Cardiovascular Agents

Introduction: Cordiovascular agents represent a group of drugs which have direct action on the heart or other parts of the vascular system so that they modify the total output of the heart or the distribution of blood to certain parts of the circulatory system. They are further classified into the following types : 1. Cardiotonic drugs (Cardiac glycosides). 2. Vasodilators. 3. Antihypertensive (hypotensive) drugs. 4. Antihypercholesterolemic drags. 5. Sclerosing drugs. 6. Antiarrhythmic drugs. Besides these, there are other classes of drugs, which do not necessarily have a direct effect on the cardiovascular system but are of considerable value in the treatment of cardiac disease. These include the diuretics and the anticoagulants. 1. Cardiotonic drugs (cardiac glycosides) These are naturally occurring drugs which are known to occur in certain plants and in toad venom. These have direct action on the heart and are used for the treatment of congestive heart failure and certain cardiac arrhythmic conditions. Ex. Digitozin. a) It is obtained from Digitalis purpurea and Digitalis lanata. It is a glycoside of digitoxigenin. b) Digoxin. It is a Digitalis lanata glycoside of digoxigenin. 2. Vasodilators. These represent a group of drugs which act primarily on the vascular system. Their therapeutic effect is due to their ability to dilate coronary vessels and are therefore used for treating coronary artery diseases and especially in angina pectoris. An ideal coronary vasodilator drug should increase the coronary blood flow without increasing the work of heart out of proportion to the myocardial blood supply and should not divert blood from the coronary circuit by an equal or greater action on other vascular beds. Its effect should be quick in onset and of fairly prolonged duration. It should not produce tolerance. Some of the important vasodilators are amyl nitrate and Glyceryl trinitrate. (a) Amyl nitrite: It is a mixture of isomeric amyl nitrites-but is principally isoamyl nitrite. It may be prepared by the action of nitrous acid on amyl alcohol.

C5H11OH + NaNO 3 + H2SO4 NaHSO4 + H2O + C 5H 11O-N=O Applications: It cannot be administered orally as it is destroyed in stomach. Therefore, it has to be taken by inhalation. Its vasodilator effect is immediate because it is easily absorbed by lung capillaries but duration is very short. It is, therefore, the drug of the choice in angina pectoris. Currently it is recommended in treating cyanide poisoning. Occasionally it is used in whooping cough, sea sickness and asthma. (b) Glyceryl trinitrate (Nitroglycerine or Glonoin): It is the trinitrate ester ofglycerol. It is prepared by adding-glycerol carefully to a mixture of nitric acid and fuming sulphuric acids.
H2C HC H2C OH OH OH
+ 3HNO3

H2SO4

H2C HC H2C

ONO2 ONO2 + H2O ONO2

Glycerine

Glyceryl trinitrate

Applications: It is used as a vasodilator. It has the action typical of nitrite but its action is developed more slowly and is of longer duration. Its side effects are occasional throbbing headaches and dizziness. Other Vasodilators are Khellin (Visammin), Pentaerythritol tetranitrate (Peritrate, Pentritol) and Theophylline ethylenediamine (aminophylline). 3. Antihypertensive agents (Hypotensive drugs): In resent times, Many persons suffer from high blood pressure or hypertension. This is harmful in the long run and may lead to death. In such patients, the small arterioles used for transferring blood from the arteries to the tissue capillaries and venus circulation get under excessive stimulation of sympathetic nervous system. This may result arteriole contraction and increased peripheral resistance to the flow of blood. As a result, blood pressure increases. Any agent used for counteracting this condition i.e., reducing blood pressure and its accompanying symptoms are known as antihypertensive or hypotensive drugs. An ideal antihypertensive drug should produce a reduction in the blood pressure through generalized vasodilatation with fewer side effects Among synthetic antihypertensive agents some important ones are as follows : (a) Hydralazine: It is syntbesised from phthalaldehydic acid (I) by reaction with hydrazine to give 1-(2H)-phthalazinone (II) which is chlorinated to give 1-chlorophthalazine (III). This is converted to its hydrazine called as hydralazine.
O COOH
+

Cl

NHNH2 NH N
H2 N NH 2

NH2 NH2

NH N

N N

CHO

phthalaldehydic acid

hydrazine

phthalazin-1(2H )-one 1-chloro-1,2-dihydro phthalazine

1-hydrazinylphthalazine

Applications: It has been in used for about 25 years for the treatment of hypertension. It is an oral vasodilator that reduces peripheral resistance by a direct relaxation of arterial smooth muscle. Side effects of this drug are initially headache, gastrointestinal disturbances, flushing and rash. On prolonged treatment a reversible lupus erythematosus like syndrone requires discontinuance of the drug. It is generally given along with hydrochlorothiazide, reserpine, or hydrochlorothiazide-r-reserpine. (b) Minoxidil: It is synthesis involves series of reactions wherein ethylcyanoacetate js condensed with guanidine under base catalysis to give the diaminopyrimidinol (I) which is chlorinated, and the resultant chloropyrimidine (II) is converted to the N-oxide (III) by reaction with m-chloroperbenzoic acid (MCPBA). Reaction of (III) with piperidine gives minoxidil (IV).
HN OEt O NH2 guanidine NH2 base H2N N ethylcyanoacetate OH N N POCl3 NH2 H2N N N Cl MCPBA N NH2 H2N N NH2 Cl N H H2N N N NH2 N

+
C

2,6-diamino pyrimidin-4-ol

O 6-chloro 2,6-diamino-4-chloro pyrimidine-2,4-diamine pyrimidine 1-oxide

O 2,6-diamino-4-(piperidin-1-yl) pyrimidine 1-oxide (Minoxidil)

Applications: It is a potent, direct-acting vasodilator that is useful in the treatment of severe

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hypertension fresulting from increased vascular resistance. It is given in combination with. propranolol and hydro--chlorothiazide. Its side effects are tachy cardia, increase in facial Jiair growth, etc. (c) Lidocaine: It is synthesized from 2,6-dimethylaniline (I) by chloroacetylation to give 2chloro-N-(2,6-dimethylphenyl) acetamide (II) which reacts with diethylamine to give lidocaine (III).
CH3 NH2 CH3 ClCH2COCl CH3 NHCOCH2Cl CH3 CH3

HN(C2H5)2 diethylamine

NHCOCH2N(C2H5)2 CH3

2-chloroacetyl chloride

2,6-dimethylaniline (I)

2-chloroN -(2,6-dimethylphenyl) acetamide (II)

2-(diethylamino)N-(2,6-dimethylphenyl)acetamide (lidocaine) (III)

Applications: It is a drug of choice for immediate control of ventricular premature extra systoles and ventricular tachycardia. Its adverse reactions are drowsiness, muscle twitch, convulsions, respiratoiy depressions, coma etc. (d) Methyldopa. Chemically, it is 3-hydroxy- -methyl-L-tyrosine. It is synthesised from 3methoxy-4-hydroxyphenyl acetone (I) and following series of reaction.
HO H3CO CH2COCH3 (1) KCN NH2

(2) HCl (3) NH4OH H3CO (II)

HO

CH2C

CN (1) NH3

NH2 HO H3CO CH2C COOH

CH3

(2) 45% HCl

CH3

4-hydroxy-3-methoxyphenyl acetone (I)

Methyldopa (III)

Applications: Methyldopa is mainly used for the treatment of moderate-hypertension. However, its side effects are sedation, mental depression, dryness of mouth, nausea, vomiting, diarrhoea and impotence. Antihypercholesterolemic drags: Cholesterol plays an important role in the development of atherosclerosis (deposition of fat in the inner linings of arteries) in human beings. This may interfere with the supply of blood, thus causing high blood pressure and heart attack. The range of serum cholesterol in normal individuals is 190 to 250 mg %, with approximately 30 % in the free state and 70 % as cholesterol esters. Three following methods are used to bring serum cholesterol levels within this range : (i) Diminish the absorption of cholesterol from the gastrointestinal tracts. (ii) Increase the metabolism and biliary excretion of cholesterol. (iii) Inhibit the synthesis of cholesterol within the liver. The drugs used to control cholesterol level are- Aluminium nicotinate, Clofibrate etc. Sclerosing agents These arc the drugs which have been found to irritate the inner most layer of the vessel wall and start a thrombus and occlude the vessels. These are used for the elimination of varicose (dilated) veins. Ex. Sodium salicylate, sodium chloride etc Antiarrhythmic Agents
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The drugs, which are used for the modification of cardiac rate and rhythm, are known as antiarrhythmic agents. An arrhythmia is a disorder of the heart rate (pulse) or heart rhythm, such as beating too fast (tachycardia), too slow (bradycardia). This may be due to diseases and the use of certain drugs. Whenever, heartbeats are more than 180 beats per minutes, this may lead to death. However, with increased rate, nearly 50 per cent of the patients are known to develop vascular collapse or pulmonary congestion. The antiarrhythmic agent to be used and the route have been found to depend on the type of arrhythmia, ventricular rate, age of the patients, electrolyte value and also the nature of other drugs taken. Ex. Propranolol and Procaine Propranolol: Propranolol presents an aryloxypropanolamine structure and has been synthesized in two steps from -naphthol, using the route shown below:
O O

OH +

Cl

H2O/KOH/Alcohol O

NH2 O

NH OH

-naphthol

epichlorhydrin

2-((naphthalen-1 -yloxy)methyl) isopropylamine oxirane

propranolol

Applications: Propranolol is the most useful nonselective adrenergic antagonist (1, 2blocker). Propranolol is used in the treatment of angina and hypertension. By antagonizing the 2-receptor, propranolol possesses serious problems to asthmatic patients. Procaine: (It is also called as Ethocaine hydrochloride, Novocaine or Scuro-caine). Chemically it is 2-(diethylamino)ethyl 4-aminobenzoate hydrochloride. Harrison D.C. and coworkers reported the Antiarrhythmic Properties of Lidocaine and Procaine Amide (1965). The synthesis is described as followsHO N

O2N

COOH

PCl5

O2N

COCl

diethylethanolamine

4-nitrobenzoic acid

4-nitrobenzoyl chloride
O O O N O N

Reduction Fe/H2O

O2N

H2N

procaine Applications:Procaine is used less frequently today since more effective (and hypoallergenic) alternatives such as lidocaine (Xylocaine) exist. Prior to the discovery of procaine, cocaine was the most commonly used local anesthetic. Like other local anesthetics (with the exception of cocaine) and mepivacaine, procaine is a vasodilator, and is often coadministered with epinephrine for the purpose of vasoconstriction. Vasoconstriction helps to reduce bleeding and prevents the drug from reaching systemic circulation in large amounts.
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