Calcium channel blockers Or Calcium antagonists

1. Calcium channel blockers Or Calcium antagonists

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

3. CCBs bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents and inphase 0 of the action potentials.

4. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), - decreased myocardial force generation (negative inotropy),- decreased heart rate (negative chronotropy), - decreased conduction velocity within the heart(negative dromotropy), particularly at the atrioventricular node.

5. 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

6. Classification • Benzothiazepines: diltiazem (t1/2 6hrs) • Phenylalkamines: verapamil(t1/24hrs) • Dihydropyridines: amlodipine (30-50 hrs) nicardipine (2-6hrs) nifedipine nimodipine Dr. ELLITHEY

7. Calcium Channel Blockers • VerapamilVery ( Cardioselective) • Nifedipine - HTN Nice (vascular sm muscle selective) • Diltiazem - arrythmiasDrugs (intermediate selectivity)

8. Protein BindING BA Dose 40-160mg TDS Amlodipine >95% 60-65% Nifedipine 95% 30-60% 5-20mg BD Diltiazem ~80% 40-60% 30-60mg tds Verapamil 90% 15-30% 40-160mg TDS MEDC 604 Anti-anginals

9. Verapamil is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias.Diltiazemis intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines

10. dihydropyridines They block calcium influx through voltage- dependant calcium channels in the smooth muscles. They dilate coronaries and peripheral arteries and reduce heart afterload.

11. Dihydropyridines reduce coronary and peripheral vascular resistance, decrease blood pressure and myocardial oxygen consumption. But they don’t have negative inotropic, chrono-tropic and dromotropic effect in comparison to verapamil and diltiazem, which increase baroreflex sensibility.

12. Uses

13. HypertensionBy causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects on venous capacitance vessels.

14. AnginaThe anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload , thereby decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem) decrease heart rate and contractility, which leads to a reduction in myocardial oxygen demand.CCBs can also dilate coronary arteries and prevent or reverse coronary vasospasm (as occurs in Printzmetal's variant angina), thereby increasing oxygen supply to the myocardium.

15. dihydropyridines They are not, however, generally used to treat angina because their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can dramatically increase myocardial oxygen demand. 

16. ArrhythmiasThe antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to decrease the firing rate of pacemaker sites within the heart, but more importantly are related to their ability to decrease conduction velocity and prolong repolarization, especially at the atrioventricular node. This latter action at the atrioventricular node helps to block reentrymechanisms, which can cause supraventricular tachycardia.

17. Class IVantiarrhythmic drugs Mainlyverapamil (p. o./i. v.) and diltiazem (only i.v.) hasspecific action on SA and AVnode (they shorten AP) ARs: headache, ankle swelling, bradycardia, AV block, negative inotropic effect (decreasing cardiac contractility) Indications: SV tachyar- rhythmias

18.  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 •  SVtachyarrhythmias: Verapamil, Diltiazem (i.v.) •  Migraine (in remission periods) • Flunarizine, Verapamil Main indications Beta-blockers + dihydropyridines: YES (OK) Beta-blockers + Verapamil orDiltiazem = NO

19. . C/I The cardiac selective, non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction (e.g., atrioventricular nodal block), and depressed contractility. Therefore, patients having preexistent bradycardia, conduction defects, or heart failure caused by systolic dysfunction should not be given CCBs, they should not be administered to patients being treated with a beta-blocker because beta-blockers also depress cardiac electrical and mechanical activity and therefore the addition of a CCB augments the effects of beta-blockade

20. 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 ) • Haemorrhagic gingivitis

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