- Author: Meena S Madhur, MD, PhD; Chief Editor: David J Maron, MD, FACC, FAHA more...
Many therapeutic agents can be used for the pharmacologic management of hypertension. The general recommendation established by JNC-7 is to initiate a thiazide-type diuretic initially for stage 1 hypertensives without compelling indications for other therapies. Drugs such as angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), beta-blockers, and diuretics are all considered acceptable alternative therapies in patients with hypertension. The available antihypertensive agents are generally equally effective in lowering blood pressure however; there may be interpatient variability that can affect the way a patient will respond to one treatment over another.
Thiazide diuretics are used as monotherapy, or they can be administered adjunctively with other antihypertensive agents. Thiazide diuretics inhibit reabsorption of sodium and chloride mostly in the distal tubules. Long-term use of these drugs may result in hyponatremia.
They also increase potassium and bicarbonate excretion and decrease calcium excretion and uric acid retention. Thiazides do not affect normal blood pressure.
Keep in mind that all available loop and thiazide diuretic agents, except ethacrynic acid, possess a sulfonamide group, which has important clinical relevance to those individuals with allergies to sulfonamide agents.
Hydrochlorothiazide is approved for the management of hypertension, alone or in combination with other antihypertensive agents. Unlike potassium-sparing combination diuretic products, hydrochlorothiazide may be used in patients who cannot risk the development of hyperkalemia, including patients taking ACE inhibitors.
Hydrochlorothiazide is available as oral tablets or capsules in doses ranging from 12.5-50 mg. The usual dose is 12.5 mg given alone or in combination with other antihypertensives, with a maximum dose of 50 mg daily. Doses greater than 50 mg are associated with hypokalemia.
Chlorthalidone is indicated for the management of hypertension either alone or in combination with other antihypertensives. The initial dosage is 25 mg as a single daily dose. Dosage can be titrated to 50 mg if the clinical response is not adequate. If additional control is required, increase the dosage to 100 mg once daily, or a second antihypertensive drug may be added. Doses greater than 100 mg daily usually do not increase effectiveness. Increases in serum uric acid and hypokalemia are dose-related over the 25-100 mg/day range.
Metolazone is approved for the treatment of hypertension either alone (uncommon) or in combination with other antihypertensives. The initial dosage for hypertension is 2.5 to 5 mg given once daily. Metolazone does not decrease glomerular filtration rate or the renal plasma flow and may be a more effective option for patients with impaired renal function.
Indapamide is chemically not a thiazide, although its structure and function are very similar. The drug enhances the excretion of sodium, chloride, and water by inhibiting the transport of sodium ions across the renal tubule. The hypovolemic action of indapamide is believed to be responsible for the drug's beneficial cardiovascular effects. The half-life of indapamide is approximately 14 hours, so the drug can be taken just once daily. Adverse effects tend to be somewhat milder than with thiazides.
The potassium-sparing diuretics interfere with sodium reabsorption at the distal tubules (primarily in the collecting duct region of the nephron), decreasing potassium secretion. Potassium-sparing diuretics have a weak diuretic and antihypertensive effect when used alone.
Triamterene is used alone or with other medications (often a kaliuretic diuretic such as hydrochlorothiazide) to treat edema and high blood pressure. Because triamterene increases potassium levels, caution is required when combining triamterene with ACE inhibitors, angiotensin receptor blockers, aliskiren, and other drugs that increase potassium levels. Potassium level should be monitored at start of treatment, dose change, and during illness that affects renal function. The recommended dose is 100 mg twice daily (maximum dose is 300 mg/d).
Amiloride is a potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. It is approved as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents for hypertension or congestive heart failure. It is unrelated chemically to other known antikaliuretic or diuretic agents. Amiloride has little additive diuretic or antihypertensive effect when added to a thiazide diuretic. Amiloride can be given at a dose of 5-10 mg daily in 1-2 divided doses for hypertension. Amiloride has a black box warning for hyperkalemia, which, if not corrected, is potentially fatal. This incidence is greater in patients with renal impairment or diabetes mellitus and in the elderly.
Loop diuretics act on the ascending limb of the loop of Henle, inhibiting the reabsorption of sodium and chloride. The loop diuretics are highly protein-bound and therefore enter the urine primarily by tubular secretion in the proximal tubule, rather than by glomerular filtration.
Loop diuretics are commonly used to control volume retention. Generally, thiazide diuretics are recommended for most patients with a diagnosis of hypertension; however, loop diuretics are more commonly prescribed for patients with decreased glomerular filtration rate or heart failure. Loop diuretics do not reduce blood pressure as effectively as thiazide diuretics when they are used as monotherapy, especially if they are dosed once daily.
Keep in mind that all available loop and thiazide diuretic agents, except ethacrynic acid, possess a sulfonamide group, which has important clinical relevance to those individuals with allergies to sulfonamide agents.
Furosemide is approved for the treatment of hypertension alone (uncommon) or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone. The initial dosing recommendations for hypertension are usually 80 mg (divided into 40 mg twice a day). If clinical response is not sufficient, additional antihypertensives may be added. Patients should be monitored carefully because furosemide is a potent diuretic. If given in excessive amounts, it can cause profound diuresis with water and electrolyte depletion. Furosemide is available as an oral tablet and injection solution.
Torsemide can be used as monotherapy or in combination with other antihypertensive agents. The initial dose is 5 mg once daily. The dose can be titrated to 10 mg once daily. If adequate response is not seen, an additional antihypertensive agent may be needed. Torsemide is available as an oral tablet and injection solution.
Bumetanide is FDA approved for the treatment of edema. It is also used off-label for the treatment of hypertension. The usual dosage range for bumetanide for hypertension is 0.5-2 mg/day given once or twice a day.
Angiotensin converting enzyme (ACE) inhibitors are the treatment of choice in patients with hypertension, chronic kidney disease, and proteinuria. ACE inhibitors reduce morbidity and mortality rates in patients with heart failure, patients with recent myocardial infarctions, and patients with proteinuric renal disease. ACE inhibitors appear to act primarily through suppression of the renin-angiotensin-aldosterone system. ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and block the major pathway of bradykinin degradation by inhibiting ACE. Accumulation of bradykinin has been proposed as an etiologic mechanism for the side effects of cough and angioedema. ACE inhibitors can cause injury or even death to a developing fetus. In pregnant patients, ACE inhibitors should be discontinued as soon as possible.
It is important to note that the blood-pressure-lowering effects of ACE inhibitors and thiazides are approximately additive, and there is also the potential for hyperkalemia when ACE inhibitors are coadministered with potassium supplements or potassium-sparing diuretics. In addition, a study by Harel et al found an increased risk for hyperkalemia when aliskiren, a direct renin inhibitor, and ACE inhibitors or angiotensin receptor blockers were used together. Careful monitoring of serum potassium levels is warranted when these agents are used in combination. Furthermore, in patients with hypertension plus type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACE inhibitor or ARB therapy.
Fosinopril may be used alone or in combination with other antihypertensive agents. Initial dose is 5 mg daily up to a maximum of 40 mg daily. May be divided into twice daily dosing. Unlike most ACE inhibitors that are primarily excreted by the kidneys, fosinopril is eliminated by both renal and hepatic pathways, making it a safer choice in patients with renal failure and heart failure patients with impaired kidney function.
Captopril is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive drugs, such as diuretics or beta-adrenergic-blocking agents. The initial dose is 25 mg given 2 to 3 times daily. If reduction of blood pressure is not achieved after 1 or 2 weeks, the dose can be titrated to 50 mg 2 or 3 times daily. If further blood reduction is required after addition of a diuretic, the dose of captopril may be increased to 100 mg 2 or 3 times daily and then, if necessary, to 150 mg 2 or 3 times daily (while continuing the diuretic).
Ramipril is indicated for the treatment of hypertension alone or in combination with thiazide diuretics. The initial dosing recommendation for ramipril is 2.5 mg daily for patients who are not receiving a diuretic. Doses can range from 2.5-20 mg/day given once or twice a day.
Enalapril is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose of enalapril is 5 mg daily. Dosage can range from 10-40 mg/day administered as a single dose or in 2 divided doses.
Lisinopril may be used as monotherapy or concomitantly with other classes of antihypertensive agents. The initial dose of lisinopril is 10 mg daily. The dosage can range from 20-40 mg/day as a single daily dose. Doses up to 80 mg/day have been used; however, they do not show a greater effect.
Quinapril may be used alone or in combination with thiazide diuretics. The initial dose is 10 to 20 mg daily for patients not on diuretics. If blood pressure is not controlled with quinapril monotherapy, adding a diuretic should be considered.
Generally, ACE inhibitors should remain the initial treatment of choice for hypertension. Angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs) are used for patients who are unable to tolerate ACE inhibitors. ARBs competitively block binding of angiotensin-II to angiotensin type I (AT1) receptors, thereby reducing effects of angiotensin II–induced vasoconstriction, sodium retention, and aldosterone release; the breakdown of bradykinin should not be inhibited. If monotherapy with an ARB is not sufficient, adding a diuretic should be considered.
ARBs can cause injury or even death to a developing fetus. If a patient becomes pregnant, ARBs should be discontinued as soon as possible.
Note that a study by Harel et al found an increased risk for hyperkalemia when aliskiren and ARBs or ACE inhibitors were used together ; therefore, careful monitoring of serum potassium levels is warranted when these agents are used in combination. Furthermore, in patients with hypertension and type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACE inhibitor or ARB therapy.
Losartan may be used alone or in combination with other antihypertensive agents, including diuretics. The initial dose is 50 mg daily; however, in patients on diuretic therapy, the initial dose is 25 mg daily. A low-dose diuretic (eg, hydrochlorothiazide) may be added if blood pressure is not controlled. Losartan can be titrated up to 100 mg daily.
Valsartan is approved for the treatment of hypertension in adults and in children 6-16 years of age. It may be used alone or in combination with other antihypertensive agents. The initial dose is 80 or 160 mg once daily when used as monotherapy in patients who are not volume depleted. The valsartan dose may be increased (maximum 320 mg/day), or a diuretic may be added if additional blood pressure reduction is required. The addition of a diuretic has a greater effect than dose increases above 80 mg.
Olmesartan is indicated for hypertension either alone or in combination with other antihypertensives. The initial dose is 20 mg daily when used as monotherapy. The dose may be titrated to 40 mg daily if greater effect is desired. Doses greater than 40 mg have not been shown to have greater effects. If monotherapy is not sufficient, adding a diuretic should be considered.
Eprosartan may be used alone or in combination with other antihypertensives, such as diuretics and calcium channel blockers. The initial dose is 600 mg once daily when used as monotherapy in patients who are not volume depleted. The dose may be titrated if clinical response is not sufficient. The usual dosage range is 400-800 mg once or twice daily.
Azilsartan is indicated for hypertension, either alone or in combination with other antihypertensives. The usual dose is 80 mg once daily. Consider starting with an initial dose of 40 mg once daily in patients receiving high-dose diuretics.
Beta-Blockers, Beta-1 Selective
Beta-blockers are generally not recommended as first-line agents for the treatment of hypertension; however, they are suitable alternatives when a compelling cardiac indication (eg, heart failure, myocardial infarction, diabetes) is present. Selective beta-blockers specifically block beta-1 receptors alone, although they can be nonselective at higher doses.
Caution should be used in administering these agents in the setting of asthma or severe chronic obstructive pulmonary disease (COPD), regardless of beta-selectivity profile. In addition, exacerbations of angina and, in some cases, myocardial infarction have been reported following abrupt discontinuance of beta-blocker therapy. The doses should be gradually reduced over at least a few weeks.
Atenolol is approved for the management of hypertension used alone or concomitantly with other antihypertensive agents, particularly with a thiazide-type diuretic. The initial dose is 50 mg daily, alone or added to diuretic therapy. If adequate clinical effect is not seen, the dose can be titrated to 100 mg daily. Other studies suggest that atenolol lacks specific potential for stroke reduction.
Metoprolol is approved for the management of hypertension alone or concomitantly with other antihypertensive agents. The initial dose for metoprolol immediate release is 100 mg daily in single or divided doses, with or without a diuretic (maximum 450 mg/day). Metoprolol extended-release formulation can be started at a dose of 25-100 mg daily in a single dose, with or without a diuretic (maximum 400 mg/day).
Propranolol is approved for the management of hypertension alone or concomitantly with other antihypertensive agents. The initial dose is 40 mg given twice daily, alone or added to diuretic therapy. Dose can be titrated based on a patient's clinical response. The maintenance dose can range from 120-240 mg/day (maximum 640 mg/day). Exacerbations of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy have been reported. The propranolol dose should be gradually reduced over at least a few weeks.
Bisoprolol is approved for the management of hypertension alone or in combination with other antihypertensive agents. This agent is a more specific beta-1 blocker than other beta-blockers. The initial dose is 5 mg once daily (reduce to 2.5 mg for patients with bronchospastic disease). The dosage can be titrated to 10 mg/day and then to 20 mg/day if necessary.
Timolol is indicated for the treatment of hypertension. It is used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose is 10 mg given twice daily. The total daily dose can be titrated to a maximum of 30 mg administered in divided doses. Avoid abrupt cessation of therapy, because of the risk of exacerbation of ischemic heart disease.
Beta-Blockers, Alpha Activity
Beta-blockers, such as labetalol and carvedilol, have peripheral vasodilatory effects that act via antagonism of the alpha-1 receptor in addition to beta-receptors.
Labetalol is indicated for the management of hypertension. Labetalol tablets may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics. The initial dose is 100 mg given twice daily. The dose may be titrated after 2-3 days in increments of 100 mg twice a day every 2-3 days (maximum 2400 mg/day).
Labetalol's actions at alpha-1 and beta-receptors lead to vasodilation and decreased total peripheral resistance, which results in decreased blood pressure without a substantial decrease in resting heart rate, cardiac output, or stroke volume.
Carvedilol is approved for the management of essential hypertension. It can be used as monotherapy or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose is 6.25 mg given twice daily. The dose can be titrated at intervals of 7-14 days to 12.5 mg twice daily, then to 25 mg twice daily as needed (maximum 50 mg/day).
Similar to labetalol, carvedilol antagonizes both alpha-1 and beta-receptors. Carvedilol lowers standing blood pressure more than supine blood pressure; orthostatic hypotension may occur.
Beta-Blockers, Intrinsic Sympathomimetic
Agents such as acebutolol and pindolol possess intrinsic sympathomimetic activity (ISA). These agents can be used alone or in combination with other antihypertensive agents, particularly with a thiazide-type diuretic.
Acebutolol is a cardioselective, beta-adrenoreceptor-blocking agent, which possesses mild intrinsic sympathomimetic activity in its therapeutically effective dose range. Initial dose in uncomplicated, mild to moderate hypertension is 400 mg daily, or twice-daily dosing may be required for adequate 24-hour blood pressure control. Optimal response is usually achieved with dosages of 400 to 800 mg/day; however, some patients have been maintained on as little as 200 mg/day.
Pindolol is indicated in the management of hypertension and can be used alone or with other antihypertensive agents, particularly with a thiazide-type diuretic. The initial dose is 5 mg twice daily alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as 2 weeks or even longer.
Vasodilators relax blood vessels to improve blood flow, thus decreasing blood pressure.
Oral hydralazine is indicated for essential hypertension, alone or as an adjunct. Initial dose is 10 mg given 4 times daily for the first 2 to 4 days, then 25 mg 4 times a day for 1 week. Hydralazine IV or IM is indicated for severe essential hypertension when the drug cannot be given orally or when there is an urgent need to lower BP. Hydralazine may lower blood pressure by exerting a peripheral, vasodilating effect through a direct relaxation of vascular smooth muscle. Caution should be used when hydralazine is administered in patients with concomitant coronary artery disease.
Minoxidil is indicated in severe hypertension that is symptomatic or associated with end-organ damage and is not manageable with maximum therapeutic doses of a diuretic plus 2 other antihypertensives. The initial dose is 5 mg/day as a single dose and can be titrated to 10, 20, and then 40 mg in single or divided doses as needed (maximum 100 mg/day). Minoxidil reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. The blood pressure response to minoxidil is dose-related and proportional to the extent of hypertension. Concomitant therapy with an antiadrenergic agent and loop diuretic is generally required.
Calcium Channel Blockers
Calcium channel blockers (CCBs) can be divided into dihydropyridines and nondihydropyridines. Dihydropyridines bind to L-type calcium channels in the vascular smooth muscle, which results in vasodilatation and a decrease in blood pressure. They are effective as monotherapy in black patients and elderly patients. Some examples of dihydropyridines include amlodipine, nifedipine, clevidipine, and felodipine. Non-dihydropyridines such as verapamil and diltiazem bind to L-type calcium channels in the sinoatrial and atrioventricular node, as well as exerting effects in the myocardium and vasculature. These agents may constitute a more effective class of medication for black patients.
Nifedipine extended-release is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. The usual dose for nifedipine is 30-60 mg once daily (maximum 90 mg/day); when used for hypertension, nifedipine can be administered to a maximum of 120 mg/day.
Clevidipine butyrate is a dihydropyridine L-type CCB that is rapidly metabolized in blood and tissues and does not accumulate in the body. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. It is indicated for the reduction of BP when oral therapy is not feasible or is not desirable.
Amlodipine is a dihydropyridine CCB that has antianginal and antihypertensive effects. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Felodipine is a dihydropyridine CCB that inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. These effects elicit an increased oxygen delivery to the myocardial tissue, a decreased total peripheral resistance, a decreased systemic blood pressure, and a decreased afterload.
Diltiazem (Cardizem CD, Cardizem LA, Cartia XT, Dilacor XR, Dilt-CD, Dilt-XR, Matzim LA, Taztia XT, Tiazac)
Diltiazem is a nondihydropyridine CCB that produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension.
Verapamil is a nondihydropyridine that produces its antihypertensive effect by a combination of vascular and cardiac effects. It acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. As a result, the systemic vascular resistance is reduced, usually without orthostatic hypotension or reflex tachycardia.
Aldosterone Antagonists, Selective
Aldosterone antagonists compete with aldosterone receptor sites, reducing blood pressure and sodium reabsorption.
Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing BP and sodium reabsorption. Although this agent is more specific than spironolactone at the mineralocorticoid receptor, it is less potent. There have also been some minimal reports of gynecomastia.
Eplerenone is indicated for the treatment of hypertension. Eplerenone may be used alone or in combination with other antihypertensive agents.
Spironolactone is usually used in combination with other drugs for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. The initial dose ranges from 50-100 mg daily in single or divided doses. Spironolactone can cause hyperkalemia; therefore, potassium supplementation should not be given concurrently. Other adverse effects include gynecomastia and impotence, which often mitigates the use of spironolactone in younger men.
Centrally acting alpha2-agonists stimulate presynaptic alpha2-adrenergic receptors in the brain stem, which reduces sympathetic nervous activity.
Methyldopa stimulates central alpha-adrenergic receptors by a false transmitter, exerting a direct effect on peripheral sympathetic nerves. Decreases in blood pressure are greatest when the patient is standing but are also significant when the patient is supine. Postural hypotension has been reported in patients receiving methyldopa. Methyldopa is not associated with a rebound effect, as with clonidine.
Clonidine stimulates alpha2-adrenoreceptors in the brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow. These effects result in a decrease in peripheral resistance, renal vascular resistance, blood pressure, and heart rate. Clonidine can be used alone or in combination with other antihypertensives. Clonidine is associated with a rebound effect, especially at higher doses or with more severe hypertension.
Guanfacine is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central alpha-2 adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. Guanfacine may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
Renin inhibitors act within the renin-angiotensin system (RAS), a hormone system important in the regulation of blood pressure, electrolyte homeostasis, and vascular growth. Renin inhibitors have an additive effect when used with diuretics. Avoid the use of these agents in pregnancy.
Aliskiren decreases plasma renin activity and inhibits conversion of angiotensinogen to angiotensin I (as a result, also decreasing angiotensin II) and thereby disrupts the renin-angiotensin-aldosterone system feedback loop. It is indicated for hypertension as monotherapy or in combination with other antihypertensive drugs. This agent remains under investigation.
Keep in mind that aliskiren can cause adverse events when used in combination with ACE-inhibitor or angiotensin-receptor-blocker (ARB) therapy. In patients who have hypertension and type 2 diabetes and renal impairment and are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACE inhibitor or ARB therapy. See the Novartis December 2011 press release, "Novartis announces termination of ALTITUDE study with Rasilez®/ Tekturna® in high-risk patients with diabetes and renal impairment."
Alpha-blockers are generally not recommended as initial monotherapy. They selectively block postsynaptic alpha1 -adrenergic receptors. They dilate arterioles and veins, thus lowering blood pressure. These drugs can be combined with any of the other antihypertensives in other drug classes. Common side effects seen in this drug class include dizziness, headache, and drowsiness, in addition to orthostatic and first-dose hypotension.
Prazosin is a competitive antagonist at postsynaptic alpha1-receptors. Prazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thus reducing peripheral vascular resistance and blood pressure.
Terazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thereby reducing peripheral vascular resistance and blood pressure. Terazosin reduces blood pressure in both the supine and the standing positions, with more dramatic effects on diastolic blood pressure.
Doxazosin is a selective alpha1-adrenergic antagonist. It inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and a decrease in total peripheral resistance and blood pressure. The antihypertensive effect of doxazosin mesylate results from a decrease in systemic vascular resistance.
Reserpine is a peripherally acting adrenergic agent. It is indicated for mild hypertension and can be used as adjunctive therapy with other antihypertensive agents in more severe forms of hypertension.
Reserpine reduces blood pressure by depleting sympathetic biogenic amines. The result of reserpine's effects on biogenic amines is sympathetic dysfunction, with a subsequent decrease in peripheral vascular resistance and a lowering of blood pressure often associated with bradycardia. This agent is also associated with depression.
Drug combinations using agents that act by different mechanisms have an additive effect. Most clinicians recommend initiating therapy with a single agent and advancing to the low-dose combination therapy. Some patients will require multiple medications to achieve their blood pressure targets and will benefit from drug combinations. Drug combination therapy may also help to improve patient compliance.
Drug combinations include—but are not limited to—the following:
- Amlodipine/benazepril (Lotrel)
- Amlodipine/olmesartan (Azor)
- Amlodipine/telmisartan (Twynsta)
- Amlodipine/valsartan (Exforge)
- Amlodipine/valsartan/hydrochlorothiazide (Exforge HCT)
- Amlodipine/aliskiren (Tekamlo)
- Amlodipine/aliskiren/hydrochlorothiazide (Amturnide)
- Olmesartan/amlodipine/hydrochlorothiazide (Tribenzor)
- Trandolapril/verapamil (Tarka)
- Benazepril/hydrochlorothiazide (Lotensin HCT)
- Captopril/hydrochlorothiazide (Capozide)
- Enalapril/hydrochlorothiazide (Vaseretic)
- Lisinopril/hydrochlorothiazide (Prinzide, Zestoretic)
- Moexipril/hydrochlorothiazide (Uniretic)
- Quinapril/hydrochlorothiazide (Accuretic)
- Candesartan/hydrochlorothiazide (Atacand HCT)
- Eprosartan/hydrochlorothiazide (Teveten HCT)
- Irbesartan/hydrochlorothiazide (Avalide)
- Losartan/hydrochlorothiazide (Hyzaar)
- Olmesartan/hydrochlorothiazide (Benicar HCT)
- Telmisartan/hydrochlorothiazide (Micardis HCT)
- Valsartan/hydrochlorothiazide (Diovan HCT)
- Atenolol/chlorthalidone (Tenoretic)
- Bisoprolol/hydrochlorothiazide (Ziac)
- Metoprolol/hydrochlorothiazide (Lopressor HCT)
- Nadolol/bendroflumethiazide (Corzide)
- Aliskiren/hydrochlorothiazide (Tekturna HCT)
- Clonidine/chlorthalidone (Clorpres)
- Spironolactone/hydrochlorothiazide (Aldactazide)
- Triamterene/hydrochlorothiazide (Dyazide, Maxzide)
Metoprolol/hydrochlorothiazide is a combination of metoprolol, a beta-blocker, and hydrochlorothiazide, a thiazide diuretic. Metoprolol is a beta1-selective blocker at low doses; at higher doses, it also inhibits beta2-adrenoreceptors. Hydrochlorothiazide inhibits sodium reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
Triamterene/hydrochlorothiazide is a fixed-combination indicated for hypertension or edema in patients who are at risk of developing hypokalemia on hydrochlorothiazide alone. Triamterene exerts a diuretic effect on the distal renal tubule, inhibiting the reabsorption of sodium in exchange for potassium and hydrogen ions. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
Valsartan/hydrochlorothiazide is a combination of valsartan, an angiotensin receptor blocker, and hydrochlorothiazide, a diuretic. Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
Valsartan/amlodipine/hydrochlorothiazide is a combination of amlodipine, a dihydropyridine calcium channel blocker, valsartan, an angiotensin receptor blocker, and hydrochlorothiazide, a diuretic. Amlodipine exhibits antianginal and antihypertensive effects by inhibiting the influx of calcium in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries. Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
Enalapril/hydrochlorothiazide is a combination of enalapril, an ACE inhibitor, and hydrochlorothiazide, a diuretic. Hydrochlorothiazide inhibits sodium reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions. Enalapril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps control blood pressure and proteinuria.
This is an angiotensin II receptor blocker (ARB) and thiazide-like diuretic combination. It is indicated as initial hypertension therapy or for the treatment of hypertension in patients whose condition is not adequately controlled with monotherapy.
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|Race/Ethnic Group||Have Hypertension, %||Have Heart Disease, %||Have Coronary Heart Disease, %||Have Had a Stroke, %|
|American Indian/Alaska Native||25.3||12.1||6.6 (this number is considered unreliable)||3.9 (this number is considered unreliable)|
|Source: Pleis JR, Lucus JW, Ward BW. Summary health statistics for US adults: National Health Interview Survey, 2008. Vital Health Stat 10. No. 242; 2009. Available at: http://www.cdc.gov/nchs/data/series/sr_10/sr10_242.pdf. Accessed: February 21, 2012.
NCHS = National Center for Health Statistics; NHIS = National Health Interview Survey.
|Chronic kidney disease||Estimated glomerular filtration rate|
|Coarctation of the aorta||Computed tomography angiography|
|Cushing syndrome; other states of glucocorticoid excess (eg, chronic steroid therapy||Dexamethasone suppression test|
|Drug-induced/drug-related hypertension*||Drug screening|
|Pheochromocytoma||24-hour urinary metanephrine and normetanephrine|
|Primary aldosteronism, other states of mineralocorticoid excess||24-hour urinary aldosterone level, specific mineralocorticoid tests|
|Renovascular hypertension||Doppler flow ultrasonography, magnetic resonance angiography, computed tomography angiography|
|Sleep apnea||Sleep study with oxygen saturation (screening would also include the Epworth Sleepiness Scale [ESS])|
|Thyroid/parathyroid disease||Thyroid stimulating hormone level, serum parathyroid hormone level|
|Adapted from: Chobanian AV, Bakris GL, Black HR, et al, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. Dec 2003;42(6):1206-52.
* Some examples of agents that induce hypertension include nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors; illicit drugs; sympathomimetic agents; oral contraceptive or adrenal steroid hormones; cyclosporine and tacrolimus; licorice; erythropoietin; and certain over-the-counter dietary supplements and medicines, such as ephedra, ma huang, and bitter orange. Drug-related causes of hypertension may be due to nonadherence, inadequate doses, and inappropriate combinations.
|Chronic hypertension||Prepregnancy or before 20 weeks’ gestation; SBP =140 mm Hg or DBP 90 mm Hg that persists >12 weeks postpartum|
|Preeclampsia||After 20 weeks’ gestation; SBP =140 mm Hg or DBP 90 mm Hg with proteinuria (>300 mg/24 h)
Can progress to eclampsia
More common in nulliparous women, multiple gestation, women with hypertension =4 years, family history of preeclampsia, previous hypertension in pregnancy, and renal disease
|Chronic hypertension with superimposed preeclampsia||New-onset proteinuria after 20 weeks in hypertensive woman
In a woman with hypertension and proteinuria before 20 weeks’ gestation
Sudden 2- to 3-fold increase in proteinuria
Sudden increase in BP
Elevated AST or ALT levels
|Gestational hypertension||Temporary diagnosis
Hypertension without proteinuria after 20 weeks’ gestation
May be a preproteinuric phase of preeclampsia or a recurrence of chronic hypertension that abated in mid-pregnancy
May lead to preeclampsia
Severe cases may cause higher rates of premature delivery and growth retardation relative to mild preeclampsia
|Transient hypertension||Diagnosis made retrospectively
BP returns to normal by 12 weeks’ postpartum
May recur in subsequent pregnancies
Predictive of future primary hypertension
|ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; DBP = diastolic BP; SBP = systolic BP.
Adapted from: Chobanian AV, Bakris GL, Black HR, et al, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. Dec 2003;42(6):1206-52.