Systemic Vasodilators: Phenoxybenzamine and Phentolamine Phenoxybenzamine
Indication
Phenoxybenzamine is a nonspecific, long-acting, a-adrenergic antagonist used in pediatric patients for the treatment of arterial hypertension, particularly when secondary to pheochromocytoma, and in the acute postoperative course of congenital or acquired cardiac anomalies. It is a potent systemic and mild pulmonary vasodilator. In some pediatric cardiac centers, it is considered to be an essential drug in the armamentarium for the treatment of low cardiac output state after weaning from cardiopulmonary bypass. It may also be useful in treating radial artery grafts before surgical coronary revascularization procedures, and it maybe used in combination with other vasodilators. Phenoxybenzamine can maintain organ perfusion on cardiopulmonary bypass and improve peripheral blood flow, as demonstrated by smaller base deficits and temperature gradients intraoperatively and in the intensive care unit as compared with nitroprusside.
It has efficacy in decreasing the incidence of sudden circulatory collapse after the first-stage Norwood operation. Lastly, it may also be beneficial in establishing more uniform rewarming after bypass and as a nonselective pulmonary vasodilator.
Mechanism of Action
Phenoxybenzamine forms a permanent and irreversible covalent bond with nitrogen atoms on the surface of α-adrenoceptors, thereby blocking epinephrine and norepinephrine from binding with these receptors. This causes systemic vasodilation, and to some extent, pulmonary vasodilation because of a reduction in vascular resistances. These activities are beneficial in controlling the effects of endogenously released catecholamines in the perioperative stress response.
By affecting postsynaptic membrane adrenoceptors in the sympathetic nervous pathway,phenoxybenzamine also acts on al and α2 receptors, reducing sympathetic activity. This resulting “chemical sympathectomy” induces further general vasodilation, miosis, an increase in gastrointestinal tract motility, secretions, and glycogen synthesis.
In addition to the α-blockade effect, phenoxybenzamine irreversibly inhibits responses to 5-hydroxytryptamine (serotonin), histamine, and acetylcholine.
There is no effect on the parasympathetic nervous system.
Phenoxybenzamine is a noncompetitive (irreversible) antagonist, meaning that receptor blockade cannot be overcome by addition of agonist drugs.
Dosing Phenoxybenzamine should be slowly titrated to the desired effect after a small initial dose and under close hemodynamic monitoring. It maybe infused in D5W or in 0.9% NaCl.
Neonates, infants, and children:
Oral: 0.2 to 1 mg/kg P.O./N.G. every 12 to 24 hours I.V.: 1 mg/kg I.V. over 2 hours, followed by 0.5mg/kg/dose every 6 to 12 hours administered over 2 hours. It may be progressively increased to 2 mg/kg once or twice a day in patients younger than 12 years, or 1 mg/kg once or twice a day in patients older than 12 years
Adults:
Oral: 5 to 10 mg P.O./N.G twice a day; dose maybe increased every other day to 20 to 80 mg two or three times a day
Note: In patients with pheochromocytoma, if persistent or excessive tachycardia occurs, the use of a concomitant β-blocker may be necessary
Pharmacokinetics
Onset of action: rapid
Absorption: when administered orally, 20 to 30% of the drug is absorbed in the active form
Duration: 3 to 4 days
Metabolism: hepatic
Half-life: the half-life of oral phenoxybenzamine is not well known; intravenously, the half-life is approximately 24 hours, and effects may persist for 3 to 4 days. Effects of daily administration are cumulative for nearly a week. The duration of action is dependent not only on the presence of the drug, but also on the rate of synthesis of a-receptors
Elimination: renal and biliary
Contraindications
Phenoxybenzamine is contraindicated in patients with hypersensitivity to the drug or any of its components. The induction of α-adrenergic blockade leaves β-adrenergic receptors unopposed. Compounds that stimulate both types of receptors may produce an exaggerated hypotensive response with reflex tachycardia.
Adverse Effects
Cardiovascular: tachycardia, arrhythmias, hypotension (mostly in patients with intravascular volume depletion), shock
Gastrointestinal: vomiting
Metabolic: water and sodium retention
Central nervous system: dizziness, drowsiness, postural hypotension
Neuromuscular and skeletal: weakness
Ophthalmological: miosis
Other: nasal congestion, irritation, fatigue, lethargy
Drug-Drug Interactions
Phenoxybenzamine interacts with compounds that stimulate both α- and β-adrenergic receptors to produce severe hypotension and tachycardia. Phenoxybenzamine blocks the hyperthermia produced by norepinephrine and blocks the hypothermia produced by reserpine.
Poisoning Information
Overdosage of phenoxybenzamine produces symptoms of sympathetic nervous system blockade; symptoms and signs include hypotension, tachycardia, dizziness or fainting, vomiting, lethargy, and shock. Treatment of overdosage consists of the following:
• Drug withdrawal
• Recumbent position with leg elevation
• I.V. volume
• Infusion of norepinephrine in cases of severe hypotension. Note: usual inotropic agents are not effective.
Epinephrine is contraindicated because it stimulates both α- and β-receptors, and, because a-receptors are blocked, epinephrine may produce further hypotension via β-receptor stimulation
• Antagonism with vasopressin has been described as effective, particularly for the treatment of phenoxybenzamine-induced side effects in patients after the Norwood procedure.
Phentolamine
Indication
Phentolamine is a reversible, competitive, nonselective, α-adrenergic antagonist that has similar affinities for al and a2 receptors. Its effects on the cardiovascular system are very similar to those of phenoxybenzamine, and, therefore, its primary action is systemic vasodilation. It may also have a positive inotropic and chronotropic effect on the heart.
The primary application for phentolamine is for the control of hypertensive emergencies, most notably caused by pheochromocytoma. It may also be used for the treatment of cocaine-induced hypertension, when one would generally avoid β-blockers and, in which case, calcium channel blockers are not effective. It has also been used to treat hypertensive crises secondary to monoamine oxidase inhibitor-sympathomimetic amine interactions and for withdrawal of clonidine, propranolol, or other antihypertensives.
In patients with congenital or acquired cardiac defects, phentolamine is used to induce peripheral vasodilation and afterload reduction after cardiopul-monary bypass surgery. Similar to phenoxybenzamine, the use of phentolamine during bypass is associated with reduced systemic anaerobic metabolism and more uniform body perfusion.
Phentolamine can be usedlocally to prevent dermal necrosis after extravasation of an α-agonist or to relieve arterial spasms caused by intra-arterial catheters.
There have been anecdotal reports regarding the usefulness of phentolamine in improving mixing in newborns with transposition of the great arteries. Presumably, improved mixing of blood would be caused by both a reduction in afterload and an alteration in the diastolic function of the right ventricle, allowing more left-to-right shunting across the atrial septal defect.
Phentolamine also has a diagnostic role in cases of pheochromocytoma and complex regional pain syndromes (e.g., reflex sympathetic dystrophy).
Interestingly, although widely used in the pediatric patients, literature describing its use is scant.
Mechanism of Action
Phentolamine is a long-acting, a-receptor blocking agent that can produce and maintain a “chemical sympathectomy” by oral administration. It increases blood flow to the skin, mucosa, and abdominal viscera, and lowers both supine and erect blood pressures. It has no effect on the parasympathetic nervous system. Phentolamine works by blocking α-receptors present in vascular smooth muscle, thereby inducing vasodilation. It also blocks receptors for serotonin, and it causes release of histamine from mast cells. Phentolamine also blocks potassium channels, which can accentuate vasodilation.
Phentolamine is a competitive antagonist, meaning that blockade can be surmounted by increasing the concentration of agonist drugs.
Dosing
Phentolamine should be slowly titrated to the desired effect after a small initial dose and with rigorous hemodynamic monitoring. It may be infused in D5W or in 0.9% NaCl.
Neonates, infants, and children:
Treatment of hypertension or to achieve afterload reduction: 0.02 to O.lmg/kg (maximum 10 mg) I.V. to be administered over 10 to 30 minutes, followed by a continuous infusion at 5 to 50 µg/kg/h I.V.
Treatment of extravasation: subcutaneous infiltration of the affected area with 0.1 to 0.2mg/kg (maximum 10 mg) in up to 5mL of sterile water for injection within 12 hours of the event
Diagnosis of pheochromocytoma: single dose of 1 mg I.V.
Adults:
Diagnosis of pheochromocytoma: single dose of 5mg I.V.
Treatment of hypertension: 2.5 to 5 mg I.V. single doses as required to control blood pressure
Pharmacokinetics
Onset of action: immediate
Duration: 30 to 45 minutes
Maximum effect: 2 minutes
Metabolism: extensively metabolized in the liver
Half-life: 19 minutes (adults)
Elimination: 10% excreted in the urine as unchanged drug
Contraindications
Phentolamine is contraindicated in patients with ischemic myocardial disease or cerebral ischemic disease and in cases of hypersensitivity to the drug or any of its components. Phentolamine should be used with additional care in patients with impairment of renal function, gastritis, peptic ulcer disease, or a history of arrhythmia or angina.
Adverse Effects
Cardiovascular: hypotension (mostly in patients with intravascular volume depletion), tachycardia, arrhythmias, shock, ischemic cardiac events
Gastrointestinal: vomiting, nausea, abdominal pain, diarrhea, exacerbation of peptic ulcer
Neuromuscular and skeletal: weakness
Central nervous system: dizziness
Other: flushing, nasal congestion
Drug-Drug Interactions
Vasoconstrictive and hypertensive effects of epinephrine and ephedrine are antagonized by phentolamine.
Poisoning Information
Similar to phenoxybenzamine, overdosage is suspected in cases of excessive tachycardia, shock, vomiting, and dizziness (symptoms of sympathetic nervous system blockade and of increased circulating epinephrine). Treatment of overdosage consists of the following:
• Drug withdrawal
• Recumbent position with leg elevation
• I.V. fluid administration
• Because this drug binds competitively as opposed to phenoxybenzamine, inotropic agents with a-agonist effects may be effective. Nevertheless, epinephrine is contraindicated, because epinephrine stimulates both α-and β-receptors, and because α-receptors are blocked, epinephrine may produce further hypotension.
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