Calcium Channel Blocking Drugs

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

Three Classes of CCBs Chemical Type Chemical Names Brand Names Phenylalkylamines verapamil Calan, Calna SR, Isoptin SR, Verelan Benzothiazepines diltiazem Cardizem CD, Dilacor XR 1,4-Dihydropyridines Nifedipine   nicardipine isradipine felodipine amlodipine Adalat CC, Procardia XL Cardene DynaCirc Plendil Norvasc

Three Classes of CCBs Verapamil Nifedipine Diltiazem H3C CH3 H3C CH3 CH3 CH CH3 H3C C CH2 CH2 CH2 N CH2 CH2 CH3 C N Verapamil NO2 CH3 S N CH2 CH2 N CH3 H3C C C CH3 C CH3 H3C CH3 N H CH3 Nifedipine Diltiazem

Widespread use of CCBs Angina pectoris Hypertension Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit III IV II I 5 6 Out In I II III IV

The expression and function of the 1C subunit is modulated by other smaller subunits NH3+ COO- b a1C a2 I II III IV d L-Type Ca2+ Channel

The Three Classes of CCBs Bind to Different Sites 1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Ca2+ pore - +

CCBs – Mechanisms of Action Increase the time that Ca2+ channels are closed Relaxation of the arterial smooth muscle but not much effect on venous smooth muscle Significant reduction in afterload but not preload

The different binding sites of CCBs result in differing pharmacological effects Voltage-dependent binding (targets smooth muscle) Use-dependent binding (targets cardiac cells) Cell membrane 1  out in  +20 -80 mV 2  Diltiazem Verapamil -30 Nifedipine

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell

Skeletal muscle relies on intracellular Ca2+ for contraction Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of Triad T

Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells Contractile Cells (atria, ventricle) L-Type Ca2+ Slow Response Cells (SA node, AV node)

Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction (graded, Ca2+ dependent contraction) L-Type Ca2+

CCBs Act Selectively on Cardiovascular Tissues Neurons rely on N-and P-type Ca2+ channels Skeletal muscle relies primarily on [Ca]i 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

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

The different binding sites of CCBs result in differing pharmacological effects Voltage-dependent binding (targets smooth muscle) Use-dependent binding (targets cardiac cells) Cell membrane 1  out in  +20 -80 mV 2  Diltiazem Verapamil -30 Nifedipine

Non -dihydropyridines: equipotent for cardiac tissue and vasculature Differential effects of different CCBs on CV cells Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Peripheral vasodilation Heart rate moderating Peripheral and coronary vasodilation SN AV Potential reflex increase in HR, myocardial contractility and O2 demand Coronary VD SN AV Reduced inotropism

Hemodynamic Effects of CCBs Verapamil Diltiazem Nifedipine Peripheral vasodilatation    Coronary vasodilatation    Preload 0/ Afterload    Contractility  0/ / * Heart rate 0/  /0 AV conduction  

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

CCBs: Pharmacokinetics Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination Half-Life (h) Verapamil >90 10-35 83-92 2.8-6.3* Diltiazem >90 41-67 77-80 3.5-7 Nifedipine >90 45-86 92-98 1.9-5.8 Nicardipine -100 35 >95 2-4 Isradipine >90 15-24 >95 8-9 Felodipine -100 20 >99 11-16 Amlodipine >90 64-90 97-99 30-50

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

Caution w/beta blockers Comparative Adverse Effects   Diltiazem Verapamil Dihydropyridines Overall 0-3% 10-14% 9-39% Hypotension ++ +++ Headaches + Peripheral Edema Constipation CHF (Worsen) AV block Caution w/beta blockers

CCBs - Monitoring heart rate blood pressure anginal symptoms signs of CHF adverse effects

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + + AV conduction defects ++ ++ Severe cardiac failure ++ + +

Outline Introduction Pharmacokinetics CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

Which CCB is most likely to cause hypotension and reflex tachycardia? Diltiazem Nifedipine Verapamil

Contraindications for CCBs include (choose all appropriate): Supraventricular tachycardias Hypotension AV heart block Hypertension Congestive heart failure

CCBs may improve cardiac function by: Reducing cardiac afterload Increasing O2 supply Decreasing cardiac preload Normalizing heart rate in patients with supraventricular tachycardias

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