Phenoxybenzamine

Name: PHENOXYBENZAMINE
Class: Antihypertensive
Risk Factor: CM

Fetal Risk Summary

Phenoxybenzamine, a long-acting a-adrenergic blocking agent, is used for the treatment of hypertension caused by pheochromocytoma. Because of the lack of well-controlled studies, the effect of phenoxybenzamine on pregnant animals is not known (B.A. Wallin, personal communication, Smith Kline & French Laboratories, 1987). Animal and in vitro experiments conducted by the manufacturer, however, have indicated the drug has carcinogenic and mutagenic activity. Neither of these adverse outcomes, nor other fetal harm, has been reported in the relatively few human studies that have been published.

In a study using pregnant rats, phenoxybenzamine, with or without the b-blocker propranolol, had no effect on implantation of the fertilized ovum, nor was there any interference with the antifertility effect of an intrauterine contraceptive device placed in the uterus of rats (1).

Only one study has evaluated the human transplacental passage of phenoxybenzamine (2). A 22-year-old woman with pheochromocytoma was treated with phenoxybenzamine, 10 mg 3 times daily, and labetalol, 100 mg 3 times daily, for 26 days beginning at 33 weeks' gestation. She received her last dose of phenoxybenzamine 2 hours before delivery. The mean concentrations of the drug (each sample analyzed in triplicate) in the cord and maternal plasma and in the amniotic fluid were 103.3, 66, and 79.3 ng/mL, respectively, representing a cord:maternal plasma ratio of 1.6. Serum samples for phenoxybenzamine obtained from the infant (also determined in triplicate) at 32 and 80 hours of age contained mean concentrations of 22.3 ng/mL and none detected (limit of detection 10 ng/mL), respectively. The 2475-g male infant had depressed respiratory effort and hypotonia at birth, and was hypotensive during the first 2 days of life. The cause of the hypotension could not be determined, but may have been caused by both drugs. He subsequently did well and was discharged home 14 days after delivery.

No reports describing the use of phenoxybenzamine early in the 1st trimester of pregnancy have been located. Early in vitro studies of phenoxybenzamine indicated the drug abolished the l-norepinephrine–stimulated contractile activity of animal and human myometrium (3,4). However, a phenoxybenzamine infusion for 3 hours had no significant effect on the uterine activity in two pregnant women (4). One study included the use of phenoxybenzamine for the treatment of essential hypertension, toxemia, and cardiovascular renal disease occurring during pregnancy (3). No adverse fetal effects were observed.

Because of the relative rarity of pheochromocytoma, only a small number of cases have been found in which phenoxybenzamine was used during pregnancy. In 23 pregnancies, phenoxybenzamine administration was begun in the 2nd or 3rd trimesters and continued for periods ranging from 1 day to 16 weeks (5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20 and 21) . Therapy was started at 10 weeks' gestation in a 24th case and continued for approximately 25 weeks when a 2665-g healthy male infant was delivered by cesarean section (22). Seventeen other pregnancies ended with either a cesarean section (N=13) or vaginal delivery (N=4) of a healthy infant before resection of the pheochromocytoma. In some of these cases the infant was growth retarded, probably secondary to uncontrolled maternal hypertension before treatment, but all survived. One fetus apparently survived the initial surgery to remove the mother's tumor, but the outcome of the pregnancy was not discussed (17). In another case, phenoxybenzamine was begun at 17 weeks' gestation and continued for 7 days before surgery (20). Following successful tumor resection, the patient's pregnancy went to term and terminated with the vaginal delivery of a normal healthy female infant.

Fetal mortality occurred in four cases. One involved a therapeutic abortion performed at approximately 12 weeks' gestation during the surgical removal of the mother's tumor (15). A second fetal death occurred when the mother, in her 5th–6th month of pregnancy, died 2 days after extensive surgery to remove a metastatic pheochromocytoma (5). Another fetal loss involved a woman whose pheochromocytoma was diagnosed at 7 months' gestation (15). Therapy with phenoxybenzamine was begun, but the fetus died in utero (details of therapy were not given). The fourth case of fetal mortality involved a 15-year-old woman at 25.5 weeks' gestation who was treated for 3 days with oral phenoxybenzamine in preparation for surgery (8). On the 3rd day of therapy, her membranes spontaneously ruptured followed by a hypertensive crisis requiring a phentolamine infusion. A spontaneous abortion occurred shortly thereafter of a severely growth-retarded fetus. Thus, only two of the fetal deaths occurred during pharmacologic therapy of the mother's disease.

The low incidences of maternal (4%; 1 of 24) and fetal (9%; 2 of 22) mortality when a-blockade with phenoxybenzamine is used is much better than the mortality observed in undiagnosed pheochromocytoma complicating pregnancy. A 1971 review of 89 cases of unsuspected tumor found that maternal and fetal mortality rates were 48% and 54.4%, respectively (23). A more recent review cited incidences of maternal and fetal mortality without a-blockade of 9% and 50%, respectively (19). When all cases of a-blockade (i.e., those receiving either phenoxybenzamine, phentolamine, or both) administered during pregnancy were considered, maternal mortality was 3% (1 of 29) and fetal loss was 19% (5 of 27) (2 cases excluded because fetal death in utero had occurred at the time of diagnosis) (19).

Long-term follow-up of infants exposed in utero to phenoxybenzamine has only been reported in three cases (7,10,13). The follow-up periods ranged from 2 to 8 years, and all three were normal healthy children.

In summary, the use of phenoxybenzamine during pregnancy to treat hypertension secondary to pheochromocytoma is indicated for the reduction of maternal and fetal mortality, especially after 24 weeks' gestation when surgical intervention is associated with high rates of these outcomes (20). Maternal a-blockade may also reduce or eliminate the adverse effect of hypertension on placental perfusion and subsequent poor fetal growth. No adverse fetal effects related to this drug treatment have been observed, but drug-induced hypotension in a newborn may have occurred.

Breast Feeding Summary

No reports describing the use of phenoxybenzamine during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. The molecular weight of the drug (about 340) is low enough, however, that passage into milk should be expected. The potential effects of this exposure on a nursing infant, including, but not limited to, hypotension, are unknown.

References

1. Sethi A, Chaudhury RR. Effect of adrenergic receptor-blocking drugs in pregnancy in rats. J Reprod Fertil 1970;21:551–4.
2. Santeiro ML, Stromquist C, Wyble L. Phenoxybenzamine placental transfer during the third trimester. Ann Pharmacother 1996;30:1249–51.
3. Maughan GB, Shabanah EH, Toth A. Experiments with pharmacologic sympatholysis in the gravid. Am J Obstet Gynecol 1967;97:764–76.
4. Wansbrough H, Nakanishi H, Wood C. The effect of adrenergic receptor blocking drugs on the human uterus. J Obstet Gynaecol Br Commonw 1968;75:189–98.
5. Brown RB, Borowsky M. Further observations on intestinal lesions associated with pheochromocytomas. A case of malignant pheochromocytoma in pregnancy. Ann Surg 1960;151:683–92.
6. Lawee D. Pheochromocytoma associated with pregnancy. Can Med Assoc J 1970;103:1185–7.
7. Simanis J, Amerson JR, Hendee AE, Anton AH. Unresectable pheochromocytoma in pregnancy. Pharmacology and biochemistry. Am J Med 1972;53:381–5.
8. Brenner WE, Yen SSC, Dingfelder JR, Anton AH. Pheochromocytoma: Serial studies during pregnancy. Am J Obstet Gynecol 1972;113:779–88.
9. Smith AM. Phaeochromocytoma and pregnancy. J Obstet Gynaecol Br Commonw 1973;80:848–51.
10. Griffith MI, Felts JH, James FM, Meyers RT, Shealy GM, Woodruff LF Jr. Successful control of pheochromocytoma in pregnancy. JAMA 1974;229:437–9.
11. Awitti-Sunga SA, Ursell W. Phaeochromocytoma in pregnancy. Case report. Br J Obstet Gynaecol 1975;82:426–8.
12. Coombes GB. Phaeochromocytoma presenting in pregnancy. Proc R Soc Med 1976;69:224–5.
13. Leak D, Carroll JJ, Robinson DC, Ashworth EJ. Management of pheochromocytoma during pregnancy. Can Med Assoc J 1977;116:371–5.
14. Burgess GE III. Alpha blockade and surgical intervention of pheochromocytoma in pregnancy. Obstet Gynecol 1979;53:266–70.
15. Modlin IM, Farndon JR, Shepherd A, Johnston IDA, Kennedy TL, Montgomery DAD, Welbourn RB. Phaeochromocytomas in 72 patients: Clinical and diagnostic features, treatment and long term results. Br J Surg 1979;66:456–65.
16. Fudge TL, McKinnon WMP, Geary WL. Current surgical management of pheochromocytoma during pregnancy. Arch Surg 1980;115:1224–5.
17. Coetzee A, Hartwig N, Erasmus FR. Feochromositoom tydens swangerskap. Die narkosehantering van ‘n pasient. S Afr Med J 1981;59:861–2.
18. Stonham J, Wakefield C. Phaeochromocytoma in pregnancy: caesarean section under epidural analgesia. Anaesthesia 1983;38:654–8.
19. Stenstrom G, Swolin K. Pheochromocytoma in pregnancy. Experience of treatment with phenoxybenzamine in three patients. Acta Obstet Gynecol Scand 1985;64:357–61.
20. Combs CA, Easterling TR, Schmucker BC, Benedetti TJ. Hemodynamic observations during paroxysmal hypertension in a pregnancy with pheochromocytoma. Obstet Gynecol 1989;74:439–41.
21. Bakri YN, Ingemansson SE, Ali A, Parikh S. Pheochromocytoma and pregnancy: report of three cases. Acta Obstet Gynecol Scand 1992;71:301–4.
22. Lyons CW, Colmorgen GHC. Medical management of pheochromocytoma in pregnancy. Obstet Gynecol 1988;72:450–1.
23. Schenker JG, Chowers I. Pheochromocytoma and pregnancy. Review of 89 cases. Obstet Gynecol Surv 1971;26:739–47.
    
    

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