CVS Pharmacology: Antianginal Drugs

Introduction/Overview

Angina pectoris represents a clinical manifestation of myocardial ischemia, often precipitated by transient coronary artery luminal narrowing. The therapeutic objective of antianginal drugs is to ameliorate ischemic burden by modulating myocardial oxygen demand or by augmenting coronary perfusion. This chapter delineates the pharmacological foundations, therapeutic indications, and safety profiles of the principal antianginal agents employed in contemporary clinical practice. The intended audience comprises medical and pharmacy trainees seeking a comprehensive evidence‑based understanding of antianginal pharmacotherapy.

Learning objectives:

• Identify the major classes of antianginal medications and their chemical properties.
• Explain the mechanistic pathways through which these agents influence myocardial oxygen supply and demand.
• Summarize the pharmacokinetic characteristics guiding dosing regimens.
• Recognize the therapeutic indications, contraindications, and adverse effect profiles of each drug class.
• Apply knowledge of drug interactions and special populations to optimize patient care.

Classification

1. Vasodilators

• Short‑acting nitrates (e.g., nitroglycerin, isosorbide mononitrate)
• Long‑acting nitrates (e.g., isosorbide dinitrate, isosorbide hexanitrate)
• Phosphodiesterase‑5 inhibitors (e.g., sildenafil, vardenafil)

2. Beta‑Adrenergic Blockers

• Selective β1‑blockers (e.g., metoprolol, atenolol)
• Non‑selective β‑blockers (e.g., propranolol, nadolol)
• Beta‑blockers with intrinsic sympathomimetic activity (e.g., pindolol)

3. Calcium Channel Blockers

• L‑type calcium channel blockers – dihydropyridines (e.g., amlodipine, nifedipine)
• L‑type calcium channel blockers – non‑dihydropyridines (e.g., verapamil, diltiazem)

4. Anti‑arrhythmic and Anti‑arrhythmic‑like Agents

• Class II agents: beta‑blockers (already listed)
• Class IV agents: verapamil, diltiazem
• Others: ranolazine (late sodium current inhibitor)

5. Miscellaneous Agents

• Ranolazine – late sodium current inhibitor
• Nicorandil – nitric oxide donor and potassium channel opener
• Spironolactone – aldosterone antagonist with anti‑anginal effects in some studies

Mechanism of Action

Vasodilators

Short‑acting nitrates are metabolized to nitric oxide (NO), which activates guanylate cyclase in vascular smooth muscle cells, increasing cyclic guanosine monophosphate (cGMP). Elevated cGMP activates protein kinase G, leading to phosphorylation of myosin light‑chain phosphatase, causing relaxation of smooth muscle and venodilation. Venodilation reduces preload, thereby decreasing myocardial oxygen demand. Long‑acting nitrates exhibit similar pathways but have slower onset due to prodrug activation.

Phosphodiesterase‑5 inhibitors inhibit cGMP‑specific phosphodiesterase, prolonging cGMP action. By enhancing NO‑mediated vasodilation, they increase coronary blood flow, particularly in the subendocardial region.

Beta‑Adrenergic Blockers

Beta‑blockers competitively antagonize β1‑adrenergic receptors in myocardial tissue, attenuating catecholamine‑induced increases in heart rate, contractility, and myocardial oxygen consumption. Non‑selective β‑blockers also block β2 receptors, potentially causing bronchoconstriction. Intrinsic sympathomimetic activity partially preserves chronotropic responses while still reducing inotropy.

Calcium Channel Blockers

Both dihydropyridines and non‑dihydropyridines inhibit L‑type calcium channels in vascular smooth muscle and cardiac myocytes. Dihydropyridines preferentially cause arterial vasodilation by reducing intracellular calcium, decreasing systemic vascular resistance and afterload. Non‑dihydropyridines additionally reduce heart rate and contractility via myocardial calcium channel blockade, lowering oxygen demand.

Late Sodium Current Inhibitors

Ranolazine selectively inhibits late inward sodium currents in cardiac myocytes. This action reduces intracellular sodium and, subsequently, calcium overload via the sodium‑calcium exchanger. The resultant decrease in diastolic tension and improved myocardial relaxation enhances subendocardial perfusion.

Potassium Channel Openers and NO Donors

Nicorandil combines an NO donor with a potassium channel opener. NO increases cGMP and induces venous and arterial dilation; the opening of ATP‑sensitive potassium channels causes hyperpolarization of vascular smooth muscle, further promoting vasodilation.

Pharmacokinetics

Short‑acting Nitrates

Absorption occurs rapidly via sublingual or transdermal routes, with peak plasma concentrations within minutes. Bioavailability is approximately 20–30% due to first‑pass metabolism. Distribution is widespread, with a volume of distribution of ~20–30 L. Metabolism occurs primarily via nitrate reductase enzymes in the liver and plasma, leading to the formation of nitric oxide. Excretion is mainly renal; the half‑life ranges from 5 to 15 minutes, necessitating frequent dosing or continuous infusion for sustained effect.

Long‑acting Nitrates

These agents are prodrugs activated in vivo to release NO. Oral absorption is modest (bioavailability 30–40%) with a slower onset of action. Distribution volume is larger (≈50–60 L). Metabolism involves hepatic reduction to active metabolites. The terminal half‑life extends to 4–6 hours, allowing once or twice daily dosing.

Beta‑Blockers

Metoprolol: oral bioavailability 50–60%; high hepatic first‑pass metabolism via CYP2D6; half‑life ~6–7 hours. Atenolol: poor hepatic metabolism, primarily renal excretion; half‑life ~6–8 hours. Nadolol: minimal metabolism, half‑life ~20 hours. Propranolol: high bioavailability (~35–50%); extensive hepatic metabolism via CYP1A2, CYP2D6; half‑life ~3–4 hours. Intravenous formulations have different pharmacokinetics, with rapid distribution and a shorter half‑life.

Calcium Channel Blockers

Dihydropyridines (amlodipine): oral bioavailability ~60%, extensive first‑pass metabolism via CYP3A4; half‑life ~30–50 hours. Nifedipine: oral bioavailability ~10–20%, rapid onset, short half‑life (~2–3 hours). Non‑dihydropyridines (verapamil): oral bioavailability ~20–30%; hepatic metabolism via CYP3A4; half‑life ~5–6 hours. Diltiazem: oral bioavailability ~25%; hepatic metabolism via CYP3A4; half‑life ~3–9 hours.

Ranolazine

Oral bioavailability ~80–90%; extensive hepatic metabolism via CYP3A4 and CYP2D6; half‑life 6–8 hours. Steady‑state achieved after 2–3 days of dosing. Food increases absorption by ~25%.

Nicorandil

Oral bioavailability ~30%; hepatic metabolism; half‑life ~6–8 hours. Transdermal patch used in certain countries; provides continuous release.

Therapeutic Uses/Clinical Applications

Stable Angina

All drug classes are approved for the prevention of exertional chest pain in patients with stable coronary artery disease. Initial therapy typically involves a short‑acting nitrate for acute relief, followed by a long‑acting nitrate or beta‑blocker for maintenance. Calcium channel blockers are often reserved for patients intolerant to beta‑blockers or with contraindications such as asthma.

Unstable Angina and Acute Coronary Syndromes

Beta‑blockers, nitrates, and calcium channel blockers are components of guideline‑directed medical therapy (GDMT) in the acute setting, aiming to reduce myocardial oxygen demand and prevent arrhythmias. Ranolazine may be added in patients with refractory angina despite standard therapy.

Variant (Prinzmetal) Angina

Calcium channel blockers and nitrates reduce coronary vasospasm. Non‑selective β‑blockers are contraindicated as they may exacerbate spasm.

Angina in the Context of Comorbid Conditions

In patients with chronic obstructive pulmonary disease (COPD) or asthma, dihydropyridine calcium channel blockers are preferred over beta‑blockers due to the risk of bronchoconstriction. Conversely, in heart failure with reduced ejection fraction, beta‑blockers and ACE inhibitors are favored for mortality benefit.

Adverse Effects

Short‑acting Nitrates

• Headache (most common)
• Hypotension and reflex tachycardia
• Tolerance development with continuous use

Long‑acting Nitrates

• Headache, dizziness, flushing
• Hypotension, tachycardia
• Tolerance, which may be mitigated by nitrate‑free intervals

Beta‑Blockers

• Bradycardia, hypotension, fatigue
• Bronchospasm (non‑selective agents)
• Metabolic effects: hyperglycemia, lipid alterations (especially atenolol)
• Sleep disturbances, depression (rare)

Calcium Channel Blockers

• Dihydropyridines: peripheral edema, flushing, constipation, reflex tachycardia
• Non‑dihydropyridines: bradycardia, AV block, constipation, constipation, dizziness
• Drug interactions via CYP3A4 inhibition/induction

Ranolazine

• Constipation, dizziness, nausea, headache
• QT prolongation (rare but requires monitoring)

Nicorandil

• Headache, flushing, hypotension
• Rare cases of pseudo‑aneurysm formation at the site of injection (transdermal)

Black Box Warnings

• No specific black box warnings for nitrates; however, caution is advised in patients on phosphodiesterase‑5 inhibitors due to risk of profound hypotension.
• Ranolazine: QT prolongation; use only in patients without pre‑existing repolarization abnormalities.
• Beta‑blockers: caution in patients with severe heart failure, bradyarrhythmias, and severe peripheral vascular disease.

Drug Interactions

Nitrates and Phosphodiesterase‑5 Inhibitors

Concurrent use can precipitate severe, potentially life‑threatening hypotension. Patients should be advised to avoid sildenafil, tadalafil, or vardenafil while on nitrates.

Beta‑Blockers and Calcium Channel Blockers

Combined blockade of heart rate and conduction may lead to profound bradycardia or AV block. Monitoring of ECG is recommended when initiating or adjusting doses.

Calcium Channel Blockers and CYP3A4 Inhibitors/Inducers

Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase plasma concentrations of dihydropyridines, heightening the risk of hypotension and edema. Inducers (e.g., rifampin, carbamazepine) decrease efficacy of these agents.

Ranolazine and CYP3A4 Inhibitors

Inhibition of CYP3A4 can elevate ranolazine levels, increasing risk of QT prolongation. Dose adjustment may be necessary.

Beta‑Blockers and CNS Depressants

Combination with opioids, benzodiazepines, or alcohol may amplify bradycardic and hypotensive effects.

Contraindications

• Beta‑blockers: acute asthma, severe COPD, second‑ or third‑degree AV block, cardiogenic shock.
• Non‑dihydropyridines: severe sinus bradycardia, second‑degree AV block (Mobitz type II).
• Nitrates: concurrent phosphodiesterase‑5 inhibitor use.
• Calcium channel blockers: untreated severe hypertension if combined with nitrates.

Special Considerations

Pregnancy and Lactation

Data are limited; most antianginal agents are categorized as pregnancy category C or D. Nitrates and beta‑blockers cross the placenta and may affect fetal cardiac function. Use is generally reserved for life‑threatening maternal ischemia. Lactation: most agents are excreted into breast milk in low concentrations; however, caution is advised, especially with beta‑blockers due to potential neonatal bradycardia.

Pediatric Considerations

Use of beta‑blockers and calcium channel blockers is occasionally employed in pediatric patients with refractory angina, but evidence is sparse. Nitrates are generally avoided in children due to risk of hypotension and headache. Off‑label use should involve careful dose titration and monitoring.

Geriatric Considerations

Elderly patients are more susceptible to orthostatic hypotension, especially with nitrates and dihydropyridines. Polypharmacy increases interaction risk; thus, drug selection should prioritize safety and tolerability. Dose adjustments may be required based on renal and hepatic function.

Renal Impairment

Metoprolol and atenolol are primarily renally excreted; dose reduction is warranted in moderate to severe renal impairment. Nitrates are mainly metabolized hepatically; however, accumulation can occur in severe renal disease, necessitating cautious use.

Hepatic Impairment

Beta‑blockers with extensive hepatic metabolism (e.g., propranolol) require dose reduction or avoidance in significant liver dysfunction. Amiodarone and other drugs with hepatotoxic potential should be monitored closely when combined with calcium channel blockers.

Summary/Key Points

• Antianginal therapy is tailored to balance myocardial oxygen supply with demand, employing nitrates, beta‑blockers, calcium channel blockers, or ranolazine as first‑line agents.
• Nitrates primarily reduce preload via venodilation; beta‑blockers decrease heart rate and contractility, thereby lowering oxygen consumption.
• Calcium channel blockers offer vasodilatory and negative chronotropic effects, with dihydropyridines favoring arterial dilation and non‑dihydropyridines providing myocardial depressant actions.
• Ranolazine and nicorandil provide adjunctive benefit in refractory angina by targeting late sodium currents or opening potassium channels, respectively.
• Drug interactions, especially between nitrates and phosphodiesterase‑5 inhibitors, must be meticulously avoided to prevent catastrophic hypotension.
• Special populations (pregnant, elderly, renal/hepatic impairment) necessitate dose adjustments and vigilant monitoring.
• Clinical decision‑making should integrate patient comorbidities, tolerability, and pharmacodynamic profiles to optimize antianginal outcomes.

References

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