Medical Pharmacology Topics   

Renal Pharmacology: Antihypertensives

Several drug classes are used to treat hypertension: diuretics, sympatholytics, vasodilators, calcium blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor antagonists.

A "stepping up" approach is used in the treatment of hypertension. Some patients may only need nonpharmacological approaches like weight control and sodium/alcohol restrictions. If the nonpharmacological aproach is not succesful, a drug is added to the treatment, either a diuretic, beta blocker, calcium blocker or ACE inhibitor. If further treatment is needed, a second drug from a different class may be added, or one drug may be substituted for another from a diferent class. A third and fourth drug may be added as needed.

Sympatholytics and Vasodilators

Sympatholytics are useful in treating hypertension because they induce vasodilation, and include guanethidine, clonidine, prazosin, labetalol, propanolol and metropolol. Guanethidine is a rarely used adrenergic receptor blocker, and can increase rening levels.

Clonidine is a an a-agonists but also acts on the CNS to decrease SNS activity, thus reducing vasoconstriction. It also decreases plasma renin levels.

Prazosin is an a-receptor antagonist, thus preventing vasoconstriction. Labetalol is both an alpha and beta blocker.

Propanolol and metoprolol are a beta blockers, and is not well understood how they lower blood pressure in hypertensive patients, while having no pressor effect on normal individuals (may be related to their blocking of renin secretion).

The calcium blockes include verapamil, diltiazem and nifedipine. These agents are not first line drugs because of their many side effects, among them headache, dizziness, alterations of heart rate, flushing and congestive heart failure. Nifedipine has a greater vasodilator effect, and thus a greater reflex tachycardia. Verapamil has good vasodilator activity and little reflex tachicardia because of its negative ionotropic action on the myocardium. Other vasodilators used to treat hypertension are hydralazyne and nitroprusside.

Inhibitors of Angiotensin Activity

Decreased renal function and/or increased sympathetic activity increase renin secretion. Renin cleaves angiotensinogen (synthsozed in the liver) to yield angiotensin I. In turn, angiotensin I is converted in the lungs to angiotensin II by angiotensin converting enzyme (ACE). The same reaction breaks down bradykinin. Bradykinin mediates vasodilation through prostaglandings (?).

Angiotensin II alters peripheral resistance, renal function and cardiovascular structure. Angiotensin is a direct vasoconstrictor, resulting in a rapid pressor response. It will also act directly to increase Na reabsorption in the proximal tubule and release aldosterone from the adrenal cortex, resulting in a slow pressor response. Angiotensin II also plays a rele in long-term vascular and cardiac remodeling and hypertrophy.

An ACE inhibitor will decrease angiotensin II and aldosterone levels, increase renin and bradykinin levels, and decrease blood pressure. In addition, ACE inhibition enhaces the response to diuretics (blunted homeostatic release of aldosterone), are potassium sparing (also due to decreased aldosterone) and seem to delay the development of diabetic nephropathy.

Examples of ACE inhibitors are captopril, enalapril and lisinopril. They ae metabolized in the liver and excreted in the urine. Enalapril is a prodrug rapidly absorbed orally that must be de-esterified to the active agent, enalaprilat (has poor oral absorption). Adverse effects of ACE inhibitors include allergic rash, fever, loss of taste, hypotension, cough, angioedema (0.1-0.2%), teratogenicity, fetal mortality, and hyperkalemia.

Angiotensin II receptor antagonists like losartan, are selective competitive inhibitors of the angiotensin receptor type 1 (AT1), which mediates vasoconstriction and aldosterone secretion. Slow dissociation kinetics make these agents act like "unsurmountable" antagonists. This is a clinical advantage, since there will be sustained recepyor blockade even with increased endogenous levels of angiotensin II, and the effects on blood pressre are sustained even after missed doses.

Angiotensin II antagonists have little effect on blood pressure when plasma renin levels are already low. Otherwise, these agents compleately block the action of angiotensin II, while ACE inhibitors may not (angiotensin from other sources). The antagonists do not affect bradykinin levels, do not produce cough and have a lower incidence of angioedema than ACE inhibitors. Adverse effects include teratogenicity, acute renal failure (especially when coadministered with other vasodilatorlike nitroprusside and hyperkalemia..

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