Pharmacology of Calcium Channel Blockers

includes the classification of CCB,
individual CCBs , their actions ,kinetics , ADR and Uses

1. Calcium Channel Blockers

2. Overview Introduction Calcium channels types Classification Pharmacological actions Individual CCBs PKS ADRs Uses

3. Calcium Channel -4 types

4. Calcium channels-voltage gated L -type T -type N-type Long lasting current / slow channels Most common Transient current /fast channel present in neurons& endocrine cells neurons Cardiac , smooth muscle, endocrine cells, neurons CCBs Blocked by ethosuxmide , flunarizine Neurotransmitter release

5. L type voltage gated calcium channel

6. Pharmacological actions Common property smooth muscle -vascular relaxation negative chronotropic, inotropic and dromotropic action on heart Verapamil- cardioselective DHP-vascular smooth muscle Diltiazem -intermediate

7. Pharmacological actions &MOAs Smooth muscle Ca2+ trigger release Ca2+ (IC) enters CCB Voltage sensitive L channel phosphorylation of MLC SM depolarized excitation –contraction coupling Relax arterioles more SM -Bronchial, biliary,intestinal , vesical,uterine

8. Pharmacological actions &MOA Heart heart rate contractility AV node- conduction velocity Coronary artery dilator Redn in peripheral vascular resistance(decrease in afterload)

9. Comparison of CCBs Verapamil nifedipine diltiazem

10. Phenyl alkylamine- Verapamil Prominent cardiac depressant action negative inotropic effects AV conduction depressed Bradycardia Vasodilator effect less- fall in BP less Coronary flow increased ADR- constipation Bradycardia, nausea Flushing,headache , ankle odema less Accentuate cardiac defects DI-Beta blockers Digitalis quinine

11. Benzothiazepine- Diltiazem Less potent vasodilator Modest direct negative inotropic action Depression of SA & AV node similar to verapamil Dilates coronaries ADR = verapamil Increase plasma digoxin levels CI- preexisting sinus, AV nodal, myocardial disease Low dose with beta blockers

12. Dihydropyridines (DHPs) All DHP –same PD profile Different in PKs Slower & long acting DHPs prefered

13. DHP- Nifedipine

14. DHP- ADRs Palpitation ,flushing ,ankle oedema Hypotension, headache, drowsiness ,nausea Nifedipine frequency of angina high mortality post MI pts Voiding difficulty in elderly GERD worsened GUM HYPERPLASIA-CCBS

15. DHPs -Amlodipine Most popular Oral absorption slow , complete Oral bioavailability higher & consistent Large volume of distribution T1/2 long

16. DHPs-Cilnidipine Inhibit N type neuronal channel also No reflex tachycardia Use – angina hypertension

17. Other DHPs felodipine Nitrendipine Lacidipine nimodipine Greater vascular selectivity Release NO from endothelium (retard atherosclerosis) Inhibit phosphodiesterase vasoselective Short acting Crosses BBB High affinity for cerebral bld vessels T1/2 22-24 hrs OD dose Ventricular contractility & AV conduction not depressed Retard progression of atherosclerosis Relax cerebral vasculature HTN Raynauds disease HTN , angina pectoris HTN Prevention & treatment of neurological deficit

18. Other DHPs Nicardipine Lercanidipine Benidipine Highly vasoselective Pronounced coronary & cerebral vasodilatation Long duration of action Long duration of action Angina & HTN IV use in hypertensive emergency HTN HTN

19. CCB- pharmacokinetics Well absorbed orally High 1 st pass metabolism High protein binding Extensive tissue distribution Active metabolite –verapamil , diltiazem Verapamil –c/c use inhibits its own metabolism oral bioavailability doubled , t1/2 prolonged Amlodipine 1 st pass metabolism less

20. Uses of CCBs Angina pectoris classical & variant angina Hypertension long acting DHP , verapamil, diltiazem Cardiac arrhythmias Verapamil, Diltiazem Hypertrophic cardiomyopathy Verapamil Other uses Premature labour & Raynauds episodes Avoid in pts with HF & low EF Amlodipine safe