Cardiovascular drugs By Dr. fatmah alomary

Hypertension is a consequence of many diseases. Hemodynamically blood pressure is a function of the amount of blood pumped by the heart and the ease with which the blood flows through the peripheral vasculature. Hypertensive-state in human can be created by: 1. Diseases affecting the components of the central and peripheral nervous system that regulate the blood pressure. 2. Diseases of the kidney. 3. Diseases of peripheral vascular network that affect blood volume. Antihypertensive Drugs

4. Abnormalities of the hormonal systems: a) Tumors of the adrenal medulla that causes release of large amounts of catecholamines create hypertensive- state known as pheochromocytoma. b) An excessive secretion of aldosterone by the adrenal cortex, often because of adenomas, also produces hypertensive disorders. c) Enhanced adrenergic activity is recognized as a peripheral contributor to essential hypertension.

Classification of antihypertensive agents

I- Peripherally acting Sympatholytics

 Reserpine depletes catecholamines and serotonin from central and peripheral neurons  It is effective orally and parenterally for the treatment of hypertension.

 Guanethidine has been classified as an adrenergic blocking agent because it can prevent the release of norepinephrine from post ganglionic neurons in response to adrenergic stimulation.  Guanethidine and other compounds have other action on the catecholamine metabolism and cause significant depletion of these amines in the adrenergic neurons.  They do not interfere with the release of epinephrine from the adrenal medulla.

Guanethidine monosulfate (Ismelin)

Selective α1-antagonists.

 Selective α 1 -antagonists are effective antihypertensive agents by blocking the vasoconstricting effect on the smooth muscle and not interfere with the activation of α 2 -receptors on the adrenergic neurons which when activated inhibit further release of norepinephrine.  Doxazosin (Cardura)  Prazocin (Minipress)  Terazocin (Hytrine)

II-Centrally acting adrenergic drugs (Selective α2-agonist)

L-α-3-(3,4-Dihydroxyphenyl)-2-methylalanine ethyl ester Hydrochloride

III-Drugs Acting Directly on Smooth muscle (Vasodilators)

1-Hydrazinophthalazine monohydrochloride  Hydralazine action appear to be centered on the relaxation of the smooth muscle of the vascular walls with a decrease in the peripheral resistance to blood flow, which is an important consideration in patient with renal insufficiency.

Potassium channel agonists

Sodium 7-Chloro-3-methyl-2H-1,2,4- benzothiadiazine-1,1-dioxide

2,4-Diamino-6-piperidinopyrimidine-3-oxide

IV-Angiotensin Converting Enzyme Inhibitors (ACEI)

1-[(2S)-3-Mercapto-2-methyl-1-oxopropionyl]L- proline

1-[N[(S)-1-Carboxy-3-phenylpropyl]-L-alanyl]-L- proline 1ó-ethyl ester maleate

V-Angiotensin II Blockers

 The prototype compound which resulted from these studies was saralasin, an octapeptide in which the Asp 1 and phe 8 residues of angiotensin II were replaced with sarcosine and N-methyl glycine.  These peptide analogs demonstrated the ability to reduce the blood pressure; however, these compounds lacked the oral bioavailability and expressed unwanted partial agonist activity.  Efforts were made till 1955, approval of losartan, a nonpeptide angiotensin II receptor antagonist.

 Losartan and a series of imidazole-5-acetic acid are developed as a nonpeptide angiotensin II receptor antagonist.  These compounds were relatively weak antagonists but they don’t possess the unwanted agonist activity in the peptide analogs.

2-Butyl-4-chloro-1-[p-(o-1H-tetrazol-5-yl-phenyl)benzyl] imidazole-5-methanol

 The angiotensin II receptor exists in at least two subtypes,  Type 1 (AT 1 ): located in brain, neuronal, vascular, renal, hepatic, adrenal and myocardial tissues  Losartan, Valsartan, irbesartan, and eprosartan all show selectivity for this receptor subtype.  They prevent and reverse all of the known effects of angiotensin II, including rapid and slow pressor responses, stimulatory effects on the peripheral sympathetic nervous system, CNS effects, release of catecholamines, secretion of aldosterone, direct and indirect renal effects, and all growth-promoting effects.

 Type 2 (AT 2 ): the function of these receptors is not as well characterized; however, they have been proposed to mediate a variety of growth, development, and differentiation processes.

N-(1-Oxopentyl)-N-[[2 َ -(1H-tetrazol-5-yl)[1,1 َ -biphenyl]- 4-yl]methyl]-L-valine