L1: Antianginal Drugs

Dr. G. A. Vaishnav
1. Antianginal Drugs - Coronary Vasodilators

Angina pectoris is the disease of the coronary artery, the

principal supplier of oxygen rich blood to all heart tissues.

Angina is the principal symptom of an ischemic heart. It is

characterized by a sudden, severe pain originating in the
chest, radiating through the left shoulder and running
down the arm.

Anti-anginal drugs mainly alleviate and prevent anginal

attacks by dilating the coronary artery. Such action
replenishes the left ventricle tissues of fresh blood
carrying oxygen and relieves anginal pain.
 • Three classes of drugs are found to be efficient in this
regard:
1.1. Organic nitrates.
1.2. Calcium channel blockers.
1.3. b-Adrenergic blockers.
1.1. Organic Nitrates (Nitrovasodilators)
They are esters of simple organic alcohols or polyols with
nitric acid. This class was developed after the anti-anginal
effect of amyl nitrite was first observed in 1857. They
include:
Amyl nitrite: Mixture of isomeric amyl nitrite but principally isoamyl nitrite
Nitroglycerin: Glyceryl Trinitrate
Erythrityl tetranitrate
Isosorbide dinitrate: 1,4:3,6-Dianhydro-D-glucitol dinitrate
Pentaerythritol tetranitrate: 2,2-bis(hydroxymethyl)-1,3-propandiol tetranitrate
Except for amyl nitrite, all are nitrate esters (R-ONO2).
 Structure

Nitrate Esters

RO H + HO N O RO N O + H2O
alcohol nitrous acid alkyl nitrite water

_ _
O O
+ +
RO H + HO N
O
RO N
O
+ H2O

alcohol nitric acid alkyl nitrate water

• Some nitrate esters are wrongly named, e.g., amylnitrite is

actually isoamylnitrite, nitroglycerin is not a nitro compound

• Nitrate esters are susceptible to hydrolysis! Shelf life is a

concern.
The chemistry of these molecule is easily predicted
based on the structures presented above as follow:

i. They are small molecules

ii. They all are non-polar.
iii. They are ester derivatives with susceptible C-O
bond. This leads to ease of hydrolysis. Thus
moisture should be avoided to minimize the loss in
principal active component.
iv. They are nitrate esters, therefore these
compounds may be explosive, especially in pure
concentrated form. Thus these compounds should
be packaged in variety of diluents with excipients.
 v. The number of nitrate ester groups may vary
from two to more than four, however, there is
no direct relationship between the number of
nitrate groups and the level of activity.

vi. The higher the lipophilicity of the drug, the

greater the potency and the longer the
vasodilatory response.
vii. The structure of the organic nitrates determines
the onset and duration of action as shown in the
following table:
 Pharmacokinetics of Nitrate Esters

Onset Duration of Action Metabolites

(min) (min)
Amyl nitrite 0.25 1
Nitroglycerin 2 30
Isosorbide dinitrate 3 60 Active
Erythrityl tetranitrate 15 180
Pentaerythritol tetranitrate 20 330

• Nitrite esters act fast! Think about the size of these molecules.
• They are rapidly metabolized in the liver (glutathione-nitrate
reductase).
• Number of nitrate groups does not linearly correspond to potency
• Nitrate esters and possibility of explosion!
• Nitrovasodilators decrease the blood pressure of patients!!
Metabolism
Organic nitrates are metabolized rapidly after oral
administration, they generate nitric oxide (NO) in situ that
forms the basis of their pharmacological action. The
mechanism of release of NO from nitrites and nitrates is not
clear.

Mechanism of Action

Nitric oxide has been shown to be an important messenger in

many signal transduction processes. This free radical gas is
naturally produced endogenously from arginine in a complete
reaction that is catalyzed by nitric oxide synthetase (NOS).
• Break
1.2. Calcium Channel Blockers
Calcium channel blockers available for anti-anginal action
are heterogeneous group of compounds. On the basis of
structural features three main subgroup can be
differentiated:
1.2.1. Phenylalkylamines  Verapamil and Bepridil
1.2.2. Dihydropyridines  Nifedipine and others
1.2.3. Benzothiazepines  Diltiazem

1.2.1. Phenylalkylamines

They are structurally characterized by central basic

nitrogen to which alkyl and aralkyl groups are attached.
Representative example for this class is Bepridil and
Verapamil
 NOR: ~20% Active CH3 CN – Verapamil is a synthetic
MeO N CH3
compound possessing structural
CH3 similarity to papaverine. It is a
MeO
chiral compound where the (+)-
O-deMe isomer is more potent than the
gives inactive MeO OMe
(-)-isomer as a calcium channel
species Verapamil blocker.

CH3
N O
Ph N CH3

Bepridil

– The essential structural features of this class of drugs are:

i. The benzene ring.
ii. A 3ry amino nitrogen, which is almost completely charged at
physiological pH.
iii. The isopropyl group is not essential for activity.
1.2.2. The 1,4-dihydropyridines.
The 1,4-dihydropyrines form a rather extensive group of
calcium antagonists. They are possessing the following
general structure: R1

R2
H
H3CO2C CO2R3

H3C N CH2R4
H

R1 R2 R3 R4 Generic Name
H Cl C2H5 OCH2CH2NH2 Amlodipine
NO2 H CH2CH2N(CH3)CH2Ph H Nicardipine
H NO2 CH3 H Nifedipine

Nifedipine: Dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-

dicarboxylate.
SAR of 1,4-DHPs
The structural features essential for activity are :
1. The 1,4-dihydropyridine ring
2. The 2ry nitrogen in the ring which remains uncharged at
physiological pH.
3. A bulky substituent (almost phenyl) in the 4 position of
dihydropyridine.
4. Nitro group and ester moieties are not essential.

X
Extensive hydroxylation to inactive species
R' R' R'' R''' X
Nifedipine NO2 CH3 H H
H3COOC COOR''
Amlodipine Cl C2H5 O-(CH2)2-NH2 X
Nicardipine H -(CH2)2-N(CH3)(CH2-Ph) H NO2
H3C N CH2R'''
H
1.2.3. Benzothiazepines
Diltiazem O
H
H
S
The 3ry basic nitrogen is essential for O CH3

activity. N-demethyl derivative as N O

Des-Ac
well as quaternization products are gives
either less active or not active N CH3 ~50%

compared to the parent compound. H3C

Diltiazem
Protein Binding of Calcium Channels Blockers

Protein Duration of Action Metabolites

Binding

Amlodipine >95% 24 h phenyl hydroxylations, inactive

Nicardipine 95% 3h phenyl hydroxylations, 1 active <1%
Diltiazem ~80% 6 h iv desacetyl derivative, ~ 50 % active
Bepridil >90% 24 h Extensive inactive metabolites
Verapamil 90% 8h N-demethyl derivative, ~ 20 % active
Biochemical Mechanism of Action
Metabolism
First-pass metabolism occurs extensively, especially for verapamil,
leading to low bioavailability. The primary metabolites are N-
demethylated products. Because of many N-methyl groups the
number of metabolites produced are numerous. These metabolites
are inactive.
The duration of action of these calcium channel blockers ranges
from 4 - 8 h. However, amlodipine is the only agent that is active
over a 24 h range and hence can be given once daily. The
suggested reason for the longer duration of action of amlodipine is
the lowered metabolism susceptibility due to the chlorine
substitution in the phenyl ring.

1.3. b-Adrenergic blockers