Anti-Anginal Drugs — Pharmacology

Overview

Types of Angina

Treatment Algorithm

Drug Classes

1. Organic Nitrates

• Nitrates are converted to nitric oxide (NO) in vascular smooth muscle
• NO activates guanylyl cyclase → ↑ cGMP → activation of cGMP-dependent protein kinase → dephosphorylation of myosin light chain → smooth muscle relaxation
• Primary effect: venodilation (↓ venous return → ↓ preload → ↓ ventricular wall tension → ↓ O₂ demand)
• At higher doses: arteriolar dilation (↓ afterload)
• Also directly dilate coronary arteries, benefiting vasospastic angina and redistributing flow to ischemic subendocardium

• NTG and ISDN undergo extensive first-pass metabolism; ISMN does not (high oral bioavailability)
• NTG is highly lipophilic and readily absorbed through skin and mucous membranes

• Continuous nitrate exposure leads to tolerance (tachyphylaxis)
• Mechanism: depletion of sulfhydryl (-SH) groups required for NO bioactivation; upregulation of PDE
• Prevention: nitrate-free interval of 10–12 hours daily (e.g., remove patch at night)

• Headache (vasodilation of meningeal vessels) — most common
• Orthostatic hypotension, reflex tachycardia
• Flushing
• Methemoglobinemia (high-dose IV NTG)

• Concurrent use of PDE-5 inhibitors (sildenafil, tadalafil) — severe, potentially fatal hypotension
• Hypotension, hypovolemia
• Right ventricular infarction
• Hypertrophic obstructive cardiomyopathy (HOCM)

2. β-Adrenergic Blockers

• Non-selective: Propranolol, Nadolol, Sotalol
• Cardioselective (β₁): Atenolol, Bisoprolol, Metoprolol, Nebivolol

• Block β₁ receptors in the heart → ↓ heart rate (negative chronotropy) + ↓ contractility (negative inotropy) → ↓ myocardial O₂ demand
• Also reduce blood pressure, further lowering cardiac workload
• Reduce frequency and severity of angina attacks
• Increase exercise duration and tolerance in effort-induced angina

• First-line antianginal therapy for stable angina (unless contraindicated)
• Proven survival benefit after MI (reduce re-infarction and death)
• Improve mortality in heart failure with reduced ejection fraction (HFrEF)
• Cardioselective β₁-blockers are preferred to minimize side effects
• β-Blockers with intrinsic sympathomimetic activity (ISA) should be avoided in angina

• Bradycardia, AV block
• Bronchoconstriction (non-selective agents)
• Fatigue, depression
• Peripheral vasoconstriction
• Masked hypoglycemia in diabetics
• Impotence

• Asthma/severe reactive airways disease (non-selective)
• Decompensated heart failure
• Significant bradycardia or AV block
• Vasospastic angina

3. Calcium Channel Blockers (CCBs)

• Dihydropyridines (DHP): Amlodipine, Nifedipine, Felodipine
• Non-dihydropyridines (non-DHP): Verapamil, Diltiazem

• Block voltage-gated L-type Ca²⁺ channels in vascular smooth muscle and cardiac muscle
• DHPs: Predominantly peripheral arterial vasodilation → ↓ afterload → ↓ O₂ demand; also dilate coronary arteries
• Non-DHPs (Verapamil, Diltiazem): Also suppress SA node automaticity and AV conduction (negative chronotropy and dromotropy) + negative inotropy
• Activity gradient (peripheral to myocardial): Amlodipine > Diltiazem > Verapamil

• All CCBs effective for stable and vasospastic angina
• First-line for Prinzmetal (vasospastic) angina — most effective
• DHPs used as add-on to β-blockers in stable angina
• Verapamil/diltiazem: alternative to β-blockers when β-blockers are contraindicated

• DHPs: Reflex tachycardia (especially nifedipine), peripheral edema, flushing, headache
• Verapamil: Constipation, bradycardia, AV block, negative inotropy
• Diltiazem: Bradycardia, AV block (less than verapamil), less negative inotropy

• Non-DHPs contraindicated in HFrEF (negative inotropy worsens function)
• Non-DHPs should not be combined with β-blockers (risk of severe bradycardia/AV block)
• Systolic blood pressure <90 mmHg

4. Ranolazine (Sodium Channel Blocker)

• Blocks late inward Na⁺ current (late I_Na) in ischemic myocardium
• Ischemia → ↑ late I_Na → intracellular Na⁺ overload → reversal of Na⁺/Ca²⁺ exchanger → intracellular Ca²⁺ overload → diastolic dysfunction and ischemic injury
• Blocking late I_Na → ↓ Ca²⁺ overload → improved diastolic relaxation → ↓ wall tension → ↓ O₂ demand
• Does not affect heart rate or blood pressure — hemodynamically neutral
• Also has mild anti-arrhythmic properties (decreases AF, SVT, ventricular arrhythmias)

• Used in patients with stable angina who have failed β-blockers, CCBs, or nitrates
• Can be used in combination with any of the above agents
• Provides additional antianginal benefit even on top of maximal conventional therapy

• QT interval prolongation (risk of torsades de pointes)
• Dizziness, nausea, constipation
• Less effective in women

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) increase ranolazine levels
• P-glycoprotein inhibitors also increase levels
• Numerous interactions — check carefully before prescribing

Antianginal Drug Therapy by Comorbidity

Summary Comparison Table

Key Clinical Points

• Sublingual NTG (tablet or spray) must be prescribed to all angina patients for acute attack relief
• β-Blockers are first-line for stable angina (proven mortality benefit post-MI)
• CCBs (especially DHPs or diltiazem) are first-line for vasospastic angina; β-blockers are contraindicated in vasospasm
• Non-DHP CCBs (verapamil, diltiazem) are contraindicated in HFrEF due to negative inotropy
• Nitrate tolerance is prevented by a 10–12 hour nitrate-free interval daily
• Nitrates + PDE-5 inhibitors = dangerous — absolutely contraindicated combination
• Ranolazine is reserved for refractory angina; prolongs QT and has extensive drug interactions
• Combination therapy (β-blocker + CCB or nitrate) is used when monotherapy is inadequate

Drug Reference (for context)

Answers

Question 1

✅ 4. With AV blockade

• β-Blockers slow conduction through the AV node. Pre-existing AV block is a direct contraindication — adding a β-blocker risks complete heart block
• Bronchospasm is a contraindication only for non-selective β-blockers (cardioselective ones may still be used cautiously)
• Acute phase of MI — β-blockers are actually indicated (unless hemodynamically unstable)
• High blood pressure — β-blockers are indicated
• Stable angina FC I — β-blockers are first-line; not contraindicated

Question 2

✅ 5. Isadrin (Isoprenaline)

• Isoprenaline is a non-selective β-agonist (β₁ + β₂)
• β₂ stimulation → bronchodilation → improves bronchial patency
• It also has antianginal effect (vasodilation via β₂), though it is rarely used today due to β₁-mediated tachycardia and increased O₂ demand
• Nitrates and propranolol do not bronchodilate; propranolol (β-blocker) actually causes bronchospasm

Question 3

✅ 1. Finoptin (Verapamil)

• Verapamil is a non-DHP CCB with pronounced negative inotropic effect — it directly reduces myocardial contractility (↓ Ca²⁺ entry into cardiomyocytes)
• This decreases O₂ demand, contributing to its antianginal effect
• Nitrates (Sustak, Nitrong, Nitrosorbite) work primarily by reducing preload/afterload — they do not reduce contractility
• Erinite (pentaerythritol nitrate) is also a nitrate — no negative inotropy

Question 4

✅ 2. Isadrin (Isoprenaline)

• Isoprenaline (β₁ + β₂ agonist) → ↑ heart rate + ↑ contractility → markedly ↑ myocardial O₂ demand
• This is why non-selective β-agonists are not standard antianginals and are actually harmful in most angina patients
• Sustak and Nitrong (nitrates) ↓ O₂ demand (↓ preload)
• Validol has no significant hemodynamic effect on myocardial demand
• Finoptin ↓ O₂ demand

Question 5

✅ 1. Eufillin + Isadrin

• Both aminophylline and isoprenaline increase myocardial O₂ demand:
  • Aminophylline → PDE inhibition → ↑ cAMP → tachycardia, ↑ contractility
  • Isoprenaline → β₁/β₂ agonism → tachycardia, ↑ contractility
• Together, this combination dramatically increases ischemic burden — catastrophic in unstable angina
• Finoptin + Anaprilin (Q5-2) is dangerous (severe bradycardia/AV block) but the question specifies "unstable angina" where demand-increasing drugs are the most dangerous
• Finoptin + nitrates is acceptable; β-blocker + CCB (non-DHP) is contraindicated in bradycardia but the most categorically harmful in unstable angina is the demand-increasing pair

Question 6

✅ 3. Increases myocardial oxygen demand

• Aminophylline inhibits phosphodiesterase → ↑ cAMP → positive chronotropy and inotropy → ↑ heart rate and contractility → ↑ myocardial O₂ demand
• It also causes systemic vasodilation (↓ peripheral resistance) but the dominant harmful effect in unstable angina is the demand increase
• In a setting of already-compromised coronary perfusion, increasing demand worsens ischemia

Question 7

✅ 1. Eufillin (Aminophylline)

• Aminophylline → PDE inhibition → ↑ cAMP in the SA node → tachycardia
• Anaprilin (propranolol) causes bradycardia (β-blocker)
• Kordanum (talinolol) causes bradycardia (β-blocker)
• Nitrong — may cause reflex tachycardia, but eufillin is the most direct chronotropic agent in the list
• Nitroglycerin can also cause reflex tachycardia, but aminophylline's tachycardia is direct and more pronounced

(Note: Nitroglycerin [option 5] also causes reflex tachycardia via baroreceptor activation, but eufillin causes direct, more severe tachycardia)

Question 8

✅ 5. Trazikor (Oxprenolol — β-blocker with ISA)

• β-Blockers → block β₂-mediated vasodilation in peripheral vessels → ↑ peripheral vascular resistance (OPS)
• This is one reason β-blockers are cautiously used in peripheral vascular disease
• Nitroglycerin, nitrosorbite, and Sustak all decrease OPS (vasodilators)
• Eufillin decreases OPS (vasodilation via PDE inhibition)
• Among the options, the β-blocker (Trazikor) is the one that raises OPS

Question 9

✅ 1. A decrease in myocardial contractility

• Verapamil blocks L-type Ca²⁺ channels in the myocardium → ↓ contractility (negative inotropy) → ↓ O₂ demand
• It also decreases heart rate (negative chronotropy) and reduces afterload to some extent
• Options 2 (↓ OPS) describes DHP-CCBs like nifedipine, not verapamil primarily
• Options 4 and 5 (increased after/preload) would worsen angina — incorrect
• The primary antianginal mechanism of verapamil is negative inotropy + chronotropy, not peripheral vasodilation

Question 10

✅ 4. Propranolol (Anaprilin)

• Propranolol (non-selective β-blocker) slows AV conduction
• In a patient with pre-existing AV block, adding propranolol risks progression to complete heart block
• Nitrates (Sustak-mite, Sustak-forte, Nitrosorbite, Erinite) do not affect AV conduction — they are safe in AV block
• Propranolol is categorically contraindicated when significant AV block is present

Quick Answer Summary