calcium channel blocker

calcium channel blocker

1. CCB Late BRKM GMCJ

2. Verapamil was developed in Germany in 1962 as a coronary dilator. It had additional cardiodepressant property, but its mechanism of action was not known. Three important classes of calcium channel blockers are examplified by: Verapamil—a phenyl alkylamine , hydrophilic papaverine congener. Nifedipine—a dihydropyridine (lipophilic). Diltiazem—a hydrophilic benzothiazepine. The dihydropyridines (DHPs) are the most potent Ca2+ channel blockers, and this subclass has proliferated exceptionally

3. Calcium channels Voltage sensitive channel: Activated when membrane potential drops to around –40 mV or lower. Receptor operated channel: Activated by Adr and other agonists—independent of membrane depolarization (NA contracts even depolarized aortic smooth muscle by promoting influx of Ca2+ through this channel and releasing Ca2+ from sarcoplasmic reticulum). Leak channel: Small amounts of Ca2+ leak into the resting cell and are pumped out by Ca2+ATPase. Mechanical stretch promotes inward movement of Ca2+, through the leak channel or through separate stretch sensitive channel.

4. DHPs are the most commonly used calcium channel blockers (CCBs). The cardiac and smooth muscles cell contraction depends upon the activation of calcium channels in the cardiac myocytes. For depolarization of cardiac and other smooth muscles cells, entry of calcium into the cells occurs through these calcium channels. CCBs inhibit the movement of calcium ions across the membranes of myocardial and arterial muscle cells, altering the action potential and blocking muscle cell contraction.

5. A loss of smooth muscle tone, vasodilation, and decreased peripheral resistance occurs. Subsequently, preload and afterload are decreased, which in turn decreases cardiac workload and oxygen consumption. Short acting DHPs like nifedipine causes reflex tachycardia and palpitations, which can be controlled and minimized by addition of a beta-blocker or giving sustained release preparations.

6. CCB Phenyl alkylamine : Verapamil Benzothiazepine: Diltiazem Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine , Lercanidipine, Benidipine

7. Comparative action of CCBs (DHPs & non-DHPs)

8. MECHANISM OF ACTION OF CCBs

9. Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

10. N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons

11. Skeletal muscle relies on intracellular Ca2+ for contraction

12. Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells

13. Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction

14. CCBs Act Selectively on Cardiovascular Tissues Neurons rely on N-and P-type Ca2+ channels Skeletal muscle relies primarily on [Ca] Cardiac muscle requires Ca2+ influx through L-type Ca2+ channels contraction (fast response cells) upstroke of AP (slow response cells) Vascular smooth muscle requires Ca2+ influx through L-type Ca2+ channels for contraction

15. Differential effects of different CCBs on CV cells

16. Hemodynamic Effects of CCBs

17. CCBs: Pharmacokinetics

18. THERAPEUTIC USES OF CCBs  Hypertension : Long acting CCBs are used for the long term treatment of hypertension. Amlodipine is the most preferred drug. Ischemic heart disease : Angina pectoris : DHPs like amlodopine with beta-blocker are used for long term management. Verapamil and diltiazem are used for prophylaxis. Vasospastic angina: Verapamil and amlodopine are the preffered agents. Unstable angina: Verapamil is used.

19. Supraventricular arrhythmia: verapamil & diltiazem are used due to their antiarrythmic properties. Peripheral vascular disease: Nifedipine, felodipine and diltiazem are used for this purpose. Nifedipine patches are also useful. Migraine prophylaxis: verapamil is useful. Nocturnal leg cramps: verapamil is useful.

20. ADVERSE EFFECTS Verapamil causes Nausea, constipation, bradycardia, aggravation of conduction defects . Ditiazem also has similar side effect profile but slightly to lesser extent. DHPs show side effects like nausea, headache, drowsiness palpitation, hypotension, flushing and ankle edema. Difficulty in micturation & worsening of gastroesophageal reflux is seen in elderly patients.

21. Comparative Adverse Effects

22. Contradication’s for CCBs

23. Drug Dose Special features Nifedipine 5-20mg BD Has fast onset of action with short duration. Causes reflex tachycardia as a prominent side effects. May increase frequency of angina attack. Amlodipine 5-10mg OD Has got consistent & good oral bioavailability. Diurnal fluctuation of BP are least. s-Amlodipine is its enatiomer and equally effective at half the dose with less ankle oedema . Felodipine 5-10mg OD Has higher vascular selectivity. Nitrendipine 5-20mg OD Has only 10-30% of bioavailabilty . Additionally also releases nitric oxide from the endothelium Useful in hypertension with angina. Nimodipine 30-60mg QID It is cerebrovascular selective due to high lipid solubility & BBB penetration. Used in patients with hemorrhagic stroke & subarachnoid hemorrhage. Lacidipine 4-6mg OD Has vasoselective activity and useful in hypertension only. Lercanidipine 10-20mg OD Long acting DHP. Useful in hypertension. Benidipine 4-8mg OD Long acting DHP. Has very slow dissociation from DHP receptors. Useful in hypertension & angina.