DEFINITION :

Hypertension is defined simply as persistently elevated arterial blood pressure [≥140/90 mm Hg].Increasing awareness and diagnosis of hypertension and     improving control of BP with appropriate treatment are considered critical public health initiatives to reduce cardiovascular morbidity and mortality.

EPIDEMIOLOGY :

Hypertension is the most common cardiovascular disease. The prevalence of hypertension increases with advancing age; for example, about 50% of people between the ages of 60 and 69 years old have hypertension, and the prevalence is further increased beyond age 70.

ETIOLOGY : Hypertension is a heterogeneous medical condition. In most patients it results from unknown pathophysiologic etiology (essential or primary hypertension). While this form of hypertension cannot be cured, it can be controlled.The patient may appear very healthy or may have the presence of additional cardiovascular risk factors:

• Age (≥55 years for men to 65 years for women)
• Diabetes mellitus
• Dyslipidemia (elevated low-density lipoprotein [LDL cholesterol, total cholesterol or triglycerides; low high-density lipoprotein [HDL] cholesterol),
• Microalbuminuria
• Family history of premature cardiovascular disease
• Obesity (body mass index≥ 30 kg/m2)
• Physical inactivity
• Tobacco

ESSENTIAL OR PRIMARY  HYPERTENSION :

Over 90% of individuals with hypertension have essential hypertension (primary hypertension). Hypertension often runs in families, indicating that genetic factors may play an important role in the development of essential hypertension.

SECONDARY HYPERTENSION : Fewer than 10% patients have secondary hypertension. In most of these cases, renal dysfunction resulting from chronic kidney disease or renovascular disease is the most common secondary cause.Certain drugs either directly or indirectly can cause hypertension ,for example, corticosteroids, estrogens, NSAID’s, anti-depressants, amphetamines, sibutramine, cyclo-sporine, tacrolimus , erythropoietin, and venlafaxine.etc.,

PATHOPHYSIOLOGY :

The most common cause of hypertension is increased peripheral vascular resistance. Multiple factors that control BP are potential contributing components in the development of hypertension.

These include :

• Humoral abnormalities involving the renin-angiotensin-aldosterone system, natriuretic hormone, or hyperinsulinemia;
• A pathologic disturbance in the CNS, autonomic nerve fibers, adrener-gic receptors, or baroreceptors;
• Abnormalities in either the renal or tissue autoregulatory processes for sodium excretion, plasma volume, and arteriolar constriction;
• A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I;
• A high sodium intake and increased circulating natriuretic hormone inhibition of intracellular sodium transport, resulting in increased vascular reactivity and a rise in BP; and
• Increased intracellular concentration of calcium, leading to altered vascu-lar smooth muscle function and increased peripheral vascular resistance.
• The main causes of death in hypertensive subjects are cerebrovascular accidents, cardiovascular (CV) events, and renal failure. The probability of premature death correlates with the severity of BP elevation.

CLINICAL FEATURES :

• Patients with uncomplicated primary hypertension are usually asymptomatic initially.
• Patients with secondary hypertension may complain of symptoms suggestive of the underlying disorder. Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, palpitations, and orthostatic hypotension. In primary aldosteronism, hypokalemic symptoms of muscle cramps and weakness may be present. Patientwith hypertension secondary to Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscular weakness.

LABORATORY TESTS :The patient may have normal values and still have hypertension.However, some may have abnormal values consistent with either additional cardiovascular risk factors or hypertension-related damage.

• Blood urea nitrogen (BUN) and serum creatinine
• Fasting lipid panel
• Fasting blood glucose
• Serum potassium
• Urinalysis

OTHER DIAGNOSTIC TESTS :

• 12-lead electrocardiogram (to detect LVH)
• Highly sensitive C-reactive protein (high concentrations are associated with increased cardiovascular risk)

TARGET-ORGAN DAMAGE :

The patient may have a previous medical history or diagnostic findings that indicate the presence of hypertension-related target-organ damage:

• Brain (stroke, transient ischemic attack, dementia)
• Eyes (retinopathy)
• Heart (left ventricular hypertrophy, angina or prior
• myocardial infarction, prior coronary revascularization,
• heart failure)
• Kidney (chronic kidney disease)
• Peripheral vasculature (peripheral arterial disease)

TREATMENT :

The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality are related to target-organ damage (e.g., cardiovascular events, cerebro vascular events, heart failure, and kidney disease). Reducing risk remains the primary purpose of hypertension therapy ,and the choice of drug therapy is influenced significantly by evidence demonstrating such risk reduction. Most patients have a goal BP of less than 140/90 mm Hg.  However ,this goal is lowered to less than 130/80 mm Hg for patients with diabetes or chronic kidney disease.

NON-PHARMACOLOGICAL TREATMENT :

All patients with prehypertension and hypertension should be prescribed lifestyle modifications. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with pre hypertension BP values. In a number of hypertensive patients with relatively good BP control while on single antihypertensive drug therapy, sodium reduction and weight loss may allow withdrawal of drug therapy.A sensible dietary program is one that is designed to reduce weight gradually for overweight and obese patients and one that restricts sodium intake with only moderate alcohol consumption. Successful implementation of dietary lifestyle modifications by clinicians requires aggressive promotion through reasonable patient education,encouragement, and continued reinforcement.

PHARMACOLOGICAL TREATMENT:

1.Diuretics

Diuretics can be used as first-line drug therapy for hypertension unless there are compelling reasons to choose another agent. Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, myocardial infarction, and congestive heart failure, all of which can cause mortality. Recent data suggest that diuretics are superior to ß-blockers for treating hypertesnion in older adults.

1. Thiazide diuretics

All oral diuretic drugs are effective in the treatment of hypertension, but the thiazides have found the most widespread use.

• 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.

1. 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.]

1. 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.

2.ß-Adrenoceptor Blocking Agents

ß-Blockers are currently recommended as first-line drug therapy for hypertension when when concomitant disease is present.

 Actions

The ß blockers reduce blood pressure primarily by decreasing cardiac output . They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys, thus decreasing the formation of angiotensin II and the secretion of aldosterone. The prototype ß-blocker is propranolol , which acts at both ß₁ and ß₂ receptors. Selective blockers of ß₁ receptors, such as metoprolol  and atenolol , are among the most commonly prescribed ß-blockers. The selective ß-blockers may be administered cautiously to hypertensive patients who also have asthma, for which propranolol is contraindicated due to its blockade of ß₂-mediated bronchodilation.

3.ACE Inhibitors

The ACE inhibitors, such as enalapril  or lisinopril , are recommended when the preferred first-line agents (diuretics or ß-blockers) are contraindicated or ineffective.

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.

4.Angiotensin II Receptor Antagonists

The angiotensin II receptor blockers (ARBs) are alternatives to the ACE inhibitors. 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.

5. 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 combined other antihypertensives, such diuretics, ACE inhibitors, ARBs, or calcium-channel blockers. Aliskiren can cause diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but probably less often than ACE inhibitors. The drug is contraindicated during pregnancy. The combination of maximum doses of aliskiren and valsartan decreased 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.

6. Calcium-Channel Blockers

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.

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

• 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.
• 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.    
• Dihydropyridines: 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 nisoldipine .

7.α-Adrenoceptor Blocking Agents

Prazosin , doxazosin , and 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. 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. 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.

8.α±ß- – Adrenoceptor Blocking Agents

Labetalol  and carvedilol  block both α₁– and ß₁– and ß₂– receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown to reduce mortality associated with heart failure.

9. Centrally Acting Adrenergic Drugs
10. 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.

1. Methyldopa

This  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. 

10. 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. 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.

11.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 . The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. Nitroprusside is metabolized rapidly  and requires continuous infusion to maintain its hypotensive action. 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.] .