Chemical Abstracts Service Registry Number: 50-06-6
Formal Names: Arco-Lase Plus, Donnatal, Gardenal, Luminal, Phenobarb, Pheno-
barbitone, Solfoton Informal Names: Phennies, Phenos Type: Depressant (barbiturate class). See page 20 Federal Schedule Listing: Schedule IV (DEA no. 2285) USA Availability: Prescription Pregnancy Category: D
Uses. This is one of the more familiar pharmaceuticals. For about a century it has been used as an anticonvulsant and was prescribed as a tranquilizer and as a migraine remedy, although all those functions are being superseded by more modern drugs. Phenobarbital is also given to treat cyclic vomiting in children and hyperbilirubinemia (a type of jaundice) in infants. The drug is used against epilepsy and against seizures with other causes, such as fever. The substance has cross-tolerance with alcohol and is given temporarily to help relieve withdrawal symptoms from opiates or alcohol. Despite acceptance of phenobarbital for that purpose, scientific proof is lacking for its usefulness in alcohol withdrawal.
Phenobarbital played a walk-on role in the history of drug manufacturing when it was discovered as a contaminant in a batch of the antibiotic sulfathia-zole. After that 1941 discovery the U.S. Food and Drug Administration created the system of manufacturing controls that has made the terms "purity" and "American pharmaceuticals" synonymous.
Drawbacks. Experimental use of the drug to treat cerebral malaria in juveniles was disastrous. The treatment halved the seizure rate but doubled the death rate, a rate that climbed even higher when diazepam was administered in combination. Some medical personnel have noted that patients taking phenobarbital tend to become more bellicose and uncooperative. A medical curiosity noted as late as the 1960s was that persons could be pronounced dead from a phenobarbital overdose and later be discovered alive.
In some research children receiving the drug for seizures show long-lasting reduction in IQ scores and in scores of other cognitive tests, but different research finds normal results after children have received the drug daily for years. Phénobarbital is known to alter adrenal and thyroid mechanisms. Persons suffering from a body chemistry disorder called porphyria are supposed to avoid the drug. Skin rashes and sores have been attributed to phenobarbital. Scientists suspect the drug causes liver damage in dogs, but an experiment testing a group of dogs for over six months was unable to confirm that suspicion.
Abuse factors. Characteristics are the same as for barbiturate class depressants in general.
Drug interactions. Birth control pills might not work properly while a woman is taking phenobarbital. The drug may interfere with medicines designed to reduce blood clotting. Phenobarbital lowers blood levels of an an-tischizophrenia medicine called clozapine and thereby affects proper dosage.
Persons taking phenobarbital in a task performance test typed more slowly but more accurately, catching and fixing more errors than when a placebo was used. Taking alcohol at the same time increased both speed and errors, but typists believed they were working as well as ever and were unaware of their worsening inaccuracy. From results in variations of the experiment the researchers concluded that alcohol boosts some effects of phenobarbital.
Cancer. In some mice experiments the drug promotes liver tumors, but complexities in the results have deterred researchers from making conclusions about the drug's ability to do the same in humans. Scientists do find that persons using the drug have higher rates of liver and lung cancer, but a cause-effect relationship has not been demonstrated. In contrast, cigarette smokers who use the drug have lower bladder cancer rates than nonsmokers; as a partial explanation, researchers suspect the drug may reduce the amount of chemicals in tobacco smoke that cause bladder cancer.
Pregnancy. In animal experiments birth defects caused by phenobarbital are described as "profound and prominent." For example, pregnant mice dosed with phenobarbital produce offspring with retarded muscle development, and pregnant rats receiving the drug produce offspring with heart defects.
Debate exists about whether phenobarbital causes human birth defects. Medical records in 151 human pregnancies from the 1970s into the 1990s gave no indication that phenobarbital alone causes malformations, a conclusion supported by another study of 178 pregnancies. In Europe phenobarbital has been classified as safe for using during pregnancy.
Yet a review of almost 20,000 pregnancies found that 4.6% of children born to women who used phenobarbital during early pregnancy had birth defects, almost twice the rate suffered by children from women who used no drugs. An international examination of almost 1,000 birth outcomes in Asia and Europe put the rate of all defects (serious or not) associated with phenobarbital at 5%. Investigations have associated phenobarbital with heart defects, facial deformities, urinary tract malformations, and incomplete development of fingers or toes. One study found that about 20% of pregnant epileptic women taking the drug gave birth to children with serious birth defects, a finding consistent with still more studies. One study compared pregnant epileptic women who used phenobarbital with those who did not and revealed that women using the drug had infants with smaller head size. As children from the phenobarbital group grew older, they had shorter attention spans and more trouble with spelling and math.
Worse deformities have been seen when phenobarbital is used in combination with some other drugs than when used alone. A review of epilepsy medicines published in 1997 said malformations from phenobarbital are no more likely than from carbamazepine, phenytoin, or valproic acid—yet those latter three substances have been found to cause birth defects. A 1994 analysis of outcomes in several hundred pregnancies concluded that birth defects were more likely from phenobarbital than from carbamazepine or phenytoin.
Phenobarbital and other epilepsy drugs may reduce vitamin K levels in a fetus, a reduction that can promote bleeding and cause disfiguring birth defects. Some researchers think that pregnant women using such drugs should ingest extra vitamin K.
Researchers believe that pregnant rats receiving phenobarbital seem to produce male offspring with "feminized behavior" and female offspring with masculine behavior. A group of humans who were prenatally exposed to phenobarbital showed higher rates of homosexual, cross-gender, and transsexual behavior when compared to a matched group that had no prenatal exposure to phenobarbital.
After phenobarbital is given to pregnant rats, their mature progeny act more nervous and uneasy than mature progeny from rats not exposed to the drug during pregnancy and also exhibit defects in reproductive ability. Mice exposed to the drug during fetal development and soon after birth show improper functioning of the hippocampus (a part of the brain affecting memory), and their brains weigh less than normal. Tests of thinking ability in adult humans whose mothers used phenobarbital and phenytoin while pregnant reveal deficiency in perceiving differences among geometrical figures. Other research has found that such adults generally have normal intelligence but are far likelier to have learning difficulties than adults who did not have prenatal exposure to the phenobarbital-phenytoin combination. Two studies have found verbal intelligence scores to be below expectations in men whose mothers took phenobarbital while pregnant, and another study found psychological maturation to be slowed in about 20% of children whose mothers received phenobarbital while pregnant. The director of a National Institutes of Health research center reported contrary findings in which offspring performed better if their mothers had used phenobarbital while pregnant, but analysts have noted methodological aspects in that study that weaken its findings.
The drug is sometimes given to pregnant women having premature labor, to reduce the hazard of infants developing bleeding inside the skull. One follow-through study found that infants born to pregnant women receiving such therapy had better nervous system development than children from mothers who did not receive such therapy, measured both in organic and cognitive factors. Another study measuring two such populations found the phenobarbital children to have lower mental development.
If a pregnant woman uses phenobarbital her infant can be born dependent on the drug; neonatal withdrawal is characterized by peevishness, vomiting, and poor muscle tone. Typically a nursing woman's milk will contain about 45% of the phenobarbital level found in her blood. Breast-feeding by mothers who use phénobarbital is considered marginally acceptable, but infants should be watched for untoward effects.
Combination products. Arco-Lase Plus combines phenobarbital, hyoscya-mine sulfate, and atropine sulfate. The product is a remedy for digestive complaints ranging from bloat and cramps to nausea, diarrhea, and ulcers. Arco-Lase Plus can impair vision and is not recommended for persons with glaucoma. The substance increases heart rate and reduces saliva production. The combination product should be avoided by persons suffering from enlarged prostate.
Donnatal combines phenobarbital, hyoscyamine sulfate, atropine sulfate, and scopolamine hydrobromide. The combination product is a treatment for assorted bowel complaints and duodenal ulcers. Normally Donnatal is considered inappropriate for persons with glaucoma or with gastrointestinal or urinary obstruction. The substance may decrease alertness, so a person taking Donnatal should not run dangerous machinery. Additional scientific information may be found in:
Joyce, C.R., et al. "Potentiation by Phenobarbitone of Effects of Ethyl Alcohol on Human Behaviour." Journal of Mental Science 105 (1959): 51-60. Lerman-Sagie, T., and P. Lerman. "Phenobarbital Still Has a Role in Epilepsy Treatment." Journal of Child Neurology 14 (1999): 820-21. "Phenobarbital." In Therapeutic Drugs, ed. C. Dollery. 2d ed. New York: Churchill Livingstone, 1999. P83-P85. Poindexter, A.R. "Phenobarbital, Propranolol, and Aggression." Journal of Neuropsychiatry and Clinical Neurosciences 12 (2000): 413. Reinisch, J.M., et al. "In Utero Exposure to Phenobarbital and Intelligence Deficits in
Adult Men." Journal of the American Medical Association 274 (1995): 1518-25. Rodgers, J.E., and M.A. Crouch. "Phenobarbital for Alcohol Withdrawal Syndrome." American Journal of Health-System Pharmacy 56 (1999): 175-78.
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