It is a long term medical condition in which the blood pressure in the arteries is persistently elevated.
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 Diastolic BP
NORMAL 120 80
Pre hypertension 120-139 80-89
Primary hypertension 140-159 90-99
Secondary hypertension >160 >100
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:
Risk factors in hypertension:
Management:
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:
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. Potassium-sparing 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.
Hypertension, blood flow, arteries
