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Calcium Channel Blockers

This document discusses calcium channel blockers (CCBs), including their mechanism of action, classification, therapeutic uses, adverse effects, and drug interactions. CCBs work by blocking calcium channels, leading to vasodilation and reduced heart rate and contractility. They are classified into dihydropyridines, benzothiazepines, and phenylalkylamines. Common uses include hypertension, angina, and arrhythmias. Side effects reflect their pharmacological actions and include flushing, constipation, and bradycardia. CCBs can interact dangerously with beta blockers due to combined cardio-depressant effects.

Health & Medicine◦
Dr Htet Htet MBBS, MMedSc (Pharmacology) CVS Pharmacology (I) Calcium channel blockers
Learning objectives • At the end of the lecture, students should be able to • Classify calcium channel blockers. • Describe • mechanism of action • pharmacological action • therapeutic uses • adverse effects • drug interactions • pharmacokinetics of calcium channel blockers.
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Normal physiological role of calcium channels in vessels L type calcium channel Calcium + calmodulin MLCK MLCK-P MLCK MLCK Actin- myosin cross bridge
Normal physiological role of calcium channels in heart
Calcium channel blockers • Effects – on vessels & heart • Nitrates – mainly venodilator • CCB – arterial dilator
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Mechanism of action of CCB • In vascular smooth muscles, • Entry of Ca2+ through L-type calcium channels lead to activation of myosin light chain kinase, which then leads to phosphorylation of light chain myosin, finally resulting actin-myosin cross bridging – and contraction of vascular smooth muscle – resulting in vasoconstriction. • CCB blocks calcium channels – resulting – vasodilation – predominantly arteriolar smooth muscle. • In cardiac myocytes, •  calcium entry through L-type calcium channels – leads to decrease in myocardial contractility, SA node pace maker rate, AV conduction velocity.
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Pharmacological action/effects on organs of CCBs • Effects on vascular smooth muscle • Vasodilation of systemic arterial smooth muscle →  systemic blood pressure • Vasodilation of coronary arterial smooth muscle →  blood supply to cardiac muscles. • Cardiac muscle • SA node → rate of nodal discharge • AV node → AV conduction •  heart rate •  myocardial contractility • conduction
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Classification of CCBs 1. Dihydropyridines (Nifedipine, amlodipine, felodipine, clevidipine) 2. Benzothiazepines (diltiazem) 3. Phenylalkylamines (verapamil) antidysrhythmic antihypertensive Antianginal Generally
Overall Therapeutic uses of different CCBs 1. Systemic hypertension 2. Arrhythmia 3. Angina.
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Status of different CCB in different conditions • Dihypyridine group • Nifedipine, amlodipine – significantly more arteriolar vasodilation, little effect on cardiac tissue. More used in systemic hypertension. Nifedipine has more vasodilation effect which can even lead to reflex tachycardia – and can precipitate angina (coronay steal syndrome). • Amlodipine is more useful – antihypertensive agent. • Celvidipine – recently approved – only IVI – management of hypertensive emergency.
Status of different CCB in different conditions • Verapamil & Diltiazem • Have more effect on heart than in vascular smooth muscle. • Causes decrease automaticity of heart, decrease conduction velocity, decrease contractility. • Useful for arrhythmia & angina (due to cardiac depressant action.)
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Pharmacokinetics of CCBs • Absorption – typically oral form, but verapamil & diltiazem – also have IV formulation. nifedipine, verapamil & diltiazem – all possess significant first pass metabolism. • Metabolism & excretion – nifedipine & verapamil – excreted by kidney. verapamil – excreted by liver.
Amlodipine or nifedipine? Amlodipine Nifedipine Bioavailability Higher Lower Onset of action Slow Rapid Chance of reflex tachycardia Less Higher chance Plasma half life Longer (about 40 hrs) Shorter Dosing Once a daily dosing Frequent dosing But extended release/slow release formulation available.
Coronary steal syndrome by nifedipine • Rapid onset of action <20 min • Produces brisk precipitous fall in BP • Drug induced hypotension – can activate severe reflex tachycardia,which can worsen the myocardial ischaemia by increasing the myocardial oxygen demand and decrease myocardial oxygen demand (by decreasing the diastolic oxygen filling time)
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Therapeutic uses of verapamil & Diltiazem 1. Exertional angina , Unstable angina , Angina due to coronary spasm (Prinzmetal angina or variant angina) 2. Systemic Hypertension 3. Atrial fibrillation, flutter , Paroxysmal supraventricular tachycardia.
Therapeutic uses of DHP groups 1. Exertional angina , Unstable angina , Coronary spasm 2. Hypertension 3. Raynaud’s phenomenon 4. Pre-eclampsia.
Other therapeutic uses of CCBs • Cerebral vasospasm and infarct following subarachnoid haemorrhage • Nicardipine • High affinity for cerebral vessels • Reduce morbidity after SAH • IVI or intraarterial infusion to prevent cerebral vasospasm associated with stroke. • Uterine relaxant • To prevent premature labor
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Adverse effects • Extension of pharmacological actions. • Flushing (common with nifedipine) • Constipation (common with verapamil – excessive smooth muscle relaxation in GI smooth muscle) • Bradycardia, atrioventricular block, heart failure (extension of negative chronotropic and inotropic effects).
Learning outline 1. Normal physiological role of calcium channels ‘ 2. Mechanism of action of CCB 3. Pharmacological actions 4. Classification 5. Status of CCB indifferent clinical conditions 6. Pharmacokinetics 7. Therapeutic uses 8. Adverse effects 9. Drug interactions
Drug interaction • CCB + beta receptor blockers – cardio-depressant action, dangerous combination.
References