THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

8. Hypertension - Benjamin Gross, PharmD, BCPS, L. Brian Cross, PharmD, CDE

8-1. Disease Overview

Introduction

• Hypertension is defined as a systolic blood pressure >140 mm Hg, a diastolic blood pressure > 90 mm Hg, or a condition in any patient requiring antihypertensive therapy.

• In the United States, 65 million people are affected by hypertension. In approximately 64% of those affected, it is controlled (

Table 8-1).

• Incidence increases with age.

• Its onset most commonly occurs in the third to fifth decades of life, and the lifetime risk of hypertension is 90% for those surviving to age 80.

• Prevalence differs by ethnic group (

Table 8-2), socioeconomic group, and geographic region.

Classification

Classification of hypertension is based on the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII).

Table 8-3 shows the JNC-VII classification.

Clinical Presentation and Complications

Cardiovascular effects

• Left ventricular hypertrophy

• Congestive heart failure (CHF)

• Peripheral arterial disease

• Angina pectoris

• Myocardial infarction

• Sudden death

Renal effects

• Nephropathy

• Renal failure

• Requirements for dialysis

Cerebrovascular effects

• Transient ischemic attacks

• Stroke

Ophthalmologic effects

• Retinal hemorrhage

• Retinopathy

• Blindness

Pathophysiology and Etiology

• Blood pressure = (stroke volume × heart rate) × peripheral resistance (

Figure 8-1)

Sympathetic nervous system activation

Central activation

• Presynaptic α2 stimulation is a negative feedback mechanism, leading to decreased norepinephrine release.

• Presynaptic β stimulation leads to increased norepinephrine release.

[Table 8-1. Trends in Awareness, Treatment, and Control of High Blood Pressure in Adults Ages 18-74]

Peripheral activation

• β1 Stimulation leads to increased heart rate and contractility, causing increased cardiac output.

• β2 Stimulation leads to arterial vasodilation.

• β Stimulation also causes increased renin release, causing increased angiotensin II production.

• α1 Stimulation leads to arterial and venous vasoconstriction.

Renin-angiotensin-aldosterone system

• Decreased renal perfusion pressure causes increases in renin levels.

• Renin reacts with angiotensinogen to produce angiotensin I (AT-I).

• Angiotensin-converting enzyme (ACE) causes AT-I to become angiotensin II (AT-II).

• AT-II is a potent vasoconstrictor and stimulates aldosterone release, which increases sodium and fluid retention.

[Table 8-2. Prevalence of Hypertension by Ethnic Group for Adults Ages 20-74 (percent)]

Water and sodium retention

• Acute: Increased fluid volume causes increased cardiac output, which causes increased blood pressure (BP).

• Chronic: Excess intracellular sodium causes vascular hypertrophy, which increases vascular resistance and response to vasoconstriction and, in turn, increases BP.

Etiology

Primary (essential) hypertension

• Unknown cause

• Found in 85-95% of all hypertension cases

Secondary hypertension

• Renovascular disease: This condition is suggested by increased blood urea nitrogen (BUN) and creatinine and by abdominal bruits.

• Primary aldosteronism: This condition is suggested by unprovoked hypokalemia.

• Cushing's syndrome: This condition is suggested by unprovoked hypokalemia and truncal obesity with purple striae.

• Pheochromocytoma: This condition is suggested by increased urinary catecholamine excretion (i.e., vanillylmandelic acid and metanephrine) accompanied by headache, palpitations, and perspiration

• Aortic coarctation: This condition is suggested by delayed or absent femoral pulses and decreased BP in the lower extremities.

[Table 8-3. Classification and Management of Blood Pressure for Adults]

[Figure 8-1. Sympathetic Nervous System Activation]

• Drug-induced hypertension: The following drugs may induce hypertension:

• Steroids and estrogens (including oral contraceptives)

• Alcohol

• Cocaine

• Cyclosporine and tacrolimus

• Sympathomimetics

• Erythropoietin

• Licorice (in chewing tobacco)

• Monoamine oxidase (MAO) inhibitors

• Tricyclic antidepressants

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

Diagnostic Criteria

Diagnosis and treatment begin with proper BP measurement, assessment, and follow-up planning (

Table 8-4). The patient should avoid ingesting caffeine and smoking for 30 minutes prior to BP measurement and should be resting for 5 minutes prior to BP measurement. BP is measured as follows:

• Position arm (brachial artery) at heart level.

• Uncover arm; do not put cuff over clothes.

• Determine proper size cuff.

[Table 8-4. Recommendations for Follow-Up Based on Initial BP Measurements for Adults]

Upper arm circumference

Cuff size required

 

16.0-22.5 cm

Pediatric cuff

 

22.6-30.0 cm

Regular adult cuff

 

30.1-37.5 cm

Large adult cuff

 

37.6-43.7 cm

Thigh cuff

 

• Position cuff 1 inch above antecubital crease.

• Ask patient about previous readings.

• Place stethoscope over brachial artery (medial to the center).

• Inflate cuff rapidly to approximately 30 mm Hg above previous readings.

• Deflate cuff slowly.

• Remember to deflate cuff completely when done.

• Wait 1-2 minutes before repeating.

• Take pressure in both arms.

• If orthostatic hypotension is suspected, take BP while patient is sitting, standing, and supine.

• If two readings are taken at least 2 minutes apart, average the readings.

• If readings differ by > 5 mm Hg, take additional readings.

Treatment Principles and Goals

Figure 8-2 and

Table 8-5 outline some important treatment principles. Goals include the following:

• To reduce end-organ damage

• To minimize or control other risk factors for cardiovascular (CV) disease

• To maintain BP, with minimal side effects, at or below the level appropriate for the patient's risk:

• 140/90 mm Hg with uncomplicated hypertension

• 140/90 mm Hg with target organ damage or CV disease

• <130/80 mm Hg with diabetes and chronic kidney disease

• <125/75 mm Hg with proteinuria > 1 g/24 h

Monitoring and Evaluation

Initial evaluation

The initial evaluation of patients with hypertension has the following goals:

• To identify known causes of high blood pressure (

Table 8-6)

[Figure 8-2. Algorithm for the Treatment of Hypertension]

[Table 8-5. Identifiable Causes, Diagnostic Tests, and Clinical Findings for Secondary Hypertension]

[Table 8-6. Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes]

• To assess presence or absence of target organ damage and CV disease, extent of the disease, and the response to therapies (Box 8-1)

• To identify other CV risk factors or concomitant disorders that may affect prognosis and guide therapy (Box 8-1)

The patient's history should be looked at in the initial evaluation:

• Duration and levels of elevated blood pressure

• History or symptoms of coronary heart disease (CHD), heart failure, cerebrovascular disease, pulmonary vascular disease, diabetes mellitus, renal disease, or dyslipidemia

• Family history of hypertension, premature CHD, stroke, diabetes, dyslipidemia, or renal disease

• Symptoms suggesting the cause of hypertension

• Recent weight changes, physical activity levels, or smoking or other tobacco use

• Dietary assessment of intake of sodium, alcohol, saturated fat, and caffeine

• Complete medication history, including prescription, over-the-counter, and herbal or natural products that may increase BP or decrease effectiveness of antihypertensive agents

• Results and adverse effects of previous antihypertensive therapy

• Psychosocial and environmental factors that may influence hypertension control

An examination should also be done:

• Two or more blood pressure measurements separated by at least 2 minutes

• Measurement of height, weight, and waist circumference

• Funduscopic exam for hypertensive retinopathy

• Exam of neck for carotid bruits, distended veins, or an enlarged thyroid gland

• Exam of heart for abnormalities in rate and rhythm, increased size, precordial heave, clicks, murmurs, and third and fourth heart sounds

• Exam of lungs for rales and evidence of bronchospasm

• Exam of abdomen for bruits, enlarged kidneys, masses, and abnormal aortic pulsation

• Exam of extremities for decreased or absent peripheral arterial pulsations, bruits, and edema

• Neurologic assessment

Box 8-1. Cardiovascular Risk Factors

Major Risk Factors

• Hypertensiona

• Cigarette smoking

• Obesitya (body mass index ≥ 30 kg/m2)

• Physical inactivity

• Dyslipidemiaa

• Diabetes mellitusa

• Microalbuminuria or estimated GFR < 60 mL/min

• Age (> 55 for men, > 65 for women)

• Family history of premature cardiovascular disease (men under age 55, women under age 45)


Target Organ Damage

Heart

• Left ventricular hypertrophy

• Angina or prior myocardial infarction

• Prior coronary revascularization

• Heart failure


Brain

• Stroke or transient ischemic attack


Kidney

• Chronic kidney disease

• End stage renal disease


Vascular System

• Peripheral arterial disease


Eyes

• Retinopathy


Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute. GFR, glomerular filtration rate.

a. Components of the metabolic syndrome.

Routine laboratory are necessary:

• Urinalysis

• Complete blood cell count

• Blood chemistries (sodium, potassium, creatinine, BUN, and glucose)

• Fasting lipid profile: total cholesterol, triglycerides, HDL (high-density lipoprotein), and LDL (low-density lipoprotein)

• Electrocardiogram (ECG)

The following laboratory tests are optional:

• Creatinine clearance

• Microalbuminuria

• 24-hour urinary protein

• Blood calcium

• Uric acid

• Glycosylated hemoglobin

• Thyroid-stimulating hormone

• Limited echocardiography

• Ankle-brachial index

• Plasma renin activity and urinary sodium determination

Follow-up evaluation

Follow-up evaluation includes any of the previous exams completed during the initial evaluation that are required to monitor both response to and possible adverse effects from prescribed antihypertensive therapies, in addition to the assessment of any new symptoms of target organ damage and the assessment of patient adherence to therapy (Box 8-2).

Box 8-2. General Guidelines to Improve Patient Adherence to Antihypertensive Therapy

• Be aware of signs of patient nonadherence to antihypertensive therapy.

• Establish the goal of therapy: to reduce blood pressure to nonhypertensive levels with minimal or no adverse effects.

• Educate patients about the disease, and involve them and their families in its treatment. Have them measure blood pressure at home.

• Maintain contact with patients; consider telecommunication.

• Keep care inexpensive and simple.

• Encourage lifestyle modifications.

• Integrate pill taking into routine activities of daily living.

• Prescribe medications according to pharmacologic principles, favoring long-acting formulations.

• Be willing to stop unsuccessful therapy and try a different approach.

• Anticipate adverse effects. Adjust therapy to prevent, minimize, or ameliorate side effects.

• Continue to add effective and tolerated drugs, stepwise, in sufficient doses to achieve the goal of therapy.

• Encourage a positive attitude about achieving therapeutic goals.

• Consider using nurse case management.


Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

8-2. Nondrug Therapy

Lifestyle modifications are recommended to improve both BP and overall cardiovascular health (

Table 8-7).

Research has shown that diets rich in fruits, vegetables, and low-fat dairy foods, and with reduced saturated and total fats, significantly lower blood pressure (

Tables 8-8 and

8-9).

8-3. Drug Therapy

Introduction

All patient factors (severity of blood pressure elevation, presence of target organ damage, and presence of CV disease or other risk factors) must be considered when initiating therapy.

Initial Therapy

• For candidates for therapy, see Figure 8-2 and Table 8-5.

• Use of lifestyle modifications (Table 8-7) should continue to be stressed to patients after the decision to initiate drug therapy has been made to further decrease the risk of complications from cardiovascular disease.

• Prehypertension represents a new classification in JNC-VII (Table 8-3) and represents a significant risk for future development of stage 1 hypertension. Lifestyle modifications should be stressed for this classification, and medication therapy should be used only for patients with compelling indications.

• JNC-VII recommends the use of thiazide diuretics as initial therapy in most patients alone or in

[Table 8-7. Lifestyle Modifications to Manage Hypertension]

[Table 8-8. Dietary Suggestions for Hypertensive Patients]

[Table 8-9. The DASH Diet Sample Menu Based on 2000 Calories per Day]

   combination with other agents (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, and calcium channel blockers) unless compelling indications for the use of other medication classes exist or if the patient has comorbid conditions that would suggest the use of classes other than thiazide diuretics (Figure 8-2, and Tables 8-5 and

8-10).

• Current data also suggest that angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and angiotensin II receptor blockers (ARBs) can also be considered as initial agents for the treatment of hypertension. European hypertension guidelines do not recommend one particular class of antihypertensive over another for first-line therapy but instead emphasize the importance of selecting a therapy for each individual on the basis of the comorbidities he or she may have.

• For patients who are 20/10 mm Hg greater than their goal blood pressure, two-drug combination therapy (one drug is a diuretic) should be strongly considered.

• If a patient requires a second agent for treatment of hypertension, it is strongly recommended that it be a diuretic if one is not chosen as the initial agent.

• All causes for inadequate response should be addressed before additional agents are added to a patient's antihypertensive regimen (Box 8-3).

• Vasodilators, α1-receptor antagonists, α2-receptor agonists, and postganglionic adrenergic neuron blockers should be avoided as initial agents for hypertension.

Diuretics

Thiazide and thiazide-like diuretics

See

Table 8-11 for a list of thiazide and thiazide-like diuretics, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

• Direct arteriole dilation

• Reduction of total fluid volume through the inhibition of sodium reabsorption in the distal tubules, which causes increased excretion of sodium, water, potassium, and hydrogen

• Increase in the effectiveness of other antihypertensive agents by preventing reexpansion of plasma volume

• Significant decrease in efficacy in renal failure: serum creatinine > 2 mg/dL or glomerular filtration rate (GFR) < 30 mL/min

• Diuretics are also available in combination with other drugs (

Table 8-12).

Patient instructions and counseling

• Medication may be taken with food or milk.

• Take early in the day to avoid nocturia.

• Medication may increase sensitivity to sunlight. Consider using sunscreen with SPF (sun protection factor) > 15.

• Medication may increase blood glucose in diabetics.

• Report problems with muscle cramps, which may indicate decreased potassium level.

Drug-drug and drug-disease interactions

• Steroids cause salt retention and antagonize thiazide action.

• NSAIDs blunt thiazide response.

• Class IA or III antiarrhythmics (that prolong the QT interval) may cause torsades de pointes with diuretic-induced hypokalemia.

• Probenecid and lithium block thiazide effects by interfering with thiazide excretion into the urine.

• Thiazides decrease lithium renal clearance and increase risk of lithium toxicity.

Parameters to monitor

• Blood pressure

• Weight

• Serum electrolytes and uric acid

• BUN and creatinine

• Cholesterol levels

Loop diuretics

See Table 8-11 for a list of loop diuretics, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

• Reduction of total fluid volume occurs through the inhibition of sodium and chloride reabsorption in the ascending loop of Henle, which causes increased excretion of water, sodium, chloride, magnesium, and calcium.

• Loop diuretics are more effective than thiazides in patients with renal failure: serum creatinine > 2 mg/dL or GFR < 30 mL/min.

Patient instructions and counseling

• Medication may be taken with food or milk.

• Take early in the day to avoid nocturia.

[Table 8-10. Considerations for Individualizing Antihypertensive Drug Therapy]

• Medication may increase sensitivity to sunlight. Consider using sunscreen with SPF > 15.

• Medication may increase blood glucose in diabetics.

• Report problems with muscle cramps, which may indicate decreased potassium level.

• Rise slowly from a lying or sitting position.

Box 8-3. Causes of Inadequate Responsiveness to Therapy

Pseudoresistance

• "White-coat hypertension" or office elevations

• Pseudohypertension in older patients

• Use of regular adult cuff on a very obese arm


Nonadherence to therapy

Volume overload

• Excess salt intake

• Progressive renal damage (nephrosclerosis)

• Fluid retention from reduction of blood pressure

• Inadequate diuretic therapy


Drug-related causes

• Doses too low

• Wrong type of diuretic

• Inappropriate combinations

• Rapid inactivation (e.g., hydralazine)

• Drug actions and interactions

• Sympathomimetics

• Nasal decongestants

• Appetite suppressants

• Cocaine and other illicit drugs

• Caffeine

• Oral contraceptives

• Adrenal steroids

• Licorice (as may be found in chewing tobacco)

• Cyclosporine or tacrolimus

• Erythropoietin

• Antidepressants

• Nonsteroidal anti-inflammatory drugs


Associated conditions

• Smoking

• Increasing obesity

• Sleep apnea

• Insulin resistance or hyperinsulinemia

• Ethanol intake of more than 1 oz (30 mL) per day

• Anxiety-induced hyperventilation or panic attacks

• Chronic pain

• Intense vasoconstriction (arteritis)

• Organic brain syndrome (e.g., memory deficit)


Identifiable causes of hypertension

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

Drug-drug and drug-disease interactions

• Aminoglycosides can precipitate ototoxicity when combined with loop diuretics.

• NSAIDs blunt diuretic response.

• Class IA or III antiarrhythmics (that prolong the QT interval) may cause torsades de pointes with diuretic-induced hypokalemia.

• Probenecid blocks loop diuretic effects by interfering with excretion into the urine.

Parameters to monitor

• Weight

• Serum electrolytes

• BUN and creatinine

• Uric acid

• Hearing (in high doses)

Potassium-sparing diuretics

See Table 8-11 for a list of potassium-sparing diuretics, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

• Potassium-sparring diuretics interfere with potassium and sodium exchange in the distal tubule, decrease calcium excretion, and increase magnesium loss.

Patient instructions and counseling

• Take early in day to avoid nocturia.

• Take after meals.

• Avoid excessive ingestion of foods high in potassium and use of salt substitutes.

• Medication may increase blood glucose in diabetics.

• Report problems with muscle cramps, which may indicate decreased potassium levels.

• Sexual dysfunction is possible.

Drug-drug and drug-disease interactions

• ACE inhibitors may increase risk of hyperkalemia.

• Indomethacin can cause decrease in renal function when combined with triamterene.

• Cimetidine increases bioavailability and decreases clearance of triamterene.

Parameters to monitor

• Weight

• Serum electrolytes (especially potassium)

• BUN and creatinine

[Table 8-11. Thiazide Diuretics, Thiazide-Like Diuretics, Loop Diuretics, Potassium-Sparing Agents, and Aldosterone-Receptor Blocker]

Adrenergic Inhibitors

Postganglionic adrenergic neuron blockers

This medication class is best avoided unless necessary to treat refractory hypertension that is unresponsive to all other agents, because the medications are poorly tolerated. See

Table 8-13 for a list of postganglionic adrenergic neuron blockers, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

Postganglionic adrenergic neuron blockers cause presynaptic inhibition of the release of the neurotransmitter from peripheral neurons by agonistic activity on the α2 receptor and depletion of the neurotransmitter

[Table 8-12. Combination Drugs for Hypertension]

[Table 8-13. Postganglionic Adrenergic Neuron Blockers]

through competitive uptake into the neurosecretory vesicles.

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Do not take over-the-counter (OTC) cold products without first asking the doctor or pharmacist.

• Rise slowly from a lying or sitting position.

• Report new fluid retention.

• Sexual dysfunction is possible.

Drug-drug and drug-disease interactions

• OTC sympathomimetics may potentiate an acute hypertensive effect.

• Tricyclic antidepressants and chlorpromazine antagonize therapeutic effects of guanethidine.

• Pheochromocytoma is a contraindication to this class of medications.

• This medication class should be avoided in patients with CHF, angina, and cerebrovascular disease.

Parameters to monitor

• History of depression (reserpine)

• Sleep disturbances, drowsiness, and lethargy (reserpine)

• Symptoms of peptic ulcer (reserpine)

Centrally active α2-agonists

See

Table 8-14 for a list of centrally active α2-agonists, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

These medications cause decreased sympathetic outflow to the cardiovascular system by agonistic activity on central α2 receptors.

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Exercise sedation precautions.

• Fever and flu-like symptoms may represent hepatic dysfunction (methyldopa).

• Report new fluid retention.

• Sexual dysfunction is possible.

Drug-drug and drug-disease interactions

• Use cautiously with other sedating medications.

• Use cautiously in patients with angina, recent myocardial infarction (MI), cerebrovascular accident (CVA), and hepatic or renal disease (guanabenz and guanfacine).

[Table 8-14. Centrally Active α2-Agonists]

Parameters to monitor

• Complete blood count (CBC)—positive Coombs test in 25% of those tested; less than 1% develop hemolytic anemia (methyldopa)

• Sleep disturbances, drowsiness, or dry mouth

• Symptoms of depression

• Impotence

• Pulse

• Rebound hypertension

Peripherally acting α1-adrenergic blockers

See

Table 8-15 for a list of peripherally acting α1-adrenergic blockers, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

• Blocks peripheral α1 postsynaptic receptors, which causes vasodilation of both arteries and veins (indirect vasodilators)

• Causes less reflex tachycardia than do direct vasodilators (hydralazine and minoxidil)

Patient instructions and counseling

• Take first dose of no more than 1 mg of any agent, and take at bedtime.

• Rise slowly from a lying or sitting position.

• Medication may cause dizziness.

• Priapism is possible.

[Table 8-15. Peripherally Acting α1-Adrenergic Blockers]

Drug-drug and drug-disease interactions

• NSAIDs decrease antihypertensive effects of α1 blockers.

• Increased antihypertensive effects occur with diuretics and β-blockers.

Parameters to monitor

• BP and pulse

• Peripheral edema

β-blockers

See

Table 8-16 for a list of β-blockers, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

These medications competitively block response to β-adrenergic stimulation:

• Block secretion of renin

• Decrease cardiac contractility, thereby decreasing cardiac output

• Decrease central sympathetic output

• Decrease heart rate, thereby decreasing cardiac output

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Exercise sedation precautions (with lipid-soluble compounds).

• Abrupt withdrawal of the drug should be avoided.

• Sexual dysfunction is possible.

Drug-drug and drug-disease interactions

• Use with caution in patients with diabetes.

• Use with caution in patients with Raynaud's phenomenon or peripheral vascular disease.

• β-blockers may decrease effectiveness of sulfonylureas.

• Nondihydropyridines may increase effect and toxicity of β-blockers.

Parameters to monitor

• ECG

• Rebound hypertension

• Cholesterol levels

• Pulse (apical and radial)

• Glucose levels

[Table 8-16. β-Blockers and Combination α- and β-Blockers]

Direct Vasodilators

This medication class is best avoided (second-line agents) unless necessary to treat refractory hypertension that is unresponsive to all other agents.

These agents should not be used alone secondary to increases in plasma renin activity, cardiac output, and heart rate and should therefore be used only when β-blockers and diuretics are part of the antihypertensive regimen.

See

Table 8-17 for a list of direct vasodilators, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

These agents cause direct relaxation of peripheral arterial smooth muscle and thereby significantly decrease peripheral resistance.

[Table 8-17. Direct Vasodilators]

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Hirsutism is possible (minoxidil).

• Report any new symptoms of fatigue, malaise, low-grade fever, and joint aches.

• Report rapid weight gain (> 5 pounds), unusual swelling, and pulse increases of > 20 beats per minute above normal.

• Rise slowly from a lying or sitting position.

Drug-drug and drug-disease interactions

• Use with caution in patients with pulmonary hypertension.

• Use with caution in patients with significant renal failure or CHF.

• Use with caution in patients with coronary artery disease or a recent MI.

Parameters to monitor

• Weight (fluid status)

• BP and pulse

• CBC with antinuclear antibody test (hydralazine)

Calcium Antagonists

Low-renin hypertensive, African American, and elderly patients respond well to this class of medications. See

Table 8-18 for a list of calcium antagonists, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

• Inhibits the influx of calcium ions through slow channels in vascular smooth muscle and causes relaxation of both coronary and peripheral arteries

• Causes sinoatrial (SA) and atrioventricular (AV) nodal depression and a decrease in myocardial contractility (nondihydropyridines)

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Constipation is possible (verapamil).

• Report any new symptoms of shortness of breath, fatigue, or increased swelling of the extremities.

• Rise slowly from a lying or sitting position.

[Table 8-18. Calcium Antagonists]

Drug-drug and drug-disease interactions

• Use with caution in patients on β-blockers (nondihydropyridines), which may increase CHF and bradycardia. This combination can also cause conduction abnormalities to the AV node.

• Use with extreme caution in patients with conduction disturbances in the SA or AV node.

• Grapefruit juice may increase the levels of some dihydropyridines.

Parameters to monitor

• ECG

• Peripheral edema

• BP and pulse

• Bowel habits

• Symptoms of conduction disturbances

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Ethnic differences exist in the response to these classes of medications. These agents are relatively ineffective as monotherapy in African American patients. However, the addition of diuretic therapy has been shown to sensitize African American patients to these agents to obtain similar responses as in non-African American patients.

See

Table 8-19 for a list of ACEIs and ARBs, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

ACEIs

• Inhibit the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor; see Figure 8-1)

[Table 8-19. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers]

• Indirectly inhibit fluid volume increases by inhibiting angiotensin II-stimulated release of aldosterone

ARBs

• Inhibit the binding of angiotensin II to the angiotensin II receptor, thereby inhibiting the vasoconstrictive properties of angiotensin II as well as its ability to stimulate release of aldosterone

• Currently considered as alternative therapy in patients not able to tolerate ACEIs because of cough

Patient instructions and counseling

• Report symptoms of dizziness or hypotension.

• Symptoms of swelling of the lips, mouth, or face should be considered an emergency. Report immediately to a doctor's office or emergency department.

• Report new rashes (especially with captopril).

• Do not use salt substitutes containing potassium, and do not take OTC potassium supplements.

• Rise slowly from a lying or sitting position.

Drug-drug and drug-disease interactions

• NSAIDs will decrease the effectiveness of ACEIs and ARBs.

• Potassium-sparing diuretics, potassium supplements, and salt substitutes will increase the risk of hyperkalemia when used in combination with ACEIs and ARBs.

• ACEIs and ARBs should be avoided in patients with bilateral renal artery stenosis or stenosis in a single kidney.

• ACEIs and ARBs should be avoided in pregnant patients.

Parameters to monitor

• Serum electrolytes (especially creatinine and potassium)

• Symptoms of angioedema

• BP

• Symptoms of hypotension

• CBC (especially with captopril and enalapril) for neutropenia, which is more common in patients with preexisting renal impairment

• Cough

• Urinary proteins

Direct Renin Inhibitor

• See

Table 8-20 for a list of direct renin inhibitors, their usual dose range, and adverse effects associated with these medications.

Mechanism of action

Direct renin inhibitors competitively inhibit human renin, which decreases plasma renin activity and inhibits the conversion of angiotensinogen to angiotensin I.

Patient instructions and counseling

• Medicine can be taken with or without food.

• Establish a routine pattern for taking aliskiren with regard to meals. High-fat meals decrease absorption significantly.

• Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light.

• Report symptoms of dizziness or hypotension.

• Diarrhea is possible.

• Symptoms of swelling of the lips, mouth, or face should be considered an emergency. Report immediately to a doctor's office or emergency department.

Drug-drug and drug-disease interactions

• Concomitant use of aliskiren with cyclosporine is not recommended.

[Table 8-20. Direct Renin Inhibitors]

• Potassium-sparing diuretics, potassium supplements, and salt substitutes will increase risk of hyperkalemia when used in combination with aliskiren.

• Blood concentrations of furosemide are significantly reduced when given with aliskiren.

• Ketoconazole significantly increases aliskiren plasma levels.

• Aliskiren should be avoided in pregnant patients.

Parameters to monitor

• Symptoms of angioedema

• BP

• Symptoms of hypotension

• Serum electrolytes (especially creatinine and potassium)

8-4. Hypertensive Urgencies and Emergencies

Introduction

The classification of hypertensive urgencies and emergencies is determined by the presence or absence of acute target-organ damage, not by BP, and determines the appropriate treatment approach.

The relative rise and rate of increase in BP is more important than the actual BP.

Hypertensive Emergencies

Acute elevations of BP (> 180 mm Hg systolic or > 120 mm Hg diastolic) with the presence of acute or ongoing target organ damage constitute a hypertensive emergency (Box 8-4). This situation requires immediate lowering of BP to prevent or minimize target organ damage.

Table 8-21 shows details of parenteral drugs used for treatment of hypertensive emergencies. Such emergencies should be treated as follows:

• As an initial goal, reduce mean arterial pressure (MAP) by no more than 25% within minutes to hours. Reach BP of 160/100 mm Hg within 2-6 hours.

• Measure BP every 5-10 minutes until goal MAP is reached and life-threatening target organ damage resolves.

• Maintain goal BP for 1-2 days, and further reduce BP toward normal over several weeks.

• Excessive falls in BP may precipitate renal, cerebral, or coronary ischemia.

• Intravenous agents are preferred because of the ability to titrate dosages on the basis of BP response; however, specific agents should be chosen on the basis of patient findings (

Table 8-22).

Hypertensive Urgencies

Hypertensive urgencies are accelerated, malignant, or perioperative elevations in blood pressure in the absence of new or progressive target organ damage; therefore, immediate lowering of BP is not required.

Table 8-23 shows the agents used to treat hypertensive urgencies. Such situations require the following considerations:

• There is no agent of choice; medications should be selected on the basis of patient characteristics.

• Oral therapy is preferred.

• Onset of action should be in 15-30 minutes, and peak effects should be seen in 2-3 hours.

• Check BP every 15-30 minutes to ensure response.

• Use of immediate-release nifedipine is inappropriate to lower BP in patients with hypertensive urgencies.

8-5. Key Points

• Hypertension is defined as a systolic blood pressure exceeding 140 mm Hg, a diastolic blood pressure exceeding 90 mm Hg, or any condition in a patient that requires antihypertensive therapy.

[Table 8-21. Parenteral Drugs for Treatment of Hypertensive Emergencies]

• Prehypertension (120-139/80-89 mm Hg) represents a new classification in JNC-VII that significantly increases the risk of developing stage 1 hypertension. Lifestyle modifications should be stressed for this classification, and medication therapy should be used only for patients with compelling indications.

• Secondary causes of hypertension include renovascular disease, primary aldosteronism, Cushing's syndrome, pheochromocytoma,

[Table 8-22. Selected Agents for Specific Hypertensive Emergencies]

   aortic coarctation, and drugs (steroids and estrogens, alcohol, cocaine, cyclosporine and tacrolimus, sympathomimetics, erythropoietin, licorice, MAO inhibitors, tricyclic antidepressants, and NSAIDs).

• Recommended lifestyle modifications to improve both BP and overall cardiovascular health include losing weight; limiting alcohol intake; increasing aerobic physical activity; reducing sodium intake; maintaining adequate dietary intake of potassium, magnesium, and calcium; stopping smoking; and reducing dietary cholesterol and saturated fat intake.

• Diuretics are considered by JNC-VII to be the initial agent for treatment of hypertension in most patients unless compelling indications for the use of other medication classes exist or the patient has comorbid conditions that would suggest the use of classes other than diuretics.

• JNC-VII considers ACEIs, ARBs, β-blockers, and CCBs equivalent choices as initial therapy for hypertension.

• Vasodilators, α1-receptor antagonists, α2-receptor agonists, and postganglionic adrenergic neuron blockers should be avoided as initial agents for hypertension.

• Antihypertensive drug therapy should be individualized. There are classifications of recommendations from JNC-VII based on the level of evidence, which include compelling indication

[Table 8-23. Agents Used to Treat Hypertensive Urgencies]

   unless contraindicated, possibility of favorable effects on comorbid conditions, and possibility of unfavorable effects on comorbid conditions.

• The classification and treatment of hypertensive urgencies and emergencies is determined by the presence or absence of acute target organ damage and not by blood pressure.

• All causes for inadequate response should be addressed before additional agents are added to a patient's antihypertensive regimen (i.e., pseudoresistance, nonadherence, volume overload, drug-related causes, associated conditions, and secondary causes of hypertension).

8-6. Questions

1.

According to the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII), all of the following agents are suitable as initial therapy for the treatment of uncomplicated hypertension except

A. hydrochlorothiazide.

B. chlorthalidone.

C. indapamide.

D. hydralazine.

E. atenolol.

 

2.

Hyperkalemia is a possible adverse effect of all the following medications except

A. trandolapril.

B. Teveten.

C. doxazosin.

D. amiloride.

E. captopril.

 

3.

A 48-year-old patient presents with a new diagnosis of hypertension. The patient is also noted to have congestive heart failure with an ejection fraction of 28%. Which agent would be an appropriate choice as initial therapy in this patient based on JNC-VII?

A. Clonidine

B. Guanethidine

C. Diltiazem

D. Perindopril

E. Nisoldipine

 

4.

A 62-year-old patient with a history of hypertension and gout presents to begin pharmacotherapy for hypertension. Which agent is the most appropriate choice as initial therapy based on JNC-VII?

A. Chlorothiazide

B. Torsemide

C. Tenormin

D. Chlorthalidone

E. Metolazone

 

5.

All of the following medications can cause bradycardia except

A. terazosin.

B. verapamil.

C. diltiazem.

D. Ziac.

E. clonidine.

 

6.

A patient requires a cardioselective β-blocker in his or her outpatient medication regimen after recent discharge from the hospital with a new myocardial infarction. You suggest he or she take

A. labetalol.

B. esmolol.

C. propranolol.

D. atenolol.

E. carvedilol.

 

7.

A patient presents to your ambulatory clinic with a blood pressure of 210/125 mm Hg. Past medical history is significant for type 2 diabetes, congestive heart failure, and renal insufficiency. Which of the following would cause the patient to be classified as a hypertensive emergency?

A. Blood glucose levels > 300 mg/dL, which increase the patient's risk for acute renal failure

B. A serum creatinine of 3 mg/dL

C. Nausea, vomiting, and diarrhea for 3 days

D. S4 gallop and a chest x-ray consistent with pulmonary edema

E. Polyuria combined with polydipsia

 

8.

What are the treatment goals for the patient with hypertensive emergency described in question 7?

A. Systolic pressure should be reduced to 120 mm Hg within the first hour of treatment to reduce the risk of further end organ damage.

B. Diastolic pressure should be reduced to 80 mm Hg within the first hour of treatment to reduce the risk of further end organ damage.

C. Blood pressure should be reduced to 160/100 mm Hg in the first 2-6 hours of therapy.

D. Mean arterial pressure should be reduced by at least 50% within the first minutes to hours of therapy.

E. Blood pressure should be reduced to no lower than 180/110 mm Hg in the first hour, because excessive falls in blood pressure may precipitate coronary ischemia.

 

9.

What would be the recommended treatment for the patient with hypertensive emergency described in question 7?

A. Clonidine orally, 0.1-0.2 mg; repeat in 1-2 hours as needed (up to 0.6 mg)

B. Labetalol orally, 100-400 mg; repeat in 2-3 hours as needed

C. Nifedipine sublingually, 10 mg; repeat in 0.5-1.0 hours as needed (up to 60 mg)

D. Labetalol intravenously, 20- to 80-mg bolus, followed by 0.5-2.0 mg/min infusion

E. Enalaprilat intravenously 1.25-5.0 mg every 6 hours

 

10.

Which of the following antihypertensive agents can cause first-dose syncope, palpitations, peripheral edema, and priapism?

A. Hydralazine

B. Nitroprusside

C. Prazosin

D. Verapamil

E. Moexipril

 

11.

Which of the following antihypertensive agents is most likely to cause lupus syndrome, postural hypotension, and peripheral neuropathy?

A. Atenolol

B. Hydralazine

C. Guanfacine

D. Mibefradil

E. Nitroprusside

 

12.

Which of the following medications is not associated with drug-induced hypertension?

A. Prednisone

B. Indomethacin

C. Rosiglitazone

D. Cocaine

E. Cyclosporine

 

13.

What is the best recommendation for antihypertensive medication in a patient who has atrial fibrillation, coronary artery disease with angina, and hyperthyroidism?

A. Minoxidil

B. Betaxolol

C. Telmisartan

D. Nicardipine

E. Amiloride

 

14.

What antihypertensive agent should not be used in a patient with essential hypertension and a history of depression with suicidal ideation?

A. Captopril

B. Prazosin

C. Metolazone

D. Reserpine

E. Amlodipine

 

15.

All of the following are secondary causes of hypertension except

A. renovascular disease.

B. pheochromocytoma.

C. systemic lupus erythematosus.

D. primary aldosteronism.

E. aortic coarctation.

 

Answer questions 16-20 on the basis of the patient medication profile provided on the next page.

A. I only is correct.

B. III only is correct.

C. I and II are both correct.

D. II and III are both correct.

E. I, II, and III are correct.

 

Date: 4/12/09

Patient name: Buddy Manwich

Address: 61 Heavenly Highway

Phone: 555-8181

Date of birth: 4/14/44

Height: 5'11"

Weight: 248 lb

Race: African American

Allergies: NKDA

Known diseases: DM (15 years), HTN (20 years), Obstructive Sleep Apnea (5 years), Osteoarthritis

Pharmacist notes and other patient information: + tobacco—1.5 ppd, 4-5 cups of coffee/day, ETOH—2 drinks/week

OTC use: Aleve, Actron

Date

Rx No.

Medication/Strength

Route

Quantity

Regimen

Refills

Pharmacist

Prescriber

1/15/09

001

Glipizide 5 mg

PO

30

1 qd

5

BCE

NTE

1/15/09

002

Lisinopril 5 mg

PO

30

1 qd

5

BCE

NTE

1/15/09

003

Hydrodiuril 12.5 mg

PO

30

1 qd

5

BBC

NPR

1/20/09

003

Ibuprofen 800 mg

PO

90

1 tid

5

REM

FTD

2/11/09

001-RF

Glipizide 5 mg

PO

30

1 qd

4

BCE

NTE

2/11/09

003-RF

Hydrodiuril 12.5 mg

PO

30

1 qd

4

BBC

NPR

2/11/09

004-RF

Ibuprofen 800 mg

PO

90

1 td

4

REM

FTD

3/13/09

001-RF

Glipizide 5 mg

PO

30

1 qd

3

BCE

NTE

3/13/09

002-RF

Lisinopril 5 mg

PO

30

1 qd

3

BCE

NTE

3/13/09

004-RF

Ibuprofen 800 mg

PO

90

1 td

3

REM

FTD

16.

Possible complications that the patient is at risk of developing secondary to uncontrolled hypertension include

I. hyperaldosteronism.

II. myocardial infarction.

III. blindness.

 

17.

Education regarding lifestyle modification issues in this patient should include

I. Limit smoking to a half pack per day and alcohol intake to no more than 2 drinks per day.

II. Maintain adequate intake of dietary magnesium, calcium, and sodium.

III. Increase aerobic physical activity, lose weight, and limit dietary saturated fat and cholesterol.

 

18.

Possible reasons for the patient's blood pressure being uncontrolled include

I. Use of NSAIDs, which cause decreased effectiveness of ACE inhibitor therapy

II. Possible problems with adherence to antihypertensive therapy

III. Lack of blood pressure response to ACE inhibitor therapy, which should not be used in combination with diuretics in an African American patient

 

19.

The appropriate initial antihypertensive agent in this patient could be

I. benazepril.

II. terazosin.

III. minoxidil.

 

20.

If the patient is not able to tolerate lisinopril because of adverse effects such as cough, an appropriate alternative agent would be

I. telmisartan.

II. labetalol.

III. guanabenz.

 

8-7. Answers

1.

D. Appropriate choices for initial agents in the treatment of uncomplicated hypertension include α-blockers and diuretics. Hydralazine is a direct vasodilator, which would never be considered a first-line agent in the treatment of hypertension.

 

2.

C. Hyperkalemia is a possible side effect with angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and potassium-sparing diuretics. Doxazosin is a peripherally acting α1 blocker, which does not cause hyperkalemia.

 

3.

D. For patients who have hypertension and congestive heart failure, JNC-VII recommends the use of ACE inhibitors, diuretics, β-blockers, and aldosterone antagonists (see Table 8-10). The only listed ACE inhibitor is perindopril.

 

4.

C. For patients who have hypertension and gout, JNC-VII recommends not using diuretic therapy, which increases the risk of gouty attacks (see Table 8-10). The only medication listed that is not a diuretic is atenolol (Tenormin), which is a β-blocker.

 

5.

A. Verapamil and diltiazem are nondihydropyridine calcium channel blockers, Ziac (bisoprolol and hydrochlorothiazide) is a β-blocker, and clonidine is a centrally acting α2 agonist. They all have negative inotropic effects on the myocardium. Terazosin is a peripherally acting α1 blocker, which does not cause bradycardia.

 

6.

D. Labetalol, propranolol, and carvedilol are all nonselective β-blockers. Esmolol is a cardioselective agent available only in injectable form and, therefore, would not be for outpatient use. Atenolol is a cardioselective β-blocker that is available as an oral tablet and, therefore, can be used for outpatient dosing.

 

7.

D. The classification of hypertensive urgencies and emergencies is determined by the presence or absence of acute target organ damage and not by the actual blood pressure measurement. Presence of an S4 gallop and a chest x-ray consistent with pulmonary edema suggests acute left ventricular failure with pulmonary edema, which represents defined target organ damage and, in turn, means the patient should be classified as a hypertensive emergency.

 

8.

C. According to JNC-VII, the initial goal of blood pressure lowering in patients with hypertensive emergencies is a drop in mean arterial pressure of no more than 25% within minutes to hours and to 160/100 mm Hg within 2-6 hours.

 

9.

E. In a patient with CHF and a hypertensive emergency, recommended treatments include nitroglycerin, nitroprusside, and enalaprilat (Table 8-21). Clonidine and labetalol (PO) are incorrect choices because the patient requires intravenous (IV) therapy. Nifedipine SL is not indicated for immediate reduction of blood pressure. Labetalol IV is not an appropriate choice in this patient with CHF because it could decrease cardiac output.

 

10.

C. Possible side effects of peripherally acting α1 blockers (prazosin) include first-dose syncope, palpitations, peripheral edema, and priapism (Table 8-15).

 

11.

B. Possible side effects of direct vasodilators (hydralazine) include postural hypotension and peripheral neuropathy. However, lupus syndrome is unique to hydralazine and does not occur with minoxidil (Table 8-17).

 

12.

C. All agents listed are possible causes of drug-induced hypertension through multiple mechanisms except rosiglitazone (Box 8-3).

 

13.

B. The diagnoses of atrial fibrillation, coronary artery disease with angina, and hyperthyroidism are all considered comorbid conditions with hypertension in which the use of β-blockers may have favorable effects.

 

14.

D. Because of its possible increased risk of depression, reserpine should not be used for patients for whom the risk for depression or suicide already exists.

 

15.

C. All listed diseases are possible causes of secondary hypertension through various mechanisms, except systemic lupus erythematosus.

 

16.

D. Uncontrolled hypertension causes multiple organ system problems, including cardiovascular (CHF, MI, and peripheral arterial disease); ophthalmologic (retinopathy and blindness); cerebrovascular (transient ischemic attack and CVA); and renovascular (nephropathy, renal failure, and dialysis) issues. Therefore, this patient is at risk for MI and blindness, not for hyperaldosteronism.

 

17.

B. Lifestyle modification issues to be considered in hypertensive patients include weight loss; limit of alcohol intake; increased aerobic activity; reduced sodium intake; maintenance of adequate dietary potassium, calcium, and magnesium intake; and smoking cessation.

 

18.

C. Possible causes for inadequate responsiveness to therapy are listed in Box 8-3.

 

19.

A. In patients with hypertension and comorbid conditions of CHF and diabetes, the initial agent should be an ACE inhibitor (Table 8-10).

 

20.

A. In patients who cannot tolerate ACE inhibitor therapy secondary to the adverse effect of cough, angiotensin II receptor antagonists are considered good alternative agents.

 

8-8. References

Carter BL, Saseen JL. Hypertension. In: DiPiro JT, Talbert RL, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2002:157-83.

JNC-VII (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure). Hypertension. 2003;42:1206-52.

JNC-7 Express (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC-7] Express). NIH Pub. No. 03-5233, May 2003. Available at www.nhlbi.gov/guidelines/hypertension/express.pdf.