The document discusses calcium channel blocking (CCB) drugs. It describes the three classes of CCBs - phenylalkylamines, benzothiazepines, and dihydropyridines - and how they bind to different sites on L-type calcium channels. This binding selectivity allows CCBs to differentially affect cardiac and vascular muscle. The document outlines CCB pharmacokinetics, adverse effects, contraindications, and how the classes compare in these areas. It explains how CCBs can improve cardiac function by reducing afterload on the heart without affecting contractility or preload.

1. Calcium Channel
Blocking Drugs

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

3. 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

4. Three Classes of CCBs
N CH2 CH2 N
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
N
H
S

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

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

7. III IV
II I
IVIII
5
6
5
6
Out
In
I II III IV
The 1C subunit of the L-type Ca2+ channel
is the pore-forming subunit

8. 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

9. The Three Classes of CCBs Bind to Different Sites
1,4-
Dihydropyridines
(nifedipine)
Phenylalkylamines
(verapamil)
Benzothiazepines
(diltiazem)
Ca2+
pore
-
- -
-+
+-

10.  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

11. 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
membranemV

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

13. Why Do CCBs Act Selectively
on Cardiac and Vascular Muscle?

14. N-type and P-type Ca2+ channels mediate
neurotransmitter release in neurons
postsynaptic cell
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+

15. Myofibril
Plasma
membrane
Transverse
tubule
Terminal
cisterna of
SR
Tubules of
SR
TriadTSR
Skeletal muscle relies on intracellular
Ca2+ for contraction

16. 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+

17. Vascular smooth muscle relies on Ca2+ influx
through L-type Ca2+ channels for contraction
(graded, Ca2+ dependent
contraction)
L-Type
Ca2+

18. 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

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

20. 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
membranemV

21. Differential effects of different CCBs on CV cells
AV
SN
AV
SN
Potential reflex
increase in
HR, myocardial
contractility
and O2 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

22. 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

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

24. 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

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

26. 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

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

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

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

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

31. Which CCB is most likely to cause
hypotension and reflex tachycardia?
A. Diltiazem
B. Nifedipine
C. Verapamil

32. Contraindications for CCBs include (choose all
appropriate):
A. Supraventricular tachycardias
B. Hypotension
C. AV heart block
D. Hypertension
E. Congestive heart failure

33. 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

34. Thank you!