High Blood Pressure / Hypertension

Hypertension

By Cardiologist on July 7th, 2011

The treatment of hypertension has been strongly influenced by the results of powerful controlled clinical trials over the past three decades and the increasing availability of novel antihypertensive drugs. In order to provide optimal therapy to individual patients, practitioners must keep abreast of developments in this broad field, which includes important elements of preventive cardiology. This section provides a foundation for therapy based on sound principles of clinical pharmacology and evidence-based medicine.

Definition and epidemiology

Hypertension is important because elevated blood pressure confers a greater risk of stroke, heart failure, renal disease, peripheral vascular disease, and coronary artery disease including angina, myocardial infarction, and sudden death. There is a continuous, direct relationship between elevations in blood pressure and increases in these risks. The US Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of Hypertension (Joint National Committee 1997) defined hypertension as a blood pressure greater than 140/90 (systolic/diastolic) mm Hg taken under defined conditions and graded the severity of the elevation of blood pressure into the following categories: stage 1 (systolic blood pressure 140–159 or diastolic blood pressure 90–99 mm Hg), stage 2 (systolic blood pressure 160–179 or diastolic blood pressure 100–109 mm Hg), or stage 3 (systolic blood pressure ≥ 180 mg Hg or diastolic blood pressure ≥ 110 mm Hg). The extent to which blood pressure is elevated plays a role in determining the pace at which the problem should be evaluated and treated. In addition, preexisting cardiovascular risk factors or target-organ damage may have a major impact on the stringency of treating hypertension in individual patients. In general, the higher the blood pressure and the greater the number of risk factors, the greater the urgency and stringency used in treating hypertension. Lowering blood pressure is just one way to prevent complications; attention must also be paid to the presence and reversal of other cardiovascular risk factors such as cigarette smoking, lipid disorders, and especially diabetes. Diabetes is observed more frequently in patients with hypertension, and diabetics have a high prevalence of hypertension. The coexistence of these risk factors greatly increases the likelihood of cardiovascular complications associated with hypertension. The presence of these risk factors should be determined during the evaluation of patients with hypertension by careful history-taking and physical examination, coupled with relatively simple laboratory tests.

Benefits versus risks of therapy

There is now overwhelming clear and convincing evidence from randomized clinical trials, some conducted decades ago, that the treatment of what was then termed moderate (diastolic blood pressure 105–114 mm Hg) or severe hypertension (diastolic blood pressure ≥ 115 mm Hg) is efficacious in the prevention of clinically important endpoints such as stroke and congestive heart failure. Antihypertensive therapy decreases risk of stroke along the lines forecast from epidemiological studies demonstrating increased risk with elevated blood pressure. However, the effects of antihypertensive therapy have been more limited than expected for improvements in risks of the complications from coronary artery disease, particularly myocardial infarction. For what has been called mild hypertension (diastolic blood pressure ≥ 105 mm Hg), results have varied more substantially in different clinical trials. Nonetheless, there is good evidence that treatment of mild hypertension has efficacy, especially in patients over age 50 and those at higher risk owing to coexisting cardiovascular risk factors such as smoking, hyperlipidemia, and diabetes. Indeed, as a general rule, the greater the risk of complications in hypertensives, the greater the absolute benefit as a consequence of treating the elevated blood pressure. Diabetics with hypertension in the Systolic Hypertension in the Elderly Program [Cooperative Research Group 1993], SYST–EUR, and HOT studies all had improved outcomes when subjected to active or more aggressive blood pressure lowering. The ≥80 mm Hg target group in the HOT study had a 50% reduction in major cardiovascular events compared with the ≥90 mm Hg target group, from more than 24 events per 1000 patient years to less than 12 events per 1000 patient years.

The first step in treating mildly hypertensive patients should be to institute potentially effective nonpharmacologic therapies where appropriate (e.g., weight loss, sodium restriction, curtailment of alcohol intake, smoking cessation, and increased exercise) for 3–6 months. If diastolic pressure remains greater than 95 mm Hg, then drug therapy should then be instituted. This conservative approach avoids premature overtreatment of patients with drugs.

Principles

Discovering a disease does not always justify pharmacologic treatment even when such treatment has been proved efficacious.

Diagnosis

Because the benefits of drug therapy in mild hypertensive patients are limited and the risks and the costs are shared by all those treated, the one should carefully measure blood pressure to avoid overdiagnosis and overtreatment (Joint National Committee 1997).

Principles

Proper therapy begins with proper diagnosis. Especially for those with modest elevations in blood pressure and no other cardiovascular risk factors, repeated measurements over a period of months, coupled with nonpharmacologic approaches to lowering blood pressure, are appropriate before considering the use of antihypertensive medications.

Risk evaluation must consider both the extent of blood pressure elevation and other cardiovascular risk factors. When the number of patients needed to be treated to prevent an undesirable clinical outcome such as stroke or myocardial infarction is very large, the costs of treatment and the potential for adverse drug events may outweigh potential benefits of therapy.

Pathophysiology

Systemic hemodynamics

The term essential hypertension arose generations ago because physicians thought that high blood pressure was “essential” for adequate tissue perfusion in patients with extensive blood vessel narrowing. Although the foundation for the term is now viewed as ironically incorrect, its use persists. It is preferable to refer to hypertension as either primary hypertension (cause unknown) or secondary hypertension associated with a known cause, such as pheochromocytoma. Only a small portion of all patients with hypertension have an underlying disease known to raise blood pressure.

Knowledge of simple hemodynamics provides a rationale for understanding hypertension and its therapy. Blood pressure is the product of cardiac output and systemic vascular resistance (blood pressure=cardiac output × systemic vascular resistance). Increases in either cardiac output or peripheral resistance can produce hypertension. Cardiac output can increase as a function of increased myocardial contractility, heart rate, or venous return. Venous return is a function of the total blood volume (regulated by the kidney) and the percentage of blood volume circulating centrally (regulated by venous tone). Arteriolar smooth muscle tone is the major determinant of systemic vascular resistance.

Because early in the course of hypertension there is frequently a high cardiac output and normal peripheral resistance, elevation in cardiac output may be the initial hemodynamic alteration in primary hypertension. When cardiac output increases, autoregulation ensues to maintain constant blood flow to tissues. The increased flow from increased cardiac output is therefore countered by vasoconstriction. This is often called functional autoregulation. As well, however, blood vessel walls can hypertrophy slowly in response to increased flow (structural autoregulation). The thickened arteriolar walls will cause disproportionate luminal narrowing for any given constrictor stimulus and amplify the tendency toward hypertension. This concept has therapeutic implications. As blood pressure is controlled, structural changes may slowly regress. With increasing duration of therapy, lesser degrees of antihypertensive therapy may suffice for maintenance of the reduction in pressure. Theoretically, this concept justifies attempts to decrease or withdraw therapy once pressure has been normalized with drugs for some time (e.g., 6–12 months).

The kidney

The kidney contributes in many ways to the control of blood pressure (see chapter 6, Renal Disorders and the Influence of Renal Function of Drug Disposition). Renin released from renal juxtaglomerular cells activates the renin–angiotensin–aldosterone axis. Renal prostaglandins and renomedullary lipids are vasodilators. However, the paramount role of the kidney in relation to control of blood pressure is regulation of blood volume. When blood pressure rises for any reason, the kidney can excrete more sodium, which lowers blood volume. In turn, the lowering of blood volume tends to decrease cardiac output and to restore pressure toward normal. From this point of view, blood pressure can be restored toward normal as long as the kidneys are functioning appropriately. Guyton (1989) hypothesized that for hypertension to exist there has to be a defect in the ability of the kidney to excrete sodium in response to a rise in blood pressure. In other words, for any given rise in blood pressure, the abnormal “hypertensive” kidney will excrete less sodium than will a normal kidney. Transplantation experiments have provided evidence to support this hypothesis; namely, transplanting a kidney from a normotensive to a nephrectomized hypertensive rat normalizes blood pressure, whereas transplantation of a hypertensive rat’s kidney into a normotensive control rat can cause hypertension.

The sympathetic nervous system

The sympathetic nervous system plays a major role in regulating both cardiac output and peripheral resistance. Blood pressure is monitored by arterial baroreceptors that transmit signals to brainstem vasomotor centers. This information is processed and coordinated with information from other areas in the brain, leading to the determination of sympathetic efferent tone. Efferent sympathetic fibers descend into the spinal cord and exit the spinal cord as preganglionic neurons. These exiting fibers then lead to sympathetic ganglia, which activate postganglionic neurons by releasing the neurotransmitter acetylcholine. These neurons, which predominantly use norepinephrine as neurotransmitter, modulate target organs throughout the body. For example, noradrenergic postganglionic neurons are found in the heart, where they increase contractility and heart rate; in arterioles, where they may enhance vasoconstriction; and in veins, where they promote smooth muscle contraction. In the kidneys, sympathetic neurons promote the secretion of renin. Secretion of renin leads to formation of angiotensin II, which enhances vasoconstriction as well as sodium retention via aldosterone effects. Elevated sympathetic nervous system activity may result in transient or sustained hypertension. Other preganglionic nerves innervate the adrenal medulla and stimulate secretion of epinephrine. Epinephrine then circulates as a hormone exerting direct sympathetic effects on distant cells. Conceptually, norepinephrine is the sympathetic neurotransmitter, and epinephrine is the circulating sympathomimetic hormone.

The catecholamines norepinephrine and epinephrine regulate cellular physiology by activating adrenergic receptors, which leads to multiple biological effects. There are three known types of adrenergic receptors, termed α₁-, α₂-, and β-adrenergic receptors. These receptors are part of the large family of cell surface receptors that signal intracellular effectors via activation of guanine nucleotide regulatory proteins (G proteins). Each of the three types of adrenergic receptors is currently known to have three molecularly cloned subtypes: α₁A, α₁B, and α₁D; α₂A, α₂B, and α₂C; and β₁, β₂, and β₃. These subtypes may share overlapping functions or may selectively activate other biologically important functions. This diversity of adrenergic receptors and their subtypes offers promise in the development of clinically significant selective adrenergic agonists and antagonists.

There is evidence that alterations in sympathetic nervous system activity may play an important pathophysiologic role in the maintenance of hypertension in some patients. As described below, there are a variety of valuable antihypertensive drugs that act on various components of the sympathetic nervous system or on adrenergic receptors. In addition, knowledge about the expression of adrenergic receptors on cells in many organs may suggest secondary (desirable or undesirable) effects of these drugs in the treatment of hypertension.

The renin–angiotensin–aldosterone axis

Renin is secreted by the kidney in response to a decrease in renal blood flow or delivery of sodium to the kidney (see chapter 6, Renal Disorders and the Influence of Renal Function of Drug Disposition). Renin secretion is also stimulated by β-adrenergic receptors in the kidney. Renin then converts angiotensinogen, made by the liver, into angiotensin I, a decapeptide. Angiotensin-converting enzyme, which is produced mainly in the lung, then cleaves angiotensin I into angiotensin II, an octapeptide and potent vasoconstrictor. Angiotensin II acts on the zona glomerulosa of the adrenal cortex, causing secretion of aldosterone that enhances reabsorption of Na⁺ from the distal renal tubule in exchange for H⁺ and K⁺, which are excreted in the urine. Activation of the renin system raises blood pressure via enhanced vasoconstriction (angiotensin II) and via increased cardiac output secondary to sodium retention (aldosterone). Angiotensin II activates biological responses via stimulation of two receptor subtypes, called AT₁ and AT₂ receptors. Angiotensin receptors (and local renin–angiotensin systems expressed in cardiovascular tissues) may also have importance in stimulating cardiac hypertrophy and vascular remodeling in patients with hypertension.

There are many other known factors and neurotransmitters involved in blood pressure regulation. These include serotonin, nitric oxide, endothelin and other peptides, as well as prostaglandins and ion pumps and channels. Some of these are the targets for available antihypertensive drugs, whereas others are possible sites for the action of experimental drugs.

Antihypertensive drugs

Drugs that inhibit adrenergic nervous system effects

Drugs that inhibit the effects of the adrenergic nervous system were among the first used to treat hypertension. This discussion includes those drugs that are clinically useful today. Adrenergic inhibiting drugs act either to decrease the amount of norepinephrine and epinephrine released from adrenergic terminals and the adrenal medulla or to block the effects of norepinephrine and epinephrine at α- and β-adrenergic receptors. Centrally acting drugs such as clonidine may reduce catecholamine release by stimulating areas of the brain that inhibit sympathetic outflow. Peripherally acting drugs such as reserpine and guanethidine work by depleting the peripheral adrenergic neurons of their catecholamine stores.

Clonidine and related drugs

Pharmacology and mechanism of action

Clonidine, a partial α₂-adrenergic agonist, was developed as a nasal vasoconstricting decongestant. Because of its nasal decongestant action, investigators anticipated that clonidine would increase blood pressure; however, it was found to actually lower blood pressure in humans. Clonidine that enters the brain has a major effect of inhibiting sympathetic outflow by activating receptors in the vasomotor center, leading to decreased systemic blood pressure. Guanabenz and guanfacine are more recently developed derivatives of clonidine. They probably have many similar actions, although their relative potencies differ from that of clonidine.

The hemodynamic effects of clonidine include decreased peripheral vascular resistance, heart rate, and cardiac output. All probably are related to decreased sympathetic (and secondarily to decreased renin) system(s) activity. In addition, when taken orally, clonidine may enhance vagal tone, which further slows resting heart rate. It has a bioavailability of about 65%. A small dose (0.1 mg) decreases blood pressure in 30 minutes, with a maximum effect achieved in 2–4 hours. The total duration of effect is up to 12 hours. Its plasma half-life is 6–12 hours and doubles in patients with renal failure. The duration of action of guanfacine may be sufficiently long to allow once daily administration (usually at night so that adverse consequences of sedation are minimized). Clonidine should be given at least twice daily for satisfactory control of blood pressure throughout the day. Blood pressure can be further decreased at oral doses up to 1.2 mg or greater per day. However, the incidence and severity of adverse effects increase progressively with doses over 0.3 mg. The marked potency of clonidine has been exploited by the development of a transdermal delivery system using skin patches because sufficient quantities of the drug are systemically available by this route. A single patch can deliver 0.1, 0.2, or 0.3 mg/day continuously for up to 7 days. This delivery system may enhance patient compliance with this medication. Unfortunately, the patch also causes annoying local skin reactions in some patients.

Clinical use and adverse effects of clonidine

Clonidine is effective as monotherapy in divided doses of 0.2 to 1.0 mg/day. However, because of its adverse-effect profile, clonidine appears to be most useful when it is used as a second-line, low-dose, antiadrenergic agent — especially in patients with increased sympathetic tone caused by diuretics and/or vasodilators. Furthermore, clonidine is efficacious in a variety of other settings, including ameliorating the hot flushes in the female menopausal syndrome and diminishing symptoms in patients undergoing withdrawal from alcohol, opiates, or nicotine. As a consequence, clonidine may have some advantages in selected hypertensive patients who are trying to withdraw from the use of either alcohol or cigarettes. These all represent “two-for-one” uses in which a single drug can positively impact on more than one indication.

Principles

Seek settings in which a single drug can positively impact on more than one indication.

Sedation and dry mouth are common adverse effects. Other adverse effects include bradycardia, orthostatic hypotension, sleep disturbances, and male sexual dysfunction. Clonidine should generally be avoided or used very cautiously in patients with a history of mental depression. Abrupt discontinuation of clonidine following its chronic use can result in a rebound withdrawal syndrome that includes marked increases in blood pressure and heart rate plus anxiety, sweating, and related symptoms due to marked activation of the sympathetic nervous system. Although the incidence of this potentially life-threatening syndrome is unknown, the risk is probably increased in patients taking higher doses of clonidine and in patients with relatively severe and poorly controlled hypertension. Patients are at risk from marked acute rises in blood pressure and from increased myocardial oxygen demands. As a consequence, caution should be used in treating patients who tend to be noncompliant with medications. This group includes some alcoholics. The clonidine withdrawal syndrome can also theoretically occur with the addition of an α₂-adrenergic antagonist such as yohimbine.

Recommendations

The adrenergic inhibiting action of central α-adrenergic agonists given in low doses makes them a rational choice for treating hypertension in conjunction with other antihypertensive agents. They are very useful in treating diseases that tend to enhance autonomic reflexes. However, adverse effects may limit them as first-line therapeutic agents, and they should be avoided in patients whose concordance with therapy is likely to be poor.

α-Methyldopa

Pharmacology and mechanism of action

α-Methyldopa was introduced in 1960 and was a mainstay of antihypertensive therapy through the 1970s. α-Methyldopa must be transformed in the brain by being converted into active α₂-adrenergic agonists (methylnorepinephrine and methylepinephrine) before it exerts its antihypertensive actions. The α-adrenergic agonist metabolites of α-methyldopa stimulate areas in the brainstem (presumably via α-adrenergic receptors) that inhibit sympathetic nerve discharge in a manner similar to that of clonidine. Although α-methyldopa is an efficacious drug, the preeminent and limiting adverse effects of α-methyldopa are related to depression of central nervous system function, particularly lassitude and drowsiness. It has some unusual adverse effects including autoimmune abnormalities that increase with the dose and duration of exposure and include positive Coombs test (rarely leading to hemolytic anemia), positive antinuclear antibody tests with occasional lupus-like syndrome, and hepatocellular dysfunction. α-Methyldopa‘s interference with production of dopamine can sometimes unmask signs of Parkinsonism. In rare cases, α-methyldopa may cause a fever.

Recommendation

α-Methyldopa remains an effective and reasonably safe antihypertensive drug when used in the lower dose ranges up to 750 mg/day. Its safety during pregnancy-related hypertension is well established. Nonetheless, its general use in North America and Western European countries has declined markedly with the development of better tolerated medications.

Reserpine

Pharmacology and mechanism of action

Reserpine is one of the active extracts of the Indian snake root plant (Rauwolfia serpentina). It was first used by the ancient Egyptians to treat snake bite. Reserpine acts primarily by depleting peripheral norepinephrine through an interaction with storage vesicles in sympathetic nerve endings. There are analogous actions on storage vesicles for norepinephrine and serotonin in the central nervous system that may contribute to the drug’s efficacy and adverse effects. Lowered sympathetic activity produces a fall in peripheral vascular resistance with little or no change in cardiac output.

The half-life of the drug can be estimated from the 2–3 weeks required to reach its maximum antihypertensive effect and the similar time span required to return to baseline pressures after discontinuation of the drug (because recovery involves synthesis of new storage vesicles).

Clinical use and adverse effects of reserpine

Historically, reserpine has played a major role in the initiation of effective therapies for hypertension; its effectiveness is enhanced with a diuretic or other agents. Reserpine was used in the early clinical trials that demonstrated that antihypertensive drugs could decrease morbidity and mortality caused by hypertension. Low once-daily doses (e.g., 0.05 mg/day) combined with a thiazide are as effective as 0.25 mg/day alone (Veteran Administration Medical Centers 1982).

Reserpine can frequently cause severe depression. Suicide was common with the early use of high doses (>2 mg/day) of the drug. There is evidence that lower doses of reserpine (0.05–0.25 mg/day) are efficacious but also are associated with many fewer central nervous system effects. Adverse effects, especially fatigue, are similar to those encountered with other centrally acting agents. Nasal stuffiness may be prominent in some patients treated with reserpine.

Reserpine is an effective and very cheap antihypertensive; when used in low doses in combination with low-dose “diuretics” or other agents that do not inhibit the adrenergic nervous system, the drug appears to have only modest adverse effects. Reports of depression and suicide understandably have limited its use but may not be warranted when the drug is used at doses not exceeding 0.25 mg/day.

Principles

Once a drug has developed a compromised reputation, even when that reputation was based on use at excessive doses, it may be difficult for it to be resuscitated.

Guanethidine

Pharmacology and mechanism of action

Guanethidine inhibits the release of norepinephrine from peripheral sympathetic nerve endings. Guanadrel is a very similar drug with a shorter duration of action. Guanethidine is taken up in sympathetic neurons via the catecholamine transporter and then enters secretory granules from which it displaces norepinephrine, leading to depletion of this neurotransmitter from the nerve endings. Because the drug appears not to enter the central nervous system, this action seems to explain the peripheral vasodilation and decrease in blood pressure caused by guanethidine. Depletion of norepinephrine from sympathetic fibers in veins frequently occurs with this drug. Serious adverse effects of the drug are likely due to depletion of norepinephrine; these effects include postural hypotension that may be severe, retrograde ejaculation, and fluid retention. Diarrhea can become marked with guanethidine, although the mechanism of action for this effect is not understood. Because the adverse effects of the drug are so severe and almost inevitable, a therapeutic trial with guanethidine should only be considered in exceptional patients who do not respond to other available antihypertensive drugs or cannot tolerate them. This resistance is exceptional with currently available medications.

α-Adrenergic receptor antagonists

β-Adrenergic receptor antagonists

Angiotensin-converting enzyme inhibitors

Angiotensin II receptor antagonists

Calcium channel blockers

Direct vasodilators: hydralazine and minoxidil

Guidelines for managing the hypertensive patient

Clinical assessment

Obtaining a thorough patient history is important to determine the following:

• the duration and severity of hypertension
• nonpharmacologic and drug therapies that were or are being used with documented responses, including adverse effects
• the presence or absence of target-organ damage
• the presence or absence of other risk factors for atherosclerosis
• whether findings can be used to reveal secondary hypertension (not discussed here)
• whether other factors might be influencing or exacerbating blood pressure
• whether other drug needs or concomitant conditions in the patient might influence the choice of therapy for hypertension.

Patients with primary hypertension are generally asymptomatic unless target-organ damage has occurred. Headache is unusual except when pressure has increased over a short period of time or is very severe (diastolic pressure exceeding 120 mm Hg).

History of drug use should be recorded. Oral contraceptives, nonsteroidal anti-inflammatory drugs, and licorice-containing compounds (including candy and some forms of chewing tobacco) all can cause or worsen treated and untreated hypertension. Inquiries about diet, especially sodium and alcohol intake, weight change, and patterns of exercise help set priorities for eventual treatment. Assessment of cardiovascular risk factors, including the possible coexistence of diabetes mellitus, should have an important impact on decisions involving selection of drug candidates and therapeutic goals. Coexisting risk factors such as hyperlipidemia, age, family history of premature cardiovascular disease, cigarette smoking, and diabetes have a marked capacity to magnify the risks of any given level of hypertension. In many patients, relatively simple laboratory investigations, generally including measurement of plasma electrolytes, particularly the potassium concentration, assessment of renal function, and possibly an ECG are sufficient studies before initiating therapy.

Treatment

In the ambulatory patient, the main goal of treatment is to reduce the incidence of target-organ complications of hypertension, such as stroke and congestive heart failure. Also, successful treatment of hypertension reduces the risk that the blood pressure will rise to immediately life-threatening heights requiring emergency treatment.

A two-pronged approach to decrease the elevated blood pressure and decrease impact of coexistent cardiovascular risk factors when possible is optimal. The use of aspirin may play a particularly important role decreasing cardiovascular risk in patients with hypertension. The HOT study involved a factorial design in which half the patients in each blood pressure goal group received aspirin (75 mg once daily) or a matching placebo in a randomized, double-blind design. There was a 36% reduction in myocardial infarction rate in the aspirin-treated patients, from 3.6 to 2.3 myocardial infarctions per 1000 patient years. However, rates of both serious (requiring hospitalization) and less serious rates of bleeding were doubled in the aspirin-treated patients. Because of this trade-off between myocardial infarction on the one hand and serious bleeding on the other, aspirin may not be appropriate for every patient with hypertension. The most useful role for aspirin is likely in older hypertensive patients who have other risk factors for myocardial infarction.

Principles

Trade-offs in medicine are common, and they involve benefits versus risks and benefits versus costs. Patients must be involved in discussions that include consideration of trade-offs.

Nonpharmacologic therapy

Keep in mind that these measures are not always benign and that they should be subjected to the same scrutiny as drug therapy for their efficacy and toxicity. For example, about 50% of the hypertensive population responds to salt restriction with reductions in blood pressure. However, it is fruitless to subject a consult-sensitive hypertensive to restrictive maneuvers that ultimately may compromise compliance with more useful measures. The typical Western diet includes 150–300 mEq of sodium per day. Modest salt restriction to 60–90 mEq can be used as a 4-week trial of therapy in hypertensive patients. If there is no effect on blood pressure, rigorous salt restriction should be discontinued. Periodic 24-hour or spot urinary sodium determinations can help monitor the overall intake of salt and encourage compliance.

Obesity confers an increased risk for cardiovascular disease, either directly or via the association of glucose intolerance and insulin resistance, low high-density lipoprotein and high low-density lipoprotein cholesterol, or hypertension. Once blood pressure has been carefully documented in an obese hypertensive patient, weight reduction should be implemented (or at least attempted). Other dietary factors have been studied in hypertensive patients, but their effectiveness is controversial. Diets containing high potassium, magnesium, and calcium intakes have been reported to lower pressure, although their clinical utility is uncertain.

Alcohol and nicotine are commonly used compounds that can raise blood pressure in susceptible people. Hypertensive patients drinking more than two standard drinks per day should be encouraged to undertake a therapeutic trial of stopping or decreasing ethanol intake in order to determine its effect on their individual blood pressure. Of course, every cigarette smoker should be helped to quit.

Aerobic exercise such as walking, jogging, or swimming for at least 30 minutes at least three times weekly can reduce blood pressure. On the other hand, isometric exercise may markedly increase blood pressure.

Principles

Substantial progress toward a therapeutic endpoint may be made when multiple maneuvers (no one of which has dramatic efficacy) are combined to accomplish the same goal.

Drug therapy

General principles of antihypertensive drug therapy

Hypertension in the elderly

Secondary hypertension

Hypertension during pregnancy

Hypertension during pregnancy is defined as blood pressure greater than 140/90 mm Hg or an increase of 30/15 mm Hg over baseline. It is important to differentiate hypertensive disorders encountered in pregnancy. The pregnant hypertensive patient may have chronic hypertension that developed before pregnancy or before the 20th week of gestation. The goal of treatment in these women is to control hypertension without exposing the fetus to undue risk. With the exception of calcium channel blockers, Angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists (contraindicated in pregnancy), most commonly used antihypertensive medications can be continued when a women becomes pregnant. Ii is interesting to note that the largest experience with an antihypertensive drug started during early pregnancy has probably been for α-methyldopa. Because of this, it remains a preferred drug in this setting. Although β-adrenergic antagonists are similarly efficacious in pregnancy, there is concern that use in early pregnancy may lead to retardation of fetal growth (Joint National Committee 1997).

A different problem in pregnant women is that of a previously normotensive woman who may develop pregnancy-induced hypertension. When this occurs in the third trimester and is associated with proteinuria and edema, the term preeclampsia is used.

Case scenarios for treatment of hypertension

Cases in hypertension

What would you do if you were asked to manage the following cases:

A 43 year-old Caucasian women, blood pressure 154/96?

• A 56-year-old woman of South Asian origin, blood pressure 144/88?
• A 74-year-old Caucasian man, blood pressure 176/84?
• A 68-year-old African-American man, blood pressure 184/112?
• A 36-year-old Hispanic woman, blood pressure 144/92?

With only this information, you would be hard pressed to make a rational decision. However, the clinical context of each case provided below will help make your management planning more solidly based. The short case histories are presented to test your knowledge of the management of hypertension under different clinical circumstances. We suggest that you answer the following questions:

• If the patient is not taking antihypertensive treatment, then should I begin treatment?
• If I should treat, then how; and should I consider nonpharmacologic therapy or drug treatments or both?
• If the patient is already on treatment, then should I discontinue or choose different treatment?
• Are other cardiovascular risk management strategies warranted?

Each vignette reflects a common clinical scenario. Review each case and select a particular treatment. The rationale and evidence for suggesting a particular approach are described below. It is hoped that this contextual approach will reinforce key learning issues presented in the chapter and reemphasize why we don’t merely “treat the numbers.”

Clinical Circumstances

Case history 1

Case 1 is a 43-year-old Caucasian woman with the following scenario: blood pressure 154/96, premenopausal, overweight but otherwise healthy, body mass index 28.3, single parent of two teenagers, “very stressed,” alimony payments often delayed, and no family history of hypertension or premature cardiovascular disease. Her lipid profile and blood glucose are unremarkable. She is a nonsmoker and consumes one to five standard drinks of alcohol each week.

Case management 1

If this level of blood pressure is confirmed under appropriate office conditions (using a large cuff if necessary), then this woman can be diagnosed as having stage 1 hypertension. Given her sex (i.e., female), premenopausal status, and lack of risk factors, she is at very low risk of a cardiovascular event within the next decade. However, her obesity, economic circumstances, and stressful lifestyle cannot be ignored. She should be counseled about weight reduction and a heart-healthy diet. Pharmacotherapy can be deferred until she has had at least 1 year of nonpharmacologic treatment. Her blood pressure, lipid status, and glucose tolerance should be monitored on an annual basis as long as she remains overweight with blood pressure at this level.

Case history 2

A 56-year-old woman of South Asian origin presents with the following: blood pressure 152/94, body mass index 28.6, type II diabetes for 6 years treated with oral hypoglycemic agents, and well-controlled blood sugars and glycosylated hemoglobin. Before antihypertensive therapy began, her blood pressure ranged from 160 to 182 mm Hg systolic and from 104 to 110 mm Hg diastolic. After a combination of Angiotensin-converting enzyme inhibitor and calcium channel blocking agent therapy, her blood pressure is now in the range of 140–146/86–90.

Case management 2

This patient likely suffers from metabolic syndrome X — a clustering of hypertension, obesity, late-onset diabetes, and hypertriglyceridemia with suboptimal high-density lipoprotein cholesterol level. Obesity in this disorder is generally of the android type (i.e., central or abdominal location rather than on the buttocks or thighs), and visceral adiposity is likely part of the pathophysiology of the disorder. Her cardiovascular risk is greatly enhanced by the combination of diabetes and hypertension. Although the potential to control her blood pressure might be considered “good,” she will benefit by setting a goal diastolic blood pressure at less than 80 through the use of a low-dose diuretic (e.g., 12.5 mg/day hydrochlorothiazide or equivalent) or a once-daily α-adrenergic receptor blocking agent (alpha-blocker) such as doxazosin or terazosin. Her glucose control and lipid profile should be monitored to ensure that thiazide therapy does not disturb her electrolyte or metabolic status.

Case history 3

This case is a 74-year-old Caucasian man who is in generally good general health apart from some urinary symptoms attributable to benign prostatic hyperplasia. He has the following scenario: body mass index 27.1 and gradually increasing blood pressure, which has been 170–176/76–84 during past 3 months. Results of an ECG showed intra-atrial conduction delay and repolarization changes, with occasional ventricular ectopic on rhythm strip.

Case management 3

This man has isolated systolic hypertension, which is usually defined as systolic blood pressure of 160 or greater and diastolic blood pressure of less than 90. A low-dose thiazide diuretic (e.g., 12.5 mg/day hydrochlorothiazide or equivalent) or a long-acting, once-daily dihydropyridine calcium channel blocking is recommended. A β-adrenergic receptor blocking agent (beta-blocker) may be added but is not recommended as first-line therapy. Some would argue that his ECG changes are a relative contraindication to the use of a diuretic, whereas his prostatic symptoms may suggest the preferential use of an alpha-blocker. A low-dose thiazide/alpha-blocker combination or a low-dose calcium channel blocking/alpha-blocker combination will likely be effective in controlling systolic blood pressure, reducing cardiovascular risk, and improving urinary track symptoms in this man, perhaps deferring the need for prostatectomy.

Case history 4

A 68-year-old African-American man has the following clinical circumstance: body mass index 23, formerly a heavy smoker, an myocardial infarction at age 62, and a below-the-knee leg amputation at age 66. His blood pressure before leg surgery was 146–152/92–96 while on calcium channel blocking therapy. He suffers from winter bronchitis with wheezing exacerbations that have required aerosol bronchodilators on visits to the emergency room and brief courses of oral steroids. His blood pressure was 184/112 and 178/110 on the last two consecutive visits. He carefully complies with current calcium channel blocking and beta-blocker therapy. Further examination reveals absent pulses below both femorals and a systolic–diastolic abdominal bruit.

Case management 4

This patient has several manifestations of arteriopathy. With recent deterioration in blood pressure control despite apparent concordance with treatment, progressive renal artery stenosis with secondary renovascular hypertension should be suspected. Appropriate diagnostic evaluation should be undertaken, and renal artery balloon angioplasty or surgical correction should be considered. Furthermore, his episodes of wheezing may be associated with acute viral bronchitis superimposed on his chronic obstructive airways disease, but a beta-blocker may aggravate bronchoconstriction and should be discontinued. Moreover, there are suitable alternatives such as Angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT₁) blocking agents that are more likely to control blood pressure in the setting of renovascular disease. Serum potassium values and renal function should be monitored carefully, especially in the setting of bilateral renal artery disease that is not amenable to revascularization.

Case history 5

This is a 36-year-old Hispanic woman who is 32 weeks pregnant. She presents with blood pressure 110–114/66–72 and body mass index 26.5 when first seen between 8 and 12 weeks of pregnancy. There is no family history of hypertension. Her current blood pressure is 144/92, and she has mild ankle swelling but no proteinuria.

Case management 5

There is clearly documented de novo increase in blood pressure in this woman, in association with her pregnancy. Although her blood pressure would not be noteworthy otherwise, the blood pressure increase, associated with ankle edema, is consistent with the diagnosis of preeclampsia that threatens both the health of the developing child and the mother herself. Rest should be encouraged, with the use of α-methyldopa or one of the beta-blockers that has a good record of safety such as atenolol. Delivery is commonly expedited between 36 and 38 weeks if blood pressure control is inadequate or if fetal development is threatened.

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