Calcium Antagonists Department of pharmacy, Institute of Medicine, MMC. Nepal

1. CALCIUM ANTAGONISTS
Presented by
Bibek Nepal
Kuber Bajgain

2. EXCITATION–CONTRACTION
COUPLING MUSCLE
o Stimulation of the cardiac cell initiates the process
of excitation, which has been related to ion fluxes
through the cell membrane. Depolarization of the
tissue in the atria of the heart is mediated by two
inwardly directed ionic currents.
i. Fast sodium current via Na+ channel
ii. Current caused by slow activation of an L-type
Ca++
channel

3. EXCITATION–CONTRACTION
COUPLING MUSCLE
Contraction of cardiac and other muscle occurs
from a reaction between actin and myosin
the contractile process in cardiac muscle involves
a complex of proteins (troponins I, C, and T and
tropomyosin) attached to myosin, which
modulates the interaction between actin and
myosin.

4. EXCITATION–CONTRACTION
COUPLING MUSCLE

5. CALCIUM CHANNEL BLOCKERS
Three important classes of CCBs
a) Verapamil - a phenyl alkylamine (hydrophilic
papaverine)
b) Nifedipine - a dihydropyridine ( lipohilic)
c) Diltiazem – a hydrophilic benzothiazepine

6. CALCIUM CHANNEL BLOCKERS
Pharmacolgical actions
All three subclasses of CCBs inhibit calcium mediated
slow channel component of AP in
a) Smooth muscle :
o The CCBs decrease intracellular availability of Ca+2
and causes relaxation
o Dihydropyridines (nifedipine) has most marked
smooth muscle relaxant property.

7. CALCIUM CHANNEL BLOCKERS
Pharmacolgical actions
b) Heart
o CCBs have negative inotropic effect
o Verapamil has shown to have higher cardiodepressant
action
* Diltiazem has shown to have intermediate cardio
depressant effect and vasodilation

8. CALCIUM CHANNEL BLOCKERS
Indications
o Angina
o Hypertension
o Raynaud’s syndrome
o Supraventricular tachycardia and arrhythmias
o Atrial fibrillation
o Delay of preterm labor
o Prophylaxis of cluster headache

9. CALCIUM CHANNEL BLOCKERS
Adverse effect
o Myocardial effects : hypotension , heart failure
o Conduction effect : heart block , arrhythmias
o Vascular smooth muscle : flushing , edema ,
headache rashes
o Other effect : constipation , nausea ,
photosensitivity

10. VERAPAMIL
o Verapamil is chemically 5-[(3,4 dimethoxyphenethyl)
methylamino]-2-(3,4 dimethoxyphenyl)-2-
isopropylvaleronitrile (Calan, Isoptin)
o a coronary vasodilator and is the prototype of the Calcium
antagonists used in cardiovascular diseases.
C H 2 C H 2 N C H 2 C H 2 C H 2 C
C H 3 C H ( C H 3 ) 2
O C H 3
O C H 3
H 3 C O
H 3 C O
C N

11. VERAPAMIL
Properties
o It is white crystalline powder, soluble in
water freely soluble in methanol,
sparingly soluble in ethanol
o It should be stored in well closed
container

12. VERAPAMIL
Synthesis:
H3CO
H3CO
C
H
CH
CN
H3C
CH3
+
OCH3
OCH3(CH2)2N
CH3
(H2C)3
Cl
3,4-Dimethoxy phenyl ethyl-N-methyl-
-3chloro propylamine
3,4- Dimethoxy-2-isopropyl
valero nitrile
CH2CH2NCH2CH2CH2C
CH3 CH(CH3)2
OCH3
OCH3
H3CO
H3CO
CN-HCl
VERAPAMIL

13. NIFEDIPINE
Nifedipine is chemically 1,4-dihydro-2, 6-dimethyl-4-
(2- nitrophenyl)-3,5-pyridinedicarboxylate dimethyl
ester (Adalat, Procardia)
N O 2
H
NH 3 C C H 3
H 3 C O O C C O O C H 3
N i f e d i p i n e

14. NIFEDIPINE
o It is yellow crystalline powder sparingly
soluble in ethanol, insoluble in water but freely
soluble in acetone
o When exposed to day light or artificial light of
certain wavelength it readily converts to
nitrosophenylpyrimidine derivative and
exposure to UV rays leads to formation of
nitrophenylpyrimidine.
o Hence it should be stored in light resistant
airtight container

15. NIFEDIPINE
Synthesis
Step 1:preparation of Methyl-[2-acetyl-3-(2-
nitropheny)]-2-propionate
CHO
NO2
2-nitro bendaldehyde
+ CH3COCH2COOCH3
Methyl acetoacetate
HC
NO2
C COOCH3
COCH3
Methyl-[2-acetyl-3-(2-nitropheny)]-2-
propionate

16. NIFEDIPINE
Step 2: preparation Methyl 3-amino 2-butenoate
C H 3 C O C H 2 C O O C H 3
M e t h y l a c e t o a c e t a t e
H 3 C C
O H
C H C O O C H 3
( E n o l f o r m )
+ N H 3
H 3 C C
N H 2
C H C O O C H 3
M e t h y l 3 - a m i n o 2 - b u t e n o a t e
- H 2 O

17. NIFEDIPINE
Step 3: condensation of step 1 and step 2 product
HC
NO2
C COOCH3
COCH3
Methyl-[2-acetyl-3-(2-nitropheny)]-2-propionate
H3C C
NH2
CHCOOCH3
Methyl 3-amino 2-butenoate
+
NO2
H
NH3C CH3
H3COOC COOCH3
Nifedipine
-H2O
Cyclisation

18. DIPYRIDAMOLE
Dipyridamole is chemically 2,2,2,2-[(4,8-di-
1piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-
tetrakisethanol (Persantine),
N
N
N
N
N
N
N
CH2CH2OH
CH2CH2OH
N
CH2CH2OH
HOH2CH2C

19. DIPYRIDAMOLE
Properties
o It is bitter, yellow crystalline powder, soluble in
dilute acids, methanol and chloroform
o A formulation containing dipyridamole and aspirin
(Aggrenox) is currently being marketed as an
antithromobotic.

20. DIPYRIDAMOLE
Pharmacological actions :
o Dipyridamole is a long-acting vasodilator. Its vasodilating
action is selective for the coronary system.
o The drug also inhibits adenosine deaminase in erythrocytes
and interferes with the uptake of the vasodilator adenosine
by erythrocytes. These actions potentiate the effect of
prostacyclin (PGI2), which acts as an inhibitor to platelet
aggregation.

21. DIPYRIDAMOLE
Side effect
More common:
Abdominal or stomach cramps, diarrhea, dizziness or
lightheadedness
Less common:
Flushing, headache, nausea or vomiting, weakness
Rare
General discomfort and/or unusual tiredness or weakness, hair
loss, joint pain or swelling, muscle pain, runny nose, sneezing