Angina Pectoris

Definition

• Robbins & Kumar Basic Pathology, block4
• Goldman-Cecil Medicine, block7

Pathophysiology

• Goldman-Cecil Medicine, block7

Classification / Types

1. Stable (Typical / Effort) Angina

• Predictable, episodic chest discomfort triggered by exertion or emotional stress
• Fixed coronary stenosis limits supply; any increase in demand precipitates ischemia
• Relieved by rest or nitroglycerin within 1-5 minutes
• Threshold may vary by time of day, temperature, meals

2. Unstable Angina

• Increasingly frequent chest pain precipitated by progressively less exertion, or occurring at rest
• Associated with plaque disruption and superimposed thrombosis, distal embolization, and/or vasospasm
• Most cases show evidence of myocyte injury - treated aggressively
• Part of the Acute Coronary Syndrome (ACS) spectrum

3. Variant (Prinzmetal) Angina

• Occurs at rest, caused by coronary artery spasm
• Can involve atherosclerotic vessels or structurally normal vessels
• Responds promptly to vasodilators (nitroglycerin, calcium channel blockers)
• Robbins & Kumar Basic Pathology, block4

Canadian Cardiovascular Society (CCS) Grading

• Goldman-Cecil Medicine, block7 | Harrison's Principles, block30

Clinical Features

Symptoms

• Heaviness, pressure, squeezing, smothering, or choking sensation - rarely described as frank "pain"
• Levine's sign: Patient places a clenched fist over the sternum to indicate the sensation
• Location: Substernal, central; radiates to shoulder, arms (especially ulnar forearm and hand), jaw, teeth, neck, back, interscapular region, and epigastrium
• Does NOT radiate to trapezius (that pattern suggests pericarditis)
• Rarely localised below the umbilicus or above the mandible
• Duration: 2-5 minutes; crescendo-decrescendo pattern
• Relieved by: Rest and sublingual nitroglycerin
• If not relieved by both, the diagnosis of angina should be questioned

Precipitants

• Exertion, hurrying, sexual activity
• Emotional stress, anger, fright, frustration
• Heavy meals, cold exposure
• Nocturnal angina - occurs with recumbency (increased intrathoracic blood volume → increased cardiac size → increased O₂ demand)

Atypical Presentations

• Women and diabetic patients may present atypically - pain may be absent or differently localised
• "Sharp, fleeting" or "prolonged dull ache in the left submammary area" is rarely ischemic
• Harrison's Principles of Internal Medicine 22E, block30

Investigations

ECG

• Resting ECG: Often normal between episodes; ST-segment changes during pain are highly diagnostic
• Exercise stress test (EST): ST depression ≥1 mm is a positive result; sensitivity ~70%, specificity ~75%

Imaging

• Stress echocardiography: Wall motion abnormalities during stress indicate ischemia
• Nuclear perfusion imaging (SPECT): Detects regional hypoperfusion at rest vs. stress; very sensitive
• CT coronary angiography: Excellent negative predictive value to exclude significant stenosis
• Coronary artery calcium (CAC) score (EBCT/MDCT): Detects calcified atherosclerosis; used as adjunctive information, NOT as sole basis for decisions
• Invasive coronary angiography: Gold standard for defining anatomy; used when revascularisation is being considered

Lab Tests

• Lipid profile, fasting glucose, HbA1c (risk factor assessment)
• Haemoglobin (exclude anaemia as precipitant)
• Thyroid function (exclude thyrotoxicosis)
• Cardiac biomarkers (to exclude MI / ACS)
• Harrison's Principles of Internal Medicine 22E, block30

Management

Goals

1. Relieve symptoms and improve quality of life
2. Prevent progression to ACS / MI
3. Reduce mortality

Non-Pharmacological (Risk Factor Modification)

• Smoking cessation
• Regular aerobic exercise (cardiac rehabilitation)
• Diet modification, weight management
• Tight control of hypertension, diabetes, and dyslipidaemia

Pharmacological

A. Anti-ischemic / Symptomatic Drugs

• Sublingual nitroglycerin (GTN): First-line for acute angina episodes; acts within 1-3 min
  • Mechanism: Releases NO → activates guanylyl cyclase → increases cGMP → smooth muscle relaxation → venodilation reduces preload; coronary vasodilation
• Long-acting nitrates (isosorbide dinitrate, isosorbide mononitrate): Oral/transdermal for prophylaxis
  • Key concern: Nitrate tolerance - requires 8-12 hour nitrate-free interval daily
  • Toxicity: Orthostatic hypotension, reflex tachycardia, headache
  • Contraindicated with PDE-5 inhibitors (sildenafil, tadalafil) - synergistic hypotension

• Propranolol (non-selective), atenolol/metoprolol (β₁-selective, preferred in asthmatics)
• Mechanism: Reduce heart rate, cardiac output, and BP → decrease myocardial O₂ demand
• Toxicity: Bronchospasm, AV block, acute heart failure, fatigue
• β₁-selective agents preferred to reduce bronchospasm risk

• Non-dihydropyridines (verapamil, diltiazem): Reduce vascular resistance, heart rate, and contractility → decreased O₂ demand; also used in Prinzmetal angina
• Dihydropyridines (nifedipine, amlodipine): Primarily vascular; greater vasodilatory effect; may cause reflex tachycardia (prompt-release nifedipine is contraindicated due to reflex tachycardia and adverse outcomes)
• CCBs are first-line for Prinzmetal/vasospastic angina
• Toxicity: AV block and heart failure (verapamil/diltiazem), ankle oedema, hypotension (dihydropyridines)

• Late sodium current inhibitor - reduces intracellular Ca²⁺ overload during ischemia
• Add-on therapy when other drugs are insufficient; does not affect heart rate or BP
• Useful in patients who cannot tolerate beta-blockers

• Selective If (funny current) channel inhibitor in the SA node - reduces heart rate without negative inotropy
• Used when beta-blockers are contraindicated or poorly tolerated; patient must be in sinus rhythm

B. Anti-platelet / Anti-thrombotic

• Aspirin 75-100 mg daily: Reduces risk of MI and cardiovascular death in all stable angina patients; cornerstone therapy
• Clopidogrel: Alternative if aspirin intolerant

C. Lipid-Lowering

• Statins (e.g., atorvastatin, rosuvastatin): Reduce LDL, stabilise plaques, reduce CV events; target LDL <55-70 mg/dL (ESC) depending on risk

D. ACE Inhibitors / ARBs

• Indicated if concomitant hypertension, diabetes, LV dysfunction, or post-MI; reduce mortality and events
• Katzung's Basic and Clinical Pharmacology 16th Ed, block3 | Harrison's Principles of Internal Medicine 22E, block30

Revascularisation

Differentials to Exclude

• Oesophageal spasm (also relieved by nitrates - a key pitfall)
• GORD / peptic ulcer disease
• Costochondritis / musculoskeletal chest pain
• Pericarditis (trapezius radiation, positional, pleuritic)
• Pulmonary embolism
• Aortic dissection (tearing, radiates to back)
• Hypertensive emergency

Prognosis

• Severity and extent of coronary artery disease
• LV systolic function (EF)
• Presence of diabetes, hypertension, renal disease
• Symptom burden (higher CCS class = worse prognosis)

Recent Evidence (2024-2026)

• A 2024 systematic review (PMID 39353703) on ischaemia with no obstructive coronary artery disease (INOCA) - which underlies much of microvascular angina - shows these patients have significant adverse long-term outcomes, reinforcing the need to investigate and treat even when coronary angiography is "normal."
• A 2025 meta-analysis (PMID 39980940) found stellate ganglion block effective and safe for refractory angina pectoris, offering a neuromodulatory option for drug-refractory cases.

Pharmacotherapy of Angina Pectoris

Overview of Drug Strategy

• Katzung's Basic and Clinical Pharmacology 16th Ed

Drug Class 1: Organic Nitrates

Prototype: Nitroglycerin (Glyceryl Trinitrate)

Mechanism of Action

• Venodilation (predominant at low doses): Reduces venous return (preload), decreases end-diastolic volume and wall tension → reduced O₂ demand
• Arteriolar dilation (at higher doses): Reduces afterload
• Coronary vasodilation: Redistributes flow to ischemic subendocardium; relieves coronary artery spasm (key in Prinzmetal angina)
• Anti-platelet effect: NO also increases cGMP in platelets → decreased platelet aggregation

Pharmacokinetics

Tolerance (Tachyphylaxis)

• Develops with continuous or prolonged exposure (oral, transdermal, IV infusion >a few hours)
• Mechanisms: reduced bioactivation → less NO release; reduced sulfhydryl donor availability; neurohormonal counter-regulation (RAAS, sympathetic activation)
• Prevention: mandatory nitrate-free interval of 8-12 hours daily (e.g., remove patch at night; use asymmetric ISMN dosing - 8 AM and 2 PM rather than 12-hourly)

Toxicity

Critical Drug Interaction

• Katzung's Basic and Clinical Pharmacology 16th Ed, block2

Drug Class 2: Beta-Adrenoceptor Blockers

Mechanism of Action

• ↓ Heart rate (chronotropy) → prolongs diastole → more time for coronary perfusion
• ↓ Contractility (inotropy) → ↓ O₂ consumption
• ↓ Blood pressure → ↓ afterload
• Net: decreases the rate-pressure product (heart rate × systolic BP) - the best clinical index of O₂ demand

Drugs & Selectivity

β₁-selective agents are preferred in patients with reactive airway disease (asthma/COPD) because they have less bronchospasm risk - though selectivity is not absolute at high doses.

Clinical Use

• First-line for prophylaxis of stable effort angina
• Reduce frequency and severity of angina attacks
• Improve exercise tolerance (raise threshold for ischemia on treadmill)
• Reduce mortality after MI - a key secondary benefit
• NOT effective in Prinzmetal (vasospastic) angina - beta-blockade may worsen spasm by leaving α-mediated vasoconstriction unopposed

Toxicity

• Bronchospasm (especially non-selective agents - caution in asthma)
• AV block - use caution in pre-existing conduction disease
• Acute heart failure - in patients with borderline cardiac function
• Fatigue, depression, sexual dysfunction
• Masking hypoglycemia in diabetics
• Rebound angina on abrupt withdrawal - taper dose gradually; abrupt cessation can precipitate MI

Combining with Nitrates (Complementary)

• Katzung's Basic and Clinical Pharmacology 16th Ed, block2 & block3

Drug Class 3: Calcium Channel Blockers (CCBs)

Mechanism of Action

Subclasses

A. Non-dihydropyridines (NDHPs) - "Heart-selective" CCBs

• Reduce cardiac rate AND contractility → directly reduce O₂ demand
• Vasodilate coronary and peripheral arteries
• Oral bioavailability: Diltiazem 40-65%; Verapamil 20-35%
• Toxicity: AV block, bradycardia, acute heart failure (particularly in patients with systolic dysfunction), constipation (verapamil)
• Contraindicated with beta-blockers in patients with LV dysfunction or conduction abnormalities due to additive negative chronotropy and inotropy

B. Dihydropyridines (DHPs) - "Vessel-selective" CCBs

• Primarily vasodilate peripheral and coronary arteries → reduce afterload
• Less cardiac depression than NDHPs
• Prompt-release nifedipine is contraindicated in angina - causes excessive hypotension and baroreceptor reflex tachycardia, which worsens ischemia (increases O₂ demand)
• Toxicity: Ankle oedema (most common), flushing, headache, reflex tachycardia (short-acting DHPs)

CCBs in Vasospastic (Prinzmetal) Angina

• Katzung's Basic and Clinical Pharmacology 16th Ed, block2 & block3

Drug Class 4: Ranolazine (Newer Anti-anginal)

• Mechanism: Inhibits the late inward sodium current (late I-Na) during ischemia → prevents Na⁺ overload → reduces secondary Ca²⁺ overload via Na⁺/Ca²⁺ exchanger → reduces diastolic tension, contractility, and wall stress
• Key advantage: Does not lower heart rate or blood pressure - safe in patients with bradycardia or hypotension
• Use: Add-on therapy for stable angina refractory to beta-blockers and/or CCBs; FDA-approved
• Toxicity: Prolongs QT interval (use cautiously in LQT syndrome, avoid with other QT-prolonging drugs); may increase digoxin and simvastatin levels
• Note: Shortens QT in LQT3 subtype - an interesting pharmacological paradox
• Katzung's Basic and Clinical Pharmacology 16th Ed, block3

Drug Class 5: Ivabradine

• Mechanism: Selectively inhibits the If (funny current / HCN channel) in the sinoatrial node → pure heart rate reduction without negative inotropy or vasodilation
• Use: Angina prophylaxis when beta-blockers are contraindicated or not tolerated; patient must be in sinus rhythm (does not work in AF)
• Toxicity: Bradycardia, visual disturbances (phosphenes - transient luminous phenomena), contraindicated in sick sinus syndrome or AV block

Disease-Modifying / Event-Prevention Drugs

Antiplatelet Therapy

Statins (HMG-CoA Reductase Inhibitors)

• Drugs: Atorvastatin 40-80 mg, Rosuvastatin 20-40 mg
• Mechanism: ↓ LDL-cholesterol; stabilise atherosclerotic plaques (reduce inflammation); improve endothelial function
• Evidence: Aggressive statin therapy reduces severity of exercise-induced ischemia and incidence of MI and cardiovascular death
• Target: LDL <55 mg/dL (ESC) or <70 mg/dL (ACC/AHA) for high-risk patients
• All patients with stable angina should be on a high-intensity statin regardless of baseline LDL

ACE Inhibitors / ARBs

• Drugs: Ramipril, perindopril, lisinopril (ACEi); valsartan, candesartan (ARB)
• Reduce adverse cardiac remodelling, prevent MI recurrence, reduce overall CV mortality
• Indicated in: concomitant hypertension, diabetes, LV systolic dysfunction, post-MI, chronic kidney disease
• HOPE trial: Ramipril reduced MI, stroke, and cardiovascular death even in patients without LV dysfunction

Unstable Angina / ACS Pharmacotherapy

1. Antiplatelet: Dual antiplatelet therapy (DAPT) - aspirin + P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel)
2. Anticoagulation: Heparin (UFH or LMWH) or fondaparinux to prevent thrombus extension
3. Beta-blockers: Reduce heart rate and O₂ demand; started early unless contraindicated
4. Nitrates: IV nitroglycerin for recurrent ischemia at rest
5. Statins: High-intensity statin started immediately
6. Early invasive strategy: Coronary angiography + PCI/CABG if high risk

"In patients with unstable angina with recurrent ischemic episodes at rest, recurrent platelet-rich nonocclusive thrombus formation is the principal mechanism. Aggressive antiplatelet therapy with aspirin and ADP receptor blockers is recommended." - Katzung block3

Drug Choice by Angina Type - Summary

Quick Reference: Drug Summary Table