There are many classes of antihypertensive drugs of which six (ACE inhibitors, ARBs, renin inhibitors, calcium channel blockers, diuretics, and beta-blockers) are suitable for initial therapy based on efficacy and tolerability. A number of considerations enter into the selection of the initial regimen for a given patient. These include the weight of evidence for beneficial effects on clinical outcomes, the safety and tolerability of the drug, its cost, demographic differences in response, concomitant medical conditions, and lifestyle issues. The specific classes of antihypertensive medications are discussed below, and guidelines for the choice of initial medications are offered.
A. Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors are commonly used as the initial medication in mild to moderate hypertension (Table 11–6). Their primary mode of action is inhibition of the RAAS, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins, and can reduce sympathetic nervous system activity. These latter actions may explain why they exhibit some effect even in patients with low plasma renin activity. ACE inhibitors appear to be more effective in younger white patients. They are relatively less effective in blacks and older persons and in predominantly systolic hypertension. Although as single therapy they achieve adequate antihypertensive control in only about 40–50% of patients, the combination of an ACE inhibitor and a diuretic or calcium channel blocker is potent.
Table 11–6.Antihypertensive drugs: renin and ACE inhibitors and angiotensin II receptor blockers. ||Download (.pdf) Table 11–6. Antihypertensive drugs: renin and ACE inhibitors and angiotensin II receptor blockers.
|Drug ||Proprietary Name ||Initial Oral Dosage ||Dosage Range ||Cost per Unit ||Cost of 30 Days of Treatment (Average Dosage)1 ||Adverse Effects ||Comments |
|Renin Inhibitors |
|Aliskiren ||Tekturna ||150 mg once daily ||150–300 mg once daily ||$7.48/150 mg ||$224.41 || |
Angioedema, hypotension, hyperkalemia.
Contraindicated in pregnancy.
|Probably metabolized by CYP3A4. Absorption is inhibited by high-fat meal. |
|Aliskiren and HCTZ ||Tekturna HCT ||150 mg/12.5 mg once daily ||150 mg/12.5 mg–300 mg/25 mg once daily ||$8.31/150 mg/12.5 mg ||$249.36 || || |
|ACE Inhibitors |
|Benazepril ||Lotensin ||10 mg once daily ||5–40 mg in 1 or 2 doses ||$0.95/20 mg ||$28.50 ||Cough, hypotension, dizziness, kidney dysfunction, hyperkalemia, angioedema; taste alteration and rash (may be more frequent with captopril); rarely, proteinuria, blood dyscrasia. Contraindicated in pregnancy. ||More fosinopril is excreted by the liver in patients with kidney dysfunction (dose reduction may or may not be necessary). Captopril and lisinopril are active without metabolism. Captopril, enalapril, lisinopril, and quinapril are approved for heart failure. |
|Benazepril and HCTZ ||Lotensin HCT ||5 mg/6.25 mg once daily ||5 mg/6.25 mg–20 mg/25 mg ||$1.07/any dose ||$32.21 |
|Benazepril and amlodipine ||Lotrel ||10 mg/2.5 mg once daily ||10 mg/2.5 mg–40 mg/10 mg ||$3.32/20 mg/10 mg ||$99.60 |
|Captopril ||Capoten ||25 mg twice daily ||50–450 mg in 2 or 3 doses ||$0.65/25 mg ||$19.50 |
|Captopril and HCTZ ||Capozide ||25 mg/15 mg twice daily ||25 mg/15 mg–50 mg/25 mg ||$2.85/25 mg/15 mg ||$171.00 |
|Enalapril ||Vasotec ||5 mg once daily ||5–40 mg in 1 or 2 doses ||$0.95/20 mg ||$28.50 |
|Enalapril and HCTZ ||Vaseretic ||5 mg/12.5 mg once daily ||5 mg/12.5 mg–10 mg/25 mg ||$1.22/10 mg/25 mg ||$36.60 |
|Fosinopril ||Monopril ||10 mg once daily ||10–80 mg in 1 or 2 doses ||$0.29/20 mg ||$8.70 |
|Fosinopril and HCTZ ||Monopril-HCT ||10 mg/12.5 mg once daily ||10 mg/12.5 mg–20 mg/12.5 mg ||$1.48/any dose ||$44.40 |
|Lisinopril ||Prinivil, Zestril ||5–10 mg once daily ||5–40 mg once daily ||$0.08/20 mg ||$2.45 |
|Lisinopril and HCTZ ||Prinzide or Zestoretic ||10 mg/12.5 mg once daily ||10 mg/12.5 mg–20 mg/12.5 mg ||$0.14/20 mg/12.5 mg ||$4.20 |
|Moexipril ||Univasc ||7.5 mg once daily ||7.5–30 mg in 1 or 2 doses ||$1.39/7.5 mg ||$41.70 |
|Moexipril and HCTZ ||Uniretic ||7.5 mg/12.5 mg once daily ||7.5 mg/12.5 mg–15 mg/25 mg ||$1.70/15 mg/12.5 mg ||$51.00 |
|Perindopril ||Aceon ||4 mg once daily ||4–16 mg in 1 or 2 doses ||$2.80/8 mg ||$84.00 |
|Perindopril and amlodipine ||Prestalia ||3.5 mg/2.5 mg once daily ||3.5 mg/2.5–14 mg/10 mg once daily ||$6.81/7 mg/5 mg ||$204.30 |
|Quinapril ||Accupril ||10 mg once daily ||10–80 mg in 1 or 2 doses ||$1.22/20 mg ||$36.60 |
|Quinapril and HCTZ ||Accuretic ||10 mg/12.5 mg once daily ||10 mg/12.5 mg–20 mg/25 mg ||$1.22/20 mg/12.5 mg ||$36.60 |
|Ramipril ||Altace ||2.5 mg once daily ||2.5–20 mg in 1 or 2 doses ||$1.80/5 mg ||$54.00 |
|Trandolapril ||Mavik ||1 mg once daily ||1–8 mg once daily ||$1.21/4 mg ||$36.30 |
|Trandolapril and verapamil ||Tarka ||2 mg/180 mg ER once daily ||2 mg/180 mg ER–8 mg/480 mg ER ||$5.29/any dose ||$158.70 |
|Angiotensin II Receptor Blockers |
|Azilsartan ||Edarbi ||40 mg once daily ||40–80 mg once daily ||$8.54/80 mg ||$256.20 ||Hyperkalemia, kidney dysfunction, rare angioedema. Combinations have additional side effects. Contraindicated in pregnancy. ||Losartan has a flat dose-response curve. Valsartan and irbesartan have wider dose-response ranges and longer durations of action. Addition of low-dose diuretic (separately or as combination pills) increases the response. |
|Azilsartan and chlorthalidone ||Edarbychlor ||40 mg/12.5 mg once daily ||40 mg/12.5–40 mg/25 mg once daily ||$8.06/any dose ||$241.80 |
|Candesartan cilexitil ||Atacand ||16 mg once daily ||8–32 mg once daily ||$3.06/16 mg ||$91.80 |
|Candesartan cilexitil and HCTZ ||Atacand HCT ||16 mg/12.5 mg once daily ||32 mg/12.5 mg once daily ||$4.72/16 mg/12.5 mg ||$141.60 |
|Eprosartan ||Teveten ||600 mg once daily ||400–800 mg in 1–2 doses ||$3.43/600 mg ||$102.90 |
|Irbesartan ||Avapro ||150 mg once daily ||150–300 mg once daily ||$0.46/150 mg ||$13.80 |
|Irbesartan and HCTZ ||Avalide ||150 mg/12.5 mg once daily ||150–300 mg irbesartan once daily ||$0.67/150 mg/12.5 mg ||$20.10 |
|Losartan and HCTZ ||Hyzaar ||50 mg/12.5 mg once daily ||50 mg/12.5 mg–100 mg/25 mg tablets once daily ||$2.47/50 mg/12.5 mg/tablet ||$74.10 || || |
|Olmesartan ||Benicar ||20 mg once daily ||20–40 mg once daily ||$6.28/20 mg ||$188.40 || || |
|Olmesartan and HCTZ ||Benicar HCT ||20 mg/12.5 mg once daily ||20 mg/12.5 mg–40 mg/25 mg once daily ||$6.28/20 mg/12.5 mg ||$188.40 || || |
|Olmesartan and amlodipine ||Azor ||20 mg/5 mg once daily ||20 mg/5 mg–40 mg/10 mg ||$3.03/20 mg/5 mg ||$90.90 || || |
|Olmesartan and amlodipine and HCTZ ||Tribenzor ||20 mg/5 mg/12.5 mg once daily ||20 mg/5 mg/12.5 mg –40 mg/10 mg/25 mg once daily ||$4.54/20 mg/5 mg/12.5 mg ||$136.20 || || |
|Telmisartan ||Micardis ||40 mg once daily ||20–80 mg once daily ||$4.34/40 mg ||$130.20 || || |
|Telmisartan and HCTZ ||Micardis HCT ||40 mg/12.5 mg once daily ||40 mg/12.5 mg–80 mg/25 mg once daily ||$4.83/40 mg/12.5 mg ||$144.90 || || |
|Telmisartan and amlodipine ||Twynsta ||40 mg/5 mg once daily ||40 mg/5 mg–80 mg/10 mg once daily ||$5.20/any dose ||$156.00 || || |
|Valsartan ||Diovan ||80 mg once daily ||80–320 mg once daily ||$2.09/160 mg ||$62.70 || || |
|Valsartan and HCTZ ||Diovan HCT ||80 mg/12.5 mg once daily ||80–320 mg valsartan once daily ||$4.84/160 mg/12.5 mg ||$145.20 || || |
|Valsartan and amlodipine ||Exforge ||160 mg/5 mg once daily ||160 mg/5 mg–320 mg/10 mg once daily ||$1.71/160 mg/10 mg ||$51.30 || || |
|Other Combination Products |
|Amlodipine and valsartan and HCTZ ||Exforge HCT ||5 mg/160 mg/12.5 mg once daily ||10 mg/320 mg/25 mg up to once daily ||$5.47/160 mg valsartan ||$164.10 || || |
ACE inhibitors are the agents of choice in persons with type 1 diabetes with frank proteinuria or evidence of kidney dysfunction because they delay the progression to end-stage renal disease. Many authorities have expanded this indication to include persons with type 1 and type 2 diabetes mellitus with microalbuminuria who do not meet the usual criteria for antihypertensive therapy. ACE inhibitors may also delay the progression of nondiabetic kidney disease. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduced the incidence of new-onset heart failure, kidney dysfunction, and new-onset diabetes in a population of patients at high risk for vascular events. Although this was not specifically a hypertensive population, the benefits were associated with a modest reduction in blood pressure, and the results inferentially support the use of ACE inhibitors in similar hypertensive patients. ACE inhibitors are a drug of choice (usually in conjunction with a diuretic and a beta-blocker) in patients with heart failure with reduced ejection fraction and are indicated also in asymptomatic patients with reduced ejection fraction.
A baseline metabolic panel should be drawn prior to starting medications that interfere with the RAAS, repeated 1–2 weeks after initiation of therapy to evaluate changes in creatinine and potassium. Minor dose adjustments of these medications rarely trigger significant shifts in these values.
An advantage of the ACE inhibitors is their relative freedom from troublesome side effects (Table 11–6). Severe hypotension can occur in patients with bilateral renal artery stenosis; significant increases in creatinine may ensue but are usually reversible with the discontinuation of the ACE inhibitor. Hyperkalemia may develop in patients with kidney disease and type IV renal tubular acidosis (commonly seen in patients with diabetes) and in older adults. A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug. Skin rashes are observed with any ACE inhibitor. Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase. Exposure of the fetus to ACE inhibitors during the second and third trimesters of pregnancy has been associated with a variety of defects due to hypotension and reduced renal blood flow.
B. Angiotensin II Receptor Blockers
ARBs can improve cardiovascular outcomes in patients with hypertension as well as in patients with related conditions, such as heart failure and type 2 diabetes with nephropathy. ARBs have not been compared with ACE inhibitors in randomized controlled trials in patients with hypertension, but two trials comparing losartan with captopril in heart failure and post–myocardial infarction left ventricular dysfunction showed trends toward worse outcomes in the losartan group. By contrast, valsartan seems as effective as ACE inhibitors in these settings. Within group heterogeneity of antihypertensive potency and duration of action might explain such observations. The Losartan Intervention for Endpoints (LIFE) trial in nearly 9000 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy—comparing losartan with the beta-blocker atenolol as initial therapy—demonstrated a significant reduction in stroke with losartan. Of note is that in diabetic patients, death and myocardial infarction were also reduced, and there was a lower occurrence of new-onset diabetes. In a subgroup analysis from the LIFE trial, atenolol appeared to be superior to losartan in blacks, while the opposite was the case in non-blacks. A similar lack of efficacy of lisinopril compared to diuretics and calcium channel blockers was observed in blacks in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attach Trial (ALLHAT), suggesting that ACE inhibitors and ARBs may not be the preferred agents in black patients. In the treatment of hypertension, combination therapy with an ACE inhibitor and an ARB is not advised because it generally offers no advantage over monotherapy at maximum dose with addition of a complementary class where necessary.
Unlike ACE inhibitors, the ARBs rarely cause cough and are less likely to be associated with skin rashes or angioedema (Table 11–6). However, as seen with ACE inhibitors, hyperkalemia can be a problem, and patients with bilateral renal artery stenosis may exhibit hypotension and worsened kidney function. Olmesartan has been linked to a sprue-like syndrome, presenting with abdominal pain, weight loss, and nausea, which subsides upon drug discontinuation. There is evidence from an observational study suggesting that ARBs and ACE inhibitors are less likely to be associated with depression than calcium channel blockers and beta-blockers.
Since renin cleavage of angiotensinogen is the rate-limiting step in the renin-angiotensin cascade, the most efficient inactivation of this system would be expected with renin inhibition. Conventional ACE inhibitors and ARBs probably offer incomplete blockade, even in combination. Aliskiren, a renin inhibitor, binds the proteolytic site of renin, thereby preventing cleavage of angiotensinogen. As a consequence, levels of angiotensins I and II are reduced and renin concentration is increased. Aliskiren effectively lowers blood pressure, reduces albuminuria, and limits left ventricular hypertrophy, but it has yet to be established as a first-line drug based on outcomes data. The combination of aliskiren with ACE inhibitors or ARBs in persons with type 2 diabetes mellitus offers no advantage and might even increase the risk of adverse cardiac or renal consequences.
D. Calcium Channel Blocking Agents
These agents act by causing peripheral vasodilation but with less reflex tachycardia and fluid retention than other vasodilators. They are effective as single-drug therapy in approximately 60% of patients in all demographic groups and all grades of hypertension (Table 11–7). For these reasons, they may be preferable to beta-blockers and ACE inhibitors in blacks and older persons. Verapamil and diltiazem should be combined cautiously with beta-blockers because of their potential for depressing atrioventricular (AV) conduction and sinus node automaticity as well as contractility.
Table 11–7.Antihypertensive drugs: calcium channel blocking agents. ||Download (.pdf) Table 11–7. Antihypertensive drugs: calcium channel blocking agents.
|Drug ||Proprietary Name ||Initial Oral Dosage ||Dosage Range ||Cost of 30 Days of Treatment (Average Dosage)1 ||Special Properties ||Contractility ||Adverse Effects ||Comments |
|Peripheral Vasodilation ||Cardiac Automaticity and Conduction |
|Nondihydropyridine Agents |
|Diltiazem ||Cardizem SR ||90 mg twice daily ||180–360 mg in 2 doses ||$283.20 (120 mg twice daily) ||++ ||↓↓ ||↓↓ ||Edema, headache, bradycardia, GI disturbances, dizziness, AV block, heart failure, urinary frequency. ||Also approved for angina. |
| ||Cardizem CD ||180 mg ER once daily ||180–360 mg ER once daily ||$42.00 (240 mg once daily) || || || || || |
| ||Cartia XT ||180 or 240 mg ER once daily ||180–480 mg ER once daily ||$42.00 (240 mg once daily) || || || || || |
| ||Dilacor XR ||180 or 240 mg ER once daily ||180–540 mg ER once daily ||$42.90 (240 mg once daily) || || || || || |
| ||Dilt-CD ||180 or 240 mg ER once daily ||180–480 mg ER once daily ||$39.00 (240 mg once daily) || || || || || |
| ||Diltia XT ||180 or 240 mg ER once daily ||180–540 mg ER once daily ||$42.00 (240 mg once daily) || || || || || |
| ||Taztia XT ||120 or 180 mg ER once daily ||120–540 mg ER once daily ||$52.80 (240 mg once daily) || || || || || |
| ||Tiazac ||120 or 240 mg ER once daily ||120–540 mg ER once daily ||$52.80 (240 mg once daily) || || || || || |
|Verapamil ||Calan ||80 mg three times daily ||80–480 mg in 3 divided doses ||$43.20 (80 mg three times daily) ||++ ||↓↓↓ ||↓↓↓ ||Same as diltiazem but more likely to cause constipation and heart failure. ||Also approved for angina and arrhythmias. |
| ||Calan SR ||180 mg ER once daily ||180–480 mg ER in 1 or 2 doses ||$49.20 (240 mg once daily) || || || || || |
| ||Verelan ||120 or 240 mg ER once daily ||240–480 mg ER once daily ||$68.70 (240 mg once daily) || || || || || |
| ||Verelan PM ||100 or 200 mg ER once daily ||100–400 mg ER once daily ||$75.90 (200 mg once daily) || || || || || |
|Amlodipine ||Norvasc ||2.5 mg once daily ||2.5–10 mg once daily ||$3.00 (10 mg once daily) ||+++ ||↓/0 ||↓/0 ||Edema, dizziness, palpitations, flushing, headache, hypotension, tachycardia, GI disturbances, urinary frequency. ||Amlodipine, nicardipine, and nifedipine also approved for angina. |
|Amlodipine and atorvastatin ||Caduet ||2.5 mg/10 mg once daily ||10 mg/80 mg once daily ||$281.10 (10 mg/40 mg daily) ||+++ ||↓/0 ||↓/0 ||Myopathy, hepatotoxicity, edema with amlodipine and atorvastatin. || |
|Felodipine ||Plendil ||5 mg ER once daily ||5–10 mg ER once daily ||$81.60 (10 mg ER daily) ||+++ ||↓/0 ||↓/0 || || |
|Isradipine ||DynaCirc ||2.5 mg twice daily ||2.5–5 mg twice daily ||$120.00 (5 mg twice daily) ||+++ ||↓/0 ||↓ || || |
|Nicardipine ||Cardene ||20 mg three times daily ||20–40 mg three times daily ||$200.70 (20 mg three times daily) ||+++ ||↓/0 ||↓ || || |
|Nifedipine ||Adalat CC ||30 mg ER once daily ||30–90 mg ER once daily ||$74.40/60 mg daily ||+++ ||↓ ||↓↓ || || |
| ||Procardia XL ||30 or 60 mg ER once daily ||30–120 mg ER once daily ||$54.90/60 mg daily || || || || || |
|Nisoldipine ||Sular ||17 mg daily ||17–34 mg daily ||$251.70 (34 mg once daily) ||+++ ||↓/0 ||↓ || || |
Initial concerns about possible adverse cardiac effects of calcium channel blockers have been convincingly allayed by several subsequent large studies that have demonstrated that calcium channel blockers are equivalent to ACE inhibitors and thiazide diuretics in prevention of coronary heart disease, major cardiovascular events, cardiovascular death, and total mortality. A protective effect against stroke with calcium channel blockers is well established, and in two trials (ALLHAT and the Systolic Hypertension in Europe trial), these agents appeared to be more effective than diuretic-based therapy.
The most common side effects of calcium channel blockers are headache, peripheral edema, bradycardia, and constipation (especially with verapamil in older adults) (Table 11–7). The dihydropyridine agents—nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and amlodipine—are more likely to produce symptoms of vasodilation, such as headache, flushing, palpitations, and peripheral edema. Edema is minimized by coadministration of an ACE inhibitor or ARB. Calcium channel blockers have negative inotropic effects and should be used cautiously in patients with cardiac dysfunction. Amlodipine is the only calcium channel blocker with established safety in patients with severe heart failure. According to a case-control study based in the Pacific Northwest of the United States, calcium channel blockers as a class may increase the risk of breast cancer by 2.5-fold, but this relationship has not been consistently observed in other studies, and calcium channel blockers do not appear to increase the risk of breast cancer recurrence.
Thiazide diuretics (Table 11–8) are the antihypertensives that have been most extensively studied and most consistently effective in clinical trials. They lower blood pressure initially by decreasing plasma volume, but during long-term therapy, their major hemodynamic effect is reduction of peripheral vascular resistance. Most of the antihypertensive effect of these agents is achieved at lower dosages than used previously (typically, 12.5 mg of hydrochlorothiazide or equivalent), but their biochemical and metabolic effects are dose related. Chlorthalidone has the advantage of better 24-hour blood pressure control than hydrochlorothiazide in clinical trials. Thiazides may be used at higher doses if plasma potassium is above 4.5 mmol/L. The loop diuretics (such as furosemide) may lead to electrolyte and volume depletion more readily than the thiazides and have short durations of action. Because of these adverse effects, loop diuretics should be reserved for use in patients with kidney dysfunction (serum creatinine greater than 2.5 mg/dL [208.3 mcmol/L]; estimated glomerular filtration rate [eGFR] less than 30 mL/min) in which case they are more effective than thiazides. Relative to beta-blockers and ACE inhibitors, diuretics are more potent in blacks, older individuals, the obese, and other subgroups with increased plasma volume or low plasma renin activity (or both). They are relatively more effective in smokers than in nonsmokers. Long-term thiazide administration also mitigates the loss of bone mineral content in older women at risk for osteoporosis.
Table 11–8.Antihypertensive drugs: diuretics (in descending order of preference). ||Download (.pdf) Table 11–8. Antihypertensive drugs: diuretics (in descending order of preference).
|Drugs ||Proprietary Names ||Initial Oral Doses ||Dosage Range ||Cost per Unit ||Cost of 30 Days of Treatment1 (Average Dosage) ||Adverse Effects ||Comments |
|Thiazides and Related Diuretics |
|Hydrochlorothiazide (HCTZ) ||Esidrix, Microzide ||12.5 or 25 mg once daily ||12.5–50 mg once daily ||$0.05/25 mg ||$1.50 ||↓K+, ↓Mg2+, ↑Ca2+, ↓Na+, ↑uric acid, ↑glucose, ↑LDL cholesterol, ↑triglycerides; rash, erectile dysfunction. ||Low dosages effective in many patients without associated metabolic abnormalities; metolazone more effective with concurrent kidney disease; indapamide does not alter serum lipid levels. |
|Chlorthalidone ||Thalitone ||12.5 or 25 mg once daily ||12.5–50 mg once daily ||$1.21/25 mg ||$36.30 || ||Chlorthalidone: better 24-hour blood pressure control than HCTZ because of longer half-life |
|Metolazone ||Zaroxolyn ||1.25 or 2.5 mg once daily ||1.25–5 mg once daily ||$1.51/5 mg ||$45.30 || || |
|Indapamide ||Lozol ||2.5 mg once daily ||2.5–5 mg once daily ||$0.83/2.5 mg ||$24.90 || || |
|Bendroflumethiazide || |
|2.5 mg once daily ||— ||— ||— ||— ||Not available in United States |
|Loop Diuretics |
|Furosemide ||Lasix ||20 mg twice daily ||40–320 mg in 2 or 3 doses ||$0.16/40 mg ||$9.60 ||Same as thiazides, but higher risk of excessive diuresis and electrolyte imbalance. Increases calcium excretion. ||Furosemide: Short duration of action a disadvantage; should be reserved for patients with kidney disease or fluid retention. Poor antihypertensive. |
|Ethacrynic acid ||Edecrin ||50 mg once daily ||50–100 mg once or twice daily ||$23.95/25 mg ||$1437.00 || || |
|Bumetanide ||(generic) ||0.25 mg twice daily ||0.5–10 mg in 2 or 3 doses ||$0.54/1 mg ||$32.40 || || |
|Torsemide ||Demadex ||5 mg once daily ||5–10 mg once daily ||$0.70/10 mg ||$21.00 || ||Torsemide: Effective blood pressure medication at low dosage. |
|Aldosterone Receptor Blockers |
|Spironolactone ||Aldactone ||12.5 or 25 mg once daily ||12.5–100 mg once daily ||$0.19/25 mg ||$5.70 ||Hyperkalemia, metabolic acidosis, gynecomastia. ||Can be useful add-on therapy in patients with refractory hypertension. |
|Amiloride ||(generic) ||5 mg once daily ||5–10 mg once daily ||$1.25/5 mg ||$37.50 || || |
|Eplerenone ||Inspra ||25 mg once daily ||25–100 mg once daily ||$4.10/25 mg ||$123.00 || || |
|Combination Products |
|HCTZ and triamterene ||Dyazide, Maxzide-25 (25/37.5 mg) ||1 tab once daily ||1 or 2 tabs once daily ||$0.27 ||$8.10 ||Same as thiazides plus GI disturbances, hyperkalemia rather than hypokalemia, headache; triamterene can cause kidney stones and kidney dysfunction; spironolactone causes gynecomastia. Hyperkalemia can occur if this combination is used in patients with advanced kidney disease or those taking ACE inhibitors. ||Use should be limited to patients with demonstrable need for a potassium-sparing agent. |
|HCTZ and amiloride ||(generic) (50/5 mg) ||½ tab once daily ||1 or 2 tabs once daily ||$1.16 ||$34.80 || || |
|HCTZ and spironolactone ||Aldactazide (25/25 mg; 50/50 mg) ||1 tab (25/25 mg) once daily ||1–4 tabs once daily ||$1.24/(25/25 mg) ||$37.20 || || |
Overall, diuretics administered alone control blood pressure in 50% of patients with mild to moderate hypertension and can be used effectively in combination with all other agents. They are also useful for lowering isolated or predominantly systolic hypertension.
The adverse effects of diuretics relate primarily to the metabolic changes listed in Table 11–8. Erectile dysfunction, skin rashes, and photosensitivity are less frequent. Hypokalemia has been a concern but is uncommon at the recommended dosages. The risk can be minimized by limiting dietary salt or increasing dietary potassium; potassium replacement is not usually required to maintain serum K+ at greater than 3.5 mmol/L. Higher serum K+ levels are prudent in patients at special risk from intracellular potassium depletion, such as those taking digoxin or with a history of ventricular arrhythmias in which case a potassium-sparing agent could be used. Compared with ACE inhibitors and ARBs, diuretic therapy is associated with a slightly higher incidence of mild new-onset diabetes. Diuretics also increase serum uric acid and may precipitate gout. Increases in blood glucose, triglycerides, and LDL cholesterol may occur but are relatively minor during long-term low-dose therapy. The potential for worsening of diabetes is outweighed by the advantages of blood pressure control, and diuretics should not be withheld from diabetic patients.
F. Aldosterone Receptor Antagonists
Spironolactone and eplerenone are natriuretic in sodium-retaining states, such as heart failure and cirrhosis, but only very weakly so in hypertension. These drugs have reemerged in the treatment of hypertension, particularly in resistant patients and are helpful additions to most other antihypertensive medications. Consistent with the increasingly appreciated importance of aldosterone in essential hypertension, the aldosterone receptor blockers are effective at lowering blood pressure in all hypertensive patients regardless of renin level, and are also effective in blacks. Aldosterone plays a central role in target-organ damage, including the development of ventricular and vascular hypertrophy and renal fibrosis. Aldosterone receptor antagonists ameliorate these consequences of hypertension, to some extent independently of effects on blood pressure.
Spironolactone can cause breast pain and gynecomastia in men through activity at the progesterone receptor, an effect not seen with the more specific eplerenone. Hyperkalemia is a problem with both drugs, chiefly in patients with chronic kidney disease. Hyperkalemia is more likely if the pretreatment plasma potassium exceeds 4.5 mmol/L.
G. Beta-Adrenergic Blocking Agents
These drugs are effective in hypertension because they decrease the heart rate and cardiac output. Even after continued use of beta-blockers, cardiac output remains lower and systemic vascular resistance higher with agents that do not have intrinsic sympathomimetic or alpha-blocking activity. The beta-blockers also decrease renin release and are more efficacious in populations with elevated plasma renin activity, such as younger white patients. They neutralize the reflex tachycardia caused by vasodilators and are especially useful in patients with associated conditions that benefit from the cardioprotective effects of these agents. These include individuals with angina pectoris, previous myocardial infarction, and stable heart failure as well as those with migraine headaches and somatic manifestations of anxiety.
Although all beta-blockers appear to be similar in antihypertensive potency, they differ in a number of pharmacologic properties (these differences are summarized in Table 11–9), including specificity to the cardiac beta-1-receptors (cardioselectivity) and whether they also block the beta-2-receptors in the bronchi and vasculature; at higher dosages, however, all agents are nonselective. The beta-blockers also differ in their pharmacokinetics, lipid solubility—which determines whether they cross the blood-brain barrier predisposing to central nervous system side effects—and route of metabolism. Metoprolol reduces mortality and morbidity in patients with chronic stable heart failure with reduced ejection fraction (see Chapter 10). Carvedilol and nebivolol maintain cardiac output and are beneficial in patients with left ventricular systolic dysfunction. Carvedilol and nebivolol may reduce peripheral vascular resistance by concomitant alpha-blockade (carvedilol) and increased nitric oxide release (nebivolol). Because of the lack of efficacy in primary prevention of myocardial infarction and inferiority compared with other drugs in prevention of stroke and left ventricular hypertrophy, traditional beta-blockers should not be used as first-line agents in the treatment of hypertension without specific compelling indications (such as active coronary artery disease). Vasodilating beta-blockers may emerge as alternative first-line antihypertensives, but this possibility has yet to be rigorously tested in outcome studies.
Table 11–9.Antihypertensive drugs: beta-adrenergic blocking agents. ||Download (.pdf) Table 11–9. Antihypertensive drugs: beta-adrenergic blocking agents.
|Drug ||Proprietary Name ||Initial Oral Dosage ||Dosage Range ||Cost per Unit ||Cost of 30 Days of Treatment (Based on Average Dosage)1 ||Special Properties ||Comments5 |
|Beta-1 Selectivity2 ||ISA3 ||MSA4 ||Lipid Solubility ||Renal vs Hepatic Elimination |
|Acebutolol ||Sectral ||400 mg once daily ||200–1200 mg in 1 or 2 doses ||$1.57/400 mg ||$47.10 ||+ ||+ ||+ ||+ ||H > R ||Positive ANA; rare LE syndrome; also indicated for arrhythmias. Doses > 800 mg have beta-1 and beta-2 effects. |
|Atenolol ||Tenormin ||25 mg once daily ||25–100 mg once daily ||$0.79/50 mg ||$23.70 ||+ ||0 ||0 ||0 ||R ||Also indicated for angina and post-MI. Doses > 100 mg have beta-1 and beta-2 effects. |
|Atenolol/chlorthalidone ||Tenoretic ||50 mg/25 mg once daily ||50 mg/25 mg–100 mg/25 mg once daily ||$1.88/50 mg/25 mg ||$56.40 ||+ ||0 ||0 ||0 ||R || |
|Betaxolol ||Kerlone ||10 mg once daily ||10–40 mg once daily ||$0.78/10 mg ||$23.40 ||+ ||0 ||0 ||+ ||H > R || |
|Bisoprolol ||Zebeta ||5 mg once daily ||5–20 mg once daily ||$1.22/10 mg ||$36.60 ||+ ||0 ||0 ||0 ||R = H ||Also effective for heart failure. |
|Bisoprolol and HCTZ ||Ziac ||2.5 mg/6.25 mg once daily ||2.5 mg/6.25 mg–10 mg/6.25 mg once daily ||$1.14/2.5/6.25 mg ||$34.20 ||+ ||0 ||0 ||0 ||R = H ||Low-dose combination approved for initial therapy. |
|Carvedilol || |
6.25 mg twice daily
20 mg ER once daily
12.5–50 mg in 2 doses
20–80 mg ER once daily
$5.40 (25 mg twice a day)
|0 ||0 ||0 ||+++ ||H > R ||Alpha:beta blocking activity 1:9; may cause orthostatic symptoms; effective for heart failure. Nitric oxide potentiating vasodilatory activity. |
|Labetalol ||Trandate ||100 mg twice daily ||200–2400 mg in 2 doses ||$0.39/200 mg ||$23.40 ||0 ||0/+ ||0 ||++ ||H ||Alpha:beta blocking activity 1:3; more orthostatic hypotension, fever, hepatotoxicity. |
|Metoprolol || |
Toprol-XL (SR preparation)
50 mg twice daily
25 mg once daily
50–200 mg twice daily
25–400 mg once daily
|+ ||0 ||+ ||+++ ||H ||Also indicated for angina and post-MI. Approved for heart failure. Doses > 100 mg have beta-1 and beta-2 effects. |
|Metoprolol and HCTZ ||Lopressor HCT ||50 mg/12.5 mg twice daily ||50 mg/25 mg–200 mg/50 mg ||$1.63/100 mg/25 mg ||$97.80 ||+ ||0 ||+ ||+++ ||H || |
|Nadolol ||Corgard ||20 mg once daily ||20–320 mg once daily ||$3.96/40 mg ||$118.80 ||0 ||0 ||0 ||0 ||R || |
|Nadolol and bendroflumethazide ||Corzide ||40 mg/5 mg once daily ||40 mg/5 mg–80 mg/5 mg once daily ||6.14/80 mg/5 mg ||$184.20 || || || || || || |
|Nebivolol ||Bystolic ||5 mg once daily ||40 mg once daily ||$6.02/5 mg ||$180.60 ||+ ||0 ||0 ||++ ||H ||Nitric oxide potentiating vasodilatory activity. |
|Pindolol ||Visken ||5 mg twice daily ||10–60 mg in 2 doses ||$1.10/5 mg ||$66.00 ||0 ||++ ||+ ||+ ||H > R ||In adults, 35% renal clearance. |
|Propranolol || |
20 mg twice daily
80 mg ER once daily
80 mg ER once nightly
40–640 mg in 2 doses
120–640 mg ER once daily
80–120 mg ER once nightly
|0 ||0 ||++ ||+++ ||H ||Also indicated for angina and post-MI. |
|Propranolol and HCTZ ||(generic) ||40 mg/25 mg twice daily ||80 mg/25 mg twice daily ||$1.41/80 mg/25 mg ||$84.60 ||0 ||0 ||++ ||+++ ||H || |
|Timolol ||(generic) ||5 mg twice daily ||10–60 mg in 2 doses ||$1.70/10 mg ||$102.00 ||0 ||0 ||0 ||++ ||H > R ||Also indicated for post-MI; 80% hepatic clearance. |
The side effects of beta-blockers include inducing or exacerbating bronchospasm in predisposed patients; sinus node dysfunction and AV conduction depression (resulting in bradycardia or AV block); nasal congestion; Raynaud phenomenon; and central nervous system symptoms with nightmares, excitement, depression, and confusion. Fatigue, lethargy, and erectile dysfunction may occur. The traditional beta-blockers (but not the vasodilator beta-blockers carvedilol and nebivolol) have an adverse effect on lipids and glucose metabolism. Beta-blockers are used cautiously in patients with type 1 diabetes, since they can mask the symptoms of hypoglycemia and prolong these episodes by inhibiting gluconeogenesis. These drugs should also be used with caution in patients with advanced peripheral vascular disease associated with rest pain or nonhealing ulcers, but they are generally well tolerated in patients with mild claudication. Nebivolol can be safely used in patients with stage II claudication (claudication at 200 m).
In treatment of pheochromocytoma, beta-blockers should not be administered until alpha-blockade (eg, phentolamine) has been established. Otherwise, blockade of vasodilatory beta-2-adrenergic receptors will allow unopposed vasoconstrictor alpha-adrenergic receptor activation with worsening of hypertension. For the same reason, beta-blockers should not be used to treat hypertension arising from cocaine use.
In addition to adverse metabolic changes associated with their use, some experts have suggested that the therapeutic shortcomings of traditional beta-blockers are the consequence of the particular hemodynamic profile associated with these drugs. Pressure peaks in the aorta are augmented by reflection of pressure waves from the peripheral circulation. These reflected waves are delayed in patients taking ACE inhibitors and thiazide diuretics, resulting in decreased central systolic and pulse pressures. By contrast, traditional beta-blockers appear to potentiate reflection of pressure waves, possibly because peripheral resistance vessels are a reflection point and peripheral resistance is increased by these drugs. This might explain why the traditional beta-blockers are less effective at controlling systolic and pulse pressure.
Great care should be exercised if the decision is made, in the absence of compelling indications, to remove beta-blockers from the treatment regimen because abrupt withdrawal can precipitate acute coronary events and severe increases in blood pressure.
H. Alpha-Adrenoceptor Antagonists
Prazosin, terazosin, and doxazosin (Table 11–10) block postsynaptic alpha-receptors, relax smooth muscle, and reduce blood pressure by lowering peripheral vascular resistance. These agents are effective as single-drug therapy in some individuals, but tachyphylaxis may appear during long-term therapy. Unlike beta-blockers and diuretics, alpha-blockers have no adverse effect on serum lipid levels. In fact, alpha-blockers increase HDL cholesterol while reducing total cholesterol; whether this is beneficial in the long term has not been established.
Table 11–10.Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators. ||Download (.pdf) Table 11–10. Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators.
|Drug ||Proprietary Names ||Initial Dosage ||Dosage Range ||Cost per Unit ||Cost of 30 Days of Treatment (Average Dosage)1 ||Adverse Effects ||Comments |
|Alpha-Adrenoceptor Blockers |
|Doxazosin || |
1 mg at bedtime
4 mg ER once daily
1–16 mg once daily
4–8 mg ER once daily
$6.74/4 mg ER
$8.70 (4 mg once daily)
$202.20 (4 mg ER once daily)
|Syncope with first dose; postural hypotension, dizziness, palpitations, headache, weakness, drowsiness, sexual dysfunction, anticholinergic effects, urinary incontinence; first-dose effects may be less with doxazosin. ||May ↑ HDL and ↓ LDL cholesterol. May provide short-term relief of obstructive prostatic symptoms. Less effective in preventing cardiovascular events than diuretics. |
|Prazosin ||Minipress ||1 mg at bedtime ||2–20 mg in 2 or 3 doses ||$0.95/5 mg ||$57.00 (5 mg twice daily) || || |
|Terazosin ||Hytrin ||1 mg at bedtime ||1–20 mg in 1 or 2 doses ||$1.60/1, 2, 5, 10 mg ||$48.00 (5 mg once daily) || || |
|Central Sympatholytics |
|Clonidine || |
Catapres TTS (transdermal patch)
0.1 mg twice daily
0.1 mg/day patch weekly
0.2–0.6 mg in 2 doses
0.1–0.3 mg/day patch weekly
$55.77/0.2 mg patch
$12.60 (0.1 mg twice daily)
$223.08 (0.2 mg weekly)
|Sedation, dry mouth, sexual dysfunction, headache, bradyarrhythmias; side effects may be less with guanfacine. Contact dermatitis with clonidine patch. Methyldopa also causes hepatitis, hemolytic anemia, fever. ||“Rebound” hypertension may occur even after gradual withdrawal. |
|Clonidine and chlorthalidone ||Clorpres ||0.1 mg/15 mg one to three times daily ||0.1 mg/15 mg–0.3 mg/15 mg ||$2.77/0.1 mg/15 mg ||$166.20/0.1 mg/15 mg twice daily || || |
|Guanfacine ||Tenex ||1 mg once daily ||1–3 mg once daily ||$0.87/1 mg ||$26.10 (1 mg once daily) || || |
|Methyldopa ||Aldochlor ||250 mg twice daily ||500–2000 mg in 2 doses ||$0.66/500 mg ||$39.60 (500 mg twice daily) || ||Methyldopa should be avoided in favor of safer agents. |
|Peripheral Neuronal Antagonists |
|Reserpine ||(generic) ||0.05 mg once daily ||0.05–0.25 mg once daily ||$1.19/0.1 mg ||$35.70 (0.1 mg once daily) ||Depression (less likely at low dosages, ie, < 0.25 mg), night terrors, nasal stuffiness, drowsiness, peptic disease, GI disturbances, bradycardia. || |
|Direct Vasodilators |
|Hydralazine ||Apresoline ||25 mg twice daily ||50–300 mg in 2–4 doses ||$0.15/25 mg ||$9.00 (25 mg twice daily) ||GI disturbances, tachycardia, headache, nasal congestion, rash, LE-like syndrome. ||May worsen or precipitate angina. |
|Minoxidil ||(generic) ||5 mg once daily ||10–40 mg once daily ||$1.28/10 mg ||$38.40 (10 mg once daily) ||Tachycardia, fluid retention, headache, hirsutism, pericardial effusion, thrombocytopenia. ||Should be used in combination with beta-blocker and diuretic. |
Side effects—Side effects are relatively common (Table 11–10). These include marked hypotension after the first dose which, therefore, should be small and given at bedtime. Post-dosing palpitations, headache, and nervousness may continue to occur during long-term therapy; these symptoms may be less frequent or severe with doxazosin because of its more gradual onset of action. In ALLHAT, persons receiving doxazosin as initial therapy had a significant increase in heart failure hospitalizations and a higher incidence of stroke relative to those receiving diuretics, prompting discontinuation of this arm of the study. Cataractectomy in patients exposed to alpha-blockers can be complicated by the floppy iris syndrome, even after discontinuation of the drug, so the ophthalmologist should be alerted that the patient has been taking the drug prior to surgery.
To summarize, alpha-blockers should generally not be used as initial agents to treat hypertension—except perhaps in men with symptomatic prostatism or nightmares linked to posttraumatic stress disorder.
I. Drugs With Central Sympatholytic Action
Methyldopa, clonidine, guanabenz, and guanfacine (Table 11–10) lower blood pressure by stimulating alpha-adrenergic receptors in the central nervous system, thus reducing efferent peripheral sympathetic outflow. There is considerable experience with methyldopa in pregnant women, and it is still used for this population. Clonidine is available in patches, which may have particular value in noncompliant patients. All of these central sympatholytic agents are effective as single therapy in some patients, but they are usually used as second- or third-line agents because of the high frequency of drug intolerance. Methyldopa has the potential to prevent type 1 diabetes through interaction with the antigen binding cleft of the major histocompatibility molecule DQ8.
Side effects include sedation, fatigue, dry mouth, postural hypotension, and erectile dysfunction. An important concern is rebound hypertension following withdrawal. Methyldopa also causes hepatitis and hemolytic anemia and should be restricted to individuals who have already tolerated long-term therapy.
J. Peripheral Sympathetic Inhibitors
These agents are now used infrequently and usually in refractory hypertension. Reserpine remains a cost-effective antihypertensive agent (Table 11–10). Its reputation for inducing mental depression and its other side effects—sedation, nasal stuffiness, sleep disturbances, and peptic ulcers—has made it unpopular, though these problems are uncommon at low dosages. Guanethidine and guanadrel inhibit catecholamine release from peripheral neurons but frequently cause orthostatic hypotension (especially in the morning or after exercise), diarrhea, and fluid retention.
Hydralazine and minoxidil (Table 11–10) relax vascular smooth muscle and produce peripheral vasodilation. When given alone, they stimulate reflex tachycardia; increase myocardial contractility; and cause headache, palpitations, and fluid retention. To counteract these effects, the agents are usually given in combination with diuretics and beta-blockers in resistant patients. Hydralazine produces frequent gastrointestinal disturbances and may induce a lupus-like syndrome. Minoxidil causes hirsutism and marked fluid retention; this very potent agent is reserved for the most refractory of cases.