Calcium channel blockers (CCBs) were first discovered in 1969 when they were observed to have vasodilating and negative inotropic effects on the heart by blocking calcium channels. There are several classes of CCBs including phenylalkylamines, benzothiazepines, dihydropiridines, and piperazines. They act primarily by interfering with calcium transport through L-type calcium channels in vascular smooth muscle and cardiac muscle. CCBs are used to treat hypertension, angina, migraines, and arrhythmias. While effective, they can cause adverse effects like headache, hypotension, and edema.

2.  The term “calcium antagonists” was 1st
coined by Fleckenstein & Colleagues in
1969.
 Investigating vasodilator effects of
prenylamine and verapamil
 Observed that they have a negative
inotropic effect on the heart
 Showed that the –ve inotropic effect can be
antagonized by calcium

3. Phenylalkylamines:
 Verapamil, desmethoxyverapamil, tiapamil,
anipamil, gallopamil, ronipamil, devapamil,
terodilin
Benzothiazepines:
 Diltiazem, fostedil

4. Dihydropiridines:
 Nifedipine, nitrendipine, nimodipine,
niludipine, niguldipine, nicardipine,
nisoldipine, amlodipine, felodipine, isradipine,
ryosidine, lacidipine
Piperazines:
 Cinnarizine, lidoflazine, flunarizine

5.  Free Ca+2 in the cytosol regulates a number of
cellular functions
 The intracellular pools of Ca+2 are replenished
by Ca+2 from the ECF
 The transport of Ca+2 takes place via the Ca+2
channels
 Interfere with Ca+2 transport over excitable
membranes in different tissues

6.  The channels have to be open for Ca+2 to
enter the cells
 opened by changes in membrane potential
(Voltage-operated Ca+2 –channels)
AND
 Through hormone/neurotransmitter
mediated changes (receptor-operated
channels)

7. Calcium antagonists act on voltage operated
channels which are differentiated into:
 T-channels (tansient):
- have small conductance and transient
opening times
-activated by small depolarisations from very
negative potentials
 Involved in the initiation of action potentials

8.  Occur in neuronal, smooth muscle, cardiac, skeletal
muscle cells
 Do not take part in intracellular Ca+2 homeostasis
 Inhibited by neurotransmitters e.g. NA & dopamine
 Not affected by calcium antagonists

9.  N-type: neuronal channels
 L-type: have a high conductance and a
prolonged opening time
 Play a central role in the regulation of intracellular
calcium concentration
 Activated by changes in membrane potential

10.  Also modulated by hormones and neurotransmitters
 Very sensitive to calcium antagonists
 Considered to be their primary receptor
 Have a wide distribution
 High concs in atria, blood vessels & skeletal muscle
T-tubules

11.  All of them dilate blood vessels
 Vasodilator effect is most pronounced with
dihydropyridines
 Within the dihydropyridines there are marked
differences of the vasodilator effect
 Vasodilator effect occurs on arteries and
resistance vessels

12.  Have negligible effect on veins
 Strongly reduce coronary and skeletal vascular
resistance
 Insignificant effect on skin
 Small effect on renal vascular resistance
 Vasodilator effect is maintained during chronic
therapy in hypertensive patients

13.  Inhibit arterial smooth muscle proliferation due
to a decrease in vascular DNA synthesis
 Inhibit platelet activation (platelets are a rich
source of vascular growth factors)

14.  Calcium antagonists are vasodilators that
reduce BP without triggering renal
compensatory mechanisms that lead to fluid
and electrolyte retention with classical
vasodilators
 Renal blood flow (RBF) & GFR are
maintained during acute and long-term
treatment with Ca+2 antagonists

15.  Have a diuretic & natriuretic effect inspite of
their relative lack of effect on GFR or RBF
which may suggest a tubular site of action

16. 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

17.  Block slow Ca+2 channels
 Block myocardial cellular Ca+2 uptake
 Reduce the amount of Ca+2 available for
interaction with troponin
 Negative inotropic effect
 Phenylalkyalamines & benzothiazepines >
dihydropyridines

18.  The relatively strong vasodilator effects of
dihydropyridines trigger a baroreflex-mediated
rise in sympathetic nerve activity
 Leads to a +ve rather than –ve inotropic effect
 Verapamil & diltiazem: direct –ve and indirect
reflexogenic inotropic effects usually cancel
each other

19.  Limited to phenylalkylamines &
benzothiazepines
 Slow AV node conduction & sinus pacemaker
activity
 Dihydropyridines & piperazines are less
effective and may increase the heart rate due to
baroreflex-mediated alteration of sympathetic
nerve activity

20.  Verapamil & diltiazem: good for treatment of
supraventricular tachyarrhythmias
 The coronary vasodilator effect of
dihydropyridines is useful for preventing
coronary spasms that are responsible for
causing angina

21.  Whereas as nitroglycerine acts predominantly
on large coronary arteries calcium antagonists
dilate large and small coronary arteries

22.  Cardiac ischaemia is followed by:
- a decrease in tissue ATP levels
-increase in free-radical production via
xanthine oxidase pathway
-alteration in ionic homeostatis
Leading to cardiac arrhythmias and structural
disorganization of the heart

23.  Upon reperfusion, cells injured by the above
mechanisms accumulate large amounts of Ca+2
(Ca+2-overload)
 This leads to further damage of the heart
 Ca+2 enters the myocardial cells via routes that
can be blocked by calcium antagonists

24. They also protect the heart from post ischaemic
injury by:
 Coronary vasodilatation
 Cardiac unloading
 Effect on adenosine metabolism
 Reduce cardiac hypertrophy due to chronic
hypertension

25.  Verapamil & diltiazem cause a modest
lowering of BP and TPR with little or no
depressive effect on cardiac function
 Dihydropyridines (nifedipine) reduce BP via a
strong fall in TPR with an early rise in CO and
HR
 Piperazines have insignificant short-term BP-
lowering activity

26. 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

27. 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

28.  Angina pectoris
 Hypertension
 Migraine
 Raynaud’s phenomenon
 Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
Widespread clinical use of CCBs

29.  Headache, constipation (verapamil), ankle
oedema(dihydropyridines)
 There is a risk of causing cardiac failure or
heart block, especially with verapamil and
diltiazem

30. 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

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

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

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

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

35. 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

36. Thank you!