calcium channel blockers (1)

Calcium Channel Blocking Drugs

Outline

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

Chemical Type Chemical Names Brand Names

Phenylalkylamines

verapamil Calan,Calna SR,Isoptin SR,Verelan

Benzothiazepines diltiazem Cardizem CD,Dilacor XR

1,4-Dihydropyridines

Nifedipine  nicardipineisradipinefelodipineamlodipine

Adalat CC,Procardia XL CardeneDynaCircPlendilNorvasc

Three Classes of CCBs

Three Classes of CCBs

N CH2 CH2N

0

CH3

0 C CH3

0

CH3

CH3

Diltiazem

C 0 CH3

NO2

CH3H3C

C0H3C

0 0

Nifedipine

C CH2 CH2 CH2CH2 CH2N

CH3

CH3

C N

CH

H3C

0H3C

0H3C

0 CH3

0 CH3

Verapamil

NH

S

Angina pectoris

Hypertension

Treatment of supraventricular

arrhythmias

- Atrial Flutter

- Atrial Fibrillation

- Paroxysmal SVT

Widespread use of CCBs

Outline

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

III IV

II IIVIII

56 5

6

Out

In

I II III IV

The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit

NH3+

NH3+

COO-

COO-

b

1C

NH3+ COO-

2

I II III IV

COO-

NH3+

d

The expression and function of the 1C subunit is modulated by other smaller subunits

L-Type Ca2+ Channel

The Three Classes of CCBs Bind to Different Sites

1,4-Dihydropyridines

(nifedipine)

Phenylalkylamines(verapamil)

Benzothiazepines(diltiazem)

Ca2+

pore

-

- -

-++-

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

CCBs – Mechanisms of Action

The different binding sites of CCBs result in differing pharmacological effects

Voltage-dependent binding (targets smooth muscle)

Use-dependent binding (targets cardiac cells)

Cellmembrane

1

out

in b

+20

-80mV 2

d

DiltiazemVerapamil

1

b

1

out

in

+20

-80-30 2

d1

Nifedipine

CellmembranemV

Outline

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 Ca2+ channels mediate neurotransmitter release in neurons

postsynaptic cell

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

MyofibrilPlasma membrane

Transverse tubule

Terminal cisterna ofSR

Tubules ofSR

TriadTSR

Skeletal muscle relies on intracellularCa2+ for contraction

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+

Ca2+ Ca2+

Slow Response Cells(SA node, AV node)

L-Type

Ca2+

Ca2+

Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction

(graded, Ca2+ dependentcontraction)

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

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)

Cellmembrane

1

out

in b

+20

-80mV 2

d

DiltiazemVerapamil

1

b

1

out

in

+20

-80-30 2

d1

Nifedipine

CellmembranemV

Differential effects of different CCBs on CV cells

AV

SN

AV

SN

Potential reflexincrease inHR, myocardialcontractilityand O2 demand

CoronaryVD

Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent forcardiac tissue and vasculature

Heart ratemoderating

Peripheraland coronaryvasodilation

Reducedinotropism

Peripheralvasodilation

Effect Verapamil Diltiazem Nifedipine

Peripheralvasodilatation

Coronaryvasodilatation

Preload 0 0 0/

Afterload

Contractility 0/ / *

Heart rate 0/ /0

AV conduction 0

Hemodynamic Effects of CCBs

Outline

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

AgentOral

Absorption(%)

Bioavail-Ability

(%)

ProteinBound

(%)

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 1.9-5.8Nicardipin

e-100 35 >95 2-4

Isradipine >90 15-24 >95 8-9

Felodipine -100 20 >99 11-16Amlodipin

e>90 64-90 97-99 30-50

CCBs: Pharmacokinetics

Outline

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

  Diltiazem Verapamil Dihydropyridines

Overall 0-3% 10-14% 9-39%

Hypotension ++ ++ +++

Headaches 0 + +++Peripheral

Edema ++ ++ +++

Constipation 0 ++ 0

CHF (Worsen) 0 + 0

AV block + ++ 0Caution w/beta

blockers+ ++ 0

Comparative Adverse Effects

heart rate

blood pressure

anginal symptoms

signs of CHF

adverse effects

CCBs - Monitoring

Outline

Introduction

CCB binding sites

Heterogeneity of action

Cardiac & hemodynamic

differentiation

Pharmacokinetics

Adverse effects

Contraindications

Summary

Contraindication Verapamil Nifedipine Diltiazem

Hypotension + ++ +

Sinus bradycardia + 0 +

AV conduction defects ++ 0 ++

Severe cardiac failure ++ + +

Contradications for CCBs

Outline

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?

A. Diltiazem

B. Nifedipine

C. Verapamil

Contraindications for CCBs include (choose all appropriate):

A. Supraventricular tachycardias

B. Hypotension

C. AV heart block

D. Hypertension

E. Congestive heart failure

CCBs may improve cardiac function by:

A. Reducing cardiac afterload

B. Increasing O2 supply

C. Decreasing cardiac preload

D. Normalizing heart rate in patients with

supraventricular tachycardias

Thank you!