Phenobarbital elimination

The most common adverse reaction associated with phenobarbital is sedation, which can range from mild sleepiness or drowsiness to somnolence. These dru > may also cause nausea, vomiting, constipation, bradycardia, hypoventilation, skin rash, headache fever, and diarrhea Agitation, rather than sedation, may occur in some patients. Some of these adverse effects may be reduced or eliminated as therapy continues. Occasionally, a slight dosage reduction, without reducing the ability of the drug to control the seizures, will reduce or eliminate some of these adverse reactions. 

Rats pretreated with xylene or phenobarbital and then exposed to -hexane by inhalation exhibited a markedly increased peak serum concentration of 2,5-hexanedione (Toftgard et al. 1983). Peak serum concentrations were approximately 4 g/mL in control rats, 11 g/mL in xylene-induced rats, and 13 g/mL in phenobarbital-induced rats. Peaks were reached in 1-2 hours. The half-life for elimination from serum was approximately one hour for both pretreated and untreated rats. The high serum 2,5-hexanedione concentrations were correlated with an induction of liver microsomal P-450 content (0.56 nmol/mg protein in control rats, 1.03 nmol/mg in xylene-induced rats, and 1.7 nmol/mg protein in phenobarbital-induced rats, respectively). 

Barbiturates Phenobarbital- (PB) Status epilepticus Epilepsy, all forms Tonic-clonic 40 to 60 Liver 25% eliminated unchanged in urine... 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

Urine alkalinization is a treatment modality that increases elimination of poisons by the intravenous administration of sodium bicarbonate to produce urine with a pH of more than or equal to 7.5 and must be supported by high urine flow. This technique might be useful for the elimination of drugs with an acid pKa such as salicylates (but not recommended for phenobarbital intoxication for which multiple-dose activated charcoal is better), chlorpropamide, 2,4-dichlorophenoyacetic acid, diflunisal, fluoride, mecoprop, methotrexate. Complications include severe alkalemia, hypokalemia, hypocalcemia and coronary vasoconstriction. 

Two main effects occur here. First, change in the pH of urine—weak bases, such as pethidine, are more easily excreted in an acid urine while alkalinisation promotes excretion of weak acids, such as salicylates and phenobarbital. Second, drugs that compete for an active excretion mechanism will reduce each other s elimination—probenecid was used in the early days of penicillin to conserve the drug, while less desirable interactions also occur, e.g. chlorpropamide and phenylbutazone interact to give increased levels of chlorpropamide and a danger of hypoglycaemia. 

The water-soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7.4. 

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. 

Kamimura, H., Koga, N., Oguri, K., and Yoshimura, H. (1992). Enhanced elimination of theophylline, phenobarbital and strychnine from the bodies of rats and mice by squalane... 

The tissue distributions of [l- C]- and [2,3- 4C]aciy lonitrile (40 mg/kg) were compared in Wistar rats after intraperitoneal and oral administration (Sapota, 1982). The relative distributions of the two labelled forms were very similar and the principal locations of C were erythrocytes, liver and kidney. After oral administration, the rate of elimination from tissues was slower for [cyano- C -than for [l,2-vz v/- 4C]acrylonitrile. After gavage administration of 46 mg/kg bw [2-i4C]acrylonitrile to Fischer 344 rats, radioactivity was well absorbed from the gastrointestinal tract and distributed to all major tissues 24 h after dosing. The highest levels were found in the forestomach, blood and urinary bladder. Prior treatment of rats with phenobarbital had little effect on the pattern of distribution and excretion of 4C, but the CYP inhibitor SKF-525A caused marked changes, with less excretion (less than 40% in urine in 24 h compared with over 60% in... 

Nonionized lipid-soluble drugs are resorbed and not eliminated. Generally, drugs that are bases are excreted when the urine is acidic, whereas acidic compounds are excreted in greater quantities if the urine is alkaline. For example, in phenobarbital (weak acid pKa of 7.3) poisoning, alkalinization of the urine with sodium bicarbonate is helpful in eliminating the phenobarbital. In amphetamine toxicity, acidification of the urine with ammonium chloride is required (Figure 1.13). 

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