The term "hypertension" literally means an abnormally raised arterial blood pressure.

There are many conditions which elevate arterial pressure, including primary renal disease, pheochromocytoma, hyperthyroidism, hyperaldosteronism and coarctation of aorta, leading to secondary hypertension. In about 80 to 85 per cent of patients of hypertension, no specific cause is evident, and such a condition is labeled as primary or essential hypertension.Most instances of hypertension (=chronically elevated blood pressure) result from increased arterial resistance, while cardiac output is in the normal range. Hence, the some of the most effective

antihypertensive drugs act by decreasing this resistance, but not necessarily via direct vasodilation, though the end result is just that. One basic problem in treating hypertension is that in the vast majority of cases (90%) the basis for the chronically elevated blood pressure is unidentified, termed primary, or essential, hypertension. Many of the interacting control

mechanisms mentioned above are altered, and often adjusting two or more of these processes is required to lower the BP. In a minority of cases, the hypertension is a consequence of a disease state, hence it is termed secondary hypertension. Obviously, the disease is addressed first, and its resolution will usually alleviate the secondary hypertension. intervention would then be considered. If not, additional, direct

Antihypertensive Drugs Most antihypertensive drugs can effectively reduce mildly elevated blood pressure, but their use is associated with many side effects. Thus the decision whether to use a drug to control borderline or mild hypertension is made on the basis of the benefit: risk ratio.

Antihypertensive Drugs Classification Drugs influence arterial blood pressure at four effector sites- arterioles (resistance vessels); veins (capacitance vessels); heart; and the kidneysby several different mechanisms. They can be classified according to their site or mode of action as follows:

1. Diuretics. 2. Beta adrenergic blockers. 3. Calcium channel blockers. 4. Angiotensin converting enzyme inhibitors. 5. Angiotensin receptor blockers. 6. Sympatholytics and adrenergic blockers. 7. Direct arterial vasodilators. iuretics Antihypertensive Drugs

Diuretics: Reduction in blood volume via facilitation of sodium excretion is the basic beneficial response to diuretic administration, usually leading to a significant drop in BP. For mild - moderate cases, restriction of dietary sodium may do the trick. If not, diuretic therapy alone is often sufficient. In more severe hypertension, other drugs are used (eg. ACE inhibitors) together with diuretics, with the latter helping to minimize sodium retention that might be triggered by a drop in renal blood pressure (while the ACEIs will block the increased release of renin trigger by the same drop in renal BP)

- Thiazides (eg. hydrochlorothiazide) considered most appropriate for mild - moderate hypertension with otherwise normal heart and kidney function numerous attendant side effects: hypokalemia (corrected using K supplements); hyperlipidemia; risk of hyperglycemia (inhibition of insulin release)

- Loop Diuretics (eg. furosemide) relied on for severe hypertension; congestive heart failure

-sparing Diuretics (eg. spironolactone) useful in congestive heart failure for patients on digitalis

Diuretics are still used as initial drugs of choice for mild hypertension in the majority of cases. They can be used alone, or in combination with other classes of antihypertensive drugs.

Centrally-acting Sympathetic Inhibitors: In moderate to severe hypertension, reduction of sympathetic outflow would usually be beneficial, but attendant side effects can be significant, greatly limiting the use of this class of drugs. Drugs in this class fall into two basic subclasses: vasomotor center-acting and ganglionic blockers - Methyldopa metabolized to methyldopamine and methylnorepinephrine enters adrenergic synaptic vesicles, replacing norepinephrine and acting as a false transmitter (also happens in peripheral adrenergic nerve endings, but, there, the false transmitter appears to act as a normal agonist) stimulate alpha-adrenoceptors (mainly alpha2: action blocked by alpha2 antagonists) in the solitary tract nucleus adverse effects: marked sedation; also nightmares, depression, vertigo - Clonidine alpha2 agonist will cause transient increase in BP, later converting to a drop in BP owing to action on alpha2 receptors and imidazoline receptors located in the rostral ventrolateral medulla to enhance inhibition of sympathetic outflow. (Newer derivatives selective for the imidazoline receptor appear to have far few side effects) other uses: analgesic; reduce withdrawal symptoms with addictive drugs; decrease intraocular pressure adverse effects: strong sedation; dry mouth; depression

 rapid withdrawal after chronic use can lead to life-threatening hypertensive crisis - Ganglionic blockers (eg. mecamylamine) historically, first effective antihypertension drugs; now used to explore function of central neuronal nicotinic acetylcholine receptors Peripherally-acting Sympathetic Inhibitors: Actually, many of the drugs in this class have actions on both central and peripheral adrenergic systems, but their effects are largely if not completely accounted for by their peripheral action. Most are used for mild-moderate hypertension; some are also used in severe hypertension in addition to powerful vasodilators. These drugs fall into three convenient subclasses: vesicle depletion, alpha-adrenergic receptor antagonists and beta-adrenergic receptor antagonists - Reserpine for mild- moderate hypertension, acts by blocking uptake of biogenic amines (DA, NE, E, and 5-HT) into synaptic vesicles largely in peripheral synapses, leading to depletion of these neurotransmitters loss of NE from sympathetic nerve endings on vessels leads to net vasodilatation (with little postural hypotension at normal doses) central action accounts for most side effects: sedation, depression, parkinsonism - Selective alpha1 blockers (eg. prasozin; terazosin) block alpha1 receptors in arterioles and venules, and cause significant vasodilatation, with empirically less tachycardia as found with non-selective blockers or direct-acting vasodilators; some risk of significant postural hypotension

- Beta blockers (eg. metoprolol; propanolol; atenolol; pindolol; labetalol) major action in decreasing cardiac output and inhibiting renin release metoprolol (Lopressor), a selective beta1 blocker, with few side effects atenolol, a relatively selectively beta1 blocker (#1 beta blocker antihypertensive), having few side effects but longer-lasting than metoprolol

propanolol useful in severe hypertension, preventing reflex tachycardia as well and acting in the kidney to inhibit renin secretion; little postural hypotension side effects: reduced cardiac reserve; possible bronchial constriction pindolol, a partial agonist, lowers BP with less attendant depression of cardiac output due to stronger agonist action at beta1 than beta2. labetolol, an alpha and beta blocker, useful for hypertensive emergencies Vasodilators: As a group, useful drugs in this class act by dilating arterioles, reducing afterload. Vasodilatation by itself will, however, cause significantly increased sympathetic outflow to the heart (via baroreceptors and renin release), leading to tachycardia and increased contraction, which may oppose their hypotensive action. Consequently, these drugs are used in combination with beta blockers and diuretics to minimize any compensatory physiological responses. Different ways of categorizing these drugs exist: route of administration; clinical use; site of action. Orally active drugs (hydralazine and minoxidil) may be useful for long-term treatment, whereas parenteral drugs (nitroprusside, nitroglycerin and diazoxide) are used for hypertensive emergencies. With regard to site of action, there are two subclasses: dilators of arterioles and dilators of both arterioles and venules. - Hydralazine precise mechanism is not known, but claimed to antagonize SR IP3receptors primarily dilates arteriolar resistance vessels, causing significant drop in BP strong sympathetic reflex: minimized by co-administration of beta blocker risk of lupus-like syndrome in 10-20% of patients receiving high dosages - Minoxidil prodrug whose long-acting metabolite appears to act by opening arteriolar K+ channels, reducing contractility via clamping of the membrane potential and causing net vasodilation

 even stronger reflex sympathetic stimulation as well as sodium retention; must be used in combination with beta blockers and only for severe hypertension poorly controlled by other drugs - Diazoxide also opens arteriolar k+channels though used only for hypertensive emergencies (given IV), can cause such severe hypotension that stroke or infarct may result (nitroprusside is preferable) inhibits insulin release (thiazide-like structure), resulting in hyperglycemia which limits longterm use - Nitroprusside; Nitroglycerin decomposed in blood via RBCs to NO, causing vasodilatation of both arterioles and venules fast-acting IV agents used in hypertensive crisis; also may be used for controlled hypotension in surgery; nitroglycerin is also used for angina adverse effects: reflex sympathetic stimulation is moderate with nitroprusside, but adverse levels of cyanide or thiocyanate may develop, limiting use to 72 h max reflex/feedback responses (including tachycardia, increased contractility, postural hypotension; sodium retention) can be severe with nitroglycerin, but without the risk of cyanide toxicity Calcium Channel Inhibitors: All of these drugs act by blocking voltage-gated calcium channels in (largely) arterioles and in cardiac muscle, resulting in vessel relaxation and decreased heart rate and contractility, the latter minimizing compensatory responses to decreased BP. They include: Verapamil (diphenylalkylamine)

significant depression of cardiac function Diltiazem (benzothiazepines) The Dihydropyridines (eg.nicardipine) more effective vasodilators than suppressors of cardiac function Main use of calcium channel blockers is in monotherapy (where appropriate) for mild-moderate hypertension, as alternatives to diuretics or beta-blockers, particularly in the elderly. Also, quite useful in patients with concomitant angina.

ACE Inhibitors/ Angiotensin receptor antagonists: Angiotensin-converting enzyme (ACE) inhibitors (eg. captopril) are very effective in reducing hypertension caused by renal artery stenosis, renal disease and malignant hypertension (arteriole inflammation), where excessive levels of renin are released, causing high levels of angiotensin II, a potent vasoconstrictor and releaser of aldosterone. ACE inhibitors lower circulating angiotensin II and increases bradykinin, a potent vasodilator. Cardiac output is unaffected in patients with normal heart function, but is significantly increased in individuals with congestive heart failure. Hence, the other major use for ACE inhibitors is for CHF. Side effects include hyperkalemia, angioedema and dry cough (due to increased bradykinin) Antagonists of angiotensin receptors (eg. losartan) are potentially more selective (no effect on bradykinin levels, hence no cough; no angioedema; independent of ACE)