Cardiovascular Pharmacology: Antihypertensives, Antiarrhythmics, and Anticoagulants

Clinical Pharmacology, Lecture 4. This lecture covers the pharmacology of drugs used in cardiovascular disease — the leading cause of mortality in New Zealand and globally — focusing on antihypertensive agents, antiarrhythmic drugs, anticoagulants, and antiplatelet therapy.

ANTIHYPERTENSIVE DRUGS

Hypertension affects approximately 30% of adults and is the single greatest modifiable risk factor for cardiovascular disease. Drug treatment is guided by the RAAS-SNS-volume triad.

ACE inhibitors (ACEi): ramipril, lisinopril, perindopril. Mechanism: inhibit angiotensin-converting enzyme, blocking conversion of angiotensin I → angiotensin II, a potent vasoconstrictor and aldosterone stimulator. Reduced angiotensin II: (1) arteriolar vasodilation (reduced afterload); (2) reduced aldosterone → natriuresis and reduced preload; (3) bradykinin accumulation (beneficial but causes dry cough in ~15% — most common reason for switching to ARB). Major indications beyond hypertension: heart failure with reduced ejection fraction (HFrEF — reduce mortality), diabetic nephropathy (reduce intraglomerular pressure and proteinuria), post-MI cardioprotection. Cautions: hyperkalaemia (block aldosterone-driven K+ excretion — do not combine with potassium-sparing diuretics without monitoring); acute renal failure in bilateral renal artery stenosis (BRAS) — ACEi removes the compensatory angiotensin II-mediated efferent vasoconstriction, causing GFR to fall precipitously; teratogenic (category D — cause foetal renal dysgenesis, oligohydramnios, limb contractures); angioedema (rare but life-threatening, mediated by bradykinin accumulation; switch to ARB only after allowing complete resolution; note ARBs have a 10-15% cross-reactivity for angioedema).

Angiotensin receptor blockers (ARBs): losartan, valsartan, candesartan, irbesartan. Mechanism: block the AT1 receptor, preventing angiotensin II effects. Haemodynamic effects identical to ACEi but WITHOUT bradykinin accumulation — no cough. First-line in ACEi-intolerant patients and in diabetic nephropathy. Same cautions as ACEi (hyperkalaemia, BRAS, teratogenicity).

Calcium channel blockers (CCBs): dihydropyridines (amlodipine, nifedipine, felodipine) act mainly on vascular smooth muscle → vasodilation and reduced peripheral resistance; minimal negative chronotropic/inotropic effect. Non-dihydropyridines: verapamil and diltiazem act on both vasculature and cardiac conduction (SA and AV nodes) — slow heart rate and reduce AV conduction; also used for rate control in atrial fibrillation and supraventricular tachycardia. Do NOT combine verapamil or diltiazem with beta-blockers — risk of complete heart block and severe bradycardia. Adverse effects of dihydropyridines: peripheral oedema (from arteriolar vasodilation causing transcapillary fluid shift — NOT fluid overload; does not respond to diuretics), reflex tachycardia (especially short-acting nifedipine — use slow-release formulation), flushing, headache.

Beta-blockers (BBs): metoprolol (β1-selective), bisoprolol (β1-selective), carvedilol (α1/β1/β2). Mechanism: competitive antagonism at beta-adrenoceptors. Effects: reduced heart rate (negative chronotropy), reduced AV conduction, reduced myocardial contractility (negative inotropy), reduced renin release. Indications: hypertension (second-line), heart failure (HFrEF — paradoxically improve survival despite short-term negative inotropy by reversing sympathetic-driven cardiac remodelling; bisoprolol, carvedilol, metoprolol succinate are proven mortality-reducing agents), post-MI, rate control in AF, angina. Cautions: avoid in asthma and COPD (β2-blockade causes bronchoconstriction — use cardioselective agents at low dose with extreme caution if no alternative); peripheral vascular disease (worsens claudication); depression (CNS-penetrant BBs); masking hypoglycaemia in diabetics (blunt sympathetic warning signs — sweating is preserved but palpitations/tremor suppressed). Do NOT abruptly stop — risk of rebound tachycardia and angina.

Thiazide and thiazide-like diuretics: hydrochlorothiazide (HCT), indapamide, chlortalidone. Mechanism: inhibit NCC (Na-Cl cotransporter) in the distal convoluted tubule → natriuresis, reduced plasma volume. Also have direct vasodilatory effects with chronic use. First-line especially in elderly and Afro-Caribbean patients. Metabolic adverse effects: hypokalaemia (requires monitoring and supplementation or co-prescribing with K+-sparing diuretic), hyperuricaemia (can precipitate gout), hyperglycaemia (reduce insulin secretion), hyperlipidaemia (minor). Chlortalidone has longer half-life and superior 24-hour BP control vs HCT.

Mineralocorticoid receptor antagonists (MRAs): spironolactone, eplerenone. Block aldosterone receptor in the collecting duct → natriuresis, K+ retention. Indicated in resistant hypertension (fourth-line agent with significant efficacy), HFrEF (spironolactone reduces mortality in RALES trial; eplerenone in EPHESUS). Adverse effects of spironolactone: gynaecomastia, menstrual irregularity (non-selective; eplerenone is selective and lacks these effects), hyperkalaemia.

ANTIARRHYTHMIC DRUGS — VAUGHAN WILLIAMS CLASSIFICATION

Class I — sodium channel blockers: reduce phase 0 depolarisation in myocytes and conducting tissue. Ia (quinidine, procainamide, disopyramide): moderate Na+ block; also block K+ channels, prolonging QT — risk of torsades de pointes; largely obsolete. Ib (lignocaine, mexiletine): rapid Na+ block; shorten action potential; lignocaine IV for VT in acute MI (largely superseded by amiodarone); mexiletine oral for certain inherited arrhythmias. Ic (flecainide, propafenone): potent Na+ block; use restricted to SVT and AF in structurally normal hearts — the CAST trial showed increased mortality in post-MI patients with ventricular ectopics treated with flecainide/encainide.

Class II — beta-blockers: reduce automaticity and AV conduction. Rate control in AF; prevent VT triggered by sympathetic activation.

Class III — potassium channel blockers: amiodarone (also has class I, II, IV effects — most effective antiarrhythmic), sotalol (also class II), dronedarone. Prolong action potential duration and effective refractory period. Amiodarone — highly effective for AF, SVT, VT, VF; long half-life (40-55 days); extensive tissue distribution; multiple adverse effects with long-term use: thyroid dysfunction (contains 37% iodine by weight — can cause hypo- or hyperthyroidism; TFTs every 6 months), pulmonary toxicity (interstitial pneumonitis — most serious; CXR + PFTs at baseline and annually), hepatotoxicity (LFTs every 6 months), corneal microdeposits (usually asymptomatic), photosensitivity and slate-grey skin discolouration, peripheral neuropathy; interactions: prolongs QT (avoid with other QT-prolonging drugs), inhibits CYP2D6 and 2C9 (increases digoxin, warfarin levels significantly). Dronedarone: less toxic than amiodarone but less effective; contraindicated in HFrEF and permanent AF.

Class IV — non-dihydropyridine CCBs: verapamil, diltiazem. AV nodal block — rate control in AF/SVT.

Digoxin: cardiac glycoside — inhibits Na+/K+ ATPase in cardiac myocytes. Effects: positive inotropy (increased intracellular Ca2+ via Na+/Ca2+ exchanger); negative chronotropy and AV nodal slowing (vagal enhancement). Use: rate control in AF (combined with beta-blocker or CCB); symptomatic relief in HFrEF. Narrow therapeutic index (therapeutic 0.6-1.2 ng/mL; toxic >2 ng/mL). Toxicity: nausea/vomiting, confusion, yellow-green visual disturbance; arrhythmias (PAT with block, complete heart block, VT). Hypokalaemia markedly increases digoxin toxicity (K+ competes for the Na+/K+ ATPase binding site). Renal excretion — dose reduce in renal impairment; monitor levels.

ANTICOAGULANTS

Warfarin: vitamin K antagonist — inhibits hepatic γ-carboxylation of clotting factors II, VII, IX, X (and anticoagulant proteins C and S). Narrow therapeutic index (INR 2-3 for AF and DVT/PE; INR 2.5-3.5 for mechanical heart valves). Multiple drug and food interactions: CYP2C9 inhibition (fluconazole, amiodarone, metronidazole → raised INR); CYP2C9 induction (rifampicin, carbamazepine → reduced INR); vitamin K-rich foods (green leafy vegetables) reduce anticoagulation. Reversal: vitamin K (oral or IV — hours to days); prothrombin complex concentrate (PCC — immediate reversal for major haemorrhage). Genetic factors: CYP2C9 and VKORC1 polymorphisms explain up to 50% of warfarin dose variability.

Direct oral anticoagulants (DOACs): dabigatran (direct thrombin/factor IIa inhibitor), rivaroxaban, apixaban, edoxaban (factor Xa inhibitors). Advantages over warfarin: predictable pharmacokinetics, no routine monitoring, fewer drug interactions, at least equivalent efficacy for AF stroke prevention, lower intracranial haemorrhage risk. Predominantly renal excretion (especially dabigatran) — dose adjust in CKD; contraindicated if GFR <15-30 mL/min depending on agent. Reversal: idarucizumab (humanised antibody fragment reverses dabigatran); andexanet alfa (modified factor Xa reverses rivaroxaban/apixaban); 4-factor PCC can be used if specific reversal agents unavailable.

Heparins: unfractionated heparin (UFH) — activates antithrombin III, dramatically accelerating inhibition of thrombin (factor IIa) and factor Xa; IV or SC; monitored by APTT (therapeutic range 1.5-2.5× control); reversed by protamine sulphate. Low molecular weight heparins (LMWH — enoxaparin, dalteparin): predominantly inhibit factor Xa; more predictable pharmacokinetics, SC once or twice daily, no routine monitoring needed (except in renal failure or extremes of weight — monitor anti-Xa levels); partially reversible with protamine. Heparin-induced thrombocytopaenia (HIT): immune-mediated — HIT antibodies form against heparin-platelet factor 4 complexes, paradoxically activating platelets → thrombocytopaenia PLUS thrombosis (venous and arterial). Occurs 5-10 days after starting heparin. 4T score helps diagnose; stop all heparin immediately; switch to argatroban or fondaparinux.

ANTIPLATELET DRUGS

Aspirin: irreversibly acetylates COX-1 in platelets → permanent thromboxane A2 synthesis block for the platelet's ~10-day lifespan. Low dose (75 mg) achieves antiplatelet effect with minimal gastrointestinal effects. Indicated in acute coronary syndrome (ACS), stable ischaemic heart disease, post-stroke/TIA, post-stenting. Not proven for primary prevention in low-risk individuals.

P2Y12 inhibitors: clopidogrel (pro-drug, requires CYP2C19 activation — poor metabolisers get reduced effect), ticagrelor (direct-acting, more predictable, preferred in ACS), prasugrel (pro-drug but more potent than clopidogrel; contraindicated in TIA/stroke due to bleeding risk). Block ADP-mediated platelet activation. Dual antiplatelet therapy (DAPT = aspirin + P2Y12 inhibitor) is standard post-ACS and post-coronary stenting.

Glycoprotein IIb/IIIa inhibitors: tirofiban, eptifibatide, abciximab — block the final common pathway of platelet aggregation (GPIIb/IIIa receptor binds fibrinogen bridges between activated platelets); IV use only; high-risk percutaneous coronary intervention.