Pharmacy Times 

Epidemiology

Risk Factors

Risk Stratification

Pathophysiology

Assessment

SECTION 2
Management

Lifestyle Modification

Pharmacotherapy

Diuretics

Beta Blockers

ACE Inhibitors

Calcium Channel Blockers

Angiotensin-II Receptor Blockers

Alpha blockers

Central Adrenergic Inhibitors

Peripheral Adrenergic Inhibitors

Direct Vasodilators

SECTION 4
Step-down Therapy

Maximixing Medication Adherence

SECTION 5  

Outpatient Treatment of Hypertension: Possibilities for Pharmacist Intervention

Kristen H. Schwetschenau, PharmD
Dr. Schwetschenau is Assistant Professor of Pharmacy Practice
and a Clinical Pharmacist in Ambulatory Care

Temple University School of Pharmacy

Hypertension is a major health problem that pharmacists encounter in daily practice. Prevention and management of hypertension presents challenges for all health care providers. Practitioners not only need to have strong clinical decision-making skills but also the ability to effectively communicate with patients and their families. A strong knowledge base in the sciences as well as clinical decision-making and communication skills are needed to effectively facilitate assessment and management of individuals with hypertension. Effective communication and interpersonal relationships between pharmacists and patient/family can empower patients to participate in their care and adhere to a management plan.¹ 

Uncontrolled hypertension is a major risk factor for myocardial infarction (MI) and stroke, and a precursor for cardiovascular and renal disease. Hypertension is a serious health threat that affects 50 million to 60 million Americans. Although hypertension can be treated effectively by oral medication, poor control continues to be a major health care problem. It has been estimated that within the first year of treatment, 16% to 50% of patients discontinue their antihypertensive medication.² Another estimate states that 30% to 55% of patients with hypertension do not adhere to their prescribed medication regimen, with some patients taking less medication than prescribed and others taking more. 

Furthermore, it has been reported that only one half to one fourth of all hypertensive patients have their blood pressure under effective control.³ Recent data from the hypertensive Medicaid population found that therapeutic nonadherence was associated with higher total health care costs. Eighty-six percent of newly initiated antihypertensive drug therapy was interrupted or discontinued during the first year. This resulted in total medical costs that were $873 per patient higher during that same year compared with hypertensives who did not have therapy interrupted or discontinued.²

Adherence with medical recommendations for hypertensive patients will improve blood pressure control and, ultimately, reduce the risk of premature cardiovascular morbidity and mortality. One study showed that blood pressure begins to fall significantly only when patients take more than 80% of their medication.⁴

Bogden and colleagues assessed the effect of a physician and pharmacist team approach to uncontrolled hypertension in a medical resident clinic for patients who failed to meet the recommended goals of the fifth Joint National Commission on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). The study was designed to gauge the effect of pharmacist intervention on hypertension. The pharmacist emphasized diet, lifestyle modification, and adherence with prescribed medical regimens. At study completion, the percentage of patients achieving national goals because of pharmacist/physician intervention was more than double the percentage in the control arm of patients who received physician care only.⁵

Epidemiology

The etiology of hypertension may be due to an unknown cause (primary/essential hypertension) or there may be an identifiable cause (secondary hypertension). Approximately 26.5 million adults in the United States are being treated for hypertension. More than 90% of these patients have essential hypertension.⁶
In 1996, high blood pressure was listed on death certificates as the primary cause of death for 41,634 Americans. High blood pressure was listed as a primary or contributory cause of death in at least 202,000 of the 2 million deaths that year. About 50 million Americans have high blood pressure, which correlates to about 1 in 4 adults.⁷ 

A higher percentage of men than women under the age of 55 have high blood pressure. Between the ages of 55 and 74, the occurrence between men and women is about equal. After the age of 74, a higher percentage of women than men have high blood pressure. High blood pressure is two to three times more common in women taking oral contraceptives for 5 years or longer than in women not taking them. 
African Americans and Caucasians in the southeastern United States have a greater prevalence of high blood pressure and higher death rates from stroke than those in other regions of the country. Compared with Caucasians, African Americans develop high blood pressure at an earlier age, and it is more severe at any decade of life. As a result, African Americans have a 1.3 times greater rate of nonfatal stroke, a 1.8 times greater rate of fatal stroke, a 1.5 times greater rate of heart disease death, and a 5 times greater rate of end-stage kidney disease. 

According to the National Health and Nutrition Examination Survey (NHANES III, 1988–1994) of the Centers of Disease Control and Prevention (CDC)/National Center for Health Statistics (NCHS), the estimated prevalence of high blood pressure for U.S. adults aged 20 to 74 was 24.4.% for Caucasian males and 19.3% for females; 35% for African American males and 34.2% for females; and 25.2% for Mexican American males and 22% for females. 

According to the Hispanic Health and Nutrition Examination Survey (HHANES, 1982–1984) of the CDC/NCHS, the estimated prevalence of high blood pressure was 22.8% for Cuban American males and 15.5% for females; 15.6% for Puerto Rican males and 11.5% for females. Almost 10% of Pacific Islander men and 8.4% of women have high blood pressure. Among American Indians, 26.8% of men and 27.5% of women have high blood pressure. Seventy-three percent of Japanese American men aged 71 to 93 have high blood pressure7 (Table 1).

Hypertension is a risk factor for stroke, MI, and sudden cardiac death.⁸ Heart disease is the leading cause of death in the United States, followed, in third place, by stroke. 
In the 1980s and early 1990s, prevention initiatives led to a greater number of individuals becoming aware of their hypertension and being treated. Dramatic reductions in age-adjusted mortality rates for stroke and coronary heart diseases were achieved. This progress has reached a plateau. Since 1993, the incidence of stroke has risen slightly, the incidence of end-stage renal disease and congestive heart failure have increased, and the incidence of coronary artery disease has remained essentially the same. Some hypothesize that these increases may be because of inadequate or undertreatment of hypertension as well as a reduction in patient awareness.^6,8
Successful prevention and treatment of hypertension are cost-effective initiatives that prevent the development of costly and debilitating complications associated with untreated or undertreated hypertension. An essential management plan would reduce risk factors that contribute to morbidity and mortality.⁶ The integration of patient education and close follow-up provides patients with the tools essential to enable and empower themselves to optimize their health.

Risk Factors 

There are several factors that are associated with patients being at an increased risk for developing hypertension. Modifiable risk factors include smoking, obesity, sedentary lifestyle, alcohol use, stress, and high intake of salt or caffeine. Being male, postmenopausal, or African American are nonmodifiable risk factors that can contribute to hypertension.⁹ 

Risk Stratification

One of the most significant new additions to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) guidelines is the inclusion of a patient risk stratification and treatment scheme. 

Blood pressure alone does not determine the risk for cardiovascular disease. Components incorporated for cardiovascular risk stratification in patients with hyper- tension include: age greater than 60 years; family history significant for cardiovascular disease in women younger than 65 years and men younger than 55 years; current smoking; dyslipidemia; and diabetes mellitus. 

Target organ damage (TOD) or clinical cardiovascular disease (CCD) also plays an important role for risk stratification. Risk factors associated with TOD and CCD include heart diseases (eg, left ventricular hypertrophy, angina or prior MI, prior coronary revascularization, or heart failure), stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy. 

Once patients are evaluated for risk factors and TOD/CCD, they are then put in a risk group. Risk group A is for all patients who do not have any risk factors or TOD/CCD. Risk group B pertains to patients with at least one risk factor (excluding diabetes) but no TOD/CCD. Risk group C is the last treatment stratification. This group correlates to patients with diabetes or who have TOD/CCD. All patients in all groups should receive education on lifestyle modifications. Patients in risk groups A and B who have stages 2 and 3 hypertension should also receive drug therapy. All patients in risk group C will receive drug therapy⁶ (Table 2).

The normal regulation of blood pressure requires interaction and feedback between the autonomic and central nervous systems, peripheral autoregulatory processes, the vascular endothelium, and serum electrolytes. Essential hypertension results when changes occur in different parts of this complex feedback system. The neural components are physiologically interrelated and changes in one can potentially affect the function of any of the others. Alpha and beta receptors are present in the presynaptic sympathetic terminals and serve to stimulate or inhibit the release of norepinephrine. Stimulation of postsynaptic alpha receptors results in vasoconstriction of arteries and veins. Stimulation of beta receptors results in increased heart rate (ß1) and increased vasodilation (ß2). The baroreceptors located in the walls of the large arteries and aortic arch are extremely sensitive to changes in arterial pressure and provide a negative feedback mechanism controlling the sympathetic nervous system. The autoregulatory process of the kidneys responds to changes in blood pressure by either retaining or excreting sodium, thus affecting plasma volume.^10,11
Humoral mechanisms that modulate blood pressure include the renin-angiotensin-aldosterone system (RAAS) and natriuretic hormone. RAAS regulates sodium and potassium levels and fluid balance. Factors that trigger the release of renin are catecholamines, perfusion pressure, angiotensin II, sodium chloride, and potassium. Renin, in turn, stimulates the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II binds to specific receptor sites—either AT1, which is located in the brain, heart, kidney, vascular system, and adrenal glands, or AT2, which is located in the adrenal medulla, uterus, and brain. Angiotensin II is a direct-acting, potent vasopressor.^6,11,12

The relationship between dietary intake of sodium, calcium, and potassium to hypertension is not clearly defined. Increased concentrations of sodium are associated with natriuretic hormone and activation of the RAAS. Reductions in dietary sodium have been demonstrated to reduce blood pressure. Alterations of vascular smooth muscle and peripheral vascular resistance caused by increased intracellular calcium may also affect blood pressure. Hypokalemia, as well as inadequate potassium intake, may increase blood pressure.^6,11

Secondary hypertension develops from a specific organic etiology. Renal artery stenosis and parenchymal disease can cause renal hypertension. Cushing’s disease, hyperaldosteronism, and pheochromocytomas can cause an elevation in blood pressure. A total of 1% to 10% of all hypertensives have a secondary cause of their high blood pressure. To control the blood pressure, the underlying cause must be addressed.^6,11

Assessment

To confirm a diagnosis of hypertension, a reading of greater than 140/90 mm Hg (or 130/85 mm Hg in individuals with diabetes) or higher must be recorded on two separate occasions. To ensure a correct blood pressure reading, the following practices are recommended: (1) use the correct size blood pressure cuff (80% of the bladder of the cuff should encircle the patient’s arm); (2) patients should not ingest caffeine or use tobacco products for 30 minutes prior to measurement; (3) patients should rest for at least 5 minutes before measurement; and (4) two readings should be taken 2 minutes apart.⁶ 

Once the diagnosis of hypertension is confirmed, the blood pressure should be staged. In the JNC VI report, the four stages have been condensed to three stages. Stage 1 encompasses all patients who have a systolic blood pressure (SBP) of >140 mm Hg but <160 mm Hg or a diastolic blood pressure (DBP) of >90 mm Hg but <100 mm Hg. Stage 2 hypertension includes patients with SBP of >160 mm Hg but <180 mm Hg or DBP of >100 mm Hg but <110 mm Hg. Lastly, patients are classified as having stage 3 hypertension if their SBP is Ž180 mm Hg or their DBP is Ž110 mm Hg. If a patient’s SBP falls within the limits of stage 1 but the DBP is within the limits of stage 2, the patient is categorized as having stage 2 hypertension (Table 3). 

Management

The basic goals of antihypertensive therapy are to reduce blood pressure and atherogenesis, to prevent stroke and target organ disease, such as left ventricular hypertrophy and retinopathy, and to modify risk factors. Management of the hypertensive patient must be individualized. The level of blood pressure elevation as well as the presence of clinical cardiovascular disease and target organ disease, risk factors, and other comorbid diseases provide direction in the algorithm for clinical decision making. 

Recommendations for the management of individuals with hypertension have been made in JNC VI. Effective management of hypertension requires lifestyle modification, pharmacologic therapy, and for most patients, a combination of lifestyle modification and pharmacotherapy.^6,9 

Lifestyle Modification

Lifestyle modification is important for all hypertensives. Recommended lifestyle modifications are as follows: (1) weight reduction, if patient is overweight, (2) smoking cessation, (3) aerobic activity, and (4) dietary modifications to reduce and/or eliminate alcohol and caffeine intake, sodium, and saturated fat. The amount of daily dietary intake of potassium, calcium, and magnesium should be evaluated to determine if daily requirements are being met since these elements contribute to the regulation of blood pressure.⁴ Lifestyle changes are difficult to implement, therefore, positive reinforcement from health care professionals is needed. These modifications are considered the initial management to reduce blood pressure and target organ disease. Lifestyle modifications for patients with high normal or stage 1 hypertension can be implemented for up to 12 months in patients in risk group A or up to 6 months in patients in risk group B. These modifications should continue to be implemented even if patients require pharmacotherapy.⁶

Pharmacotherapy

Pharmacologic management should be individualized for each patient. It is important that health care professionals understand the mechanism of action of each individual drug class, which patient populations respond most effectively to each class, which drug classes have compelling indications, which drug classes have favorable effects on comorbid conditions, what clinical problems are associated with each drug class, patient education, and monitoring parameters related to each drug class. 

Diuretics

Acutely, diuretics decrease blood pressure by decreasing plasma volume as well as stroke volume, which results in a decreased cardiac output. With prolonged use, plasma volume returns to normal but peripheral vascular resistance decreases. This resultant decrease in peripheral vascular resistance is responsible for their long-term antihypertensive effect.^11,13 

Based on randomized controlled trials, diuretics are one of the drugs of choice for uncomplicated hypertension. Thiazide diuretics are more effective antihypertensives than loop diuretics or potassium-sparing diuretics, although thiazide diuretics are ineffective at a creatinine clearance level of <25 to 30 mL/min. African Americans respond well to diuretics since they, as a whole, are typically volume overloaded. African Americans are also more sensitive to sodium intake and, therefore, should make a conscious effort to decrease its intake. Caucasian patients also respond well to diuretics. Diuretics have an additive/synergistic effect with other antihypertensives (eg, beta blockers, ACE inhibitors, and angiotensin-II receptor antagonists). They have the potential to cause electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hyponatremia, and hypochloremia) and hyperuricemia. Lipid abnormalities are generally not seen at doses of <25 mg of hydrochlorothiazide.¹⁴ 

There are two compelling indications for the use of diuretics. Patients who have both hypertension and heart failure can be treated with diuretics. In the early stages of heart failure, thiazide diuretics may be utilized versus later stage heart failure, which responds better to loop diuretics and spironolactone. 

Diuretics are also the preferred treatment for isolated systolic hypertension (which is defined as an SBP of >160 mm Hg and DBP of <80 mm Hg).^6,15 Low-dose diuretics may have a favorable effect for patients with type 2 diabetes mellitus because of their low incidence of adverse effects on glucose homeostasis, lipid profile, and renal function. Since thiazide diuretics decrease calcium excretion, they may also have a favorable effect on osteoporosis. Gout might be aggravated in certain patients because thiazides have the ability to cause hyperuricemia.⁶ Diuretics may initially increase urination, which should subside after a few weeks. Diuretics, therefore, should be taken in the morning. Patients should notify their health care provider if any of the following occur: muscle pain, weakness, cramps, nausea, vomiting, restlessness, excessive thirst, increased heart rate, or significant sudden joint pain. Patients should also be counseled not to interrupt, discontinue or adjust their dose, even if they are feeling better. Patients should have a baseline serum creatinine, blood urea nitrogen (BUN), potassium, sodium, chloride, bicarbonate, glucose, uric acid, and calcium. These laboratory tests should be repeated 1 week after initiation and then periodically thereafter. A baseline fasting lipid profile should also be obtained. Frequency of blood pressure monitoring depends on the stage and comorbid conditions of the patient.¹³

Beta Blockers

Beta blockers work by decreasing heart rate, which, in turn, decreases cardiac output. Beta blockers also block renin release, decrease plasma volume, competitively antagonize catecholamines at the receptor site, increase vasodilatory prostaglandins, and increase baroreflex sensitivity.¹¹ Young patients respond better to beta blockers than elderly patients. One hypothesis for this phenomenon is that the elderly may have decreased beta receptors. In addition to diuretics, beta blockers are the other drug of choice for uncomplicated hypertension. Combinations that work well with beta blockers are diuretics, ACE inhibitors, and alpha blockers. At equipotent doses, antihypertensive effects are similar among all beta blockers. 

Beta blockers have the ability to cause central nervous system depression, myocardial depression, bronchial effects (eg, wheezing), peripheral vascular spasm and constriction, decreased exercise capacity (eg, muscle fatigue), sexual dysfunction, and depression. Beta blockers are also thought to interfere with insulin release, resulting in hyperglycemia. This is usually a transient phenomenon. They also have the potential to blunt the natural response to hypoglycemia. This is because hypoglycemia episodes are mediated by the sympathetic nervous system, which is blocked by beta blockers. Since sweating is a cholinergic effect, this is the only hypoglycemic event not masked by beta blockers.^10,16 

Agents without intrinsic sympathomimetic activity (ISA) may cause lipid alterations. Non-ISA beta blockers are the treatment of choice for patients who have had an MI. There are many clinical situations where beta blockers may have an added benefit for patients with hypertension. Unless otherwise contraindicated, patients with angina, atrial tachycardia and fibrillation, essential tremor, hyperthyroidism, migraine, and preoperative hypertension are good candidates for beta blocker therapy. Beta blockers may aggravate patients with bronchospastic disease, depression, diabetes mellitus, dyslipidemia, second- or third-degree heart block, and peripheral vascular disease. Beta blockers should either not be used in these situations or with extreme care. Patients should be counseled not to abruptly discontinue their medicine, since this may result in rebound hypertension. Patients should notify their health care provider if they have difficulty breathing, excessive lightheadedness, confusion, or depression. Beta blockers may also produce drowsiness or lightheadedness. Caution while driving should be observed.

Patients taking beta blockers should have a baseline fasting lipid profile, glucose level, and heart rate. These parameters should be monitored periodically thereafter. Assessment of blood pressure depends on patient variables and comorbidities.^6,9,14 

ACE Inhibitors

As discussed earlier, ACE breaks down bradykinins and converts angiotensin I to angiotensin II. ACE inhibitors inhibit both pathways, thereby increasing the amount of bradykinins and decreasing the amount of angiotensin II available for the body.¹¹ High renin populations respond the best to ACE inhibitors.¹⁷ Caucasians are typically high renin while African Americans are typically low renin. ACE inhibitors are effective in both young and elderly patients. They also work well with diuretics, alpha blockers, and calcium channel blockers. They are effective in mild-to-severe hypertension and are lipid neutral. 

A total of 10% to 15% of patients may experience an ACE inhibitor cough, which appears to be caused from an accumulation of bradykinins. The cough is usually nonproductive and creates a tickling sensation in the back of the throat. It may worsen in the supine position and may be severe enough to cause hoarseness and vomiting. Several small studies have looked at pharmacologic treatment for ACE inhibitor cough. Antitussives, cromolyn, baclofen, theophylline, sulindac, and anesthetics have all been studied. Cromolyn is the most studied and has minimal toxicity and, therefore, is, considered the first choice if drug therapy is prescribed.18 ACE inhibitors also have the potential to increase serum creatinine, BUN, and potassium. Because of their mechanism of action, ACE inhibitors are contraindicated in bilateral renal artery stenosis. Angioedema can be another serious adverse effect of ACE inhibitors. Due to their ability to cause teratogenicity, they are contraindicated in pregnant patients. Compelling indications where ACE inhibitors would be warranted are type 1 diabetics with proteinuria, patients with systolic heart failure, and patients who have systolic dysfunction after an MI. ACE inhibitors may have a favorable effect on type 1 and type 2 diabetics with proteinuria or patients with renal insufficiency who have hypertension. 
Patients should notify their health care provider if they develop a sore throat, fever, swelling of hands or feet, irregular heartbeat, chest pain, or skin rash. Patients should also be counseled on the possibility of developing dizziness and lightheadedness during the first couple of days of treatment. The possibility of a persistent dry cough should also be discussed. Lastly, patients should be educated on not using salt substitutes containing potassium without consulting their health care provider first. Monitoring should include obtaining a baseline serum creatinine, BUN, sodium, potassium, bicarbonate, and glucose. These laboratory tests should be repeated within 1 week when initiating the drug and when changing a drug or a dose of ACE inhibitor.^6,9

Calcium Channel Blockers

While there are different classes of calcium channel blockers, they all block the slow calcium channels in the cardiac and smooth muscles. The differences among them is that they all act at specific receptors. The density and distribution of these receptors varies from tissue to tissue. Therefore, the non-dihydropyridine (non-DHP) calcium channel blockers (verapamil and diltiazem) decrease heart rate and atrioventricular (AV)-nodal conduction while dihydropyridine calcium channel blockers (nifedipine, amlodipine, felodipine, isradipine, and nicardipine) cause vasodilation, which increases heart rate; they also have no effect on AV-nodal conduction.11 These differences are important to determine which patients would benefit most from which calcium channel blocker. African Americans respond better than Caucasians. Elderly and young patients respond well to calcium channel blockers. They are effective in mild-to-severe hypertension and are lipid and glucose neutral. Non-DHP calcium channel blockers can cause bradycardia, second- and third-degree heart block, and constipation. DHP calcium channel blockers can cause tachycardia, headache, peripheral edema, and proteinuria. Multiple reports state that sustained preparations should be the only dosage form given for the treatment of hypertension.^19-22

Although diuretics are preferred for treatment of isolated systolic hypertension, long-acting DHPs have also been shown to be beneficial. All calcium channel blockers are beneficial for patients who have hypertension and angina. Non-DHP calcium channel blockers are also beneficial for patients with hypertension and atrial tachycardia and fibrillation, type 1 or type 2 diabetes mellitus with proteinuria, non–Q-wave MI, migraines, or diastolic heart failure. Non-DHP calcium channel blockers should not be used in patients who have a history of second- and third-degree heart block. Calcium channel blockers, except amlodipine and felodipine, should not be used in patients with systolic heart failure. 

Patients should notify their primary care physician if they develop an irregular heart beat, shortness of breath, swelling of the hands and feet, pronounced dizziness, or constipation. Patients should have a baseline electrocardiogram. Heart rate and blood pressure should be monitored according to patient characteristics and severity of blood pressure.^6,9,11

Angiotensin-II Receptor Blockers 

Angiotensin-II receptor blockers (AT II blockers) selectively inhibit the ability of angiotensin II to bind to the AT2 receptor. Both young and elderly patients respond to AT II blockers.11,23 They are lipid and glucose neutral, do not increase uric acid levels, and are synergistic with diuretics. AT II blockers, such as ACE inhibitors, can increase serum creatinine, BUN, and potassium. They are also contraindicated in renal artery stenosis and pregnancy. AT II blockers do not cause cough, because they do not interfere with bradykinin breakdown. Losartan may be of benefit in patients with systolic heart failure and hypertension. Patients should have a baseline serum creatinine, BUN, sodium, potassium, bicarbonate, chloride, and glucose. These laboratory tests should be repeated within 1 week of initiating the drug or when changing a drug or dose.^6,9,11,23

Alpha Blockers

These compounds are alpha-1 selective and block peripheral postsynaptic alpha-1 receptors. This action reduces vascular resistance from sympathetic activation, which results in a decreased peripheral vascular resistance. Vasodilation also occurs, which induces vascular smooth muscle relaxation in both the arteriolar and venous vessels. Alpha blockers do not cause reflex tachycardia.11 Alpha blockers work in African Americans and Caucasians as well as the young and elderly. They are more effective in stage 1 hypertension and are not usually effective as monotherapy in severe hypertensives. Alpha blockers work well with ACE inhibitors, calcium channel blockers, and diuretics. They also have a positive effect on lipid profiles. Tolerance may occur over time, which might be due to fluid retention. Alpha blockers can cause “first-dose syncope” as well as orthostasis, headache, and weakness. Alpha blockers may have a favorable effect on patients who have dyslipidemia or benign prostatic hypertrophy and hypertension. 

There are currently no unfavorable effects on comorbid conditions with alpha blockers. Patients should be educated about the possibility of “first-dose syncope” and orthostasis. Patients should avoid driving for 12 to 24 hours after their first dose, after a dosage increase, or after interruption of therapy when treatment is resumed. Caution should also be used when rising from a sitting or lying position. If dizziness or palpitations are bothersome, they should be reported to their health care provider. Frequency of blood pressure monitoring is based on the individual patient.^6,9,11

Central Adrenergic Inhibitors (Central Alpha-agonists)

Central alpha-agonists (clonidine, methyldopa, guanfacine, and guanabenz) stimulate the central postsynaptic alpha-2 receptors in the brain stem, which decreases sympathetic activity to the periphery, thereby decreasing plasma norepinephrine levels. They also suppress plasma renin activity.¹¹ 

Central alpha-agonists are very potent antihypertensives and are effective as monotherapy. The combination of a central alpha-agonist with a peripheral alpha blocker may result in a decreased response rate. ACE inhibitors, calcium channel blockers, and diuretics work well with central alpha-agonists. A clonidine patch, which is applied once a week, can help with compliance. Following complete removal, clonidine levels stay constant for 8 hours and then slowly decrease over 2 days. 

Central alpha-agonists can cause sodium and water retention. Therefore, they may need to be given in conjunction with a diuretic. Sedation, dry mouth, constipation, sexual dysfunction, and bradycardia can also occur. Methyldopa can cause forgetfulness, depression, positive alpha-agonists with lupuslike syndrome, nasal stuffiness, and rare, drug-induced hepatitis. Therefore, it should never be used in patients with liver disease. The dose of clonidine should be decreased in patients with renal failure. Methyldopa is the drug of choice for pregnant patients. All central alpha-agonists can cause dry mouth. Patients should be counseled not to abruptly stop their medication because this can cause rebound hypertension.^6,9,11

Peripheral Adrenergic Inhibitors

Peripheral adrenergic inhibitors (reserpine, guanethidine, and guanadrel) act by initially inhibiting the release of catecholamines in the peripheral sympathetic nerve endings. Continual use leads to a depletion of catecholamine stores, which results in a decrease in peripheral vascular resistance, heart rate, and cardiac output. The peripheral adrenergic inhibitors are reserved for severe refractory hypertension.¹¹ They are potent antihypertensives and are very effective in combination with hydrochlorothiazide. 

Reserpine has a long duration of action and, therefore, provides a constant antihypertensive effect even when it is taken irregularly. High-dose reserpine can cause depression. Reserpine can also cause nasal stuffiness and an increase in gastric acid secretion.²⁴ 

Guanethidine and guanadrel can cause postural hypertension, fluid retention, diarrhea, and sexual dysfunction.^6,9,11

Direct Vasodilators

Direct vasodilators (hydralazine, and minoxidil) cause direct arteriolar smooth muscle relaxation. This direct arteriolar vasodilation activates the baroreceptor reflexes which results in an increase in sympathetic outflow. This leads to an increase in heart rate, cardiac output, and renin release. Therefore, hypotensive effectiveness will diminish over time unless the patient is also taking a sympathetic inhibitor and a diuretic to counteract the effects of the baroreceptors.¹¹ Because of the need for combination therapy to prevent or manage side effects, direct vasodilators are not considered first-line agents. Typically they should not be used as monotherapy and should be reserved for refractory patients.

Hydralazine may be beneficial in patients who have hypertension and systolic heart failure. A side effect of the drug is that it can cause a lupuslike syndrome. Patients prescribed hydralazine should be counseled to notify their health care provider if they experience any unexplained prolonged general tiredness, fever, muscle or joint aching, or chest pain. Patients taking minoxidil should usually be taking at least two other antihypertensive medications. Patients should be educated that minoxidil may enhance hair growth and darkening of fine body hair and may also cause fluid retention.^6,9,11

Step-Down Therapy

Although the treatment of hypertension is typically a lifelong endeavor, an effort to decrease the number and/or dosage of antihypertensive drugs should be considered in certain individuals. Patients who have been effectively controlled for at least 1 year may be eligible for step-down treatment. The reduction should be done slowly over an extended period of time. Step-down treatment is most successful in patients who have implemented lifestyle modifications. Although patients may have successfully decreased the number or dosage of antihypertensive medications, blood pressure may increase again in the future. Therefore, careful follow-up for step-down patients is needed.⁶ 

Maximizing Medication Adherence

As discussed earlier, patient education and involvement in their health care empowers the patient and increases their adherence. As pharmacists, we can reinforce general information that patients should know about their medications. Patients should know the name of their medication, what it is used for, the dose or strength, and when it should be taken. They should also be aware of how it should be timed with meals and other medications, common side effects, activities that should be avoided while taking the medication, and how long they will be taking it. Patients should also be counseled to never take another person’s medication, never stop taking their medication without contacting their health care provider, never change the dose of the medication on their own, and never take old or outdated medications. It is also important to inform them that they should not take medication with alcoholic beverages nor should they transfer pills from an original container to another container with a different label. These counseling points can help enhance patients’ knowledge and increase their adherence to better control their hypertension.²⁵

Questions 3 through 8 of the quiz are based on the following case:
JJ is a 64-year-old Caucasian male. His past medical history is significant for hypertension, cerebral vascular event, hypercholesterolemia, gout, retinopathy, and gall stones. He smokes one package of cigarettes per day and drinks one beer a day. He states he exercises by “walking to the mailbox every day.” He is retired and says that he “enjoys his quiet life.” Vital signs: blood pressure 166/76; pulse = 72. Labs = within normal limits. No allergies. Medications: lisinopril 20 mg po daily; EC ASA 325 mg po daily; pravastatin 20 mg po daily.

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    and ß-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Arch Intern Med. 1999;159:551-558.

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16. Antihypertensive agents in diabetic patients. Arch Intern Med. 1999;159:541-542.

17. Preston RA, Materson BJ, Reda DJ, et al. Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. JAMA. 1998;280:1168-1172.

18. Luque CA, Ortiz MV. Treatment of ACE inhibitor-induced cough. Pharmacother. 1999;19:804-810.

19. Kaplan NM, Gifford RW. Choice of initial therapy for hypertension. JAMA. 1996;275:1577-1580.

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