1468 Cardiovascular

Phenindione may discolour the urine pink orange and OT in severe shock (p. 1279.3) and in the treatment of urinary r ti this is independent of any haematuria. retention (p. 2349.2). P.r.�P.(]. <:J ?n.� ...... Phenoxybenzamine is used as the hydrochloride. It is ProprietaryPreparations (details are given in Volume B) Effects on the gastrointestinal tract. There haw been given orally or by intravenous infusion as a dilute solution. Single·ingredient Prepara�ons. Austral.: Dibenylinet; Austria: cases of paralytic ileus, one fatal, associated wiLh phen­ In phaeochromocytoma it is used to control the Dibenzyran; Ger.: Dibenzyran; Gr.: Dibenyline; Dibenzyran; indione.1·2 hypertension associated with excessive catecholamine Hong Kong: Dibelinet; Dibenyline; India: Biophenox; Feno­ ben; Fenoxene; Israel: Dibenyline; NZ: Dibenyline; S.Afr. : 1. Menon IS. Phenindione and paralytic ileus. Lanat l966; i: 1421- release during the pre-operative period and in patients 2. Nash AG. Phenindione and paralytic ileus. ii: 5�-2. whose tumours are inoperable. A beta blocker may also be Dibenylinet; UK: Dibenyline; USA: Dibenzyline. given to control tachycardia, but not before alpha blockade PharmacopoeialPrepara�ons Precautions has completely suppressed the pressor effects of the BP 2014: Phenoxybenzamine Capsules; USP 36: Phenoxybenzamine Hydrochloride Capsules. As for Warfarin Sodium, p. 1529.2. phaeochromocytoma. The usual initial oral dose of Phenindione is not recommended in prcgnmr:y. phenoxybenzamine hydrochloride is 10 mg once or twice daily, increased gradually, according to the patient's Breast feeding. Phenindione is distributed into response, to a usual dose of 1 to 2 mglkg daily in 2 divided milk, with reported concentrations micro­ doses. It may be given intravenously for operative cover in l I to 5 patients with phaeochromocytoma in a daily dose of grams/mL after a single dose of 50 or 15 rug. A wmnan I mglkg in 200 mL of sodium chloride 0. 9% infused over at given phenindione 50mg each morning ann 50 and 25 mg on alternate nights breast fed her infant son,2 who least 2 hours. A similar intravenous dose in 200 to 500 mL of required a herniotomy at 5 weeks. After surgery he had sodium chloride 0.9% has been given in the n1anagement of an enormous scrotal haematoma with ooLing frmn the severe shock. wound and was found to have extended prothrombin and For urinary retention due to neurogenic bladder an partial thromboplastin times. Last available guidance from oral dose of lOmg twice daily has been given. the American Academy of Pediatrics therefore considered3 that phenindione should be given with GlL�don to breast­ feeding mothers. Adverse Effects and Treatment Gognel M, et a!. Therapeutique antico g du l. a ulante e� alliliu:nwnt:f'1"11de The adverse effects of phenoxybenzamine are mainly due to Uses and Administration de Ia phCnyl-2-dioxo, 1,3 iml.ane dans k ]Phenprocoumon is an oral coumarin anticoagulant with HB, Jack B. Breast-feeding and anticoagui.Jn< orthostatic hypotension and dizziness, reflex tachycardia, 2. tbci·c,py. Lancet actions similar to those of warfarin (p. 1527.2). It is used in 1970; 672-3. i: nasal congestion, and miosis. Inhibition of ejaculation may the management of thromboembolic disorders (p. 1273.2). occur. These effects may be minimised by using a low initial Initial doses are upto 9 mgon the first day followed by 6 mg dose, and may diminish with continued use, but the on the second day. Maintenance doses are usually from 1.5 hypotensive effect can be exaggerated by exercise, heat, a to 6 mg daily, depending on the response. large meal, or alcohol ingestion. Other adverse effects include dry mouth, decreased sweating, drowsiness, fatigue,

Adverse-- .. ····- Effects, Treatment, and Precautions Interactions and confusion. Gastrointestinal effects are usually slight. ··-······ When phenoxybenzamine is given intravenously, idiosyn� As for Warfarin Sodium, p. 1528.2. The interactions associated with oral anticoagulants are cratic profound hypotension can occur within a few described in detail under warfarin (p. 1529.3), Specific Effects on the liver. A woman who had twice previously references to interactions involving phenindione can be minutes of starting the infusion. Convulsions have been developed jaundice while taking phenprocoumon devel­ found there under tbe headings for the following drug reported after rapid intravenous infusion of phenoxybenz­ oped jaundice and parenchymal liver damage when, after groups: antibacterials; antifungals; antiplatelets; anxiolytic amine. some years, phenprocoumon was again given. 1 Other sedatives; gastrointestinal drugs; lipid regulating drugs; and Severe hypotension may occur in overdose and treatment includes support of the circulation by postural cases of phenprocoumon -associated liver damage have sex hormones. - measures and parenteral fluid volume replacement. been reported.2 4 Sympathomimetics are considered to be of little value, and I. den Boer W, Loeliger EA. Phenprocoumon-induced jaundice. Lancet Pharmacokinetics adrenaline is contra-indicated since it also stilnulates beta 1976; i: 912. 2. Slagboom G, Loeliger EA. Coumarin-associated hepatitis: report of two Phenindione is completely absorbed from the gastrointest­ receptors causing increased hypotension and tachycardia. cases. Arch lntern Med 1980; 140: 1028-9. inal tract, with peak plasma levels attained after 1 to 3 hours Sources differ as to the value of noradrenaline in 3. Cordes A, et al. Phenprocoumon-induziertes Leberversagen. Dtsch Med and a half-life of 5 to 6 hours. It crosses the placenta 1nd is overcoming alpha-receptor blockade. Wochenschr 2003; 128: 1884-6. 4. Bulang T, et al. Akutes Leberversagen durch Phenprocoumon-drei distributed into breast milk. Metabolites phcnL..1di.one Phenoxybenzamine has been shown to be mutagenic in JI Fallberichte. Z Gastroenterol 2004; 42: 1055-8. excreted in the urine are responsible for any discoloration in vitro tests and carcinogenic in rodents. There have been that may occur. case reports of carcinoma in patients given long-term treatment with phenoxybenzamine for bladder dysfunc­ Interactions t tion; US licensed product information therefore advises The interactions associated with oral anticoagulants are P.r�p(]_r(]_ i?n.�...... against long-term use. discussed in detail under warfarin (p. 1529.3). Specific Proprietary Preparations (details are given in Volume B) references to interactions involving phenprocoumon can be Single-ingredient Preparations. Austral.: Dindevan; Gr, : Solu­ found there under the headings for the following drug thrombine; India: Dindevan; Rus.: Phenylin (1J:l, avoid extravasation. Contamination of the skin should also compound. Phenprocoumon is given as a racemic mixture; !3enzyl(2:d1ioroethyi)(l"rnethyh2. -phenoxyethyllamine be avoided since contact sensitisation may occur. the S-isomer is more potent. The stereo-isomers have hyqrochlorlde; different pharmacokinetics. C,acenocoumarol. Clin Pharmacokinet2005; enhance the cardiac-accelerating and hypotensive action of 44: 1227-46. phenoxybenzamine. 4. Werner D, et al. Pharmacogenetic characteristics of patients with 65: complicated phenprocoumon dosing. Bur 1 Clin Pharmacal 2009; BP 2014: (Phenoxybenzamine Hydrochloride). 783-8. almost white, odourless or almost odourlcss, crystalline Pharmacokinetics powder. Sparingly soluble in water; freely soluble in alcohol Phenoxybenzarnine is incompletely and variably absorbed and in chloroform. from the gastrointestinal tract. After oral dosage the onset of Proprietary Preparations (details are given in Volume B) action is gradual over several hours; the maximum effect is Single-ingredient Preparations. Austria: Marcoumar; Belg. : Mar­ Uses and Administration attained in about 1 hour after an intravenous dose. The coumar; Braz.: Marcoumar; Denm.: Marcoumar; Ger.: Fali­ Phenoxybenzamine is a powerful alpha-adrenoccptor duration of action is usually 3 or 4 days and is thought to thromt; Marcumar; marcuphen; Phenpro; Phenprogarnma; blocker (p. 1243.1) with a prolonged duration of action; it depend on the rate of synthesis of new alpha receptors after Neth.: Marcoumar; Switz.: Marcoumar. binds covalently to alpha receptors in smooth muscle to irreversible covalent bonding to existing alpha receptors by produce an irreversible ('non-competitive') blockade. A a reactive intermediate of phenoxybenzamine. The plasma single large dose of phenoxybenzamine can cause alpha­ half-life after intravenous dosage is about 24 hours. adrenoceptor blockade for 3 days or longc:c. Phenoxybenzarnine ismetabolised in the liver and excreted Phenoxybenzamine is used in the m.:magcment of in the urine and bile, but small amounts remain in the body pbaeochromocytoma (p. 1278.1).1t has also been employed for several days.

All cross-references refer to entries in Volume �'· 1469

lamina mesdatas; Mesiiato de fentolamlna; Phentolamine, in severe cases. Phentolamine has been tried as an alterna­ eparations Mesi!at€: de; Phentoiarnir:e Mesylate; Phentolamlne.Metha­ tive. Improvement in symptoms has been reported1 in 2 P.r. . nesulphonate: Phentolamini lv1.esilas;. Phehtolaminmesilat; patients with generalised hyperhidrosis given 100 mg of Proprietary Preparations (details are given in Volume B) phentolamine mesilate by intravenous infusion over 6 (J)eHTOflcMl1Ha Mewmar. Single-ingredientPreparations. Arg.: Regitina: Austral.: Regitine: 3-[N-(2-Imidazotin-2-ylmethyl)-t:>-Picotamide (BANI sal injection of local anaesthetic preparations containing vasoconstrictors (below). It has been used in the treatment Adverse Effects and Treatment G-1 37; ficotamida; PicoJ:amld¢, monqhydrate cW;l1lco tamiU­ of erectile dysfunction (p. 2348.2). m0nohldrat; Picotamidum Monohydricum; . f>ikotamld The adverse effects of phentolamine are primarily due to its . Phentolamine is given by injection as the mesilate. monohyd nit Pik()tamldimononyd�atti; PikbtjjmkfmGll;qhy, alpha-adrenoceptor blocking activity and include ortho· · · · In patients with hypertensive crises during surgery for drat; Plkotamid€> rnonohidratas. static hypotension and tachycardia. Myocardial infarction phaeochromocytoma, a dose of 2 to 5mg of phentol­ 4, Methoxy-N,N'-bfs(3·pyrldlnylmetl:iyl)-'l and cerebrovascular spasm or occlusion have been reported ;3-benzenec!icar­ amine mesilate is given intravenously and repeated if boxa mide monohydrate. necessary: blood pressure should be monitored. The occasionally, usually in association with marked hypo­ tension; flushing, sweating, and feelings of apprehension Cr, H2.,N40j,Hl0"394.4 . intramuscular route may be used pre-operatively and for 8053u.03�8: CAS • 52828-81-2 (anhydrous . picatamide}; · . diagnostic procedures. may accompany hypotensive episodes. Anginal pain and � . For prevention of dermal necrosis during intravenous arrhythmias have beeu reported rarely. Nausea, vomiting, (picotair1ilfl! tri&nohydmte}. · and diarrhoea may also occur. Other adverse effects include ATC BO IAC03. infusion of noradrenaline, l 0 mg of phentolamine mesilate is added to each litre of solution containing noradrenaline. weakness, dizziness, flushing, and nasal congestion. AT.C Vtl -'- 0B01AC03. For treatment of extravasation of noradrenaline, 5 to l 0 mg Hypoglycaemia has been reported after overdosage. lJN!! - 654G2VCI4Q, Severe hypotension may occur in overdosage although of phentolamine mesilate in 10 mL of sodium chloride 0. 9% Pharmacopoeias. In Bur. (see p. vii). is injected into the affected area. phentolamine has a short duration of action. Treatment Ph. Em. 8: (Picotamide Monohydrate). A white or almost For reversal of soft-tissue anaesthesia in the mouth, may include support of the circulation by postural measures white, polymorphic, crystalline powder. Slightly soluble in phentolamine mesilate is given using the same location and and parenteral fluid volume replacement. Noradrenaline water; soluble in dehydrated alcohol and in dichlor­ technique as for the local anaesthetic. The dose depends on may be given cautiously to overcome alpha -adrenoceptor omethane; dissolves in dilute mineral acids. the amount of local anaesthetic used and ranges from 200 to blockade. Adrenaline is contra-indicated since it also 800 micrograms. stimulates beta receptors causing increased hypotension For erectile dysfunction, phentolamine mesilate is and tachycardia. Profile given by injection into the corpora cavernosa of the penis. It When injected into the corpus cavernosum of the penis Picotamide is a thromboxane synthase inhibitor and is usually given with papaverine, but a preparation phentolamine has been associated with local pain; thromboxane receptor antagonist with antiplatelet activity. containing phentolamine with aviptadil (vasoactive intes­ induration and fibrosis may occur with repeated use. It is given orally in thromboembolic disorders (p. 1273.2) in tinal peptide) may also be used. Phentolamine has also been Priapism has occurred. initial doses of 900 to 1200 mg daily in divided doses, tried orally. reducing to a maintenance dose of 300 to 600 mg daily. For doses in children, see below. Precautions Reviews. Administration in children. In the treatment of hyperten­ Phentolamine should not generally be given to patients I. Celestini A, Violi F. A review of picotamide in the reduction of sive crises during surgery for phaeochromocytoma, chil­ with angina pectoris or other evidence of ischaemic heart cardiovascular events in diabetic patients. Vase Health Risk Manag 2007; 3: 93-8. dren may be given phentolamine mesilate intravenously disease. Care should be taken in patients with peptic ulcer (or intramuscularly when used pre-operatively) in a dose disease, which may be exacerbated. of 1 mg. Alternatively, doses of 50 to 100micrograms/kg ACE inhibitor·induced cough. Cough is a recognised or 3 mg/m2 have been suggested. The dose may be adverse effect of ACE inhibitors (see p. 1285.3). Picota­ repeated if necessary. Interactions mide led to the disappearance of cough in 8 of 9 patients For reversal of soft-tissue anaesthesia in the mouth, Since phentolamine only blocks alpha receptors, use with taking enalapril for hypertension, 1 suggesting that throm­ phentolamine mesilate is given to children aged 6 years aud drugs such as adrenaline may lead to severe hypotension boxanes were involved in the aetiology of ACE inhibitor­ over and weighing 15 to 30 kg in a dose of up to and tachycardia due to unopposed beta-adrenoceptor induced cough. 200 micrograms. The dose depends on the amount of local stimulation. l. Malini PL, et al. Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor. Lancet 1997; 3SO: 15-18. anaesthetic used, and should be given using the same location and technique as for the local anaesthetic. Pharmacokinetics r r P.. �p� (J_Ii()_��...... Hyperhidrosis.Hyperhidrosis (p. 1685.1) is usually treated After intravenous dosage, the half-life of phentolamine has Proprietary Preparations (details . are.. given in Volume. B) with topical aluminium salts or topical antimuscarinics, been reported to be 19 minutes. It is extensively but intradermal botulinum A toxin or procedures such as metabolised and about 13% of an intravenous dose is Single·ingredientPreparations. Ital.: Plactidil. endoscopic transthoracic sympathectomy may be needed excreted unchanged in the urine.

The symbol t denotes a preparation no longer actively marketed The symbol ® denotes a substance whose use may be restricted in certain sports (see p. viii)