Pharmacology of Antianginal Drugs

Introduction / Overview

Angina pectoris remains a frequent manifestation of coronary artery disease, exerting a substantial burden on patient quality of life and healthcare systems worldwide. Antianginal pharmacotherapy is central to symptom control, reduction of ischemic episodes, and prevention of adverse cardiovascular events. A comprehensive understanding of the pharmacological principles guiding antianginal drug selection, dosing, and monitoring is therefore essential for both medical and pharmacy trainees.

Learning objectives for this monograph include:

• Identify the principal drug classes employed in angina management and recognize their chemical classifications.
• Describe the pharmacodynamic mechanisms underlying the antianginal effects of each drug class.
• Explain key pharmacokinetic parameters that influence therapeutic efficacy and safety.
• Apply evidence-based knowledge to clinical decision‑making, including patient‑specific considerations.
• Recognize potential adverse reactions, drug interactions, and contraindications associated with antianginal agents.

Classification

Major Antianginal Drug Classes

Antianginal agents are traditionally grouped according to their principal mechanisms of action. The principal categories include:

• Beta‑adrenergic blockers (β‑blockers)
• Calcium channel blockers (CCBs)
• Nitrates and nitrate‑like vasodilators
• Other vasodilators and metabolic modulators (e.g., ranolazine, nicorandil)
• Anti‑inflammatory and antiplatelet adjuncts (e.g., nicorandil, trimetazidine)

Chemical Classification

Within these classes, agents can be further distinguished by chemical structure:

• β‑blockers: propranolol, atenolol, metoprolol (benzylamine derivatives); carvedilol, labetalol (heteroaryl‑alkylamines)
• CCBs: dihydropyridines (amlodipine, nifedipine); phenylalkylamines (verapamil); benzothiazepines (diltiazem)
• Nitrates: organic nitrates (nitroglycerin, isosorbide mononitrate); inorganic nitrates (sodium nitroprusside)
• Metabolic modulators: ranolazine (sulfonamide derivative); trimetazidine (benzene‑di‑nitro derivative)

Mechanism of Action

Beta‑Adrenergic Blockers

β‑blockers attenuate sympathetic stimulation by competitively inhibiting β‑adrenergic receptors on cardiac myocytes and vascular smooth muscle. This action reduces intracellular cyclic adenosine monophosphate (cAMP), leading to decreased calcium influx via L‑type calcium channels. The net effect is a reduction in heart rate, myocardial contractility, and oxygen consumption. Selective β1‑adrenergic antagonists preferentially target cardiac tissue, whereas non‑selective agents also block β2 receptors in pulmonary and vascular beds, potentially causing bronchoconstriction and vasodilation.

Calcium Channel Blockers

CCBs inhibit L‑type calcium channels in cardiac and vascular smooth muscle cells. Dihydropyridines primarily induce vasodilation of coronary and systemic arteries, thereby decreasing afterload and oxygen demand. Phenylalkylamines and benzothiazepines exhibit both vasodilatory and negative inotropic properties, directly reducing myocardial oxygen consumption. The modulation of calcium entry diminishes myocyte contraction and slows conduction through the atrioventricular node, providing antianginal benefit.

Nitrates and Nitrate‑Like Vasodilators

Nitrates are metabolized to nitric oxide (NO) via mitochondrial aldehyde oxidoreductase. NO activates soluble guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) and promoting smooth muscle relaxation. Vasodilation of venous capacitance vessels reduces preload, while arterial vasodilation decreases afterload. Nicorandil combines nitrate‑like NO release with ATP‑sensitive potassium channel opening, conferring both vasodilatory and ischemic preconditioning effects.

Metabolic Modulators (Ranolazine, Trimetazidine)

Ranolazine selectively inhibits late sodium current (I_lateNa) in cardiomyocytes, reducing intracellular sodium and consequently calcium overload via the sodium‑calcium exchanger. This mechanism improves myocardial relaxation and reduces oxygen consumption. Trimetazidine shifts myocardial metabolism from fatty acid oxidation to glucose oxidation, enhancing efficiency and decreasing oxygen demand. Both agents lack direct vasodilatory effects but mitigate ischemia by optimizing myocyte energetics.

Pharmacokinetics

Beta‑Adrenergic Blockers

Absorption rates vary: propranolol exhibits high oral bioavailability (~80 %), whereas atenolol is poorly absorbed (~50 %). Lipophilic agents undergo extensive hepatic metabolism via CYP450 enzymes, yielding metabolites with reduced activity. Hydrophilic β1‑selective blockers are primarily eliminated unchanged by the kidneys. Half‑lives range from 3 h (atenolol) to 12 h (metoprolol). Dosing schedules are adjusted to maintain steady‑state concentrations, minimizing peak‑trough variations that could precipitate ischemia.

Calcium Channel Blockers

Dihydropyridines are absorbed rapidly, with peak plasma concentrations reached within 1–2 h. Liver metabolism via CYP3A4 produces active metabolites; hepatic impairment may prolong exposure. Phenylalkylamines and benzothiazepines have longer half‑lives (>12 h), allowing once‑daily dosing. Plasma protein binding is high (≥90 %) for most CCBs, influencing distribution to cardiac tissue. Renal excretion is minimal for dihydropyridines; however, verapamil and diltiazem undergo significant hepatic clearance.

Nitrates and Nitrate‑Like Vasodilators

Acute‑release nitroglycerin is absorbed via the buccal route, achieving peak plasma levels within minutes. Oral isosorbide mononitrate exhibits a bioavailability of 30–40 % due to first‑pass metabolism. Metabolism involves nitrate reductase and aldehyde oxidoreductase pathways, producing nitrite and subsequent NO. The elimination half‑life ranges from 1 h (nitroglycerin) to 6 h (isosorbide dinitrate). Metabolic tolerance develops rapidly with continuous use, necessitating drug holidays or alternate‑day dosing to maintain efficacy.

Metabolic Modulators

Ranolazine is absorbed orally with a bioavailability of 60 %. Hepatic metabolism via CYP3A4 leads to active metabolites with half‑lives of 8–10 h. Renal excretion accounts for 30–40 % of the dose. Trimetazidine demonstrates a half‑life of ~10 h, with hepatic metabolism via CYP2E1. Both agents exhibit dose‑dependent pharmacokinetics, requiring careful titration in hepatic impairment.

Therapeutic Uses / Clinical Applications

Approved Indications

All major drug classes are indicated for stable angina pectoris, exertional chest pain, and variant angina (Prinzmetal). β‑blockers are also recommended post‑myocardial infarction to reduce mortality. CCBs are preferred in patients with contraindications to β‑blockers, such as asthma or heart block. Nitrates remain first‑line for acute anginal relief and chronic prevention when combined with β‑blockers or CCBs. Ranolazine and trimetazidine are indicated for refractory angina despite optimal conventional therapy.

Off‑Label Uses

Low‑dose propranolol is employed in chronic fatigue syndrome and hyperthyroidism. Nitrates have been trialed in peripheral vascular disease and migraine prophylaxis, though evidence is limited. Ranolazine has been investigated for arrhythmia suppression in atrial fibrillation, yet clinical application remains experimental.

Adverse Effects

Common Side Effects

β‑blockers: bradycardia, fatigue, hypotension, sexual dysfunction, and bronchospasm with non‑selective agents. CCBs: peripheral edema, flushing, constipation, dizziness, and bradyarrhythmias. Nitrates: headache, hypotension, tachyphylaxis, and reflex tachycardia. Ranolazine: dizziness, constipation, and nausea. Trimetazidine: gastrointestinal upset, dysgeusia, and rare reports of peripheral neuropathy.

Serious / Rare Adverse Reactions

β‑blockers can precipitate heart failure exacerbation in advanced disease. CCBs may worsen conduction defects. Nitrate toxicity can lead to methemoglobinemia, particularly with sodium nitroprusside. Ranolazine is associated with QT interval prolongation, especially when combined with other QT‑prolonging agents. Trimetazidine has been linked to peripheral neuropathy, prompting caution in long‑term use.

Black Box Warnings

Ranolazine carries a boxed warning for QTc prolongation and torsades de pointes, particularly when combined with other QT‑prolonging drugs or in patients with electrolyte disturbances. Sodium nitroprusside is warned against prolonged use due to cyanide toxicity risk.

Drug Interactions

Major Drug‑Drug Interactions

β‑blockers: potent CYP2D6 inhibitors (e.g., fluoxetine) increase plasma concentrations, heightening bradycardic risk. CCBs: CYP3A4 inhibitors (e.g., ketoconazole) elevate CCB levels, increasing hypotension and edema. Nitrates: phosphodiesterase‑5 inhibitors (e.g., sildenafil) can cause severe hypotension. Ranolazine: strong CYP3A4 inhibitors (e.g., clarithromycin) raise ranolazine exposure, raising QT risk. Trimetazidine: CYP2E1 inhibitors (e.g., disulfiram) may augment drug levels.

Contraindications

β‑blockers: severe asthma or chronic obstructive pulmonary disease; second‑degree AV block without pacemaker. CCBs: sick sinus syndrome, high‑grade AV block, severe aortic stenosis. Nitrates: concurrent phosphodiesterase‑5 inhibitors, severe hypotension, or nitrate tolerance. Ranolazine: significant hepatic impairment; concomitant QT‑prolonging agents. Trimetazidine: pregnancy category D; renal failure with significant accumulation risk.

Special Considerations

Pregnancy / Lactation

β‑blockers are classified as category C; limited data suggest fetal growth restriction with high doses. Nitrates are category B; evidence does not indicate teratogenicity but use is limited to severe cases. CCBs are mainly category C; caution advised, particularly in the first trimester. Ranolazine and trimetazidine lack sufficient safety data; avoidance is recommended.

Pediatric / Geriatric Considerations

Pediatric dosing relies on weight‑based calculations; pharmacokinetics differ due to immature hepatic enzymes. Geriatric patients exhibit reduced renal function and altered protein binding, necessitating dose reductions and careful monitoring for bradycardia, hypotension, or drug accumulation. Age‑related comorbidities, such as chronic kidney disease, further complicate pharmacotherapy.

Renal / Hepatic Impairment

Beta‑blockers: atenolol and sotalol require dose adjustments in renal insufficiency. CCBs: verapamil and diltiazem are metabolized hepatically; hepatic impairment may prolong half‑life. Nitrates: isosorbide dinitrate and mononitrate are safe in mild hepatic dysfunction but require caution in severe disease. Ranolazine: dose reduction by 50 % in moderate hepatic impairment; contraindicated in severe hepatic disease. Trimetazidine: contraindicated in severe hepatic and renal dysfunction due to accumulation risk.

Summary / Key Points

• Antianginal therapy encompasses β‑blockers, CCBs, nitrates, and metabolic modulators, each with distinct mechanisms targeting myocardial oxygen demand and supply.
• Pharmacokinetic variability, particularly hepatic metabolism and renal excretion, dictates dosing strategies and necessitates individualized adjustments.
• Adverse effect profiles differ among classes; vigilance for hypotension, bradycardia, and QT prolongation is essential.
• Drug interactions, especially involving CYP450 enzymes, can significantly alter therapeutic outcomes and safety.
• Special populations—pregnant patients, the elderly, and those with organ impairment—require tailored regimens and close monitoring.
• Refractory angina may benefit from metabolic modulators such as ranolazine and trimetazidine, yet their use should be reserved for patients inadequately controlled by conventional therapy.

By integrating pharmacodynamic insights with clinical pharmacokinetic principles, prescribers can optimize antianginal therapy, balancing efficacy with safety across diverse patient populations.

References

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