General Principles

Hypertension is defined as the presence of a blood pressure (BP) elevation to a level that places patients at increased risk for target organ damage in several vascular beds including the retina, brain, heart, kidneys, and large conduit arteries (Table 3-1 and Table 3-2).

Table 3-1: Manifestations of Target Organ Disease
Organ SystemManifestation
Large vesselAneurysmal dilation
Accelerated atherosclerosis
Aortic dissection
CardiacAcute: Pulmonary edema, myocardial infarction
Chronic: Clinical or ECG evidence of CAD; LVH by ECG or echocardiogram
CerebrovascularAcute: Intracerebral bleeding, coma, seizures, mental status changes, TIA, stroke
Chronic: TIA, stroke
RenalAcute: Hematuria, azotemia
Chronic: Serum creatinine >1.5 mg/dL, proteinuria >1+ on dipstick
RetinopathyAcute: Papilledema, hemorrhages
Chronic: Hemorrhages, exudates, arterial nicking

CAD, coronary artery disease; LVH, left ventricular hypertrophy; TIA, transient ischemic attack.

Table 3-2: Classification of Blood Pressure for Adults Age 18 Years and Oldera
CategorySystolic Pressure 
(mm Hg)Diastolic Pressure 
(mm Hg)
Elevated blood pressure120–129<80
Hypertension, stage 1130–13980–89
Hypertension, stage 2≥140≥90

Data from Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2018;71:e127-e248.  [PMID:29146535]

aNot taking antihypertensive drugs and not acutely ill. When systolic and diastolic pressures fall into different categories, the higher category should be selected to classify the individual’s blood pressure status.


  • Normal BP is defined as systolic blood pressure (SBP) <120 mm Hg and diastolic blood pressure (DBP) <80 mm Hg; pharmacologic intervention is not indicated.
  • Elevated blood pressure is defined as SBP of 120–129 mm Hg and DBP of <80 mm Hg. These patients should engage in comprehensive lifestyle modifications to delay progression or prevent the development of hypertension.
  • In stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg), pharmacologic therapy should be initiated in addition to lifestyle modification in patients with diabetes mellitus (DM), chronic kidney disease (CKD), clinical cardiovascular disease (CVD), or age ≥65 years to lower BP <130/80 mm Hg. In patients age ≥65, treatment to a BP goal of <130/80 mm Hg is recommended if therapy is tolerated without adverse side effects. In patients ≤65 years of age without DM, CKD, or clinical CVD, pharmacologic therapy should be initiated in addition to lifestyle modifications for primary prevention of CVD if the 10-year atherosclerotic cardiovascular disease (ASCVD) risk is ≥10%.1
  • In stage 2 hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg), pharmacologic therapy should be initiated in addition to lifestyle modification to lower BP to <130/80 mm Hg. Patients with BP levels >20/10 mm Hg above their treatment target will often require more than one medication to achieve adequate control, and a two-drug regimen may be initiated as initial therapy. Patients with an average BP of 180/120 mm Hg or greater require immediate therapy and, if symptomatic end-organ damage is present, hospitalization.1,2
  • Hypertensive crisis includes hypertensive emergencies and urgencies. It usually develops in patients with a previous history of elevated BP but may arise in those who were previously normotensive. The severity of a hypertensive crisis correlates not only with the absolute level of BP elevation but also with the rapidity of development because autoregulatory mechanisms have not had sufficient time to adapt.
    • Hypertensive urgencies are defined as a substantial increase in BP, usually with a DBP >120 mm Hg, and occur in approximately 1% of hypertensive patients. Hypertensive urgencies (i.e., upper levels of stage 2 hypertension, hypertension with optic disk edema, progressive end-organ complications rather than damage, and severe perioperative hypertension) warrant BP reduction within several hours.3
    • Hypertensive emergencies include accelerated hypertension, typically defined as an SBP >180 mm Hg and DBP >120 mm Hg presenting with headaches, blurred vision, or focal neurologic symptoms and malignant hypertension (which requires the presence of papilledema). Hypertensive emergencies require immediate BP reduction by 20%–25% over the first hour to prevent or minimize end-organ damage (i.e., hypertensive 
encephalopathy, intracranial hemorrhage, unstable angina [UA] pectoris, acute myocardial infarction [MI], acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, progressive renal failure, or eclampsia).
    • Isolated systolic hypertension, defined as an SBP ≥140 mm Hg and DBP <90, occurs frequently in the elderly (beginning after the fifth decade and increasing with age). Nonpharmacologic therapy should be initiated with medications added as needed to lower SBP to the appropriate level based on age and comorbidities.
    • Resistant hypertension is defined as BP ≥130/80 in hypertensive patients on ≥3 antihypertensive agents, one of which is a diuretic, or controlled BP on ≥ 4 antihypertensive agents. Causes of resistant hypertension include inaccurate BP measurement, inadequate regimen, nonadherence, ingestion of exogenous substances (e.g., decongestants, oral contraceptives, appetite suppressants, sympathomimetics, venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs], chlorpromazine, some herbal supplements [ma huang], steroids, NSAIDs, cyclosporine, caffeine, thyroid hormones, cocaine, alcohol use, erythropoietin) and secondary causes of hypertension.1


  • The public health burden of hypertension is enormous. According to the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, hypertension affects an estimated 103 million American adults.4 For nonhypertensive individuals aged 55–65 years, the lifetime risk of developing hypertension is 90%.5
  • Data derived from the Framingham Study have shown that hypertensive patients have a fourfold increase in cerebrovascular accidents and a sixfold increase in congestive heart failure (CHF) when compared with normotensive control subjects.
  • Disease-associated morbidity and mortality, including ASCVD, stroke, heart failure (HF), and renal insufficiency, increase with higher levels of SBP and DBP.
  • Over the last three decades, aggressive treatment of hypertension has resulted in a substantial decrease in death rates from stroke and coronary heart disease (CHD). Although the incidence of end-stage renal disease (ESRD) has stabilized and hospitalizations for CHF have overall decreased,6 BP control rates remain poor, with 53% of treated hypertensive patients with BP above target goal.4


  • BP rises with age. Other contributing factors include overweight/obesity, increased dietary sodium intake, decreased physical activity, increased alcohol consumption, and lower dietary intake of fruits, vegetables, and potassium.
  • Of all hypertensive patients, more than 90% have primary or essential hypertension. The remainder have secondary hypertension because of causes such as renal parenchymal disease, renovascular disease, pheochromocytoma, Cushing syndrome, primary hyperaldosteronism, coarctation of the aorta, obstructive sleep apnea, and uncommon autosomal dominant or autosomal recessive diseases of the adrenal–renal axis, which result in salt retention.


Clinical Presentation

  • BP elevation is usually discovered in asymptomatic individuals during routine health visits.
  • Optimal detection and evaluation of hypertension require accurate noninvasive BP measurement, which should be obtained in a seated patient with the arm resting level with the heart. A calibrated, appropriately fitting BP cuff (inflatable bladder encircling at least 80% of the arm) should be used because falsely high readings can be obtained if the cuff is too small.
  • Two readings should be taken, separated by 2 minutes on 2 separate occasions. SBP should be noted with the appearance of Korotkoff sounds (phase I) and DBP with the disappearance of sounds (phase V).
  • In certain patients, the Korotkoff sounds do not disappear but are present at 0 mm Hg. In this case, the initial muffling of Korotkoff sounds (phase IV) should be taken as the DBP. One should be careful to avoid reporting spuriously low BP readings because of an auscultatory gap, which is caused by the disappearance and reappearance of Korotkoff sounds in hypertensive patients and may account for up to a 25-mm Hg gap between true and measured SBP.
  • Hypertension should be confirmed in both arms, and the higher reading should be used.


  • History should seek to discover secondary causes of hypertension and note the presence of medications and supplements that can affect BP (e.g., decongestants, oral contraceptives, appetite suppressants, sympathomimetics, venlafaxine, tricyclic antidepressants, MAOIs, chlorpromazine, some herbal supplements [ma huang], steroids, NSAIDs, cyclosporine, caffeine, thyroid hormones, cocaine, alcohol use, erythropoietin).
  • A diagnosis of secondary hypertension should be considered in the following situations:
    • Age at onset younger than 30 years.
    • Onset of diastolic hypertension in persons older than 65 years.
    • Hypertension that is difficult to control after therapy has been initiated.
    • Stable hypertension that becomes difficult to control.
    • Resistant hypertension.
    • Clinical occurrence of a hypertensive crisis.
    • The presence of signs or symptoms of a secondary cause such as hypokalemia or metabolic alkalosis that is not explained by diuretic therapy.
  • In patients who present with significant hypertension at a young age, a careful family history may give clues to forms of hypertension that follow simple Mendelian inheritance.

Physical Examination

Physical examination should include investigation for target organ damage or a secondary cause of hypertension by noting the presence of carotid bruits, an S3 or S4, cardiac murmurs, neurologic deficits, elevated jugular venous pressure, rales, retinopathy, unequal pulses, enlarged or small kidneys, cushingoid features, and abdominal bruits.

Differential Diagnosis

  • Hypertension may be partly due to withdrawal from drugs, including alcohol, cocaine, and opioid analgesics. Rebound increases in BP may be seen in patients who abruptly discontinue antihypertensive therapy, particularly β-adrenergic antagonists and central α2-agonists (see Complications).
  • Cocaine and other sympathomimetic drugs (e.g., amphetamines, phencyclidine hydrochloride) can produce hypertension in the setting of acute intoxication and when the agents are discontinued abruptly after chronic use. Hypertension is often complicated by other end-organ insults, such as ischemic heart disease, stroke, and seizures. Phentolamine is effective in acute management, and sodium nitroprusside or nitroglycerin can be used as an alternative. β-Adrenergic antagonists should be avoided because of the risk of unopposed α-adrenergic activity, which can exacerbate hypertension.

Diagnostic Testing

  • Tests are needed to help identify patients with possible target organ damage, to assess cardiovascular risk, and to provide a baseline for monitoring the adverse effects of therapy.
  • Basic laboratory data should include urinalysis, hematocrit, plasma glucose, serum potassium, serum creatinine, calcium, uric acid, and fasting lipid levels.
  • Other testing includes ECG and chest radiography. Echocardiography may be of value for certain patients to assess cardiac function or detection of left ventricular hypertrophy (LVH).


  • The goal of treatment is to prevent long-term sequelae (i.e., target organ damage) while controlling other modifiable cardiovascular risk factors. BP should be reduced to a goal of <130/80 mm Hg. Discretion is warranted in prescribing medication to lower BP that may affect cardiovascular risk adversely in other ways (e.g., glucose control, lipid metabolism, uric acid levels).
  • In the absence of hypertensive crisis, BP should be reduced gradually to avoid end-organ (e.g., cerebral) ischemia.
  • Lifestyle modifications should be encouraged in all hypertensive patients regardless of whether they require medication (Table 3-3). These changes may have beneficial effects on other cardiovascular risk factors.
  • Barring an overt need for immediate pharmacologic therapy, most patients should be given the opportunity to achieve a reduction in BP over an interval of 3–6 months by applying nonpharmacologic modifications and pharmacologic therapies.
Table 3-3: Lifestyle Modifications and Effects
ModificationApproximate SBP Reduction (mm Hg)
Weight reduction (for every 10-kg weight loss)5–20
Adoption of DASH eating plan8–14
Dietary sodium reduction (intake <2 g/d)2–8
Physical activity (150 min/wk)4–9
Moderation of alcohol consumption (intake <2 drinks/d)2–4

DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure.


  • BP measurements should be performed on multiple occasions under nonstressful circumstances (e.g., rest, sitting, empty bladder, comfortable temperature) to obtain an accurate assessment of BP in a given patient.
  • Hypertension should not be diagnosed based on one measurement alone, unless it is >180/120 mm Hg or accompanied by target organ damage (i.e., hypertension urgency or emergency). Two or more abnormal readings should be obtained, preferably over a period of several weeks, before therapy is considered.
  • Care should also be used to exclude pseudohypertension, which usually occurs in elderly individuals with stiff, noncompressible vessels. A palpable artery that persists after cuff inflation (Osler sign) should alert the physician to this possibility.
  • Home and ambulatory BP monitoring can be used to assess a patient’s true average BP, which correlates better with target organ damage.7,8,9 Circumstances in which ambulatory BP monitoring might be of value include the following:
    • Suspected “white coat hypertension” (increases in BP associated with the stress of physician office visits), which should be evaluated carefully.
    • Evaluation of possible drug resistance, where suspected.


  • Initial drug therapy

    Drug interactions, cost, and coexistent factors such as age, race, angina, HF, renal insufficiency, LVH, obesity, hyperlipidemia, gout, and bronchospasm should be considered in initial drug choice. The BP response is usually consistent within a given class of agents; therefore, if a drug fails to control BP, another agent from the same class is unlikely to be effective. At times, however, a change within drug class may be useful in reducing adverse effects. The lowest possible effective dosage should be used to control BP, adjusted every 1–2 months as needed (Table 3-4).

    Table 3-4: Commonly Used Antihypertensive Agents by Functional Class
    Drugs by ClassPropertiesInitial DoseDosage 
Range (mg)
    β-Adrenergic Antagonists
    AtenololaSelective50 mg PO daily25–100
    BetaxololaSelective10 mg PO daily5–40
    BisoprololaSelective5 mg PO daily2.5–20
    MetoprololSelective50 mg PO bid50–450
    Metoprolol XLSelective50–100 mg PO daily50–400
    Nebivolola,bSelective with vasodilatory properties5 mg PO daily5–40
    NadololaNonselective40 mg PO daily20–240
    PropranololNonselective40 mg PO bid40–240
    Propranolol LANonselective80 mg PO daily60–240
    TimololNonselective10 mg PO bid20–40
    PindololISA5 mg PO daily10–60
    Labetalolα- and β-antagonist properties100 mg PO bid200–1200
    Carvedilolα- and β-antagonist properties6.25 mg PO bid12.5–50
    Carvedilol CRbα- and β-antagonist properties10 mg PO daily10–80
    AcebutololaISA, selective200 mg PO bid, 400 mg PO daily200–1200
    Calcium Channel Antagonists
    AmlodipineDHP5 mg PO daily2.5–10
    30 mg PO qid90–360
    Diltiazem LA
    180 mg PO daily120–540
    Diltiazem CD
    180 mg PO daily120–480
    Diltiazem XR
    180 mg PO daily120–540
    Diltiazem XT
    180 mg PO daily120–480
    IsradipineDHP2.5 mg PO bid2.5–10
    NicardipinebDHP20 mg PO tid60–120
    NifedipineDHP10 mg PO tid30–120
    Nifedipine XL (or CC)DHP30 mg PO daily30–90
    NisoldipineDHP20 mg PO daily20–40
    80 mg PO tid80–480
    Verapamil SR
    120 mg PO daily120–480
    Angiotensin-Converting Enzyme Inhibitorsc
    10 mg PO bid10–40
    25 mg PO bid–tid50–450
    5 mg PO daily2.5–40
    10 mg PO daily10–40
    10 mg PO daily5–40
    7.5 mg PO daily7.5–30
    10 mg PO daily5–80
    2.5 mg PO daily1.25–20
    1–2 mg PO daily1–4
    4 mg PO daily2–16
    Angiotensin II Receptor Blockersc
    40 mg PO daily40–80
    8 mg PO daily8–32
    600 mg PO daily600–800
    150 mg PO daily150–300
    20 mg PO daily20–40
    50 mg PO daily25–100
    40 mg PO daily20–80
    80 mg PO daily80–320
    Direct Renin Inhibitorc
    150 mg PO daily150–300
    ChlorthalidoneThiazide diuretic25 mg PO daily12.5–50
    HydrochlorothiazideThiazide diuretic12.5 mg PO daily12.5–50
    HydroflumethiazidebThiazide diuretic50 mg PO daily50–100
    IndapamideThiazide diuretic1.25 mg PO daily2.5–5
    MethyclothiazideThiazide diuretic2.5 mg PO daily2.5–5
    MetolazoneThiazide diuretic2.5 mg PO daily1.25–5
    BumetanideLoop diuretic0.5 mg PO daily (or IV)0.5–5
    Ethacrynic acidbLoop diuretic50 mg PO daily (or IV)25–100
    FurosemideLoop diuretic20 mg PO daily (or IV)20–320
    TorsemideLoop diuretic5 mg PO daily (or IV)5–10
    AmiloridePotassium-sparing diuretic5 mg PO daily5–10
    TriamterenebPotassium-sparing diuretic50 mg PO bid50–200
    EplerenoneAldosterone antagonist25 mg PO daily25–100
    SpironolactoneAldosterone antagonist25 mg PO daily25–100
    α-Adrenergic Antagonists
    1 mg PO daily1–16
    1 mg PO bid–tid1–20
    1 mg PO at bedtime1–20
    Centrally Acting Adrenergic Agents
    0.1 mg PO bid0.1–1.2
    Clonidine patch
    TTS 1/wk (equivalent to 0.1 mg/d release)0.1–0.3
    1 mg PO daily1–3
    4 mg PO bid4–64
    250 mg PO bid–tid250–2000
    Direct-Acting Vasodilators
    10 mg PO qid50–300
    5 mg PO daily2.5–100
    0.5 mg PO daily0.01–0.25

    aAdjusted in renal failure.

    bAvailable only in brand name. Assume all drugs are available in generic form unless otherwise denoted by superscript “b.”

    cRenal function should be considered for all angiotensin-converting enzyme inhibitors before initiation.

    DHP, dihydropyridine; ISA, intrinsic sympathomimetic activity; TTS, transdermal 
therapeutic system.

  • Diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) should be considered as first-line therapy for the general nonblack population, including those with diabetes (those with chronic kidney disease are discussed below). Multiple large randomized controlled trials have shown comparable effects on decreasing overall cardiovascular and cerebrovascular mortality for all four drug classes.2
  • In the general black population, including those with diabetes, a diuretic or CCB can be considered for first-line therapy. Data from the ALLHAT trial have shown decreased cardiovascular and cerebrovascular morbidity and mortality with the use of thiazide diuretics or CCB over an ACE inhibitor.10
  • In patients with chronic kidney disease stage 3 or higher, or CKD with albuminuria (>300 mg/d), initial or combination therapy with an ACE inhibitor or ARB is recommended.1
  • Additional therapy: When a second drug is needed, it should generally be chosen from among the other first-line agents.
  • Adjustments of a therapeutic regimen: Before considering a modification of therapy because of inadequate response to the current regimen, other possible contributing factors should be investigated. Poor patient compliance, use of antagonistic drugs (i.e., sympathomimetics, venlafaxine, tricyclic antidepressants, MAOIs, chlorpromazine, some herbal supplements [ma huang], steroids, NSAIDs, cyclosporine, caffeine, thyroid hormones, cocaine, erythropoietin), inappropriately high sodium intake, or increased alcohol consumption may be the cause of inadequate BP response. Secondary causes of hypertension should be considered when a previously effective regimen becomes inadequate and other confounding factors are absent.
  • Diuretics (see Table 3-4) are effective agents in the therapy of hypertension and have been shown to reduce the incidence of stroke and cardiovascular events. Several classes of diuretics are available, generally categorized by their site of action in the kidney.
  • Thiazide and thiazide-like diuretics (e.g., hydrochlorothiazide, chlorthalidone) block sodium reabsorption predominantly in the distal convoluted tubule by inhibition of the thiazide-sensitive Na/Cl cotransporter. Thiazide diuretics can produce weakness, muscle cramps, and impotence. Metabolic side effects include hypokalemia, hypomagnesemia, hyperlipidemia (with increases in low-density lipoproteins [LDLs] and triglyceride levels), hypercalcemia, hyperglycemia, hyperuricemia, hyponatremia, and rarely azotemia. Thiazide-induced pancreatitis has also been reported. Metabolic side effects may be limited when thiazides are used in low doses (e.g., hydrochlorothiazide, 12.5–25.0 mg/d).
  • Loop diuretics (e.g., furosemide, bumetanide, ethacrynic acid, torsemide) block sodium reabsorption in the thick ascending loop of Henle through inhibition of the Na/K/2Cl cotransporter and are the most effective agents in patients with renal insufficiency (estimated glomerular filtration rate [GFR] <35 mL/min/1.73 m). Loop diuretics can cause electrolyte abnormalities such as hypomagnesemia, hypocalcemia, and hypokalemia and can also produce irreversible ototoxicity (usually dose related and more common with parenteral therapy).
  • Spironolactone and eplerenone, potassium-sparing agents, act by competitively inhibiting the actions of aldosterone on the kidney. Triamterene and amiloride are potassium-sparing drugs that inhibit the epithelial Na+ channel in the distal nephron to inhibit reabsorption of Na+ and secretion of potassium ions. Potassium-sparing diuretics are weak agents when used alone; thus, they are often combined with a thiazide for added potency. Aldosterone antagonists reduce morbidity and mortality in heart failure with reduced ejection fraction and may have an additional benefit in improving myocardial function; this effect may be independent of its effect on renal transport mechanisms. Spironolactone and eplerenone can produce hyperkalemia. The gynecomastia that may occur in men and breast tenderness in women are not seen with eplerenone. Triamterene (usually in combination with hydrochlorothiazide) can cause renal tubular damage and renal calculi. Unlike thiazides, potassium-sparing and loop diuretics do not cause adverse lipid effects.
  • Calcium channel antagonists (see Table 3-4) generally have no significant central nervous system (CNS) side effects and can be used to treat diseases, such as angina pectoris, which can coexist with hypertension. Because of the concern that the use of short-acting dihydropyridine calcium channel antagonists may increase the number of ischemic cardiac events, they are not indicated for hypertension management11; long-acting agents are considered safe in the management of hypertension.12,13
    • Classes of calcium channel antagonists include diphenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine). The dihydropyridines include many newer second-generation drugs (e.g., amlodipine, felodipine, isradipine, and nicardipine), which are more vasoselective and have longer plasma half-lives than nifedipine. Verapamil and diltiazem have negative cardiac inotropic and chronotropic effects. Nifedipine also has a negative inotropic effect, but in clinical use, this effect is much less pronounced than that of verapamil or diltiazem because of peripheral vasodilation and reflex tachycardia. Less negative inotropic effects have been observed with the second-generation dihydropyridines. All calcium channel antagonists are metabolized in the liver; thus, in patients with cirrhosis, the dosing interval should be adjusted accordingly. Some of these drugs also inhibit the metabolism of other hepatically cleared medications (e.g., cyclosporine). Verapamil and diltiazem should be used with caution in patients with cardiac conduction abnormalities, and they can worsen HF in patients with decreased left ventricular function.
    • Side effects of verapamil include constipation, nausea, headache, and orthostatic hypotension. Diltiazem can cause nausea, headache, and rash. Dihydropyridines can cause lower extremity edema, flushing, headache, and rash. Calcium channel antagonists can also cause gingival hyperplasia. They have no significant effects on glucose tolerance, electrolytes, or lipid profiles.
  • Inhibitors of the renin–angiotensin system (see Table 3-4) include ACE inhibitors, ARBs, and a direct renin inhibitor.
    • ACE inhibitors may have beneficial effects in patients with concomitant HF or kidney disease. One study has also suggested that ACE inhibitors (ramipril) may significantly reduce the rate of death, MI, and stroke in patients without HF or low ejection fraction.14 Additionally, they can reduce hypokalemia, hypercholesterolemia, hyperglycemia, and hyperuricemia caused by diuretic therapy and are particularly effective in states of hypertension associated with a high renin state (e.g., scleroderma renal crisis). Side effects associated with the use of ACE inhibitors are infrequent. They can cause a dry cough (up to 20% of patients), angioneurotic edema, and hypotension, but they do not cause levels of lipids, glucose, or uric acid to increase. ACE inhibitors that contain a sulfhydryl group (e.g., captopril) may cause taste disturbance, leukopenia, and a glomerulopathy with proteinuria. Because ACE inhibitors cause preferential vasodilation of the efferent arteriole in the kidney, worsening of renal function may occur in patients who have decreased renal perfusion or who have preexisting severe renal insufficiency. ACE inhibitors can cause hyperkalemia and should be used with caution in patients with a decreased GFR who are taking potassium supplements or who are receiving potassium-sparing diuretics.
    • ARBs are a class of antihypertensive drugs that are effective in diverse patient populations.15 ARBs are useful alternatives in patients with HF who are unable to tolerate ACE inhibitors.16 Side effects of ARBs occur rarely but include angioedema, allergic reaction, and rash.
    • The direct renin inhibitor class consists of one agent, aliskiren, which is indicated solely for the treatment of hypertension (see Table 3-4). It may be used in combination with other antihypertensive agents; however, combined use with ACE inhibitors or ARBs is contraindicated in patients with diabetes and increases the risk of hyperkalemia17,18 (Food and Drug Administration [FDA] Drug Safety Communication, April 2012).
  • β-Adrenergic antagonists (see Table 3-4) are part of medical regimens that have been proven to decrease the incidence of stroke, MI, and HF. β-Adrenergic antagonists work via competitive inhibition of the effects of catecholamines at β-adrenergic receptors, which decreases heart rate and cardiac output. These agents also decrease plasma renin and cause a resetting of baroreceptors to accept a lower level of BP. β-Adrenergic antagonists cause release of vasodilatory prostaglandins, decrease plasma volume, and may also have a CNS-mediated antihypertensive effect.
    • Classes of β-adrenergic antagonists can be subdivided into those that are cardioselective, with primarily β1-blocking effects, and those that are nonselective, with β1- and β2-blocking effects. At low doses, the cardioselective agents can be given with caution to patients with mild chronic obstructive pulmonary disease, DM, or peripheral vascular disease. At higher doses, these agents lose their β1 selectivity and may cause unwanted effects in these patients. β-Adrenergic antagonists can also be categorized according to the presence or absence of partial agonist or intrinsic sympathomimetic activity (ISA). β-Adrenergic antagonists with ISA cause less bradycardia than do those without it. In addition, there are agents with mixed properties having both α- and β-adrenergic antagonist actions (labetalol and carvedilol). Nebivolol is a highly selective β-adrenergic antagonist that is vasodilatory through an unclear mechanism.
    • Side effects include high-degree atrioventricular block, HF, Raynaud phenomenon, and impotence. Lipophilic β-adrenergic antagonists, such as propranolol, have a higher incidence of CNS side effects including insomnia and depression. Propranolol can also cause nasal congestion. β-Adrenergic antagonists can cause adverse effects on the lipid profile; increased triglyceride and decreased high-density lipoprotein (HDL) levels occur mainly with nonselective β-adrenergic antagonists but generally do not occur when β-adrenergic antagonists with ISA are used. Pindolol, a selective β-adrenergic antagonist with ISA, may increase HDL and nominally increase triglycerides. Side effects of labetalol include hepatocellular damage, postural hypotension, a positive antinuclear antibody (ANA) test, a lupus-like syndrome, tremors, and potential hypotension in the setting of halothane anesthesia. Carvedilol appears to have a similar side effect profile to other β-adrenergic antagonists. Both labetalol and carvedilol have negligible effects on lipids. Rarely, reflex tachycardia may occur because of the initial vasodilatory effect of labetalol and carvedilol. Because β-receptor density is increased with chronic antagonism, abrupt withdrawal of these agents can precipitate angina pectoris, increases in BP, and other effects attributable to an increase in adrenergic tone.
  • Selective α-adrenergic antagonists such as prazosin, terazosin, and doxazosin have replaced nonselective α-adrenergic antagonists such as phenoxybenzamine (see Table 3-4) in the treatment of essential hypertension. Based on the ALLHAT trial, these drugs appear to be less efficacious than diuretics, CCBs, and ACE inhibitors in reducing primary end points of CVD when used as monotherapy.10

    Side effects of these agents include a “first-dose effect,” which results from a greater decrease in BP with the first dose than with subsequent doses. Selective α1-adrenergic antagonists can cause syncope, orthostatic hypotension, dizziness, headache, and drowsiness. In most cases, side effects are self-limited and do not recur with continued therapy. Selective α1-adrenergic antagonists may improve lipid profiles by decreasing total cholesterol and triglyceride levels and increasing HDL levels. Additionally, these agents can improve the negative effects on lipids induced by thiazide diuretics and β-adrenergic antagonists. Doxazosin specifically may be less effective at lowering SBP than thiazide diuretics and may be associated with a higher risk of HF and stroke in patients with hypertension and at least one additional risk factor for coronary artery disease (CAD).10

  • Centrally acting adrenergic agents (see Table 3-4) are potent antihypertensive agents. In addition to its oral dosage forms, clonidine is available as a transdermal patch that is applied weekly.

    Side effects may include bradycardia, drowsiness, dry mouth, orthostatic hypotension, galactorrhea, and sexual dysfunction. Transdermal clonidine causes a rash in up to 20% of patients. These agents can precipitate HF in patients with decreased left ventricular function, and abrupt cessation can precipitate an acute withdrawal syndrome (AWS) of elevated BP, tachycardia, and diaphoresis. Methyldopa produces a positive direct antibody (Coombs) test in up to 25% of patients, but significant hemolytic anemia is much less common. If hemolytic anemia develops secondary to methyldopa, the drug should be withdrawn. Severe cases of hemolytic anemia may require treatment with glucocorticoids. Methyldopa also causes positive ANA test results in approximately 10% of patients and can cause an inflammatory reaction in the liver that is indistinguishable from viral hepatitis; fatal hepatitis has been reported. Guanabenz and guanfacine decrease total cholesterol levels, and guanfacine can also decrease serum triglyceride levels.

  • Direct-acting vasodilators are potent antihypertensive agents (see Table 3-4) now reserved for refractory hypertension or specific circumstances such as the use of hydralazine in pregnancy.
    • Hydralazine in combination with nitrates is useful in treating patients with hypertension and HF with reduced ejection fraction (see Chapter 5, Heart Failure and Cardiomyopathy). Side effects of hydralazine therapy may include headache, nausea, emesis, tachycardia, and postural hypotension. Asymptomatic patients may have a positive ANA test result, and a hydralazine-induced systemic lupus-like syndrome may develop in approximately 10% of patients. Patients at greater risk for the latter complication include those treated with excessive doses (e.g., >400 mg/d), those with impaired renal or cardiac function, and those with the slow acetylation phenotype. Hydralazine should be discontinued if clinical evidence of a lupus-like syndrome develops and a positive ANA test result is present. The syndrome usually resolves with discontinuation of the drug, leaving no adverse long-term effects.
    • Side effects of minoxidil include weight gain, hypertrichosis, hirsutism, ECG abnormalities, and pericardial effusions.
  • Reserpine, guanethidine, and guanadrel (see Table 3-4) were among the first effective antihypertensive agents available. Currently, these drugs are not regarded as first- or second-line therapy because of their significant side effects.

    Side effects of reserpine include severe depression in approximately 2% of patients. Sedation and nasal stuffiness also are potential side effects. Guanethidine can cause severe postural hypotension through a decrease in cardiac output, a decrease in peripheral resistance, and venous pooling in the extremities. Patients who are receiving guanethidine with orthostatic hypotension should be cautioned to arise slowly and to wear support hose. Guanethidine can also cause ejaculatory failure and diarrhea.

  • Parenteral antihypertensive agents are indicated for the immediate reduction of BP in patients with hypertensive emergencies. Judicious administration of these agents (Table 3-5) may also be appropriate in patients with hypertension complicated by HF or MI. These drugs are also indicated for individuals who have perioperative hypertensive urgency or are in need of emergency surgery. If possible, an accurate baseline BP should be determined before the initiation of therapy. In the setting of hypertensive emergency, the patient should be admitted to an intensive care unit for close monitoring, and an intraarterial monitor should be used when available. Although parenteral agents are indicated as a first-line treatment in hypertensive emergencies, oral agents may also be effective in this group; the choice of drug and route of administration must be individualized. If parenteral agents are used initially, oral medications should be administered shortly thereafter to facilitate rapid weaning from parenteral therapy.
    • Sodium nitroprusside, a direct-acting arterial and venous vasodilator, is the drug of choice for most hypertensive emergencies (see Table 3-5). It reduces BP rapidly and is easily titratable, and its action is short lived when discontinued. Patients should be monitored very closely to avoid an exaggerated hypotensive response. Therapy for more than 48–72 hours with a high cumulative dose or renal insufficiency may cause accumulation of thiocyanate, a toxic metabolite. Thiocyanate toxicity may cause paresthesias, tinnitus, blurred vision, delirium, or seizures. Serum thiocyanate levels should be kept at <10 mg/dL. Patients on high doses (>2–3 mg/kg/min) or those with renal dysfunction should have serum levels of thiocyanate drawn after 48–72 hours of therapy. In patients with normal renal function or those receiving lower doses, levels can be drawn after 5–7 days. Hepatic dysfunction may result in accumulation of cyanide, which can cause lactic acidosis, dyspnea, vomiting, dizziness, ataxia, and syncope. Hemodialysis should be considered for thiocyanate poisoning. Nitrites and thiosulfate can be administered intravenously for cyanide poisoning.
      Table 3-5: Parenteral Antihypertensive Drug Preparations
      DrugAdministrationOnsetDuration of ActionDosageAdverse Effects and Comments
      FenoldopamIV infusion<5 min30 min0.1–0.3 μg/kg/minTachycardia, nausea, vomiting
      Sodium nitroprussideIV infusionImmediate2–3 min0.5–10 μg/kg/min (initial dose, 0.25 μg/kg/min for eclampsia and renal insufficiency)Hypotension, nausea, vomiting, apprehension; risk of thiocyanate and cyanide toxicity is increased in renal and hepatic insufficiency, respectively; levels should be monitored; must shield from light
      DiazoxideIV bolus15 min6–12 h50–100 mg q5–10min, up to 600 mgHypotension, tachycardia, nausea, vomiting, fluid retention, hyperglycemia; may exacerbate myocardial ischemia, heart failure, or aortic dissection
      LabetalolIV bolus5–10 min3–6 h20–80 mg q5–10min, up to 300 mgHypotension, heart block, heart failure, bronchospasm, nausea, vomiting, scalp tingling, paradoxical pressor response; may not be effective in patients receiving α- or β-antagonists
      IV infusion0.5–2 mg/min
      NitroglycerinIV infusion1–2 min3–5 min5–250 μg/minHeadache, nausea, vomiting. Tolerance may develop with prolonged use
      EsmololIV bolus1–5 min10 min500 μg/kg/min for first 1 minHypotension, heart block, heart failure, bronchospasm
      IV infusion50–300 μg/kg/min
      PhentolamineIV bolus1–2 min3–10 min5–10 mg q5–15minHypotension, tachycardia, headache, angina, paradoxical pressor response
      Hydralazine (for treatment of eclampsia)IV bolus10–20 min3–6 h10–20 mg q20min (if no effect after 20 mg, try another agent)Hypotension, fetal distress, tachycardia, headache, nausea, vomiting, local thrombophlebitis. Infusion site should be changed after 12 h
      Methyldopate (for treatment of eclampsia)IV bolus30–60 min10–16 h250–500 mgHypotension
      NicardipineIV infusion1–5 min3–6 h5 mg/h, increased by 1.0–2.5 mg/h q15min, up to 15 mg/hHypotension, headache, tachycardia, nausea, vomiting
      ClevidipineIV infusion2–4 min5–15 min1–2 mg/h, double dose every 90 seconds up to 16 mg/hHypotension, reflex tachycardia
      EnalaprilatIV bolus5–15 min1–6 h0.6255 mg q6hHypotension
    • Nitroglycerin given as a continuous IV infusion (see Table 3-5) may be appropriate in situations in which sodium nitroprusside is relatively contraindicated, such as in patients with severe coronary insufficiency or advanced renal or hepatic disease. It is the preferred agent for patients with moderate hypertension in the setting of acute coronary ischemia or after coronary artery bypass surgery because of its more favorable effects on pulmonary gas exchange and collateral coronary blood flow. In patients with severely elevated BP, sodium nitroprusside remains the agent of choice. Nitroglycerin reduces preload more than afterload and should be used with caution or avoided in patients who have inferior MI with right ventricular infarction and are dependent on preload to maintain cardiac output.
    • Labetalol can be administered parenterally (see Table 3-5) in hypertensive crisis, even in patients in the early phase of an acute MI, and is the drug of choice in hypertensive emergencies that occur during pregnancy. When given intravenously, the β-adrenergic antagonist effect is greater than the α-adrenergic antagonist effect. Nevertheless, symptomatic postural hypotension may occur with IV use; thus, patients should be treated in a supine position. Labetalol may be particularly beneficial during adrenergic excess (e.g., clonidine withdrawal, pheochromocytoma, post–coronary bypass grafting). Because the half-life of labetalol is 5–8 hours, intermittent IV bolus dosing may be preferable to IV infusion. IV infusion can be discontinued before oral labetalol is begun. When the supine DBP begins to rise, oral dosing can be initiated at 200 mg PO, followed in 6–12 hours by 200–400 mg PO, depending on the BP response.
    • Esmolol is a parenteral, short-acting, cardioselective β-adrenergic antagonist (see Table 3-5) that can be used in the treatment of hypertensive emergencies in patients in whom β-blocker intolerance is a concern. Esmolol is also useful for the treatment of aortic dissection. β-Adrenergic antagonists may be ineffective when used as monotherapy in the treatment of severe hypertension and are frequently combined with other agents (e.g., with sodium nitroprusside in the treatment of aortic dissection).
    • Nicardipine is an effective IV calcium channel antagonist preparation (see Table 3-5). Side effects include headache, flushing, reflex tachycardia, and venous irritation. Nicardipine should be administered via a central venous line. If it is given peripherally, the IV site should be changed q12h. Fifty percent of the peak effect is seen within the first 30 minutes, but the full peak effect is not achieved until after 48 hours of administration. Clevidipine, an IV calcium channel antagonist, has a quicker onset of action and shorter half-life than nicardipine.
    • Enalaprilat is the active de-esterified form of enalapril (see Table 3-5) that results from hepatic conversion after an oral dose. Enalaprilat (as well as other ACE inhibitors) has been used effectively in cases of severe and malignant hypertension. However, variable and unpredictable results have also been reported. ACE inhibition can cause rapid BP reduction in hypertensive patients with high renin states such as renovascular hypertension, concomitant use of vasodilators, and scleroderma renal crisis; thus, enalaprilat should be used cautiously to avoid precipitating hypotension. Therapy can be changed to an oral preparation when IV therapy is no longer necessary.
    • Diazoxide and hydralazine are only rarely used in hypertensive crises and offer little or no advantage to the agents discussed previously. It should be noted, however, that hydralazine is a useful agent in pregnancy-related hypertensive emergencies because of its established safety profile.
    • Fenoldopam is a selective agonist to peripheral dopamine-1 receptors, and it produces vasodilation, increases renal perfusion, and enhances natriuresis. Fenoldopam has a short duration of action; the elimination half-life is <10 minutes. The drug has important application as parenteral therapy for high-risk hypertensive surgical patients and the perioperative management of patients undergoing organ transplantation.
  • Oral loading of antihypertensive agents (captopril, clonidine, hydralazine, nifedipine) has been used successfully in patients with hypertensive crisis when urgent but not immediate reduction of BP is indicated.

    Oral clonidine loading is achieved by using an initial dose of 0.2 mg PO followed by 0.1 mg PO q1h to a total dose of 0.7 mg or a reduction in diastolic pressure of 20 mm Hg or more. BP should be checked at 15-minute intervals over the first hour, 30-minute intervals over the second hour, and then hourly. After 6 hours, a diuretic can be added, and an 8-hour clonidine dosing interval can begin. Sedative side effects are significant. Sublingual nifedipine has an onset of action within 30 minutes but can produce wide fluctuations and excessive reductions in BP. Because of the potential for adverse cardiovascular events (stroke/MI), sublingual nifedipine should be avoided in the acute management of elevated BP. Side effects include facial flushing and postural hypotension.

Special Considerations

  • Hypertensive crisis: In hypertensive emergency, control of acute or ongoing end-organ damage is more important than the absolute level of BP. BP control with a rapidly acting parenteral agent should be accomplished as soon as possible (within 1 hour) to reduce the chance of permanent organ dysfunction and death. A reasonable goal is a 20%–25% reduction of mean arterial pressure over a period of minutes to hours and then a reduction to normal BP over 24–48 hours. A precipitous fall in BP may occur in patients who are elderly, volume depleted, or receiving other antihypertensive agents. BP control in hypertensive urgencies can be accomplished more slowly and with use of oral antihypertensives. Excessive or rapid decreases in BP should be avoided to minimize the risk of cerebral hypoperfusion or coronary insufficiency. Normal BP can be attained gradually over several days as tolerated by the individual patient.
  • Aortic dissection
    • All patients with aortic dissection, including those treated surgically, require acute and chronic antihypertensive therapy to provide initial stabilization and to prevent complications (e.g., aortic rupture, continued dissection). Medical therapy of chronic stable aortic dissection should seek to maintain SBP ≤120 mm Hg and heart rate <60 bpm if tolerated.19 Antihypertensive agents with negative inotropic properties, including calcium channel antagonists, β-adrenergic antagonists, methyldopa, clonidine, and reserpine, are preferred for management in the postacute phase.
    • β-Blockers are considered the initial drug of choice and should precede vasodilator therapy. β-Blockers are effective in lowering the heart rate and counteracting the reflex tachycardia and increased inotropy seen with vasodilator therapy. IV labetalol has been used successfully as a single agent in the treatment of acute aortic dissection. Labetalol produces a dose-related decrease in BP and lowers contractility. It has the advantage of allowing for oral administration after the acute stage of dissection has been managed successfully. Esmolol, a cardioselective class intravenous β-adrenergic antagonist with a very short duration of action, may be preferable, especially in patients with relative contraindications to β-antagonists. If esmolol is tolerated, a longer-acting β-adrenergic antagonist should be used. In patients intolerant of β-blockade, CCBs diltiazem and verapamil may be used.
    • Vasodilator therapy in combination with β-blockade allows for more effective and rapid reduction in BP. Sodium nitroprusside is considered the initial vasodilator drug of choice because of the predictability of response and absence of tachyphylaxis. Nitroprusside alone causes an increase in left ventricular contractility and subsequent arterial shearing forces, which contribute to ongoing intimal dissection. Thus, when using sodium nitroprusside, adequate simultaneous β-adrenergic antagonist therapy is essential. Nicardipine, clevidipine, nitroglycerin, enalaprilat, and fenoldopam may also be used.
  • The elderly hypertensive patient (age >65 years) is generally characterized by increased vascular resistance, decreased plasma renin activity, and greater LVH than in younger patients. Often, elderly hypertensive patients have coexisting medical problems that must be considered when initiating antihypertensive therapy. SBP <140 mm Hg has been associated with decreased major adverse cardiovascular events.20,21

    Drug doses should be increased slowly to avoid adverse effects and hypotension. Diuretics as initial therapy have been shown to decrease the incidence of stroke, fatal MI, and overall mortality in this age group.22 Calcium channel antagonists decrease vascular resistance, have no adverse effects on lipid levels, and are also good choices for elderly patients. ACE inhibitors and ARBs may be effective agents in this population.

  • African American hypertensive patients generally have a lower plasma renin level, higher plasma volume, and higher vascular resistance than do Caucasian patients. Thus, African American patients respond well to diuretics, alone or in combination with calcium channel antagonists. ACE inhibitors, ARBs, and β-adrenergic antagonists are also effective agents in this population, particularly when combined with a diuretic.
  • The obese hypertensive patient is characterized by more modest elevations in vascular resistance, higher cardiac output, expanded intravascular volume, and lower plasma renin activity at any given level of arterial pressure. Weight reduction is the primary goal of therapy and is effective in reducing BP and causing regression of LVH.
  • The diabetic patient with nephropathy may have significant proteinuria and renal insufficiency, which can complicate management (see Chapter 13, Renal Diseases). Control of BP is the most important intervention shown to slow down loss of renal function. In the setting of proteinuria, ACE inhibitors should be used as first-line therapy because they have been shown to decrease proteinuria and to slow down progressive loss of renal function independent of their antihypertensive effects. ACE inhibitors may also be beneficial in reducing the rates of death, MI, and stroke in diabetics who have cardiovascular risk factors but lack left ventricular dysfunction. Hyperkalemia is a common side effect in diabetic patients treated with ACE inhibitors, especially in those with moderate to severe impairment of their GFR. ARBs are also effective antihypertensive agents and have been shown to slow down the rate of progression to ESRD, thus supporting a renal protective effect.23
  • The patient with chronic renal insufficiency has hypertension that usually is partially volume dependent. Retention of sodium and water exacerbates the existing hypertensive state, and diuretics are important in the management of this problem. When estimated GFR is <30–35 mL/min/1.73 m, loop diuretics are the most effective class. In the presence of proteinuria, ACE inhibitors/ARBs should be considered because higher urinary excretion of protein is associated with a more rapid decline in GFR, regardless of the cause of renal insufficiency.
  • The hypertensive patient with LVH is at increased risk for sudden death, MI, and all-cause mortality. Although there is no direct evidence, regression of LVH could be expected to reduce the risk for subsequent complications. Aggressive BP control and renin–angiotensin system blockade with ACE inhibitors/ARBs appear to have the greatest effect on regression.24,25,26
  • The hypertensive patient with CAD is at increased risk for UA and MI. β-Adrenergic antagonists can be used as first-line agents in these patients because they can decrease cardiac mortality and subsequent reinfarction in the setting of acute MI and can decrease progression to MI in those who present with UA. β-Adrenergic antagonists also have a role in secondary prevention of cardiac events and in increasing long-term survival after MI. Care should be exercised in those with cardiac conduction system disease. ACE inhibitors are beneficial in patients with CAD and decrease mortality in individuals who present with acute MI, especially those with left ventricular dysfunction.27,28,29,30
  • The hypertensive patient with heart failure with reduced ejection fraction (HFrEF) is at risk for progressive left ventricular dilatation and sudden death. Patients should be prescribed guideline-directed medical therapy to attain a BP <130/80 mm Hg. In this population, ACE inhibitors decrease mortality,28 and in the setting of acute MI, they decrease the risk of recurrent MI, hospitalization for HF, and mortality.31 ARBs have similar beneficial effects, and they appear to be an effective alternative in patients who are unable to tolerate an ACE inhibitor.16 β-Adrenergic antagonist therapy has been shown to decrease morbidity and mortality. Agents shown to have proven benefit include metoprolol succinate, carvedilol, and bisoprolol.12,32,33 Nitrates and hydralazine also decrease mortality in patients with HF irrespective of hypertension, but hydralazine can cause reflex tachycardia and worsening ischemia in patients with unstable coronary syndromes and should be used with caution. Mineralocorticoid receptor antagonists have been shown to decrease mortality in patients with HFrEF. Nondihydropyridine calcium channel antagonists should generally be avoided.
  • The hypertensive patient with heart failure with preserved ejection fraction (HFpEF) may present with signs of volume overload and thus diuretics may be used as initial therapy. The optimal treatment regimen for hypertension in patients with HFpEF is unclear. ACE inhibitors/ARBs have the greatest effect on regression of LVH and thus may improve diastolic function.34
  • In the pregnant patient with hypertension, there is concern for potential maternal and fetal morbidity and mortality associated with elevated BP and the clinical syndromes of preeclampsia and eclampsia. The possibility of teratogenic or other adverse effects of antihypertensive medications on fetal development also should be considered.
    • Classification of hypertension during pregnancy has been proposed by the American College of Obstetrics and Gynecology.35
      • Preeclampsia–eclampsia: Diagnosis is established if there is new-onset hypertension after 20 weeks of gestation and the presence of proteinuria. Elevated SBP ≥140 mm Hg or DBP ≥90 mm Hg on two occasions at least 4 hours apart or a one-time measurement of SBP ≥160 mm Hg or DBP ≥110 mm Hg qualifies as hypertension. If no proteinuria is present, then hypertension along with one of the following qualifies: platelets <100,000/μL, creatinine >1.1 mg/dL (or doubling from baseline), liver transaminases greater than twice the normal, pulmonary edema, or cerebral/visual symptoms. Eclampsia encompasses these parameters in addition to generalized seizures.
      • Chronic (preexisting) hypertension: This disorder is defined by a BP ≥140/90 mm Hg before the 20th week of pregnancy.
      • Chronic hypertension with superimposed preeclampsia: This classification is used when a woman with chronic hypertension develops worsening hypertension and new proteinuria and/or other features of preeclampsia as outlined previously.
      • Gestational hypertension: This disorder is defined by a BP ≥140/90 mm Hg after the 20th week of pregnancy without proteinuria or other features of preeclampsia.
    • Therapy: Treatment of hypertension in pregnancy should begin if SBP is ≥160 mm Hg or DBP is ≥100 mm Hg.
      • Nonpharmacologic therapy, such as weight reduction and vigorous exercise, is not recommended during pregnancy.
      • Alcohol and tobacco use should be strongly discouraged.
      • Pharmacologic intervention with labetalol, nifedipine, or methyldopa is recommended as first-line therapy because of its proven safety. Other antihypertensives have theoretical disadvantages, but none except the ACE inhibitors have been proven to increase fetal morbidity or mortality.
      • If a patient is suspected of having preeclampsia or eclampsia, urgent referral to an obstetrician who specializes in high-risk pregnancy is recommended.
  • MAOIs: MAOIs used in association with certain drugs or foods can produce a catecholamine excess state and accelerated hypertension. Interactions are common with tricyclic antidepressants, meperidine, methyldopa, levodopa, sympathomimetic agents, and antihistamines. Tyramine-containing foods that can lead to this syndrome include certain cheeses, red wine, beer, chocolate, chicken liver, processed meat, herring, broad beans, canned figs, and yeast. Nitroprusside, labetalol, and phentolamine have been used effectively in the treatment of accelerated hypertension associated with MAOI use (see Table 3-5).


Withdrawal syndrome associated with discontinuation of antihypertensive therapy: In substituting therapy in patients with moderate-to-severe hypertension, it is reasonable to increase doses of the new medication in small increments while tapering the previous medication to avoid excessive BP fluctuations. On occasion, an AWS develops, usually within the first 24–72 hours. Occasionally, BP rises to levels that are much higher than those of baseline values. The most severe complications of AWS include encephalopathy, stroke, MI, and sudden death. AWS is associated most commonly with centrally acting adrenergic agents (particularly clonidine) and β-adrenergic antagonists but has been reported with other agents as well, including diuretics. Discontinuation of antihypertensive medications should be done with caution in patients with preexisting cerebrovascular or cardiac disease. Management of AWS by reinstitution of the previously administered drug is generally effective.


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