free interval), and contraindicated with PDE-5 inhibitors, in right ventricular infarction and hypertrophic cardiomyopathy.
• Calcium channel blockers: dihydropyridines reduce afterload for angina and hypertension (adverse: ankle oedema, flushing, reflex tachycardia, gingival hyperplasia); verapamil/diltiazem reduce rate and contractility for angina, rate control and SVT (adverse: constipation with verapamil, bradycardia, AV block, worsening systolic failure).
• Hydralazine: direct arteriolar dilator → reduced afterload. Used in hypertensive emergencies, pregnancy, and with a nitrate in heart failure. Adverse: reflex tachycardia, fluid retention, and drug-induced lupus (anti-histone).
• Nitroprusside: releases NO, dilating both arteries and veins — used for hypertensive emergencies with a very short half-life. Adverse: cyanide toxicity (treat with hydroxocobalamin/thiosulfate).
• Fenoldopam: a dopamine D1 agonist → arteriolar dilatation with increased renal perfusion and natriuresis — useful in hypertensive emergency with renal impairment. Adverse: hypotension, tachycardia; avoid in glaucoma (raises intraocular pressure).
• Ranolazine: inhibits the late sodium current, reducing calcium overload and diastolic wall tension. It relieves angina without changing heart rate or blood pressure — useful when other agents are limited by bradycardia or hypotension. Adverse: constipation, dizziness, QT prolongation.
• Ivabradine: blocks the funny current (I_f) in the SA node → slows the rate only, with no effect on contractility or blood pressure. Used in HFrEF with a persistently high rate on maximal beta-blockade, and in angina. Adverse: bradycardia and luminous visual phenomena (phosphenes); requires sinus rhythm.
• Digoxin: inhibits the Na/K ATPase → raised intracellular sodium → less sodium-calcium exchange → more intracellular calcium (positive inotropy); it also increases vagal tone (rate control). Used in heart failure symptoms and atrial fibrillation. Adverse: narrow therapeutic index — nausea, confusion, yellow-green visual halos, arrhythmia; toxicity is worsened by hypokalaemia and renal failure. Treat with digoxin-specific antibody fragments.
• Sacubitril-valsartan (ARNI): neprilysin inhibition plus AT1 blockade — superior to an ACE inhibitor in HFrEF. Adverse: hypotension, hyperkalaemia, angioedema; wait 36 hours after stopping an ACE inhibitor.

Lipid-lowering agents — target, effect and harm

• Statins — inhibit HMG-CoA reductase (the rate-limiting step of cholesterol synthesis), which upregulates LDL receptors. Largest LDL fall and the only class with consistent mortality benefit. Adverse: myopathy/rhabdomyolysis (worse with fibrates), raised transaminases.
• Bile acid resins (cholestyramine, colesevelam) — prevent bile acid reabsorption in the terminal ileum, so the liver consumes cholesterol to make more. Adverse: GI upset, malabsorption of fat-soluble vitamins and other drugs, and a rise in triglycerides.
• Ezetimibe — blocks NPC1L1, the intestinal cholesterol absorption transporter. Mild LDL fall; well tolerated (rare transaminase rise), often added to a statin.
• Fibrates (fenofibrate, gemfibrozil) — PPAR-alpha agonists that upregulate lipoprotein lipase, giving the greatest triglyceride reduction and a modest HDL rise. Adverse: myopathy (especially with statins), gallstones, transaminase rise.
• Niacin — inhibits hepatic VLDL synthesis and adipose lipolysis; the greatest HDL rise. Adverse: prostaglandin-mediated flushing (reduced by aspirin), hyperglycaemia, hyperuricaemia/gout.
• PCSK9 inhibitors (alirocumab, evolocumab) — monoclonal antibodies preventing LDL-receptor degradation, so receptors recycle. Very large LDL fall. Adverse: injection-site reactions; high cost.
• Fish oil / omega-3 fatty acids — reduce hepatic triglyceride production; used for severe hypertriglyceridaemia. Adverse: fishy aftertaste, bleeding risk, atrial fibrillation at high dose.

Antiarrhythmics by class

• Class IA (quinidine, procainamide, disopyramide) — moderate sodium channel block plus potassium block → slowed phase 0 and prolonged QT. Used for atrial and ventricular arrhythmias and in WPW. Adverse: torsades, procainamide → drug-induced lupus, quinidine → cinchonism (tinnitus, headache).
• Class IB (lidocaine, mexiletine) — weak sodium block that shortens the action potential and preferentially binds depolarised/ischaemic tissue. Best for ventricular arrhythmias after MI and digoxin-induced arrhythmia. Adverse: CNS effects (tremor, seizures).
• Class IC (flecainide, propafenone) — strong sodium block, markedly slowed conduction with little effect on repolarisation. Used for SVT/atrial fibrillation in structurally normal hearts. Contraindicated after MI or with structural disease (proarrhythmic).
• Class II — beta-blockers (metoprolol, esmolol) — block beta-1/Gs → less cAMP → slowed SA node rate and AV conduction (phase 4 suppression). Used for rate control, post-MI and heart failure. Adverse: bradycardia, AV block, fatigue, bronchospasm (non-selective), masking of hypoglycaemia; avoid abrupt withdrawal.
• Class III — potassium channel blockers (amiodarone, sotalol, dofetilide, ibutilide) — prolong phase 3 repolarisation and refractoriness (long QT). Amiodarone is broadly effective; adverse: pulmonary fibrosis, hypo/hyperthyroidism (it is iodine-rich), hepatotoxicity, corneal deposits, blue-grey skin — check thyroid, liver and lung function. Sotalol also beta-blocks and risks torsades.
• Class IV — calcium channel blockers (verapamil, diltiazem) — block L-type calcium channels in nodal tissue → slowed AV conduction and rate control. Adverse: bradycardia, AV block, constipation, worsening systolic heart failure.
• Adenosine — acts on A1 receptors (Gi) → increased potassium efflux and hyperpolarisation → transient complete AV nodal block. Diagnostic and therapeutic in SVT; half-life is seconds. Adverse: flushing, chest tightness, transient asystole, bronchospasm; blocked by caffeine/theophylline.
• Magnesium — first-line for torsades de pointes and digoxin toxicity arrhythmias; stabilises the myocardial membrane.

High-yield revision notes; verify against a primary source before clinical use.