This document provides information on antianginal drugs including vasodilators and calcium channel blockers. It discusses several classes of drugs used to treat angina pectoris including organic nitrates, calcium channel blockers, and beta-blockers. Specific drugs discussed in detail include nitroglycerin, isosorbide dinitrate, dipyridamole, nifedipine, amlodipine, felodipine, nicardipine, nimodipine, verapamil, and bepridil. The mechanisms of action, effects, metabolism and uses of these drugs are described.

1. Antianginal Drugs
(Vasodilators and Calcium Channel Blockers)
for
B Pharm Sem V (PCI)
by
Prof. Jayshree Patil
Department of Pharmaceutical Chemistry,
AIKTC School of Pharmacy, New Panvel

2. Vasodilators
✓ Amyl nitrite,
✓ Nitroglycerin*,
✓ Pentaerythritol tetranitrate,
✓ Isosorbide dinitrite*,
✓ Dipyridamole.

3. Angina Pectoris
Angina
Typical angina is the result of an
advanced state of atherosclerosis and
is provoked by food, exercise, and
emotional factors.
It is characterized by an increase in
the ST segment of the
electrocardiogram.
Variant or acute angina results from
sudden spasm in the coronary artery
unrelated to atherosclerotic narrowing
of the coronary circulation and can
occur at rest.
It is characterized by low ST segment
of the electrocardiogram.

4. Antianginal Drugs
Therapy of angina is directed mainly toward alleviating and
preventing anginal attacks by altering the oxygen
supply/oxygen demand ratio to the cardiac muscle or dilating
the coronary vessels.
Three classes of drugs are found to be very efficient in
this regard, although via different mechanisms.
These include
✓ organic nitrates,
✓ calcium channel blockers, and
✓ b-adrenergic blockers.

5. NITROVASODILATORS

6. Smooth Muscle Relaxation
The contractile activity of all types of muscle (smooth, skeletal) is regulated primarily by the
reversible phosphorylation of myosin.
Myosin of smooth muscle consists of two heavy chains (molecular weight [MW] 200,000
each) that are coiled to produce a filamentous tail.
Each heavy chain is associated with two pairs
of light chains (MW 20,000 and 16,000) that
serve as substrates for calcium- and
calmodulin dependent protein kinases in the
contraction process.
Together with actin (MW 43,000), they
participate in a cascade of biochemical events
that are part of the processes of muscle
contraction and relaxation.

7. Cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and, especially, cyclic
guanosine monophosphate (cGMP) play important roles in the regulation of smooth
muscle tension.
cAMP is the mediator associated with the smooth muscle relaxant properties of drugs such as-
adrenergic agonists. It activates the protein kinases that phosphorylate myosin light-chain kinase
(MLCK). Phosphorylation of MLCK inactivates this kinase and prevents its action with Ca2
and calmodulin to phosphorylate myosin, which interacts with actin to cause contraction of
smooth muscle.
The activity of cGMP in smooth muscle relaxation is affected by exogenous and endogenous agents.
It is suggested that nitrovasodilators undergo metabolic transformation in vascular smooth
muscle cells to form nitric oxide (NO). NO mediates smooth muscle relaxation by activating
guanylate cyclase to increase intracellular concentrations of cGMP. cGMP activates protein
kinases that can regulate free Ca2 levels in the muscle cell and cause relaxation of smooth
muscle by phosphorylating MLCK.

8. Regulation of smooth muscle contraction
✓ Contraction is triggered by an influx of
Ca2. The increase of free Ca2 causes
binding to calmodulin (CM).
✓ The Ca2MCM complex binds to myosin
light-chain kinase (MLCK) and causes
its activation (MLCK*).
✓ MLCK* phosphorylates myosin, which
combines with actin to produce
contraction of smooth muscle.
✓ Myosin is dephosphorylated in the
presence of myosin phosphatase to cause
muscle relaxation.
✓ The-agonists activate adenylate cyclase
(AC) to raise levels of cAMP, which in
turn activates kinases that phosphorylate
MLCK, inactivating it to prevent muscle
contraction.
Myosin phosphatase

9. ✓ Nitric oxide (NO) formed in smooth
muscle from nitro vaso dilatorsmor from
endothelial cells (EDRF) activates
guanylate cyclase (GC*).
✓ GC* activates cGMP-dependent protein
kinases that phosphorylate myosin light-
chain kinase (MLCK), causing its
inactivation and subsequent muscle
relaxation.
Mechanism of nitro vasodilators
A short-lived free radical gas, NO is widely distributed in the body and plays an important role by its
effect through cGMP on the smooth muscle vasculature. It is synthesized in the vascular endothelial
cell from the semi essential amino acid L-arginine by NO synthase.
After production in the cell, it diffuses to the smooth muscle cell, where it activates the enzyme
guanylate cyclase, which leads to an increase in cGMP and then muscle relaxation. Endothelium
derived relaxing factor (EDRF), released from the endothelial cell to mediate its smooth muscle–
relaxing properties through cGMP, is identical with NO.

10. Amyl nitrite
Pentaerythritol tetranitrate
Isosorbide dinitrate
Nitroglycerin

11. Adverse Effects
➢ Headache and postural hypotension are the most common side effects of organic nitrates.
➢ Dizziness, nausea, vomiting, rapid pulse, and restlessness are among the additional side
effects reported.
➢ Another concern associated with prophylactic nitrate use is the development of tolerance.
Tolerance, usually in the form of a shortened duration of action, is commonly observed
with chronic nitrate use.
Drug Interactions
➢ The most significant interactions of organic nitrates are with vasodilators, alcohol, and
tricyclic
Antidepressants cause hypotension.
➢ On the other hand, concurrent administration with sympathomimetic amines, such as
ephedrine and norepinephrine, can lead to a decrease in the antianginal efficacy of the
organic nitrates.

12. Dipyridamole
It may be used for coronary and myocardial insufficiency.
Its biggest use today, however, is as an antithrombotic in patients with prosthetic heart valves.
Dipyridamole is a long-acting vasodilator. Its vasodilating action is selective for the coronary system; it
is indicated for long-term therapy of chronic angina pectoris.
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.

13. Calcium Channel Blockers
✓ Verapamil,
✓ Bepridil hydrochloride,
✓ Diltiazem hydrochloride,
✓ Nifedipine,
✓ Amlodipine,
✓ Felodipine,
✓ Nicardipine,
✓ Nimodipine.

14. The second major therapeutic approach to the treatment of angina is the use of calcium
channel blockers.
In the 1906s, it was recognized that inhibition of calcium ion (Ca2+) influx into myocardial
cells can be advantageous in preventing angina.
Currently, the classes of calcium channel blockers approved for use in the prophylactic
treatment of angina include the dihydropyridines nifedipine, nicardipine, and amlodipine; the
benzothiazepine derivative diltiazem; the aralkyl amine derivative verapamil; the
benzazepinone zatebradine, and the diaminopropanol ether bepridil.
These classes of drugs are reserved for treatment failures because serious arrhythmias can
occur.

15. Calcium channel blockers can be divided conveniently into the three different chemical classes of the
prototype drugs that have been used: 1,4-dihydropyridines (nifedipine), phenylalkylamines
(verapamil), benzothiazepines (diltiazem) and diaminopropanol ether (bepridil).
The specific Ca2 channel antagonists verapamil, nifedipine, and diltiazem interact at specific sites on the
calcium channel protein. These blockers do not occlude the channel physically but bind to sites in the
channel, because they can promote both channel activation and antagonism.
Affinity for binding sites on the channel varies, depending on the status of the channel. The channel can
exist in either an open (O), resting (R), or inactivated (I) state, and the equilibrium between them is
determined by stimulus frequency and membrane potential.
https://www.researchgate.net/publication/300084862_ICEPO_The_ion_channel_electrophysiology_ontology/figures?lo=1

16. Verapamil and diltiazem do not bind to a channel in the resting state, only after the channel has been
opened. They are ionized, water-soluble Ca2-entry blockers that reach their binding sites by the
hydrophilic pathway when the channel is open.
Nifedipine is a neutral molecule at physiological pH and can cause interference with the Ca2 in the
open or closed state. In the closed state, nifedipine can traverse the phospholipid bilayer to reach its
binding site because of its lipid solubility.
http://pittmedneuro.com/actionpotentials.html

17. Mechanism of Action
https://www.researchgate.net/publication/300084862_ICEPO_The_ion_channel_electrophysiology_ontology/figures?lo=1

18. ✓ The depolarization and contraction of the myocardial cells are mediated, in part, by calcium influx.
✓ The overall process consists of two distinct, inward ion currents: First, sodium ions flow rapidly into
the cell through the “fast channels,” and subsequently, calcium enters more slowly through the “slow
channels.”
✓ The calcium ions trigger contraction indirectly by binding and inhibiting troponin, a natural
suppressor of the contractile process. Once the inhibitory effect of troponin is removed, actin and
myosin can interact to produce the contractile response.
✓ The calcium channel blockers produce a negative inotropic effect by interrupting the contractile
response.
✓ In vascular smooth muscles, calcium causes constriction by binding to a specific intracellular
protein calmodulin to form a complex that initiates the process of vascular constriction.
✓ The calcium channel blockers inhibit vascular smooth muscle contraction by
depriving the cell from the calcium ions.

19. The effects of the different classes of calcium channel blockers on the myocardium and the arteries vary
from class to class. Although verapamil and diltiazem affect both the heart and the arteriolar bed, the
dihydropyridines have much less effect on the cardiac tissues and higher specificity for the arteriolar
vascular bed.
Therefore, both verapamil and diltiazem are used clinically in the management of angina,
hypertension, and cardiac arrhythmia, whereas the dihydropyridines are used more frequently as
antianginal and antihypertensive agents.

20. 1,4 Dihydropyridines

21. Nifedipine
1,4-dihydro-2, 6-dimethyl-4-(2- nitrophenyl)-3,5-pyridinedicarboxylate dimethyl ester, is a
dihydropyridine derivative that bears no structural resemblance to the other calcium antagonists.
2,6 position duration of action
Mechanism:
➢ The prototype of this class, nifedipine, has potent peripheral vasodilatory properties.
➢ It inhibits the voltage-dependent calcium channel in the vascular smooth muscle but has little or
no direct depressant effect on the SA or AV nodes, even though it inhibits calcium current in
normal and isolated cardiac tissues.
✓ positions 3 and 5 are carboxylic
groups that must be protected with
an ester functional group.
✓ Distribution of drug
position 4 requires an aromatic
substitution possessing an electron-
withdrawing group (i.e., Cl or
NO2) in the ortho and/or meta
position
Its nitro group is
essential for its
antianginal effect
SAR
1
3
2
4
5
6

22. Metabolism:
• Nifedipine is absorbed efficiently on oral or buccal administration.
• A substantial amount (90%) is protein bound.
• Systemic availability of an oral dose of the drug may be approximately 65%.
• Two inactive metabolites are the major products of nifedipine metabolism and are found in
equilibrium with each other. Only a trace of unchanged nifedipine is found in the urine
Uses:
▪ Nifedipine is more effective in patients whose anginal episodes are caused by coronary
vasospasm and is used in the treatment of vasospastic angina as well as classic angina pectoris.
▪ Because of its strong vasodilatory properties, it is used in selected patients to treat hypertension.

23. Amlodipine
Amlodipine, 2-[(2-aminoethoxy)methyl]4- (2-chlorophenyl)-
1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl
5-methyl ester (Norvasc), is a second generation 1,4-
dihyropyridine derivative of the prototypical molecule
nifedipine.
Like most of the second-generation dihydropyridine
derivatives, it has greater selectivity for the vascular smooth
muscle than myocardial tissue, a longer half-life (34 hours),
and less negative inotropy than the prototypical nifedipine.
Amlodipine is used in the treatment of chronic stable angina
and in the management of mild-to-moderate essential
hypertension.
Amlodipine was approved in September 2007 as a combination product with olmesartan
(Azor), an angiotensin II receptor antagonist for the treatment of hypertension.
Amlodipine is also marketed as a combination therapy with atorvastatin under the tradename
Norvasc for the management of high cholesterol and high blood pressure.

24. Felodipine
4-(2,3-dichlorophenyl)-1,4-dihydro- 2,6-dimethyl-
3,5-pyridinedicarboxylic acid ethyl methyl ester, is
a second-generation dihydropyridine channel
blocker of the nifedipine type. It is more selective
for vascular smooth muscle than for myocardial
tissue and serves as an effective vasodilator.
The drug is used in the treatment of angina and
mild-to-moderate essential hypertension.
Felodipine, like most of the dihydropyridines,
exhibits a high degree of protein binding and has a
half-life ranging from 10 to 18 hours.
Nicardipine
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)
3,5-pyridinedicarboxylic acid methyl 2-
[methyl(phenylmethyl)amino]ethyl ester
hydrochloride, is a more potent vasodilator of
the systemic, coronary, cerebral, and renal
vasculature and has been used in the
treatment of mild, moderate, and severe
hypertension. The drug is also used in the
management of stable angina.

25. Nimodipine
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 3,5-
pyridinedicarboxylic acid 2-methoxyethyl 1-
methylethyl ester, is another dihydropyridine
calcium channel blocker but differs in that it dilates
the cerebral blood vessels more effectively than do
the other dihydropyridine derivatives.
This drug is indicated for treatment of subarachnoid
hemorrhage-associated neurological deficits.

26. PHENYLALKYLAMINES

27. Verapamil
5-[(3,4-dimethoxyphenethyl) methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile,
was introduced in 1962 as a coronary vasodilator and is the prototype of the Ca2 antagonists
used in cardiovascular diseases.
Mechanism:
➢ Verapamil’s major effect is on the slow Ca2
channel. The result is a slowing of AV
conduction and the sinus rate.
➢ It is categorized as a class IV
antiarrhythmic
➢ The drug reduces systemic vascular
resistance and mean blood pressure, with
minor effects on cardiac output.
Verapamil is a synthetic compound possessing slight structural similarity to papaverine.
It can be separated into its optically active isomers, of which the levorotatory enantiomer is the
most potent.
https://www.youtube.com/watch?v=9DFrOlyRaEw

28. Metabolism:
➢ It is absorbed rapidly after oral
administration. The drug is
metabolized quickly and, as a result,
has low bioavailability.
➢ The liver is the main site of first-pass
metabolism, forming several products.
➢ The preferential metabolic step
involves N-dealkylation, followed by
O-demethylation, and subsequent
conjugation of the product before
elimination.
➢ The metabolites have no significant
biological activity. Verapamil has an
elimination half-life of approximately
5 hours.
Uses:
It is used in the treatment of
✓ angina pectoris,
✓ arrhythmias from ischemic myocardial
syndromes
✓ supraventricular arrhythmias.

29. BENZOTHIAZEPINES

30. Diltiazem
3-(acetoxy)-5-[2(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)1,5-benzothiazepin-4-one,
was developed and introduced in Japan as a cardiovascular agent to treat angina pectoris.
It was observed to dilate peripheral arteries and arterioles. The drug increases myocardial oxygen
supply by relieving coronary artery spasm and reduces myocardial oxygen demand by decreasing heart
rate and reducing overload.
Diltiazem hydrochloride is used in patients with variant angina. The drug has electrophysiological
properties similar to those of verapamil and is used in clinically similar treatment conditions as an
antiarrhythmic agent, but it is less potent.

31. Metabolism:
Diltiazem hydrochloride is metabolized extensively after oral dosing, by first-pass metabolism. As a
result, the bioavailability is about 40% of the administered dose. The drug undergoes several
biotransformations, including deacetylation, oxidative O- and N-demethylations, and conjugation of
the phenolic metabolites. Of the various metabolites only the primary metabolite, deacetyldiltiazem,
is pharmacologically active. Deacetyldiltiazem has about 40% to 50% of the potency of the parent
compound.

32. DIAMINOPROPANOL
ETHER

33. Bepridil β-[(2- methylpropoxy)methyl]-N-phenyl-N-(phenylmethyl)-1- pyrrolidineethylamine, is a
second generation alkylamine-type channel blocker, structurally unrelated to the dihydropyridines.
Its actions are less specific than those of the three prototypical channel blockers, verapamil,
diltiazem, and nifedipine.
In addition to being a Ca2 channel blocker, it inhibits sodium flow into the heart tissue and lengthens
cardiac repolarization, causing bradycardia.
Caution should be used if it is given to a patient with hypokalemia.
Bepridil hydrochloride is used for stable angina. The drug has a half-life of 33 hours and is highly
bound to protein (99%).

34. REFERENCE BOOKS:
1. Foye’s Principles of Medicinal Chemistry, Thomas L. Lemke, David A Williams, Lippincott
Williams & Wilkins.
2. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, John M.
Beale, John H. Block, Lippincott Williams & Wilkins.