Hypertension and Miscellaneous Antihypertensive Medications

http://evolve.elsevier.com/Edmunds/NP/

Class	Generic Name	Trade Name
Peripheral α₁-receptor blockers (adrenergic agonists)	doxazosin	Cardura
	prazosin	Minipress
	terazosin	Hytrin
Centrally acting α₂-agonists (antiadrenergics)	clonidine	Catapres
	methyldopa	Aldomet
Peripheral vasodilators	hydralazine	Apresoline
	minoxidil	Loniten
Renin inhibitors	aliskiren	Tekturna

Key drug.

INDICATIONS

Hypertension (HTN)

Other indications and unlabeled uses include the following:

• α₁-Receptor blockers: indicated or unlabeled use for the signs and symptoms of benign prostatic hyperplasia (BPH); prazosin has been used for posttraumatic stress disorder and Raynaud’s phenomenon

• Clonidine: many unlabeled uses, including alcohol and opiate withdrawal, smoking cessation, atrial fibrillation, attention-deficit/hyperactivity disorder, menopausal flushing, constitutional growth delay in children, diabetic diarrhea, restless leg syndrome, ulcerative colitis, and the diagnosis of pheochromocytoma

• Methyldopa (unlabeled): hypertension in pregnancy

• Hydralazine (unlabeled): (CHF), pulmonary hypertension

• Minoxidil (indication): topical treatment for baldness

The management of hypertension in general is discussed, with emphasis on the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines. Many alternative treatment protocols have been proposed. The JNC 8 is due to be published in 2013. The drugs most commonly used for hypertension are diuretics, β-blockers, calcium channel blockers, ACE inhibitors, and angiotensin II receptor blockers (ARBs). How these drugs are used to treat hypertension is discussed in this chapter. Detailed information on these antihypertensives is given in the specific drug chapters (Table 17-1). This chapter provides detailed information on other antihypertensive medications used in primary care.

TABLE 17-1

Drugs Commonly Used for Hypertension (listed in order of use)

Additional information related to these drugs can be found in the chapters listed below.
Drug	Abbreviation	Chapter
Thiazide diuretics	THIAZ	32
β-Blockers	BBs	20
Angiotensin-converting enzyme	ACE	22
Angiotensin II receptor blockers	ARBs	22
Calcium channel blockers	CCBs	21
Aldosterone antagonist	ALDO ANT	32

Therapeutic Overview of Hypertension

Anatomy and Physiology

Blood pressure (BP) must be kept at a level that is adequate to maintain tissue perfusion as the blood moves into the capillaries. Peripheral resistance, heart rate, and stroke volume interact to determine the mean arterial pressure and capillary flow. Peripheral resistance is determined by the diameter of the arterioles; constriction of the arterioles raises BP. Other factors that influence BP include changes in body position, muscular activity (which causes local warmth, thus dilating vessels), and circulating blood volume. Baroreceptors respond to local changes in BP by constricting or relaxing local smooth muscle to change blood flow. Many hormones also cause contraction or relaxation of arteriolar smooth muscle to bring blood flow to a specific organ. The renin-angiotensin system is an important regulatory feedback loop component of this system. A drop in BP to the renal arteries stimulates the secretion of renin. Renin activates the renin-angiotensin system by cleaving angiotensinogen produced in the liver to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme. Angiotensin II then constricts blood cells, increases the secretion of antidiuretic hormone (ADH) and aldosterone, and causes reabsorption of sodium in the kidneys, thus leading to water retention, increased blood volume, and increased BP.

Some conditions produce secondary hypertension as a consequence of other disease. The hypertension that results from these conditions is often treatable (see Table 17-3). The cause of primary hypertension (which accounts for approximately 95% of cases of hypertension) remains unknown. Although these are not completely understood, many factors have been linked to primary hypertension, including some that are genetically determined. Involved mechanisms include elevated peripheral resistance, alteration in the cell membrane related to elevated lipids, endothelial dysfunction, changes in sodium or calcium levels, and hyperinsulinemia. Sympathetic nervous system hyperactivity caused by insensitivity of the baroreflexes may contribute to hypertension accompanied by tachycardia and elevated cardiac output in younger patients.

TABLE 17-3

Secondary Causes of Hypertension

Pathology	Signs and Symptoms	Diagnostic Studies
Coarctation of the aorta	Delayed or absent femoral arterial pulses, decreased BP in lower extremities	ECG, chest x-ray studies, echocardiography, Doppler ultrasonography
Cushing’s syndrome	Long-term steroid use: truncal obesity with purple striae, moon facies	Morning plasma cortisol after 1 mg hour of sleep dexamethasone
Pheochromocytoma	Labile HTN, tachycardia, headache, palpitations, pallor, sweating, or tremors	Spot urine for metanephrine
Primary aldosteronism	Muscle weakness, polydipsia, polyuria	Hypokalemia, excessive urinary potassium excretion, suppressed levels of plasma renin activity, elevated sodium level
Chronic kidney disease	Abdominal or flank masses (polycystic kidneys)	Urinalysis, creatinine, renal ultrasound
Renovascular disease	Epigastric or renal artery bruits, atherosclerotic disease of aorta or peripheral arteries	Renal duplex ultrasound, renal arteriography
Sleep apnea	Fatigue, loud cyclic snoring	Polysomnography
Hyperthyroidism	Weight loss, fatigue, tachycardia	TSH, T₄, free T₄, free T₄ index
Hypothyroidism	Weight gain, fatigue	May be due to decreased tissue metabolism leading to low production of vasodilating metabolites
Hyperparathyroidism	Renal stones, polyuria, constipation	Serum and urine calcium, urine phosphate, serum parathyroid hormone

Dysregulation of the renin-angiotensin system leads to hypertension, although this does not appear to be a major factor in the origin of hypertension. African Americans with hypertension and older adult patients tend to have lower plasma renin activity. Approximately 10% of hypertensive individuals have high levels, 60% have normal, and 30% have low renin levels.

Some patients have a decreased ability to excrete sodium, which leads to increased blood volume and increased BP. Sodium restriction may be necessary in these individuals. Abnormalities in sodium transport mechanisms lead to an increased level of intracellular sodium in blood cells. This may result in the increased vascular smooth muscle tone characteristic of hypertension.

Environmental, lifestyle, and dietary factors also play important, and modifiable, roles. Obesity leads to increased intravascular volume and increased cardiac output. Alcohol increases BP by increasing plasma catecholamines. Cigarette smoking raises BP by increasing plasma norepinephrine.

NSAIDs cause fluid retention, which can lead to hypertension. Excessive intake of sodium (salt) or low levels of potassium can contribute to hypertension by increasing blood volume. Physical inactivity is a recently recognized risk factor.

Hypertension is a powerful risk factor for cardiac disease. The higher the BP, the greater is the risk for ischemic heart disease, heart attack, heart failure, stroke, and kidney disease. In adults, each increase of 20 mm Hg in systolic blood pressure (SBP) or 10 mm Hg in diastolic blood pressure (DBP) doubles the patient’s risk of cardiovascular disease (CVD). This knowledge has led to an emphasis on the lower spectrum of BP, resulting in the classification of “prehypertension,” which is new to JNC 7.

A “metabolic syndrome” has recently been identified as a major cardiac risk factor. This constellation of symptoms is also referred to as syndrome X, the insulin resistance syndrome, or the obesity dyslipidemia syndrome. A patient who has abdominal obesity, hypertension, insulin resistance, and a lipid disorder has a greatly elevated risk of CVD. Instead of serving as separate risk factors, they work together to increase risk. Table 17-2 lists the major cardiovascular risk factors. The WHO diabetes group proposed a set of criteria for diagnosing the metabolic syndrome in 1998 and later updated these (Grundy et al, 2004). This definition is as follows:

TABLE 17-2

Major Cardiovascular Risk Factors for Hypertension

Metabolic syndrome

Hypertension

Dyslipidemia

Obesity (body mass index [BMI] ≥30)^∗

Diabetes mellitus

Cigarette smoking

Physical inactivity

Microalbuminuria or estimated glomerular filtration rate (GFR) <60 ml/min

Family history of premature cardiovascular disease (men younger than age 55 or women younger than 65 years)

^∗Body mass index is calculated as:

Weight(in kg)Height(in kg)

From Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Education Program: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, NIH publication No. 03-5233, Bethesda, MD, May 2003, National Institutes of Health, National Heart, Lung, and Blood Institute.

Hyperinsulinemia (defined as the upper quartile of a measure of insulin resistance in the nondiabetic population) OR a fasting plasma glucose (FPG) greater than or equal to 110 mg/dl (6.1 mmol/L) or a plasma glucose two hours after an oral glucose tolerance test greater than or equal to 200 mg/dl (11.1 mmol/L)

PLUS at least two of the following:

1. Abdominal obesity, defined as a waist-to-hip ratio greater than 0.90, a body mass index (BMI) ≥30 kg/m², or a waist-to-girth ratio ≥0.9 in men and 0.85 in women

2. Dyslipidemia, defined as serum triglycerides 150 mg/dl (1.7 mmol/L)

3. HDL cholesterol <35 mg/dl (0.9 mmol/L) in men or <39 mg/dl (1.0 mmol/L) in women

4. BP ≥140/90 mm Hg or the administration of antihypertensive drugs

5. Urinary albumin excretion rate >20 mcg/min or albumin-to-creatinine ratio >30 mg/g

Disease Process

Fifty million Americans have hypertension, and the prevalence increases with age. Only about 34% of these people are adequately treated. Hypertension is a risk factor for CVD, stroke, CHF, renal failure, and peripheral vascular disease. CVD and stroke are the most common causes of death in the United States. Current levels of cardiovascular morbidity and mortality show that much greater effort is required to control hypertension (ALLHAT, 2002).

The pendulum continues to swing regarding which factor is the most important to control: systolic or diastolic BP. Systolic BP was first considered to be most important; subsequently, focus shifted to diastolic BP. Some researchers are exploring the significance of pulse pressure (i.e., difference between systolic and diastolic BP). However, ongoing research suggests that management scenarios must address both systolic and diastolic BP levels.

Assessment

The diagnosis of hypertension is based on the average of readings taken at an initial screening and two or more readings taken at each of two or more subsequent visits. The readings on these three separate occasions should not be influenced by any other known mechanism, such as recent exercise, anxiety, or an acute illness. Initial evaluation includes a thorough history, physical examination, and laboratory screening (Box 17-1).

BOX 17-1 Clinical and Diagnostic Evaluation for Patients with Documented Hypertension

Three Main Purposes

• Identify known causes of hypertension.

• Assess presence/absence of TOD and CVD, extent of disease, and response to therapy.

• Identify other cardiovascular risk factors and comorbid conditions; continue/modify treatment as indicated.

History

• BP history, including duration

• Age of onset (<20 or >50 years, think secondary hypertension)

• Levels of hypertension (>180/110 mm Hg, think secondary hypertension)

• Laboratory or diagnostic testing

• All previous treatments and responses to therapy, including adverse events (resistance to therapy, think secondary hypertension)

• Personal or family history or patient symptoms of coronary heart disease (CHD; especially premature in family), heart failure, cerebrovascular disease, peripheral vascular disease, renal disease, diabetes mellitus, dyslipidemia, or other comorbidity, such as gout or sexual dysfunction

• Listen for symptoms that suggest causes of hypertension (secondary hypertension), such as headache, daytime somnolence, fatigue, tachycardia, claudication, cold feet, sweating, thinning of skin, flank pain, muscle weakness, and tremor.

• Lifestyle assessment, including recent weight changes, physical activity profile, cigarette smoking, dietary intake of sodium, alcohol, saturated fat, and caffeine

• Medication history, including over-the-counter drugs, herbal remedies, and illicit drugs

• Psychosocial and environmental factors that may influence hypertension control

Physical Examination

• In particular, look for signs of secondary hypertension, such as variable pressures with tachycardia, sweating or tremors, hyperdynamic apical pulse, murmurs at anterior or posterior thorax, abnormal pulsations in neck, abdominal bruit, abdominal or flank masses, truncal obesity with purple striae, weak femoral pulses, or absent pedal pulses.

• Two or more BP measurements, 2 minutes apart, patient either supine or seated and after standing for at least 2 minutes

• Verification in contralateral arm (higher value should be used)

• Height, weight, and waist circumference

• Funduscopic examination

• Examination of neck (assess for carotid bruits, jugular venous distention, or thyroid enlargement)

• Examination of heart (assess for precordial heaves, enlargement, abnormal rate or rhythm, extra sounds, including murmurs, clicks, S3, S4)

• Examination of lungs (assess for evidence of congestion or bronchospasm)

• Examination of abdomen (assess for abnormal aortic pulsations, bruits, enlarged kidneys, masses)

• Examination of extremities (assess for arterial pulses, bruits, or edema)

Neurologic Assessment

Initial Diagnostic Screening

• Before initiation of therapy, focus on determining TOD or other risk factors

• Urinalysis

• CBC

• Blood chemistries (e.g., sodium, potassium, creatinine, fasting glucose, and total and HDL cholesterol)

• Twelve-lead electrocardiogram

Optional Laboratory Tests

• 24-hour urine for microalbuminuria, creatinine clearance, or urinary protein

• Serum calcium

• Uric acid

• Fasting triglycerides and LDL cholesterol

• Glycosylated hemoglobin

• Sensitive TSH

• Limited echocardiography to determine presence of LVH

From Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Education Program: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, NIH Publication No. 03-5233, Bethesda, MD, May 2003, National Institutes of Health, National Heart, Lung, and Blood Institute.

Material on secondary causes modified from Kaplan NM: Clinical hypertension, Baltimore, 1998, Williams & Wilkins.

Once the diagnosis of hypertension is made, further evaluation of three factors that are affecting the patient’s risk is necessary. Severity should be determined according to the classification in Table 17-4. Next, target organ damage (Table 17-5), which is the damage the hypertension has already caused, should be evaluated. Finally, assessment should be completed for compelling indications (Table 17-6), which include conditions managed in parallel with HTN. These three factors will affect management.

TABLE 17-4

JNC 7 Classification and Management of Blood Pressure for Adults

			INITIAL DRUG THERAPY
BP Classification	SBP, mm Hg	DBP, mm Hg	Without Compelling Indication	With Compelling Indication (see Table 17-5)
Normal	<120	and <80	None indicated	Drugs for compelling indications
Prehypertension	120-139	or 80-89	None indicated
Stage 1 HTN	140-159	or 90-99	Thiazide-type diuretics for most	Drug(s) for compelling indications
			May consider ACEI, ARB, BB, CCB, or combination	Other antihypertensive drugs (diuretics, ACEIs, ARBs, BBs, CCBs) as needed
Stage 2 HTN	≥160	or ≥100	Two-drug combination for most (usually, thiazide-type diuretic and ACE or ARB or BB or CCB)	Same as above

From Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Education Program: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, NIH Publication No. 03-5233, Bethesda, MD, May 2003, National Institutes of Health, National Heart, Lung, and Blood Institute.

TABLE 17-5