HYPERTENSION

Hypertension (HTN) or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. It is the opposite of hypotension. Hypertension is classified as either primary (essential) hypertension or secondary hypertension; About 90–95% of cases are categorized as "primary hypertension," which means high blood pressure with no obvious medical cause. The remaining 5–10% of cases (Secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system.


The lowering of even moderately elevated blood pressure has been shown to significantly reduce cardiovascular morbidity and mortality.


Monitor blood pressure when starting an antihypertensive drug and during titration, as well as periodically when desired blood pressure is achieved.

THIAZIDES AND RELATED DIURETICS (eg, hydrochlorothiazide): The hypotensive effect of this group is mediated by arteriolar vasodilatation. In part, this is a consequence of the natriuretic action of thiazides and subsequent reduction in plasma volume. Thiazide antihypertensive dose-response is flat, therefore the greatest effect will be attained at a low dose. Although the duration of diuretic action varies, this does not reflect the duration of antihypertensive activity. Thiazides are generally well tolerated and enhance the efficacy of other antihypertensive agents. Unwanted metabolic effects of thiazides include hypokalemia, hyperuricemia, hypercalcemia, glucose intolerance, hypercholesterolemia, and hypertriglyceridemia, although these can be minimized by using a low dosage. The thiazides may precipitate acute gout, cause impotence, rash, photosensitivity, or fatigue and may be ineffective in renal failure. 

β-BLOCKERS: The antihypertensive effect of β-blockers is not fully understood. β₁-blockers competitively inhibit receptors in the heart, β₂-blockers inhibit receptors in the peripheral vasculature, bronchi, pancreas, kidney and liver. β-blockers decrease cardiac rate, force of contraction and output, and renin secretion. Some may have direct CNS activity, although this is unlikely to account for an antihypertensive effect. Their efficacy as monotherapy is equivalent to thiazides. 


First generation β-blockers (eg, propranolol) are non-cardioselective and generally well tolerated, although they may produce peripheral ischemia, CNS disturbances, bronchospasm, exacerbate congestive heart failure and reduce exercise tolerance. Metabolically, they adversely affect plasma lipids and reduce hepatic glucose mobility.


Second generation β-blockers (eg, atenolol, metoprolol) have greater cardioselectivity and less, yet still demonstrable, adverse effects on triglycerides and HDL-cholesterol.


As with the more selective drugs, those with intrinsic sympathomimetic activity (eg, acebutolol, pindolol) are less likely to cause coldness of the extremities and produce less effect on resting heart rate and cardiac output. β-blockers that have low lipid solubility (eg, atenolol) may be less likely to cause CNS side effects. Combined receptor antagonists (eg, labetalol) have both α- and β-receptor activity and similar adverse reactions to non-selective β-blockers. Non-cardioselective β-blockers are not recommended for hypertensive patients with obstructive airway disease or insulin-dependent diabetes.


ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS (eg, captopril, enalapril): ACE inhibitors block angiotensin converting enzyme and prevent the formation of angiotensin II, a powerful vasoconstrictor and indirect facilitator of the sympathetic nervous system. This action results in arteriolar and venous dilation, reducing total peripheral resistance and arterial blood pressure. ACE inhibitors also suppress aldosterone secretion, increase renal blood flow (and hence natriuresis), and increase circulating levels of the vasodilating cytokine, bradykinin. The antihypertensive effect is dose-related and dose titration may be required.


The most common adverse effect is a chronic dry cough. ACE inhibitors are generally free from metabolic side effects, and have little effect on heart rate and airway resistance. They are, therefore, useful in patients with cardiac failure, asthma, COPD, peripheral vascular disease and diabetes. ACE inhibitors can cause cough, taste disturbances and rash. They are contraindicated in pregnancy during the second and third trimesters. Orthostatic hypotension is a potential problem in patients on diuretics or those who are hypovolemic. In patients with renal arterial stenosis, ACE inhibitors may precipitate acute renal failure, and with renal insufficiency they may induce hyperkalemia. Serum creatinine levels should be measured before and during ACE inhibitor therapy. Concomitant potassium-sparing diuretics, potassium supplements, and potassium-containing salt substitutes should be avoided unless specifically indicated.


ANGIOTENSIN II RECEPTOR BLOCKERS (eg, losartan): The angiotensin receptor blockers (ARBs) act by blocking the effect of angiotensin II on specific tissue receptors. Unlike ACE inhibitors, these drugs do not inhibit the enzyme which catalyzes the conversion of angiotensin I to angiotensin II, nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Like ACE inhibitors, the angiotensin II receptor blockers appear to work better in non-black than in black patients, and they should be avoided in pregnant patients. Volume-depleted patients should be given a lower starting dose, or hypovolemia should be corrected prior to initiation of therapy, since symptomatic hypotension may result. They are sometimes used in combination with ACE inhibitors in certain clinical situations where their synergistic effects are desirable.


DIRECT RENIN INHIBITORS (eg, aliskiren): Direct renin inhibitors decrease plasma renin activity (PRA) and inhibit the conversion of angiotensinogen to angiotensin I. Unlike ACE inhibitors and ARBs, whose effects suppress the negative feedback loop leading to a compensatory rise in plasma renin concentration, direct renin inhibitors block the effect of increased renin levels so that PRA, angiotensin I and angiotensin II are reduced. Direct renin inhibitors may be administered with other antihypertensive agents, however it is not known whether additive effects are present when they are used with ACE inhibitors or β-blockers.


CALCIUM CHANNEL BLOCKERS: These drugs inhibit calcium influx through slow calcium channels during membrane depolarization. This action leads to arteriolar smooth muscle relaxation and decreases in peripheral vascular resistance. Despite a common mode of action, calcium channel blockers vary in their affinities for vascular and cardiac muscle. They are classified by their chemical structure.


Dihydropyridines (eg, nifedipine) are potent vasodilators. After initial doses of short-acting dihydropyridines, mild to moderate reflex tachycardia may occur. Due to their steep dose-response, titration is usually required with calcium channel blockers. They are useful with or as an alternative to β-blockers.


The major problems with short-acting calcium channel blockers are vasodilatory side effects such as headache, flushing, palpitation, and ankle edema. With the exception of edema, these are less common with the slow-release, long-acting products (eg, amlodipine). Calcium channel blockers do not adversely affect plasma lipids, glucose metabolism, cause sodium/water/uric acid retention, or activate the renin-angiotensin system. 


Diphenylalkylamines (eg, verapamil) and benzothiazepines (eg, diltiazem) are selective for the cardiovascular system. Both have relatively lower vasodilator action and also have negative inotropic and chronotropic properties and therefore should be used with caution in conjunction with β-blocker therapy, but never in patients with conduction disturbances. Both drugs have an intrinsic heart rate lowering effect which ensures against reflex tachycardia, but are associated with bradycardia or sino-atrial dysfunction and 2^nd or 3^rd degree heart block. Both verapamil and diltiazem may precipitate heart failure in predisposed patients.


α₁-ANTAGONISTS: The α₁-antagonists can be subdivided into selective (eg, prazosin) and non-selective (eg,phenoxybenzamine) agents. They lower blood pressure by arteriolar dilation mediated by antagonism of post-synaptic α₁-adrenergic receptors. They also have vasodilator properties. The major adverse effect of α-antagonists is first-dose syncope and orthostatic hypotension, which can be minimized by initial low dose and withdrawal of concomitant diuretics. Use α-antagonists with caution in the elderly, if orthostatic hypotension is a problem. Symptomatic side effects include fatigue, weakness, nasal congestion and headache. α₁-antagonists are essentially devoid of adverse effects on glucose tolerance, uric acid and potassium levels. They confer beneficial effects on lipids, reducing total cholesterol and triglycerides while increasing HDL cholesterol.


CENTRAL α-AGONISTS (eg, clonidine, methyldopa): These drugs reduce sympathetic vasoconstriction and decrease total peripheral vascular resistance. Sedation and drowsiness are major dose-related side effects. Methyldopa is of particular value in pregnancy hypertension, but its use is cautioned in elderly patients due to risk of orthostatic hypotension. Abrupt discontinuance of clonidine results in rebound hypertension.


OTHER CLASSES: Hydralazine and minoxidil decrease peripheral vascular resistance by direct relaxation of vascular smooth muscle. Side effects include GI disturbances and fluid retention. Minoxidil may cause hirsutism.
The adrenergic neuron blockers (eg, guanethidine) prevent the release of norepinephrine in response to sympathetic stimulation. They are displaced by indirect-acting sympathomimetic agents and tricyclic 
antidepressants. Side effects include orthostatic hypotension, fluid retention, bradycardia and diarrhea.


Aldosterone blockers (eg, eplerenone): Aldosterone binds to mineralocorticoid receptors in epithelial and non-epithelial tissues, and it increases blood pressure by inducing sodium retention. Aldosterone blockers bind to the mineralocorticoid receptors thereby mitigating this effect. Eplerenone produces sustained increases in plasma renin and serum aldosterone, but these do not overcome the effect of eplerenone on blood pressure. Eplerenone may cause hyperkalemia.


Note: Sustained-release products containing the same quantity of a given drug are unlikely to have the same pharmacokinetic profiles. Therefore, it is important that such products be prescribed by brand name and patients are not transferred from one product to another without full clinical assessment and retitration