Professional Documents
Culture Documents
231]
Review Article
Abstract
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
Introduction • Prazosin
• Tamsulosin
Phenoxybenzamine (PBZ) was initially used in the treatment
• Terazosin
of hypertension, especially that caused by pheochromocytoma.
• Silodosin.
It was also the first alpha blocker to be used for the treatment
of benign prostatic hyperplasia; it has been used in the Selective α2‑adrenergic receptor antagonists include:
treatment of hypoplastic left heart syndrome (HLHS). It is an • Atipamezole
alpha‑receptor blocker. The other alpha receptor blockers are • Idazoxan
listed below. • Mirtazapine
• Yohimbine.
Alpha‑blockers act as antagonists of α‑adrenergic receptors.
The agents carvedilol and labetalol are both α‑ and β‑blockers.
The types include:
• α1‑blockers act on α1‑adrenoceptors PBZ is a potent alpha‑adrenergic blocking agent used routinely
• α2‑blockers act on α2‑adrenoceptors. for the management of hypertension in pheochromocytoma.[1]
The indications of PBZ extend to the management of pulmonary
Examples of non‑selective α‑adrenergic receptor antagonists
hypertension in cardiac disease patients, balancing of systemic
include:
and pulmonary blood flow in HLHS, benign prostatic
• PBZ
hypertrophy, malignant essential hypertension, hypotensive
• Phentolamine
anesthesia, sausage, and so on.[2] However, the side effects,
• Tolazoline
• Trazodone
• Typical and atypical antipsychotics. Address for correspondence: Dr. Sambhunath Das,
Department of Cardiac Anaesthesia, 7th Floor, Cardio Thoracic
Selective α1‑adrenergic receptor antagonists include: Sciences Centre, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi ‑ 110 029, India.
• Alfuzosin E‑mail: sambhunathds833@gmail.com
• Doxazosin
Access this article online This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak,
Quick Response Code: and build upon the work non‑commercially, as long as the author is credited and the
Website: new creations are licensed under the identical terms.
www.j‑pcs.org
For reprints contact: reprints@medknow.com
DOI:
10.4103/jpcs.jpcs_42_16 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.
© 2017 Journal of the Practice of Cardiovascular Sciences | Published by Wolters Kluwer - Medknow 11
[Downloaded free from http://www.j-pcs.org on Monday, July 17, 2017, IP: 139.193.54.231]
such as persistent hypotension, muscle weakness, and postural in the actions of most other chemical class.[8] Subsequent to
hypotension, limit its use by many physicians. Some physicians blockade of receptors by PBZ, the conjugate became fixed
are in favor of using alternative drugs for control of blood and does not allow adrenaline and noradrenalin for binding.
pressure (BP) and systemic vascular resistance (SVR) with This stage is referred to as nonequilibrium blockade and
less potency and short acting.[3,4] However, still many centers is the result of stable covalent bond formation between
use PBZ in situations such as perioperative hemodynamic the antagonist and the receptors. PBZ increases the rate of
management of pheochromocytoma, HLHS, arterial switch peripheral norepinephrine turnover, which is associated with
operation (ASO), single‑ventricle physiology, pulmonary increased tyrosine turnover resulting in increased tyrosine
artery hypertension, and congenital cardiac surgery with a hydroxylase activity.[1]
better outcome.[3‑7] The evidence from different studies and
PBZ and its congeners inhibit the uptake of catecholamines
reports in respect to the current uses and limitations of PBZ
into both adrenergic nerve terminals and extraneuronal tissues
necessitates update.
called uptake 1 and 2, respectively. However, the block of
This review article discusses the pharmacological aspects, uptake 2 is probably important in causing potentiation of
mechanism of action, indications, side effects, controversies, responses and augmentation of the outflow of norepinephrine
and management of complications related to PBZ. All the during the stimulation of sympathetic nerves to an organ. As
publications and literatures are searched from PubMed and a nonselective alpha receptor antagonist, PBZ affects both
Google Scholar using the keywords of PBZ, cardiovascular postsynaptic α1 and presynaptic α2 receptors in the nervous
disease, HLHS, pheochromocytoma, pulmonary arterial system, and hence reduce sympathetic activity. PBZ is used
hypertension, and alternate uses of PBZ for the last 16 years. for the treatment of pheochromocytoma; with extended use, it
establishes a “chemical sympathectomy.” The haloalkylamines
Pharmacology can inhibit responses to 5‑hydroxytryptamine, serotonin,
histamine, and acetylcholine (Ach).[8] Effective blockade of
PBZ is a haloalkylamine derivative.[1] PBZ is an adrenergic responses to Ach usually requires relatively high dose.
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 Pharmacokinetics
amine ring.[8] In consequence of the chemical reactions, a PBZ are effectively administered by all routes, but injection
covalent bond is formed between the drug and the α‑adrenergic should be given only intravenously because of their irritant
receptor [Figure 1].[8] properties.[1] Absorption from the intestine is incomplete
and somewhat unreliable. Approximately 30% of orally
Mechanism of Action administered PBZ appears to be absorbed in active forms.
PBZ blocks both α1‑ and α2‑adrenergic receptors with more PBZ has high lipid solubility at body pH, and accumulation
affinity for α1‑receptor.[1] The presence of a catecholamine or in fat may occur after large doses. However, a stable bonding
an α‑adrenergic blocking agent of the competitive type during to tissue constituents rather than slow release from fat is
the development of blockade by PBZ can reduce the degree responsible for the prolonged action. Over 50% of the
of block. intravenously administered PBZ is excreted in 12 h and
over 80% in 24 h, but small amounts remain in various tissues
There is competition for the same population of receptors, for at least a week. Blockade by PBZ develops relatively slowly,
indicating that the initial approximation of the PBZ to its site reaching a peak effect in 1 h, or more after IV administration.
of action is due to weak ionic and hydrogen bond involved 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.
Most commonly a dose of 0.25–1 mg/kg is diluted and infused commonly results from the slow intravenous infusion of the
slowly over a period of at least 30 min.[9] usual blocking dose of PBZ in man and tiredness and lethargy
may accompany oral medication.[1]
Pharmacodynamics Metabolic effects
Cardiovascular system The receptors involved in metabolic responses to catecholamine
Blood pressure are preferentially β, but important α adrenergic action is also
The usual blocking dose of PBZ is 1 mg/kg given slowly involved. Inhibitory action of epinephrine on insulin secretion
intravenously. The fall in systemic BP is less in healthy, is blocked by PBZ. It does not antagonize the effects of
recumbent, normovoluemic subjects. Severe hypotension catecholamine on glycogenolysis of liver or muscle.[1] It does
may occur in a situation involving compensatory sympathetic not inhibit catecholamine augmented lipolysis.
vasoconstriction, such as upright posture and hypovolemia. In
addition, impairment of compensatory vasoconstriction sensitizes Other effects
to the hypotensive effects of a variety of agents and condition that PBZ effectively antagonizes the wide variety of responses
tend to produce vasodilatation such as anesthetized patients.[1] to endogenous and exogenous sympathomimetic amines
that are mediated by α‑adrenergic receptors. These include
Blood flow contraction of the retractor penis, erector pili, and the uteri.
PBZ produces a considerable increase in cardiac output Salivary secretion of water and electrolyte evoked by cervical
and decrease of total peripheral resistance in normal sympathetic nerve stimulation or injected sympathomimetic
recumbent subjects.[1] Cerebral and coronary resistance are not drugs is blocked. The volume and enzyme content of pancreatic
significantly altered by adrenergic blockade. Cerebral flow is exocrine secretion are increased by α and decreased by
less affected unless the BP is greatly reduced, and coronary β‑adrenergic blockade. The limited adrenergic sweating
flow increases in parallel with reflex cardiac stimulation. PBZ observed in man, particularly of the hands and axillae are
increases resting muscle blood flow and in a cool environment also blocked.[1]
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 Toxicity and Side Effects
as hypovolemia or norepinephrine infusion. PBZ increases the Untoward effects of PBZ are largely due to the blockade of
flow to a major degree in both these areas. Pulmonary arteries α‑adrenergic receptors.[9] Loss of vasomotor control results
and veins are also relaxed, however, because of a greater in hypotension and reflex tachycardia. Conditions such as
systemic vasodilatation; blood volume in the pulmonary circuit exercise, eating a large meal, or consuming alcohol precipitate
is usually decreased.[1] Pressure responses to epinephrine the side effects [Table 1].
and other sympathomimetic amines are blocked or reversed
Side effects such as local tissue irritation, sedation, and a
by PBZ. It effectively blocks pathological effects of infused
epinephrine or norepinephrine, including pulmonary edema, generalized feeling of weakness and tiredness are not related
reduction in plasma volume, accumulation of pericardial fluid, to α‑blockade. Nausea and vomiting occur after large oral
adrenocortical necrosis, and changes in hepatic cells.[1] doses due to local irritation of gastrointestinal tract mucosa,
especially when administered empty stomach.
Cardiac effects
The chronotropic and inotropic effects of epinephrine, In patients having carbohydrate intolerance, α‑adrenergic-
norepinephrine, and direct or reflex sympathetic nerve receptor blockade may reduce fasting blood sugar levels due to
stimulation on the mammalian myocardium are not inhibited lack of inhibition of insulin release mediated by α‑adrenergic
by the PBZ.[3] PBZ induces reflex tachycardia in response receptor stimulation,
to peripheral vasodilatation and may be accumulated by
altered norepinephrine release as well as by postjunctional Indications
potentiation. They are used as antihypertensives because they The clinical uses of PBZ are listed [Table 2].
block alpha‑receptor‑mediated vasoconstriction. The block on
alpha‑2 receptors further potentiates beta‑effects, increasing
cardiac output.[1] Table 1: Side effects of phenoxybenzamine
Postural hypotension
Central nervous system Reflex tachycardia
PBZ stimulates the central nervous system to cause nausea, Miosis
vomiting, hyperventilation, motor excitability, and even Nasal stuffiness
convulsions, particularly when large dose is rapidly injected Inhibition of ejaculation
intravenously. 1In man, a characteristic loss of time perception GI irritation‑nausea and vomiting
may occur. These effects develop and terminate much more Sedation, generalized feeling of weakness and tiredness
rapidly than does the blockade. Mild‑to‑moderate sedation GI: Gastrointestinal
after coronary artery bypass graft surgery along with 12th ed. U.S.A.: McGraw‑Hill Companies, Inc.; 2011. p. 148‑87.
nitrates, phosphodiesterase inhibitors, or calcium channel 2. Sambhunath D, Pankaj K, Usha K. Role of phenoxybenzamine in
perioperative clinical practice. Ann Card Anaesth 2015;18:577‑8.
blockers.[22,23] It has been found useful in peripheral vascular 3. Agrawal R, Mishra SK, Bhatia E, Mishra A, Chand G, Agarwal G,
disease.[1] et al. Prospective study to compare peri‑operative hemodynamic
alterations following preparation for pheochromocytoma surgery by
The combined use of PBZ with dopamine was recommended phenoxybenzamine or prazosin. World J Surg 2014;38:716‑23.
because PBZ will block α‑adrenergic action of dopamine, 4. Bruynzeel H, Feelders RA, Groenland TH, van den Meiracker AH,
whereas peripheral perfusion is improved with intact van Eijck CH, Lange JF, et al. Risk factors for hemodynamic instability
during surgery for pheochromocytoma. J Clin Endocrinol Metab
beta‑adrenergic stimulation.[24] The combination of dobutamine 2010;95:678‑85.
and PBZ is as effective as newer drugs such as enoximone, 5. Bisoi AK, Sharma P, Chauhan S, Reddy SM, Das S, Saxena A, et al.
an inotrope/vasodilator after cardiac surgery in children.[25] Primary arterial switch operation in children presenting late with
d‑transposition of great arteries and intact ventricular septum. When is
Management of side effects it too late for a primary arterial switch operation? Eur J Cardiothorac
When exogenous sympathomimetics are administered after α Surg 2010;38:707‑13.
6. Das S, Nanda SK, Bisoi A, Makhija N. Effect of two doses of
receptor blockade, their vasoconstrictive effects are inhibited. phenoxybenzamine during cardiopulmonary bypass in infants
The effect of phenylephrine is completely blocked. Despite undergoing arterial switch operation for transposition of great arteries.
its irreversible binding to the receptor, the recommended J Cardiovasc Med Surg 2015;1:17‑21.
treatment of PBZ‑induced hypotension is norepinephrine 7. Tweddell JS, Hoffman GM, Fedderly RT, Berger S, Thomas JP Jr.,
Ghanayem NS, et al. Phenoxybenzamine improves systemic oxygen
infusion because some of the receptors remain free of the delivery after the Norwood procedure. Ann Thorac Surg 1999;67:161‑7.
drug. Vasopressin is an effective antidote to this vasodilation. 8. Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A.
Vasopressin acts on smooth muscle V1 receptors, which Phenoxybenzamine binding reveals the helical orientation of the
have preserved activity even in the presence of PBZ, and can third transmembrane domain of adrenergic receptors. J Biol Chem
2001;276:31279‑84.
overcome its effect.[26] Epinephrine administrations after the 9. Guzzetta NA. Phenoxybenzamine in the treatment of hypoplastic left
use of PBZ cause severe hypotension and tachycardia because heart syndrome: A core review. Anesth Analg 2007;105:312‑5.
of refractory α‑receptor blockade and unopposed ß receptor 10. Prys‑Roberts C. Phaeochromocytoma – Recent progress in its
activity.[1] This is known as vasomotor reversal of Dale or management. Br J Anaesth 2000;85:44‑57.
11. Kassim TA, Clarke DD, Mai VQ, Clyde PW, Mohamed Shakir KM.
Dale’s phenomena. Catecholamine‑induced cardiomyopathy. Endocr Pract 2008;14:1137‑49.
12. Bajwa SS, Bajwa SK. Implications and considerations during
Conclusion pheochromocytoma resection: A challenge to the anesthesiologist.
Indian J Endocrinol Metab 2011;15 Suppl 4:S337‑44.
PBZ has a promising therapeutic option for the treatment 13. Mossad E, Motta P, Sehmbey K, Toscana D. The hemodynamic effects
of hypertension in pheochromocytoma, control of SVR in of phenoxybenzamine in neonates, infants, and children. J Clin Anesth
2008;20:94‑8.
HLHS and pulmonary hypertension of varied origin. The 14. Motta P, Mossad E, Toscana D, Zestos M, Mee R. Comparison of
improvement in perfusion parameters during CPB in neonatal phenoxybenzamine to sodium nitroprusside in infants undergoing
and pediatric cardiac surgery by PBZ therapy is established surgery. J Cardiothorac Vasc Anesth 2005;19:54‑9.
by different studies. It offers convenient and versatile dosing 15. Tweddell JS, Hoffman GM, Mussatto KA, Fedderly RT, Berger S,
Jaquiss RD, et al. Improved survival of patients undergoing palliation of
because of the oral and parenteral administration. The hypoplastic left heart syndrome: Lessons learned from 115 consecutive
intraoperative, postoperative, and intensive care setting use patients. Circulation 2002;106 12 Suppl 1:I82‑9.
is safer with hemodynamic monitoring and delivers the best 16. Kiran U, Makhija N, Das SN, Bhan A, Airan B. Combination of
results with excellent patient outcome. The therapeutic use phenoxybenzamine and nitroglycerin: Effective control of pulmonary
artery pressures in children undergoing cardiac surgery. J Cardiothorac
should be decided rationale considering the benefits and risks. Vasc Anesth 2005;19:274‑5.
The potent hypotensive effects alarm the judicious and titrated 17. Odegard KC, Laussen PC. Approach to the fetus, premature, and
use of PBZ. However, rigorous, blinded, placebo‑controlled, full‑term infant. In: Andropoulos DB, Stayer SA, Russell I, Mossad EB,
multicenter, randomized studies are required to confirm the editors. Anesthesia for Congenital Heart Disease. Ch. 14. Oxford, UK:
Wiley‑Blackwell; 2010. p. 244‑61.
efficacy of PBZ for single or as a combination therapy with 18. Wise RA, Wigley FM, White B, Leatherman G, Zhong J, Krasa H,
other drugs. Noncardiac uses based on different evidence also et al. Efficacy and tolerability of a selective alpha(2C)‑adrenergic
need further study for establishing the efficacy and safety of receptor blocker in recovery from cold‑induced vasospasm
PBZ. in scleroderma patients: A single‑center, double‑blind,
placebo‑controlled, randomized crossover study. Arthritis Rheum
Financial support and sponsorship 2004;50:3994‑4001.
19. Inchiosa MA Jr., Kizelshteyn G. Treatment of complex regional pain
Nil. syndrome type I with oral phenoxybenzamine: Rationale and case
reports. Pain Pract 2008;8:125‑32.
Conflicts of interest 20. Brown TC. Early experiences of vasodilators and hypotensive anesthesia
There are no conflicts of interest. in children. Paediatr Anaesth 2012;22:720‑2.
21. Katzung B, Masters S, Trevor A. Katzung and Trevor’s Pharmacology
Examination and Board Review. 12th ed. New York: McGraw‑Hill
References Professional; 2012. p. 286.
1. Westfall TC, Westfall DP. Adrenergic, agonists and antagonists. 22. Kulik A, Rubens FD, Gunning D, Bourke ME, Mesana TG, Ruel M.
Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. Radial artery graft treatment with phenoxybenzamine is clinically safe
and may reduce perioperative myocardial injury. Ann Thorac Surg 25. Innes PA, Frazer RS, Booker PD, Allsop E, Kirton C, Lockie J,
2007;83:502‑9. et al. Comparison of the haemodynamic effects of dobutamine with
23. He GW, Yang CQ. Vasorelaxant effect of phosphodiesterase‑inhibitor enoximone after open heart surgery in small children. Br J Anaesth
milrinone in the human radial artery used as coronary bypass graft. 1994;72:77‑81.
J Thorac Cardiovasc Surg 2000;119:1039‑45. 26. O’Blenes SB, Roy N, Konstantinov I, Bohn D, Van Arsdell GS.
24. Paragliola RM, Ricciato MP, Gallo F, De Rosa A, Ianni F, Locantore P, Vasopressin reversal of phenoxybenzamine‑induced hypotension
et al. Preoperative and postoperative management of adrenal masses. after the Norwood procedure. J Thorac Cardiovasc Surg
G Chir 2010;31:332‑5. 2002;123:1012‑3.