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


nicardipine
isradipine
felodipine
amlodipine

Adalat CC,
Procardia XL

Cardene
DynaCirc
Plendil
Norvasc

Three Classes of CCBs
Three Classes of CCBs
N CH
2
CH
2
N

0

CH
3
0

C CH
3
0

CH
3
CH
3
Diltiazem
C 0

CH
3
NO
2
CH
3
H
3
C
C

0

H
3
C
0

0

Nifedipine
C CH
2
CH
2
CH
2
CH
2
CH
2
N
CH
3
CH
3
C N
CH

H
3
C
0

H
3
C
0

H
3
C
0

CH
3
0

CH
3
Verapamil
N
H
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 I
IV III
5
6
5
6
Out
In
I II III IV
The 1C subunit of the L-type Ca
2+
channel
is the pore-forming subunit
NH
3
+
NH
3
+
COO
-
COO
-
b
1C
NH
3
+
COO
-
2
I II III IV
COO
-
NH
3
+
d
The expression and function of the 1C subunit
is modulated by other smaller subunits
L-Type Ca
2+
Channel
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
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
b
+20
-80
mV

2
d
Diltiazem
Verapamil

1
b

1
out

in
+20
-80
-30

2
d

1
Nifedipine
Cell
membrane
mV
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 Ca
2+
channels mediate
neurotransmitter release in neurons
postsynaptic cell
Ca
2+
Ca
2+
Ca
2+
Ca
2+
Ca
2+
Myofibril
Plasma
membrane
Transverse
tubule
Terminal
cisterna of
SR
Tubules of
SR
Triad T
SR
Skeletal muscle relies on intracellular
Ca
2+
for contraction
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

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)
Cell
membrane

1

out
in
b
+20
-80
mV

2
d
Diltiazem
Verapamil

1
b

1
out

in
+20
-80
-30

2
d

1
Nifedipine
Cell
membrane
mV
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

Effect


Verapamil


Diltiazem


Nifedipine

Peripheral
vasodilatation










Coronary
vasodilatation










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
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

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


+


++


0

Caution 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 O
2
supply
C. Decreasing cardiac preload
D. Normalizing heart rate in patients with
supraventricular tachycardias
Thank you!