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This section will summarize treatment of arterial hypertension in the clinic, where this therapy is most often prescribed. Such treatment also occurs in the emergency department, where the presentation may be a true hypertensive emergency or, now more often, a life-threatening event,52 or one of lesser risk in which hypertension is part of a more complex picture, a hypertensive urgency.
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The rationale for treatment of hypertension is to prevent future cardiovascular and renal disease. There are two components to treatment: improvement in lifestyle patterns and prescription of antihypertensive drugs. The minimum goal as reflected in several guidelines has been to achieve clinic pressures of less than 140/90 mm Hg (systolic/diastolic).5,53 A recent advisory from panel members of the JNC 8 process, on the basis of a conservative examination of trial evidence, accepted a higher goal of less than 150/90 mm Hg for older patients.6 This view is controversial and has been criticized as too permissive and could result in failure to treat some who might benefit.54,55 Publication of the SPRINT trial, for nondiabetic hypertensive patients, provides the basis for a lower goal for systolic pressure—in the range of 120 to 130 mm Hg.8 For diabetic hypertensives, best available evidence suggests a goal of about 135 mm Hg systolic pressure.28,56,57 It is unknown, at present, whether antihypertensive drug treatment will provide effective prevention for those with office/clinic hypertension, but normal pressures outside the office (white coat hypertension) as documented by either 24-hour ambulatory blood pressure monitoring or home pressure monitoring. However, lifestyle improvement is recommended for those who are overweight, underexercised, smoke, or otherwise have risky habits.
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Lifestyle Intervention
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For those with pretreatment clinic blood pressures in the range of 140 to 150 mm Hg, lifestyle improvement may be effective in achieving the desired goal. Weight reduction, avoiding a high dietary salt intake, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, and increased exercise may be effective. In 6- to 12-month studies of those with stage 1 hypertension, the DASH diet lowered systolic and diastolic blood pressures, respectively, to 6 to 8 mm Hg and 3 to 4 mm Hg more than controls.58 Reduced fat intake may also be beneficial for lowering low-density lipid cholesterol and serum triglycerides.59 Smoking cessation, while having no effect on blood pressure, is nonetheless mandatory for cardiovascular prevention.
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Antihypertensive Drug Treatment: Overview
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The value of antihypertensive drug therapy for prevention of fatal and nonfatal cardiovascular disease has been firmly established by well-controlled randomized clinical trials. At present, there is an abundant array of drug classes to be prescribed to achieve control of hypertension (see Table 25–4). A fairly small fraction of people with hypertension, about 15% to 20%, can be often controlled with a single drug class, as is the case with younger patients. Most with higher average pressures will require two or more drug classes to achieve current goals.
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The most effective two-drug combinations consist of a renin-system blocking agent (angiotensin-converting enzyme inhibitor [ACEI] or angiotensin-receptor blocker [ARB]) and a thiazide-type diuretic or a renin system blocker and a calcium channel blocker (CCB). When the two-drug combination is not fully effective, adding the third component will often be successful (ie, renin system blocker, diuretic, and CCB). The benefit of adding a drug class appears to be substantially greater than up-titrating dosage with a single drug class.59
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Resistant Hypertension
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When blood pressure remains above treatment goals, despite combining drugs from three classes, it is referred to as “resistant” hypertension. Despite a substantial increase in control of hypertension in many countries, resistant hypertension still has a prevalence of 20% to 30%.60 Frequently, apparent resistant hypertension is caused by a lack of adherence to prescribed medication. This lack may result from a variety of causes, such as limited health knowledge, unavailable primary care facilities, inability to pay, or lack of insurance. A large white coat effect may obscure the much lower average pressures at home, so that pseudo–resistant hypertension is present. Use of 24-hour ambulatory blood pressure monitoring or home pressure monitoring is justified when the white coat effect is suspected. Conversely, out-of-office monitoring of blood pressure may reveal masked hypertension for which more intensive antihypertensive treatment is necessary to prevent target organ pathology.61
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Identifiable hypertension may be present in resistant hypertension, such as bilateral renal artery stenosis or primary aldosteronism.62 Treatment of definite resistant hypertension may include maximizing drug doses as well as addition of alternate drug classes and counseling to increase adherence.60,63 Even when primary aldosteronism is not confirmed, addition of spironolactone may be effective in drug treatment of resistant hypertension.64 Minoxidil or high-dose nifedipine has also been shown to be effective for treatment of definite resistant hypertension, if these drugs are tolerated.65,66
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True resistant hypertension conveys increased risk of future cardiovascular disease leading to exploration of interventional modalities: baroreflex activation therapy (BAT)67 and bilateral renal denervation (RDN).68 BAT requires neck surgery with planting of stimulating electrodes on the right, left, or both carotid sinus nerves. Substantial reduction in blood pressure has been reported in small series. At this time, it remains a research intervention with an uncertain future because of the small size of series and practical considerations.69 RDN has been extensively evaluated in uncontrolled series and in randomized trials compared to sham procedures. Results have been inconsistent. Meta-analyses of RDN compared to various comparison groups in trials and a large registry have reported that RDN was not significantly more effective than use of antihypertensive drug treatment in the comparison groups.70,71 RDN is approved for treatment of resistant hypertension in some countries, but health authorities in the United States, Canada, and the United Kingdom consider the procedure to be a research intervention.
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Hypertensive Emergencies
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A hypertensive emergency is defined by rapid increase in blood pressure linked to an immediate threat to target organs: aortic dissection, pulmonary congestion, symptomatic coronary heart disease, progressive renal disease, stroke, or encephalopathy.52,72 A distinct form of cerebral edema, posterior leukoencephalopathy, has been associated with hypertensive emergencies explaining the encephalopathy that may cause loss of vision, altered mental status, and seizures.73 Although there is no blood pressure threshold for the diagnosis of hypertensive emergencies, most end-organ damage is noted with systolic blood pressures exceeding 220 mm Hg or diastolic blood pressures exceeding 120 mm Hg. The condition is usually related to a rapid increase in pressure from already high levels in established hypertension, perhaps related in poor adherence to antihypertensive medications. However, abrupt increases in pressure with threat to target organs may appear without prior warning as in some patients with pheochromocytoma or some forms of renal disease (eg, scleroderma renal crisis). The medical history should include queries about use of nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, and substance use. Alcohol withdrawal syndromes may mimic hypertensive encephalopathy. Cocaine or diet pill overdose may raise pressure quickly and even cause cerebral hemorrhage. In hypertensive emergencies in these patients, immediate but monitored reduction of pressure, often accomplished with parenteral medications, is essential to prevent long-term damage.
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In addition to very high arterial pressure, people with hypertensive emergencies may have signs of (1) increased intracranial pressure (papilledema, retinal hemorrhages, and exudates), (2) aortic dissection, and (3) pulmonary congestion. The electrocardiogram may show left ventricular enlargement, and the chest x-ray will indicate congestion. Often, renal function will be impaired with proteinuria and microscopic hematuria.
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Patients with a hypertensive emergency must be treated in an emergency department or intensive care unit with rapid-acting, controllable medications and continued monitoring to achieve reduction in arterial pressure until stable or the immediate threat is dealt with (eg, proximal aortic dissection requiring surgery). Intravenous medications are usually required to reduce pressure to the range of 150–160/less than 110 mm Hg within a few hours. The medications described below should be considered for intravenous use in achieving the therapeutic goal. Once blood pressure reduction to a safe range has been achieved, patients can be transitioned to oral medications, usually two- or three-drug combinations. Close follow-up and adjustment of medications in the clinic are necessary to achieve long-term control of hypertension in patients admitted for hypertensive emergencies, regardless of the cause.
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Sodium nitroprusside is the drug of choice for most hypertensive emergencies because it has an immediate onset of action and can be titrated quickly and accurately. The duration of effect is 1 to 2 minutes. Thiocyanate levels must be followed in patients who have hepatic or renal insufficiency to prevent toxic buildup.
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Parenteral labetalol is another first-line agent for hypertensive emergency. Its onset of action is 5 to 10 minutes, and the duration of action is about 3 to 6 hours. Labetalol can be used safely in most patients, but caution should be exercised in patients who have severe bradycardia, congestive heart failure, or bronchospasm.
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Nicardipine is a dihydropyridine CCB administered parenterally by continuous infusion for hypertensive crises. The onset of action of this drug is 5 to 10 minutes, and the duration of action is 1 to 4 hours after discontinuing the infusion. Nicardipine is contraindicated in patients with heart failure.
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Esmolol is a cardioselective β-blocker with a short duration of action. It reduces systolic blood pressure and mean arterial pressure, as well as heart rate, cardiac output, and stroke volume. There is a notable decrease in myocardial oxygen consumption. Peak effects are generally seen within 6 to 10 minutes after a bolus dose, and the effects resolve 20 minutes after discontinuing the infusion.
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Fenoldopam is the first selective dopamine-1 receptor agonist approved for in-hospital short-term management of severe hypertension up to the first 48 hours of treatment. Fenoldopam is a good choice in these patients because of the improvement in renal perfusion, diuresis, and lack of production of toxic metabolites. Tolerance develops to fenoldopam after 48 hours.
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Phentolamine is available for intravenous use and is an alpha-receptor adrenergic antagonist that is valuable for treating a hypertensive emergency in patients with pheochromocytoma. When tachycardia occurs in this setting, a rapid beta-blocker, such as esmolol or intravenous metoprolol, can be given to control heart rate.
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Intravenous nitroglycerine may be considered when the clinical picture indicates significant myocardial ischemia. This is used as a temporizing step in stabilizing a patient who will most often be prepared for a cardiac intervention.
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Intravenous furosemide, a rapidly acting loop diuretic, may be useful in management of acute pulmonary congestion associated with severe hypertension. Duration of action is short, a few hours, so that repeated dosing may be needed.
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Hypertensive Urgencies
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A hypertensive urgency is defined as the presence of a very high blood pressure (eg, > 180/110 mm Hg) in the absence of the characteristics of a hypertensive emergency, as described above. Although the blood pressure may be markedly elevated, the major problem can be another critical medical event, such as myocardial ischemia or stroke.72 Some may seek emergency care because of high pressures, without any associated symptoms. The increased use of home blood pressure monitoring may account, in part, for this emerging pattern. The role of anxiety or pain in those patients without cardiac or cerebrovascular disease needs study. In the absence of other medical problems that require emergency care, immediate management of hypertensive urgencies is problematic. Often, without specific treatment, blood pressure will fall substantially and patients can be discharged from the emergency department within a few hours. The role of antihypertensive medication for hypertensive emergencies is entirely uncertain with regard to future risk. Although several drugs may rapidly lower pressure, there is a risk of hypotension as well. When the patient is asymptomatic and clinically stable, outpatient management with close follow-up is appropriate. Long-term blood pressure control is essential, but the reduction can be achieved over a period of weeks. Patient education to achieve understanding of the real risk of elevated blood pressure, value of daily medication, and periodic follow-up is crucial because those with hypertensive urgencies are at greater risk for long-term cardiovascular pathology.74
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Properties of Antihypertensive Drug Classes
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This section will provide an overview and concise description of the currently used antihypertensive drug classes.
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Thiazide-Type Diuretics
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The thiazides and related drugs (eg, chlorthalidone, indapamide) have been the mainstay of antihypertensive drug treatment since the 1960s as single agents or in effective two-drug combinations together with (1) potassium-sparing diuretics and (2) beta-receptor blockers, ACEIs, and ARBs. Adverse reactions to these drugs are well characterized, the most frequent being hypokalemia and elevated uric acid. The latter may be a cause of gout. Hypercalcemia may occur with thiazide diuretics and might result from underlying hyperparathyroidism. Chlorthalidone was used in several of the early clinical trials; it has the advantage of a longer duration of action compared to hydrochlorothiazide and may be slightly more effective, but it is also more likely to elicit hypokalemia.75
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Potassium-Sparing Diuretics
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The two available mineralocorticoid receptor antagonists, spironolactone and eplerenone, may be valuable for treatment of primary aldosteronism or for thiazide-related hypokalemia. When renal function is normal, these drugs infrequently cause hyperkalemia at usual doses. Spironolactone has been found to be effective for resistant hypertension, often in combination with several other drugs, including renin system blockers (ACEIs, ARBs, or direct renin antagonists). In this setting, careful monitoring for hyperkalemia is necessary.76
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Amiloride and triamterene block the sodium epithelial channel of the distal renal tubule. This channel mediates the action of aldosterone, so that these agents can also correct the hypokalemia of thiazide-type diuretics. They have very little effect on blood pressure.
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Loop-Active Diuretics
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Furosemide, bumetanide, torsemide, and ethacrynic acid are diuretics whose site of action is proximal to the thiazide site. They are more effective than thiazides when renal function is impaired. Their adverse reactions are similar to those of the thiazides, except for the lack of hypercalcemia. In general, the loop diuretics are preferred in the presence of congestive heart failure. The unique feature of ethacrynic acid is the lack of a sulfur group, so that it may be used for those infrequent patients with allergic reactions to both the thiazides and furosemide. The loop diuretics are often given together with renin system blockers for effective combinations in those with reduced glomerular filtration rates. Combining a loop diuretic with a thiazide-type diuretic (eg, furosemide and metolazone) may be effective for refractory edema, but very close monitoring for hypokalemia or hyponatremia is required.77
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Renin System Blockers
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The differences in the effects of the renin system blockers is important when testing the renin system for identifiable hypertension. Blockade of the renin system with two or three drugs is not recommended because of the risk of hyperkalemia and lower glomerular filtration rate.83,84
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Angiotensin-Converting Enzyme Inhibitors
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The ACEIs were the first renin system blockers to become widely used antihypertensive drugs, most often in combination with thiazide-type diuretics. This combination is highly effective for sustained reduction in blood pressure and usually well tolerated. The ACEIs are also kininase inhibitors that may account for characteristic adverse effects: dry cough (5%–10%) and rare occurrence of urticarial angioedema reactions (swelling of the lips or tongue) that can be fatal. When used in renal disease with proteinuria, most often diabetic nephropathy, ACEIs reduce urinary protein excretion and may retard progression of renal impairment. Similarly, ACEIs may be beneficial for retardation of renal impairment in African Americans with chronic renal disease.78 ACEIs, like all renin system blockers, may reduce aldosterone secretion when the renin-angiotensin-aldosterone system is normal but not when primary aldosteronism is present.
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Angiotensin II Receptor Antagonists
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The ARBs block the angiotensin II type 1 receptor that mediates vasoconstriction by vascular smooth muscle and also stimulation of adrenal aldosterone production. The effects of ARBs are similar to those of the ACEIs except that kinin potention is absent. Cough with use of ARBs is not different from placebo administration in controlled blinded trials or when ARBs are given to patients with ACEI cough.79,80 An ARB has been shown to significantly lower blood pressure in prehypertensives for a year, preventing new hypertension in comparison with placebo.81 At the end of the trial, most people had an increase in pressure to pretreatment levels but some remained at lower levels. A small fraction of hypertensives will have full control of hypertension when taking ARBs, but these drugs are most effective in combination with a thiazide type diuretic or a CCB.
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Direct Renin Inhibitors
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Aliskiren is a direct-acting renin inhibitor that is an effective antihypertensive agent that, as monotherapy, has a similar effect on blood pressure as an ARB.82 Like the other renin system blockers, aliskiren is more effective in combination with either a thiazide diuretic or CCB. ACEIs or ARBs increase plasma renin activity and lower aldosterone in those with normal renin systems. Unlike ACEIs or ARBs, aliskiren reduces the assay of plasma renin activity and serum aldosterone.
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Calcium Channel Blockers
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Dihydropyridine Calcium Channel Blockers
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There are many dihydropyridine calcium channel blockers (DHP CCBs). Several either have prolonged duration of action (eg, amlodipine) or have been formulated in long-acting delivery systems (eg, nifedipine ER), so that they are effective when given once daily. The hemodynamic effect of these agents is to reduce peripheral resistance with minimal reflex increase in heart rate—and with minimal effects on the renin-angiotensin system. DHP CCBs are widely used and are effective as monotherapy but often combined with renin system blocker for greater effectiveness (eg, benazepril and amlodipine). The first-pass intestinal absorption of CCBs is increased by concurrent intake of grapefruit or natural grape fruit juice; the most effect has been found with felodipine.85,86,87,88 The increased levels of felodipine may be sufficient to lower blood pressure, a possible adverse effect in elderly patients. The major adverse effect for this class is pedal or ankle edema that can be bothersome and, occasionally, severe. Prolonged use of DHP CCBs may lead to gingival hyperplasia, requiring dental care.
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Non–Dihydropyridine Calcium Channel Blockers
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Diltiazem and verapamil are like DHP CCBs blockers of the L-channel of smooth muscle and cardiac tissue. They are effective antihypertensive agents, often given together with inhibitors of the renin system. However, their antihypertensive effect overlaps that of the thiazide-type diuretics with little additive potential. These two drugs differ from the DHP CCBs by inhibiting cardiac AV conduction, so can be used for management of supraventricular arrhythmias. They should not be combined with beta-receptor blockers because of the risk of bradycardia. These drugs are usually well tolerated, but they may cause edema. Verapamil can cause bothersome constipation.
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Antiadrenergic Drugs Used for Hypertension
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Beta-Receptor Blockers
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At one time, beta-receptor blockers, especially when combined with thiazide-type diuretics, were a major component of antihypertensive drug treatment and had an important role in several clinical trials. The effectiveness of beta-blockers either as monotherapy or in combination with a diuretic, for prevention of cardiovascular disease in the absence of coronary artery disease (especially for stroke), has been questioned, particularly now that combinations of renin system blockers and either diuretics or CCBs have become available.89,90 However, the value of beta-blockers for management of coronary heart disease, especially angina, remains well accepted.91 In general, the most used beta-receptor blockers have a long duration of action, are more selective beta1-blockers with no beta2-blocking action, and have no sympathomimetic effect. Beta-receptor blockers combined with alpha-blockers (carvedilol, labetalol) or agents with vasodilator activity (nebivolol) are now available. Whether they are more effective for treatment of hypertension with coronary artery disease remains uncertain.
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Adverse effects of beta-blockers are well known and include bradycardia, fatigue, bronchospasm, or worsening of asthma (for beta-blockers that act on the beta2 receptor such as propranolol or timolol). Cold fingers, simulating Raynaud’s phenomenon, may occur.
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Alpha-Receptor Blockers
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The prototype alpha-receptor blocker is prazosin, which produces vasodilation by blocking vascular alpha receptors. This drug has a relatively short duration of action; terazosin (twice a day) or doxazosin (once a day) are preferable. The alpha-blockers may be combined with a beta-blocker as combined antiadrenergic receptor antagonism for persons with highly variable blood pressure associated with tachycardia. Like the alpha-receptor blocker phenoxybenzamine, doxazosin may be used to treat hypertension associated with pheochromocytoma. The alpha-receptor blockers are effective for reducing symptoms of prostatism, so they offer a “two for one” benefit for men with hypertension and bothersome prostatic enlargement. However, doxazosin was associated with increased occurrence of heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), so careful monitoring for signs of heart failure is warranted when this drug is used.92
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Centrally Acting Antiadrenergic Drugs and Neuron Depletor
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Methyldopa is considered safe for use in pregnancy-related hypertension, including preeclampsia, but has been superseded by recently developed drugs; see section on Pregnancy and Hypertension, below. Clonidine, an alpha-receptor agonist, acts within the brain and may also reduce peripheral neuron release by presynaptic inhibition. As an oral preparation, clonidine must be given two to three times daily; withdrawal overshoot hypertension is a risk of missed doses. The transdermal therapeutic system for transcutaneous delivery of clonidine over a 7-day period may be useful for nonadherent patients or those who cannot take oral medication.93,94
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Hydralazine, a direct-acting vasodilator, may release nitric oxide as part of its action. This drug has a short duration of action and must be given three times daily to be effective; no long-acting formulation is available. Adverse reactions to hydralazine include fluid retention, tachycardia, and drug-induced lupus erythematosus.
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Minoxidil is a very potent vasodilator with a longer duration of action; it can be given once or twice daily. Minoxidil opens the ATP-potassium channel of vascular smooth muscle cells.65 This drug may reduce blood pressure in highly resistant hypertension, when alternatives fail. However, edema and tachycardia need management, usually with a loop diuretic (eg, furosemide) and a beta-blocker. When used to treat hypertension, minoxidil can cause hair growth that may be disfiguring, so adherence to treatment is problematic. High-dose nifedipine has reduced the need for minoxidil for treatment of resistant hypertension.95