2. Calcium antagonists (Summary) Dr Ivan Lambev (itlambev@mail.bg)

3. Calcium antagonists (calcium channel blockers) They block calcium influx through voltage- dependant calcium channels in the smooth muscles. They dilate coronaries and peripheral arteries and reduce heart afterload.

4. VDCC ROCC Receptor AP Ca 2+ Sarcoplasmatic reticulum Cell wall NA (–) Calcium antagonists AP – action potential, NA – noradrenaline VDCC – voltage-dependent calcium channels ROCC – receptor operating calcium channels

5. Regulation of intracelullular calcium

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

7. Calcium antagonists block predominantly L-type calcium channels, localized in myocardium and myocytes of blood vessels. L-type channels are connected to the plateau of the AP. Plateau phase of AP

8. Calcium antagonists reduce coronary and peripheral vascular resistance, decrease blood pressure and myocardial oxygen consumption. Dihydropyridines (nifedipine, amlodipine etc) don’t have negative inotropic, chrono- tropic and dromotropic effect in comparison to verapamil and diltiazem, which increase baroreflex sensibility.

9.  Dihydropyridines ● Norm frequent (with normal heart rate) and 24-hours long effect: Amlodipine, Felodipine ● Other dihydropyridines produce tachycardia (increase baroreflex sensibility): Isradipine, Lacidipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine  Phenylalkylamines: Verapamil SR  Benzotiazepines: Diltiazem SR  Flunarizine type Cinnarizine, Flunarizine

10.  Arterial hypertension a) Dihydropyridines b) Verapamil SR and Diltiazem SR  Coronary heart disease a) Dihydropyridines b) Verapamil SR and Diltiazem SR  Ischemic cerebral stroke Cinnarizine, 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 Main indications

11. Calcium antagonists Amlodipine norm frequent dihydropyridine t 1/2 31–47 h, 55–91% p.o. bioavailability 5–10 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)

12. Class IV antiarrhythmic drugs  Mainly verapamil (p. o./i. v.) and diltiazem (only i.v.) has specific action on SA and AV node (they shorten AP)  Indications: SV tachyar- rhythmias ARs: headache, ankle swelling, bradycardia, AV block, negative inotropic effect (decreasing cardiac contractility)

13. Atrial flutter with a 4:1 conduction ratio.

14. 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