IntroductionAngina pectoris, usually referred to as angina, denotes severe chest pain which may be caused by ischemia (lack of blood, and hence lack of oxygen supply) of heart muscle. This ischemia is the result of obstruction or spasm of coronary artery (vessels supplying blood to heart). Thus, the main cause of angina is coronary artery disease which results from atherosclerosis of the cardiac arteries.Unstable angina (usually grouped with similar conditions as the acute coronary syndrome) may have symptoms like:1) Worsening (“crescendo”) of angina attacks, 2) Sudden onset of angina at rest, and 3) Angina lasting more than 15 minutes.Presence of these conditions may lead to myocardial infarction (a heart attack), thus, needs medical aid on an urgent basis. Anti-anginal drug therapy aims at restoring the balance between the supply and demand of oxygen in the ischemic area of the myocardium.4.1.2. ClassificationThe anti-anginal drugs are classified as follows: 1) Vasodilators (Organic Nitrites and Nitrates): Amyl nitrite, Sodium nitrite, Nitroprusside sodium, Isosorbide dinitrate, Isosorbide mononitrate, Erythrityl tetranitrate, and Nitroglycerine.2) Calcium Channel Blockersi) Arylalkylamines: Bencyclane, Bepridil hydrochloride, Caroverine, Cetiedil citrate, Diltiazem hydrochloride, Doprenilamine, Etafenone, Fendiline, Mecinarone, Prenylamine, Proadifen, and Terodiline.ii) Phenyldihydropyridine Derivatives: Amlodipine, Darodipine, Felodipine, Flordipine, Isrodipine, Mesudipine, Nicardipine, Nifedipine, Niludipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Oxodipine, and Riodipine.iii) Piperazine Derivatives: Cinnarizine, Flunarizine, and Lidoflazine.iv) Verapamil and Related Drugs: Anipamil, Dagapamil, Devapamil, Emopamil, Falipamil, Gallopamil, Methoxyverapamil, Ronipamil , Tiapamil, and Verapamil hydrochloride.v) Miscellaneous Agents: Flutonidine, Fostedil, Perhexiline, and Piprofurol.
3) Potassium Channel Opener: Nicorandil.4) -Adrenoceptor Antagonists (-Blockers): Atenolol, Metoprolol, Nadolol, and Propranolol.5) Metabolic Modifiers: Ranolazine and Trimetazidine.4.1.3. UsesThe different classes of anti-anginal drugs have the following therapeutic uses:1) Organic Nitrates: These are one of the several classes of drugs employed for treating ischemic symptoms of angina. These are also employed in the treatment of congestive h eart failure by acting through nitric oxide (NO)replacement therapy so that the bioavailability of impaired NO can be overpowered.2) Calcium Channel Blockers: Both the forms of angina (i.e., stable and variant) are treated using calcium channel blockers. In stable angina, these drugs stimulate peripheral arteriolar relaxation. As a result, the afterload decreases which in turn diminishe s oxygen demand of the heart. In variant angina, these drugs stimulate relaxation of coronary artery spasm. As a result, oxygen supply to the heart increases. Verapamil and diltiazem suppress the heart rate and contractility, thereby, further decreasing ox ygen demand moderately.3) Potassium Channel Openers: These drugs are administered to symptomatic patients waiting to undergo surgery or angioplasty and in whom ideal management with other drugs has already been carried out.4) β-Adrenergic Blockers: These drugs are administered in combination with nitrates for treating angina patients. Drugs from two or more classes are employed in the treatment of persistent angina, e.g., a combination of β-adrenergic blockers with long-acting nitrates or calcium channel blockers. The anti-hypertensive action of β-adrenergic blockers makes them the most ideal drug for patients suffering from both hypertension and coronary artery disease. The β-adrenergic blockers are also the drugs of choice for prophylactic treatment of chron ic angina. Once a patient has suffered an acute myocardial infarction, propranolol is employed for prophylactic treatment for 1.5-3 years, so that ischemic damage could be decreased. 4.1.4. Structure-Activity RelationshipIn most of the anti -anginal drugs, the lipophilicity and steric factors play an important role. The electronic factors are important in some cases. Lipophilicity is the most common factor regulating the anti -anginal activity of β-blockers and nitrates; while steric factors are responsible for the activity of calcium channel blockers. The steric factors hold importance in drug -receptor interactions involving hydrophobic interactions as well as electronic interactions (to a lesser extent). The requirements for anti-anginal activity are:1) β-Blockers: The structural features which are responsible for the activity of β-blockers are:
i) The O-CH2 group between the aromatic ring and ethylamino side chain is
responsible for the antagonistic property.
ii) Replacement of c atechol hydroxyl group with chlorine or phenyl ring
retains the β-blocking activity.
iii) N,N-di-substitution decrease β-blocking activity. Activity is maintained
when phenylethyl, hydroxyl phenylethyl or methoxy phenyl ethyl groups
are added to amine as a part of molecule.
iv) The two carbon side chains are essential for the activity.
v) Nitrogen atom should be of secondary amine for optimum β-blocking
vi) The carbon side chain having hydroxyl group must be S -configuration
for optimum affinity to β-receptor. (e.g., Levobunolol and Timolol).
vii) The aryloxypropanolamines are more potent than aryl ethanolamines.
viii) Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2
or N–CH3 decreases the β-blocking activity.
ix) The most effective substituents at amino group are isopropyl and tertiary
x) The aromatic portion of the molecules could be varied with good
xi) Converting the aromatic portion to phenanthrene or anthracene decreases
xii) Cyclic alkyl substituents are better than corresponding open chain
substituents at nitrogen atom of amine.
xiii) The α-methyl group at side chain decreases the activity.
2) Calcium Channel Blockers: The structural features responsible for the
activity of phenyl-dihydropyridine derivatives are:
i) The dihydropyridine ring,
ii) The secondary nitrogen in the ring which remains un altered at
physiological pH, and
iii) A bulky substituent (such as phenyl) in the 4 -position of the heterocyclic
Subject:- Medicinal chemistry 2
Semester:- Sem 5
Course:- Bachelor of pharmacy