Hypertension is a common and major cause of stroke and other cardiovascular disease. There are many causes of hypertension, including defined hormonal and genetic syndromes, renal disease and multifactorial racial and familial factors. It is one of the leading causes of morbidity and mortality in the world and will increase in worldwide importance as a public health problem by 2020 (Murray and Lopez 1997).
Blood pressure (BP) is defined as the amount of pressure exerted, when heart contract against the resistance on the arterial walls of the blood vessels. In a clinical term high BP is known as hypertension. Hypertension is defined as sustained diastolic BP greater than 90 mmHg or sustained systolic BP greater than 140 mmHg. The maximum arterial pressure during contraction of the left ventricle of the heart is called systolic BP and minimum arterial pressure during relaxation and dilation of the ventricle of the heart when the ventricles fill with blood is known as diastolic BP (Guyton and Hall 2006).
Hypertension is commonly divided into two categories of primary and secondary hypertension. In primary hypertension, often called essential hypertension is characterised by chronic elevation in blood pressure that occurs without the elevation of BP pressure results from some other disorder, such as kidney disease. Essential hypertension is a heterogeneous disorder, with different patients having different causal factors that lead to high BP. Essential hypertension needs to be separated into various syndromes because the causes of high BP in most patients presently classified as having essential hypertension can be recognized (Carretero and Oparil 2000). Approximately 95% of the hypertensive patients have essential hypertension. Although only about 5 to 10% of hypertension cases are thought to result from secondary causes, hypertension is so common that secondary hypertension probably will be encountered frequently by the primary care practitioner (Beevers and MacGregor 1995).
In normal mechanism when the arterial BP raises it stretches baroceptors, (that are located in the carotid sinuses, aortic arch and large artery of neck and thorax) which send a rapid impulse to the vasomotor centre that resulting vasodilatation of arterioles and veins which contribute in reducing BP (Guyton and Hall 2006). Most of the book suggested that there is a debate regarding the pathophysiology of hypertension. A number of predisposing factors which contributes to increase the BP are obesity, insulin resistance, high alcohol intake, high salt intake, aging and perhaps sedentary lifestyle, stress, low potassium intake and low calcium intake. Furthermore, many of these factors are additive, such as obesity and alcohol intake (Sever and Poulter 1989).
The pathophysiology of hypertension is categorised mainly into cardiac output and peripheral vascular resistant, renin- angiotensin system, autonomic nervous system and others factors. Normal BP is determined and maintained the balance between cardiac output and peripheral resistant. Considering the essential hypertension, peripheral resistant will rise in normal cardiac output because the peripheral resistant is depend upon the thickness of wall of the artery and capillaries and contraction of smooth muscles cells which is responsible for increasing intracellular calcium concentration (Kaplan 1998). In renin-angiotensin mechanism endocrine system plays important role in maintain blood pressure; especially the juxtaglomerular cells of the kidney secrete renin in order to response glomerular hypo-perfusion. And also renin is released by the stimulation of the sympathetic nervous system which is later convert to angiotensin I then again it converts to angiotensin II in the lungs by the effect of angiotensin- converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor and also it released aldosterone from the zona glomerulosa of the adrenal gland which is responsible for sodium and water retention. In this way, renin-angiotensin system increases the BP (Beevers et al 2001). Similarly, in autonomic nervous system sympathetic nervous system play a role in pathophysiology of hypertension and key to maintaining the normal BP as it constricts and dilates arteriolar. Autonomic nervous system considers as an important in short term changes in BP in response to stress and physical exercise. This system works together with renin-angiotensin system including circulating sodium volume. Although adrenaline and nor-adrenaline doesn’t play an important role in causes of hypertension, the drugs used for the treatment of hypertension block the sympathetic nervous system which had played proper therapeutic role (Beevers et al 2001). Others pathophysiology includes many vasoactive substance which are responsible for maintaining normal BP. They are enothelin bradikinin, endothelial derived relaxant factor; atrial natriuretic peptide and hypercoagulability of blood are all responsible in some way to maintain the BP (Lip G YH 2003).
The seventh report of the Joint National Committee (JNC-VII) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines some important goals for the evaluation of the patient with elevated BP which are detection and confirmation of hypertension; detection of target organ disease (e.g. renal damage, congestive heart failure); identification of other risk factors for cardiovascular disorders (e.g. diabetes mellitus, hyperlipidemia) and detection of secondary causes of hypertension (Chobanian et al 2003).
Most hypertensive patients remain asymptomatic until complications arise. Potential complications include stroke, myocardial infarction, heart failure, aortic aneurysm and dissection, renal damage and retinopathy (Zamani et al 2007).The drug selection for the pharmacologic treatment of hypertension would depend on the individual degree of elevation of BP and contradictions. Treatment of non-pharmacologic hypertension includes life-style, weight reduction, exercise, sodium, potassium, stop smoking and alcohol, relaxation therapy and dietary improvements, followed by pharmacology therapy.
Commonly used antihypertensive drugs include thiazide diuretics, β-blockers, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, direct vasodilators and α-receptor antagonists which are shown in the following table.
Diuretics have been used for decades to treat hypertension and recommended as first-line therapy by JNC-VII guidelines after antihypertensive and lipid-lowering treatment to prevent heart attack trail (ALLHAT) success. They reduce circulatory volume, cardiac output and mean arterial pressure and are most effective in patients with mild-to- moderate hypertension who have normal renal function. Thiazide diuretics (e.g. hydrochlorothiazide) and potassium sparing diuretics (e.g. spironolactone) promote Na+ and Cl- excretion in the nephrone. Loop diuretics (e.g. furosemide) are generally too potent and their actions too short-lived, however, they are useful in lowering blood pressure in patients with renal insufficiency, who often does not respond to other diuretics. Diuretics may result in adverse metabolic side effects, including elevation of creatinine; glucose, cholesterol, triglyceride levels, hypokalemia, hyperuricemia and decreased sexual function are potential side effects. The best BP lowering response is seen from low doses of Thiazide diuretics (Kaplan 1998).
Β-blocker such as propranolol are believed to lower BP through several mechanisms, including reducing cardiac output through a decrease heart rate and a mild decrease in contractility and decreasing the secretion of renin, which lead to a decrease in total peripheral resistant. Adverse effects of b-blockers include bronchospam, fatigue, impotence, and hyperglycemia and alter lipid metabolism (Zamani et al 2007).
Centrally acting α2-adrenergic agonists such as methyldopa and clonidine reduce sympathetic outflow to the heart, blood vessels and kidneys. Methyldopa is safe to use during pregnancy. Side effect includes dry mouth, sedation, drowsiness is common; and in 20% of patients methyldopa causes a positive antiglobulin test, rarely haemolytic anaemia and clonidine causes rebound hypertension if the drug is suddenly withdrawn (Neal M J 2009). Systemic a1-antagonists such as prazosin, terazosin and doxazosin cause a decrease in total peripheral resistance through relaxation of vascular smooth muscle.
Calcium channel blockers (CCB) reduce the influx of Ca++ responsible for cardiac and smooth muscle contraction, thus reducing cardiac contractility and total peripheral resistant. Thus long-acting members of this group are frequently used to treat hypertension. There are two classes of CCB dihyropyridines and non- dihyropyridines. The main side effect of CCB is ankle oedema, but this can sometimes be offset by combining with β-blockers (Lip G YH 2003).
Direct vasodilators such as Hydralazine and minoxidil lower BP by directly relaxing vascular smooth muscle of precapillary resistance vessels. However, this action can result in a reflex increase heart rate, so that combined β-blocker therapy is frequently necessary (Neal M J 2009).
ACE inhibitors works by blocking the renin-angiotensin system thereby inhibiting the conversion of angiotensin I to angiotensin II. ACE inhibitors may be most useful for treating patients with heart failure, as well as hypertensive patients who have diabetes. Using ACE inhibitors can lead to increased levels of bradikinin, which has the side effect of cough and the rare, but severe, complication of angioedema. Recent study demonstrated that captopril was as effective as traditional thaizides and β-blockers in preventing adverse outcomes in hypertension (Lip G YH 2003).
Angiotensin II antagonists act on the renin-angiotensin system and they block the action of angiotensin II at its peripheral receptors. They are well tolerated and very rarely cause any significant side-effects (Zamani et al 2007).
Another helpful principle of antihypertensive drug therapy concerns the use of multiple drugs. The effects of one drug, acting at one physiologic control point, can be defeated by natural compensatory mechanism (e.g. diuretic decrease oedema occurring secondary to treatment with a CCB). By using two drugs with different mechanisms of action, it is more likely that BP and its complication are controlled and with the low dose range of combined drugs also help to reduce the side-effects as well (Frank 2008) . The following two-drug combinations have been found to be effective and well tolerated which are diuretic and β-blocker; diuretic and ACE inhibitor or angiotensin receptor antagonist; CCB (dihydropyridine) and β-blocker; CCB and ACE inhibitor or angiotensin receptor antagonist; CCB and b-diuretic; α-blocker and β-blocker and other combinations (e.g. with central agents, including α2-adrenoreceptor agonists and imidazoline- I2 receptor modulators, or between ACE inhibitors and angiotensin receptor antagonists) can be used (ESH and ESC 2003). If necessary, three or four drugs may be required in many cases for the treatment. The use of a single drug will lower the BP satisfactorily in up to 80% of patients with hypertension but combining two types of drugs will lower BP about 90%. If the diastolic pressure is above 130 mmHg then the hypertensive emergency is occurred. Although it is desirable to reduce the diastolic pressure below 120 mmHg within 24 hours in accelerated hypertension, it is usually unnecessary to reduce it more rapidly and indeed it may be dangerous to do so. This is because the mechanisms that maintain cerebral blood flow at a constant level independent of peripheral BP are impaired in hypertension. However, it is important to reduce the BP quickly by giving the intravenous drugs but caution should be taken to avoid cerebrovascular pressure inducing cerebral ischemia (Grahame-Smith and Aronson 2002).
In conclusion, hypertension emerges as an extremely important clinical problem because of its prevalence and potentially devastating consequences. The major classes of antihypertensive drugs: diuretics, β-blockers, CCB, ACE inhibitors and angiotensin receptor antagonists, are suitable for the initiation and maintenance of antihypertensive therapy which helps in reduction of cardiovascular morbidity and mortality.