A number of drug classes are effective for initial and subsequent management of hypertension. Drug selection and use in the treatment of stable hypertension is discussed elsewhere. For drug treatment of hypertensive emergencies, see table Parenteral Drugs for Hypertensive Emergencies.
(See also Overview of Hypertension.)
Adrenergic modifiers include central alpha-2-agonists, postsynaptic alpha-1-blockers, and peripheral-acting non-selective adrenergic blockers (see table Adrenergic Modifiers for Hypertension).
Adrenergic Modifiers for Hypertension
Alpha-2-agonists (eg, methyldopa, clonidine, guanabenz, guanfacine) stimulate alpha-2-adrenergic receptors in the brain stem and reduce sympathetic nervous activity, lowering BP. Because they have a central action, they are more likely than other antihypertensives to cause drowsiness, lethargy, and depression; they are no longer widely used. Clonidine can be applied transdermally once a week as a patch; thus, it may be useful for nonadherent patients (eg, those with dementia).
Postsynaptic alpha-1-blockers (eg, prazosin, terazosin, doxazosin) are no longer used for primary treatment of hypertension because evidence suggests no reduction in mortality. Also, doxazosin used alone or with antihypertensives other than diuretics increases risk of heart failure. However, they may be used in patients who have prostatic hypertrophy and need a 4th antihypertensive or in people with high sympathetic tone (ie, with high heart rate and spiking blood pressures) already on the maximum dose of a beta-blocker.
ACE inhibitors (see table Oral ACE Inhibitors and Angiotensin II Receptor Blockers for Hypertension) reduce blood pressure by interfering with the conversion of angiotensin I to angiotensin II and by inhibiting the degradation of bradykinin, thereby decreasing peripheral vascular resistance without causing reflex tachycardia. These drugs reduce BP in many hypertensive patients, regardless of plasma renin activity. Because these drugs provide renal protection, they are the drugs of choice for patients with diabetes. They are not recommended for initial treatment in blacks, in whom they appear to increase the risk of stroke when used for initial treatment.
A dry, irritating cough is the most common adverse effect, but angioedema is the most serious and, if it affects the oropharynx, can be fatal. Angioedema is most common among blacks and smokers. ACE inhibitors may increase serum potassium and creatinine levels, especially in patients with chronic kidney disease and those taking potassium-sparing diuretics, potassium supplements, or nonsteroidal anti-inflammatory drugs (NSAIDs). ACE inhibitors are the least likely of the antihypertensives to cause erectile dysfunction. ACE inhibitors are contraindicated during pregnancy. In patients with a renal disorder, serum creatinine and potassium levels are monitored at least every 3 months. Patients who have stage 3 nephropathy (estimated glomerular filtration rate [GFR] of < 60 mL/minute to > 30 mL/minute) and are given ACE inhibitors can usually tolerate up to a 30 to 35% increase in serum creatinine above baseline. ACE inhibitors can cause acute kidney injury in patients who have hypovolemia, severe heart failure, severe bilateral renal artery stenosis, or severe stenosis in the artery to a solitary kidney.
Thiazide-type diuretics enhance the antihypertensive activity of ACE inhibitors more than that of other classes of antihypertensives. Spironolactone and eplerenone also appear to enhance the effect of ACE inhibitors.
Oral Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers for Hypertension
Angiotensin II receptor blockers (see table Oral ACE Inhibitors and Angiotensin II Receptor Blockers for Hypertension) block angiotensin II receptors and therefore interfere with the renin-angiotensin system. Angiotensin II receptor blockers and ACE inhibitors are equally effective as antihypertensives. Angiotensin II receptor blockers may provide added benefits via tissue ACE blockade. The 2 classes have the same beneficial effects in patients with left ventricular failure or with nephropathy due to type 1 diabetes. An angiotensin II receptor blocker should not be used together with an ACE inhibitor, but when used with a beta-blocker may reduce the hospitalization rate for patients with heart failure. Angiotensin II receptor blockers may be safely started in people < 60 with initial serum creatinine of ≤ 3 mg/dL (≤ 265 micromol/L).
Incidence of adverse events is low; angioedema occurs but much less frequently than with ACE inhibitors. Precautions for use of angiotensin II receptor blockers in patients with renovascular hypertension, hypovolemia, and severe heart failure are the same as those for ACE inhibitors (see table Oral ACE Inhibitors and Angiotensin II Receptor Blockers for Hypertension). Angiotensin II receptor blockers are contraindicated during pregnancy.
Beta-blockers (see table Oral Beta-Blockers for Hypertension) slow heart rate and reduce myocardial contractility, thus reducing blood pressure. All beta-blockers are similar in antihypertensive efficacy. In patients with diabetes, chronic peripheral arterial disease, or chronic obstructive pulmonary disease (COPD), a cardioselective beta-blocker (acebutolol, atenolol, betaxolol, bisoprolol, metoprolol) may be preferable, although cardioselectivity is only relative and decreases as dose increases. Even cardioselective beta-blockers are contraindicated in patients with asthma or in patients with COPD with a prominent bronchospastic component.
Oral Beta-Blockers for Hypertension
Beta-blockers are particularly useful in patients who have angina, who have had a myocardial infarction, or who have heart failure, although atenolol may worsen prognosis in patients with coronary artery disease (CAD). These drugs are no longer considered problematic for the elderly.
Beta-blockers with intrinsic sympathomimetic activity (eg, acebutolol, pindolol) do not adversely affect serum lipids; they are less likely to cause severe bradycardia.
Beta-blockers have central nervous system (CNS) adverse effects (sleep disturbances, fatigue, lethargy) and exacerbate depression. Nadolol affects the CNS the least and may be best when CNS effects must be avoided. Beta-blockers are contraindicated in patients with 2nd- or 3rd-degree atrioventricular block, asthma, or sinus node dysfunction.
Dihydropyridines (see table Oral Calcium Channel Blockers for Hypertension) are potent peripheral vasodilators and reduce blood pressure by decreasing total peripheral vascular resistance (TPR); they sometimes cause reflexive tachycardia.
The nondihydropyridines verapamil and diltiazem slow the heart rate, decrease atrioventricular conduction, and decrease myocardial contractility. These drugs should not be prescribed for patients with 2nd- or 3rd-degree atrioventricular block or with left ventricular failure.
Oral Calcium Channel Blockers for Hypertension
Long-acting nifedipine, verapamil, or diltiazem is used to treat hypertension, but short-acting nifedipine and diltiazem are associated with a high rate of myocardial infarction and are not recommended.
Aliskiren, a direct renin inhibitor, is used in the management of hypertension. Dosage is 150 to 300 mg orally once a day, with a starting dose of 150 mg.
As with ACE inhibitors and angiotensin II receptor blockers, aliskiren causes elevation of serum potassium and creatinine. Aliskiren should not be combined with ACE inhibitors or angiotensin II receptor blockers in patients with diabetes or renal disease (estimated GFR < 60 mL/min).
Direct vasodilators, including minoxidil and hydralazine (see table Direct Vasodilators for Hypertension), work directly on blood vessels, independently of the autonomic nervous system. Minoxidil is more potent than hydralazine but has more adverse effects, including sodium and water retention and hypertrichosis, which is poorly tolerated by women. Minoxidil should be reserved for severe, refractory hypertension.
Hydralazine is used during pregnancy (eg, for preeclampsia) and as an adjunct antihypertensive. Long-term, high-dose (> 300 mg/day) hydralazine has been associated with a drug-induced lupus syndrome, which resolves when the drug is stopped.
Direct Vasodilators for Hypertension
Main classes of diuretics used for hypertension (see table Oral Diuretics for Hypertension) are
Diuretics modestly reduce plasma volume and reduce vascular resistance, possibly via shifts in sodium from intracellular to extracellular loci.
Loop diuretics are used to treat hypertension only in patients who have lost > 50% of kidney function; these diuretics are given at least twice a day (except for torsemide which can be given once a day).
Although the potassium-sparing diuretics do not cause hypokalemia, hyperuricemia, or hyperglycemia, they are not as effective as thiazide-type diuretics in controlling hypertension and thus are not used for initial treatment. Potassium-sparing diuretics or potassium supplements are not needed when an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker is used because these drugs increase serum potassium.
Thiazide-type diuretics are most commonly used. In addition to other antihypertensive effects, they cause a small amount of vasodilation as long as intravascular volume is normal. All thiazides are equally effective in equivalent doses; however, thiazide-type diuretics have longer half-lives and are relatively more effective at similar doses. Thiazide-type diuretics can increase serum cholesterol slightly (mostly low-density lipoprotein) and also increase triglyceride levels, although these effects may not persist > 1 year. Furthermore, levels seem to increase in only a few patients. The increase is apparent within 4 weeks of treatment and can be ameliorated by a low-fat diet. The possibility of a slight increase in lipid levels does not contraindicate diuretic use in patients with dyslipidemia.
All diuretics except the potassium-sparing distal tubular diuretics cause significant potassium loss, so serum potassium is measured monthly until the level stabilizes. Unless serum potassium is normalized, potassium channels in the arterial walls close and the resulting vasoconstriction makes achieving the blood pressure (BP) goal difficult. Patients with potassium levels < 3.5 mEq/L (< 3.5 mmol/L) are given potassium supplements. Supplements may be continued long-term at a lower dose, or a potassium-sparing diuretic (eg, daily spironolactone 25 to 100 mg, triamterene 50 to 150 mg, amiloride 5 to 10 mg) may be added. Potassium supplements or addition of a potassium-sparing diuretic is also recommended for any patients who are also taking digitalis, have a known heart disorder, have an abnormal ECG, have ectopy or arrhythmias, or develop ectopy or arrhythmias while taking a diuretic.
In most patients with diabetes, thiazide-type diuretics do not affect control of diabetes. Uncommonly, diuretics precipitate or worsen type 2 diabetes in patients with metabolic syndrome.
A hereditary predisposition probably explains the few cases of gout due to diuretic-induced hyperuricemia. Diuretic-induced hyperuricemia without gout does not require treatment or discontinuation of the diuretic.
Diuretics may slightly increase mortality in patients with a history of heart failure who do not have pulmonary congestion, particularly in those who are also taking an ACE inhibitor or angiotensin II receptor blocker and who do not drink at least 1400 mL (48 oz) of fluid daily. The increased mortality is probably related to diuretic-induced hyponatremia and hypotension.