Continuing Education Activity

Phenoxybenzamine is a medication used in the management and treatment of paroxysmal hypertension and sweating resulting from pheochromocytoma. It is in the nonselective, irreversible antagonist of the alpha-adrenergic receptors class of drugs. This activity reviews the indications, action, and contraindications for phenoxybenzamine as a valuable agent in the treatment of paroxysmal hypertension and sweating resulting from pheochromocytoma and benign prostate hyperplasia. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with pheochromocytoma and related conditions.

Objectives:

• Identify the mechanism of action of phenoxybenzamine.
• Describe the adverse effects of phenoxybenzamine.
• Review the appropriate monitoring of phenoxybenzamine.
• Outline some interprofessional team strategies for improving care coordination and communication to advance phenoxybenzamine and improve outcomes.

Indications

Phenoxybenzamine is FDA approved for the treatment of paroxysmal hypertension and sweating associated with the rare adrenal gland tumor, pheochromocytoma, which caused autonomic nervous system dysfunction as well as surges in catecholamines from the chromaffin cells located in the adrenal medulla.[1][2] The typical use of phenoxybenzamine is prior to the resection of the pheochromocytoma. Phenoxybenzamine works to mitigate the risk of a hypertensive crisis commonly occurring during general anesthesia but can also occur during tumor handling intraoperatively.[3]

Phenoxybenzamine was first used in 1976 to treat benign prostate hyperplasia because of its known alpha-adrenergic blockade, although now, it is rarely used for this purpose.[4]

Off-Label Use

• Sympathomimetic amines causing hypertensive crises
• Partial prostate obstruction
• Micturition problems associated with neurogenic bladder
• Functional outlet obstruction
• Phenoxybenzamine has also been used in patients with hypoplastic left heart syndrome, a congenital disability that develops during pregnancy in which the left side of the heart is malformed, affecting blood flow through the heart.[5] Phenoxybenzamine is able to work for these patients through vasodilation and decreasing afterload. 
• Complex regional pain syndrome is a chronic pain condition (> or = 6 months) that commonly affects one limb, usually after an injury.[6]

Further Studies

Researchers are studying phenoxybenzamine to determine its utility as a male contraceptive. The hypothesis is that because of its known alpha-adrenergic blockade; this would result in blockage of the vas deferens muscles.[7]

Mechanism of Action

Phenoxybenzamine is a nonselective, irreversible antagonist of the alpha-adrenergic receptors.[8] Alpha-adrenergic receptors subdivide into alpha-1 and alpha-2 receptors.

Phenoxybenzamine is an antagonist of both alpha-1 (located in smooth muscle tissue and the central nervous system, gastrointestinal tract, and endocrine system) and alpha-2 receptors (found throughout the central nervous system). The mechanism by which phenoxybenzamine works is by covalently bonding with a component of the alpha-adrenergic receptor, most likely a cysteine residue, which reduces the sympathetic effects of the two hormones.[9] This action results in an overall decrease in vasoconstriction (catecholamine-meditated) and a decrease in system vascular resistance (SVR).[10][11] 

The mechanisms described create a vasodilative effect since the alpha-adrenergic receptors are present throughout the walls of all blood vessels), which leads to the drop in blood pressure seen. Since there is a decrease in peripheral vascular tone, the result can be a baroreceptor-mediated increase in the sympathetic tone, characterized by reflex tachycardia (increased heart rate).[11] Phenoxybenzamine is often given with a beta-adrenergic antagonist to avoid the reflex tachycardia just described. 

The mechanism of phenoxybenzamine involved in the urogenital system is by producing a long-lasting noncompetitive alpha blockade of the postganglionic synapses present in smooth muscles and endocrine glands. Phenoxybenzamine relaxes the urethra and, in turn, increases the opening of the bladder for easier emptying. The drug is metabolized in the liver, with 10% excreted in the urine as an unchanged drug.

Administration

The initial phenoxybenzamine dose is once to twice daily, usually 10 mg, with an increase of 10 to 20 mg in divided doses every two to three days as needed as a means to controlling blood pressure and spells. Most commonly, the patient is usually ready for surgery within the first 7 to 14 days after initiation of phenoxybenzamine. The final dose is most typically between 20 to 100 mg daily.

Dosing: Adult

• Pheochromocytoma: Oral: Initially, the patient receives 10 mg twice daily, which may increase slowly every other day until achieving a goal optimal blood pressure response; usual dosage range: 20 to 40 mg 2 (BID) to 3 (TID) times daily. Doses as high as 240 mg daily have been reported.[12]
• Micturition disorders (off-label use): Oral: 10 to 20 mg 1 to 2 times daily.[13] Selective alpha-1 blocking agents (prazosin, terazosin, or doxazosin) are largely preferred for long-term treatment over phenoxybenzamine due to their lower side-effect profiles and cost-effectiveness. 

Dosing: Pediatric

• Pheochromocytoma, preoperative management: Children and Adolescents: Oral: Initial: 0.2 to 0.25 mg/kg/dose once or twice daily; maximum dose: 10 mg/dose; slowly titrate to effect; increments of 0.2 mg/kg/day have been also reported; reported maintenance dose ranges from 0.4 to 3 mg/kg/day every 6 to 8 hours in divided doses; maximum single maintenance dose is 40 mg/dose with a maximum daily dose: 4 mg/kg/day.[14][15][16]

Adverse Effects

The following adverse effects may occur during treatment with phenoxybenzamine[17]:  

• Drowsiness
• Fatigue
• Inhibited ejaculation
• Orthostatic hypotension
• Tachycardia (reflex tachycardia)
• Miosis
• Gastrointestinal irritation
• Nasal congestion

Almost all cases will present with fatigue, nasal stuffiness, and orthostasis. Retrograde ejaculation may also occur, so men taking phenoxybenzamine should receive counsel.   

Contraindications

These are the following contraindications and precautions when taking phenoxybenzamine[17]:

Contraindications

• Hypersensitivity to the drug or any components
• conditions in which a fall in blood pressure may be undesirable.

Warnings/Precautions

Concerns related to adverse effects:

• Concurrent administration with compounds that stimulate both alpha- and beta-adrenergic receptors may result in extreme hypotensive response and tachycardia.
• Caution with use in patients with renal impairment
• May aggravate respiratory infections symptoms by increasing congestion

Concurrent drug therapy issues:

• Potentially significant interactions with other medications may exist, requiring frequency or dose adjustments, alternative therapy, and/or additional monitoring. 

Dosage form specific issues:

• Some dosages of phenoxybenzamine may contain benzyl alcohol
  • Large amounts of benzyl alcohol can be potentially fatally toxic ("gasping syndrome") in newborns
    • "Gasping syndrome" includes the following
      • Respiratory distress
      • Metabolic acidosis
      • Hypotension and cardiovascular collapse
      • CNS dysfunction (convulsions, intracranial hemorrhage)
      • Gasping respirations
      • Benzoate may displace bilirubin from protein binding sites; it is advised to use caution with forms containing benzyl alcohol in neonates.[18] 

Other warnings/precautions:

• Due to case reports of cancer in humans, long-term use is not recommended.

Blackbox Warnings: 

There are no blackbox warnings for phenoxybenzamine. 

Monitoring

Phenoxybenzamine in Pregnancy and Nursing Mothers

Pregnancy Considerations

• It is unknown whether or not phenoxybenzamine can affect reproductive capacity.
• According to the FDA, phenoxybenzamine is pregnancy risk category C
  • It is unknown whether phenoxybenzamine can cause harm to the fetus when administered to a pregnant woman.

Breast-Feeding Considerations

• It is unknown whether or not phenoxybenzamine is excreted in breast milk.
• There are potentially serious adverse reactions that may occur in nursing infants. The recommended decision is either discontinuing nursing or discontinuing the drug, accounting for the importance of ongoing therapy to the mother.

 Cardiovascular Monitoring

• Blood pressures need continual monitoring twice daily in outpatient settings with patients in both seated (based on age and comorbid disease; the target is low-normal, less than 120/80 mmHg) and standing positions (based on age and comorbid disease; target with systolic blood pressure greater than 90 mmHg), due to potential extreme hypotension and tachycardia. Patients with marked cerebral and coronary disease may suffer from serious adverse effects when treated with phenoxybenzamine.
• After alpha-blockade is initiated (within 1 to 3 days), patients are encouraged to start a diet high in sodium (>5000 mg daily) because of volume contraction and orthostasis induced by catecholamines and alpha-adrenergic blockade, respectively. Although encouraged, a high degree of volume expansion may be contraindicated in patients suffering from renal insufficiency or congestive heart failure. 
• Typically two to three days preoperatively, after achieving an adequate alpha-adrenergic blockade, beta-adrenergic blockade is initiated. Never start beta-adrenergic blockade first due to severe vasodilatory effects from peripheral beta-adrenergic receptors and unopposed stimulation of alpha-adrenergic receptors. This effect can lead to a further elevation in blood pressure.[4]
• Chronic catecholamine excess may result in cardiomyopathy, which may become evident with beta-adrenergic blockade imitation and result in acute pulmonary edema. Proceed with caution and lose dose with administering beta-adrenergic blockade. 

Toxicity

Overdose of phenoxybenzamine may result in a block of the sympathetic nervous system and circulating adrenaline hormones (epinephrine), resulting in postural hypotension presenting with tachycardia (especially postural), dizziness or fainting, lethargy, vomiting, and shock.

According to the FDA drug label, case reports have shown the development of carcinoma associated with long-term treatment; therefore, long-term therapy is not recommended.[17]

Enhancing Healthcare Team Outcomes

It is essential to appropriately manage the sympathetic nervous system symptoms of patients suffering from pheochromocytoma with first-line medication, phenoxybenzamine, an alpha-adrenergic blocker. Beta-adrenergic blockers are to be avoided before using alpha-adrenergic blockers due to possible profound unopposed alpha-mediated vasoconstriction that may lead to pulmonary edema and hypertensive crisis. Concurrent administration with compounds that stimulate both alpha- and beta-adrenergic receptors may result in extreme hypotensive response and tachycardia. Cardiovascular monitoring of blood pressure readings should be taken at least twice daily in both seated and standing positions. 

Proper management of a drug overdose with phenoxybenzamine requires an interprofessional team of healthcare professionals that includes clinicians, specialists, nurses, and pharmacists. Morbidity and mortality of phenoxybenzamine overdose may be high if not properly managed. Once a patient with phenoxybenzamine overdose is under the care of an interprofessional team, the following should take place for the best patient outcome:

• Order blood and urine levels/toxicology 
• Patient monitoring for signs and symptoms of respiratory depression and cardiovascular collapse with treatment initiation
• Consult toxicology, nephrology, cardiology, psychiatry, and other healthcare professionals, if necessary

The clinicians will initiate therapy and chart the overall course of treatment, while nursing can answer patient questions and provide counsel on what to expect as well as potential adverse effects of the medication. These points can be reinforced by the pharmacists, who will also examine the patient's record for drug interactions, and appropriate dosing and answer medication-related questions. This approach will yield optimal therapeutic results with the fewest adverse events. [Level 5]

As mentioned previously, phenoxybenzamine is not recommended for long-term use due to case reports showing the development of carcinoma.