Medical School · Year 2 · Pharmacology · includes a quiz and discussion video

Lecture 04: Cardiovascular Pharmacology

Unit 2.12: Pharmacology

Learning Objectives

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

1. Describe antihypertensive drug classes and their mechanisms
2. Explain antianginal therapy
3. Describe drugs used in heart failure
4. Explain antiarrhythmic drug classification
5. Describe anticoagulant and antiplatelet therapy
6. Explain lipid-lowering agents

Lecture Outline

I. Antihypertensive Drugs - Overview

Antihypertensive medications constitute one of the most prescribed drug classes worldwide, addressing a condition that affects approximately one-third of adults and represents a major modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease. Multiple drug classes with distinct mechanisms are available, allowing individualized therapy based on patient comorbidities, contraindications, and response. The primary goal of antihypertensive therapy is to reduce blood pressure to target levels that minimize cardiovascular risk while avoiding adverse effects that impair quality of life or medication adherence. Understanding the mechanisms, efficacy, and adverse effect profiles of each class enables rational selection and combination of agents for optimal blood pressure control.

The major antihypertensive drug classes act through fundamentally different mechanisms to lower blood pressure. Diuretics reduce blood volume initially and subsequently decrease vascular resistance through mechanisms that are incompletely understood. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) interrupt the renin-angiotensin-aldosterone system (RAAS) at different points, reducing angiotensin II-mediated vasoconstriction and aldosterone-mediated volume retention. Calcium channel blockers cause vasodilation and, in the case of non-dihydropyridines, reduce cardiac contractility and heart rate. Beta-adrenergic blockers decrease heart rate, cardiac output, and renin release, though their exact antihypertensive mechanism remains debated. Direct vasodilators relax vascular smooth muscle through various mechanisms, lowering peripheral resistance.

First-line antihypertensive selection is guided by compelling indications from comorbid conditions and evidence from large clinical trials. For the general population without compelling indications, thiazide diuretics, calcium channel blockers, and ACE inhibitors or ARBs are appropriate first-line options with equivalent efficacy in reducing cardiovascular events. Black patients demonstrate better blood pressure response to thiazides and calcium channel blockers compared to RAAS inhibitors, influencing initial drug selection. Patients with diabetes and proteinuria benefit specifically from RAAS inhibition due to renoprotective effects beyond blood pressure lowering. Heart failure patients require ACE inhibitors or ARBs and beta-blockers as foundational therapy, while post-myocardial infarction patients benefit from beta-blockers and ACE inhibitors for secondary prevention.

Diuretics remain a cornerstone of antihypertensive therapy, with thiazide-type diuretics preferred for most patients with hypertension. Thiazides such as hydrochlorothiazide and chlorthalidone inhibit sodium reabsorption in the distal convoluted tubule, producing a modest diuretic effect but substantial antihypertensive action. Loop diuretics like furosemide inhibit sodium-potassium-chloride cotransport in the thick ascending limb of the loop of Henle, producing potent diuresis but less sustained antihypertensive effect; they are reserved for hypertensive patients with concurrent heart failure or advanced kidney disease. Potassium-sparing diuretics include aldosterone antagonists (spironolactone, eplerenone) that provide additional neurohormonal blockade and are particularly useful in resistant hypertension. Thiazide adverse effects follow a predictable pattern of electrolyte disturbances: hypokalemia from increased distal potassium secretion, hyperuricemia from reduced uric acid excretion (potentially triggering gout), hyperglycemia from impaired insulin release, hyperlipidemia, hypercalcemia from enhanced calcium reabsorption, and hyponatremia, particularly in elderly patients.

<image>Panel A: Blood pressure control mechanisms diagram showing cardiac output and peripheral resistance as determinants of blood pressure, with drug classes acting on each: beta-blockers reducing cardiac output, diuretics reducing volume, and vasodilators plus CCBs reducing resistance. Panel B: Algorithm for first-line antihypertensive selection showing general population (thiazide, CCB, or ACEI/ARB), Black patients (thiazide or CCB preferred), diabetes with proteinuria (ACEI/ARB), heart failure (ACEI/ARB plus beta-blocker), and post-MI (beta-blocker plus ACEI). Panel C: Nephron diagram showing sites of diuretic action: thiazides at distal convoluted tubule, loop diuretics at thick ascending limb, and potassium-sparing agents at collecting duct. Panel D: Thiazide side effects illustrated as electrolyte changes with mnemonics: hypokalemia, hyperuricemia (gout crystal shown), hyperglycemia, hyperlipidemia, hypercalcemia, and hyponatremia.</image>

II. RAAS Inhibitors

The renin-angiotensin-aldosterone system (RAAS) serves as a major therapeutic target in hypertension, heart failure, and chronic kidney disease, with ACE inhibitors and angiotensin receptor blockers providing effective interruption of this pathway. Renin, released from juxtaglomerular cells in response to reduced renal perfusion, cleaves angiotensinogen to angiotensin I, which is then converted to the potent vasoconstrictor angiotensin II by angiotensin-converting enzyme primarily in the pulmonary vasculature. Angiotensin II raises blood pressure through direct vasoconstriction, aldosterone release promoting sodium and water retention, and sympathetic nervous system activation. ACE inhibitors block the conversion of angiotensin I to angiotensin II and also inhibit the breakdown of bradykinin, a vasodilatory peptide, contributing to both their therapeutic effects and certain adverse effects.

ACE inhibitors are widely prescribed for hypertension, heart failure, diabetic nephropathy, and post-myocardial infarction management, with several agents available differing primarily in pharmacokinetic properties. Lisinopril is a commonly prescribed ACE inhibitor with once-daily dosing and renal excretion, requiring dose adjustment in kidney disease. Enalapril is a prodrug converted to the active enalaprilat in the liver, available in both oral and intravenous formulations. Ramipril has demonstrated particular benefit in high-risk cardiovascular patients and post-MI patients in clinical trials. Captopril has the shortest duration of action requiring three-times-daily dosing but offers rapid onset useful in acute settings. The blood pressure-lowering effect of ACE inhibitors results primarily from reduced angiotensin II-mediated vasoconstriction and decreased aldosterone secretion. Cardioprotective effects include prevention of adverse cardiac remodeling following myocardial infarction. Renoprotective effects result from preferential dilation of the efferent glomerular arteriole, reducing intraglomerular pressure and proteinuria.

Angiotensin receptor blockers (ARBs) selectively antagonize the angiotensin II type 1 (AT1) receptor, providing an alternative mechanism for RAAS blockade without affecting bradykinin metabolism. Losartan was the first ARB and has a unique uricosuric effect that may benefit patients with hyperuricemia or gout. Valsartan has extensive evidence in heart failure and post-MI patients and is a component of the combination product sacubitril/valsartan. Olmesartan has been associated with a rare sprue-like enteropathy causing severe chronic diarrhea and weight loss. Telmisartan has the longest half-life among ARBs and may offer advantages for blood pressure control during the trough period. ARBs are generally considered equivalent to ACE inhibitors in efficacy and cardiovascular outcomes, with the principal advantage being absence of cough, making them appropriate alternatives for patients intolerant of ACE inhibitors due to this side effect.

Both ACE inhibitors and ARBs share important adverse effects and contraindications that require careful patient selection and monitoring. Hyperkalemia results from reduced aldosterone secretion and is particularly concerning in patients with chronic kidney disease, diabetes, or those taking potassium supplements or potassium-sparing diuretics; serum potassium should be monitored after initiation and dose changes. Acute kidney injury can occur in patients with bilateral renal artery stenosis or stenosis of a solitary functioning kidney, where glomerular filtration depends on angiotensin II-mediated efferent arteriolar constriction; serum creatinine should be checked after initiation. Angioedema is a potentially life-threatening complication more common with ACE inhibitors than ARBs, involving swelling of the lips, tongue, and airways; patients experiencing angioedema on ACE inhibitors should not be rechallenged and require caution if ARBs are considered. Cough occurs in 10-15% of patients on ACE inhibitors due to accumulation of bradykinin and is the most common reason for discontinuation; switching to an ARB typically resolves this adverse effect. Both drug classes are teratogenic and absolutely contraindicated in pregnancy due to fetal renal dysgenesis, oligohydramnios, and other fetal abnormalities.

<image>Panel A: RAAS cascade diagram showing renin acting on angiotensinogen to produce angiotensin I, ACE converting angiotensin I to angiotensin II (blocked by ACE inhibitors), and angiotensin II acting at AT1 receptors (blocked by ARBs) to cause vasoconstriction, aldosterone release, and sympathetic activation. Panel B: Comparison of ACE inhibitors showing lisinopril (once daily, renal excretion), enalapril (prodrug), ramipril (post-MI benefit), and captopril (short-acting, TID), with mechanism of bradykinin accumulation causing cough. Panel C: Renal effects diagram showing glomerulus with afferent and efferent arterioles, demonstrating how RAAS inhibition dilates efferent arteriole, reduces intraglomerular pressure, and decreases proteinuria. Panel D: RAAS inhibitor adverse effects showing hyperkalemia (with monitoring recommendations), acute kidney injury (bilateral renal artery stenosis contraindication), angioedema (more with ACEI), cough (ACEI only, switch to ARB), and teratogenicity (pregnancy contraindication).</image>

III. Calcium Channel Blockers

Calcium channel blockers (CCBs) comprise two pharmacologically distinct subclasses with different therapeutic profiles: the dihydropyridines, which predominantly affect vascular smooth muscle, and the non-dihydropyridines, which have significant cardiac effects. All CCBs work by blocking L-type voltage-gated calcium channels, reducing calcium influx into cells and producing relaxation of vascular smooth muscle and, in the case of non-dihydropyridines, depression of cardiac automaticity, conduction, and contractility. The differential tissue selectivity arises from differences in binding characteristics to calcium channels in their various conformational states. Understanding these differences is essential for appropriate drug selection based on the clinical indication and patient characteristics.

Dihydropyridine calcium channel blockers are potent vasodilators with minimal direct cardiac effects, making them excellent antihypertensive agents. Amlodipine is the most widely prescribed CCB, featuring a very long half-life (30-50 hours) that provides smooth 24-hour blood pressure control with once-daily dosing and minimal peak-to-trough variation. Nifedipine produces pronounced vasodilation and was historically associated with reflex tachycardia and adverse cardiovascular events when used in immediate-release form; extended-release formulations have mitigated these concerns. Felodipine is another long-acting dihydropyridine used primarily for hypertension. Clevidipine is an intravenous dihydropyridine with ultrashort half-life (approximately 1 minute) due to ester hydrolysis by blood esterases, providing highly titratable blood pressure control in acute settings. The vasodilatory selectivity of dihydropyridines means they do not significantly reduce heart rate or cardiac contractility; in fact, baroreceptor-mediated reflex tachycardia may occur, particularly with rapid-acting agents.

Non-dihydropyridine calcium channel blockers include verapamil and diltiazem, which produce significant effects on both cardiac and vascular tissue. Verapamil has the greatest cardiac selectivity among CCBs, strongly depressing sinoatrial node automaticity, atrioventricular node conduction, and myocardial contractility; a notable adverse effect is constipation from effects on gastrointestinal smooth muscle. Diltiazem has balanced cardiac and vascular effects, producing vasodilation comparable to moderate-potency dihydropyridines while also slowing heart rate and AV conduction. Both non-dihydropyridines are useful for rate control in atrial fibrillation and flutter, variant (Prinzmetal) angina where coronary vasospasm is the mechanism, and stable angina where heart rate reduction decreases myocardial oxygen demand. Critically, non-dihydropyridines should generally be avoided in combination with beta-blockers due to the risk of excessive bradycardia, heart block, and cardiac depression; this combination is contraindicated in patients with impaired left ventricular function.

Comparing the two CCB subclasses highlights their complementary therapeutic niches based on distinct pharmacological profiles. Vasodilatory potency is greatest with dihydropyridines, producing more pronounced blood pressure reduction per dose. Cardiac depression is absent with dihydropyridines but significant with non-dihydropyridines, affecting heart rate, AV conduction, and contractility. Heart rate effects differ dramatically: dihydropyridines may cause reflex tachycardia while non-dihydropyridines decrease heart rate. Peripheral edema occurs with both subclasses but is more common and pronounced with dihydropyridines due to preferential arteriolar dilation without venodilation, causing capillary hydrostatic pressure increase; this edema is not responsive to diuretics. Clinical selection favors dihydropyridines (particularly amlodipine) for most hypertension patients, while non-dihydropyridines are preferred when rate control is also needed, such as in atrial fibrillation or angina. For Raynaud phenomenon, dihydropyridines provide vasodilation without cardiac depression.

<image>Panel A: L-type calcium channel diagram showing calcium channel in vascular smooth muscle (dihydropyridine site) and cardiac muscle (non-dihydropyridine site), with different binding affinities producing selective tissue effects. Panel B: Dihydropyridine comparison showing amlodipine (very long half-life, once daily), nifedipine (extended-release preferred), felodipine, and clevidipine (ultrashort IV), all producing vasodilation with reflex tachycardia risk. Panel C: Non-dihydropyridine comparison showing verapamil (most cardiac selective, constipation) and diltiazem (balanced), both causing bradycardia and AV block, with contraindication for combination with beta-blockers illustrated. Panel D: Side-by-side comparison chart of DHP versus non-DHP showing vasodilation (+++/+), cardiac depression (-/+++), heart rate effect (reflex increase/decrease), AV conduction (none/decreased), and peripheral edema (++/+) with clinical implications for each pattern.</image>

IV. Antianginal Drugs

Antianginal drugs address the fundamental pathophysiology of angina pectoris, which results from an imbalance between myocardial oxygen supply and demand, most commonly due to fixed atherosclerotic coronary artery obstruction. Therapeutic strategies aim either to reduce myocardial oxygen demand by decreasing heart rate, contractility, or wall tension, or to increase oxygen supply by dilating coronary arteries and improving blood flow to ischemic regions. Multiple drug classes with complementary mechanisms are often combined for optimal symptom control. Understanding the mechanisms of each class enables rational combination therapy and selection based on patient characteristics and contraindications.

Nitrates are the oldest and most widely used antianginal agents, providing rapid symptomatic relief through vasodilation that primarily reduces cardiac preload. Nitroglycerin is available in multiple formulations: sublingual tablets or spray for acute anginal episodes providing relief within 1-3 minutes, intravenous infusion for unstable angina and acute coronary syndromes, and transdermal patches for prophylaxis. Isosorbide dinitrate is an oral nitrate with moderate duration (4-6 hours) requiring multiple daily doses. Isosorbide mononitrate is the active metabolite with longer duration and more predictable pharmacokinetics, available in extended-release formulations. Nitrates work by releasing nitric oxide, which activates guanylyl cyclase, increases cyclic GMP, and produces vascular smooth muscle relaxation. The predominant effect is venodilation, which reduces venous return and cardiac preload, decreasing ventricular wall tension and myocardial oxygen demand. Coronary artery dilation, particularly of epicardial vessels and collaterals, improves blood flow to ischemic regions. Tolerance develops with continuous nitrate exposure, necessitating a nitrate-free interval of 10-12 hours daily (typically overnight) to maintain efficacy.

Beta-blockers are considered first-line therapy for chronic stable angina because they address the most important determinant of myocardial oxygen demand. By blocking beta-1 adrenergic receptors in the heart, these agents reduce heart rate (negative chronotropy), decrease myocardial contractility (negative inotropy), and lower blood pressure, all of which reduce myocardial oxygen consumption. An additional benefit is prolongation of diastole, the phase during which coronary perfusion predominantly occurs, thereby improving oxygen supply to the myocardium. Beta-blockers have demonstrated mortality benefit in patients with prior myocardial infarction and those with heart failure, making them particularly appropriate for angina patients with these comorbidities. Beta-1 selective agents (metoprolol, atenolol, bisoprolol) are generally preferred to minimize beta-2-mediated bronchospasm in patients with reactive airway disease. Contraindications include severe bradycardia, high-degree AV block, and decompensated heart failure.

Ranolazine represents a novel antianginal mechanism distinct from hemodynamic agents, making it useful for refractory angina despite optimal traditional therapy. The drug inhibits the late sodium current in cardiac myocytes, a current that is enhanced during ischemia and contributes to calcium overload and diastolic dysfunction. By reducing this late sodium current, ranolazine decreases intracellular sodium accumulation and subsequent calcium overload via the sodium-calcium exchanger, improving myocardial relaxation and reducing oxygen consumption. A significant advantage of ranolazine is that it produces anti-ischemic effects without altering heart rate or blood pressure, making it well-tolerated in combination with other antianginals. The primary adverse effect is QT prolongation, requiring caution in patients with baseline prolonged QT or those taking other QT-prolonging drugs. Ranolazine is typically used as add-on therapy when symptoms persist despite beta-blockers and nitrates, or when these agents are contraindicated or not tolerated.

<image>Panel A: Myocardial oxygen balance diagram showing demand determinants (heart rate, contractility, wall tension) reduced by beta-blockers, and supply determinants (coronary blood flow, oxygen content) improved by nitrates, with angina resulting from supply-demand mismatch. Panel B: Nitrate mechanism showing nitroglycerin releasing NO, activating guanylyl cyclase, increasing cGMP, causing venodilation that reduces preload and wall tension; tolerance development requiring nitrate-free interval illustrated. Panel C: Beta-blocker antianginal effects showing reduced heart rate, reduced contractility, and reduced blood pressure all decreasing myocardial oxygen demand, plus prolonged diastole increasing coronary perfusion time. Panel D: Ranolazine mechanism showing late sodium current during ischemia, sodium accumulation leading to calcium overload via NCX, and ranolazine blocking late sodium current to reduce calcium overload and improve diastolic relaxation without hemodynamic effects.</image>

V. Heart Failure Drugs

Heart failure management has evolved from purely symptomatic treatment to disease-modifying therapy with neurohormonal antagonists that reduce mortality and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF). Guideline-directed medical therapy (GDMT) now comprises four foundational drug classes that each independently improve survival: RAAS inhibitors (ACE inhibitors, ARBs, or ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors. The pathophysiology of HFrEF involves maladaptive neurohormonal activation with excessive sympathetic tone and RAAS activity that initially compensates for reduced cardiac output but ultimately promotes adverse remodeling, fibrosis, and disease progression. Blocking these neurohormonal pathways counterintuitively improves cardiac function and survival despite their short-term negative inotropic effects.

The angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan represents a major therapeutic advance combining RAAS blockade with enhancement of endogenous natriuretic peptides. Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides (BNP and ANP), leading to increased levels of these cardioprotective hormones that promote vasodilation, natriuresis, and inhibition of cardiac remodeling. Valsartan provides AT1 receptor blockade, preventing the increased angiotensin II that would otherwise result from neprilysin inhibition (angiotensin II is also a neprilysin substrate). Clinical trials demonstrated superiority of sacubitril/valsartan over ACE inhibitor therapy for reducing cardiovascular death and heart failure hospitalization in HFrEF. ARNI is now recommended as first-line RAAS inhibition in HFrEF, replacing ACE inhibitors for eligible patients. A critical safety requirement is a 36-hour washout period when switching from an ACE inhibitor to ARNI to avoid angioedema risk from combined ACE and neprilysin inhibition.

Digoxin, a cardiac glycoside derived from the foxglove plant, has been used for heart failure for over 200 years and remains useful despite lacking mortality benefit. The mechanism involves inhibition of the sodium-potassium ATPase pump in cardiac myocytes, leading to increased intracellular sodium, which in turn reduces calcium efflux via the sodium-calcium exchanger, resulting in increased intracellular calcium and enhanced contractility (positive inotropy). Digoxin also has vagotonic effects that slow heart rate and AV conduction, useful in patients with atrial fibrillation. In HFrEF, digoxin reduces symptoms and heart failure hospitalizations but does not improve survival; it is therefore reserved for patients who remain symptomatic despite optimal GDMT or for rate control in atrial fibrillation. The narrow therapeutic index requires careful dosing and monitoring, with toxicity manifesting as arrhythmias, visual disturbances, and gastrointestinal symptoms. Factors predisposing to digoxin toxicity include renal impairment, hypokalemia, hypomagnesemia, and drug interactions.

Acute decompensated heart failure requires a different pharmacological approach focused on hemodynamic stabilization rather than long-term neurohormonal blockade. Loop diuretics (furosemide, bumetanide, torsemide) are the mainstay of treatment for volume overload, producing rapid diuresis to relieve pulmonary and peripheral edema; they are typically given intravenously for immediate effect with dose escalation as needed for diuretic resistance. Intravenous vasodilators including nitroglycerin reduce preload and improve pulmonary congestion, particularly useful in patients with hypertensive pulmonary edema. Inotropic agents are reserved for patients with evidence of low cardiac output (cardiogenic shock), as their use has been associated with increased arrhythmias and mortality in less severely ill patients. Dobutamine is a beta-1 agonist that increases contractility and cardiac output with modest vasodilatory effects. Milrinone is a phosphodiesterase-3 inhibitor that increases cardiac output through both positive inotropy and vasodilation ("inodilator"); it may be preferred in patients on chronic beta-blocker therapy where dobutamine response may be blunted.

<image>Panel A: Neurohormonal activation in heart failure showing reduced cardiac output triggering sympathetic activation and RAAS activation, leading to vasoconstriction, sodium retention, and cardiac remodeling, with four foundational drug classes (ACEI/ARB/ARNI, beta-blockers, MRAs, SGLT2i) blocking these pathways. Panel B: ARNI mechanism diagram showing sacubitril inhibiting neprilysin, increasing natriuretic peptides (BNP, ANP) with their beneficial effects (vasodilation, natriuresis, anti-remodeling), while valsartan blocks AT1 receptor to prevent angiotensin II effects; 36-hour ACEI washout requirement noted. Panel C: Digoxin mechanism at cellular level showing Na/K-ATPase inhibition, increased intracellular sodium, reduced NCX calcium efflux, increased intracellular calcium, and enhanced contractility; toxicity predisposing factors listed. Panel D: Acute heart failure treatment algorithm showing volume overload treated with IV loop diuretics, hypertensive pulmonary edema with IV nitroglycerin, and low output/cardiogenic shock with inotropes (dobutamine for beta-1 effect, milrinone as inodilator).</image>

VI. Antiarrhythmic Drugs

Antiarrhythmic drugs are classified according to the Vaughan Williams system based on their predominant mechanism of action on cardiac ion channels and receptors. Class I drugs block sodium channels, reducing the rapid upstroke of the action potential and slowing conduction; they are subdivided into Ia, Ib, and Ic based on their effects on action potential duration and channel binding kinetics. Class II drugs are beta-adrenergic blockers that reduce sympathetic stimulation of the heart. Class III drugs block potassium channels, prolonging repolarization and the action potential duration. Class IV drugs are non-dihydropyridine calcium channel blockers that primarily affect sinoatrial and atrioventricular nodal tissue. While this classification provides a useful framework, many antiarrhythmic drugs have actions spanning multiple classes, and the clinical utility of a drug does not always correlate with its class assignment.

Amiodarone is the most effective and widely used antiarrhythmic drug, with actions spanning all four Vaughan Williams classes, providing broad-spectrum efficacy against both supraventricular and ventricular arrhythmias. Its primary mechanism is potassium channel blockade (Class III), prolonging action potential duration and the effective refractory period. Additionally, amiodarone blocks sodium channels (Class I), beta-adrenergic receptors (Class II), and calcium channels (Class IV), contributing to its antiarrhythmic versatility. The extremely long half-life (40-55 days) necessitates loading doses to achieve therapeutic tissue concentrations and means that both effects and adverse effects persist long after discontinuation. Amiodarone is effective for maintaining sinus rhythm in atrial fibrillation, suppressing ventricular tachycardia, and is the drug of choice for hemodynamically unstable ventricular arrhythmias. However, its widespread tissue distribution produces a characteristic pattern of toxicities affecting multiple organ systems: thyroid dysfunction (both hypo- and hyperthyroidism due to high iodine content and effects on thyroid hormone metabolism), pulmonary fibrosis (potentially fatal), hepatotoxicity, corneal microdeposits (usually asymptomatic but may cause visual halos), and bluish skin discoloration with chronic use.

Other Class III antiarrhythmic drugs offer alternatives to amiodarone with different adverse effect profiles. Sotalol combines non-selective beta-blockade (Class II) with potassium channel blockade (Class III), useful for atrial fibrillation and ventricular arrhythmias; its major concern is QT prolongation and risk of torsades de pointes, requiring in-hospital initiation with telemetry monitoring and dose adjustment for renal function. Dofetilide is a pure potassium channel blocker requiring strict renal dose adjustment and in-hospital initiation due to significant QT prolongation risk; it is effective for maintaining sinus rhythm in atrial fibrillation. Ibutilide is an intravenous Class III agent used for acute conversion of atrial fibrillation or flutter to sinus rhythm, with significant risk of torsades de pointes requiring continuous monitoring. Dronedarone is structurally similar to amiodarone but without the iodine moiety, resulting in fewer thyroid and pulmonary toxicities; however, it is less effective and is contraindicated in permanent atrial fibrillation and heart failure due to increased mortality in these populations.

The clinical approach to atrial fibrillation involves a choice between rate control and rhythm control strategies, both requiring appropriate anticoagulation based on thromboembolic risk assessment. Rate control aims to achieve acceptable ventricular rates during atrial fibrillation without attempting to restore sinus rhythm, typically using beta-blockers, non-dihydropyridine calcium channel blockers, or digoxin; this approach is appropriate for many patients, particularly the elderly and those with minimal symptoms. Rhythm control attempts to restore and maintain sinus rhythm using antiarrhythmic drugs or catheter ablation; drugs used include flecainide or propafenone (Class Ic, contraindicated in structural heart disease), sotalol, dronedarone, or amiodarone. Clinical trials have generally shown equivalent outcomes between rate and rhythm control strategies, making the decision individualized based on symptoms, patient preference, and feasibility. Regardless of strategy, anticoagulation decisions are based on stroke risk assessment (typically CHA2DS2-VASc score) and are required whenever indicated, as maintenance of sinus rhythm does not eliminate thromboembolic risk.

<image>Panel A: Vaughan Williams classification diagram showing cardiac action potential with each class affecting different phases: Class I (sodium channel block, upstroke), Class II (beta-blockade, phase 4), Class III (potassium channel block, repolarization), and Class IV (calcium channel block, plateau and nodal tissue), with example drugs for each class. Panel B: Amiodarone comprehensive profile showing four-class mechanism, very long half-life, loading dose requirement, broad spectrum efficacy, and organ-specific toxicities (thyroid, lung, liver, cornea, skin) with monitoring requirements. Panel C: Class III drug comparison showing sotalol (beta-block + K-block, QT risk, renal dosing), dofetilide (pure K-block, strict renal dosing, in-hospital start), ibutilide (IV, acute AF conversion), and dronedarone (amiodarone-like, less toxicity, contraindications in HF and permanent AF). Panel D: Atrial fibrillation management algorithm showing rate control drugs (beta-blockers, non-DHP CCBs, digoxin) versus rhythm control drugs (flecainide, sotalol, amiodarone), with anticoagulation decision based on CHA2DS2-VASc score independent of rhythm strategy.</image>

VII. Anticoagulants

Anticoagulant drugs prevent and treat venous thromboembolism and prevent stroke in atrial fibrillation by interfering with the coagulation cascade at various points. The coagulation cascade converges on the common pathway where factor X is activated to factor Xa, which then converts prothrombin to thrombin; thrombin (factor IIa) is the final enzyme that converts fibrinogen to fibrin. Therapeutic targets include enhancing endogenous anticoagulant mechanisms (heparins activating antithrombin), inhibiting coagulation factor synthesis (vitamin K antagonists), or directly inhibiting thrombin or factor Xa (direct oral anticoagulants). Each drug class has distinct pharmacological properties, monitoring requirements, and reversal strategies that influence clinical selection.

Heparins are parenteral anticoagulants that work by binding to and activating antithrombin, a serine protease inhibitor that inactivates thrombin and other coagulation factors. Unfractionated heparin (UFH) is a heterogeneous mixture of polysaccharide chains with variable anticoagulant activity, requiring weight-based dosing with continuous intravenous infusion and monitoring by activated partial thromboplastin time (aPTT); its advantages include short half-life (approximately 1 hour) and complete reversibility with protamine. Low-molecular-weight heparins (LMWH) such as enoxaparin and dalteparin are fractionated to produce more consistent anticoagulant effects with better bioavailability allowing subcutaneous administration, longer half-life permitting once- or twice-daily dosing, and predictable dose-response usually obviating monitoring except in special populations (renal impairment, obesity, pregnancy) where anti-Xa activity is measured. Protamine reverses UFH completely but LMWH only partially (60-80%). Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated complication caused by antibodies against complexes of heparin and platelet factor 4, paradoxically causing thrombosis rather than bleeding; HIT requires immediate heparin discontinuation and alternative anticoagulation with direct thrombin inhibitors (argatroban, bivalirudin).

Warfarin, the prototypical vitamin K antagonist, has been used for anticoagulation for over 70 years and remains important despite newer alternatives. Its mechanism involves inhibiting vitamin K epoxide reductase, the enzyme that recycles vitamin K to its active form needed for gamma-carboxylation of clotting factors II, VII, IX, and X, as well as anticoagulant proteins C and S. Because warfarin affects synthesis rather than function of clotting factors, onset of anticoagulation is delayed (3-5 days) until existing factors are cleared, with initial transient hypercoagulability possible as protein C (shorter half-life) decreases before factors II and X. Monitoring uses the international normalized ratio (INR), with target ranges typically 2.0-3.0 for most indications and 2.5-3.5 for mechanical heart valves. Warfarin has numerous drug and food interactions affecting its metabolism (primarily CYP2C9) or vitamin K intake, requiring frequent INR monitoring and dose adjustments. Reversal options include vitamin K (for non-urgent reversal, requires 24-48 hours for effect), prothrombin complex concentrate (PCC, for urgent reversal), and fresh frozen plasma (less preferred due to volume and time requirements).

Direct oral anticoagulants (DOACs) have largely replaced warfarin for many indications due to their predictable pharmacokinetics, fixed dosing, and lack of routine monitoring requirements. Dabigatran is a direct thrombin inhibitor with predominantly renal excretion, requiring dose reduction in moderate renal impairment and avoidance in severe renal dysfunction; idarucizumab is a specific reversal agent that binds and inactivates dabigatran. Rivaroxaban, apixaban, and edoxaban are direct factor Xa inhibitors with varying degrees of renal excretion. Rivaroxaban is dosed once daily with the largest dose taken with food to optimize absorption. Apixaban is dosed twice daily and has the least renal excretion among DOACs, making it preferred in patients with renal impairment. Edoxaban has the unique property of paradoxically reduced efficacy at high creatinine clearances (greater than 95 mL/min), contraindicating its use in patients with supranormal renal function. Andexanet alfa is a recombinant modified factor Xa that reverses factor Xa inhibitors by serving as a decoy. DOACs offer advantages of fixed dosing, rapid onset and offset, and fewer interactions, but disadvantages include higher cost, need for dose adjustment in renal impairment, and limited ability to monitor anticoagulant effect when needed.

<image>Panel A: Coagulation cascade diagram showing intrinsic and extrinsic pathways converging at factor X, common pathway through thrombin to fibrin, with drug targets indicated: heparins enhancing antithrombin (affecting thrombin and Xa), warfarin inhibiting factor synthesis (II, VII, IX, X), dabigatran directly inhibiting thrombin, and rivaroxaban/apixaban/edoxaban directly inhibiting factor Xa. Panel B: Heparin comparison showing UFH (IV, short half-life, aPTT monitoring, protamine reversal, HIT risk) versus LMWH (SC, longer half-life, anti-Xa if needed, partial protamine reversal, less HIT), with HIT mechanism and management. Panel C: Warfarin mechanism showing vitamin K cycle, VKORC1 inhibition, delayed onset due to existing factor clearance, INR monitoring, numerous interactions, and reversal with vitamin K or PCC. Panel D: DOAC comparison showing dabigatran (thrombin inhibitor, renal excretion, idarucizumab reversal), rivaroxaban (Xa, once daily with food), apixaban (Xa, BID, least renal), and edoxaban (Xa, avoid if CrCl >95), with andexanet alfa for Xa inhibitor reversal.</image>

VIII. Antiplatelet Drugs

Antiplatelet drugs prevent arterial thrombosis by inhibiting platelet activation and aggregation, which play central roles in atherothrombotic disease including acute coronary syndromes, ischemic stroke, and peripheral arterial disease. Platelets adhere to damaged endothelium, become activated by various agonists (thrombin, collagen, ADP, thromboxane A2), and aggregate through fibrinogen bridges between glycoprotein IIb/IIIa receptors on adjacent platelets. Different antiplatelet agents target different steps in this process, and combination therapy addresses multiple pathways for enhanced efficacy, particularly in high-risk situations such as acute coronary syndromes and following coronary stenting.

Aspirin remains the cornerstone of antiplatelet therapy due to its efficacy, safety, low cost, and extensive clinical experience spanning decades. The mechanism involves irreversible inhibition of cyclooxygenase-1 (COX-1) in platelets, preventing synthesis of thromboxane A2, a potent platelet activator and vasoconstrictor. Because platelets lack nuclei and cannot synthesize new COX-1, aspirin's effect persists for the platelet's lifespan (7-10 days), explaining why low doses (81-325 mg) are sufficient for antiplatelet effect despite rapid elimination. Aspirin is used for both primary prevention (in selected high-risk patients, with benefits weighed against bleeding risk) and secondary prevention (established cardiovascular disease, where benefit clearly outweighs risk). The major adverse effect is increased bleeding risk, particularly gastrointestinal bleeding, which can be mitigated by proton pump inhibitor co-therapy in high-risk patients. Aspirin resistance, defined as inadequate platelet inhibition despite aspirin therapy, has been described but routine testing is not recommended.

P2Y12 receptor inhibitors block the platelet ADP receptor, providing antiplatelet effects complementary to aspirin and forming the basis of dual antiplatelet therapy (DAPT) following acute coronary syndromes and coronary stenting. Clopidogrel is a thienopyridine prodrug requiring hepatic activation primarily by CYP2C19, with significant interpatient variability in activation and response; patients with CYP2C19 loss-of-function alleles (poor metabolizers) have reduced clopidogrel efficacy and increased cardiovascular event risk, prompting consideration of alternative agents. Prasugrel is a more potent thienopyridine with faster and more consistent activation, producing greater platelet inhibition than clopidogrel but with increased bleeding risk, particularly in elderly patients and those with low body weight or prior stroke. Ticagrelor is a direct-acting P2Y12 inhibitor (not a prodrug) that binds reversibly to the receptor, providing more consistent and potent antiplatelet effect than clopidogrel with twice-daily dosing; a unique adverse effect is dyspnea, possibly related to adenosine reuptake inhibition. Cangrelor is an intravenous P2Y12 inhibitor with rapid onset and offset (half-life approximately 3-6 minutes), useful when rapid antiplatelet effect is needed perioperatively.

Glycoprotein IIb/IIIa inhibitors block the final common pathway of platelet aggregation by preventing fibrinogen binding to the GP IIb/IIIa receptor. Abciximab is a monoclonal antibody fragment with high receptor affinity and long duration of platelet inhibition despite short plasma half-life. Eptifibatide is a cyclic peptide and tirofiban is a non-peptide small molecule, both with shorter durations of action than abciximab. These potent antiplatelet agents are used intravenously during high-risk percutaneous coronary intervention and in acute coronary syndromes, with significant bleeding risk limiting their use. Dual antiplatelet therapy duration following coronary stenting depends on the clinical context: following drug-eluting stent placement in ACS, 12 months of DAPT is typically recommended, while stable coronary disease with drug-eluting stent may require only 6 months. Following bare-metal stent placement, shorter durations (1-3 months) are acceptable. Aspirin is continued indefinitely following any coronary stenting or cardiovascular event.

<image>Panel A: Platelet activation and aggregation diagram showing adhesion to damaged endothelium, activation by agonists (thrombin, collagen, ADP, TXA2), and aggregation via fibrinogen bridges between GP IIb/IIIa receptors, with drug targets indicated at each step. Panel B: Aspirin mechanism showing COX-1 inhibition preventing TXA2 synthesis, irreversible effect lasting platelet lifespan, low-dose efficacy, and indication for primary and secondary prevention with GI bleeding as major adverse effect. Panel C: P2Y12 inhibitor comparison showing clopidogrel (prodrug, CYP2C19 activation, variable response), prasugrel (potent, more bleeding), ticagrelor (direct, reversible, dyspnea), and cangrelor (IV, rapid on/off), all blocking ADP-mediated platelet activation. Panel D: DAPT duration recommendations showing 12 months for ACS with drug-eluting stent, 6 months for stable CAD with DES, 1-3 months for bare-metal stent, and indefinite aspirin following any stent or cardiovascular event.</image>

IX. Lipid-Lowering Drugs

Lipid-lowering therapy, particularly with HMG-CoA reductase inhibitors (statins), represents one of the most effective interventions for reducing cardiovascular morbidity and mortality in patients with or at risk for atherosclerotic cardiovascular disease. Low-density lipoprotein cholesterol (LDL-C) is causally related to atherosclerotic plaque development, and the relationship between LDL-C levels and cardiovascular risk is log-linear without a clear lower threshold of benefit. Statins reduce LDL-C by 30-50% depending on the specific agent and dose, and their cardiovascular benefits exceed what would be predicted from LDL-C lowering alone, attributed to pleiotropic effects including plaque stabilization and anti-inflammatory actions. Non-statin lipid-lowering agents provide options for patients who cannot tolerate statins or require additional LDL-C lowering beyond maximum statin therapy.

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis, reducing intracellular cholesterol and triggering upregulation of LDL receptors on hepatocyte surfaces to increase LDL-C clearance from plasma. Available statins differ in their LDL-lowering potency and pharmacokinetic properties. Rosuvastatin is the most potent statin, achieving LDL-C reductions of 50-60% at maximum dose, with low lipophilicity reducing CYP450 interactions. Atorvastatin is a high-potency statin with long half-life allowing flexible dosing timing, and extensive clinical trial evidence. Simvastatin is a moderate-potency statin with significant CYP3A4 metabolism leading to important drug interactions, including contraindicated use with certain drugs and a dose ceiling of 40 mg when used with amlodipine. Pravastatin has low potency but minimal CYP450 interactions, making it useful when drug interactions are a concern. Beyond LDL-C lowering, statins provide pleiotropic benefits including improved endothelial function, reduced inflammation, plaque stabilization, and decreased thrombogenicity.

Statin adverse effects are generally mild but occasionally limit therapy, with myopathy being the most clinically important concern. Myopathy ranges from myalgias (muscle aches without creatine kinase elevation) to myositis (elevated CK) to rare but serious rhabdomyolysis (severe muscle breakdown with myoglobinuria and acute kidney injury). Risk factors for statin myopathy include higher doses, drug interactions increasing statin levels (particularly with simvastatin and lovastatin), hypothyroidism, advanced age, and possibly genetic variants in SLCO1B1 affecting hepatic statin uptake. Management includes checking CK in symptomatic patients, discontinuing statins if CK is significantly elevated, and considering rechallenge with a different statin at lower dose or alternate-day dosing. The combination of statins with gemfibrozil significantly increases myopathy risk and should be avoided; fenofibrate is a safer fibrate to combine with statins when needed. Hepatotoxicity is rare, and routine liver function monitoring is no longer recommended, though baseline LFTs are reasonable. Statins slightly increase the risk of new-onset diabetes, but cardiovascular benefits substantially outweigh this risk in appropriate patients.

Non-statin lipid-lowering agents address residual cardiovascular risk when statins alone are insufficient or not tolerated. Ezetimibe inhibits intestinal cholesterol absorption by blocking the Niemann-Pick C1-Like 1 (NPC1L1) transporter, reducing LDL-C by approximately 15-20% as monotherapy and providing additional reduction when combined with statins; clinical trials have demonstrated cardiovascular benefit for ezetimibe added to statin therapy. PCSK9 inhibitors (evolocumab, alirocumab) are monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9, preventing PCSK9-mediated degradation of LDL receptors and dramatically increasing LDL receptor availability; LDL-C reductions of 50-60% on top of statin therapy are achievable, with demonstrated cardiovascular outcome benefits in high-risk patients. Fibrates (fenofibrate, gemfibrozil) are peroxisome proliferator-activated receptor alpha (PPARalpha) agonists that primarily reduce triglycerides and modestly increase HDL-C, with primary indication being severe hypertriglyceridemia to prevent pancreatitis rather than cardiovascular risk reduction. Icosapent ethyl, a purified EPA (eicosapentaenoic acid) fish oil derivative, reduces triglycerides and has demonstrated significant cardiovascular benefit in statin-treated patients with elevated triglycerides and established cardiovascular disease or diabetes, representing a novel therapeutic option beyond statin therapy.

<image>Panel A: Cholesterol metabolism diagram showing hepatic cholesterol synthesis (HMG-CoA reductase, statin target), intestinal absorption (NPC1L1, ezetimibe target), LDL receptor expression on hepatocytes, and PCSK9-mediated LDL receptor degradation (PCSK9 inhibitor target). Panel B: Statin potency comparison showing LDL-C reduction ranges for rosuvastatin (most potent, 45-55%), atorvastatin (high potency, 40-50%), simvastatin (moderate, CYP3A4 interactions), and pravastatin (low potency, fewest interactions), with intensity categories for dosing. Panel C: Statin adverse effect spectrum showing myalgia (common, CK normal), myositis (elevated CK), and rhabdomyolysis (rare, severe), with risk factors and management approach including rechallenge strategy. Panel D: Non-statin lipid agents showing ezetimibe (intestinal absorption, add to statin), PCSK9 inhibitors (dramatic LDL reduction, injectable), fibrates (triglycerides, pancreatitis prevention), and icosapent ethyl (EPA, CV benefit in high-TG patients on statins).</image>

X. Other Cardiovascular Drugs

Positive inotropic agents increase myocardial contractility and are used primarily in acute settings of hemodynamic compromise, though with recognition that most (except digoxin for specific indications) lack mortality benefit and may increase arrhythmia risk. Digoxin, as discussed in heart failure, inhibits the sodium-potassium ATPase, indirectly increasing intracellular calcium and contractility; its unique vagotonic effects also slow heart rate, making it useful in heart failure with concomitant atrial fibrillation. Dobutamine is a synthetic catecholamine that predominantly activates beta-1 receptors, increasing contractility and cardiac output with modest beta-2-mediated vasodilation; it is the first-line inotrope for cardiogenic shock. Milrinone is a phosphodiesterase-3 inhibitor that increases cAMP in cardiac and vascular smooth muscle, producing positive inotropy plus vasodilation (inodilator effect); it may be preferred when patients are on chronic beta-blocker therapy that might blunt dobutamine response. Dopamine has dose-dependent receptor effects: low doses activate dopamine receptors causing renal and splanchnic vasodilation, moderate doses activate beta-1 receptors increasing cardiac output, and high doses activate alpha-1 receptors causing vasoconstriction.

Direct vasodilators relax vascular smooth muscle through mechanisms distinct from calcium channel blockers or autonomic drugs, providing options for severe or resistant hypertension. Hydralazine directly relaxes arteriolar smooth muscle through mechanisms that remain incompletely understood, reducing peripheral resistance and blood pressure; reflex tachycardia and fluid retention necessitate combination with beta-blockers and diuretics. The combination of hydralazine plus isosorbide dinitrate (arterial plus venous dilation) provides mortality benefit in heart failure with reduced ejection fraction, particularly in African American patients. Minoxidil is a potent arteriolar dilator that opens ATP-sensitive potassium channels in vascular smooth muscle, reserved for severe refractory hypertension due to marked reflex tachycardia and fluid retention; a side effect of hypertrichosis led to its development as a topical hair growth treatment. Sodium nitroprusside releases nitric oxide, producing both arterial and venous dilation with immediate onset, used for hypertensive emergencies; prolonged use or high doses can cause cyanide toxicity requiring monitoring of thiocyanate levels and avoidance in renal impairment. Fenoldopam is a selective dopamine D1 receptor agonist producing renal and systemic vasodilation, useful for hypertensive emergencies, particularly in patients with renal impairment.

Pulmonary arterial hypertension (PAH) requires specialized vasodilator therapy targeting the pulmonary vasculature, with multiple drug classes now available that improve symptoms and survival. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) block the vasoconstrictor and proliferative effects of endothelin-1, which is overproduced in PAH; hepatotoxicity monitoring is required for bosentan. Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) prevent cGMP breakdown in pulmonary vascular smooth muscle, potentiating NO-mediated vasodilation; these drugs are familiar from erectile dysfunction use but are used at different doses for PAH. Prostacyclin pathway agents include epoprostenol (continuous IV infusion required due to very short half-life, most effective but complex), treprostinil (SC, IV, inhaled, or oral), iloprost (inhaled), and selexipag (oral prostacyclin receptor agonist); these produce vasodilation and antiproliferative effects. Soluble guanylate cyclase (sGC) stimulators (riociguat) directly stimulate sGC and sensitize it to NO, providing an alternative mechanism to enhance cGMP signaling.

Hypertensive emergencies require parenteral therapy with titratable agents to safely lower blood pressure without causing cerebral or myocardial hypoperfusion. Sodium nitroprusside provides immediate onset with second-to-second titrability but requires arterial line monitoring and has cyanide toxicity risk with prolonged use. Nicardipine is an intravenous dihydropyridine CCB with smooth onset over 5-10 minutes and 30-minute offset, providing predictable and controllable blood pressure reduction without the need for arterial line. Labetalol provides combined alpha and beta blockade, useful when tachycardia accompanies hypertension, with 5-minute onset; it is safe in pregnancy-related hypertensive emergencies. Clevidipine is an ultrashort-acting IV dihydropyridine with 1-minute half-life, allowing extremely precise blood pressure control. Hydralazine has slower onset (10-30 minutes) and longer duration, making it less titratable but appropriate for preeclampsia and other pregnancy-related hypertension where more rapid agents may be concerning. The general approach to hypertensive emergencies is to lower mean arterial pressure by no more than 25% in the first hour to avoid ischemic complications from excessive reduction.

<image>Panel A: Inotrope mechanism comparison showing digoxin (Na/K-ATPase inhibition, increased intracellular calcium), dobutamine (beta-1 activation, increased cAMP), milrinone (PDE3 inhibition, increased cAMP, inodilator), and dopamine (dose-dependent receptor activation), with clinical situations favoring each agent. Panel B: Direct vasodilator mechanisms showing hydralazine (arteriolar, reflex tachycardia), minoxidil (K-ATP channel opener, severe HTN), nitroprusside (NO release, arterial plus venous, cyanide risk), and fenoldopam (D1 agonist, renal-protective). Panel C: Pulmonary arterial hypertension drug classes showing endothelin antagonists (bosentan), PDE5 inhibitors (sildenafil), prostacyclin pathway (epoprostenol, treprostinil, selexipag), and sGC stimulators (riociguat), all targeting pulmonary vascular resistance. Panel D: Hypertensive emergency drug comparison showing nitroprusside (immediate onset, cyanide risk), nicardipine (5-10 min onset, predictable), labetalol (alpha-beta block, pregnancy safe), clevidipine (ultrashort, precise control), and hydralazine (slower, preeclampsia), with BP reduction goal of 25% in first hour.</image>

Summary

• First-line antihypertensives include thiazide diuretics, calcium channel blockers, and ACEI/ARBs, with selection guided by compelling indications from comorbidities
• RAAS inhibitors (ACE inhibitors and ARBs) provide cardiovascular and renal protection but cause hyperkalemia, cough (ACEI only), angioedema, and are teratogenic
• Calcium channel blockers divide into dihydropyridines (vascular selective, hypertension) and non-dihydropyridines (cardiac effects, rate control), with non-DHPs contraindicated with beta-blockers
• Antianginal therapy includes nitrates (reduce preload), beta-blockers (reduce oxygen demand, first-line), and ranolazine (late sodium current inhibitor for refractory angina)
• Heart failure with reduced ejection fraction requires quadruple therapy: ACEI/ARB/ARNI, beta-blockers, MRAs, and SGLT2 inhibitors, all providing mortality benefit
• Antiarrhythmic drugs follow Vaughan Williams classification: Class I (sodium), II (beta-blockers), III (potassium), IV (calcium channel blockers), with amiodarone having all four class effects and multiple organ toxicities
• Anticoagulants include heparins (antithrombin activation), warfarin (vitamin K antagonist with INR monitoring), and DOACs (direct thrombin or Xa inhibition with fixed dosing)
• Antiplatelet agents include aspirin (irreversible COX-1 inhibition) and P2Y12 inhibitors (clopidogrel, ticagrelor) used in combination following ACS and coronary stenting
• Statins are first-line for LDL-C lowering with cardiovascular mortality benefit; ezetimibe and PCSK9 inhibitors provide additional LDL reduction when needed
• Hypertensive emergencies require IV titratable agents (nitroprusside, nicardipine, labetalol) with blood pressure reduction limited to 25% in the first hour

Key Terms

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