improve the symptoms of BPH by reducing urethral tone and

alleviating bladder outlet obstruction. Terazosin and doxazosin

are both approved for the treatment of BPH. Prazosin should not

be used because of the need for frequent dosing. Improvements

in BPH symptoms with α-blockers are dose-related. A high dose

is often needed, and this increases the risk of side effects, such as

orthostatic hypotension. In J.L., an α-blocker will lower his BP

and improve his urinary symptoms.

CASE 14-12, QUESTION 3: J.L. prefers to try doxazosin

rather than undergo surgery to relieve his symptoms of BPH.

How should this agent be started?

For J.L., it would be best to add a low dose of doxazosin to

his present regimen. Based on his BP response and tolerance, the

dose can be titrated up. One of his other antihypertensive agents

can be decreased if he becomes hypotensive. The initial dose of

doxazosin should not exceed 1 mg daily and it should be given at

bedtime. This can minimize orthostatic hypotension, which is the

most frequent side effect ofα-blockers. This complication is most

pronounced with the first dose, but can persist in some patients.

Moreover, if an α-blocker is selected as add-on therapy in patients

like J.L. with resistant hypertension, nighttime administration of

an α-blocker has been shown to be effective in further lowering

BP.156

CASE 14-12, QUESTION 4: How should J.L. be counseled

regarding side effects of doxazosin?

α-Blockers are well tolerated if dosed appropriately. J.L. could

experience side effects, such as drowsiness, headache, weakness,

palpitations from reflex tachycardia, and nausea, but these do

not occur in all patients. Patients starting an α-blocker should be

instructed to take the initial dose at bedtime and to anticipate the

first-dose effect of orthostatic hypotension. Specifically, patients

should be counseled to rise more slowly from a seated or supine

position.

Miscellaneous Agents

MIXED α/β-BLOCKERS

CASE 14-13

QUESTION 1: R.P. is a 68-year-old man with hypertension

and a history of ischemic stroke (1 year ago). Two months

ago, his BP values were 164/94 mm Hg (162/98 mm Hg

when repeated), with a heart rate of 62 beats/minute while

on atenolol 50 mg daily. He was started on benazepril/HCTZ

10/12.5 mg daily 2 months ago. His BP today is 142/82 mm

Hg (144/82 mm Hg when repeated). All his laboratory values

are normal except his serum creatinine, which is 1.9 mg/dL.

J.L. has implemented lifestyle modification to the best of his

ability. Could his atenolol be replaced with an agent such as

labetalol and carvedilol?

Labetalol and carvedilol (Table 14-15) are nonselective

β-blockers that also have α1-receptor blocking activity. Their

antihypertensive effects are only somewhat similar to a combination of a nonselective β-blocker with an α1-antagonist.

These agents produce vasodilation because of the α-blocker

effects. The only other β-blocker that provides vasodilation is

nebivolol. However, nebivolol produces vasodilation without

blockade of α-receptors. The same precautions and contraindications relevant to nonselective β-blockers apply to both carvedilol

and labetalol because they block both β1- and β2-receptors

(Table 14-10).

Carvedilol is approved for both hypertension and left ventricular dysfunction. Carvedilol has been shown to reduce morbidity

and mortality in a wide range of patients with left ventricular

dysfunction.157,158 Labetalol and carvedilol have no clear advantage over other β-blockers in most patients with hypertension,

with the exception that they offer a dual mechanism of action

within a single drug formulation. In patients with type 2 diabetes, carvedilol has been shown to have no significant effect

on glucose in comparison to metoprolol, which may slightly

increase glucose.159 However, R.P. does not have diabetes. If R.P.

had the compelling indication of left ventricular dysfunction,

switching to carvedilol would be reasonable. His heart rate is 62

beats/minute, so increasing the atenolol dose to 100 mg daily is

possible but may induce heart block. Atenolol is renally eliminated, so his present dose is probably causing more BP lowering than usual doses based on his elevated serum creatinine.

Increasing his ACEI will help to control both his BP and preserve his kidney function. This can be done without increasing

his HCTZ by switching his fixed-dose combination product to

benazepril/HCTZ 20/12.5 mg daily or simply increasing both the

ACE and HCTZ by doubling his current dose.

DIRECT RENIN INHIBITORS

CASE 14-13, QUESTION 2: How is aliskiren different from

an ACEI or ARB?

Aliskiren is a direct renin inhibitor. It inhibits the first step of

the RAAS, which results in reduced PRA and BP lowering. This

is different from the decreased production of angiotensin II with

ACEIs and the blocked angiotensin II receptor effects with ARBs;

however, BP-lowering effects are similar to those with ACEIs and

ARBs. Aliskiren has a 24-hour half-life and, similar to most ACEIs

and ARBs, is dosed once daily.

Some similarities and some differences exist among the side

effects associated with aliskiren when compared with ACEIs and

ARBs. Aliskiren should not be used in pregnancy because of

the known teratogenic effects from blocking the RAAS system.

Increases in serum creatinine and serum potassium have been

associated with aliskiren. These are similar to ACEI and ARB

therapy, and are mediated by the inhibition of angiotensin II

vasoconstrictive effects on the efferent arterioles of the kidney

and blocking of aldosterone. Monitoring of serum creatinine

and serum potassium should be done in patients treated with

aliskiren, particularly in those treated with the combination of

aliskiren and an ACEI, ARB, potassium-sparing diuretic, or aldosterone antagonist. Angioedema has been also reported in

patients treated with aliskiren.

CASE 14-13, QUESTION 3: What is the role of aliskiren in

treating R.P.’s hypertension? Can aliskiren be added to his

drug regimen considering he is on an ACEI?

The exact role of aliskiren in treatment of hypertension is

unclear. It is approved as monotherapy or in combination therapy.

328 Section 2 Cardiac and Vascular Disorders

The BP reductions with aliskiren as monotherapy are similar to

those seen with an ACEI, ARB, or CCB (specifically amlodipine).

Aliskiren provides additive BP lowering when used in combination with HCTZ, ACEI, ARB, and CCB. Its efficacy in combination with maximal doses of ACEI is unknown, however. Aliskiren

is an alternative antihypertensive agent at this time because of

unknown long-term effects on CV events.

CENTRAL α2-AGONISTS

The antihypertensive effects of α2-agonists (Table 14-16) are

attributed to their central α2-agonist activity. Stimulation of α2-

receptors in the CNS inhibits sympathetic outflow (via negative feedback) to the heart, kidneys, and peripheral vasculature,

resulting in peripheral vasodilation. Although the α2-agonists

effectively lower BP, they have many potential side effects and

have not been evaluated in trials focused on CV events.

CLONIDINE

CASE 14-14

QUESTION 1: T.M. is a 43-year-old man. He is a truck driver

with a 5-year history of hypertension. His Framingham risk

score is less than 10%, and he does not have hypertensionassociated complications or any compelling indications. Secondary causes have been ruled out. His regimen is losartan/HCTZ 100/25 mg daily and sustained-release diltiazem

240 mg daily. Other antihypertensive drugs have failed

because of various side effects (captopril and lisinopril,

dry cough; atenolol and carvedilol, fatigue; nifedipine and

amlodipine, edema; terazosin, orthostasis). T.M. has been

adherent with his present medications and lifestyle modification, but has been unable to quit smoking. His clinic values

have been similar and averaged 150/95 mm Hg for the past

3 months. Clonidine 0.1 mg twice daily is added to his regimen. What problems might occur if T.M. is not adherent

with clonidine therapy?

α2-Agonists are most effective when used with a diuretic

because they all can cause fluid retention. Ideally, they should be

used with agents that have different mechanisms of action and

with agents that do not affect other central adrenergic receptors. Clonidine can cause rebound hypertension when abruptly

stopped. T.M.’s occupation may place him at risk for this complication if he misses doses because of unusual work hours or

prolonged travel.

CASE 14-14, QUESTION 2: How should T.M.’s clonidine

dose be titrated?

Clonidine should be started at a low dosage and gradually

increased to achieve optimal BP lowering with minimal side

effects. The immediate-release tablet is started as 0.1 mg twice

daily, with 0.1- or 0.2-mg/day increases every 2 to 4 weeks until

his BP goal is achieved or side effects appear. Clonidine also

is available as an extended-release tablet and as a transdermal

patch. The patch formulation releases drug at a controlled rate

for 7 days and may have fewer side effects than the oral dosage

form. The onset of initial BP effect may be delayed for 2 to 3

days after application; thus, rebound hypertension might occur

when oral clonidine is switched to transdermal. To prevent this,

an oral dose should be taken on the first day that the transdermal

patch is used. Anticholinergic side effects, such as sedation and

dry mouth, are the most frequent and bothersome side effects of

clonidine. These are especially problematic in elderly patients.

CASE 14-14, QUESTION 3: After several months, T.M.’s BP

is 148/84 mm Hg with clonidine 0.2 mg twice daily. However, he is now experiencing daytime somnolence and dry

mouth. What other α2-agonists are available?

METHYLDOPA

Methyldopa has been extensively evaluated and is considered

safe in pregnancy. Therefore, it is recommended as a first-line

agent when hypertension is first diagnosed during pregnancy.160

Beyond that, little role exists for methyldopa in the management

of hypertension. The usual initial dose is 250 mg administered

twice daily up to 2,000 mg/day. Methyldopa causes side effects

similar to those associated with clonidine, including sedation,

lethargy, postural hypotension, dizziness, dry mouth, headache,

and rebound hypertension. These may decrease with continued

use. Other significant side effects include hemolytic anemia and

hepatitis. Although these are both rare, they necessitate discontinuing the medication.

OTHERS

Guanfacine and guanabenz have a high incidence of side effects.

These agents can cause dry mouth, sedation, dizziness, orthostatic hypotension, insomnia, constipation, and impotence.

Guanfacine has a long half-life and may have less rebound hypertension than other α2-agonists. The adverse effects of other α2-

agonists (methyldopa, guanfacine, and guanabenz) are nearly

identical to those of clonidine. In general, patients who do not

tolerate one α2-agonist will not tolerate the others. An antihypertensive agent from a different class (aldosterone antagonist,

aliskiren, reserpine, or an arterial vasodilator) should be chosen

for T.M.

RESERPINE

CASE 14-14, QUESTION 4: Would reserpine be a reasonable option for T.M.?

Reserpine is one of the oldest antihypertensive agents currently available. It is extremely effective in lowering BP when

added to a thiazide diuretic. Reserpine is inexpensive, and is

dosed once daily. Several of the landmark trials that demonstrated reduced morbidity and mortality with BP lowering in

hypertension used reserpine. The SHEP trial used reserpine as a

second-step agent added to chlorthalidone in patients who could

not take atenolol.47

Low-dose reserpine (0.05–0.1 mg once daily) is effective at

lowering BP and has significantly fewer side effects compared

with high doses. Reserpine can cause nasal stuffiness in many

patients. Gastrointestinal ulcerations have been reported, but

they are associated with either parenteral administration or very

large doses. T.M. is a candidate for low-dose reserpine. He is

already taking a thiazide diuretic, which should always be used

with reserpine, and his therapeutic options are limited. Of all the

agents remaining for T.M., other than aliskiren, reserpine has the

most favorable side effect profile.

Many clinicians avoid reserpine because of the myth that it

can cause depression. This fear was generated from case reports

in the 1950s when high doses (0.5–1.0 mg/day) were used. Many

of the patients described in these cases would not meet modern

criteria for depression; rather, they would be considered oversedated. When reserpine is limited to a maximum of 0.25 mg daily,

depression is no more frequent than with other antihypertensive

agents.

329Essential Hypertension Chapter 14

ARTERIAL VASODILATORS

HYDRALAZINE

CASE 14-15

QUESTION 1: C.M. is a 56-year-old woman with a history

of hypertension and severe CKD (estimated GFR of 14 mL/

minute/1.73 m2). Her antihypertensive regimen consists of

torsemide 40 mg daily, amlodipine/olmesartan 10/40 mg

daily, metoprolol succinate 200 mg daily, and lisinopril 40

mg daily. She started hydralazine 25 mg three times daily

4 weeks ago when her BP was 148/92 and 146/90 mm Hg.

She has been very compliant, and her BP is now 146/88 mm

Hg with a heart rate of 82 beats/minute. Her lung fields are

clear, with 1+ bilateral pitting edema. Serum electrolytes

are within normal limits. Why was hydralazine used in C.M.?

Hydralazine causes direct relaxation of arteriolar smooth

muscle. Arterial vasodilators are infrequently used, except for

patients with severe CKD. In this population, hypertension is

difficult to control and often requires four or five agents. Severe

CKD results in increased renin release and increased fluid retention. Potent vasodilation, in combination with diuresis, is often

effective in lowering BP under these conditions. This vasodilation, however, stimulates the sympathetic nervous system and

results in a reflex tachycardia, increased PRA, and fluid retention. Thus, the hypotensive effects of direct arterial vasodilators

can quickly diminish with time when used as monotherapy. To

prevent this, arterial vasodilators should always be used in combination with both a β-blocker to counteract reflex tachycardia,

as well as a diuretic (often a loop diuretic if used in severe CKD)

to minimize fluid retention.

CASE 14-15, QUESTION 2: After 18 months, C.M.’s

hydralazine dose is 50 mg three times daily, and her BP

is at goal. She now complains of joint pain in both her right

and left hands, which extends to the wrists, and generalized weakness with frequent fevers. Laboratory findings for

C.M. showed a positive antinuclear antibodies test (diffuse),

a white blood cell count of 3,500/μL, and an erythrocyte

sedimentation rate of 45 mm/hour, and she is diagnosed

with drug-induced lupus. How should this be managed?

C.M.’s symptoms are consistent with drug-induced lupus

(DIL). Hydralazine is one of the most common agents reported

to cause DIL. Musculoskeletal pains are the most frequent

symptoms, but systemic symptoms and rash may also occur.

Hydralazine doses as low as 100 mg/day can cause DIL, and the

risk significantly increases when greater than 200 mg/day is used.

Hydralazine should be discontinued. Symptoms should subside within days or weeks, and complete resolution can be

expected.

MINOXIDIL

CASE 14-15, QUESTION 3: What alternatives to hydralazine

are available for C.M.?

C.M.’s BP responded to hydralazine, so she would likely benefit from another arterial vasodilator. Minoxidil, a potent arterial

vasodilator, is similar to hydralazine with regard to reflex tachycardia, increased CO, increased PRA, and fluid retention. Therefore, concomitant β-blocker and diuretic therapy is still needed.

Minoxidil should be reserved for patients such as C.M. who have

severe CKD or possibly for resistant hypertension.

CASE 14-15, QUESTION 4: How should C.M. be counseled

if minoxidil is started?

Hypertrichosis is a common adverse effect of oral minoxidil,

occurring in 80% to 100% of patients. The hair growth is not

associated with an endocrine abnormality and begins within the

first few weeks. It commonly occurs on the temples, between

the eyebrows, on the cheeks, and on the pinna of the ear. Hair

growth can extend to the back of the legs, arms, and scalp with

continued use. Some patients, especially women, find the hypertrichosis so intolerable that they stop treatment. Topical minoxidil is an approved therapy for male pattern baldness, but topical

administration does not provide BP-lowering effects.

Fluid retention with minoxidil is common, presenting as

edema and weight gain. If adequate diuresis is not maintained

during minoxidil therapy, left ventricular dysfunction may be

precipitated or worsened. This also occurs with hydralazine. The

compensatory reflex tachycardia with minoxidil also may precipitate angina in patients who have, or are at risk for, CAD.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e.Below are the key references

and websites for this chapter, with the corresponding reference

number in this chapter found in parentheses after the citation.

Key References

ACCORD Study Group et al. Effects of intensive blood-pressure

control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575.

(23)

Arguedas JA et al. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev. 2009(3):CD004349. (19)

Beckett NS et al. Treatment of hypertension in patients 80 years

of age or older. N Engl J Med. 2008;358:1887. (24)

Calhoun DA et al. Resistant hypertension: diagnosis, evaluation,

and treatment: a scientific statement from the American Heart

Association Professional Education Committee of the Council

for High Blood Pressure Research. Circulation. 2008;117:e510.

(13)

Chobanian AV et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of

High Blood Pressure. Hypertension. 2003;42:1206. (3)

Dorsch MP et al. Chlorthalidone reduces cardiovascular events

compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57:689. (131)

Ernst ME, Moser M. Use of diuretics in patients with

hypertension [published correction appears in N Engl J Med.

2010;363:1877]. N Engl J Med. 2009;361:2153. (37)

Flack JM et al. Management of high blood pressure in Blacks: an

update of the International Society on Hypertension in Blacks

consensus statement. Hypertension. 2010;56:780. (82)

Jamerson K et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.N Engl J Med. 2008;

359:2417. (115)

ONTARGET Investigators et al. Telmisartan, ramipril, or both

in patients at high risk for vascular events. N Engl J Med. 2008;

358:1547. (121)

330 Section 2 Cardiac and Vascular Disorders

Rosendorff C et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific

statement from the American Heart Association Council for

High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention [published correction appears in Circulation. 2007;116:e121]. Circulation. 2007;115:

2761. (15)

Key Websites

The American Heart Association. http://my.americanheart.

org

National Cholesterol Education Program. Risk Assessment

Tool for Estimating 10-year Risk of Developing Hard CHD

(Myocardial Infarction and Coronary Death). http://hp2010.

nhlbihin.net/atpiii/calculator.asp?usertype=prof

National Heart Lung and Blood Institute. The Seventh Report

of the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure (JNC 7).

http://www.nhlbi.nih.gov/guidelines/hypertension

National Kidney Foundation. Calculators for Health Care Professionals. http://www.kidney.org/professionals/KDOQI/

gfr calculator.cfm

Peripheral Vascular Disorders 15

Patricia M. Schuler and C. Wayne Weart

CORE PRINCIPLES

CHAPTER CASES

PERIPHERAL ARTERIAL DISEASE (PAD)

1 PAD is a sometimes-painful complication from stenosis or occlusion in the

peripheral arteries of the legs, usually caused by atherosclerosis. Intermittent

claudication can be associated with PAD, and is described as aching, cramping,

tightness, or weakness of the legs, which usually occurs during exertion.

Case 15-1 (Question 1)

2 Treatment for PAD should include therapeutic lifestyle changes and pharmacologic

intervention based on risk factors present. Specific interventions may include

smoking cessation; exercise; management of dyslipidemia, hypertension, and

diabetes; antiplatelet therapy; and verapamil.

Case 15-1 (Questions 2–9)

RAYNAUD’S PHENOMENON (RP)

1 RP is an exaggerated vasospastic response to cold or emotion, likely mediated

through sympathetic response to the precipitating stimuli. RP is classified as

primary or secondary, in which secondary causes include connective tissue diseases

and occupational-related neural damage.

Case 15-2 (Question 1)

2 Treatment for RP should include therapeutic lifestyle changes and pharmacologic

intervention based on clinical presentation and underlying etiology. First-line

interventions may include avoidance of cold stimuli and medications associated

with vasoconstriction, and treatment with calcium-channel blockers. Several other

therapies may be emerging as possible therapeutic options, including

renin-angiotensin-aldosterone inhibitors, topical nitroglycerin, statins, peripheral

α-adrenergic blockers, intravenous prostanoids, endothelin antagonists, and oral

phosphodiesterase inhibitors.

Case 15-2 (Questions 2–4)

NOCTURNAL LEG MUSCLE CRAMPS

1 Nocturnal leg muscle cramps are idiopathic, involuntary contractions occurring at

rest that cause a visible and palpable knot in the affected muscle, usually occurring

in the early hours of sleeping.

Case 15-3 (Question 1)

2 The primary treatment goal of nocturnal leg muscle cramps is the prevention of

episodes. Recommendations include stretching practices, alteration of sleeping

position, and treatment of modifiable causes (i.e., electrolyte abnormalities).

Case 15-3 (Question 2)

PERIPHERAL ARTERIAL DISEASE

Peripheral arterial disease (PAD) is a common and sometimes

painful complication from stenosis or occlusion in the peripheral arteries of the legs, usually caused by atherosclerosis. Some

clinicians and patients have characterized claudication pain as

“angina” of the legs. The association with coronary disease

becomes clear when considering the risk factors and pathology

of intermittent claudication (IC).

Intermittent claudication is described as aching, cramping,

tightness, or weakness of the legs, which usually occurs during

exertion. Claudication pain is relieved when the physical activity

is discontinued. Moreover, tissue ischemia, marked by numbness

or continuous pain in the toes or foot, may be present and can

331

332 Section 2 Cardiac and Vascular Disorders

lead to ulceration. IC is a painful condition that can severely limit

mobility and lead to tissue necrosis or amputation of the affected

limb. Many patients with PAD, however, are asymptomatic or

have atypical lower limb symptoms, such as leg fatigue, difficulty

walking, or similar nonspecific complaints. Patients may not seek

medical attention until the condition is advanced because of the

gradual onset of symptoms associated with IC.

Epidemiology

Peripheral arterial disease is a relatively common condition that

affects men and women equally, with a prevalence of 12%,1

although men have a twofold increased prevalence of symptomatic IC.2 The annual incidence of IC increases dramatically

with age (Table 15-1). Most patients with PAD are largely asymptomatic, although their risk of developing symptoms of IC in the

future is greatly increased. In a population with only a 2% prevalence of IC symptoms, 11.7% of patients had detectable large

vessel atherosclerosis of the lower extremities.3 This disparity

between IC symptoms and the presence of PAD contributes to

the observation that 50% to 90% of patients with IC do not mention the symptoms to their physician. Patients attribute the symptoms of IC to normal walking difficulties associated with aging,

not a medical condition requiring treatment.4 Public knowledge

of the definition of PAD, risk factors for the development of the

disease, associated symptoms and disease states, and amputation risk were evaluated in adults older than 50 years of age in

a cross-sectional, population-based telephone survey. Unfortunately, only 25% of the population reported awareness of PAD;

moreover, public awareness of PAD was lowest among respondents who were older, male, and nonwhite with a lower socioeconomic class and education level.5

Risk factors for developing occlusive PAD are similar to those

for coronary artery disease. Longstanding diabetes is the most

significant risk factor, with 30% of patients with diabetes affected

by PAD.6 PAD is five times more common in patients with diabetes than in patients without diabetes; in patients with diabetes,

it develops at a younger age and progresses more rapidly. Each

1% increase in glycosylated hemoglobin is associated with a 28%