Calcium Channel Blocking Drugs

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

Introduction

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

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

Angina pectoris

Hypertension

Treatment of supraventricular

arrhythmias

- Atrial Flutter

- Atrial Fibrillation

- Paroxysmal SVT

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

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

The Three Classes of CCBs Bind to Different Sites 1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Ca 2+ pore - - - - + + -

Increase the time that Ca 2+ channels are closed Relaxation of the arterial smooth muscle but not much effect on venous smooth muscle Significant reduction in afterload but not preload CCBs – Mechanisms of Action

Increase the time that Ca 2+ channels are closed

Relaxation of the arterial smooth muscle but not

much effect on venous smooth muscle

Significant reduction in afterload but not preload

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

Introduction

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 Ca 2+ channels mediate neurotransmitter release in neurons postsynaptic cell Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+

Skeletal muscle relies on intracellular Ca 2+ for contraction Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of SR Triad T SR

Cardiac cells rely on L-type Ca 2+ channels for contraction and for the upstroke of the AP in slow response cells Contractile Cells (atria, ventricle) L-Type Ca 2+ Ca 2+ Ca 2+ Slow Response Cells (SA node, AV node) L-Type Ca 2+ Ca 2+

Vascular smooth muscle relies on Ca 2+ influx through L-type Ca 2+ channels for contraction (graded, Ca 2+ dependent contraction) L-Type Ca 2+

CCBs Act Selectively on Cardiovascular Tissues Neurons rely on N-and P-type Ca 2+ channels Skeletal muscle relies primarily on [Ca] i Cardiac muscle requires Ca 2+ influx through L-type Ca 2+ channels - contraction (fast response cells) - upstroke of AP (slow response cells) Vascular smooth muscle requires Ca 2+ influx through L-type Ca 2+ channels for contraction

Neurons rely on N-and P-type Ca 2+ channels

Skeletal muscle relies primarily on [Ca] i

Cardiac muscle requires Ca 2+ influx through

L-type Ca 2+ channels

- contraction (fast response cells)

- upstroke of AP (slow response cells)

Vascular smooth muscle requires Ca 2+ influx

through L-type Ca 2+ channels for contraction

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

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

Differential effects of different CCBs on CV cells AV SN AV SN Potential reflex increase in HR, myocardial contractility and O 2 demand Coronary VD Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation Reduced inotropism Peripheral vasodilation

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

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

Introduction

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

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

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

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

heart rate

blood pressure

anginal symptoms

signs of CHF

adverse effects

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

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + +

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

Introduction

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

Diltiazem

Nifedipine

Verapamil

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

Supraventricular tachycardias

Hypotension

AV heart block

Hypertension

Congestive heart failure

CCBs may improve cardiac function by: Reducing cardiac afterload Increasing O 2 supply Decreasing cardiac preload Normalizing heart rate in patients with supraventricular tachycardias

Reducing cardiac afterload

Increasing O 2 supply

Decreasing cardiac preload

Normalizing heart rate in patients with

supraventricular tachycardias

Thank you!