Transcript Document
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
Adalat CC,
Procardia XL
nicardipine
isradipine
felodipine
amlodipine
Cardene
DynaCirc
Plendil
Norvasc
Three Classes of CCBs
H3C
H3C
0
CH3
0
CH3
CH
H3C
0
CH3
C
CH2
C
N
CH2
CH2
N
CH2
0
CH2
CH3
Verapamil
NO2
CH3
S
H3C
0
0
0
C
C
H3C
N
H
CH3
N
CH2
N
CH3
0
CH3
0
C
CH3
0
0
CH3
Nifedipine
CH2
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
5
6
IV
III IV
II
I
The expression and function of the 1C subunit
is modulated by other smaller subunits
2
1C
I
II
III
IV
NH3+
COONH3+
COONH3+
d
b
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
mV
-80
out
Cell
membrane
in
1
1
2
d
b
Diltiazem
Verapamil
Voltage-dependent binding (targets smooth muscle)
+20
-30
-80
mV
out
Cell
membrane
in
1
b
1
2
d
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
mV
-80
out
Cell
membrane
in
1
1
2
d
b
Diltiazem
Verapamil
Voltage-dependent binding (targets smooth muscle)
+20
-30
-80
mV
out
Cell
membrane
in
1
b
1
2
d
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
Verapamil
Diltiazem
Nifedipine
Peripheral
vasodilatation
Coronary
vasodilatation
0
0
0/
Afterload
Contractility
0/
/ *
Heart rate
0/
/0
AV conduction
0
Effect
Preload
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
0
+
+++
Peripheral
Edema
++
++
+++
Constipation
0
++
0
CHF (Worsen)
0
+
0
AV block
+
++
0
Caution w/beta
blockers
+
++
0
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
+
0
+
AV conduction
defects
++
0
++
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!