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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 3
| Issue : 1 | Page : 11-17 |
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Alpha blockers: A relook at phenoxybenzamine
Sambhunath Das1, Pankaj Kumar1, Usha Kiran1, Balram Airan2
1 Department of Cardiac Anaesthesia, All India Institute of Medical Sciences, New Delhi, India
2 Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 17-Jul-2017 |
Correspondence Address:
Sambhunath Das
Department of Cardiac Anaesthesia, 7th Floor, Cardio Thoracic Sciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpcs.jpcs_42_16
Phenoxybenzamine (PBZ) is an alpha adrenergic antagonist, used for the management of hypertension. PBZ acts by blocking alpha-adrenergic receptors, leading to vasodilatation and low systemic vascular resistance. This helps in control of blood pressure in pheochromocytoma, improvement of systemic oxygen delivery, and optimization of the Qp/Qs in pediatric cardiac surgery such as hypoplastic left heart syndrome and improving perfusion parameters during open heart surgery. The uses have further extended to causalgia, Raynaud's phenomenon, autonomic hyperreflexia, and even for patency of radial artery conduit in coronary artery bypass grafting surgery. However, its prolonged hypotensive effect limits the regular use. In this review, we discussed the mechanism of action, pharmaco-physiology of PBZ, perioperative uses in different clinical setting and controversies for its uses; publications in different scientific journals from the previous years. Keywords: Cardiovascular disease, hypoplastic left heart syndrome, pheochromocytoma, phenoxybenzamine, pulmonary arterial hypertension
How to cite this article:
Das S, Kumar P, Kiran U, Airan B. Alpha blockers: A relook at phenoxybenzamine. J Pract Cardiovasc Sci 2017;3:11-7 |
| Introduction | |  |
Phenoxybenzamine (PBZ) was initially used in the treatment of hypertension, especially that caused by pheochromocytoma. It was also the first alpha blocker to be used for the treatment of benign prostatic hyperplasia; it has been used in the treatment of hypoplastic left heart syndrome (HLHS). It is an alpha-receptor blocker. The other alpha receptor blockers are listed below.
Alpha-blockers act as antagonists of α-adrenergic receptors.
The types include:
- α1-blockers act on α1-adrenoceptors
- α2-blockers act on α2-adrenoceptors.
Examples of non-selective α-adrenergic receptor antagonists include:
- PBZ
- Phentolamine
- Tolazoline
- Trazodone
- Typical and atypical antipsychotics.
Selective α1-adrenergic receptor antagonists include:
- Alfuzosin
- Doxazosin
- Prazosin
- Tamsulosin
- Terazosin
- Silodosin.
Selective α2-adrenergic receptor antagonists include:
- Atipamezole
- Idazoxan
- Mirtazapine
- Yohimbine.
The agents carvedilol and labetalol are both α- and β-blockers.
PBZ is a potent alpha-adrenergic blocking agent used routinely for the management of hypertension in pheochromocytoma.[1] The indications of PBZ extend to the management of pulmonary hypertension in cardiac disease patients, balancing of systemic and pulmonary blood flow in HLHS, benign prostatic hypertrophy, malignant essential hypertension, hypotensive anesthesia, sausage, and so on.[2] However, the side effects, such as persistent hypotension, muscle weakness, and postural hypotension, limit its use by many physicians. Some physicians are in favor of using alternative drugs for control of blood pressure (BP) and systemic vascular resistance (SVR) with less potency and short acting.[3],[4] However, still many centers use PBZ in situ ations such as perioperative hemodynamic management of pheochromocytoma, HLHS, arterial switch operation (ASO), single-ventricle physiology, pulmonary artery hypertension, and congenital cardiac surgery with a better outcome.[3],[4],[5],[6],[7] The evidence from different studies and reports in respect to the current uses and limitations of PBZ necessitates update.
This review article discusses the pharmacological aspects, mechanism of action, indications, side effects, controversies, and management of complications related to PBZ. All the publications and literatures are searched from PubMed and Google Scholar using the keywords of PBZ, cardiovascular disease, HLHS, pheochromocytoma, pulmonary arterial hypertension, and alternate uses of PBZ for the last 16 years.
| Pharmacology | | |
PBZ is a haloalkylamine derivative.[1] PBZ is an adrenergic blocking agent chemically related to nitrogen mustard. The molecular structure responsible for blockade is the highly reactive carbonium ion formed by cleavage of the tertiary amine ring.[8] In consequence of the chemical reactions, a covalent bond is formed between the drug and the α-adrenergic receptor [Figure 1].[8]
| Mechanism of Action | | |
PBZ blocks both α1- and α2-adrenergic receptors with more affinity for α1-receptor.[1] The presence of a catecholamine or an α-adrenergic blocking agent of the competitive type during the development of blockade by PBZ can reduce the degree of block.
There is competition for the same population of receptors, indicating that the initial approximation of the PBZ to its site of action is due to weak ionic and hydrogen bond involved in the actions of most other chemical class.[8] Subsequent to blockade of receptors by PBZ, the conjugate became fixed and does not allow adrenaline and noradrenalin for binding. This stage is referred to as nonequilibrium blockade and is the result of stable covalent bond formation between the antagonist and the receptors. PBZ increases the rate of peripheral norepinephrine turnover, which is associated with increased tyrosine turnover resulting in increased tyrosine hydroxylase activity.[1]
PBZ and its congeners inhibit the uptake of catecholamines into both adrenergic nerve terminals and extraneuronal tissues called uptake 1 and 2, respectively. However, the block of uptake 2 is probably important in causing potentiation of responses and augmentation of the outflow of norepinephrine during the stimulation of sympathetic nerves to an organ. As a nonselective alpha receptor antagonist, PBZ affects both postsynaptic α1 and presynaptic α2 receptors in the nervous system, and hence reduce sympathetic activity. PBZ is used for the treatment of pheochromocytoma; with extended use, it establishes a “chemical sympathectomy.” The haloalkylamines can inhibit responses to 5-hydroxytryptamine, serotonin, histamine, and acetylcholine (Ach).[8] Effective blockade of responses to Ach usually requires relatively high dose.
| Pharmacokinetics | | |
PBZ are effectively administered by all routes, but injection should be given only intravenously because of their irritant properties.[1] Absorption from the intestine is incomplete and somewhat unreliable. Approximately 30% of orally administered PBZ appears to be absorbed in active forms.
PBZ has high lipid solubility at body pH, and accumulation in fat may occur after large doses. However, a stable bonding to tissue constituents rather than slow release from fat is responsible for the prolonged action. Over 50% of the intravenously administered PBZ is excreted in 12 h and over 80% in 24 h, but small amounts remain in various tissues for at least a week. Blockade by PBZ develops relatively slowly, reaching a peak effect in 1 h, or more after IV administration. PBZ has a half-life of approximately 24 h.1 The actual duration of action depends on fresh PBZ receptor synthesis since the drug inactivates alpha-adrenergic receptors irreversibly, and therefore the duration of its effect is dependent not only on its presence but also on the rate of synthesis of alpha-adrenergic receptors.
| Route of Administration and Dosage | | |
It is available for oral use in 10 mg capsules; ampoule for intravenous use are available as 100 mg in 2 ml and also 50 mg in 1 ml.[1] The oral dose usually varies between 20 and 200 mg per day and must be increased by small increments. Pediatric dose ranges from 1 to 2 mg/kg/day in 3–4 divided doses. Postoperatively, in intensive care unit, a dose of 0.3–0.5mg/kg at 8–12 h interval is used.[4] PBZ must be well diluted and infused slowly before intravenous administration. Most commonly a dose of 0.25–1 mg/kg is diluted and infused slowly over a period of at least 30 min.[9]
| Pharmacodynamics | | |
Cardiovascular system
Blood pressure
The usual blocking dose of PBZ is 1 mg/kg given slowly intravenously. The fall in systemic BP is less in healthy, recumbent, normovoluemic subjects. Severe hypotension may occur in a situation involving compensatory sympathetic vasoconstriction, such as upright posture and hypovolemia. In addition, impairment of compensatory vasoconstriction sensitizes to the hypotensive effects of a variety of agents and condition that tend to produce vasodilatation such as anesthetized patients.[1]
Blood flow
PBZ produces a considerable increase in cardiac output and decrease of total peripheral resistance in normal recumbent subjects.[1] Cerebral and coronary resistance are not significantly altered by adrenergic blockade. Cerebral flow is less affected unless the BP is greatly reduced, and coronary flow increases in parallel with reflex cardiac stimulation. PBZ increases resting muscle blood flow and in a cool environment enhances cutaneous blood flow. Splanchnic and renal blood flows are not altered remarkably in the presence of the increased adrenergic vasoconstrictor tone induced by circumstances such as hypovolemia or norepinephrine infusion. PBZ increases the flow to a major degree in both these areas. Pulmonary arteries and veins are also relaxed, however, because of a greater systemic vasodilatation; blood volume in the pulmonary circuit is usually decreased.[1] Pressure responses to epinephrine and other sympathomimetic amines are blocked or reversed by PBZ. It effectively blocks pathological effects of infused epinephrine or norepinephrine, including pulmonary edema, reduction in plasma volume, accumulation of pericardial fluid, adrenocortical necrosis, and changes in hepatic cells.[1]
Cardiac effects
The chronotropic and inotropic effects of epinephrine, norepinephrine, and direct or reflex sympathetic nerve stimulation on the mammalian myocardium are not inhibited by the PBZ.[3] PBZ induces reflex tachycardia in response to peripheral vasodilatation and may be accumulated by altered norepinephrine release as well as by postjunctional potentiation. They are used as antihypertensives because they block alpha-receptor-mediated vasoconstriction. The block on alpha-2 receptors further potentiates beta-effects, increasing cardiac output.[1]
Central nervous system
PBZ stimulates the central nervous system to cause nausea, vomiting, hyperventilation, motor excitability, and even convulsions, particularly when large dose is rapidly injected intravenously. 1 In man, a characteristic loss of time perception may occur. These effects develop and terminate much more rapidly than does the blockade. Mild-to-moderate sedation commonly results from the slow intravenous infusion of the usual blocking dose of PBZ in man and tiredness and lethargy may accompany oral medication.[1]
Metabolic effects
The receptors involved in metabolic responses to catecholamine are preferentially β, but important α adrenergic action is also involved. Inhibitory action of epinephrine on insulin secretion is blocked by PBZ. It does not antagonize the effects of catecholamine on glycogenolysis of liver or muscle.[1] It does not inhibit catecholamine augmented lipolysis.
Other effects
PBZ effectively antagonizes the wide variety of responses to endogenous and exogenous sympathomimetic amines that are mediated by α-adrenergic receptors. These include contraction of the retractor penis, erector pili, and the uteri. Salivary secretion of water and electrolyte evoked by cervical sympathetic nerve stimulation or injected sympathomimetic drugs is blocked. The volume and enzyme content of pancreatic exocrine secretion are increased by α and decreased by β-adrenergic blockade. The limited adrenergic sweating observed in man, particularly of the hands and axillae are also blocked.[1]
| Toxicity and Side Effects | | |
Untoward effects of PBZ are largely due to the blockade of α-adrenergic receptors.[9] Loss of vasomotor control results in hypotension and reflex tachycardia. Conditions such as exercise, eating a large meal, or consuming alcohol precipitate the side effects [Table 1].
Side effects such as local tissue irritation, sedation, and a generalized feeling of weakness and tiredness are not related to α-blockade. Nausea and vomiting occur after large oral doses due to local irritation of gastrointestinal tract mucosa, especially when administered empty stomach.
In patients having carbohydrate intolerance, α-adrenergic-receptor blockade may reduce fasting blood sugar levels due to lack of inhibition of insulin release mediated by α-adrenergic receptor stimulation,
| Indications | | |
The clinical uses of PBZ are listed [Table 2].
Pheochromocytoma
PBZ is mainly recommended for the treatment of pheochromocytoma, tumors of the adrenal medulla, and sympathetic neurons-secreting enormous quantities of catecholamines. PBZ is used to prepare the patient for surgical removal of tumor. PBZ restores plasma volume by counteracting the vasoconstrictive effects of high levels of catecholamines.[3] Reexpansion of fluid volume may cause decrease in hematocrit. PBZ initial dose should be 20–30 mg orally 2–3 times a day.[1] Maximum dose in a day may go up to 250 mg. The efficacy of therapy should be judged by the reduction in symptoms, especially sweating and stabilization of BP.
Preoperatively, PBZ aids in BP control permits the correction of the contracted plasma volume, and protects against catecholamine-induced cardiac damage.[10] The use of PBZ appeared to produce better attenuation of intraoperative hypertension but may necessitate vasopressors in the postoperative period. Preoperative α-adrenergic receptor blockade resolved ST-T changes in electrocardiogram and clinical manifestation of catecholamine-induced myocarditis.[10],[11],[12] Therapy may be limited by postural hypotension. Prolonged treatment with PBZ may be necessary in patients with inoperable or malignant pheochromocytoma. Metyrosine, a competitive inhibitor of tyrosine hydroxylase, may be a useful adjuvant. Beta-receptor antagonists also are used in the treatment pheochromocytoma only after the administration of α-receptor antagonist.
Cardiac surgery
The use of PBZ during cardiac surgery facilitates higher pump flow rate during cardiopulmonary bypass (CPB) and is associated with less metabolic acidosis postoperatively.[13] In addition, PBZ was found to be more effective than sodium nitroprusside in improving tissue perfusion after CPB, as measured by smaller peripheral-to-core temperature gradients and lower base deficits in PBZ-treated patients [Table 3].[14]
After the early neonatal period, there is a progressive increase in afterload with reduction in the contractility, reaching a plateau at the age of 4 years. Neonatal heart is more susceptible to exogenous catecholamines-induced cardiotoxicity. Sympathetic innervations, reduced norepinephrine stores, and less efficient contractile power are the mechanisms involved. The newborn's heart is more susceptible to ischemia than adult's but recovers faster from short periods of ischemia <30 min. Hence, vasodilatory therapy can play a key role in pediatric cardiac surgery, improving cardiac output by decreasing afterload without affecting the contractility. PBZ has been tried in infants and children with congenital heart disease undergoing open cardiac repair, providing a more balanced pulmonary-to-systemic blood flow by lowering SVR.[5],[15] A combination of PBZ and nitroglycerin (NTG) is a low-cost alternative for perioperative control of pulmonary arterial pressure in children with congenital heart disease undergoing cardiac surgery because PBZ is known for its pulmonary vasodilating effect, thereby decreasing right ventricular load [Table 4].[16]
Hypoplastic left heart syndrome
Contractile tissue in neonatal hearts is around 30% of the myocardial mass and is characterized by a lower velocity of shortening and a diminished length-tension relationship.[17] Thus, the neonatal heart has a reduced compliance, a relatively fixed stroke volume, and cardiac output is a heart-rate dependent. As a result, the neonatal heart has poor response to increase in afterload.
Neonates undergoing Norwood procedure suffer from the above intrinsic limitations as well as the factors unique to HLHS.[7] First, functional limitations of the postoperative myocardium are further compounded by myocardial depression from cardioplegia and CPB. Second, the single ventricle must perform the work of both pulmonary and systemic ventricle in a setting that may include a low diastolic pressure and alterations in coronary artery blood flow. Third, sympathetic responses to stress that result in increases in SVR and subsequent increases in the Qp/Qs further reduce myocardial performance and systemic organ perfusion. Consequently, perioperative management strategies to increase survival have mainly focused on improving post-bypass myocardial function and systemic organ perfusion. PBZ fundamentally decreases SVR by vasodilatation and hence improves systemic oxygen delivery and stabilizes Qp/Qs.[1],[9] Tweddel et al. studied the effect of PBZ on the oxygen delivery in patients undergoing Stage 1 palliative repair of HLHS; PBZ caused a significant improvement in the early postoperative course of the patients who received the drug.[7]
The authors have been are using PBZ in cardiovascular disease patients for the last 2 decades. The main uses are during hypothermic CPB in all neonates, ASO, and Norwood operation. Cardiac surgery for ventricular septal defect closure, total anomalous pulmonary venous connection repair, persistent truncus arteriosus, aortopulmonary window, and total cavopulmonary connection/Fontan operation receives PBZ during operation, ICU, and postoperative ward.[16] The use helps in uniform cooling and rewarming during CPB, improved pump flow, less acidosis, and higher tissue oxygenation.[6] The SVR is managed perfectly in ASO and Norwood patients and helps in improving LV function of regressed LV.[5] The balance in Qp/Qs ratio by PBZ facilitates to reduce and manage pulmonary hypertension.[16] The combination of PBZ, NTG, and sildenafil in perioperative period helps to treat hypertensive crisis and successful weaning from CPB and extracorporeal membrane oxygenator.
Miscellaneous uses
PBZ may be useful in the treatment of Raynaud's phenomenon, but their side effects often curtail extended use.[18] PBZ has been found to be alternative treatment for causalgia.[19] There is less morbidity in comparison to surgical sympathectomy. It was found useful in the first 3 months after diagnosis. Sudeck's atrophy, characterized by severe trophic changes, skin changes, and osteoporosis might occur after the onset of causalgia. PBZ occasionally has been used for this. PBZ has been reported to be used for hypotensive anesthesia in children.[20] Due to its 5-HT2A receptor antagonism, PBZ is useful in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin.[21]
Lower doses of PBZ was found to be beneficial for endothelial viability and potentially the long-term patency of the graft after coronary artery bypass graft surgery along with nitrates, phosphodiesterase inhibitors, or calcium channel blockers.[22],[23] It has been found useful in peripheral vascular disease.[1]
The combined use of PBZ with dopamine was recommended because PBZ will block α-adrenergic action of dopamine, whereas peripheral perfusion is improved with intact beta-adrenergic stimulation.[24] The combination of dobutamine and PBZ is as effective as newer drugs such as enoximone, an inotrope/vasodilator after cardiac surgery in children.[25]
Management of side effects
When exogenous sympathomimetics are administered after α receptor blockade, their vasoconstrictive effects are inhibited. The effect of phenylephrine is completely blocked. Despite its irreversible binding to the receptor, the recommended treatment of PBZ-induced hypotension is norepinephrine infusion because some of the receptors remain free of the drug. Vasopressin is an effective antidote to this vasodilation. Vasopressin acts on smooth muscle V1 receptors, which have preserved activity even in the presence of PBZ, and can overcome its effect.[26] Epinephrine administrations after the use of PBZ cause severe hypotension and tachycardia because of refractory α-receptor blockade and unopposed ß receptor activity.[1] This is known as vasomotor reversal of Dale or Dale's phenomena.
| Conclusion | | |
PBZ has a promising therapeutic option for the treatment of hypertension in pheochromocytoma, control of SVR in HLHS and pulmonary hypertension of varied origin. The improvement in perfusion parameters during CPB in neonatal and pediatric cardiac surgery by PBZ therapy is established by different studies. It offers convenient and versatile dosing because of the oral and parenteral administration. The intraoperative, postoperative, and intensive care setting use is safer with hemodynamic monitoring and delivers the best results with excellent patient outcome. The therapeutic use should be decided rationale considering the benefits and risks. The potent hypotensive effects alarm the judicious and titrated use of PBZ. However, rigorous, blinded, placebo-controlled, multicenter, randomized studies are required to confirm the efficacy of PBZ for single or as a combination therapy with other drugs. Noncardiac uses based on different evidence also need further study for establishing the efficacy and safety of PBZ.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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