Join Now | Sign in

Arterial Hypertension Health Article

Marketplace

Licensed from

Page: < Back 1 2 3 4 5 6 7 Next >

Prevention And Treatment Of Primary Hypertension

Because primary hypertension cannot be cured, it requires lifelong treatment. However, it can usually be controlled by a combination of lifestyle modifications and medications. The objective is to reduce the blood pressure and associated metabolic abnormalities sufficiently to reduce the risk of cardiovascular and renal target organ disease without compromising the patient's quality of life.

LIFESTYLE MODIFICATIONS

Every antihypertensive regimen should include lifestyle modifications. If implemented in childhood and sustained, these nondrug strategies would likely prevent millions of cases of hypertension. Once hypertension is established, however, lifestyle modifications alone are rarely sufficient to obviate the need for medications. These modifications, however, can decrease medication requirements, affect associated cardiovascular risk factors, and emphasize the active role patients can play in controlling their blood pressure.

The most consistently effective lifestyle modification is weight loss for overweight hypertensives: losing only 10 to 12 pounds often lowers blood pressure by 10/5 mm Hg. ¹ Moderate dietary sodium reduction on average lowers blood pressure by 5/2 mm Hg and should be part of every antihypertensive regimen despite the variable response from one patient to the next and the fact that the full benefits are not seen for 5 weeks. In addition to independent blood pressure-lowering effects, dietary sodium reduction can dramatically improve the efficacy of ACE inhibitors, angiotensin-receptor blockers (ARBs), and β-blockers, and it can permit a reduction in the dose of diuretic and the associated need for potassium supplementation. Most dietary sodium comes from processed foods rather than the salt shaker. Without draconian measures, daily salt consumption can be reduced from 10 to 6 g (6 g of NaCl = 2.4 g of Na ⁺ = 100 mmol of Na ⁺) by teaching patients to read food labels. The Dietary Approaches to Stop Hypertension (DASH) study showed that individuals with high normal blood pressure or stage 1 hypertension can lower their blood pressures even without decreased caloric or sodium intake if they adhere to a diet rich in fresh fruits and vegetables (for high potassium content) and use low-fat dairy products. The DASH diet (www.nhlbi.nih.gov/health/public/heart/hbp/dash/) is strongly recommended because the blood pressure-lowering effects can approach the magnitude of drug monotherapy, can be enhanced by dietary sodium reduction, and are seen in all ethnic groups, especially in African-Americans. ² How to effect these dietary changes in free-living individuals remains a considerable challenge, but these impressive trial results document what could be achieved if dietary habits could be changed throughout the population.

Smokers should be counseled in the best methods to quit because smoking is such a potent cardiovascular risk factor, not only for coronary heart disease but also for progression of hypertensive nephrosclerosis. Because blood pressure increases transiently by 10 to 15 mm Hg after each cigarette, smokers of more than 20 cigarettes per day often have higher blood pressures out of the office. Blood pressure increases similarly with the first morning cup of coffee, but the pressor response to caffeine habituates throughout the day. Thus, caffeine consumption need not be eliminated.

Excessive alcohol consumption is one of the most frequently overlooked reversible factors contributing to hypertension. The relation between alcohol consumption and mortality is J-shaped. Cardiovascular death rates are 50% lower in moderate drinkers (one or two drinks a day) than in teetotalers. Red wine may be the most cardioprotective because of its high content of polyphenols, which decrease production of endothelin. However, individuals who drink more than two standard-sized drinks a day are at greatly increased risk of developing hypertension, possibly because large quantities of alcohol activate the sympathetic nervous system. In those who drink three or more standard portions of alcohol per day, reducing alcohol consumption can improve control of hypertension. ³

In hypertensive individuals, regular aerobic exercise can exert modest reductions in blood pressure, averaging 5/2 mm Hg. Although small in magnitude, these reductions can persist for up to 16 hours after a bout of aerobic exercise. ⁴ Relaxation techniques (e.g., meditation, biofeedback, hypnosis) can decrease blood pressure acutely but generally produce little effect on chronic hypertension. In some individuals, however, in whom overwhelming home or job strain is a major determinant of high blood pressure, as determined by ambulatory monitoring, stress management techniques or anxiolytics may be beneficial. Because patients often associate hypertension directly with life stress, patients should be counseled that stress management alone rarely is sufficient to control their hypertension.

PHARMACOLOGIC THERAPY

Historical Perspective

The current approach to the treatment of the hypertensive patient began in the 1960s, with the sequential development of effective antihypertensive medications. The memoirs of President Franklin Roosevelt's physician chronicle the frustrations of trying to manage severe hypertension with only bed rest and sedatives, which were the ineffective mainstays of antihypertensive therapy through the end of World War II. Shortly thereafter, Kempner demonstrated the blood pressure-lowering effects of treating overweight hypertensives with a rigorously low-sodium/low-calorie diet, the first effective lifestyle modification for hypertension. With the development of the first antihypertensive drugs in the late 1950s, the vanguard VA Cooperative Studies demonstrated that lowering blood pressure with medications prolongs life and reduces morbidity, not only in patients with very severe hypertension but also in those with moderate and even mild degrees of hypertension.

Probably no other field of clinical medicine enjoys a greater scientific base. Increasingly detailed understanding of the basic mechanisms involved in blood pressure regulation has fueled the identification of new drug targets and therapeutic agents. More than 70 antihypertensive medications are marketed. Randomized controlled trials have provided unequivocal proof that lowering blood pressure with medications dramatically reduces target organ damage and the resultant morbidity and mortality. There also is mounting but still incomplete evidence that certain classes of antihypertensive agents exert organoprotective effects above and beyond their ability to lower blood pressure. Thus, in certain circumstances, all antihypertensive medications are not equal, and the treatment of hypertension is no longer totally empiric.

The major challenges now are (1) to identify the key gene-environment interactions that cause hypertension and those that confer protection from it, thereby providing the conceptual framework for preventing or curing the disordered blood pressure regulation, and in the meantime, (2) to eliminate the patient and physician barriers that impede the control of hypertension with available measures. To improve the dissemination of the rapid advances in the field, practice guidelines are regularly updated (e.g., the Joint National Committee [JNC] 7 Report).

Target Blood Pressure Levels

Based on each patient's overall cardiovascular risk, a target level of blood pressure needs to be set, achieved, and sustained. For most patients, the goal is to intensify the medical regimen until blood pressure is lowered to systolic and diastolic values that are consistently below 140/90 mm Hg. For those with diabetes or chronic kidney disease, the high risk associated with these comorbid conditions requires that blood pressure be lowered further to values that are below 130/80 mm Hg. Unfortunately, in the United States, one third of all hypertensive individuals are unaware of their diagnosis, one half are not receiving treatment, and two thirds do not have their pressure controlled to a value less than 140/90 mm Hg. This worldwide problem (see Fig. 63-2) is not limited to underserved areas. In a survey of adults in Olmsted County, Minnesota, a well-educated community in proximity to the Mayo Clinic, 39% of the hypertensive participants were unaware of their diagnosis and only 17% of the affected individuals had their hypertension treated and controlled. A study from five Veterans Administration hospitals in the northeastern United States showed that, despite patients' having ample access to clinic care by attending physicians, antihypertensive therapy was intensified during only 7% of hypertension-related visits over a 2-year period, resulting in persistently poor rates of control; blood pressure remained greater than 160/90 mm Hg in 40% of the patients. Similarly disconcerting figures have been found in numerous practice settings.

In contrast, randomized clinical trials have demonstrated that teams of physicians and nurses who adhere to a forced titration schedule can achieve target blood pressures in up to two thirds of patients. With current regimens, diastolic pressures of less than 90 mm Hg can be achieved in more than 90% of hypertensive patients, whereas systolic pressures of less than 140 mm Hg can be achieved in more than 60%. New medications with greater efficacy for systolic blood pressure are under investigation.

To improve hypertension control rates in clinical practice, a number of principles can be borrowed from the successful conduct of multicenter trials. First, greater attention needs to be paid to titrating blood pressure medications to achieve target goals. Lowering blood pressure by the additional 10/5 mm Hg often needed to achieve, rather than almost achieve, current treatment goals has been proved repeatedly to confer a remarkable degree of added protection from adverse cardiovascular outcomes. ⁵ Almost is not good enough. Second, to achieve these goals, most patients require two or three antihypertensive medications. To achieve the more stringent blood pressure goals indicated for diabetics and patients with chronic renal failure, three or four medications are usually needed. Third, to achieve and sustain patient compliance with multidrug regimens, greater attention needs to be paid to the patient's quality of life.

Compliance and Quality of Life

The importance of honest patient dialogue and patient education cannot be overemphasized. Despite decades of nationwide blood pressure education programs about the "silent killer," many patients perceive hypertension as being episodic and symptomatic. Because hypertension requires lifelong treatment and because medications can produce side effects, quality of life becomes a major issue that affects patients' compliance. Medication costs are considerable and beyond the means of some patients. For patients who must pay for some or all of their medications, costs can be cut drastically by prescribing generic drugs.

Men are often concerned about medication-induced sexual dysfunction. However, sexual dysfunction often precedes the initiation of antihypertensive therapy. In a double-blind, prospective, placebo-controlled trial, thiazide diuretics were the only one of the six major classes of antihypertensive drugs associated with more new cases of male sexual dysfunction over the next year than placebo. Thus, the incidence of medication-induced sexual dysfunction previously has been overstated. Much of the blame assigned to the drugs is caused by impaired endothelial function (impaired nitric oxide-mediated dilation of the corpus cavernosum) due to obesity-induced insulin resistance, cigarette smoking, hyperlipidemia, and uncontrolled hypertension. Indeed, patients generally rate their overall quality of life as significantly improved when their blood pressures are controlled with medical therapy compared with when uncontrolled on placebo. In addition to these considerations, several additional principles have been shown to facilitate patients' complian (1) titrating medical therapy based on home readings, which engages the patient's active participation; (2) using long-acting preparations with once-a-day dosing; (3) using low-dose combinations of medications from different drug classes to achieve synergistic effects on blood pressure while avoiding dose-dependent side effects; and (4) using fixed-dose combinations to reduce the overall number of pills.

Choice of Initial Drug Therapy

The choice of the initial antihypertensive medication is less important now than in the stepped-care era of the 1970s (which encouraged high-dose monotherapy) because most patients require multiple medications (Table 63-5). There is increasing movement toward initiating treatment with low-dose combination therapy. Based on the recent results of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ⁶ and other recent treatment trials, it takes at least two medications of different classes to treat most cases of mild hypertension and three or four different medications to treat the more difficult cases and to reach more stringent blood pressure goals in high-risk patients. ⁷ The JNC 7 Report recommends starting a two-drug combination regimen for patients with stage 2 hypertension. As a rule of thumb, an additional medication will be needed for each 10 mm Hg of systolic blood pressure above goal. The great majority of these multi-drug regimens should include a low-dose diuretic.

DIURETICS

Mechanism of Action.

With initiation of diuretic therapy, contraction of blood volume explains the initial fall in blood pressure. With continued diuretic therapy, blood volume is partially restored, and vasodilator mechanisms (e.g., opening of ATP-sensitive potassium channels) sustain the antihypertensive action. Based on their sites of action in the kidney, there are three main classes of diuretics. Loop diuretics are the most potent because they block Na ⁺ /K ⁺ /2Cl ^- transport in the thick ascending loop of Henle, where a large portion of the filtered Na ⁺ is reabsorbed. Thiazide diuretics and the indoline derivative indapamide are less potent because they block Na ⁺ /Cl ^- cotransport in the distal convoluted tubule, where a small portion of the filtered sodium is reabsorbed. The potassium-sparing diuretics are the weakest because they act most distally in the collecting duct. Spironolactone prevents aldosterone from activating the mineralocorticoid receptor, thereby inhibiting activation of ENaC, the final common pathway for reabsorption of Na ⁺ from the distal nephron. Triamterene and amiloride block ENaC directly. Because less Na ⁺ is presented to the Na ⁺ ,K ⁺ -ATPase on the apical surface (i.e., vascular side) of the collecting duct cells, less K ⁺ is excreted in the urine.

Side Effects and Contraindications.

Thiazides and prolonged exposure to loop diuretics cause renal potassium wasting because increased Na ⁺ is presented to the Na ⁺ ,K ⁺ -ATPase. The hypokalemia is dose dependent and minimized by using lower doses the equivalent of 6.25 to 12.5 mg of hydrochlorothiazide (HCTZ). Hypokalemia predisposes to ventricular arrhythmias and negates the cardioprotective benefit of lowering blood pressure. Serum Na ⁺ also needs to be followed because thiazide diuretics occasionally cause hyponatremia, which in older patients can be severe. Although thiazides are said to elevate plasma LDL cholesterol, the effect is negligible with lower doses. Although thiazides can increase blood glucose, the effect is small with low doses, and thiazide-based therapy has been proved to reduce cardiovascular morbidity and mortality in diabetic hypertensives. They occasionally cause erectile dysfunction. Thiazide diuretics are relatively contraindicated in patients with hyperuricemia because they can precipitate gout. Potassium-sparing diuretics are contraindicated in patients who are prone to hyperkalemia, especially patients with renal failure and diabetics with hyporeninemic hypoaldosteronism. In high doses, spironolactone antagonizes the testosterone receptor, thereby producing sexual dysfunction and painful gynecomastia in men. Except for ethacrynic acid, all diuretics contain a sulfur moiety, can cause photosensitivity, and should be avoided in patients with a history of allergic reaction to sulfa drugs. Furosemide can rarely cause interstitial nephritis.

Compelling Indications and Therapeutic Principles.

Diuretics are the oldest, least expensive, and still among the best antihypertensive medications. With the marketing of new classes of antihypertensive agents since the 1970s, the number of prescriptions written for diuretics unfortunately has fallen steadily. Hopefully, this trend will change with publication of the ALLHAT, which documented that thiazide-type diuretics are at least as effective as (and in some instances more effective than) newer agents in lowering blood pressure and preventing the attendant cardiovascular morbidity and mortality. As first line therapy, the thiazide-type diuretic (chlorthalidone) was equally effective as the ACE inhibitor (lisinopril) or the dihydropyridine CCB (amlodipine) in preventing the primary endpoint of combined fatal coronary heart disease and nonfatal myocardial infarction. The effectiveness of the diuretic-based therapy was demonstrated in all patient subgroups including older persons, women, African Americans, and those with diabetes. When combined with other classes of antihypertensive medications, diuretics exert a synergistic effect on blood pressure. The most common cause of apparent drug-resistant hypertension is the failure to include a diuretic or dose it correctly in the therapeutic regimen. Thus, thiazides remain the first drug of choice for the majority of hypertensive patients. Thiazide diuretics exert a larger effect on systolic than diastolic blood pressure and, based on hard outcomes data, are the initial drugs of choice for isolated systolic hypertension. ⁸ Almost every antihypertensive regimen should include a low-dose diuretic or at least a low-sodium diet.

Because of their long half-lives, thiazide diuretics are much more effective than the short-acting loop diuretics in the long-term management of chronic hypertension. Very low doses of HCTZ (6.25 mg/day in combination or 12.5 mg/day alone) maintain much of the antihypertensive efficacy while greatly minimizing the adverse metabolic profile associated with the much larger doses (50 to 100 mg/day) used previously. Chlorthalidone, the thiazide-type diuretic used in the ALLHAT and many other landmark hypertension treatment trials, is more potent and has a much longer duration of action than HCTZ, which for decades has replaced chlorthalidone as the main thiazide-type diuretic used in clinical practice. According to some experts, 25 mg of chlorthalidone is roughly equivalent to 40 mg of HCTZ. Combinations of HCTZ with potassium-sparing diuretics reduce, but do not always eliminate, the need for potassium supplements; serum K ⁺ levels must be followed after initiating therapy. Adherence to a moderately low-salt diet also reduces the need for potassium supplements in patients taking diuretics. Thiazide diuretics, except for metolazone, are ineffective when the glomerular filtration rate falls below 30 mL/min.

Loop diuretics are the diuretics of choice for treating hypertension in patients with chronic renal insufficiency or heart failure. Because the duration of action of furosemide is 6–8 hours, twice daily dosing is required for sustained lowering of blood pressure. Torsemide may be a better alternative because of its longer half-life. The addition of low-dose metolazone (2.5 mg/day) to a loop diuretic can sometimes restore blood pressure responsiveness in patients with resistant hypertension due to severe volume expansion in the setting of advanced chronic renal failure. However, metolazone and the potent loop diuretics are not appropriate treatment for the vast majority of patients with uncomplicated hypertension.

Spironolactone (50 to 200 mg/day) is the drug of choice for the medical treatment of primary aldosteronism. Low-dose spironolactone (12.5 to 25 mg/day) also can be effective in some patients with primary low-renin hypertension. Eplerenone, a more specific mineralocorticoid receptor antagonist that does not block the testosterone receptor, is in the final stages of clinical trials and could have broad implications for the treatment of primary hypertension. Amiloride is the drug of choice for treating primary aldosteronism in men and is the drug of choice for patients with Liddle's syndrome.

β-ADRENERGIC RECEPTOR BLOCKERS

Mechanism of Action.

Interaction of epinephrine or norepinephrine with β 1 -adrenoreceptors in the heart causes G protein-linked activation of adenylate cyclase, resulting in positive chronotropic and inotropic effects. Interaction of catecholamines with β 2 -adrenoreceptors relaxes bronchiolar and arteriolar smooth muscle. With the initiation of β-blocker therapy, blood pressure at first is little affected because the fall in cardiac output is offset by a compensatory increase in peripheral resistance. Over several weeks, blood pressure falls progressively as the peripheral vasculature relaxes. Thus, the antihypertensive effect of β-blockade involves decreases in cardiac output (β 1 -receptors), renin release (β 1 -receptors), and norepinephrine release (prejunctional β 2 -receptors).

All 11 β-blockers are antihypertensive. First-generation agents (e.g., propranolol) nonselectively block both β 1 - and β 2 -receptors. Second-generation agents (e.g., metoprolol, atenolol, acebutolol, bisoprolol) are relatively cardioselective. In low doses, they exert a greater inhibitory effect on β 1 - than on β 2 -receptors, but selectivity is lost at high doses. Other agents cause vasodilatation either by stimulating β 2 -adrenoreceptors (i.e., intrinsic sympathomimetic activity ) (e.g., pindolol) or by blocking α 1 -adrenoreceptors (labetalol, carvedilol) on vascular smooth muscle.

Side Effects and Contraindications.

β-Adrenergic receptor blockade can cause adverse side effects through (1) contraction of smooth muscle (bronchospasm, Raynaud's phenomenon), (2) exaggeration of therapeutic negative chronotropic and inotropic effects (heart failure, heart block), and (3) penetration of the central nervous system (CNS) (depression, nightmares). Contraindications to β-blockers include asthma and other forms of reactive airway disease, heart block, acutely decompensated heart failure, Prinzmetal's angina, and depression. In brittle type I diabetes, β-blockers can mask the adrenergic signs of hypoglycemia, but this effect often can be avoided with a cardioselective β-blocker. Before starting β-blockers for hypertension, it should be appreciated that chronic β-blocker therapy has been associated with a 28% increased risk of developing type II diabetes. In patients with known or suspected coronary disease, β-blockers must be tapered slowly to avoid rebound angina.

Compelling Indications and Therapeutic Principles.

For the treatment of hypertension, the long-acting (once-a-day) and cardioselective β-blockers are preferred, but all β-blockers are effective, particularly when combined with a diuretic. Although numerous clinical trials have demonstrated that treating hypertension with β-blockers reduces cardiovascular outcomes, in most cases the β-blocker has been combined with a thiazide diuretic. β-Blockers, which are very effective in reducing myocardial oxygen demands, are first-line therapy for hypertensive patients with coronary disease and should be prescribed in all patients who also have sustained a myocardial infarction and who can tolerate them. β-Blockers also can be very useful in hypertensive patients who have anxiety disorders.

CALCIUM CHANNEL BLOCKERS

Mechanism of Action.

The CCBs block the opening of voltage-gated (L-type) Ca ²⁺ channels, thereby preventing the entry of Ca ²⁺ into cardiac myocytes and vascular smooth muscle cells. The resultant decrease in the cytosolic Ca ²⁺ signal decreases heart rate and ventricular contractility and relaxes vascular smooth muscle. The major classes of CCBs are the dihydropyridines (e.g., nifedipine, felodipine, amlodipine) and the nondihydropyridines (verapamil and diltiazem). Dihydropyridines are more potent antihypertensive agents, but any directly negative chronotropic or inotropic effects are offset by reflex sympathetic activation. By comparison, the nondihydropyridines are weaker antihypertensive drugs because they cause less peripheral vasodilation, but they exert more pronounced negative chronotropic and inotropic effects (especially verapamil), thereby decreasing cardiac output.

Side Effects and Contraindications.

The CCBs are generally very well tolerated. Because of their negative inotropic and negative chronotropic actions, the nondihydropyridine CCBs are contraindicated in patients with severe left ventricular dysfunction and those with impaired cardiac conduction because they can precipitate heart failure or heart block. Verapamil often causes considerable constipation by blocking contraction of smooth muscle in the gut. The most frequent annoying side effects of the dihydropyridines'headaches, flushing, and ankle edema'are all related to arterial vasodilation. In the absence of venodilation, arterial vasodilation increases capillary hydrostatic pressure, leading to dose-dependent ankle edema. Short-acting dihydropyridines should not be used to treat hypertension. By triggering an abrupt fall in blood pressure with reflex sympathetic activation, these rapidly acting vasodilators can precipitate myocardial ischemia, infarction, stroke, and death.

Compelling Indications and Therapeutic Principles.

Controversy has arisen on the indications for long-acting dihydropyridine CCBs, which cause much less (but still some) reflex sympathetic activation. A meta-analysis suggests that, for the majority of patients with hypertension, cardiovascular outcomes with dihydropyridine CCBs are on balance equivalent to those seen with other classes of antihypertensive medications, with the caveat that they possibly provide less protection against myocardial infarction and heart failure but greater protection against stroke and dementia. ⁹ With the publication of ALLHAT, much of the conroversy around dihydropyridine CCBs has ended. After five years of treatment with a long-acting dihydroperidine CCB, the primary outcome of fatal coronary heart disease and nonfatal myocardial infarction was identical to that seen with the ACE inhibitor or the diuretic. For patients with proteinuric renal insufficiency, there is mounting evidence that dihydropyridine CCB-based therapy is less renoprotective than ARB or ACE inhibitor-based therapy. ¹⁰ However, in the vast majority of patients with renal disease, multiple classes of medications, including dihydropyridines , are required to achieve blood pressure goals. The key point is that a dihydropyridine should not be used as first-line therapy for hypertension in patients with proteinuric renal disease but may be used as adjunctive therapy once the dose of the ACE inhibitor or ARB has been maximized in combination with an appropriate diuretic. Dihydropyridine CCB-based therapy has been proved to improve cardiovascular outcomes, especially stroke, dramatically in older hypertensives and particularly in older hypertensive patients with diabetes.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

Mechanism of Action.

The renin-angiotensin system is one of the most important targets for antihypertensive drugs (Fig. 63-8). The interaction of Ang II with G protein-coupled receptors termed AT 1 receptors accelerates numerous cellular processes that contribute not only to hypertension but also to its end-organ damage, including (1) aldosterone secretion, which produces renal salt and water retention, as well as collagen deposition leading to cardiac fibrosis; (2) peripheral vasoconstriction; (3) growth of cardiac and vascular smooth muscle cells, leading to cardiac and vascular hypertrophy; (4) production of superoxide anions and other reactive oxygen species that inactivate nitric oxide, thereby inhibiting endothelium-dependent vasodilatation; and (5) augmentation of both central sympathetic outflow and prejunctional modulation of norepinephrine release from peripheral sympathetic nerve terminals, thereby leading to excessive stimulation of α adrenergic receptors. For these reasons, blockade of the renin-angiotensin-aldosterone system may exert organoprotective effects above and beyond the lowering of blood pressure. ACE inhibitors block the conversion of Ang I to Ang II, leading to a dramatic fall in plasma Ang II levels with the initiation of therapy. However, with continued treatment with an ACE inhibitor, plasma Ang II levels return to normal in part because ACE inhibitors do not block alternative pathways that generate Ang II. The sustained antihypertensive action of ACE inhibitors is explained in part by their ability to block the metabolism of bradykinin, a potent endothelial-dependent vasodilator, to inactive fragments. By comparison, ARBs lower blood pressure specifically by blocking the interaction of Ang II on the AT 1 receptors. Thus, ARBs do not increase bradykinin, which has been implicated in both the therapeutic and side effects of ACE inhibitors.

Side Effects and Contraindications.

The ACE inhibitors are generally well tolerated, but the ARBs have the best side effect profile to date. The most common side effect of ACE inhibitors is a dry cough, which occurs in 3 to 39% of patients and resolves in a few days after the drug is discontinued. The incidence is higher in African Americans than whites and highest in Asians. Because the cough seems to be bradykinin mediated, this annoying side effect is avoided by switching to an ARB. The rare (1 : 2000) but most serious side effect of ACE inhibitors, angioedema, also has been blamed on bradykinin, and thus is even rarer with ARBs. Angioedema, which can occur at any time during the course of treatment, is more common in African Americans and can be fatal. With either ACE inhibitors or ARBs, hyperkalemia can result from reduced aldosterone secretion or impairment of renal function; however, even in the setting of significant renal disease, the risk of hyperkalemia requiring drug discontinuation is low (<2%) and is seen mainly when these drugs are administered to diabetics with hyporeninemic hypoaldosteronism or are mistakenly used in patients who are also taking potassium supplements, an error that should be avoided. ACE inhibitors and ARBs can precipitate acute renal failure in patients with bilateral renal artery stenosis or hypovolemia. After correction of hypovolemia, the ACE inhibitor or ARB usually can be restarted safely at a lower dose. These drugs are contraindicated in pregnancy because they are teratogenic.

Compelling Indications and Therapeutic Principles.

Because of their low side effect profiles and ancillary benefits, ACE inhibitors and ARBs are gaining popularity for the general treatment of hypertension. At present, however, diabetic nephropathy, nondiabetic renal insufficiency, and heart failure are considered (by many authorities) to be the compelling indications for initiating hypertension treatment with an ACE inhibitor or ARB. ^11, ^12, ¹³ Randomized trials have dispelled the fear that ACE inhibitors and ARBs are contraindicated for patients with mild or moderate degrees of renal impairment by showing that the incidence of hyperkalemia or acute renal failure is very low and that renoprotection is provided. Although serum creatinine and potassium need to be monitored in all patients receiving an ACE inhibitor or ARB, small and typically transient increases at the onset of therapy are not an indication to discontinue these drugs.

All ARBs have approximately comparable antihypertensive efficacy. Losartan, the prototype, differs from the other ARBs in two ways: a shorter duration of action, requiring twice-daily dosing if used as monotherapy, and a uricosuric effect, which may be beneficial in patients with hyperuricemia.

α-ADRENERGIC BLOCKERS

Mechanism of Action.

By blocking the interaction of norepinephrine on vascular α-adrenergic receptors, these drugs cause peripheral vasodilation, thereby lowering blood pressure. By increasing skeletal muscle blood flow, they increase insulin sensitivity. By dilating urethral smooth muscle, they improve symptoms of prostatism. Prazosin, doxazosin, and terazosin selectively block α 1 -adrenoreceptors, whereas phenoxybenzamine blocks both α 1 - and α 2 -receptors.

Side Effects and Contraindications.

The most troubling side effect is orthostatic hypotension, which is less often seen with the second-generation agents with a slower onset of action.

Compelling Indications and Therapeutic Principles.

Phenoxybenzamine remains the drug of choice for preoperative management of pheochromocytoma; after α-blockade is achieved, a β-blocker should be added to block an otherwise excessive reflex tachycardia. The selective α 1 -blockers are effective general antihypertensive agents and are particularly useful in older men with prostatism. It is important to emphasize that α-blockers should not be used as monotherapy because their propensity to cause fluid retention can lead to tachyphylaxis and unmask heart failure. ¹⁴ When prescribed correctly in combination with a diuretic, there is no evidence to contraindicate their use.

CENTRAL SYMPATHOLYTICS

Mechanism of Action.

Stimulation of α 2 -adrenergic receptors and imidazoline receptors in the CNS lowers central sympathetic outflow, whereas stimulation of presynaptic α 2 -receptors causes feedback inhibition of norepinephrine release from peripheral sympathetic nerve terminals. The combined effect is reduced sympathetic drive to the heart and peripheral circulation, leading to decreased heart rate, cardiac output, and peripheral vascular resistance.

Side Effects and Contraindications.

Although highly effective as antihypertensive agents, the clinical utility of these agents is limited by their side effects profile. The major CNS side effects are sedation, dry mouth, and depression. Depression is a contraindication to all available central sympatholytic agents. These side effects are lessened with more selective imidazoline receptor blockers that are available in Europe. Central sympatholytics should not be combined with a β-blocker because excessive bradycardia can ensue. Reserpine also depletes norepinephrine stores from sympathetic nerve terminals, causing dose-dependent orthostatic hypotension. α-Methyldopa can cause autoimmune hemolytic anemia and lupus erythematosus. Although clonidine does not cause these latter side effects, rebound hypertension is a major problem if oral clonidine is discontinued abruptly. Rebound hypertension is reduced by using longer acting preparations (guanfacine or transdermal clonidine).

Therapeutic Principles.

Central sympatholytics can be effective as add-on therapy for patients with difficult-to-control hypertension. Aldomet remains the drug of choice for nonemergent hypertension in pregnancy.

DIRECT VASODILATORS

Mechanism of Action.

Minoxidil and hydralazine are potent hyperpolarizing arterial vasodilators that work by opening vascular ATP-sensitive potassium channels.

Side Effects and Contraindications.

By causing selective arterial dilation, both drugs cause profound reflex sympathetic activation and tachycardia as well as peripheral edema. When hydralazine is administered parenterally, the magnitude of the blood pressure lowering is unpredictable and can result in extreme hypotension. Chronic treatment with high doses of oral hydralazine can cause a lupus-like syndrome. Minoxidil causes diffuse hirsutism.

Therapeutic Principles.

Hydralazine has largely been replaced by the dihydropyridine CCBs because of side effect profiles. However, hydralazine remains the treatment of choice for acute severe hypertension in pregnancy. Difficult-to-control hypertension in chronic renal failure is the main indication for minoxidil, which must be combined with a β-blocker, to prevent excessive reflex tachycardia, and with a loop diuretic, to prevent excessive fluid retention.

COMBINATION THERAPY.

Some drug combinations are particularly effective for treating hypertension, and some should be avoided. Because higher doses of diuretics cause reflex activation of both the renin-angiotensin and sympathetic nervous systems, preventing such activation with the addition of an ACE inhibitor, an ARB, or a β-blocker produces synergistic effects on blood pressure. With fixed-dose combinations, the dose of HCTZ should be 12.5 mg or, even better, 6.25 mg. Unfortunately, many fixed-dose combinations contain 25 mg of HCTZ, which often is too high. Combining HCTZ with a potassium-sparing diuretic may obviate unpleasant potassium supplements, but again the dose of the HCTZ component often is too high, requiring that pills be cut in half.

Because dihydropyridine CCBs also produce reflex increases in plasma renin and sympathetic activity, the addition of an ACE inhibitor or ARB produces synergistic effects on blood pressure (and potentially on end-organ protection). In addition, high doses of dihydropyridine CCBs cause ankle edema because these drugs preferentially dilate arteries rather than veins, producing elevated hydrostatic pressure in the cutaneous circulation. This elevated hydrostatic pressure and the resulting ankle edema often can be relieved by the addition of an ACE inhibitor or ARB, which dilates veins as well as arteries. In contrast, the hydrostatic edema is not relieved by addition of a diuretic.

Furthermore, combining a dihydropyridine CCB with a diuretic produces less blood pressure synergy because of excessive reflex neurohormonal activation. This combination should be avoided in patients with ischemic heart disease unless a β-blocker also is used. β-Blockers generally should not be combined with nondihydropyridine CCBs or with clonidine or other central sympatholytics because these combinations can lead to excessive bradycardia and depression, particularly in older persons. Labetalol, although marketed for its α-blocking action, is primarily a β-blocker and should not be combined with other β-blockers.

Vasopeptidase inhibitors, a new class of agent under final stages of clinical investigation, inhibit both ACE and neutral endopeptidase (NEP), the enzyme that breaks down the endogenous natriuretic peptides. As a result, the natriuretic and vasodilatory actions of these peptides are enhanced. NEP inhibition alone has very little effect on blood pressure because of compensatory activation of the renin-angiotensin-aldosterone system. In contrast, simultaneous inhibition of NEP and ACE by this single molecule produces a powerful antihypertensive effect that may be particularly useful in treating systolic hypertension. However, clinical safety trials showed a greater incidence of life-threatening angioedema with the first vasopeptidase inhibitor than with a conventional ACE inhibitor. Whether serious angioedema is an unavoidable side-effect of this class of drugs remains to be determined. Studies also are under way to determine if combining an ACE inhibitor with an ARB provides more complete blockade of the renin-angiotensin system than maximal doses of either drug alone.

MAJOR DRUG INTERACTIONS THAT AFFECT BLOOD PRESSURE CONTROL.

Grapefruit juice (even a single glass) increases the bioavailability of dihydropyridine CCBs by inhibiting the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. This effect is marked with felodipine, which has the least bioavailability of the dihydropyridines, and less with amlodipine and nifedipine, which have greater bioavailability. By inhibiting renal sodium excretion, nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase (COX)-2 inhibitors, can markedly impair the antihypertensive action of diuretics as well as drugs that block the renin-angiotensin system. Because a fall in renin and Ang II levels is a compensatory mechanism that normally serves to counter volume-dependent hypertension, the blood pressure-raising effects of NSAIDs appear to be particularly problematic during ACE inhibitor-based therapy, which interrupts this mechanism. Similar problems may occur with daily doses of aspirin in excess of 325 mg but do not seem to occur with 81 mg per day.

Which Drugs for Which Patients?

Ideally, precise genetic and phenotypic markers would allow each patient to be treated with the best combination of drugs. In the absence of such ideal scientific information, one approach is renin profiling, which is the measurement of PRA to divide primary hypertension into two broad pathophysiologic subsets: (1) PRA of less than 0.65, which implies volume-dependent hypertension requiring diuretics as first-line therapy, and (2) PRA of greater than 0.65, which implies renin-dependent hypertension requiring first-line therapy with one or more drugs that block the renin-angiotensin system, such as β-blockers, ACE inhibitors, or ARBs. In hypertensive populations, PRA shows a normal distribution, with the lowest values occurring in mineralocorticoid-induced hypertension, the highest values in renovascular hypertension, and a broad distribution of values in primary hypertension. However, because of feedback inhibition of renin release and progressive loss of nephrons, PRA can decrease secondarily with increasing severity and duration of chronic hypertension regardless of the etiology. Whether renin-guided therapy improves patient outcomes remains to be determined.

Pharmacogenetic profiling is another possible approach. A few single-nucleotide polymorphisms have been associated with greater blood pressure reductions with specific drugs. However, none of the reported effects have been large enough to make specific treatment recommendations.

For most patients, the current recommendation is to choose drugs based on comorbidities and the optimization of cardiovascular-renal protection (Table 63-6).

HYPERTENSION IN AFRICAN AMERICANS.

The lower plasma renin levels common in African American hypertensives may suggest volume-dependent hypertension requiring diuretic therapy. Alternatively, lower plasma renin levels may be caused by a longer duration and greater severity of hypertension or by concomitant nephrosclerosis, with the latter being a compelling indication for ACE inhibitor-based therapy (see later). As monotherapy, an ACE inhibitor or a β-blocker yields a smaller decrease in blood pressure in older hypertensive African American men than in white men. The key point, however, is that when higher doses of an ACE inhibitor, an ARB, or a β-blocker are used in combination with a thiazide diuretic (or low-sodium diet), antihypertensive efficacy is amplified, and ethnic differences seem to disappear. Because combination therapy is required to reach blood pressure goals in most hypertensive patients, especially those with more severe hypertension and additional cardiovascular risk factors, the results achieved with monotherapy have less and less practical relevance to modern clinical practice.

HYPERTENSIVE PATIENTS WITH NEPHROSCLEROSIS.

Hypertension is the second most common cause of chronic renal failure, accounting for 25% of cases. Hypertensive nephrosclerosis is thought to result from severe constriction of the afferent renal arteriole, resulting in chronic glomerular ischemia. Typically, proteinuria is mild (<0.5 g/24 hr), and the diagnosis should be questioned in the presence of heavier degrees of proteinuria or in the absence of additional target organ damage (retinopathy, LVH). Mild-to-moderate non-diabetic renal insufficiency is now considered to be a compelling indication for ACE inhibitor-based antihypertensive therapy. ¹¹ ACE inhibitors preferentially dilate the efferent renal arteriole, thereby minimizing intraglomerular hypertension. In contrast, arterial vasodilators such as dihydropyridine CCBs, when used without an ACE inhibitor or ARB, preferentially dilate the afferent arteriole, thereby promoting intraglomerular hypertension. This adverse effect on the renal microcirculation opposes the beneficial effect of lowering systemic blood pressure. In addition, dihydropyridine CCB monotherapy reflexively increases the activity of the sympathetic and renin-angiotensin systems, which could promote glomerular hypertrophy. In contrast, monotherapy with an ACE inhibitor decreases sympathetic activity in patients with nondiabetic renal insufficiency. In African Americans with moderate hypertensive nephrosclerosis and baseline proteinuria, an ACE inhibitor (ramipril)-based regimen is superior to a dihydropyridine CCB (amlodipine)-based regimen in slowing the progression to renal failure. The ACE inhibitor should be withdrawn only if the rise in serum creatinine exceeds 30% of the baseline value or the serum K ⁺ increases to greater than 5.6 mmol/L.

DIABETIC HYPERTENSIVE PATIENTS.

Compared with its 25% prevalence in the general adult population, hypertension is present in 70% of diabetic patients and is a major factor contributing to excessive risk of myocardial infarction, stroke, heart failure, microvascular complications, and diabetic nephropathy progressing to end-stage renal disease. To reduce these risks, three current principles should guide therapy. First, in all diabetic patients, blood pressures should be lowered to less than 130/80 mm Hg. ¹⁵ Compared with less intensive treatment, more intensive reduction of blood pressure has been proved repeatedly to reduce cardiovascular and microvascular end points dramatically in patients with diabetes. In one study, for example, lowering diastolic blood pressure to 81 versus 85 mm Hg led to a 60% decrease in coronary events, a 43% reduction in stroke, and an impressive 77% decrease in mortality. The cardiovascular benefits of tight blood pressure control in diabetic patients cannot be overemphasized because they exceed and are additive to those of tight glucose control. In addition, tight blood pressure control is the key to retarding the progression of diabetic nephropathy. In those with heavy proteinuria (>1 g/24 hr), additional renal protection may be obtained if blood pressure is lowered to less than 125/75 mm Hg.

Second, to achieve such stringent blood pressure goals typically requires three or four drugs. According to most authorities, the first drug should be an ACE inhibitor or ARB, the second drug a diuretic, and the third a dihydropyridine CCB and/or a β-blocker. The rationale is as follows.

The third therapeutic principle is that an ACE inhibitor or ARB should be the drug of first choice for the hypertensive diabetic because of mounting evidence that these agents provide special renoprotective and perhaps cardioprotective effects. ^10, ^12, ¹³ Type I diabetes with renal insufficiency is a compelling indication for ACE inhibitor-based antihypertensive therapy. Based on consistent results of three recent multicenter trials that examined renal outcomes, type II diabetes with renal insufficiency is now considered by some authorities to be a compelling indication for ARB-based antihypertensive therapy because similar data do not yet exist for ACE inhibitor-based regimens in type II diabetics. ^10, ¹³ However, an ACE inhibitor or ARB alone rarely achieves the stringent blood pressure goals in diabetic patients with renal insufficiency. A loop diuretic is usually needed to shrink the expanded plasma volume. A dihydropyridine CCB is usually needed for antihypertensive synergy. The dihydropyridine CCB should not be started until antihypertensive therapy has been initiated with an ACE inhibitor or ARB. A β-blocker should be added if the patient has coronary disease, which is prevalent in diabetes or heart failure.

HYPERTENSIVE PATIENTS WITH CORONARY ARTERY DISEASE.

To lower myocardial oxygen demands in patients with coronary artery disease, the antihypertensive regimen should reduce blood pressure without causing reflex tachycardia. β-Blockers and CCBs are both antianginal and antihypertensive, but dihydropyridine CCBs should not be used without a β-blocker. β-Blockers are indicated for hypertensive patients who have sustained a myocardial infarction and, in low doses, for most patients with chronic heart failure. ACE inhibitors are indicated for almost all patients with left ventricular systolic dysfunction and may be considered for post-myocardial infarction patients even in the absence of ventricular dysfunction. In patients with very high cardiovascular risk profiles but without known left ventricular dysfunction, the ACE inhibitor ramipril (10 mg/day) reduces cardiovascular outcomes, an effect that may or may not be beyond what can be explained by blood pressure reductions alone.

ISOLATED SYSTOLIC HYPERTENSION IN OLDER PERSONS.

In older persons with isolated systolic hypertension, lowering systolic pressure from greater than 160 to less than 150 mm Hg has been unequivocally proved to reduce the risk of stroke by 30%, myocardial infarction by 23%, and overall cardiovascular mortality by 18%, and to slow the progression of dementia. ^6, ¹⁴

Because of slower drug metabolism, slower postural autonomic reflexes, and more prevalent coronary artery disease in older persons, it is important to start with low doses of antihypertensive medications and titrate slowly (over months). Lifestyle modifications such as weight loss and moderate salt reduction reduce medication requirements. To prevent the development of orthostatic hypotension, medications should be titrated to standing blood pressure. For nondiabetic patients, low-dose thiazide diuretics (combined with a potassium-sparing diuretic) are the first-line drugs of choice because of their proved benefit in reducing risks of myocardial infarction and stroke as well as osteoporosis. HCTZ may need to be combined with an ACE inhibitor, an ARB, or a β-blocker. However, in older persons, β-blockers should be restricted to those with coronary disease and should be used with caution because they are more likely to precipitate heart block, impair exercise tolerance, or cause depression. For older hypertensive patients with diabetes, dihydropyridine CCBs are considered by many authorities to be the drugs of choice (in combination with an ACE inhibitor or ARB) because of even better cardiovascular outcomes than with thiazide-based therapy. ¹⁷ Trial data do not yet exist in older persons to determine whether the treatment of isolated elevations in systolic pressure between 140 and 160 mm Hg is beneficial; however, in the absence of such data, most authorities recommend treatment to prevent progression of systolic hypertension. To avoid precipitating myocardial ischemia, antihypertensive drugs may need to be reduced if diastolic (i.e., coronary perfusion) pressure falls below 65 mm Hg while attempting to lower systolic pressure below 140 mm Hg.

BLOOD PRESSURE LOWERING FOR SECONDARY PREVENTION OF STROKE.

Most authorities do not recommend blood pressure reduction during an acute stroke. In middle-aged or older patients whose clinical condition was stable at least 2 weeks after a stroke or transient ischemic attack, lowering blood pressure by 12/5 mm Hg with a combination of the thiazide diuretic indapamide plus the ACE inhibitor perindopril was shown to reduce the risk of recurrent stroke by 43% in both hypertensive and normotensive patients. In such patients, therefore, a reasonable approach is to lower blood pressure slowly over several months beginning with a thiazide diuretic, adding an ACE inhibitor or additional drugs as needed. ¹⁸

HYPERTENSIVE DISORDERS OF WOMEN

Hypertension Associated with Oral Contraceptives.

Oral contraceptives, particularly current low-dose estrogen preparations, cause a small increase in blood pressure in most women but rarely cause a large increase into the hypertensive range. The mechanism is unknown, but women over 35 and those who smoke or are overweight appear to be at increased risk. If hypertension develops, oral contraceptive therapy should be discontinued in favor of other methods of contraception.

Hypertension in Pregnancy.

Hypertension, the most common nonobstetric complication of pregnancy, is present in about 10% of all pregnancies. Of these cases, one third are caused by chronic hypertension and two thirds are due to preeclampsia, which is defined as an increase in blood pressure to 140/90 mm Hg or greater after the twentieth week of gestation accompanied by proteinuria and pathologic edema, sometimes accompanied by renal and hepatic abnormalities, and a tendency toward seizures (eclampsia). Given the current trend of childbearing in women over age 35, the incidence of chronic hypertension in pregnancy is rising. α-Methyldopa remains the drug of choice for chronic hypertension in pregnancy, and hydralazine remains the drug of choice for preeclampsia. In the latter condition, magnesium sulfate is predictably effective in preventing seizures but, despite being a vasodilator, has inconsistent effects on blood pressure.

Hypertension after Menopause.

In large clinical trials, oral estrogen replacement therapy has a neutral effect on blood pressure. In normotensive women, transdermal estrogen therapy has been shown to cause a small but consistent decrease in blood pressure. It is unclear whether routes of administration that bypass hepatic first-pass metabolism may unmask an antihypertensive effect of estrogen replacement therapy.

RESISTANT HYPERTENSION.

Defined as blood pressure that is not less than 140/90 mm Hg despite treatment with adequate doses of three different classes of medications, resistant hypertension is the most common reason for referral to a hypertension specialist. In practice, the problem usually falls into one of four categories: (1) pseudo-resistance, (2) an inadequate medical regimen, (3) noncompliance or ingestion of pressor substances, or (4) secondary hypertension. Pseudo-resistant hypertension is caused by either the white coat effect or panic attacks and is best diagnosed with ambulatory monitoring. The most common cause of apparent drug resistance is the absence of appropriate diuretic therapy: either no diuretic, inappropriate use of a loop diuretic in a patient with normal renal function, infrequent dosing with a short-acting loop diuretic (e.g., once-a-day furosemide), or a thiazide diuretic in a patient with impaired renal function. It is important to remember that significant impairment in renal function can be present with serum creatinine in the 1.2 to 1.4 mg/dL range or even lower. Other common shortcomings of the medical regimen include reliance on monotherapy and inadequate dosing. Several common causes of resistant hypertension are related to the patient's behavior: noncompliance with the medical regimen, noncompliance with lifestyle modifications (obesity, a high-salt diet, excessive alcohol intake), or habitual use of pressor substances such as sympathomimetics (tobacco, cocaine, amphetamines, phenylephrine-containing herbal remedies) or NSAIDs, with the latter causing renal sodium retention. Once these causes of resistant hypertension have been excluded, the search should begin for secondary causes of hypertension (see earlier).

ACUTE, SEVERE HYPERTENSION.

Twenty-five percent of all emergency department patients present with an elevated blood pressure. Hypertensive emergencies are acute, severe elevations in blood pressure that are accompanied by progressive target organ dysfunction such as myocardial or cerebral ischemia/infarction, pulmonary edema, or renal failure. Hypertensive urgencies are acute, severe elevations in blood pressure without evidence of progressive target organ dysfunction. Thus, the key distinction and approach to the patient depend on the clinical state of the patient and not the absolute level of blood pressure. Chronically elevated blood pressure, even when severe, does not necessitate urgent treatment. The full blown clinical picture of a hypertensive emergency is a critically ill patient who presents with a blood pressure greater than 220/140 mm Hg, headaches, confusion, blurred vision, nausea and vomiting, seizures, grade III or IV hypertensive retinopathy, heart failure, and oliguria. Hypertensive emergencies require immediate intensive care unit (ICU) admission for intravenous therapy and continuous blood pressure monitoring, whereas hypertensive urgencies often can be managed with oral medications and appropriate outpatient follow-up in 24 to 72 hours. The most common hypertensive cardiac emergencies include acute aortic dissection, hypertension after coronary artery bypass graft surgery, acute myocardial infarction, and unstable angina. Other hypertensive emergencies include eclampsia, head trauma, severe body burns, postoperative bleeding from vascular suture lines, and epistaxis that cannot be controlled with anterior and posterior nasal packing. Neurologic emergencies'acute ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, and hypertensive encephalopathy'can be difficult to distinguish from one another. Hypertensive encephalopathy is characterized by severe hypertensive retinopathy (retinal hemorrhages and exudates, with or without papilledema) and a posterior leukoencephalopathy (affecting mainly the white matter of the parieto-occipital regions) seen on cerebral MR imaging or CT scanning. A new focal neurologic deficit suggests a stroke-in-evolution, which demands a much more conservative approach to the elevated blood pressure.

In most other hypertensive emergencies, the goal of parenteral therapy is to achieve a controlled and gradual lowering of blood pressure. A good rule of thumb is to lower the initially elevated arterial pressure by 10% in the first hour and by an additional 15% over the next 3 to 12 hours to a target blood pressure of about 170/110 mm Hg. Blood pressure can be reduced to a more normal value over the next 48 hours. The principal exceptions to this rule are aortic dissection and postoperative bleeding from vascular suture lines, two situations that demand much more rapid normalization of blood pressure. In most other cases, unnecessarily rapid correction of the elevated blood pressure to completely normal values places the patient at high risk for worsening cerebral, cardiac, and renal ischemia. In chronic hypertension, cerebral autoregulation is reset to higher-than-normal blood pressures. This compensatory adjustment prevents tissue over-perfusion (increased intracranial pressure) at very high blood pressures, but it also predisposes to tissue underperfusion (cerebral ischemia) when an elevated blood pressure is lowered too quickly . In patients with coronary disease, overly rapid or excessive reduction in diastolic blood pressure in the ICU can precipitate myocardial ischemia or infarction.

After the blood pressure has been brought under acute control, oral labetalol and dihydropyridine CCBs are particularly useful agents in weaning patients from parenteral therapy so they can be transferred from the ICU. A few doses of intravenous furosemide are often needed to overcome drug resistance due to secondary volume expansion resulting from parenteral vasodilator therapy.

Secondary causes of hypertension should be considered in every patient admitted to the ICU with a hypertensive crisis. Normal 24-hour urinary catecholamines or a normal plasma normetanephrine and metanephrine collected when the blood pressure is the highest (first 24 hours in ICU) effectively rules out pheochromocytoma. Renal artery stenosis and other secondary causes should be excluded after the patient has been transferred out of the ICU but before being discharged from the hospital.

Parenteral Agents for Hypertensive Emergency.

Sodium nitroprusside, a nitric oxide donor that causes both venous and arterial dilation, is the most popular agent because it can be titrated rapidly to control blood pressure (Table 63-7 and Table 63-8). Intravenous nitroglycerin, another nitric oxide donor, is useful for reducing moderately elevated blood pressure in the setting of myocardial ischemia or infarction, but, compared with nitroprusside, the lowering of blood pressure is less predictable. Nicardipine is a parenteral dihydropyridine CCB that is particularly useful in the postoperative cardiac patient. Fenoldopam is a selective dopamine-1 receptor agonist that causes both systemic and renal vasodilation, as well as increased glomerular filtration, natriuresis, and diuresis. Intravenous labetalol is an effective treatment of hypertensive crisis particularly in the setting of myocardial ischemia with preserved ventricular function.

Oral Medications for Hypertensive Urgencies.

Most patients who present to the emergency department with hypertensive urgencies either are noncompliant with their medical regimen or are being treated with an inadequate regimen. To expedite the necessary changes in medications, outpatient follow up should be arranged within 72 hours. To manage the patient during the short interim period, labetalol is effective in a dose of 200 to 300 mg, which can be repeated in 2 to 3 hours and then prescribed in twice-daily dosing. If a β-blocker is contraindicated, clonidine is effective in an initial dose of 0.1 or 0.2 mg followed by additional hourly doses of 0.1 mg. Patients can be discharged on 0.1 to 0.2 mg twice daily. Captopril, a short-acting ACE inhibitor, lowers blood pressure within 15 to 30 minutes of oral dosing. A small test dose of 6.25 mg should be used to avoid an excessive fall in blood pressure in hypovolemic patients; then, the full oral dose is 25 mg, which can be repeated in 1 to 2 hours and prescribed as 25–75 mg twice daily.

Page: < Back 1 2 3 4 5 6 7 Next >