Htn pharmacotherapy

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13HYPERTENSIONJoseph J. Saseen and Barry L. Carter

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The risk of cardiovascular morbidity and mortality is di-1rectly correlated with blood pressure (BP). Starting at a BP of115/75 mm Hg, risk of cardiovascular disease doubles withevery 20/10-mm Hg increase. Even patients with prehyper-tension have an increased risk of cardiovascular disease.Outcome trials have shown that antihypertensive drug ther-apy substantially reduces the risks of cardiovascular eventsand death.

Essential hypertension is usually an asymptomatic condi-2tion. A diagnosis cannot be made based on one elevated BPmeasurement. An elevated value from the average of twoor more measurements on two or more clinical encountersis needed to diagnose hypertension.

The overall goal of treating hypertension is to reduce3hypertension-associated morbidity and mortality. The se-lection of specific drug therapy is based on evidence thatdemonstrates risk reduction.

A goal BP of less than 140/90 mm Hg is appropriate for most4patients. Achieving lower BP values has not been provento provide additional risk reduction, except in patients withdiabetes or chronic kidney disease. These patients have agoal BP of less than 130/80 mm Hg.

Lifestyle modifications should be prescribed in all patients5with hypertension and prehypertension. However, theyshould never be used as a replacement for antihyperten-sive drug therapy in patients with hypertension.

Thiazide diuretics are first-line agents for the management6of hypertension in most patients. This recommendation is

supported by clinical trials showing reduced morbidity andmortality with these agents. Comparative data from thelandmark clinical trial, the ALLHAT, confirm the first-linerole of thiazide diuretics.

Compelling indications are comorbid conditions where7specific drug therapies have been shown in outcome trialsto provide unique long-term benefits. Drug therapy recom-mendations for compelling indications are either in combi-nation with or in place of a thiazide diuretic.

Patients with diabetes are at very high risk for cardiovascular8disease. All patients with diabetes and hypertension shouldbe managed with either an angiotensin-converting enzyme(ACE) inhibitor or an angiotensin II receptor blocker (ARB),typically in combination with one or more other antihy-pertensive agents. Multiple agents frequently are needed tocontrol BP.

Older patients with isolated systolic hypertension are of-9ten at risk for orthostatic hypotension when drug ther-apy is started. This is particularly prevalent with diuret-ics, ACE inhibitors, and ARBs. Although overall treatmentshould be the same, initial doses should be very lowand dose titrations gradual to minimize risk of orthostatichypotension.

Most patients require combination therapy to achieve goal10BP values. Combination regimens should include a diuretic,preferably a thiazide. If a diuretic was not the first drug, itshould be the second drug add-on therapy.

Hypertension is a common disease that is defined simply as persis-tently elevated arterial blood pressure (BP). Although elevated BP wasperceived to be necessary for adequate perfusion of essential organsduring the early and middle 1900s, it is now identified as one of themost significant risk factors for cardiovascular disease in the UnitedStates. Increasing awareness and diagnosis of hypertension and im-proving control of BP with appropriate treatment are considered crit-ical public health initiatives to reduce cardiovascular morbidity andmortality.

The Seventh Report of the Joint National Committee on theDetection, Evaluation, and Treatment of High Blood Pressure(JNC7) is the national clinical guideline that was developed to aidclinicians in the management of hypertension.1 This chapter reviewsrelevant components of this evidence-based guideline with a focuson the pharmacotherapy of hypertension. Data from the National

Health and Nutrition Examination Survey from 1999 to 2000 indi-cate that of the population of Americans with hypertension, 68.9%are aware that they have hypertension, and only 58.4% are on someform of antihypertensive treatment.2 Moreover, only 34% of all pa-tients have controlled BP, which increases to only 53.1% whenonly those on treatment are evaluated.2 Therefore, there are am-ple opportunities for clinicians to improve the care of hypertensivepatients.


It is estimated that approximately 30% of the population (50 millionAmericans) has high BP (140/90 mm Hg).2,3 Estimates from theNational Health and Nutrition Examination Survey from 19992000



indicate that the prevalence is 30.1% and 27.1% among men andwomen, respectively.2 This represents a significant increase of 5.6%in women from 1988 to 2000, whereas the prevalence in men hasremained unchanged. Prevalence rates are highest in non-Hispanicblacks (33.5%), followed by non-Hispanic whites (28.9%) andMexican-Americans (20.7%).

BP values increase with age, and hypertension is very common inthe elderly. The lifetime risk of developing hypertension among those55 years of age and older who are normotensive is 90%.1 Most patientshave prehypertension BP values before they are diagnosed with hy-pertension, and most hypertension diagnoses occur between the thirdand fifth decades of life. Up to the age of 55 years, more men thanwomen have hypertension. From the ages of 55 to 74 years, slightlymore women have hypertension than men, with this sex differencebecoming greater in the very elderly (75 years). In the older pop-ulation (age 60 years), the prevalence of hypertension is 65.4%(estimated in 2000), which is significantly higher than the 57.9%prevalence estimated in 1988.2


Hypertension is a heterogeneous medical condition. In most patients itresults from unknown pathophysiologic etiology (essential or primaryhypertension). While this form of hypertension cannot be cured, it canbe controlled. A small percentage of patients have a specific cause oftheir hypertension (secondary hypertension). There are many poten-tial secondary causes that are either concurrent medical conditionsor are endogenously induced. If the cause of secondary hypertensioncan be identified, hypertension in these patients potentially can becured.


Over 90% of individuals with hypertension have essential hyper-tension (primary hypertension).1 Numerous mechanisms have beenidentified that may contribute to the pathogenesis of this form ofhypertension, so identifying the exact underlying abnormality is notpossible. Hypertension often runs in families, indicating that geneticfactors may play an important role in the development of essen-tial hypertension. Data suggest that there are monogenic and poly-genic forms of BP dysregulation that may be responsible for essentialhypertension.4,5 Many of these genetic traits feature genes that affectsodium balance,5 but genetic mutations altering urinary kallikreinexcretion, nitric oxide release, aldosterone excretion, other adrenalsteroids, and angiotensinogen are also documented.4 In the future,identifying individuals with these genetic traits could lead to alterna-tive approaches to preventing or treating hypertension; however, thisis not currently recommended.


Fewer than 10% of patients have secondary hypertension, where ei-ther a comorbid disease or a drug is responsible for elevating BP1(see Table 131). In most of these cases, renal dysfunction resultingfrom chronic kidney disease or renovascular disease is the most com-mon secondary cause.6 Certain drugs, either directly or indirectly, cancause hypertension or exacerbate hypertension by increasing BP. Themost common agents are listed in Table 131. Some of these agents areherbal products. Although these are not technically drugs, they havebeen identified as causes of elevated BP and secondary hypertension.When a secondary cause is identified, removing the offending agentor treating/correcting the underlying comorbid condition should bethe first step in management.

TABLE 131. Secondary Causes of Hypertension

Disease Drugs Associated with Hypertension in Humans

Chronic kidney disease Prescription drugsCushings syndrome Corticosteroids,a ACTH

Coarctation of the aorta Estrogensa (usually oral contraceptives with high estrogenic activity)

Obstructive sleep apnea Nonsteroidal anti-inflammatory drugs,a COX-2 inhibitorsa

Parathyroid disease Phenylpropanolaminea and analoguesa

Pheochromocytoma Cyclosporinea and tacrolimusa

Primary aldosteronism Erythropoetina

Renovascular disease Sibutraminea

Thyroid disease Antidepressants (especially venlafaxine), bromocriptine, buspirone,

carbamazepine, clozapine, desfulrane, ketamine, metoclopramide

Clonidine/-blocker combination

Pheochromocytoma: -blocker without -blocker first

Street Drugs and Other Natural ProductsCocainea and cocaine withdrawala

Ma huang,a herbal ecstasy,a other phenylpropanolamine analoguesa

Nicotine and withdrawal, anabolic steroids, narcotic withdrawal,

methylphenidate, phencyclidine, ketamine, ergotamine and other

ergot-containing herbal products, St. Johns wort

Food SubstancesSodiuma



Tyramine-containing foods if taking a monoamine oxidase inhibitor

Chemical Elements and Other Industrial ChemicalsLead, mercury, thallium and other heavy metals, lithium

aAgents of most clinical importance.



A clear understanding of arteri