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Drugs for Hypertension

by George L. Bakris, MD

A number of drug classes are effective for initial and subsequent management of hypertension. For drug treatment of stable hypertension, see also Drugs. For drug treatment of hypertensive emergencies, see Table: Parenteral Drugs for Hypertensive Emergencies.

Diuretics

Main classes (see Table: Oral Diuretics for Hypertension) are

  • Thiazide-type diuretics

  • Loop diuretics

  • K-sparing diuretics

Diuretics modestly reduce plasma volume and reduce vascular resistance, possibly via shifts in Na from intracellular to extracellular loci.

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 yr. Furthermore, levels seem to increase in only a few patients. The increase is apparent within 4 wk of treatment and can be ameliorated by a low-fat diet. The possibility of a slight increase in lipid levels does not contraindicate diuretics in hyperlipidemic patients.

Loop diuretics are used to treat hypertension only in patients who have lost > 50% of kidney function; these diuretics are given twice daily.

Although the K-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. K-sparing diuretics or supplements are not needed when an ACE inhibitor or angiotensin II receptor blocker is used because these drugs increase serum K.

All diuretics except the K-sparing distal tubular diuretics cause significant K loss, so serum K is measured monthly until the level stabilizes. Unless serum K is normalized, K channels in the arterial walls close and the resulting vasoconstriction makes achieving the BP goal difficult. Patients with K levels < 3.5 mEq/L are given K supplements. Supplements may be continued long-term at a lower dose, or a K-sparing diuretic (eg, daily spironolactone 25 to 100 mg, triamterene 50 to 150 mg, amiloride 5 to 10 mg) may be added. Supplements or addition of a K-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.

Oral Diuretics for Hypertension

Drug

Usual Dose*

Selected Adverse Effects

Thiazides and the thiazide-type diuretics (chlorthalidone and indapamide)

Bendroflumethiazide

2.5–5 mg once/day (maximum: 20 mg)

Hypokalemia (which increases digitalis toxicity), hyperuricemia, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, hypercalcemia, sexual dysfunction in men, weakness, rash; possibly increased blood levels of lithium

Chlorothiazide

62.5–500 mg bid (maximum: 1000 mg)

Chlorthalidone

12.5–50 mg once/day

Hydrochlorothiazide

12.5–50 mg once/day

Hydroflumethiazide

12.5–50 mg once/day

Indapamide

1.25–5 mg once/day

Methyclothiazide

2.5–5 mg once/day

Metolazone (immediate-release)

0.5–1 mg once/day

Metolazone (extended-release)

2.5–5 mg once/day

K-sparing diuretics

Amiloride

5–20 mg once/day

Hyperkalemia (particularly in patients with renal failure and in patients treated with an ACE inhibitor, angiotensin II receptor blocker, or NSAID), nausea, GI distress, gynecomastia, menstrual irregularities (with spironolactone); possibly increased blood levels of lithium

Eplerenone

25–100 mg once/day

Spironolactone

25–100 mg once/day

Triamterene

25–100 mg once/day

Loop diuretics

Bumetanide

0.5–2 mg bid

Hyperkalemia, hyponatremia, hypomagnesemia, dehydration, postural hypotension, tinnitus, hearing loss

Ethacrynic acid

25–100 mg once/day

Furosemide

20–320 mg bid

Torsemide

5–100 mg once/day

*Larger doses may be required in patients with renal failure.

Aldosterone receptor blockers.

β-Blockers

These drugs (see Table: Oral ß-Blockers for Hypertension) slow heart rate and reduce myocardial contractility, thus reducing BP. All β-blockers are similar in antihypertensive efficacy. In patients with diabetes, chronic peripheral arterial disease, or COPD, a cardioselective β-blocker (acebutolol, atenolol, betaxolol, bisoprolol, metoprolol) may be preferable, although cardioselectivity is only relative and decreases as dose increases. Even cardioselective β-blockers are contraindicated in patients with asthma or in patients with COPD with a prominent bronchospastic component.

Oral β -Blockers for Hypertension

Drug

Usual Dose

Selected Adverse Effects

Comments

Acebutolol* ,†

200–800 mg once/day

Bronchospasm, fatigue, insomnia, sexual dysfunction, exacerbation of heart failure, masking of symptoms of hypoglycemia, triglyceridemia, increased total cholesterol and decreased high- density lipoprotein cholesterol (except for pindolol, acebutolol, penbutolol, carteolol, and labetalol)

Contraindicated in patients with asthma, greater than 1st-degree atrioventricular block, or sick sinus syndrome

Should be used cautiously in patients with heart failure or insulin -treated diabetes

Should not be stopped abruptly in patients with coronary artery disease

Carvedilol approved for treating heart failure

Atenolol*

25–100 mg once/day

Betaxolol*

5–20 mg once/day

Bisoprolol*

2.5–20 mg once/day

Carteolol

2.5–10 mg once/day

Carvedilol

6.25–25 mg bid

Carvedilol (controlled-release)

20–80 mg once/day

Labetalol , §

100–900 mg bid

Metoprolol*

25–150 mg bid

Metoprolol (extended-release)

50– 400 mg once/day

Nadolol

40–320 mg once/day

Nebivolol

5–40 mg once/day

Penbutolol

10–20 mg once/day

Pindolol

5–30 mg bid

Propranolol

20–160 mg bid

Propranolol, long-acting

60–320 mg once/day

Timolol

10–30 mg bid

*Cardioselective.

With intrinsic sympathomimetic activity.

α-β-Blockers. Labetalol can also be given IV for hypertensive emergencies. For IV administration, it is started as 20 mg up to a maximum 300 mg.

§ Can also be given for hypertensive emergencies; for IV administration, started as 20 mg up to a maximum 300 mg.

β-Blockers are particularly useful in patients who have angina, who have had an MI, or who have heart failure (HF), although atenolol may worsen prognosis in patients with coronary artery disease (CAD). These drugs are no longer considered problematic for the elderly.

β-Blockers with intrinsic sympathomimetic activity (eg, acebutolol, carteolol, penbutolol, pindolol) do not adversely affect serum lipids; they are less likely to cause severe bradycardia.

β-Blockers have 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. β-Blockers are contraindicated in patients with 2nd- or 3rd-degree atrioventricular block, asthma, or sick sinus syndrome.

Ca channel blockers

Dihydropyridines (see Table: Oral Calcium Channel Blockers for Hypertension) are potent peripheral vasodilators and reduce BP 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

Drug

Usual Dose

Selected Adverse Effects

Comments

Benzothiazepine derivatives

Diltiazem, sustained-release

60–180 mg bid

Headache, dizziness, asthenia, flushing, edema, negative inotropic effect; possibly liver dysfunction

Contraindicated in heart failure due to systolic dysfunction, in sick sinus syndrome, or in greater than 1st-degree atrioventricular block

Diltiazem, extended-release

120–360 mg once/day

Diphenylalkylamine derivatives

Verapamil

40–120 mg tid

Same as for benzothiazepine derivatives, plus constipation

Same as for benzothiazepine derivatives

Verapamil, sustained-release

120–480 mg once/day

Dihydropyridines

Amlodipine

2.5–10 mg once/day

Dizziness, flushing, headache, weakness, nausea, heartburn, pedal edema, tachycardia

Contraindicated in heart failure, possibly except for amlodipine

Use of short-acting nifedipine possibly associated with higher MI rate

Felodipine

2.5–20 mg once/day

Isradipine

2.5–10 mg bid

Nicardipine

20–40 mg tid

Nicardipine, sustained-release

30–60 mg bid

Nifedipine, extended-release

30–90 mg once/day

Nisoldipine

10–60 mg once/day

Long-acting nifedipine, verapamil, or diltiazem is used to treat hypertension, but short-acting nifedipine and diltiazem are associated with a high rate of  MI and are not recommended.

A Ca channel blocker is preferred to a β-blocker in patients with angina pectoris and a bronchospastic disorder, with coronary spasms, or with Raynaud syndrome.

ACE inhibitors

These drugs (see Table: Oral ACE Inhibitors and Angiotensin II Receptor Blockers for Hypertension) reduce BP 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 K and creatinine levels, especially in patients with chronic kidney disease and those taking K-sparing diuretics, K supplements, or 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 K levels are monitored at least every 3 mo. Patients who have stage 3 nephropathy (estimated GFR of  < 60 mL/min to > 30 mL/min) 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 HF, 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 ACE Inhibitors and Angiotensin II Receptor Blockers for Hypertension

Drug

Usual Dose

Selected Adverse Effects

ACE inhibitors*

Benazepril

5–40 mg once/day

Rash, cough, angioedema, hyperkalemia (particularly in patients with renal insufficiency or taking NSAIDs, K-sparing diuretics, or K supplements), dysgeusia, reversible acute kidney injury if stenosis affecting one or both kidneys threatens renal function, proteinuria (rare at recommended doses), neutropenia (rare), hypotension with initiation of treatment (particularly in patients with high plasma renin activity or with hypovolemia due to diuretics or other conditions)

Captopril

12.5–150 mg bid

Enalapril

2.5–40 mg once/day

Fosinopril

10–80 mg once/day

Lisinopril

5–40 mg once/day

Perindopril

4–8 mg once/day

Quinapril

5–80 mg once/day

Ramipril

1.25–20 mg once/day

Trandolapril

1–4 mg once/day

Angiotensin II receptor blockers

Azilsartan

80 mg once/day

In patients > 65, initial dose 40 mg once/day

Dizziness, angioedema (very rare); theoretically, same adverse effects as ACE inhibitors on renal function (except proteinuria and neutropenia), serum K, and BP

Candesartan

8–32 mg once/day

Eprosartan

400–1200 mg once/day

Irbesartan

75–300 mg once/day

Losartan

25–100 mg once/day

Olmesartan

20–40 mg once/day

Telmisartan

20–80 mg once/day

Valsartan

80–320 mg once/day

*All ACE inhibitors and angiotensin II receptor blockers are contraindicated in pregnancy (category C during 1st trimester; category D during 2nd and 3rd trimesters).

Angiotensin II receptor blockers

These drugs (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 β-blocker may reduce the hospitalization rate for patients with HF. Angiotensin II receptor blockers may be safely started in people <  60 with initial serum creatinine of 3 mg/dL.

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 HF 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.

Direct renin inhibitor

Aliskiren, a direct renin inhibitor, is used in the management of hypertension. Dosage is 150 to 300 mg po once/day, with a starting dose of 150 mg. Clinical trials are ongoing to assess its efficacy for reducing mortality in HF.

As with ACE inhibitors and angiotensin II receptor blockers, aliskiren causes elevation of serum K 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).

Adrenergic  modifiers

This class (see Table: Adrenergic Modifiers for Hypertension) includes central α 2 -agonists, postsynaptic α 1 -blockers, and peripheral-acting adrenergic blockers.

Adrenergic Modifiers for Hypertension

Drug*

Usual Dose

Selected Adverse Effects

Comments

α 2 -Agonists (central acting)

Clonidine

0.05–0.3 mg bid

Drowsiness, sedation, dry mouth, fatigue, sexual dysfunction, rebound hypertension with abrupt discontinuance (particularly if doses are high or concomitant β-blockers are continued), localized skin reaction to clonidine patch; possibly liver damage, Coombs-positive hemolytic anemia with methyldopa

Should be used cautiously in elderly patients because of orthostatic hypotension

Interferes with measurements of urinary catecholamine levels by fluorometric methods

Clonidine TTS (patch)

0.1–0.3 mg once/wk

Guanabenz

2–16 mg bid

Guanfacine

0.5–3 mg once/day

Methyldopa

250–1000 mg bid

α 1 -Blockers

Doxazosin

1–16 mg once/day

First-dose syncope, orthostatic hypotension, weakness, palpitations, headache

Should be used cautiously in elderly patients because of orthostatic hypotension

Relieves symptoms of benign prostatic hyperplasia

Prazosin

1–10 mg bid

Terazosin

1–20 mg once/day

*Peripheral-acting adrenergic blockers (eg, guanadrel, guanethidine, reserpine) are no longer available.

TTS = transdermal therapeutic system.

α 2 -Agonists (eg, methyldopa, clonidine, guanabenz, guanfacine) stimulate α 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/wk as a patch; thus, it may be useful for nonadherent patients (eg, those with dementia).

Postsynaptic α 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 HF. 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 β-blocker.

Direct vasodilators

These drugs (including minoxidil and hydralazine—see Table: Direct Vasodilators for Hypertension) work directly on vessels, independently of the autonomic nervous system. Minoxidil is more potent than hydralazine but has more adverse effects, including Na 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

Drug

Usual Dose

Selected Adverse Effects*

Comments

Hydralazine

10–50 mg qid

Positive antinuclear antibody test, drug-induced lupus (rare at recommended doses)

Augments vasodilating effects of other vasodilating drugs

Minoxidil

1.25–40 mg bid

Na and water retention, hypertrichosis; possibly new or worsening pleural and pericardial effusions

Reserved for severe, refractory hypertension

*Both drugs may cause headache, tachycardia, and fluid retention and may precipitate angina in patients with coronary artery disease.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • DYRENIUM
  • LASIX
  • No US brand name
  • MICROZIDE
  • ZAROXOLYN
  • MIDAMOR
  • DIURIL
  • DEMADEX
  • INSPRA
  • THALITONE
  • ALDACTONE
  • LITHOBID
  • ZEBETA
  • BETOPTIC
  • LOPRESSOR, TOPROL-XL
  • TENORMIN
  • INDERAL
  • TIMOPTIC
  • CORGARD
  • SECTRAL
  • COREG
  • BYSTOLIC
  • OCUPRESS
  • SULAR
  • CARDENE
  • PLENDIL
  • CARDIZEM, CARTIA XT, DILACOR XR
  • CALAN
  • ADALAT CC, PROCARDIA
  • NORVASC
  • AVAPRO
  • MICARDIS
  • COZAAR
  • DIOVAN
  • ALTACE
  • ATACAND
  • ACCUPRIL
  • MAVIK
  • BENICAR
  • LOTENSIN
  • CAPOTEN
  • VASOTEC
  • TEVETEN
  • PRINIVIL, ZESTRIL
  • EDARBI
  • TEKTURNA
  • No brand name
  • TENEX
  • MINIPRESS
  • CARDURA
  • CATAPRES
  • HYTRIN
  • ROGAINE

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