Calcium Channel

Blocking Drugs

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

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

H 3C

H 3C

CH3

0
CH3

CH
H 3C

CH3

CH2

CH2

CH2

CH2

CH2

CH3

Verapamil

NO2

CH3
S

H 3C

H 3C

N
H

CH3

Nifedipine

CH2

CH2

N
CH3

CH3

0
0
CH3

CH3

Diltiazem

Widespread use of CCBs

Angina pectoris

Hypertension

Treatment of supraventricular

arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

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

is the pore-forming subunit
I

II

III

IV
Out
In

III

5
6

IV

III IV
II

The expression and function of the 1C subunit

is modulated by other smaller subunits
2

1C
I

II

III

IV

NH3+

COONH3+

COONH3+

L-Type Ca2+ Channel

NH3+

COO-

COO-

The Three Classes of CCBs Bind to Different Sites

1,4Dihydropyridines
(nifedipine)

Phenylalkylamines
(verapamil)

+
Ca2+
pore

Benzothiazepines
(diltiazem)

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
Use-dependent binding (targets cardiac cells)
+20

out

mV

Cell
membrane

-80

in

Diltiazem
Verapamil

Voltage-dependent binding (targets smooth muscle)

+20
-30
-80
mV

out
Cell
membrane
in

Nifedipine

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

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
SR

SR

T Triad

Cardiac cells rely on L-type Ca2+ channels for contraction

and for the upstroke of the AP in slow response cells
Ca2+

Ca2+

L-Type

Ca2+

L-Type

Ca2+
Ca2+

Contractile Cells
(atria, ventricle)

Slow Response Cells

(SA node, AV node)

Vascular smooth muscle relies on Ca2+ influx

through L-type Ca2+ channels for contraction
Ca2+
L-Type

(graded, Ca2+ dependent

contraction)

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

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

The different binding sites of CCBs result in differing

pharmacological effects
Use-dependent binding (targets cardiac cells)
+20

out

mV

Cell
membrane

-80

in

Diltiazem
Verapamil

Voltage-dependent binding (targets smooth muscle)

+20
-30
-80
mV

out
Cell
membrane
in

Nifedipine

Differential effects of different CCBs on CV cells

Dihydropyridines: Selective vasodilators

Peripheral
vasodilation

Non -dihydropyridines: equipotent for

cardiac tissue and vasculature

Heart rate
moderating

SN
AV

Potential reflex
increase in
HR, myocardial
contractility
and O2 demand

SN
AV

Coronary
VD
Reduced
inotropism

Peripheral
and coronary
vasodilation

Hemodynamic Effects of CCBs

Effect
Peripheral
vasodilatation
Coronary
vasodilatation
Preload
Afterload
Contractility
Heart rate
AV conduction

Verapamil

Diltiazem

Nifedipine

0/

0/

/ *

0/

/0

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

CCBs: Pharmacokinetics
Agent

Oral
Absorption
(%)

BioavailAbility
(%)

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

35

>95

2-4

15-24

>95

8-9

20

>99

11-16

64-90

97-99

30-50

Nicardipine
Isradipine
Felodipine
Amlodipine

-100
>90
-100
>90

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

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

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

Contradications for CCBs

Contraindication

Verapamil

Nifedipine

Diltiazem

Hypotension

++

Sinus
bradycardia

AV conduction
defects

++

++

Severe cardiac
failure

++

Outline

Introduction

Pharmacokinetics

CCB binding sites

Adverse effects

Heterogeneity of action

Contraindications

Cardiac & hemodynamic

Summary

differentiation

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!