VA Class:AU200
Phenoxybenzamine hydrochloride is a haloalkylamine α-adrenergic blocking agent.
Phenoxybenzamine is used to control or prevent paroxysmal hypertension and sweating in patients with pheochromocytoma. Because phenoxybenzamine has a longer duration of action than phentolamine, most clinicians consider phenoxybenzamine the drug of choice for the medical management of patients with pheochromocytoma until surgery is performed and for prolonged treatment of hypertension caused by a pheochromocytoma not amenable to surgery. An α-adrenergic blocking agent alone is usually sufficient for management of the signs and symptoms of pheochromocytoma. Propranolol (a β-adrenergic blocking agent), however, may be used as an adjunct to α-adrenergic blocking agents to control symptoms resulting from excessive β-receptor stimulation in patients with inoperable or metastatic pheochromocytoma, or to control tachycardia prior to or during pheochromocytomectomy. In order to prevent severe hypertension due to unopposed α-adrenergic stimulation in patients with pheochromocytoma, treatment with an α-adrenergic blocking agent must always be instituted prior to the use of propranolol and continued during propranolol therapy.
Although phenoxybenzamine has been used IV† to treat hypertensive crisis caused by sympathomimetic amines† (e.g., methoxamine, phenylephrine) or by certain foods or drugs in patients taking monoamine oxidase (MAO) inhibitors† (e.g., isocarboxazid [no longer commercially available in the US], tranylcypromine), IV phentolamine is generally preferred because it has a more rapid onset of action. Phenoxybenzamine is not used in the treatment of essential hypertension because of the frequency and severity of adverse effects, especially postural hypotension and tachycardia.
Phenoxybenzamine has been used as adjunctive therapy in the treatment of peripheral vasospastic disorders associated with increased α-adrenergic activity†, such as Raynaud's syndrome, acrocyanosis, and frostbite sequelae, but its efficacy in the treatment of peripheral vascular disease has not been established. Well-controlled clinical studies demonstrating the usefulness of vasodilators, such as phenoxybenzamine, in the treatment of these disorders are not available. Some clinicians believe phenoxybenzamine is effective in the treatment of Raynaud's syndrome†, but the drug's usefulness may be limited by its adverse effects. Phenoxybenzamine should not be used in diseases affecting large blood vessels. The drug is not a substitute for appropriate medical or surgical programs for the treatment of peripheral vascular disease.
Phenoxybenzamine has been used IV† in patients with shock to estimate the adequacy of fluid volume replacement or to mobilize sequestered fluid and restore blood pressure when hypotension persists following adequate fluid volume replacement†. If fluid volume replacement is inadequate in these patients, phenoxybenzamine may further lower blood pressure. (See Cautions: Precautions and Contraindications.)
Micturition Disorders and Urinary Retention
Phenoxybenzamine has been used with good results in appropriately selected patients for the treatment of micturition disorders† resulting from neurogenic bladder,100 functional outlet obstruction,100 or partial prostatic obstruction100, 101, 102, 103 and for the prevention and treatment of acute postoperative urinary retention†, 105, 106, 107, 108 including that associated with the use of epidural morphine.107, 108
Phenoxybenzamine hydrochloride is administered orally. GI irritation may be reduced by giving the drug with milk or in divided doses.
Dosage of phenoxybenzamine hydrochloride must be adjusted according to the patient's response and tolerance. Initially, small doses are administered and dosage is increased slowly until the desired effect is attained or adverse effects from α-adrenergic blockade become troublesome. Patients should be observed after each increase in dosage before subsequent increases are made. Dosage should be adjusted such that symptomatic relief and/or objective improvement is attained without intolerable adverse effects from α-adrenergic blockade.
For the control of hypertension and sweating in adults with pheochromocytoma, the usual initial oral dosage of phenoxybenzamine hydrochloride is 10 mg twice daily. Dosage is then increased every other day, usually to 20-40 mg 2 or 3 times daily, until an adequate response is achieved; some patients may require higher dosages.
Although the manufacturer has not established pediatric dosage recommendations for the treatment of hypertension caused by pheochromocytoma, some clinicians have suggested an initial oral phenoxybenzamine hydrochloride dosage of 0.2 mg/kg or 6 mg/m2 once daily. An initial oral dose should not exceed 10 mg. Dosage may be increased gradually until an adequate response is achieved. The usual pediatric maintenance dosage is 0.4-1.2 mg/kg or 12-36 mg/m2 daily.
In the treatment of peripheral vascular diseases†, the usual adult oral dosage of phenoxybenzamine has been the same as that used for the control of hypertension and sweating in patients with pheochromocytoma.
Phenoxybenzamine hydrochloride has been administered IV† for the adjunctive treatment of shock†. Some clinicians have recommended that 0.2-2 mg/kg of the drug be diluted in 250-500 mL of 5% dextrose or 0.9% sodium chloride injection and infused over a period of at least 1 hour.
The most common adverse effects of phenoxybenzamine are related to its α-adrenergic blocking activity and vary according to the degree of blockade. These adverse effects may be minimized by starting with small doses initially and increasing dosage gradually until the desired effect is obtained or troublesome adverse effects occur. Generally, phenoxybenzamine's adverse effects decrease as therapy is continued.
Nasal congestion, miosis, postural hypotension with dizziness, and tachycardia occur commonly. Postural hypotension and tachycardia may disappear with continued therapy, but these adverse effects may recur when vasodilation is induced by conditions such as exercise, eating a large meal, or alcohol ingestion. Drowsiness, fatigue, weakness, lassitude, malaise, confusion, headache, dry mouth, and inhibition of ejaculation occur less frequently. GI irritation with nausea, vomiting, and diarrhea occurs rarely. Allergic contact dermatitis has occurred. A syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported in at least one patient during phenoxybenzamine therapy.109
Precautions and Contraindications
Phenoxybenzamine-induced tachycardia may precipitate frank congestive heart failure and angina in patients with compensated congestive heart failure or coronary artery disease. The drug should be used with caution in patients with marked cerebral or coronary arteriosclerosis or renal damage and is contraindicated when a decrease in blood pressure is undesirable. Because the drug may further lower blood pressure if fluid volume replacement is inadequate, IV phenoxybenzamine should not be given in the treatment of shock unless the central venous pressure has been increased by administration of IV infusion fluids without an adequate circulatory response. Additional fluid volume replacement may be required if phenoxybenzamine causes a sharp drop in blood pressure in these patients.
Phenoxybenzamine's α-adrenergic blocking effect may aggravate symptoms of respiratory infections.
Mutagenicity and Carcinogenicity
Phenoxybenzamine hydrochloride did exhibit mutagenic activity in vitro in the Ames microbial mutagen test and mouse lymphoma assay but not in the micronucleus test in mice. Peritoneal sarcomas were observed in rats and mice following repeated intraperitoneal administration of the drug. Malignant tumors of the GI tract, principally in the nonglandular stomach, were observed in rats following chronic oral administration of the drug. Ulcerative and/or erosive gastritis also occurred in rats following chronic oral administration of phenoxybenzamine; these changes probably were related to the drug. The clinical importance of these test results is not known, but the mutagenic and carcinogenic potentials of phenoxybenzamine should be considered when determining whether therapy with the drug is indicated.
Animal reproduction studies have not been performed with phenoxybenzamine, and it is not known whether the drug can cause fetal harm when administered to pregnant women. The drug has been used in a limited number of women during the third trimester of pregnancy in the treatment of hypertension caused by pheochromocytoma without apparent harm to the woman or fetus. Phenoxybenzamine should be used during pregnancy only when clearly needed.
It is not known whether phenoxybenzamine is distributed in human milk. Because of the potential for serious adverse reactions to phenoxybenzamine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
The effects of α-adrenergic stimulating sympathomimetic agents are antagonized by phenoxybenzamine. Drugs that stimulate both α- and β-adrenergic receptors (e.g., epinephrine) cause vasodilation, an increased hypotensive response, and tachycardia in patients receiving phenoxybenzamine.
Overdosage of phenoxybenzamine may produce postural hypotension associated with dizziness and fainting; tachycardia (especially postural), vomiting, lethargy, and shock may also occur.
If ingestion of phenoxybenzamine is recent, emesis or gastric lavage may reduce absorption. Support of circulation is most important in the treatment of phenoxybenzamine overdosage. Management of overdosage includes placing the patient in the supine position with the legs elevated or with the head down. Application of leg bandages and an abdominal binder may also be used. Prolonged monitoring of patients who have received an overdose may be necessary, since the drug has a prolonged effect; it may be necessary for the patient to remain in the supine position for 24 hours or longer. If hypotension is severe, measures to treat shock (e.g., adequate fluid volume replacement) should be instituted. Most vasopressor drugs are ineffective and epinephrine is contraindicated. (See Drug Interactions.) IV norepinephrine may be effective, since it principally stimulates α-adrenergic receptors and sufficient doses may overcome phenoxybenzamine-induced α-adrenergic blockade.
Phenoxybenzamine inhibits responses (primarily excitatory responses of smooth muscle and exocrine glands) to adrenergic stimuli by noncompetitively blocking α-adrenergic receptors. β-Adrenergic receptors are not affected. The precise mechanism of action has not been fully elucidated, but phenoxybenzamine cyclicizes in the body to form a reactive ethylenimonium intermediate and a highly reactive carbonium ion which forms stable covalent bonds with sulfhydryl, phosphate, amino, and carboxyl groups of α-adrenergic receptors. In contrast to phentolamine, the onset of action of phenoxybenzamine is relatively slow and α-adrenergic blockade is complete and persists for several days. Phenoxybenzamine blocks α-adrenergic responses to circulating epinephrine and/or norepinephrine and to norepinephrine released at the adrenergic nerve ending. The drug acts on vascular smooth muscle to block epinephrine- and norepinephrine-induced vasoconstriction and causes peripheral vasodilation and reflex tachycardia. Phenoxybenzamine reverses the pressor effect of epinephrine (“epinephrine reversal”) and blocks, but does not reverse, the vasoconstrictor effects of norepinephrine. Doses of phenoxybenzamine which cause α-adrenergic blockade cause postural hypotension in both normotensive and hypertensive subjects. Cutaneous blood flow is increased, but cerebral and skeletal muscle blood flow are generally unchanged. In patients with hypovolemia or in those receiving a norepinephrine infusion, phenoxybenzamine increases splanchnic and renal blood flow.
Through its α-adrenergic blocking action, phenoxybenzamine also blocks pupillary dilation, lid retraction, and in laboratory animals, nictitating membrane contraction. The drug also decreases uterine motility in the nonpregnant uterus. adrenergically mediated sweating is blocked.
Although most of the effects of phenoxybenzamine result from α-adrenergic blockade, the drug may also inhibit responses to serotonin, histamine, and acetylcholine.
Phenoxybenzamine appears to be variably absorbed from the GI tract. Following oral administration, the drug has a gradual onset of action over a period of several hours and after administration of fixed daily doses, α-adrenergic blocking effects are cumulative for about 7 days. Following administration of a single oral dose of phenoxybenzamine, α-adrenergic blockade persists for 3-4 days. The prolonged action of the drug is probably due to formation of a stable covalent bond between an intermediate of phenoxybenzamine and the receptor.
Phenoxybenzamine is highly lipid soluble and may accumulate in fat following administration of large doses. It is not known if the drug crosses the placenta. It is not known whether phenoxybenzamine appears in milk.
Phenoxybenzamine has a half-life of approximately 24 hours.
Phenoxybenzamine is dealkylated to form N -phenoxyisopropyl-benzylamine. Following IV administration of radiolabeled phenoxybenzamine, at least 50% of the radioactivity is excreted in 12 hours and 80% in 24 hours in the urine and bile. Small amounts of the drug remain in the body for at least a week.
Phenoxybenzamine hydrochloride is a haloalkylamine α-adrenergic blocking agent. The drug occurs as a white, crystalline powder and has a pKa of 4.4. Phenoxybenzamine hydrochloride has solubilities of approximately 40 mg/mL in water and 167 mg/mL in alcohol at 25°C.
Phenoxybenzamine hydrochloride capsules should be stored in well-closed containers at a temperature less than 40°C, preferably between 15-30°C.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 10 mg |
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103. Anon. Phenoxybenzamine for symptoms of bladder neck obstruction. Drug Ther Bull . 1983; 21(4):15-6. [PubMed 6187524]
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105. Eftaiha MS, Amshel AL, Shonberg IL. Comparison of two agents in prevention of urinary retention after benign anorectal surgery. Dis Colon Rectum . 1980; 23:470-2. [PubMed 7438948]
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108. Evron S, Samueloff A, Sadovsky E et al. The effect of phenoxybenzamine on postoperative urinary complications during extradural morphine analgesia. Eur J Anaesthesiol . 1984; 1:45-54. [PubMed 6536506]
109. Aron NB. Phenoxybenzamine-induced hyponatremia simulating the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med . 1987; 107:119-20. [PubMed 3592437]