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PH4.8 | PH4.8 | Ischemic Heart Disease Pharmacotherapy — SDL Guide

Learning Objectives

• Classify drugs used for ischaemic heart disease and peripheral vascular disease by mechanism and describe their pharmacokinetics, pharmacodynamics, therapeutic uses, and adverse effects.
• Explain the pharmacological management of chronic stable angina, acute coronary syndrome (STEMI and NSTEMI), and peripheral arterial disease.
• Devise a pharmacological management plan for a patient with acute STEMI including reperfusion strategy and long-term secondary prevention.
• Identify contraindications to fibrinolytic therapy and distinguish the major antithrombotic agents used in ACS.

INSTRUCTIONS

Ischaemic heart disease kills more people globally than any other single condition. As a junior doctor you will face two types of situations: the chronic patient with stable angina — where your goal is to relieve symptoms and prevent events — and the acute STEMI patient arriving in the emergency department where minutes to reperfusion determine whether viable myocardium survives. This SDL covers the pharmacology of anti-anginal drugs, acute coronary syndrome agents, and the long-term secondary prevention framework that reduces the risk of recurrent events.

References

• Tripathi KD. Essentials of Medical Pharmacology, 9th ed., Ch. 37 (Antianginal & Vasodilator Drugs), Ch. 34 (Antithrombotic Drugs) (textbook)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., Ch. 30 (Blood Coagulation), Ch. 27 (Treatment of Myocardial Ischaemia) (textbook)

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Version 2.0 | NMC CBUC 2024

Pathophysiology of IHD: Oxygen Supply-Demand Imbalance and the ACS Spectrum

Ischaemic heart disease arises when myocardial oxygen demand exceeds supply — most commonly because of atherosclerotic narrowing of one or more coronary arteries. The clinical manifestation depends on the severity and acuity of the supply-demand mismatch.

In stable angina, a fixed coronary stenosis (typically >70% luminal narrowing) limits coronary flow reserve — the ability to increase flow with demand. At rest, supply is adequate; with exertion or emotional stress, demand increases (↑HR, ↑BP, ↑contractility) and outstrips the fixed supply → transient, reversible ischaemia → chest pain that resolves with rest or nitrate. The atherosclerotic plaque is stable (fibrous cap intact).

In acute coronary syndrome (ACS), a vulnerable plaque undergoes rupture or erosion — the fibrous cap is breached, exposing the thrombogenic lipid-rich necrotic core to flowing blood. Platelets adhere to exposed collagen via GP1b-vWF, activate (release ADP, TXA2, serotonin), and aggregate to form a platelet-rich white thrombus, which is then consolidated by the coagulation cascade into a red fibrin-rich clot. If the thrombus is occlusive, STEMI results (complete occlusion → transmural infarction); if partially occlusive or fragmented (distal microemboli), NSTEMI or unstable angina results.

Pharmacological intervention targets multiple steps in this cascade: antiplatelets prevent initial platelet aggregation and propagation; anticoagulants prevent fibrin formation; fibrinolytics dissolve formed clot (STEMI only); and anti-anginal drugs reduce the oxygen demand imbalance.

Peripheral vascular disease (PVD) — also mandated by PH4.8 — shares the same atherosclerotic mechanism but in the limb arteries. Claudication (exertional calf pain) results from fixed arterial stenoses limiting limb perfusion; critical limb ischaemia represents severe, rest-pain disease. Pharmacological management: antiplatelet therapy (aspirin, clopidogrel), statin therapy, and cilostazol for claudication.

Therapeutic Goals in IHD: Symptom Relief and Event Prevention

The pharmacological management of IHD pursues two distinct but complementary goals that must not be confused: symptomatic relief (reducing anginal frequency and severity) and event prevention (reducing the risk of MI, stroke, and cardiovascular death — the MACE endpoints).

Symptomatic relief drugs (reduce ischaemia): nitrates (venodilators → ↓preload; vasodilators → ↓afterload), beta-blockers (↓HR → more diastolic perfusion time; ↓O2 demand), CCBs (↓afterload; non-DHP also ↓HR). These drugs do NOT prolong survival in stable angina. They improve quality of life.

Event prevention drugs (reduce MACE, prolong life): antiplatelets (aspirin + P2Y12 inhibitors), anticoagulants (in ACS and for post-ACS bridging), high-intensity statins (plaque stabilisation + LDL lowering), ACEi/ARBs (post-MI remodelling prevention, afterload reduction in HFrEF), beta-blockers (post-MI survival benefit). These drugs do NOT necessarily relieve acute symptoms but are obligatory for secondary prevention.

In practice, the prescribing plan for any IHD patient addresses both pillars simultaneously. A patient presenting with STEMI receives: (1) antiplatelets + anticoagulant + reperfusion (fibrinolysis or PCI) for the acute event, and (2) statin + ACEi + beta-blocker + DAPT for long-term secondary prevention.

Stable angina management hierarchy: lifestyle modification → sublingual GTN for acute attacks (on-demand) → beta-blocker ± long-acting nitrate or DHP-CCB (first-line prophylaxis) → combination of beta-blocker + CCB → add ranolazine (second-line) → revascularisation assessment if pharmacologically refractory.

Classification of IHD Drugs

The pharmacological armamentarium for IHD is most usefully organised into three clinical categories, each addressing a distinct aspect of the disease.

Category A — Anti-Anginal Drugs (chronic stable angina):
1. Organic nitrates: GTN (sublingual for acute attacks; transdermal/oral for prophylaxis); isosorbide dinitrate (ISDN); isosorbide mononitrate (ISMN — active metabolite of ISDN, preferred for predictable bioavailability).
2. Beta-blockers: atenolol, metoprolol, bisoprolol — reduce HR and contractility → ↓O2 demand; first-line for effort angina.
3. Calcium channel blockers: amlodipine (DHP) for add-on; verapamil or diltiazem (non-DHP) when beta-blockers contraindicated.
4. Ranolazine: late Na-channel inhibitor → reduces Na-overload → reduces Ca-overload (via Na-Ca exchanger) → reduces diastolic tension; reduces anginal frequency without affecting HR or BP; used as add-on.

Category B — Acute Coronary Syndrome drugs:
1. Antiplatelets: aspirin (irreversible COX-1 inhibitor); P2Y12 inhibitors: clopidogrel (thienopyridine prodrug, CYP2C19-dependent), ticagrelor (reversible, not a prodrug), prasugrel (prodrug, faster).
2. Anticoagulants: unfractionated heparin (UFH), low-molecular-weight heparin — enoxaparin (subcutaneous, predictable), fondaparinux (selective factor Xa inhibitor), bivalirudin (direct thrombin inhibitor).
3. Fibrinolytics (STEMI only): streptokinase (bacterial protein, non-fibrin-specific, 1.5 MIU IV over 60 min, one-time use only due to antibodies); alteplase (recombinant tPA, fibrin-specific, IV bolus + infusion), tenecteplase (IV bolus, weight-based, fibrin-specific).

Category C — Secondary Prevention:
High-intensity statin + aspirin + P2Y12 inhibitor (DAPT 12 months post-ACS) + ACEi or ARB + beta-blocker (if LVEF reduced or HF) + PPI (gastroprotection during DAPT).

Category D — Peripheral Vascular Disease:
Cilostazol (PDE3 inhibitor → cAMP → platelet inhibition + vasodilation → improves claudication symptoms); aspirin or clopidogrel (antiplatelet); high-intensity statin; risk-factor control.