1 Cardiovascular drugs Antihypertensive Drugs Hypertension is a persistent elevation of arterial blood pressure (over 90/140 mm.Hg.), it is the most common cardiovascular disease and the major factor of many diseases such as coronary artery disease, heart failure, stroke and renal failure. Hemodyna mically, 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. Drug therapy in hypertension management must be for every individual and adjusted on co-existing risk factors such as: 1-Degree of blood pressure elevation. 2-Severity of the disease. 3-The presence of underlying other cardiovascular risk factor. 4-Response to the therapy 5-Tolerance to drug induced side effects. Large % of patients use a combination of 2 drugs at low doses with different mechanism of action, so a synergestic blood pressure lowering occur with minimal side effects. 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: i-Tumors of the adrenal medulla that causes release of large amounts of catecholamines create hypertensive-state known as pheochromocytoma. ii-An excessive secretion of aldosterone by the adrenal cortex, often because of adenomas, also produces hypertensive disorders. iii-Enhanced adrenergic activity is r ecognized as a peripheral contributo r to essential hypertension. Antihype rtensive agents are classified into:- Classifi cation of antihypertensive drugs: 1-Sympatholytics: yCentrally acting drugs. yGanglionic blocker drugs.
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The parent compound -methyldopa was found to be an inhibitor of dopa decarboxylase (L-amino acid decarboxylase, an
enzyme involved in the biosynthesis of NE and epinephrine) and the compound found to be an effective antihypertensiveagent. Detailed studies, however, showed that its hypertension effect not be explained by the inhibition of dopa
decarboxylase in the peripheral nerves, but it was found also that -methylnorepinephrinedisplaces NE in nerve terminals
Hydralazine action appear to be centered on the relaxation of the smooth muscle of the vascular walls especiallyof the arteries with a decrease in the peripheral resistance to blood flow, which is an important consideration in patient
with renal insufficiency.
The mechanism of action is proposed that hydralazine interferes with Ca2+ entry and Ca2+ release from
intracellular stores. It has also been reported that hydralazine causes activation of guanylatecyclase, resulting in
increasinglevels of c-GMP. All of these biochemical events can cause vasodilatation. The diastolic blood pressure usually
is decreased more than diastolic one.
Side effects:
1-Its reduction in blood pressure and peripheral resistance causes a reflex response which is accompanied by
increase in the heart rate, cardiac output and plasma rennin activity. These effects limits its effectiveness.
2-It also causes sodium and water retension with expansion of blood volume which could develop tolerance to its
hypertensive effect during prolonged therapy. So co-administration of a diuretic improves the therapeutic outcome.
Therapeutic applications:
1- It is used in the management of moderate to severe hypertension. It is generally used for patients who fails torespond to any hypertensive regimen.
2- Parenteral hydralazine is used for management of severe hypertension when the drug can not be taken orally
or blood pressure must be lowered immediately.
Metabolism:
It is metabolized by NH2 acetylation or OH of the phenyl ring followed by N- or O- glucuronide conjugation.
3-They produce accumulation of cyanide which binds to haemoglobinproducing methemoglobinemia
4-It can bind to vitamin B6 and interfere with its distribution and metabolism.
III-Potassium channel agonists
Mechanism of action:
These drugs are called potassium channel opener. They activate ATP sensitive potassium channel in the vascular
smooth muscles (VSM) which lead to increase efflux of K + ion to the cells, in addition to decrease in the intracellular
calcium and reduce excitability of smooth muscles. The increased efflux of potassium from the cell results in
hyperpolarization of the membrane and hence decreased excitation.
With less calcium available to combine with protein so less phosphorylation of myosin light chains occurs leading
to relaxation and vasodilatation.
Diazoxide (Hyperstate IV)
Sodium 7-Chloro-3-methyl-2H-1,2,4-
benzothiadiazine1,1-dioxide
Diazoxide is a non diuretic hypotensive agent, it also has hyperglycemic activity. Although it is structurally
related to thiazide diuretics, it causes sodium and water retension with decrease in urinary output which can result inexpansion of plasma and extracellular fluid volume, edema and conjestive heart failure especially with prolonged
administration.
Mechanism of action:
It is suggested to act by
1-depleting an intracellular pool of Ca2+, inhibiting the release of Ca2.
2-It prolongs the opening of K
+
channel sustaining greater vasodilation on arterioles than in veins.
3-It causes increase in blood glucose level by inhibit insulin secretion, and increase hepatic release of glucose.
Therapeutic application:
1-IV drug is used in emergencies which need urgent decrease in diastolic pressure especially in adults with severe
hypertension, and with children with acute severe hypertension.
All commercially available angiotensin II antagonists are analogs of the following general formula.
Acidic gr u
N
N
R
Acidic gr u COOH
HOOC
NHN
N
N
A B C
1- The acidic group is thought to mimic either the Tyr 4 phenol or the Asp1 carboxylate of angiotensin II. Groups capable
of such a role include the carboxylic acid (A), a phenyl tetrazole (B), or phenyl carboxylate (C).
2-
In the biphenyl series, the tetrazole and carboxylic groups must be in the ortho position for optimal activity (theterazole group is superior in terms of metabolic stability, lipophilicity, and bioavailability).
3- The n-butyl group of the model compounds provides hydrophobic binding and most likely mimics the side chain of
Ile5 of angiotensin II.
4- The imidazole ring or an isosteric equivalent is required to mimic the His6 side chain of angiotensin II.
5- Substitution with a variety of R groups including a carboxylic acid, methyl alcohol, an ether, or an alkyl chain is
required to mimic the Phe8 of angiotensin II. all of these groups are thought to interact with the AT1 receptor, some
through ionic or ion-dipole bonds and others through hydrophobic interactions.