Download antihypertensive agents

ANTIHYPERTENSIVE AGENTS
It is the most common cardiovascular disease arising from different etiologies that may
be complex and interrelated.
Hypertension is defined as elevation of systolic blood pressure or diastolic blood
pressure.
Classification of hypertension:
Hypertension is classified as:
Class of blood pressure
Systolic BP
NORMAL
Diastolic BP
120
80
Pre hypertension
120-139
80-89
Primary hypertension
140-159
90-99
>160
>100
Secondary hypertension
Stages of hypertension:
Basing on the systemic arterial blood pressure of certain threshold values, the
hypertension can be divided into 2 stages.
Stage 1: The patients with systolic blood pressure 140-159 mm of Hg and diastolic blood
pressure 90-99 mm of Hg.
Stage 2: In this stage includes patients with systolic blood pressure >160 and or diastolic blood
pressure > 100 mm of Hg.
Causes of hypertension:
Primary causes: a major cause of hypertension is stress.
Stress
High ambition
High workload
High stress
Leads to hypertension
Secondary causes: Diabetic nephropathy, hyperthyroidism, chronic nephritis, hypercalcaemia,
hypothyroidism, due to drugs like steroids, NSAIDs etc.
Complications:

Cardiovascular
risk:
Angina,
heart
failure,
stroke,
myocardial
infarction,
hyperlipidemia.

Renal complication: chronic kidney disease, albuminuria.

Cerebrovascular complication: Dementia, loss of vision, stroke.
Risk factors in hypertension:
 Modifiable – Intake of excess salts, smoking, overweight, obesity, physical inactivity,
stress, diabetes, consumption of high amount of alcohol.
 Unmodifiable – Age, gender, family history
Management:
 Avoidance of cigarette smoking, emotional stress, eating heavy meals
 If there is an identifiable cause, it should be treated.
Diagnosis:
By using sphygmomanometer
Ambulatory blood pressure measurement machine
Treatment:
Non pharmacological therapy: Weight control, diet management, stress management, tobacco
cessation and intake of alcohol must be restricted.
Pharmacological therapy:
1. Diuretics:
A. Thiazide diuretics: Hydrochlorothiazide, Chlorthiazide, chlorthalidone
B. Loop diuretics: Frusemide, ethacrynic acid, bumetanide
C. Potassium sparing diuretics: Amiloride, Spiranolactone, triamterene
2. Sympatholytic drugs:
A. Centrally acting drugs: Methyldopa, clonidine, guanabenz
B. Ganglionic blocking agents: Pentolinum, trimethophan
C. Adrenergic neuron blocking agents: Reserpine, gaunithidine
D. Beta adrenoblockers: Propranolol, atenolol, metoprolol
E. Alpha adrenergic blockers: Prazosin, terazocin, doxazocin
F. Alpha plus beta adrenoblockers: Carvedilol
G. Calcium channel blockers: Amlodipine, Verapamil
H. Vasodilators: Sodium nitroprusside, minoxidil, hydralazine
I. ACE inhibitors: Captopril, enalapril, lisinopril
J. Angiotensin II blocker: Losartan, Candesartan, valsartan, telmisartan, eprosartan,
irbesartan, and olmesartan
Thiazide diuretics: All the oral diuretics are effective in the treatment of hypertension, but the
thiazides have found the most widespread use.
Mechanism of Actions: Thiazide diuretics, such as hydrochlorothiazide, lower blood pressure
initially by increasing sodium and water excretion. This causes a decrease in extracellular
volume, resulting in a decrease in cardiac output and renal blood flow. With long-term treatment,
plasma volume approaches a normal value, but peripheral resistance decreases. Potassiumsparing diuretics are often used combined with thiazides.
Pharmacokinetics: Thiazide diuretics are orally active. Absorption and elimination rates vary
considerably, although no clear advantage is present for one agent over another. All thiazides are
ligands for the organic acid secretory system of the nephron, and as such, they may compete with
uric acid for elimination.
Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 percent of
patients and hyperglycemia in 10 percent of patients. Hypomagnesaemia may also occur. Left
ventricular hypertrophy, ischemic heart disease, or chronic heart failure.
Loop diuretics: The loop diuretics act promptly, even in patients with poor renal function or who
have not responded to thiazides or other diuretics. Loop diuretics cause decreased renal vascular
resistance and increased renal blood flow. Loop diuretics increase the Ca2+ content of urine,
whereas thiazide diuretics decrease it.
Potassium-sparing diuretics: Amiloride and triamterene
(inhibitors of epithelial sodium
transport at the late distal and collecting ducts) as well as spironolactone and eplerenone
(aldosterone-receptor antagonists) reduce potassium loss in the urine. Spironolactone has the
additional benefit of diminishing the cardiac remodeling that occurs in heart failure.
Centrally acting sympatholytic drugs: Centrally acting sympathoplegic drugs were once
widely used in the treatment of hypertension. With the exception of clonidine, these drugs are
rarely used today.
Mechanisms of Action: These agents reduce sympathetic outflow from vasomotor centers in the
brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor
control. Accordingly, the antihypertensive and toxic actions of these drugs are generally less
dependent on posture than are the effects of drugs that act directly on peripheral sympathetic
neurons.
Methyldopa:
This centrally acting agonist is converted to neither methyl nor epinephrine centrally to diminish
the adrenergic outflow from the CNS. This leads to reduced total peripheral resistance and a
decreased blood pressure. Cardiac output is not decreased, and blood flow to vital organs is not
diminished. Because blood flow to the kidney is not diminished by its use. The most common
side effects of methyldopa are sedation and drowsiness. It has been used in hypertensive
pregnant patients.
Clonidine: Clonidine is used primarily for the treatment of hypertension that has not responded
adequately to treatment with two or more drugs. Clonidine does not decrease renal blood flow or
glomerular filtration and, therefore, is useful in the treatment of hypertension complicated by
renal disease. Clonidine is absorbed well after oral administration and is excreted by the kidney.
Because it may cause sodium and water retention, clonidine may be administered in combination
with a diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying
of the nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine.
The drug should therefore be withdrawn slowly if the clinician wishes to change agents. Blood
pressure lowering by clonidine results from reduction of cardiac output due to decreased heart
rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance.
Ganglion-blocking agents: Historically, drugs that block activation of postganglionic
autonomic neurons by acetylcholine were among the first agents used in the treatment of
hypertension. Most such drugs are no longer available clinically because of intolerable toxicities
related to their primary action. Ganglion blockers competitively block nicotinic cholinoceptors
on postganglionic neurons in both sympathetic and parasympathetic ganglia.
Adverse effects: Excessive orthostatic hypotension and sexual dysfunction, constipation, urinary
retention, precipitation of glaucoma, blurred vision, dry mouth.
Adrenergic neuron-blocking agents: These drugs lower blood pressure by preventing normal
physiologic release of nor epinephrine from postganglionic sympathetic neurons.
Guanethidine:
Mechanism of action: Guanethidine inhibits the release of nor epinephrine from sympathetic
nerve endings. This effect is probably responsible for most of the sympathoplegia that occurs in
patients. Guanethidine is transported across the sympathetic nerve membrane by the same
mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the
drug’s action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles,
where it replaces norepinephrine. Because it replaces norepinephrine, the drug causes a gradual
depletion of norepinephrine stores in the nerve ending.
Reserpine: Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia
serpentina, was one of the first effective drugs used on a large scale in the treatment of
hypertension.
Mechanism of action: Reserpine blocks the ability of aminergic transmitter vesicles to take up
and store biogenic amines, probably by interfering with the vesicular membrane-associated
transporter. This effect occurs throughout the body, resulting in depletion of dopamine, nor
epinephrine, and serotonin in both central and peripheral neurons. Chromaffin granules of the
adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the
vesicles of neurons. Reserpine readily enters the brain, and depletion of cerebral amine stores
causes sedation, mental depression, and Parkinsonism symptoms. At lower doses, it is used in the
treatment of mild hypertension, Reserpine lowers blood pressure by a combination of decreased
cardiac output and decreased peripheral vascular resistance.
Beta-adrenoceptor–blocking agents: The pharmacologic properties of several of these agents
differ in ways that may confer therapeutic benefits in certain clinical situations.
Propranolol: Propranolol was the first β blocker shown to be effective in hypertension and
ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers
such as metoprolol and atenolol. All β-adrenoceptor–blocking agents are useful for lowering
blood pressure in mild to moderate hypertension. In severe hypertension, β blockers are
especially useful in preventing the reflex tachycardia that often results from treatment with direct
vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction
and some also reduce mortality in patients with heart failure; they are particularly advantageous
for treating hypertension in patients with these conditions.
Mechanism of Action: Propranolol decreases blood pressure primarily as a result of a decrease
in cardiac output. Propranolol inhibits the stimulation of renin production by catecholamines. It
is likely that propranolol’s effect is due in part to depression of the renin-angiotensinaldosterone
system. In mild to moderate hypertension, Propranolol produces a significant reduction in blood
pressure without prominent postural hypotension.
Alpha adrenoblockers: Prazosin, terazosin, and doxazosin produce most of their
antihypertensive effects by selectively blocking α 1 receptors in arterioles and venules. These
agents produce less reflex tachycardia when lowering blood pressure than do nonselective α
antagonists such as phentolamine. Alpha 1 -receptor selectivity allows norepinephrine to exert
unopposed negative feedback (mediated by presynaptic α 2 receptors) on its own release. Alpha
blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As
expected, blood pressure is reduced more in the upright than in the supine position. Retention of
salt and water occurs when these drugs are administered without a diuretic.
Alpha plus beta adrenoblockers: Carvedilol is administered as a racemic mixture. The S (–)
isomer is a nonselective β-adrenoceptor blocker, but both S (–) and R (+) isomers have
approximately equal α-blocking potency. The isomers are stereo selectively metabolized in the
liver. The average half-life is 7–10 hours. The usual starting dosage of carvedilol for ordinary
hypertension is 6.25 mg twice daily. Carvedilol reduces mortality in patients with heart failure
and is therefore particularly useful in patients with both heart failure and hypertension.
Calcium channel blockers: Calcium channel blockers reduce peripheral resistance and blood
pressure. The mechanism of action in hypertension is inhibition of calcium influx into arterial
smooth muscle cells. Calcium-channel blockers are recommended when the preferred first-line
agents are contraindicated or ineffective. They are effective in treating hypertension in patients
with angina or diabetes. High doses of short-acting calcium-channel blockers should be avoided
because of increased risk of myocardial infarction due to excessive vasodilation and marked
reflex cardiac stimulation.
Verapamil is the only member of this class that is currently approved in the United States.
Verapamil is the least selective of any calcium-channel blocker and has significant effects on
both cardiac and vascular smooth muscle cells. It is used to treat angina, supra ventricular tachy
arrhythmias, and migraine headache.
Adverse effects: Constipation, headache, feeling of fatigue, and dizziness.
Vasodilators:
Sodium nitroprusside: It is a powerful parenterally administered vasodilator that is used in
treating severe heart failure as well as hypertensive emergencies. Nitroprusside dilates both
arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return.
The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or
by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes
vascular smooth muscle.
The direct-acting smooth muscle relaxants, such as minoxidil and hydralazine, have
traditionally not been used as primary drugs to treat hypertension. Vasodilators act by producing
relaxation of vascular smooth muscle, which decreases resistance and, therefore, blood pressure.
These agents produce reflex stimulation of the heart, resulting in the competing reflexes of
increased myocardial contractility, heart rate, and oxygen consumption. These actions may
prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.
Vasodilators also increase plasma renin concentration, resulting in sodium and water retention.
These undesirable side effects can be blocked by concomitant use of a diuretic and a β-blocker.
Hydralazine: This drug causes direct vasodilation, acting primarily on arteries and arterioles.
This results in a decreased peripheral resistance, which in turn prompts a reflex elevation in heart
rate and cardiac output. Hydralazine is used to treat moderately severe hypertension.
Adverse effects: Headache, tachycardia, nausea, sweating, arrhythmia, and precipitation of
angina. A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation
of the drug.
Minoxidil: This drug causes dilation of resistance vessels. Minoxidil is administered orally for
treatment of severe to malignant hypertension that is refractory to other drugs. Reflex
tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic
and a beta-blocker. Minoxidil causes serious sodium and water retention, leading to volume
overload, edema, and congestive heart failure.
ACE Inhibitors: The ACE inhibitors, such as enalapril or lisinopril are recommended when the
preferred first-line agents.
Mechanism of Actions: The ACE inhibitors lower blood pressure by reducing peripheral
vascular resistance without reflexively increasing cardiac output, rate, or contractility. These
drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II.
The converting enzyme is also responsible for the breakdown of bradykinin. ACE inhibitors
decrease angiotensin II and increase bradykinin levels. Vasodilation occurs as a result of the
combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the
potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels,
ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and
water retention.
Adverse effects: Dry cough, rash, fever, altered taste, hypotension, hyperkalemia. Reversible
renal failure can occur in patients with severe bilateral renal artery stenosis.ACE inhibitors are
fetotoxic and should not be used by women who are pregnant.
Angiotensin receptor blockers (ARBs): These drugs block the AT1 receptors. Losartan is the
prototypic ARB; currently, there are six additional ARBs. Their pharmacologic effects are
similar to those of ACE inhibitors in that they produce arteriolar and venous dilation and block
aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention.
ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making
them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of
ACE inhibitors, although the risks of cough and angioedema are significantly decreased. ARBs
are also fetotoxic.