99

M.R. was experiencing chest pain, and had tachycardia on admission; these signs

and symptoms are most likely caused by his severely elevated BP and the presence of

acute left ventricular failure. Even though labetalol may have alleviated M.R.’s

angina, the negative inotropic action could acutely compromise his left ventricular

dysfunction, an effect that outweighs the potential benefit of afterload reduction. In

addition, even though labetalol is one of the safest β-blocking drugs when used in

patients with asthma,

100 β-blocker therapy should be avoided as initial treatment in

patients with asthma. Labetalol should be used only if alternative methods of

reducing M.R.’s pressure fail.

p. 342

p. 343

LABETALOL

CASE 16-3

QUESTION 1: C.M., a 52-year-old Caucasian man, is admitted to the hospital with a 3-day history of

increasing exertional substernal chest pain (without shortness of breath), diaphoresis, nausea, and vomiting. His

history is significant for poorly controlled hypertension, glaucoma, and angina pectoris. Prior medications include

dorzolamide ophthalmic drops, atenolol, hydrochlorothiazide, and oral nitrates. Physical examination reveals an

anxious man who is alert and oriented. He has a BP of 210/146 mm Hg without orthostasis and a regular pulse

of 115 beats/minute. Bilateral hemorrhages and exudates are present on funduscopic examination. The lungs

are clear and the point of maximal impulse is displaced. There are no murmurs or gallops. Examination of the

abdomen is unremarkable, and there is no peripheral edema. The neurologic examination is normal.

Significant laboratory values include the following:

Urea nitrogen, 49 mg/dL

Serum creatinine, 2.8 mg/dL

Serum creatinine was previously noted to be 1.2 mg/dL. Urinalysis shows proteinuria and hematuria. The

electrocardiogram demonstrates sinus tachycardia with left-axis deviation, left ventricular hypertrophy, and

nonspecific ST-T wave changes. The chest radiograph reveals mild cardiomegaly.

C.M. is given nitroglycerin sublingually and 1 inch of nitroglycerin ointment is applied topically. He is started

on IV labetalol. Is this choice of treatment reasonable, considering C.M.’s angina and acute kidney injury?

The presence of chest pain, retinopathy, and new-onset renal disease, as well as

the magnitude of the BP elevation in C.M., classifies his presentation as a

hypertensive emergency that warrants a prompt reduction in BP. Sublingual and

topical nitroglycerin may help in acutely and temporarily lower his BP and relieve

his chest pain while waiting for more definitive treatment to be implemented.

IV labetalol has been used successfully in hypertensive emergencies.

92–98 Labetalol

blocks both β- and α-adrenergic receptors and also may exert a direct vasodilator

effect. The β-blockade is nonselective with β- to α-potency of 3:1 for oral and 7:1

for IV. Labetalol is advantageous in C.M. because the immediate onset of action will

reduce peripheral vascular resistance without causing reflex tachycardia. Myocardial

oxygen demand will be reduced and coronary hemodynamics will be improved,

making this agent an excellent choice for patients such as C.M., with anginal

symptoms or MI. In addition, IV labetalol does not significantly reduce cerebral

blood flow; therefore, it may be useful in patients with cerebrovascular disease.

1,23

Fenoldopam or nitroprusside could also be used to treat C.M. Fenoldopam could

be considered, but C.M.’s history of glaucoma would preclude its use. Additionally,

fenoldopam would not be preferred due to the potential for reflex tachycardia and

risk of worsening ischemia. Treatment with nitroprusside would expose C.M. to the

potential risk of cyanide and thiocyanate toxicity with his new-onset acute kidney

injury. In contrast, labetalol has been used successfully in patients with renal disease

without deleterious side effects.

101,102 Labetalol is eliminated by glucuronidation in

the liver, with less than 5% of the dose being excreted unchanged in the urine.

Contraindications and Precautions

CASE 16-3, QUESTION 2: What cautions should be exercised when using labetalol in C.M.?

Labetalol’s disadvantages are primarily related to its β-blocking effects.

Therefore, it should not be used in patients with asthma, heart block greater than first

degree, or sinus bradycardia, and it should be used with caution in patients with

decompensated HF

93,97,103

(see Case 16-2, Question 10). None of these are present in

C.M. Like other β-blockers, labetalol should also be used with caution in patients

with β.

104 Labetalol has been effective in the treatment of hypertension associated

with pheochromocytoma and excess catecholamine states as well as those with

rebound hypertension from β-blocker withdrawal.

105 However, because labetalol is

primarily a β-blocker, paradoxic hypertension may occur in patients with

pheochromocytoma. These individuals have adrenal tumors that excrete high amounts

of norepinephrine, which results in relatively unopposed α-receptor stimulation.

106

More clinical experience is required before labetalol can be recommended in

patients with pheochromocytoma.

6,92

CASE 16-3, QUESTION 3: How should parenteral labetalol be given to C.M.?

IV labetalol can be given by pulse administration or continuous infusion.

92–97 Bolus

injections are administered, beginning with 20 mg given over 2 minutes, followed by

40 to 80 mg every 10 to 15 minutes until the desired response is achieved or a

cumulative dose of 300 mg is reached. The desired response is usually achieved with

a mean dose of 200 mg in 90% of patients.

93 The maximal effect occurs within 10

minutes,

95 and the antihypertensive response may persist for more than 6 hours.

107

Because the rate of BP reduction is accelerated with an increase in infusion rate,

95 a

controlled continuous infusion may provide a more gradual reduction in arterial

pressure with less frequent adverse effects.

97,108 The infusion can then be started at a

rate of 2 mg/minute and titrated until a satisfactory response is achieved or until a

cumulative dose of 300 mg is reached.

Parenteral to Oral Conversion

CASE 16-3, QUESTION 4: C.M. was treated with a labetalol infusion and required a cumulative dose of 180

mg to achieve a DBP of 100 mm Hg. His anginal symptoms resolved almost immediately, but 3 hours after the

infusion, C.M. became faint and dizzy while ambulating. Should oral labetalol be withheld in C.M.?

Postural hypotension and dizziness are dose related and more commonly

associated with the IV route of administration.

99,103 C.M. should remain in a supine

position after the IV administration of labetalol, and his ability to tolerate an upright

position should be established before permitting ambulation. Oral labetalol can be

given to C.M. when his symptoms resolve. There is no correlation between the oral

maintenance dose and the total initial IV dose. C.M. should be started on an empiric

dose of 100 to 200 mg of oral labetalol 2 to 3 times per daily, and this should be

titrated as necessary.

CASE 16-3, QUESTION 5: What other side effects can occur with labetalol therapy?

Other side effects commonly associated with labetalol include nausea, vomiting,

abdominal pain, and diarrhea in up to 15% of the patients.

103 Scalp tingling is an

unusual side effect that has been reported in a few patients after IV administration; it

tends to disappear with continued treatment. Other side effects include tiredness,

weakness, muscle cramps, headache, and skin rashes.

NITROGLYCERIN

CASE 16-3, QUESTION 6: Would parenteral nitroglycerin be an acceptable alternative to labetalol for

C.M.?

p. 343

p. 344

Hypertensive emergencies in the setting of unstable angina or MI requires an

immediate reduction in BP. Nitroprusside has been used successfully, but IV

nitroglycerin can have more favorable effects on collateral coronary flow in patients

with ischemic heart disease.

109 By diminishing preload, nitroglycerin decreases left

ventricular diastolic volume, diastolic pressure, and myocardial wall tension, thus

reducing myocardial oxygen consumption.

110 These changes favor redistribution of

coronary blood flow to the subendocardium, which is more vulnerable to ischemia.

At high dosages, nitroglycerin dilates arteriolar smooth muscles, and this reduction in

afterload also decreases myocardial wall tension and oxygen consumption.

111

IV nitroglycerin has a rapid onset of action and a short duration, and is easily

titratable. It is generally appropriate to begin IV nitroglycerin in the dose range of 5

to 10 mcg/minute, increased as needed to control pressure and symptoms. The usual

dose is in the range of 40 to 100 mcg/minute. The major limiting side effects are

headache and the development of tolerance. In general, IV nitroglycerin is well suited

for use in patients such as C.M. who have angina or in patients who have

hypertensive emergency associated with MI or coronary artery bypass surgery.

HYDRALAZINE

CASE 16-4

QUESTION 1: T.M., a 30-year-old Caucasian man with a history of chronic glomerulonephritis and poorly

controlled hypertension, came to the emergency department complaining of early morning occipital headaches

during the past week. He has no other complaints. He has not taken any BP medication in a month. Physical

examination revealed an afebrile man in no acute distress with a BP of 160/128 mm Hg without orthostasis and

a regular pulse of 90 beats/minute. Funduscopic examination revealed bilateral exudates without hemorrhages

or papilledema. The lungs were clear. Cardiac examination was pertinent for cardiomegaly and an S4

gallop.

The remainder of the physical workup was normal.

Laboratory results include the following values:

Hematocrit, 32%

Blood urea nitrogen, 40 mg/dL

Serum creatinine, 2.5 mg/dL (baseline serum creatinine 1.9 mg/dL)

Bicarbonate, 18 mEq/L

Urinalysis reveals 2+ protein, 2+ hemoglobin with 4 to 10 red blood cells per high-power field. The

electrocardiogram demonstrates normal sinus rhythm with left ventricular hypertrophy. The chest radiograph is

unremarkable.

T.M.’s presentation meets criteria for a hypertensive emergency (i.e., DBP >120 mm Hg and presence of

worsening renal function). IV antihypertensive therapy is required for T.M. T.M. was given 20 mg hydralazine

IV, and a repeat BP after 1 hour was 150/100 mm Hg. What are the advantages and disadvantages of

parenteral hydralazine, and when should it be used to acutely lower BP?

Hydralazine is a direct vasodilator that reduces total peripheral resistance through

relaxation of the arterial smooth muscle. It is rarely used to treat hypertensive

emergencies because its antihypertensive response is less predictable than that of

other parenteral agents. Additionally, hydralazine has a prolonged half-life, which

can be problematic if too fast correction or hypotension occurs.

22

It is not consistently

effective in controlling crises associated with essential hypertension.

Contraindications

Hydralazine should not be used in patients with coronary heart disease because the

reflex tachycardia causes an increase in myocardial oxygen demand, which may

result in the development or worsening of ischemic symptoms. In addition,

hydralazine should be avoided in patients with aortic dissection because of its reflex

cardiostimulating effect. In contrast, hydralazine can be useful in patients such as

T.M., who have chronic renal failure because the reflex increase in cardiac output is

accompanied by an increase in organ perfusion.