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.

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.

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)

N

HN NH

NH2

[2-(Hexahydro-1-azocinyl) ethyl] guanidine

Selective α1-antagonists are effective

antihypertensive agents by blocking the

vasoconstricting effect on the smooth muscle

and not interfere with the activation of α2-

receptors on the adrenergic neurons which

when activated inhibit further release of

norepinephrine.

Doxazosin (Cardura)

Prazocin (Minipress)

Terazocin (Hytrine)

N

N N

N

H3CO

H3CO

NH2

O

O

O

Doxazosin: 1-(4-Amino-6,7-dimethoxy-2-quinazoliny)-4- (1,4-benzodioxan-2-ylcarbonyl)piperazine

N

N N

NO

H3CO

H3CO

NH2

O

PrazosinN

N N

NO

H3CO

H3CO

NH2

O

Terazosin

Cl

Cl

HN NH2

O NH

Guanfacine

N

HN

NH

Cl

Cl

H

Clonidine: [(2,6-Dichlorophenyl)imino]imidazolidine HCl

.HCl

Cl

Cl

N

HN NH2

NH

Guanabenz

HO

HO

H2C C

NH2

CH3

COOC2H5

.HCl

OH

OH

H2C C COOH

NH2

CH3

L-amino acid

decarboxyase

OH

OH

H2C C H

NH2

CH3

OH

OH

CH

C H

NH2

CH3

Dopamine

Hydroxylase

HO

Methyldopa -Methyldopamine -Methylnorepinephrine

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

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.

N

N

HN NH2 .HCl

NH2NH2

N

NH

O

N

N

OH

POCl3

N

N

Cl

N

N

HN NH2

.HCl NH2NH2

O

O

OH

Fe

CN

CNNC

CN

CN

ON

-2

.2H2ONa2

Sodium nitroferricyanide, disodium pentacyanonitrosyle ferate Na2[Fe(CN)NO].

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

benzothiadiazine-1,1-dioxide

N

N

OS

O

CH3

NaCl

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

N

N NH2H2N

N

OMinoxidil(Inactive)

N

N NH2H2N

N

Minoxidil Sulfate (Actine)

Sulfotransferase

SO3

reduced blood pressure

Renin

Lowered Sodium excretion

Angiotensinogen Angiotensin I

Angiotensin II

Converting Enzyme

In active fragments

Angiotensinases (Peptidases)

Vasoconstrictionaldosterone secretion

Renin-Angiotensin System of Blood Pressure Control

Sodium and fluid retention

Increased Peripheral resistanceIncreased cardiac output

Elevated blood pressure

Angiotensin III

(CH2)n Binding group

Zn+2

CN

Ring

X

O

HS CH2

(A)HC NH

COOH

P

O

O(B) (C)

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

proline

N SH

O

CH3

COOH

SH2C C

H

CH3

C

O

N C O

O

Zn+2 +

X

H

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

N

HN

COOHO

CH3C2H5O O

HC

HC

COOH

COOH

The prototype compound which resulted from these studies was saralasin, an octapeptide in

which the Asp1 and phe8 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

N

N N

NH NN

ClCH2OH

The angiotensin II receptor exists in at least two subtypes,

Type 1 (AT1): 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 (AT2): 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-[[2َ-(1H-tetrazol-5-yl)[1,1َ-biphenyl]-4-yl]methyl]-L-valine

N

N N

NH NO

HOOC CH3

CH3