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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
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