Hypertension

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HYPERTENSION & REGULATION OF BLOOD PRESURE

INTRODUCTION:

Hypertension is the most common cardiovascular disease. In a survey carried out in 2000, hypertension was found in 28% of American adults. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. According to a Framingham study of blood pressure trends in middle-aged and older individuals, approximately 90% of Caucasian Americans will develop hypertension in their lifetime. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. Unfortunately, several surveys indicate that only one third of Americans with hypertension have adequate blood pressure control. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. As a result, rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients.

HYPERTENSION:

Hypertension is defiend as either a continued systolic blood pressure(SBP) of greater than 140 mm hg or a sustained diastolic blood pressure (DBP) of greater than 90 mm hg.Hypertension results from increased peripheral vascular smooth muscle tone,which leads to increased arteriolar resistance and reduced capacitance of the venous system.In most cases,the cause of the increased vascular tone is unknown.Elevated blood pressure is an extremely common disorder,affecting approximatelty of 15% of the population of United States(60 million people).Although many individuals have no symptoms,chronic hypertension either systolic or diastolic can lead to cereberovascular accidents(stroke),congestive heart failure,myocardial infaction and renal demage.The incidence of morbidity and mortality significantly decreases when hypertension is diagnosed early and is properly treated.In recognition of the progressive nature of moderate hypertension ,the seventh report of the Joint National Committee classifies hypertension in to 4 categories for the purpose of treatment hypertension.The categories are normal (SBP/SBP,<120/<80),prehypertension (SBP/DBP,120-139/80-89),stage 1 hypertension (SBP/DBP,140-159/90-99), and stage 2 hypertension (SBP/DBP≥160/≥100).

HYPERTENSION & REGULATION OF BLOOD PRESURE:
DIAGNOSIS:

The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure. The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension.

Even mild hypertension (blood pressure 140/90 mm Hg) increases the risk of eventual end organ damage. Starting at 115/75 mm Hg cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pressure range. Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. The risks¾and therefore the urgency of instituting therapy¾increase in proportion to the magnitude of blood pressure elevation. The danger of end organ damage at any level of blood pressure or age is greater in African-Americans and relatively less in premenopausal women than in men. Other positive risk factors include smoking, hyperlipidemia, diabetes, manifestations of end organ damage at the time of diagnosis, and a family history of cardiovascular disease.It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end organ damage is imminent or has already occurred.

ETIOLOGY OF HYPERTENSION

Although hypertension may occur secondary to other disease processes, more than 90 percent of patients have essential hypertension, a complaint of unknown origin affecting the blood pressure regulating mechanism. A family history of hypertension increases the likelihood that an individual will develop hypertensive disease. The incidence of essential hypertension is four-fold more frequent among blacks than among whites. It occurs more often among middle-aged males than among middle-aged females, and its incidence increases with age and obesity. Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking, further predispose an individual to the occurrence of hypertension.
NORMAL REGULATION OF BLOOD PRESSURE

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment parameter of cardiac output and peripheral vascular resistance, exerted at three anatomic sites

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1.ARTERIOLES,

2.POSTCAPILLARY VENULES (CAPACITANCE VESSELS)

3.HEART.

.Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be "set" at a high-level of blood pressure. All antihypertensive drugs act by inquisitive with these normal mechanisms, which are reviewed below.

A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by changeable the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressureFor example, endothelin-1 constricts and nitric oxide dilates blood vessels.Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance

A. POSTURAL BAROREFLEX

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Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture. Central sympathetic neurons arising from the vasomotor area of the medulla are topically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral vascular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex amplify in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure.

(eg, due to hemorrhage or to loss of salt and water via the kidney).

B. RENAL RESPONSE TO DECREASED BLOOD PRESSURE

By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water.

(1) direct constriction of resistance vessels

(2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidneyIn addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via adrenoceptors) stimulates production of renin,which increases production of angiotensin II Angiotensin II causes

TREATMENT STRATEGIES:

The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. The connection between blood pressure and the risk of a cardiovascular event is continuous, and thus lowering of even moderately elevated blood pressure significantly reduces cardiovascular disease. The newly added classification of prehypertension recognizes this relationship and emphasizes the need for decreasing blood pressure in the general population by education and adoption of blood pressure lower behaviors. Mild hypertension can often be controlled with a single drug; however, most patients require more than one drug to achieve blood pressure control.If blood pressure is inadequately controlled, a second drug is added, with the selection based on minimizing the adverse effects of the combined regimen. Current recommendations are to initiate therapy with a thiazide diuretic unless there are compelling reasons to employ other drug classes

According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR)

INDIVIDUALIZED CARE

Certain subsets of the hypertensive population respond better to one class of drug than they do to another Similarly, calcium-channel blockers, ACE inhibitors, and diuretics are favored for treatment of hypertension in the elderly, whereas β²-blockers and α-antagonists are less well tolerated.

For example, black patients respond well to diuretics and calcium-channel blockers, but therapy with β²-blockers or ACE inhibitors is often less efficient.

CONCOMITANT

DISEASE

HIGH-RISK

ANGINA PECTORIS

Diuretics

β Blockers

ACE inhibitors

Ca²⁺ channel blockers

DIABETES

Diuretics

β Blockers

ACE inhibitors

ARBs

Ca²⁺ channel blockers

RECURRENT STROKE

Diuretics

ACE inhibitors

HEART FAILURE

Diuretics

β Blockers

ACE inhibitors

ARBs

PREVIOUS MYOCARDIAL

INFARCTION

β Blockers

ACE inhibitors

TREATMENT OF HYPERTENSION IN PATIENTS WITH CONCOMITANT DISEASES.DRUG SHOWN IN PURPLE COLORS PROVIDE IMPROVMENT IN OUTCOME

PATIENT COMPLIANCE IN ANTIHYPERTENSIVE THERAPY

Lack of patient compliance is the most common reason for failure of antihypertensive therapy. The hypertensive patient is usually asymptomatic and is diagnosed by schedule screening before the occurrence of overt end-organ damage. Thus, therapy is generally directed at preventing future disease squealed rather than relieving the patient's present discomfort..

BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS

INTRODUCTION

A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act. All antihypertensive agents act at one or more of the four anatomic control sites depicted in and produce their effects by interfering with normal mechanisms of blood pressure regulation.Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following:

(1) Diuretics: Which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms.

(2) Sympathoplegic agents: Which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac meaning, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their supposed sites of action in the sympathetic reflex arc

(3) Direct vasodilators: Which reduce stress by relaxing vascular smooth muscle, thus dilating resistance vessels and¾ to varying degrees¾ rising capacitance as well.

(4) Agents that block production or action of angiotensin: Thereby reduce peripheral vascular resistance and (potentially) blood volume.

DIURETICS

The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity.

Many antihypertensive drugs have their primary action on systemic vascular resistance. Some of these drugs produce vasodilation by interfering with sympathetic adrenergic vascular tone (sympatholytics) or by blocking the formation of angiotensin II or its vascular receptors.By reducing sympathetic efferent activity, centrally acting drugs decrease arterial pressure by decreasing systemic vascular resistance and cardiac output. Other drugs are direct arterial dilators, and some are mixed arterial and venous dilators. Although less commonly used because of a high incidence of side effects, there are drugs that act on regions in the brain that control sympathetic autonomic outflow.Some antihypertensive drugs, most notably beta-blockers, depress heart rate and contractility (this decreases stroke volume) by blocking the influence of sympathetic nerves on the heart. Calcium-channel blockers, especially those that are more cardioselective, also reduce cardiac output by decreasing heart rate and contractility. Calcium-channel blockers, especially those that are more cardioselective, also reduce cardiac output by decreasing heart rate and contractility.

DRUGS THAT ALTER SODIUM & WATER BALANCE:
INTRODUCTION:

Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients.However, there is now general agreement that dietary control of blood pressure is a relatively nontoxic therapeutic measure and may even be preventive. With the advent of diuretics, sodium restriction was thought to be less important.Several studies have shown that even modest dietary sodium restriction lowers blood pressure (although to varying extents) in many hypertensive persons.

MECHANISMS OF ACTION & HEMODYNAMIC EFFECTS OF DIURETICS:

Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. These effects are reversed by diuretics or sodium restriction. After 6-8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium.

Some diuretics have direct vasodilating effects in addition to their diuretic action. Indapamide is a nonthiazide sulfonamide diuretic with together diuretic and vasodilator activity. As a consequence of vasodilation, cardiac output remains unchanged or increase slightly. Amiloride inhibits smooth muscle responses to contractile stimuli, probably through effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion.

Thus, in severe hypertension, when multiple drugs are used, blood pressure may be well controlled when blood volume is 95% of normal but much too high when blood volume is 105% of normal.Diuretics are effective in lowering blood pressure by 10-15 mm Hg in most patients, and diuretics, the ability to either constrict or dilate¾is diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube. As blood pressure becomes exquisitely 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. Vascular responsiveness¾iesensitive to blood volume.

USE OF DIURETICS:

The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. More powerful diuretics (eg, those acting on the loop of Henle) are needed in severe hypertension, when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration speed is less than 30 or 40 mL/min; and in cardiac failure or cirrhosis, where sodium retention is marked.

Potassium-sparing diuretics are useful both to avoid excessive potassium reduction, particularly in patients taking digitalis, and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure. ), when used as a single agent, lower doses (25-50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.

Some pharmacokinetic characteristics and the initial and usual maintenance dosages of hydrochlorothiazide are listed in.Although thiazide diuretics are more natriuretic at higher doses (up to 100-200 mg of hydrochlorothiazide).

TOXICITY OF DIURETICS:

In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to reabsorption of sodium, and restriction of dietary sodium intake will therefore minimize potassium loss. Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction Diuretics increase uric acid concentrations and may precipitate gout. The use of low doses minimizes these adverse metabolic effects without impairing the antihypertensive action. Several case-control studies have reported a small but significant excess risk of renal cell carcinoma associated with diuretic use. Potassium-sparing diuretics may produce hyperkalemia, particularly in patients with renal insufficiency and those taking ACE inhibitors or angiotension receptor blockers; spironolactone (steroid) is associated with gynecomastia.

BETA-ADRENOCEPTOR-BLOCKING AGENTS
INTRODUCTION

Of the large number of β blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ from those of propranolol in ways that may confer therapeutic benefits in certain clinical situations.

Decrease In Blood pressure

1.METOPROLOL:

Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of b1 adrenoceptors such as those in the heart but 50- to 100-fold less potent than propranolol in blocking b2 receptors. Even though metoprolol is in other respects very similar to propranolol, its relative cardioselectivity may be advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Studies of small numbers of asthmatic patients have shown that metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of b1 adrenoceptor responses. The cardioselectivity is not complete, however, and asthmatic symptoms have been exacerbated by metoprolol.

2. PINDOLOL, ACEBUTOLOL, & PENBUTOLOL:

Pindolol, acebutolol, and penbutolol are partial agonists, ie, b blockers with some intrinsic sympathomimetic activity. They lower blood pressure by decreasing vascular resistance and appear to sadden cardiac output or heart rate less than other b blockers, perhaps because of significantly greater agonist than antagonist effects at b2 receptors. This may be particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease. Daily doses of pindolol start at 10 mg; of acebutolol, at 400 mg; and of penbutolol, at 20 mg.

3. NADOLOL, CARTEOLOL, ATENOLOL, BETAXOLOL, & BISOPROLOL:

Nadolol and carteolol, nonselective b-receptor antagonists, and atenolol, a b1-selective blocker, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are b1-selective blockers that are primarily metabolized in the liver but have long half-lives. Because of these moderately long half-lives, these drugs can be administered once daily. Nadolol is usually begun at a dosage of 40 mg/d, atenolol at 50 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days. Patients with reduced renal function should receive correspondingly reduced doses of nadolol, carteolol, and atenolol. It is claimed that atenolol produces fewer central nervous system-related effects than other more lipid-soluble b antagonists.

4. LABETALOL & CARVEDILOL:

Labetalol has a 3:1 ratio of b:a antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output. Because of its combined a- and b-blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20-80 mg to treat hypertensive emergencies.
Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers¾the (S,S)- and (R,S)-isomers¾are relatively inactive, a third (S,R)- is a potent a blocker, and the last (R,R)- is a potent b blocker. The b-blocking isomer is thought to have selective b2 agonist and nonselective b antagonist action.

Carvedilol, like labetalol, is administered as a racemic mixture. The S(-) isomer is a nonselective b-adrenoceptor blocker, but both S(-) and R(+) isomers have approximately equal a-blocking potency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. The average half-life is 7-10 hours. The usual starting dosage of carvedilol for ordinary hypertension is 6.25 mg twice daily.

5. ESMOLOL:

Esmolol is a b1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short half-life (9-10 minutes) and is administered by constant intravenous infusion.Esmolol is used for managing of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia. Esmolol is generally administered as a loading dose (0.5-1 mg/kg), followed by a constant infusion. The infusion is typically started at 50-150 mcg/kg/min, and the dose increased every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the desired therapeutic effect.

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS:
INTRODUCTION:

CAPTOPRIL:

Drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator, which works at least in part by stimulating release of nitric oxide and prostacyclin. The hypotensive action of captopril results both from an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein-kinin system The latter mechanism has been confirmed by showing that a bradykinin receptor antagonist, icatibant blunts the blood pressure-lowering effect of captopril.

ENALAPRIL:

It is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver.

Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease.Accordingly, renin profiling is unnecessary.ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure). These benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and after myocardial infarction, and there is recent evidence that ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk The absence of reflex tachycardia may be due to downward resetting of the baroreceptors or to enhanced parasympathetic activity.Although converting enzyme inhibitors are most effective in conditions associated with high plasma renin activity, there is no good correlation among subjects between plasma renin activity and antihypertensive response.

PHARMACOKINETICS AND DOSAGE:

Captopril's pharmacokinetic parameters and dosing recommendations are set forth in. Peak concentrations of enalaprilat, the active metabolite, occur 3-4 hours after dosing with enalapril. The half-life of enalaprilat is about 11 hours. Typical doses of enalapril are 10-20 mg once or twice daily. Lisinopril.All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses of these drugs should be reduced in patients with renal insufficiency. Typical doses of enalapril are 10-20 mg once or twice daily. Lisinopril has a half-life of 12 hours. Doses of 10-80 mg once daily are effective in most patients.

TOXICITY:

Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes. Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition.The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. Modern evidence also implicates first trimester exposure to ACE inhibitors in increased teratogenic risk.Minor toxic effects seen more typically include altered sense of taste, allergic skin rashes, and drug fever, which may occur in as many as 10% of patients.Important drug interactions include those with potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia. Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykinin-mediate vasodilation, which is at least in part, prostaglandin mediated.

ANGIOTENSIN RECEPTOR-BLOCKING AGENTS:

Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently, candesartan, eprosartan, irbesartan, and telmisartan have been released. They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors.

Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently, candesartan, eprosartan, irbesartan, and telmisartan have been released. They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors.

RENIN INHIBITORS:

A selective renin inhibitor, aliskiren has been released for the treatment of hypertension. Aliskiren directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system than ACE inhibitors or ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. It can also be collective other antihypertensives, such diuretics, ACE inhibitors, ARBs, or calcium-channel blockers. Aliskiren can cause diarrhea, especially at the higher doses..The drug is contraindicated during pregnancy. The combination of maximum doses of aliskiren and valsartan decrease blood pressure more than maximum doses of either agent alone but not more than would be expected with dual therapy consisting of agents of different classes. Hyperkalemia was significantly more common in patients who received both valsartan and aliskiren. Aliskiren can cause diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but most likely less often than ACE inhibitors.

CALCIUM-CHANNEL BLOCKERS

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.

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.

CLASSES OF CALCIUM-CHANNEL BLOCKERS

The calcium-channel blockers are divided into three chemical classes, each with different pharmacokinetic properties and clinical indications

* Benzothiazepines: Diltiazem is the only member of this class that is currently approved in the United States. Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil. Diltiazem has a favorable side-effect profile.

* Diphenylalkylamines: 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, supraventricular tachyarrhythmias, and migraine headache

Dihydropyridines:These second-generation calcium-channel blockers differ in pharmacokinetics, approved uses, and drug interactions. All dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. This rapidly expanding class of calcium-channel blockers includes the first-generation nifedipine and five second-generation agents for treating cardiovascular disease: amlodipine felodipine isradipine nicardipine and nisoldipineThey are therefore particularly attractive in treating hypertension.

Some of the newer agents, such as amlodipine and nicardipine, have the advantage that they show little interaction with other cardiovascular drugs, such as digoxin or warfarin, which are often used concomitantly with calcium-channel

ACTIONS

The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in the contraction of the myocardium. Calcium enters muscle cells through special voltage-sensitive calcium channels.Calcium-channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium

PHARMACOKINETICS

Sustained-release preparations are available and permit less frequent dosing. Amlodipine has a very long half-life and does not required a sustained-release formulation. Most of these agents have short half-lives (3 to 8 hours) following an oral dose. Treatment is required three times a day to maintain good control of hypertension.

THERAPEUTIC USES

Calcium-channel blockers have an intrinsic natriuretic effect and, therefore, do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease

THERAPEUTIC

INDICATIONS

HYPERTENSION

VERAPAMIL

DILTIAZEM

NIFEDIPINE

FELODIPINE

ISRADIPINE

AMLODIPINE

ANGINA

VERAPAMIL

DILTIAZEM

NIFEDIPINE

AMLODIPINE

SUPREVENTICULAR TACHYCARDIA ARRYTHMIA

VERAPAMIL

DILTIAZEM

SAFE IN MILD TO MODERATE HEART FAILURE

FELODIPINE

ISRADIPINE

AMLODIPINE

SAFE WITH β BLOCKERS

DILTIAZEM

NIFEDIPINE

FELODIPINE

ISRADIPINE

AMLODIPINE

Figure 4 Therapeutic actions of Calcium Channel Blockers

ADVERSE EFFECTS

Constipation occurs in 10 percent of patients treated with verapamil. Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines (Figure 19.13). Verapamil should be avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects.

ALPHE ADRENORECEPTOR BLOCKING AGENT:

Proposing,oxazosin ,terazosin produce a competitive block of α1-adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation of both arterial and venous smooth muscle.Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Reflex tachycardia and first-dose syncope are almost universal adverse effects. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia does not occur, but salt and water retention does Concomitant use of a β-blocker may be necessary to blunt the short-term effect of reflex tachycardia. An increased rate of congestive heart failure occurs in patients taking doxazosin alone compared to those taking a thiazide diuretic alone. Because of the side-effect profile, development of tolerance, and the advent of safer antihypertensives, αblockers are seldom used in the treatment of hypertension. Tamsulosin, an β blocker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia.

ADRENOCEPTOR BLOCKING AGENTS:

Labetalol and carvedilol block both α1- and β1- and β2- receptors. Carvedilol has been shown to reduce mortality associated with heart failure. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure.

DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION

INTRODUCTION

In patients with moderate to severe hypertension, most effective drug regimens include an agent that inhibits function of the sympathetic nervous system. Drugs in this group are classified according to the site at which they impair the sympathetic reflex arc.This neuroanatomic classification explains prominent differences in cardiovascular effects of drugs and allows the clinician to predict interactions of these drugs with one another and with other drugs.

Finally, one should note that all of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For these reasons, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic. Most importantly, the subclasses of drugs exhibit different patterns of potential toxicity. Drugs that lower blood pressure by actions on the central nervous system tend to cause sedation and mental depression and may produce disturbances of sleep, including nightmares. Drugs that act by inhibiting transmission through autonomic ganglia produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade. Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause effects that are similar to those of surgical sympathectomy, including inhibition of ejaculation, and hypotension that is increased by upright posture and after exercise. Drugs that block postsynaptic adrenoceptors produce a more selective spectrum of effects depending on the class of receptor to which they bind.

CENTRALLY ACTING SYMPATHOPLEGIC DRUGS

MECHANISMS & SITES OF ACTION

These agents reduce sympathetic outflow from vasopressor 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 (L METHYL-3,4-DIHYDROXYPHENYLALANINE):

It is an analog of L-dopa and is converted to a-methyldopamine and a-methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, However, this replacement of norepinephrine by a false spreader in peripheral neurons is not responsible for methyldopa's antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the a adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. Direct electrical inspiration of sympathetic nerves in methyldopa-treated animals produces sympathetic responses similar to those observed in untreated animals.

In fact, methyldopa's antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine, based on the following evidence:

(1) Much lower doses of methyldopa are required to lower blood pressure in animals when the drug is administered centrally by injection into the cerebral ventricles rather than intravenously.

(2) Potent inhibitors of dopa decarboxylase, administered centrally, block methyldopa's antihypertensive effect, thus showing that metabolism of the parent drug in the central nervous system is necessary for its action.

(3) Alpha-receptor antagonists, especially a2-selective antagonists, administered centrally, block the antihypertensive effect of methyldopa, whether the latter is given centrally or intravenously.

CLONIDINE 2-IMIDAZOLINE DERIVATIVE:

It was discovered in the course of testing the drug for use as a topically applied nasal decongestant.After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension.The drug is classified as a partial agonist at a receptors because it also inhibits pressor effects of other a agonists. The pressor response is due to direct stimulation of a adrenoceptors in arterioles.

These observations suggest that clonidine sensitizes brainstem pressor centers to inhibition by baroreflexes. Considerable evidence indicates that the hypotensive effect of clonidine is exerted at a adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of a antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels.Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and a-methylnorepinephrine bind more tightly to a2 than to a1 adrenoceptors.

As noted in , α2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and a-methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic a2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effect.

Methyldopa and clonidine produce slightly different hemodynamic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of act. They may act primarily on different populations of neurons in the vasomotor centers of the brainstem.

GUANABENZ AND GUANFACINE:

They are centrally active antihypertensive drugs that share the central -adrenoceptor-stimulating effects of clonidine. They do not appear to offer any advantages over clonidine.

CENTRALLY ACTING ADRENERGIC DRUGS
αMETHYLDOPA

This α2-agonist is converted to methylnorepinephrine 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, α-methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of α-methyldopa are sedation and drowsiness. It has been used in hypertensive pregnant patients.

CLONIDINE

This α2-agonist diminishes central adrenergic outflow. 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. 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. 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.

VASODILATORS

The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, 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.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 βblocker. 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.

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 monotherapy is an accepted method of controlling blood pressure in pregnancy-induced hypertension. Adverse effects of hydralazine therapy include 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. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a β-blocker, such as propranolol (to balance the reflex tachycardia), and a diuretic (to decrease sodium retention). Together, the three drugs decrease cardiac output, plasma volume, and peripheral vascular resistance

MINOXIDIL

This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs.Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure.Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness. . Reflex tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic and a β-blocker.

HYPERTENSIVE EMERGENCY

Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP>210 mm Hg) in an otherwise healthy person or >130 mm Hg in an individual with preexisting complications,The therapeutic goal is to rapidly reduce blood pressure. such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis.

SODIUM NITROPRUSSIDE

Nitroprusside is administered intravenously and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension.Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide. Nitroprusside is light sensitive, and when in solution, it should be protected from light. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle.Because nitroprusside also acts on the veins, it can reduce cardiac preload. Nitroprusside is metabolized rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action.

CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS:

INTRODUCTION

Hypertension presents a unique problem in therapeutics. It is usually a lifelong disease that causes few symptoms until the advanced stage. For effective treatment, medicines that may be expensive and often produce adverse effects must be consumed daily. Persistence of hypertension, particularly in persons with mild elevation of blood pressure, should be established by finding an elevated blood pressure on at least three different office visits. Ambulatory blood pressure monitoring may be the best predictor of risk and therefore of need for therapy in mild hypertension. Isolated systolic hypertension and hypertension in the elderly also benefit from therapy. Thus, the physician must establish with certainty that hypertension is persistent and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures.

Once the decision is made to treat, a therapeutic regimen must be developed. Selection of drugs is dictated by the level of blood pressure, the presence and severity of end organ damage, and the presence of other diseases. Severe high blood pressure with life-threatening complications requires more rapid treatment with more efficacious drugs. Most patients with essential hypertension, however, have had elevated blood pressure for months or years, and therapy is best initiated in a gradual fashion. Once the presence of hypertension is established, the question of whether or not to treat and which drugs to use must be considered. The level of blood pressure, the age and sex of the patient, the severity of organ damage (if any) due to high blood pressure, and the presence of cardiovascular risk factors must all be considered. At this stage, the patient must be educated about the nature of hypertension and the importance of treatment so that he or she can make an informed decision regarding therapy.

OUT PATIENT THERAPY OF HYPERTENSION

The initial step in treating hypertension may be nonpharmacologic.A sodium restriction may be effective treatment for many patients with mild hypertension. which can be achieved by not salting food during or after cooking and by avoiding processed foods that contain large amounts of sodium. Eating a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat, and moderation of alcohol intake (no more than two drinks per day) also lower blood pressure. The average American diet contains about 200 mEq of sodium per day. A reasonable dietary goal in treating hypertension is 70-100 mEq of sodium per day,

Weight reduction even without sodium restriction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients.

The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, ACE inhibitors are particularly useful in patients with evidence of chronic kidney disease. Beta blockers or calcium channel blockers are useful in patients who also have angina; diuretics, ACE inhibitors, angiotension receptor blockers, or  blockers in patients who also have heart failure; and 1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: African-Americans respond better to diuretics and calcium channel blockers than to  blockers and ACE inhibitors. Chinese are more sensitive to the effects of  blockers and may require lower doses. For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug. However, most patients with hypertension require two or more antihypertensive medications. Thiazide diuretics,  blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of hypertension and may be used for initial drug therapy. There has been concern that diuretics, by adversely affecting the serum lipid profile or impairing glucose tolerance, may add to the risk of coronary disease, thereby offsetting the benefit of blood pressure reduction. However a recent large clinical trial comparing different classes of antihypertensive mediations for initial therapy found that chlorthalidone (a thiazide diuretic) was as effective as other agents in reducing coronary heart disease death and nonfatal myocardial infarction, and was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke.

Fixed-dose combinations have the drawback of not allowing for titration of individual drug doses but have the advantage of allowing fewer pills to be taken, potentially enhancing compliance. If a single drug does not adequately control blood pressure, drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity ("stepped care"). If a diuretic is not used initially, it is often selected as the second drug. If three drugs are required, combining a diuretic, a sympathoplegic agent or an ACE inhibitor, and a direct vasodilator (eg, hydralazine or a calcium channel blocker) is often effective. In the USA, fixed-dose drug combinations containing a  blocker, an ACE inhibitor, or an angiotensin receptor blocker plus a thiazide, and a calcium channel blocker plus an ACE inhibitor are available.

Systolic hypertension ( 140 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 50 years of age and should be treated. In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume (this can be measured directly), and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, over-the-counter sympathomimetics, abuse of stimulants (amphetamine or cocaine), or excessive doses of caffeine and oral contraceptives that can interfere with actions of some antihypertensive drugs or directly raise blood pressure.Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient. The recent large Hypertension Optimal Treatment study suggests that the optimal blood pressure end point is 138/83 mm Hg. Lowering blood pressure below this level produces no further benefit. In diabetic patients, however, there is a continued reduction of event rates with progressively lower blood pressures.

PREVENTION OF HYPERTENSION (HIGH BLOOD PRESSURE):

VITAMIN C LOWERS BLOOD PRESSURE:

Augusta .Researcher at the Medical College of Georgia have confirmed that people with a high vitamin C concentration in their blood have lower blood pressures than do people with little vitamin C.Among their findings: plasma ascorbic acid levels were 11% higher in supplement users than in non-users; both diastolic and systolic blood pressure were about 5 mm lower in people having a high plasma level of vitamin C than in people having a low level. Blood levels of selenium, vitamin A and vitamin E were not found to affect blood pressure, but both obesity and smoking had a significant adverse effect. They tested 168 healthy people, 56 of which were taking supplements containing ascorbic acid.

POTASSIUM SUPPLEMENTATION LOWERS BLOOD PRESSURE

Baltimore,Maryland. Researchers at the Johns Hopkins University School of Medicine have come out in favour of using supplementation with potassium in the treatment and prevention of hypertension (high blood pressure).The average observed decrease in hypertensive patients was 4.4 mm Hg and 2.5 mm Hg for systolic and diastolic pressure respectively. In people with normal blood pressure the observed decreases were 1.8 mm and 1.0 mm. The amount of elemental potassium used in the studies varied from 60 mmol (2.5 grams) to 120 mmol (5.0 grams) daily. Sixty mmol of potassium is equivalent to 4.5 grams of potassium chloride, 6 grams of potassium bicarbonate or 20 grams of potassium citrate. A group of seven medical researchers reviewed 33 randomized, controlled supplementation trials involving over 2600 participants. They conclude that potassium supplementation is effective in lowering both systolic and diastolic blood pressure. Oral potassium supplementation appeared to be well tolerated in all the studies examined. The researchers conclude that potassium supplementation "should be considered as part of recommendations for prevention and treatment of hypertension." Potassium supplementation is particularly important in people who are unable to reduce their intake of sodium.

MAINTAINING A HEALTHY WEIGHT

Even small amounts of weight loss can make a big difference in helping to prevent and treat high blood pressure.Being overweight can make you two to six times more likely to develop high blood pressure than if you are at your desirable weight

GETTING REGULAR EXERCISE:

People who are physically active have a lower risk of getting high blood pressure -- 20%-50% lower -- than people who are not active.Even light activities, if done daily, can help lower your risk. You don't have to be a marathon runner to benefit from physical activity

REDUCING SALT INTAKE:

Cutting back on salt also prevents blood pressure from rising.Often, when people with high blood pressure

DRINKING ALCOHOL IN MODERATION, IF AT ALL:

The "Dietary Guidelines for Americans" recommend that for overall health, women should limit their alcohol to no more than one drink a day.Drinking too much alcohol can raise your blood pressure. So to help prevent high blood pressure, if you drink alcohol, limit how much you drink to no more than two drinks a day

REDUCE STRESS:

Stress can make blood pressure go up and over time may contribute to the cause of high blood pressure. There are many steps you can take to reduce your stress. The article on easing stress will get you started.

REFERENCES:

A.Harvey, R. (4th edition). Pharmacology. Wliams & Weilkans.

G, B. Pharamacology. California: Mc Graw Hill.

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