Antianginal Pharmacology

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Overview of Angina Pectoris

Clinical syndrome characterized by chest discomfort resulting from transient myocardial ischemia
Occurs when myocardial oxygen demand exceeds supply
Ischemia triggers pain via accumulation of metabolic byproducts (adenosine, H⁺, K⁺) that stimulate cardiac sensory nerves
Angina is a symptom of underlying coronary artery disease (CAD) or coronary dysfunction
Not all myocardial ischemia causes angina — silent ischemia is common, especially in diabetic patients

                        High-Yield: The balance between oxygen supply and demand determines the presence and severity of angina

                    

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Types of Angina

Stable (Classic) Angina

Also known as angina of effort or exercise-induced angina
Underlying cause: fixed atherosclerotic coronary artery occlusion
Precipitated by physical exertion, emotional stress, or increased metabolic demand
Pain is predictable and reproducible
Relieved by rest or sublingual nitroglycerin
Coronary blood flow reserve is limited due to fixed stenosis

Vasospastic (Variant) Angina

Also called Prinzmetal angina
Underlying cause: reversible, transient coronary artery vasospasm
Often occurs at rest, typically in the early morning hours
Not necessarily associated with exertion or stress
Pain can be severe and may occur in the absence of significant fixed coronary stenosis
Responds to vasodilators (nitrates, calcium channel blockers)
Beta-blockers are contraindicated because they may worsen vasospasm

Exam Trap: Beta-blockers are effective for stable angina but can be harmful in vasospastic angina — they block β₂-mediated vasodilation and may unmask α-mediated vasoconstriction, worsening coronary spasm

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Pathophysiology of Myocardial Ischemia

Myocardial oxygen supply is determined by coronary blood flow and arterial oxygen content
Myocardial oxygen demand is determined by heart rate, contractility, and wall stress (preload and afterload)
Ischemia develops when demand exceeds supply
Reduced supply can result from:
- Fixed atherosclerotic stenosis (stable angina)
- Dynamic vasospasm (variant angina)
- Thrombosis or emboli (acute coronary syndromes)
Increased demand can result from:
- Tachycardia
- Hypertension (increased afterload)
- Increased preload (volume overload)
- Increased contractility (sympathetic stimulation)

Ischemia → Anaerobic metabolism → ↓ ATP → ↑ Lactate, H⁺, adenosine → Anginal pain

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Drug Treatment Strategies

Reduce Oxygen Demand

Decrease heart rate (beta-blockers, some CCBs)
Decrease contractility (beta-blockers, CCBs)
Decrease preload (nitrates, venodilation)
Decrease afterload (nitrates, CCBs, vasodilators)
Mechanism: ↓ TPR, ↓ CO, or both

Increase Oxygen Supply

Relieve coronary vasospasm (nitrates, CCBs)
Dilate epicardial coronary arteries
Improve collateral blood flow
Reduce platelet aggregation (aspirin)
Mechanism: ↑ coronary blood flow

Drug Class	Primary Mechanism	Stable Angina	Vasospastic Angina
Nitrates	↓ preload, ↓ afterload, coronary vasodilation	Yes	Yes
Beta-blockers	↓ HR, ↓ contractility	Yes	No
CCBs	↓ afterload, coronary vasodilation, ↓ HR (non-dihydropyridines)	Yes	Yes (dihydropyridines preferred)
Ranolazine	↓ Na⁺/Ca²⁺ overload, ↓ demand	Yes	Limited

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Nitrates

Nitrates are prodrugs that release nitric oxide (NO) through biotransformation
NO activates soluble guanylate cyclase → ↑ cGMP → smooth muscle relaxation
Primary vascular effects:
- Venodilation → ↓ preload → ↓ myocardial wall tension → ↓ oxygen demand
- Arteriolar dilation (at higher doses) → ↓ afterload → ↓ cardiac work
- Coronary artery vasodilation → ↑ oxygen delivery, especially in vasospastic angina
Reduction in infarct size and post-MI mortality in appropriate settings

Drugs & Formulations

Nitroglycerin
- Sublingual: rapid onset (1–3 min), short duration (~30 min) — acute episode
- Transdermal: sustained release — chronic prophylaxis
- IV: hospital use for unstable angina, acute MI, or hypertensive emergencies
Isosorbide dinitrate / mononitrate
- Oral formulations: longer duration than sublingual nitroglycerin
- Extended-release for chronic maintenance therapy
- Active metabolite: isosorbide-5-mononitrate

Adverse Effects

Flushing (cutaneous vasodilation)
Headache (vasodilation of cerebral vessels) — common, often subsides with continued use
Orthostatic hypotension — due to venous pooling
Reflex tachycardia — compensatory sympathetic response to hypotension
Fluid retention — may require concurrent diuretic therapy

Cautions & Contraindications

Tachyphylaxis — tolerance develops with repeated or continuous exposure
- Due to depletion of sulfhydryl groups, neurohormonal activation, and plasma volume expansion
- Managed by providing a nitrate-free interval (8–12 hours) each day
Phosphodiesterase-5 (PDE5) inhibitor interaction — absolute contraindication
- Sildenafil, vardenafil, tadalafil inhibit PDE5 → ↑ cGMP → vasodilation
- Concurrent use with nitrates causes synergistic vasodilation → profound hypotension
- Risk of cardiovascular collapse, MI, and death
Use with caution in patients with severe aortic stenosis or hypertrophic cardiomyopathy

Critical Warning: Nitrates + PDE5 inhibitors (sildenafil, vardenafil, tadalafil) = potentially fatal hypotension. Never co-administer.

                        High-Yield: Nitroglycerin is the preferred agent for acute management of both stable angina (↓ oxygen demand) and vasospastic angina (direct coronary vasodilation).

                    

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Beta-Blockers

First-line therapy for stable angina of effort
Mechanism:
- β₁-receptor blockade in the heart → ↓ heart rate, ↓ contractility, ↓ AV conduction
- Reduces myocardial oxygen demand at rest and during exercise
- Prolongs diastolic filling time → ↑ coronary perfusion
Contraindicated in vasospastic (Prinzmetal) angina
- Unopposed α-adrenergic activity may exacerbate coronary vasospasm
- Can worsen ischemia if vasospasm is the primary cause
Carvedilol — non-selective β-blocker with α₁-blocking activity
- Clinically equivalent to isosorbide in stable angina of effort
- Additional vasodilatory effect due to α₁ blockade
- Beneficial in heart failure with reduced ejection fraction

Property	Beta-Blockers	Carvedilol
Receptor targets	β₁ (selective) or β₁/β₂ (non-selective)	β₁, β₂, α₁
Vasodilation	No (except some with ISA)	Yes (α₁ blockade)
Use in stable angina	First-line	Effective
Use in vasospastic angina	Contraindicated	Contraindicated

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Calcium Channel Blockers (CCBs)

All CCBs are effective in angina but with different profiles
Mechanisms:
- Block L-type calcium channels in vascular smooth muscle and cardiac myocytes
- Reduce calcium influx → vasodilation → ↓ afterload → ↓ oxygen demand
- Dilate coronary arteries → ↑ oxygen supply (especially in vasospasm)

Dihydropyridines

Examples: amlodipine, nifedipine, felodipine
Predominant vascular smooth muscle effect
Minimal negative inotropic effect
Reflex tachycardia possible (especially short-acting formulations)
Preferred in vasospastic angina

Non-Dihydropyridines

Examples: verapamil, diltiazem
Negative chronotropic and inotropic effects
Decrease heart rate and AV conduction
Useful in stable angina, especially with atrial arrhythmias
Caution in patients with bradycardia, heart block, or heart failure

                        High-Yield: Dihydropyridine CCBs (especially amlodipine) are the cornerstone of therapy for vasospastic angina.

                    

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Ranolazine

Novel antianginal agent with a unique mechanism
Mechanism:
- Blocks the late inward sodium current (late I_Na) in cardiac myocytes
- Reduces intracellular sodium accumulation
- Decreases calcium overload via the Na⁺/Ca²⁺ exchanger
- Reduces myocardial oxygen consumption without affecting heart rate or blood pressure significantly
- Also blocks K⁺ channels (hERG), prolonging the QT interval
Side effects:
- Constipation
- Nausea
- Dizziness
- QT prolongation (dose-dependent)
Contraindications:
- Long QT syndrome (congenital or acquired)
- Concurrent use with other drugs that prolong the QT interval
- Severe hepatic impairment
Used as adjunctive therapy in patients with chronic stable angina who remain symptomatic despite first-line agents

Exam Trap: Ranolazine prolongs the QT interval. Avoid in patients with long QT syndrome, and be cautious when co-administering with other QT-prolonging drugs (e.g., certain antiarrhythmics, antipsychotics, macrolides).

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Comparison & Clinical Pearls

Drugs That Decrease Mortality in Stable Angina

Aspirin — antiplatelet effect reduces thrombotic events
Nitroglycerin — reduces ischemia and infarct size when used appropriately
Beta-blockers — reduce mortality post-MI and in heart failure

Smooth Muscle Relaxation Pathway

Nitrate (prodrug) → NO release → ↑ sGC → ↑ cGMP → ↓ intracellular Ca²⁺ → Vasodilation

Feature	Stable Angina	Vasospastic Angina
Trigger	Exertion, stress	Rest, often early morning
Coronary pathology	Fixed atherosclerotic stenosis	Reversible vasospasm
First-line acute	Sublingual nitroglycerin	Sublingual nitroglycerin
First-line chronic	Beta-blockers, CCBs, nitrates	Dihydropyridine CCBs, nitrates
Beta-blockers	Effective	Contraindicated
Prognostic drugs	Aspirin, beta-blockers, nitrates	CCBs, nitrates

                        Clinical Pearl: Nitroglycerin is effective for both types of angina — it reduces demand (venodilation) and increases supply (coronary vasodilation).

                    

Key Exam Distinction: Beta-blockers are first-line for stable angina but are contraindicated in vasospastic angina. Dihydropyridine CCBs are the preferred chronic therapy for vasospastic angina.

Tachyphylaxis Prevention

Nitrate tolerance develops with continuous exposure
Prevention: nitrate-free interval of 8–12 hours daily
Example: transdermal patch removed at night, or use of oral isosorbide in a twice-daily schedule with a long evening gap