GUANETHIDINE

Drugs in Pregnancy and Lactation.

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Name: GUANETHIDINE
Class: Sympatholytic (Antihypertensive)
Risk Factor:    CM

Fetal Risk Summary

Guanethidine is a peripherally acting, antiadrenergic agent used in the treatment of hypertension. In nonpregnant adults, the drug is often combined with diuretics. Because orthostatic hypotension resulting from adrenergic inhibition and unopposed parasympathetic function is a common problem with this agent, its usefulness in the pregnant patient is markedly reduced (1,2,3 and 4).

In a reproduction study in pregnant rats, guanethidine 10 mg/kg/day (average human dose <1.0 mg/kg/day) produced no adverse effects in the offspring (5). Guanethidine was listed in a later Reference as a drug that causes maternal death before any effect on the fetus is observed (6). Without citing details, another publication cited guanethidine as a drug capable of producing embryopathy (i.e., death or malformation or both) in laboratory animals (7).

Guanethidine neurotoxicity has been observed in newborn rats and mice who were given the drug early in postnatal life (8,9). In one study, newborn rats were given guanethidine (50 mg/kg SC) once daily for 5 days starting on postnatal day 2 (8). In contrast to adult rats, a possible drug-induced delay in cellular proliferation resulting in initially low brain weights occurred that was thought to be related to passage of guanethidine into the brain because of immature function of the neonatal blood-brain barrier (8). An earlier study found a dysfunctional blood-brain barrier in newborn mice, but not in adult mice, when administration of guanethidine caused a long-lasting reduction in brain catecholamine (norepinephrine and dopamine) levels (9). It is not known if these neurotoxicities would have occurred in the animal fetuses from exposure to the much smaller amounts of drug that would have presumably resulted after placental transfer.

No studies relating to the placental transfer of guanethidine in animals or humans have been located. The commercially available form of the drug, guanethidine monosulfate, has a molecular weight of about 296 that is low enough that passage to the fetus in measurable amounts should occur.

Several reports have described the use of guanethidine during all phases of human pregnancy (10,11,12,13,14,15 and 16). The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 13 of whom had 1st trimester exposure to a miscellaneous group of antihypertensives, 2 of which were exposed to guanethidine (10). There was 1 infant with a malformation from the total group of 13.

Three References described the use of guanethidine during the 3rd trimester for the treatment of preeclampsia (11,12 and 13). Although the outcomes of many of these pregnancies were poor, including fetal death, they appeared to be related to the severity of the mother's disease rather than to the drug therapy. In a fourth Reference, the use of guanethidine, tolazoline, phentolamine, and methyldopa for severe hypertension of pregnancy were curtailed over a 3-year period in favor of reserpine and phenoxybenzamine because the authors concluded that the latter two agents gave better control of hypertension, improvement of renal function, and greater predictability of results (14). No fetal or newborn adverse effects were mentioned. A fifth Reference also concluded that guanethidine was not an effective antihypertensive, in comparison to other available agents, for the treatment of severe hypertension presenting late in pregnancy (15).

A 1977 report described a 29-year-old woman who was treated with guanethidine (10 mg/day) and hydrochlorothiazide (50 mg twice daily) for hypertension during the first 12 weeks of pregnancy (16). This therapy was stopped, and she was eventually diagnosed with pheochromocytoma that was resected during delivery of a healthy, full-term, 5400-g female infant. The infant was alive and well at 8 years of age.

In summary, although most reports of guanethidine have not been associated with drug-induced adverse fetal or newborn outcome, only three cases of 1st trimester exposure have been described. Two of these were reported in a surveillance study in which one malformed infant was delivered from a group of 13 women who took miscellaneous antihypertensives. Thus, the available data are too limited to assess its safety during early human pregnancy. Moreover, the use of this potent antihypertensive has been supplanted by safer, more effective agents for pregnant women. Because of this, it probably should be considered as a drug of last choice during pregnancy (1).

Breast Feeding Summary

The manufacturer states that very small amounts of guanethidine are excreted into milk (17), but published reports describing the use of guanethidine during lactation have not been located. The relatively low molecular weight (about 296) of the commercially available form, guanethidine monosulfate, is consistent with the passage of the drug into milk. Because neurotoxicity has been observed in newborn mice and rats given the drug directly (see above) and because of the potential adverse effects on an infant's blood pressure, use during human lactation is not recommended.

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References

  1. Sullivan JM. Blood pressure elevation in pregnancy. Prog Cardiovasc Dis 1974;16:375–94.
  2. Finnerty FA Jr. Hypertension in pregnancy. Clin Obstet Gynecol 1975;18:145–54.
  3. Kelly JV. Drugs used in the management of toxemia of pregnancy. Clin Obstet Gynecol 1977;20:395–409.
  4. Berkowitz RL. Anti-hypertensive drugs in the pregnant patient. Obstet Gynecol Surv 1980;35:191–204.
  5. West GB. Drugs and rat pregnancy. J Pharm Pharmacol 1962;14:828–30.
  6. West GB. Pregnancy tests using new drugs (abstract). Biochem Pharmacol 1963;12(Suppl):246–7.
  7. Woollam DHM. Principles of teratogenesis: mode of action of thalidomide. Proc R Soc Med 1965;58:497–501.
  8. Bartolome J, Bartolome M, Seidler FJ, Anderson TR, Slotkin TA. Effects of early postnatal guanethidine administration on adrenal medulla and brain of developing rats. Biochem Pharmacol 1976;25:2387–90.
  9. Liuzzi A, Foppen FH, Angeletti PU. Adrenaline, noradrenaline and dopamine levels in brain and heart after administration of 6-hydroxydopamine and guanethidine to newborn mice. Biochem Pharmacol 1974;23:1041–4.
  10. Heinonen OP, Sloan D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:372–3.
  11. Coyle MG, Greig M, Walker J. Blood-progesterone and urinary pregnanediol and oestrogens in foetal death from severe pre-eclampsia. Lancet 1962;2:275–7.
  12. Daftary SN, Desa Souza JM, Kumar A, Mandrekar SS, Lotlikar KD, Sheth UK. A controlled clinical trial of guanethidine in toxemia of pregnancy. Indian J Med Sci 1963;17:812–8.
  13. Wallace SJ, Michie EA. A follow-up study of infants born to mothers with low oestriol excretion during pregnancy. Lancet 1966;2:560–3.
  14. Maughan GB, Shabanah EH, Toth A. Experiments with pharmacologic sympatholysis in the gravid. Am J Obstet Gynecol 1967;97:764–76.
  15. Ratnam SS, Lean TH, Sivasamboo R. A comparison of hypotensive drugs in patients with hypertensive disorders in late pregnancy. Aust N-Z J Obstet Gynaecol 1971;11:78–84.
  16. Leak D, Carroll JJ, Robinson DC, Ashworth EJ. Management of pheochromocytoma during pregnancy. Can Med Assoc J 1977;116:371–5.
  17. Product information. Ismelin. Ciba Pharmaceutical, 1995.

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