Hypertension-1

AMJAD MOUAWIA ALI

 Cardiovascular drugs
[1] Antihypertensive Agents
u Hypertension is the most common cardiovascular disease.
u Hypertension is defined as an sustained elevation of arterial blood pressure
above an arbitrarily defined normal value.
u The normal value for blood pressure differs according to gender, age and
race; men have higher average pressures than women, and in most
populations older individuals have higher pressure than younger subjects.
u The American Heart Association defines hypertension as arterial blood
pressure higher than 140/90 mm Hg, whereas the World Health
Organization uses the value 160/95 mm hg.

Normal range 120/80

u Hypertension, unless rapid in onset and severe, dose not produce noticeable
symptoms. Sustained arterial hypertension damages blood vessels in kidney,
heart and brain and leads to:
 The Heart → atherosclerotic changes and left ventricular hypertrophy can lead to
several heart disorders.
 The Brain → hypertension may result in catastrophic strokes.
 The Kidney → kidney failure may be precipitated by changes in renal vasculature.
 The Eye → retinal haemorrhage may occur.
u Hypertension is there fore a serious – and increasing – public health
problem. It has a definite deleterious effect upon:
u The sufferer’s Life Expectancy and Quality of Life.
u However:
 A minority of hypertensive patients can be cured (by removing the cause).
 The majority of hypertensive patients can be treated (with the several potent
drugs available.
u Effective pharmacologic lowering of blood pressure has been shown to
prevent damage to blood vessels and to substantially reduce morbidity and
mortality rates.
u Risk factors:
u Hypertension itself is undoubtedly dangerous; however, the danger is
significantly increased when other risk factors are present. These include:
Cigarette smoking.
Hyperlipidemia.
Diabetes.
Obesity.
Manifestations of end organ damage at the time of diagnosis.
Family history of cardiovascular disease.
u The risk of end organ damage at any level of blood pressure or age greater
in black people and relatively less in premenopausal women than men.
u There are 2 basic types of hypertension:
A- Essential hypertension → cause unknown
B- Secondary hypertension → result from identifiable Disease.
u Secondary hypertension is often curable; essential hypertension is not,
although it can be satisfactory treated.
u A- Essential hypertension:-
u The cause of essential (or primary) hypertension is not known, it appears to
be a multifactorial disease.
u The basic cause may be genetic aberration leading to:
Failure to handle excessive salt intake.
Inability to cope with stress.
u Several mechanisms may account for the onset and maintenance of
essential hypertension. This involves:
disturbances of the Endocrine system.
disturbances of the Sympathetic nervous system.
impairment of the Regulatory mechanisms.
u B- Secondary hypertension:
u Which accounts for 10 – 20% of all hypertension, occur as the result of an
identifiable disease. For example:
u Kidney disease, renal artery constriction.
u Adrenal gland disease e.g. Cushing’s disease.
u Pheochromocytoma. Benign iflamation
u Primary aldosteronism.
u Vascular disease e.g. Co – arctation of the aorta.
u Toxemia of pregnancy.
u Normal Regulation of Blood Pressure:-
u Arterial blood pressure (BP) is directly proportionate to the product of the
blood flow (cardiac out put, co) and the resistance to passage of blood
through precapillary arterioles (peripheral vascular resistance, PVR):
u BP = COX PVR
u Physiologically, in both normal and hypertensive individuals, blood pressure
is maintained by moment – to – moment regulation of cardiac out put and
peripheral vascular resistance, exerted at many anatomic sites:
 1- Arterioles.
 2- Postcapillary venules (capacitance vessels).
 3- Heart.
 4- The kidney: contributes to maintenance of blood Pressure by regulating the
volume of intravascular fluid.
u Baroreflexes, mediated by autonomic nerves, act in combination with
humoral mechanisms, including the rennin – angiotensin aldosterone system,
to coordinate function at these four control sites and to maintain normal
blood pressure.
u Local release of hormones from vascular endothelium may also be involved
in the regulation of vascular resistance e.g. nitric oxide dilated and
endothelin – 1 constricts blood vessels.
u Blood pressure in a hypertensive patient is controlled by the same
mechanisms that are operative in normotensive subjects. Regulation of
blood pressure in hypertensive differs from normal in that the baroreceptors
and the renal blood volume – pressure control systems appear to be “set” at
a higher level of blood pressure.
u All antihypertensive drugs act by interfering with these normal mechanisms.
u * Classification of antihypertensive agents:-
u A useful classification of these agents categorizes them according to the
principal regulatory site or mechanism on which they act. The categories
include the following:
u 1- Diuretics:
u Lower blood pressure by depleting the body of the sodium and reducing
blood volume and perhaps by other mechanisms.
u 2- Sympathoplegic:
u Lower blood pressure by reducing peripheral vascular resistance, inhibiting
cardiac function, and increasing venous pooling in capacitance vessels.
u These agents are further subdivided according to their putative sites of
action in the sympathetic reflex arc.
u 3- Direct vasodilators:
u Reduce pressure by relaxing vascular smooth muscle, thus dilating
resistance vessels and – to varying degrees – increasing capacitance as
well.
u 4- Agents that block production or action of angiotensin:
u And thereby reduce peripheral vascular resistance and (potentially) blood
volume.
u *** The fact that these drug groups act by different mechanism permits the
combination of drugs from two or more groups with increased efficacy and,
in some cases, decreased toxicity.
u [1] Drugs that alter sodium and water balance:
Diuretics lower blood pressure primarily by depleting body sodium stores.
Diuretics are effective in lowering blood pressure by 10 – 15 mm Hg in most
patients, and diuretics alone often provide adequate treatment for mild or
moderate essential hypertension.
In more severe hypertension, diuretics are used in combination with
sympathoplegic and vasodilator drugs to control the tendency toward sodium
retention caused by these agents.
u * Selection of diuretics:-
Thiazide diuretics are appropriate for most patients with mild or moderate
hypertension and normal renal and cardiac function.
More powerful diuretics (e.g. those acting on the loop of Henle) are necessary in
severe hypertension.
Potassium – sparing diuretics are useful both to avoid excessive potassium
depletion, particularly in patients taking digitalis, and to enhance the natriuretic
effects of other diuretics.
• [2] Drugs that alter sympathetic nervous system function:
• In patients with moderate to severe hypertension, most effective drug regimens
include an agent that inhibits function of the sympathetic nervous system.
• A- Centrally acting sympathoplegic drugs:
• I- Methyldopa:- Alpha receptors

• Mechanism of action:
• Methyldopa is an analog of L-dopa and is converted to α-methyldopamine and α-
methylnorepinephrine.
• α- methylnorepinephrine is stored in adrenergic nerve vesicles, where it replaces
norepinephrine, and is released by nerve stimulation to interact with postsynaptic
adrenoceptors (false transmitter not responsible for methyldopa’s
antihypertensive effect).
• Methyldopa’s antihypertensive action appears to be due to stimulation of central
α-adrenoceptors by α-methylnorepinephrine or α-methyldopamine.
• Methyldopa is useful in the treatment of mild to moderately severe hypertension.
• Methyldopa lowers blood pressure chiefly by reduction of peripheral vascular
resistance, with a variable reduction in heart rate and cardiac output.

Very weak used for 2-3 per day

• Pharmacokinetics:
• It has extensive first-pass metabolism, therefore the bioavailability is low
averaging 25% and varies among individuals.
• About two-thirds of the drug that reaches the systemic circulation is cleared by
renal excretion, with a terminal elimination half-life of 2hours.
• An oral dose of methyldopa produces its maximal antihypertensive effect in 4 – 6
hours, and the effect can persist for up to 24 hours.
• Toxicity:
• Overt sedation (particularly at the onset of treatment), persistent mental lassitude
and impaired mental concentration (with long – term therapy).
• Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but
are relatively infrequent.
• Lactation, associated with increased prolactin secretion, can occur both in men
and women treated with methyldopa.
• II- Clonidine:
• Mechanism of action:-
• The hypertensive effect of clonidine is exerted at α-adrenoceptors in the medulla
of the brain.
• Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1
adrenoceptors.
• It is possible that clonidine and methylnorepinephrine act in the brain to reduce
norepinephrine release out to relevant receptor sites.
• Toxicity:
• Dry mouth and sedation are frequent and may be severe.
• The drug should not be given to patients who are at risk of mental depression
and should be withdrawn if depression occurs during therapy.
• Concomitant treatment with tricyclic antidepressant may block the
antihypertensive effect of clonidine.
• Withdrawal of clonidine after protracted use, particularly with high dosages
(greater than 1 mg/d), can result in life - threatening hypertensive crisis mediated
by increased sympathetic nervous activity. Patients exhibit nervousness,
tachycardia, headache, and sweating after omitting one or two doses of the drug.
• B- Ganglion – Blocking Agents:
• Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic
neurons in both sympathetic and parasympathetic ganglia.
• I – Trimethaphan:
• Trimethaphan is administered intravenously for its rapid action in treating
hypertensive crisis, acute aortic dissection, and to induce controlled for
neurosurgery.
• Adverse effects:
• Sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and
parasympathoplegia (constipation, urinary retention, precipitation of glaucoma,
blurred vision, dry mouth, ect).