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 9-9).

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.

108,109 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 with metoprolol, which may slightly increase

glucose.

110

p. 158

p. 159

Table 9-15

Common β-Blockers in Hypertension

Drug

Usual Dosage

Range (mg/day)

Dosing

Frequency

Half-Life

(hours) β1-Selectivity

Lipid

Solubility

Atenolol 25–100 Daily to BID 6–7 ++ Low

Bisoprolol 5–20 Daily 9–12 +++ High

Carvedilol 12.5–50 BID 6–10 0 High

Carvedilol 10–80 Daily 6–10 0 High

Labetalol 200–800 BID 6–8 0 Moderate

Metoprolol

tartrate

100–400 BID 3–7 + Moderate to

high

Metoprolol

succinate

25–400 Daily 3–7 + Moderate to

high

Nebivolol 5–10 Daily 12–19 +++ High

Propranolol 40–180 Daily (LA and

XL) or BID

3–5 0 High

BID, 2 times daily.

CENTRAL α2

-AGONISTS

The antihypertensive effects of α2

-agonists (Table 9-14) 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 9-11

QUESTION 1: T.M. is a 43-year-old man. He is a truck driver with a 5-year history of hypertension. He does

not have hypertension-associated complications. 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 9-11, 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 is also 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 9-11, 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.

111 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 9-11, QUESTION 4: Would reserpine be a reasonable option for T.M.?

p. 159

p. 160

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.

88

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.

ARTERIAL VASODILATORS

Hydralazine

CASE 9-12

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 m

2

). Her antihypertensive regimen consists of torsemide 40 mg daily,

amlodipine/olmesartan 10/40 mg daily, and metoprolol succinate 200 mg daily. She started hydralazine 25 mg 3

times daily 4 weeks ago when her BPs were 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 need to be used in

combination with agent that can slow down heart rate (e.g., β-blocker or

nondihydropyridine CCB) to counteract reflex tachycardia, as well as a diuretic

(often a loop diuretic if used in severe CKD) to minimize fluid retention.

CASE 9-12, QUESTION 2: After 18 months, C.M.’s hydralazine dose is 50 mg 3 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 (DIL). How should this be managed?

C.M.’s symptoms are consistent with 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 9-12, 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 9-12, 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 may also 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/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

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Key References

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