Calcium antagonists(Summary)

Dr Ivan Lambev(itlambev@mail.bg)

Calcium antagonists(calcium channel blockers)

They block calcium influx through voltage-dependant calcium channels in the smoothmuscles. They dilatecoronaries andperipheral arteriesand reduceheart afterload.

VDCC ROCC

Receptor

AP

Ca2+

Ca2+

Sarcoplasmaticreticulum

Cellwall

NA

(–)

Calciumantagonists

AP – action potential, NA – noradrenalineVDCC – voltage-dependent calcium channelsROCC – receptor operating calcium channels

Regulation of intracellular calcium

In the cell membranes there are three types of calcium channels: Voltage-dependent (L, N, O, P, Q, R, T) Receptor operating Stretch activated

Calcium antagonists block predominantly L-typecalcium channels, localized in the myocardiumand myocytesof bloodvessels.L-type channelsare connectedto the plateauof the AP.

Plateau phase of AP

Calcium antagonists reduce coronary and peripheral vascular resistance, decreaseblood pressure and myocardial oxygenconsumption.

Dihydropyridines (nifedipine, amlodipine,etc) don’t have cardionegative inotropic, chronotropic, and dromotropic effect incomparison with verapamil and diltiazem.

Dihydropyridines ● Norm frequent (with normal heart rate) and24-hours long effect: Amlodipine, Felodipine ● Other dihydropyridines produce tachycardia (increase baroreflex sensibility): Isradipine, Lacidipine, Nicardipine, Nifedipine, Nisoldipine, Nitrendipine ● cerebral vasodilators (Nimodipine) Phenylalkylamines: Verapamil Benzotiazepines: Diltiazem Flunarizine type (cerebral vasodilators) Cinnarizine, Flunarizine

Arterial hypertensiona) Dihydropyridinesb) Verapamil and Diltiazem

Coronary heart diseasea) Dihydropyridinesb) Verapamil and Diltiazem

Ischemic cerebral strokeCinnarizine, Flunarizine, Nimodipine

SV tachyarrhythmias: Verapamil, Diltiazem (i.v.) Migraine (in remission periods)

Flunarizine, Verapamil

Beta-blockers + dihydropyridines: YES (OK)Beta-blockers + Verapamil or Diltiazem = NO

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Amlodipine norm frequent dihydropyridinet1/2 31–47 h, 55–91% p.o. bioavailability5–10 mg/24 h p.o. (once daily)

Nifedipine (tachycardia!)– effective in vasospastic angina

Diltiazem (in SR dosage forms)Verapamil (Isoptin SR® – tabl. 240 mg)

(22% p.o. bioаvailability, first pass effect –extensive liver metabolism)

Class IV antiarrhythmic drugs

Indications: SV tachyar- rhythmias

ARs: headache, ankle swelling,bradycardia, AV block, negativeinotropic effect (decreasingcardiac contractility)

Mainly verapamil (p. o./i. v.) and diltiazem (only i.v.) has specific action on ..the… SA and AV node (they shorten AP)

Atrial flutter with a 4:1 conduction ratio.

ARs of calcium antagonists•Arterial dilation: headache, flush, dizziness,ankle swelling (resistant to treatment with diuretics but not with ACE inhibitors).•Bradycardia and AV block (verapamil).•Verapamil + beta-blockers: potentiate cardiodepression.•Tachycardia (nifedipine, nisoldipine).•Constipation (verapamil 8%; nifedipine 3%)•Haemorrhagic gingivitis