CCBs and Nitrates

Calcium channel blockers (CCBs) are a chemically and pharmacologically heterogeneous class of drugs that share a common property: they antagonise Ca2+ movement across cell membranes by blocking voltage-gated L-type calcium channels (LTCC blockers). L-type channels are abundant in cardiac and vascular smooth muscle and are responsible for the plateau phase of cardiac action potentials. T-type channels are found on neurons and pacemaker cells.

Three CCB subtypes exist with distinct tissue selectivities: dihydropyridines (e.g. amlodipine) are vasoselective — preferentially block L-type channels on arterial smooth muscle; phenylalkylamines (e.g. verapamil) are cardioselective — preferentially act on cardiac muscle; benzothiazipines (e.g. diltiazem) are also cardioselective. This selectivity arises from different binding sites on the Ca2+ channel and different channel state preferences.

Pharmacological effects of CCBs: vasodilation of peripheral arterioles (reduced TPR/afterload); reduced cardiac contractility (negative inotropy); decreased SA node rate (negative chronotropy); slowed AV conduction (negative dromotropy). Veins lack voltage-gated L-type Ca2+ channels; therefore CCBs do not affect preload.

Amlodipine: binds and stabilises the inactivated state of L-type Ca2+ channels. Arterial SM channels exist more frequently in the inactivated state (longer depolarisations than cardiac muscle); arterial SM channels also have a slightly different alpha-1 subunit structure. PK: once-daily oral; slow onset (peak 6-12h); Css achieved in ~7 days; hepatic CYP3A4 metabolism; renal impairment has little effect; hepatic impairment requires dose reduction. Indications: HTN, angina. ADRs: peripheral oedema.

Verapamil: binds open L-type Ca2+ channels; slows recovery from inactivation; cardioselective. Rapid oral absorption but extensive first-pass CYP3A4 metabolism; IV route bypasses first-pass. Indications: angina, HTN, AF rate control, arrhythmias. Contraindications: heart failure, combination with beta-blockers (profound cardiac depression), bradycardias, conduction defects.

Diltiazem: same MOA as verapamil. CYP3A4 and P-gp inhibitor — affected by drugs modifying these (e.g. erythromycin increases diltiazem levels; carbamazepine decreases). Indications: AF rate control, angina, vasospasm. Contraindications: heart failure, combination with beta-blockers.

CCB ADRs: hypotension, bradycardia, AV block, heart failure (excessive doses); facial flushing, constipation (smooth muscle relaxation). Avoid verapamil/diltiazem with beta-blockers.

Nitrodilators mimic the vasodilatory actions of endogenous NO by releasing NO in plasma or forming NO within cells. NO → guanylate cyclase → cGMP → PKG → smooth muscle relaxation (Ca2+ efflux via SERCA). cGMP is terminated by PDE5 (phosphodiesterase isoform specific for cGMP). Sildenafil (PDE5 inhibitor) is absolutely contraindicated with nitrates — profound and potentially fatal hypotension.

Primary actions: venous dilation → reduced preload → decreased diastolic wall stress → improved subendocardial blood flow; arterial dilation → reduced afterload → enhanced CO while reducing wall stress and O2 demand.

Glyceryl trinitrate (GTN/nitroglycerin): short-acting; sublingual spray or tablet; avoids first-pass metabolism; effective within 2-5 min; lasts ~30 min. Isosorbide mononitrate/dinitrate: long-acting; oral; ~100% bioavailability; T½ 2-6h; used for prophylaxis. Nitrate tolerance develops with frequent dosing — requires nitrate-free intervals. Avoid abrupt withdrawal after prolonged use (rebound angina).