Medical School · Year 1 · Cardiovascular · includes a quiz and discussion video

Lecture 18: Cardiovascular Pharmacology

Unit 1.7: Cardiovascular System

Learning Objectives

By the end of this lecture, students will be able to:

1. Classify cardiovascular drugs by mechanism of action
2. Describe the pharmacology of antihypertensive agents
3. Explain the mechanisms and uses of drugs for heart failure
4. Describe antianginal therapy and its mechanisms
5. Explain the pharmacology of antithrombotic agents
6. Apply pharmacologic principles to clinical scenarios

Lecture Content

Drugs Acting on the Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system represents one of the most important targets in cardiovascular pharmacology, with multiple drug classes interrupting this pathway at different points to reduce blood pressure, prevent cardiac remodeling, and protect renal function.

ACE inhibitors, exemplified by lisinopril, enalapril, and ramipril, block the angiotensin-converting enzyme that catalyzes the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. By reducing angiotensin II levels, these drugs produce vasodilation (lowering blood pressure), decrease aldosterone secretion (reducing sodium and water retention), and attenuate the direct growth-promoting effects of angiotensin II on cardiac and vascular tissue. ACE also degrades bradykinin, so ACE inhibitors increase bradykinin levels, contributing to their vasodilatory effect but also explaining their most common side effect: dry cough occurring in five to twenty percent of patients due to bradykinin accumulation in the airways. More seriously, bradykinin accumulation can cause angioedema, a rare but potentially life-threatening adverse effect. Other important considerations include hyperkalemia (due to reduced aldosterone), the risk of acute kidney injury in patients with bilateral renal artery stenosis (where angiotensin II-mediated efferent arteriolar constriction maintains glomerular filtration), and teratogenicity requiring avoidance during pregnancy. Clinical benefits extend beyond blood pressure lowering, with proven mortality reduction in heart failure, renal protection in diabetic nephropathy, and post-myocardial infarction benefits.

Angiotensin receptor blockers, including losartan, valsartan, and candesartan, directly block the AT1 receptor through which most pathological effects of angiotensin II are mediated. Because ARBs do not affect bradykinin metabolism, they do not cause cough, making them appropriate alternatives for patients who develop ACE inhibitor-induced cough. The therapeutic benefits are similar to ACE inhibitors, and the precautions regarding hyperkalemia and pregnancy also apply. ARBs should not be combined with ACE inhibitors routinely, as trials have shown increased adverse events without additional benefit.

Aldosterone antagonists include spironolactone and eplerenone, both of which block the mineralocorticoid receptor. Spironolactone is nonselective, also binding androgen and progesterone receptors, which explains its side effects of gynecomastia and menstrual irregularities. Eplerenone is selective for the mineralocorticoid receptor, minimizing these endocrine effects but at higher cost. Both agents have demonstrated mortality reduction in heart failure with reduced ejection fraction and are valuable in resistant hypertension and primary aldosteronism. Hyperkalemia represents the primary concern, requiring monitoring particularly when combined with ACE inhibitors or ARBs.

The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan combines an ARB with an inhibitor of neprilysin, the enzyme that degrades natriuretic peptides. By preventing natriuretic peptide breakdown while blocking angiotensin II effects, this combination enhances beneficial vasodilation, natriuresis, and anti-fibrotic effects. Clinical trials have demonstrated superiority over ACE inhibitors alone in heart failure with reduced ejection fraction, making this combination a cornerstone of contemporary heart failure therapy.

<image>Panel A: RAAS cascade showing renin from juxtaglomerular cells cleaving angiotensinogen to angiotensin I, then ACE converting to angiotensin II, with ACE inhibitors blocking this step and causing bradykinin accumulation leading to cough and angioedema. Panel B: Angiotensin II effects on AT1 receptors causing vasoconstriction and aldosterone release, with ARBs blocking the AT1 receptor and aldosterone antagonists blocking the mineralocorticoid receptor. Panel C: ARNI dual action with sacubitril inhibiting neprilysin to prevent breakdown of natriuretic peptides promoting vasodilation and natriuresis, combined with valsartan blocking AT1. Panel D: Clinical benefits and adverse effects summary for each class including BP reduction, cardiac remodeling prevention, renal protection, hyperkalemia risk, and pregnancy contraindication.</image>

Diuretics

Diuretics reduce blood volume and cardiac preload by increasing renal sodium and water excretion. Different classes act at distinct nephron segments with varying potency and side effect profiles, making selection dependent on the clinical indication.

Thiazide diuretics, including hydrochlorothiazide, chlorthalidone, and metolazone, inhibit the sodium-chloride cotransporter in the distal convoluted tubule. Despite acting at a site that handles only about five percent of filtered sodium, they effectively lower blood pressure through mechanisms that extend beyond volume reduction to include decreased vascular resistance. Their relatively mild natriuretic effect makes them appropriate for hypertension but insufficient for significant volume overload. Chlorthalidone has longer duration of action and more robust evidence for cardiovascular outcome reduction compared to hydrochlorothiazide. Thiazides decrease calcium excretion, useful in nephrolithiasis prevention but potentially causing hypercalcemia. Their metabolic effects include hypokalemia (from increased distal sodium delivery stimulating potassium secretion), hyponatremia (particularly in elderly patients), hyperuricemia (which can precipitate gout), and mild hyperglycemia and hyperlipidemia.

Loop diuretics, including furosemide, bumetanide, and torsemide, inhibit the sodium-potassium-two-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. This segment normally reabsorbs approximately twenty-five percent of filtered sodium, making loop diuretics the most potent available. They are essential for managing volume overload in heart failure, acute pulmonary edema, and edematous states with reduced GFR (where thiazides become ineffective below approximately 30 mL/min). Loop diuretics also increase calcium excretion, useful in hypercalcemia treatment but potentially causing hypocalcemia with chronic use. Potassium and magnesium wasting require monitoring and supplementation. Ototoxicity represents an important adverse effect, particularly with rapid intravenous administration or concurrent aminoglycoside use.

Potassium-sparing diuretics act in the collecting duct to reduce potassium excretion. Aldosterone antagonists were discussed above. Amiloride and triamterene directly block the epithelial sodium channel (ENaC) in principal cells, reducing sodium reabsorption and the electrochemical gradient driving potassium secretion. Their weak natriuretic effect makes them useful primarily as adjuncts to prevent hypokalemia when combined with thiazides or loops rather than as primary diuretics.

<image>Panel A: Thick ascending limb showing loop diuretics blocking the NKCC2 transporter at the site reabsorbing 25% of filtered sodium, with side effects of hypokalemia, hypomagnesemia, hypocalcemia, and ototoxicity. Panel B: Distal convoluted tubule showing thiazide diuretics blocking the Na-Cl cotransporter at the site reabsorbing 5% of filtered sodium, with decreased calcium excretion and side effects of hypokalemia, hyponatremia, and hyperuricemia. Panel C: Collecting duct showing aldosterone antagonists blocking the mineralocorticoid receptor and ENaC blockers directly blocking the sodium channel, with potassium retention and hyperkalemia risk. Panel D: Summary table showing potency ranking of loops greater than thiazides greater than potassium-sparing, primary indications for each class, and electrolyte effects.</image>

Beta-Blockers

Beta-adrenergic receptor blockers represent a diverse class with differing selectivity, ancillary properties, and clinical applications. Their cardiovascular effects result primarily from blocking beta-1 receptors in the heart and beta-1 receptors in juxtaglomerular cells.

Cardiac beta-1 receptor blockade reduces heart rate (negative chronotropy), contractility (negative inotropy), and conduction velocity through the AV node (negative dromotropy). These effects decrease myocardial oxygen demand, explaining the benefit in angina. The reduction in heart rate also allows more time for coronary filling during diastole, potentially improving myocardial perfusion. In heart failure, although the acute negative inotropic effect seems counterproductive, chronic beta-blockade reduces the harmful effects of sustained sympathetic activation, slows adverse remodeling, and has proven mortality benefit. Blockade of juxtaglomerular beta-1 receptors reduces renin release, contributing to blood pressure lowering.

Beta-blocker selectivity has important clinical implications. Non-selective agents such as propranolol and nadolol block both beta-1 and beta-2 receptors. Beta-2 blockade in bronchial smooth muscle causes bronchoconstriction, making these agents problematic in asthma and COPD. Beta-2 blockade in peripheral vessels causes vasoconstriction, potentially worsening peripheral arterial disease and Raynaud phenomenon. Beta-2 blockade interferes with glycogenolysis and may mask hypoglycemia symptoms in diabetics. Beta-1 selective agents (cardioselective) such as metoprolol, atenolol, and bisoprolol preferentially block cardiac receptors, reducing but not eliminating these concerns; selectivity is dose-dependent and diminishes at higher doses.

Some beta-blockers have additional vasodilatory properties through alpha-1 receptor blockade (carvedilol, labetalol) or nitric oxide release (nebivolol). These combined alpha-beta blockers are particularly useful in heart failure and hypertension, where the vasodilation offsets the peripheral vasoconstriction that pure beta-blockers can cause.

Intrinsic sympathomimetic activity, present in pindolol and acebutolol, means these agents provide partial agonism at beta receptors, attenuating the degree of receptor blockade. This theoretically reduces bradycardia and negative inotropy but has not translated into clinical advantages, and these agents lack the mortality benefit demonstrated by other beta-blockers in heart failure and post-myocardial infarction settings.

Common adverse effects include fatigue, depression (more with lipophilic agents that cross the blood-brain barrier), cold extremities, erectile dysfunction, and exacerbation of heart failure in decompensated patients. Beta-blockers should not be discontinued abruptly due to risk of rebound sympathetic activation causing tachycardia, hypertension, or angina.

<image>Panel A: Classification matrix showing non-selective agents propranolol and nadolol, beta-1 selective agents metoprolol, atenolol, and bisoprolol, alpha-beta blockers carvedilol and labetalol, agents with ISA pindolol and acebutolol, and nebivolol with NO release. Panel B: Target organ effects showing cardiac beta-1 blockade decreasing heart rate and contractility, renal beta-1 blockade decreasing renin, bronchial beta-2 blockade risking bronchoconstriction, and hepatic beta-2 blockade impairing glycogenolysis. Panel C: Clinical uses including heart failure with mortality benefit from carvedilol, metoprolol succinate, and bisoprolol, post-MI, angina with reduced oxygen demand, arrhythmia rate control, and thyrotoxicosis symptom control. Panel D: Common adverse effects including fatigue, depression, cold extremities, and erectile dysfunction, with cautionary note about rebound sympathetic activation with abrupt discontinuation.</image>

Calcium Channel Blockers

Calcium channel blockers inhibit L-type voltage-gated calcium channels, reducing calcium entry into cardiac and vascular smooth muscle cells. The two major subclasses, dihydropyridines and non-dihydropyridines, differ substantially in their tissue selectivity and clinical applications.

Dihydropyridines, including amlodipine, nifedipine, and felodipine, act predominantly on vascular smooth muscle with minimal cardiac effects at therapeutic doses. By reducing calcium-mediated contraction in arteriolar smooth muscle, they cause vasodilation that lowers peripheral resistance and blood pressure. The vasodilation also reduces cardiac afterload, benefiting patients with angina. Reflex sympathetic activation in response to vasodilation causes tachycardia, particularly with short-acting formulations. Modern long-acting formulations minimize this reflex. Common adverse effects result from vasodilation: peripheral edema (a vasodilatory phenomenon, not fluid retention, and therefore not responsive to diuretics), flushing, and headache. Gingival hyperplasia occurs with chronic use.

Non-dihydropyridines include the benzothiazepine diltiazem and the phenylalkylamine verapamil. These agents have significant cardiac effects in addition to vasodilation. They reduce heart rate through effects on the sinoatrial node, slow conduction through the atrioventricular node, and decrease myocardial contractility. These properties make them useful for rate control in atrial fibrillation and for terminating supraventricular tachycardias but also create important contraindications. Non-dihydropyridines should be avoided in heart failure with reduced ejection fraction because the negative inotropic effect worsens pump function. Combination with beta-blockers requires caution due to additive effects on heart rate and AV conduction, potentially causing severe bradycardia or heart block. Verapamil causes constipation more frequently than diltiazem due to effects on gastrointestinal smooth muscle.

Drug interactions deserve attention. Verapamil inhibits P-glycoprotein and increases digoxin levels, requiring dose reduction when co-administered. Both diltiazem and verapamil inhibit CYP3A4, affecting metabolism of numerous drugs.

<image>Panel A: L-type calcium channel structure showing binding sites for dihydropyridines with vascular preferential action and non-dihydropyridines with cardiac and vascular effects. Panel B: Comparison table showing dihydropyridines with strong vasodilation, reflex tachycardia, and no cardiac conduction effects, versus non-dihydropyridines with moderate vasodilation, direct heart rate reduction, decreased contractility, and slowed AV conduction. Panel C: Dihydropyridine effects showing arteriolar vasodilation reducing peripheral resistance with peripheral edema from pre-capillary dilation, and non-dihydropyridine effects on SA node, AV node, and myocardial contractility. Panel D: Clinical use mapping with caution boxes: avoid non-dihydropyridines in HFrEF, avoid combining with beta-blockers due to severe bradycardia risk, and verapamil increases digoxin levels.</image>

Vasodilators

Vasodilators reduce blood pressure and cardiac preload or afterload through direct relaxation of vascular smooth muscle. Different agents preferentially affect veins, arteries, or both, with varying mechanisms of action.

Organic nitrates, including nitroglycerin and isosorbide compounds, are converted to nitric oxide within vascular smooth muscle. Nitric oxide activates guanylyl cyclase, increasing cyclic GMP, which promotes smooth muscle relaxation through multiple mechanisms including reduced intracellular calcium. Nitrates preferentially dilate veins at low doses, reducing preload and ventricular filling pressures. This venodilation decreases myocardial wall stress and oxygen demand while also reducing pulmonary congestion in heart failure. At higher doses, arterial dilation occurs, reducing afterload. Coronary artery dilation can relieve vasospasm and improve blood flow to ischemic regions. Sublingual nitroglycerin acts within minutes, providing rapid relief of angina. Longer-acting oral formulations (isosorbide dinitrate, isosorbide mononitrate) and transdermal patches provide sustained effect for angina prophylaxis. Intravenous nitroglycerin allows titrated therapy in acute settings. The major limitation is tolerance development with continuous exposure, necessitating a nitrate-free interval of at least eight to twelve hours daily. Headache from cerebral vasodilation is the most common side effect. Hypotension may occur, particularly with concurrent phosphodiesterase-5 inhibitors (sildenafil, tadalafil), which potentiate nitrate effects by preventing cGMP degradation; this combination is absolutely contraindicated.

Hydralazine directly relaxes arteriolar smooth muscle through mechanisms that remain incompletely understood but may involve interference with calcium release from the sarcoplasmic reticulum. The selective arterial vasodilation reduces afterload without venodilation, and the consequent reflex sympathetic activation causes tachycardia, typically requiring concurrent beta-blocker administration. Hydralazine combined with isosorbide dinitrate (providing both arterial and venous dilation) has mortality benefit in heart failure, particularly in African American patients. Hydralazine is safe in pregnancy, making it useful for hypertensive emergencies in this population. A lupus-like syndrome can occur with chronic use, particularly in slow acetylators.

Minoxidil is a potent arteriolar dilator that opens ATP-sensitive potassium channels, hyperpolarizing vascular smooth muscle and causing relaxation. Its potency limits use to severe, refractory hypertension, and the marked reflex sympathetic activation and fluid retention require concurrent beta-blocker and diuretic therapy. Hypertrichosis (excessive hair growth) is a common and bothersome side effect.

<image>Panel A: Nitrate pharmacology showing nitroglycerin conversion to NO, activation of guanylyl cyclase, increased cGMP, and smooth muscle relaxation, with venous dilation at low doses and arterial dilation at higher doses, and absolute contraindication with PDE-5 inhibitors. Panel B: Nitrate cardiac effects including reduced preload and wall stress, coronary vasodilation, tolerance mechanism from sulfhydryl depletion requiring 8-12 hour nitrate-free intervals. Panel C: Hydralazine showing selective arteriolar dilation with reflex tachycardia requiring beta-blocker, safety in pregnancy, lupus-like syndrome in slow acetylators, and combination with isosorbide dinitrate for heart failure. Panel D: Minoxidil showing potassium channel opening mechanism with potent vasodilation requiring concurrent beta-blocker and diuretic, and clinical applications summary for acute angina, chronic prophylaxis, heart failure, and hypertensive emergencies.</image>

Positive Inotropic Agents

Positive inotropes increase myocardial contractility, useful in acute heart failure and cardiogenic shock but generally not for chronic therapy due to increased mortality with long-term use.

Cardiac glycosides, with digoxin being the primary agent in clinical use, inhibit the sodium-potassium ATPase in cardiac myocytes. The resulting increase in intracellular sodium reduces the activity of the sodium-calcium exchanger (which normally extrudes calcium in exchange for sodium entry), leading to intracellular calcium accumulation and enhanced contractility. Beyond this inotropic effect, digoxin has important autonomic effects: it increases vagal tone, slowing heart rate and AV nodal conduction. This dual action makes digoxin useful in heart failure (for symptom improvement, though without mortality benefit) and for rate control in atrial fibrillation. The narrow therapeutic window creates significant toxicity risk. Symptoms of toxicity include gastrointestinal manifestations (nausea, vomiting, anorexia), neurological effects (confusion, visual disturbances with yellow-green halos), and cardiac arrhythmias (virtually any arrhythmia can occur, but characteristic patterns include accelerated junctional rhythm, atrial tachycardia with block, and bidirectional ventricular tachycardia). Hypokalemia and hypomagnesemia lower the threshold for toxicity by enhancing digoxin binding to the sodium-potassium ATPase. Treatment of severe toxicity involves digoxin-specific antibody fragments (Fab), which bind and neutralize circulating digoxin.

Sympathomimetic inotropes act through adrenergic receptors. Dobutamine predominantly stimulates beta-1 receptors, increasing contractility with modest heart rate increase; it also stimulates beta-2 receptors, causing vasodilation that partially offsets the increased cardiac output. Dobutamine is used in acute decompensated heart failure and cardiogenic shock. Dopamine has dose-dependent effects: low doses stimulate dopamine receptors (renal vasodilation, though clinical significance is debated), intermediate doses activate beta-1 receptors (inotropy), and high doses engage alpha-1 receptors (vasoconstriction). Norepinephrine potently stimulates alpha-1 receptors causing vasoconstriction, useful in distributive shock to restore vascular tone, with additional beta-1 effects providing inotropy. Epinephrine stimulates all adrenergic receptors and is used in cardiac arrest and anaphylaxis.

Phosphodiesterase-3 inhibitors, including milrinone, prevent degradation of cyclic AMP in cardiac and vascular smooth muscle. The resulting increase in cAMP enhances contractility in the heart while causing vasodilation peripherally, earning these agents the designation "inodilators." Milrinone is used in acute decompensated heart failure, particularly when vasodilation is desirable and when beta receptors may be desensitized from chronic catecholamine exposure. Arrhythmias and hypotension are the primary concerns.

<image>Panel A: Digoxin mechanism showing Na/K-ATPase inhibition leading to increased intracellular sodium, reduced Na/Ca exchanger activity, increased intracellular calcium, and enhanced contractility, with vagal effects slowing heart rate and AV conduction. Panel B: Digoxin narrow therapeutic window with toxicity manifestations including GI nausea, visual yellow halos, and cardiac arrhythmias, treated with digoxin-specific Fab antibodies. Panel C: Sympathomimetic receptor profiles: dobutamine predominantly beta-1, dopamine dose-dependent from dopaminergic to beta-1 to alpha-1, norepinephrine alpha-1 dominant, and epinephrine activating all adrenergic receptors. Panel D: PDE-3 inhibitor milrinone blocking phosphodiesterase in cardiac myocytes increasing contractility and in vascular smooth muscle causing vasodilation, producing the inodilator effect for acute heart failure.</image>

Antiarrhythmic Drugs

Antiarrhythmic drugs modify cardiac electrical activity to prevent or terminate arrhythmias. The Vaughan-Williams classification organizes these agents by their predominant mechanism, though many have multiple effects.

Class I agents block sodium channels, reducing the slope of phase 0 depolarization and slowing conduction. They are subdivided based on kinetics of binding and effects on action potential duration. Class Ia agents (quinidine, procainamide, disopyramide) exhibit moderate binding kinetics and also block potassium channels, prolonging action potential duration and the QT interval. This QT prolongation creates risk of torsades de pointes. Class Ib agents (lidocaine, mexiletine) have fast binding kinetics with preferential effects on ischemic or depolarized tissue, shortening action potential duration. Lidocaine is used for ventricular arrhythmias in the acute setting. Class Ic agents (flecainide, propafenone) bind slowly with potent conduction slowing and no effect on action potential duration. They are effective for atrial fibrillation and supraventricular tachycardias but are contraindicated in structural heart disease due to proarrhythmic risk demonstrated in the CAST trial.

Class II agents are beta-blockers, discussed above. Their antiarrhythmic effects result from blocking sympathetic stimulation of cardiac automaticity and conduction.

Class III agents block potassium channels, prolonging repolarization and the refractory period. Amiodarone is the prototypical agent, though it actually has activity across all four classes. Its efficacy against both atrial and ventricular arrhythmias, combined with relatively low proarrhythmia risk compared to other antiarrhythmics, makes it widely used despite substantial toxicity with chronic use: pulmonary fibrosis, thyroid dysfunction (both hyper- and hypothyroidism due to its iodine content), hepatotoxicity, corneal deposits, and skin discoloration. Sotalol combines class III effects with non-selective beta-blockade; it prolongs QT and carries torsades risk, requiring initiation in a monitored setting. Dofetilide and ibutilide are pure class III agents with significant torsades risk.

Class IV agents are the non-dihydropyridine calcium channel blockers diltiazem and verapamil, which slow conduction through the AV node by reducing calcium-dependent depolarization.

Additional agents include adenosine, which acts on A1 receptors to activate acetylcholine-sensitive potassium channels, causing hyperpolarization and transient AV block; it is the drug of choice for terminating regular narrow-complex supraventricular tachycardias. Magnesium is the treatment of choice for torsades de pointes.

<image>Panel A: Ventricular action potential with phases 0-4 and ion currents labeled, with Class I drugs mapped to phase 0 sodium current block: Ia with moderate block and QT prolongation, Ib with fast block shortening APD for ischemic VT, and Ic with slow block and proarrhythmia risk in structural heart disease. Panel B: Class II beta-blockers affecting phase 4 depolarization, Class III potassium channel blockers prolonging phase 3 with amiodarone having multi-class effects, and Class IV non-dihydropyridine CCBs affecting AV nodal conduction. Panel C: Adenosine mechanism activating A1 receptors causing AV block for SVT termination, and magnesium as treatment of choice for torsades de pointes. Panel D: Drug selection guide: SVT termination with adenosine or verapamil, AF rate control with beta-blocker or diltiazem, AF conversion with amiodarone or flecainide, VT with amiodarone or lidocaine, with proarrhythmia warnings emphasized.</image>

Antianginal Therapy

Antianginal therapy aims to restore the balance between myocardial oxygen supply and demand, either by increasing supply, decreasing demand, or both. Understanding the determinants of oxygen supply and demand guides rational drug selection.

Myocardial oxygen demand depends on heart rate (more beats require more oxygen), contractility (stronger contractions require more oxygen), and wall stress (proportional to ventricular pressure and volume). Heart rate is particularly important because it affects both oxygen consumption and the time available for coronary perfusion during diastole. Oxygen supply depends on coronary blood flow, which in turn depends on coronary perfusion pressure, coronary vascular resistance, and the duration of diastole.

Organic nitrates primarily reduce oxygen demand by decreasing preload (venodilation reduces ventricular volume and wall stress) and, at higher doses, afterload (arteriolar dilation reduces the pressure the heart must generate). They also increase supply through direct coronary vasodilation and relief of coronary spasm. Nitrates are particularly effective for variant (Prinzmetal) angina caused by coronary vasospasm.

Beta-blockers reduce oxygen demand by slowing heart rate, decreasing contractility, and lowering blood pressure. The slower heart rate also increases diastolic time, potentially improving coronary perfusion. Beta-blockers are first-line for chronic stable angina and are particularly important in patients with prior myocardial infarction.

Calcium channel blockers reduce demand through vasodilation (reduced afterload) and, for non-dihydropyridines, through reduced heart rate and contractility. They also increase supply through coronary vasodilation. Non-dihydropyridines are preferred for angina when tachycardia is problematic or when beta-blockers are contraindicated. Dihydropyridines may cause reflex tachycardia and should generally be combined with beta-blockers for angina.

Ranolazine represents a newer mechanism, inhibiting the late sodium current that is enhanced in ischemic myocardium. The resulting reduction in intracellular sodium and calcium accumulation decreases diastolic wall tension without affecting heart rate, blood pressure, or contractility. It is used as add-on therapy for chronic angina. QT prolongation occurs and requires monitoring.

Combination therapy often provides greater benefit than single agents. Beta-blockers combined with nitrates are particularly complementary: nitrates reduce preload and cause reflex tachycardia, while beta-blockers counteract the tachycardia and provide additional heart rate reduction. Combining beta-blockers with non-dihydropyridine calcium channel blockers requires caution due to additive negative chronotropic and inotropic effects.

<image>Panel A: Balance scale showing oxygen demand factors of heart rate, contractility, and wall stress versus supply factors of coronary blood flow, perfusion pressure, and diastolic time. Panel B: Drug effects on the balance: nitrates decreasing demand through reduced preload and wall stress while increasing supply through coronary vasodilation, and beta-blockers decreasing demand through reduced heart rate and contractility while increasing diastolic time. Panel C: CCB effects decreasing demand through reduced afterload and increasing supply through coronary vasodilation, and ranolazine decreasing diastolic tension via late sodium current inhibition without affecting heart rate or blood pressure. Panel D: Combination therapy showing nitrates plus beta-blocker as synergistic with beta-blocker preventing reflex tachycardia, caution for beta-blocker plus non-dihydropyridine CCB due to additive bradycardia, and clinical scenario guide for drug selection.</image>

Antithrombotic Agents

Antithrombotic therapy prevents pathological clot formation through three major mechanisms: inhibiting platelet aggregation, interfering with the coagulation cascade, or promoting fibrinolysis. Selection depends on the clinical context, with arterial thrombosis (as in coronary disease) being more platelet-driven and venous thrombosis being more coagulation-driven.

Antiplatelet drugs interfere with various steps in platelet activation and aggregation. Aspirin irreversibly acetylates cyclooxygenase-1, preventing production of thromboxane A2, a potent platelet aggregator and vasoconstrictor. The irreversible nature means the effect lasts for the platelet lifespan (seven to ten days). Low doses (75-325 mg daily) suffice for cardiovascular prevention. Aspirin is the cornerstone of secondary prevention in atherosclerotic disease and acute coronary syndromes. P2Y12 receptor antagonists block the platelet ADP receptor, preventing ADP-mediated platelet activation. Clopidogrel is a prodrug requiring hepatic activation with variable response due to genetic polymorphisms in CYP2C19. Prasugrel provides more consistent and potent platelet inhibition but carries higher bleeding risk. Ticagrelor directly and reversibly blocks the P2Y12 receptor with rapid onset and offset but requires twice-daily dosing. Dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor) is standard after acute coronary syndromes and coronary stenting. Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the final common pathway of platelet aggregation and are used in high-risk percutaneous coronary intervention.

Anticoagulants interfere with the coagulation cascade. Unfractionated heparin binds antithrombin, enhancing its inhibition of thrombin and factor Xa, requiring aPTT monitoring due to variable response. Low-molecular-weight heparins (enoxaparin, dalteparin) provide more predictable anticoagulation with predominantly anti-Xa activity, allowing weight-based dosing without routine monitoring. Warfarin inhibits vitamin K-dependent synthesis of clotting factors (II, VII, IX, X) and natural anticoagulants (proteins C and S), requiring INR monitoring due to numerous drug and food interactions and genetic variability. Direct oral anticoagulants include dabigatran (direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct factor Xa inhibitors). These agents have predictable pharmacokinetics allowing fixed dosing without routine monitoring, fewer drug interactions, and in some cases, specific reversal agents.

Fibrinolytics activate plasminogen to plasmin, which degrades fibrin clots. Alteplase (tissue plasminogen activator) and tenecteplase are used in acute STEMI when primary PCI is not available, in acute ischemic stroke within the appropriate time window, and in massive pulmonary embolism with hemodynamic compromise.

<image>Panel A: Platelet activation pathway showing aspirin blocking COX-1 and thromboxane A2 release, P2Y12 inhibitors blocking ADP-mediated activation, and GPIIb/IIIa inhibitors blocking the final common aggregation pathway. Panel B: Simplified coagulation cascade with anticoagulant targets: unfractionated heparin enhancing antithrombin, LMWH predominantly anti-Xa, warfarin inhibiting vitamin K-dependent factors, dabigatran as direct thrombin inhibitor, and rivaroxaban, apixaban, edoxaban as direct Xa inhibitors. Panel C: Fibrinolytic pathway showing tPA and tenecteplase converting plasminogen to plasmin for fibrin degradation, used in STEMI, stroke, and massive PE. Panel D: Clinical guidance showing antiplatelet therapy for arterial thrombosis, anticoagulation for venous thrombosis and AF, and monitoring requirements with aPTT for UFH and INR for warfarin while DOACs need no routine monitoring.</image>

Lipid-Lowering Agents

Lipid-lowering therapy, particularly with statins, has revolutionized cardiovascular prevention by reducing LDL cholesterol and providing additional pleiotropic benefits including plaque stabilization and anti-inflammatory effects.

Statins (HMG-CoA reductase inhibitors) are the cornerstone of lipid-lowering therapy. By inhibiting the rate-limiting enzyme in cholesterol synthesis, they reduce intracellular cholesterol, leading to upregulation of LDL receptors and increased clearance of LDL from circulation. Statins reduce LDL by thirty to fifty percent depending on potency and dose. High-intensity statins (rosuvastatin 20-40 mg, atorvastatin 40-80 mg) lower LDL by more than fifty percent and are recommended for secondary prevention and high-risk primary prevention. Beyond LDL reduction, statins have pleiotropic effects including improved endothelial function, reduced inflammation, and plaque stabilization that contribute to cardiovascular risk reduction. Myopathy is the most significant adverse effect, ranging from myalgias to rare rhabdomyolysis. Risk increases with higher doses, certain drug interactions (particularly with gemfibrozil), and patient factors including advanced age and hypothyroidism. Hepatotoxicity is rare. A small increased risk of new-onset diabetes exists but is outweighed by cardiovascular benefit in indicated patients.

Ezetimibe blocks intestinal cholesterol absorption by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) transporter. It reduces LDL by fifteen to twenty percent and is typically used in combination with statins when additional LDL lowering is needed or as an alternative when statins are not tolerated.

PCSK9 inhibitors (evolocumab, alirocumab) are monoclonal antibodies that bind PCSK9, a protein that promotes LDL receptor degradation. By preventing this degradation, more LDL receptors remain on hepatocyte surfaces, increasing LDL clearance and reducing LDL by fifty to sixty percent. These injectable agents are reserved for patients with familial hypercholesterolemia or those who cannot achieve LDL goals with other therapies.

Fibrates (fenofibrate, gemfibrozil) activate peroxisome proliferator-activated receptor alpha (PPARα), reducing triglycerides by thirty to fifty percent and modestly raising HDL. They are primarily used for severe hypertriglyceridemia to prevent pancreatitis. Gemfibrozil increases statin-related myopathy risk; fenofibrate is preferred when combination therapy is needed.

Niacin (nicotinic acid) has favorable effects on the lipid profile, reducing LDL, triglycerides, and Lp(a) while raising HDL. However, trials have not demonstrated cardiovascular benefit when added to statin therapy, and side effects (flushing, hepatotoxicity, glucose intolerance) limit its use.

<image>Panel A: Cholesterol metabolism showing dietary absorption blocked by ezetimibe at NPC1L1, hepatic synthesis blocked by statins at HMG-CoA reductase, hepatic LDL receptor upregulated by statins and protected from degradation by PCSK9 inhibitors, and triglyceride metabolism affected by fibrates via PPARalpha. Panel B: LDL reduction potency comparison: statins 30-50% with high-intensity above 50%, ezetimibe 15-20%, PCSK9 inhibitors 50-60%, with statin intensity tiers defined for high-intensity and moderate-intensity. Panel C: Stepwise clinical approach: Step 1 statin therapy with high-intensity for ASCVD, Step 2 add ezetimibe if LDL still elevated, Step 3 consider PCSK9 inhibitor for high-risk patients still above goal. Panel D: Side effect considerations: statins with myopathy and rare hepatotoxicity and small diabetes risk, fibrates with myopathy especially with gemfibrozil, and niacin with flushing and glucose intolerance.</image>

Summary

Cardiovascular pharmacology encompasses drugs acting on the RAAS (ACE inhibitors reducing angiotensin II and increasing bradykinin, ARBs blocking AT1 receptors without cough, aldosterone antagonists providing mortality benefit in heart failure, and ARNI combining neprilysin inhibition with angiotensin blockade), diuretics (thiazides for hypertension, loops for volume overload, potassium-sparing as adjuncts), beta-blockers (providing mortality benefit in heart failure and post-MI through negative chronotropic and inotropic effects, with selectivity determining side effect profile), and calcium channel blockers (dihydropyridines causing vasodilation, non-dihydropyridines adding cardiac effects useful for rate control but contraindicated in heart failure). Nitrates provide venodilation and coronary vasodilation for angina and heart failure, requiring nitrate-free intervals to prevent tolerance. Positive inotropes include digoxin (inhibiting sodium-potassium ATPase with narrow therapeutic index), sympathomimetics (dobutamine for acute heart failure, norepinephrine for shock), and phosphodiesterase inhibitors (milrinone as an inodilator). Antiarrhythmic drugs are classified by mechanism: class I sodium channel blockers, class II beta-blockers, class III potassium channel blockers (amiodarone being the most widely used despite toxicity), and class IV non-dihydropyridine calcium channel blockers. Antithrombotic therapy includes antiplatelet agents (aspirin inhibiting COX-1, P2Y12 inhibitors blocking ADP-mediated activation) for arterial thrombosis and anticoagulants (heparins, warfarin, DOACs) for venous thrombosis and atrial fibrillation. Statins remain the cornerstone of lipid-lowering therapy with proven cardiovascular outcome benefit.

Key Terms

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