Glutethimide
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Mechanism of action
Glutethimide seems to be a GABA agonist which helps induce sedation. It also induces CYP 2D6. When taken with codeine, it enables the body to convert higher amounts of codeine (higher than the average 5 - 10%) to morphine. This combination of effects enhances sedation.
Glutethimide has CNS depressant effects similar to those of the barbiturates. The mechanism of action of the drug is not known. In doses used for hypnosis, glutethimide produces cerebral depression and quiet, deep sleep. Like barbiturates, usual hypnotic doses of glutethimide significantly suppress rapid eye movement (REM) or dreaming stage of sleep. Although some tolerance develops to the REM-suppressant effects during intermediate-term chronic administration, REM rebound occurs when the drug is withdrawn, and the patient may experience markedly increased dreaming, nightmares, and/or insomnia.
Glutethimide exhibits anticholinergic activity manifested by mydriasis and inhibition of salivary secretions and intestinal motility. Toxic doses of the drug often produce marked mydriasis, adynamic ileus, and urinary bladder atony. Hypnotic doses of glutethimide do not produce reliable analgesic, antipyretic, anticonvulsant, antiemetic, or antitussive effects. Glutethimide induces liver microsomal enzymes and thus may alter the metabolism of other drugs.
Glutethimide directly blocks electron transfer in cellular respiration.
Pharmacodynamics
Glutethimide, like the barbiturates, is a hypnotic sedative. It was introduced in 1954 as a safer alternative to barbiturates but was soon determined to be just as likely to cause addiction and withdrawal symptoms.
Pharmacokinetics
Half-life
10-12 hours
Half-life about 10 to 12 hours.
The decline of serum concentrations of glutethimide is biphasic; the half-life for the first phase is about 4 hrs and the half-life for the second phase is 10-12 hours. The apparent serum half-life of the drug in patients severely intoxicated with glutethimide has been reported to be prolonged, but this may have been due to continued absorption of the drug.
In a series of patients with glutethimide overdose, mean serum half-life has been found to be prolonged to around 40.1 hr. The definition of biologic half-life for glutethimide is somewhat difficult because of the rapidly appearing inactive metabolites (glucuronides). The half-life of the inactivated dose (effective biologic half-life) and the time when half of the dose is excreted (maximal biologic half-life) are different; the effective biologic half-life is approximately 10 hr, and the maximal biologic half-life is approximately 16 hr.
The spontaneous decline of glutethimide blood levels follows a biphasic curve, with an initial rapid phase and a later slow phase. During the initial rapid phase, a mean serum half-life of 3.9 hr is obtained... The decline in drug concentration during the second, slower phase gives a mean serum half-life of 11.6 hr, this being brought about by loss of drug from tissue compartments and blood (or central compartment) through metabolism and excretion.
Absorption
Variable
glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the faeces.
Glutethimide appears to be irregularly absorbed from the GI tract. Plasma concentrations of the drug required for sedative or hypnotic effects are not known. In limited studies, oral administration of 500 mg and 1 g single doses of glutethimide produced peak plasma concentrations of 2.9-7.1 ug/mL and 6.2-6.8 ug/mL, respectively, within 1-6 hours. The onset of action of glutethimide is rapid; sleep is usually induced within 30 minutes and lasts 4-8 hours following usual hypnotic doses.
Once absorbed, glutethimide quickly becomes concentrated in organs containing fat such as brain and adipose tissues, with a volume of distribution larger than that of whole body water. The drug recirculates from fat stores and is carried to the liver where it undergoes biotransformation, somewhat reminiscent of redistribution of ultra short acting barbiturates like thiopental.
Distribution studies indicate that there is extensive tissue localization of glutethimide, particularly in adipose tissue. In addition, glutethimide (and/or its metabolites) has been detected in liver, kidneys, brain, and bile. Glutethimide crosses the placenta, and small quantities of the drug are distributed into milk. When 1 g doses of glutethimide were administered to pregnant women 2 hours before delivery, maternal and neonatal plasma concentrations of glutethimide were essentially the same immediately after delivery.
In vitro, about 54% of the drug appears to be bound to plasma proteins.
Metabolism
Hepatic. Glutethimide is almost completely metabolized.
Hepatic biotransformation. Glutethimide is almost completely metabolized.
The metabolic fate of glutehimide has not been completely elucidated, particularly following toxic doses of the drug. There is considerable evidence that therapeutic doses of glutethimide are almost completely metabolized in the liver by hydroxylation of the ethyl side chain (levorotatory isomer) and excreted in urine chiefly as glucuronides. About 2% of a dose is metabolized to glutaconimide which has some hypnotic activity. ... 4-Hydroxy-2-ethyl-2 phenylglutarimide is a metabolite which accumulates in the plasma and tissues (including the brain) of patients who have ingested large doses of glutethimide. Several phenolic metabolites and others yet to be identified have been found in urine following acute glutethimide overdosage.
Although glutethimide blood concentrations greater than 10 ug/mL are generally associated with intoxication, there is a poor correlation between glutethimide plasma concentration and the clinical course of the patient, possibly because of the formation and accumulation of an active metabolite, 4-hyroxy-2-ethyl-2-phenylglutarimide.
Glutethimide has an asymmetric carbon atom and gives two optical isomers, both of which are metabolized in a different fashion. The D-isomer is hydrolyzed at the glutarimide ring, loses water, and breaks down into alpha-phenyl-alpha-ethylglutaconimide, which is excreted in the urine as a nonconjugated metabolite in approximately 2% of the administered dose. A major portion of the hydrolyzed D-isomer is combined with glucuronic acid and is excreted in the urine in approximately 45% of the administered dose. The L-isomer is hydrolyzed with release of acetaldehyde from a-phenyl glutarimide. This metabolite is isolated in the urine in approximately 4 percent of the administered dose. The remaining major portion is also combined with glucuronic acid and is excreted in the urine in approximately 45 % of the administered dose. Both glucuronides are water soluble but not fat soluble and no longer possess sedative activity.
For more Metabolism/Metabolites (Complete) data for GLUTETHIMIDE (7 total), please visit the HSDB record page.
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