Glutethimide

The miscellaneous anxiolytics, sedatives and hypnotics are a diverse group of drugs mostly with unknown mechanisms of action that produce central nervous system depression in overdose. Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the benzodiazepines. In relatively small doses, the older agents can cause a profound, prolonged and occasionally cyclical coma, respiratory depression and death (especially when cardiac arrhythmias accompany the toxic profile). Toxicity is even more severe with sedative coingestants, especially alcohol and opiates, and advanced age is an additional risk factor for severe toxicity. These features have led to a questioning of their therapeutic role (1). Death has been reported after overdose with all the older agents.

In any discussion of toxic doses of sedative-hypnotic drugs, there will always be considerable variation due to interindividual differences in tolerance and the contribution or otherwise of active metabolites.

Six of 63 patients hospitalised with glutethimide overdose died including all three aged 60 years or older. Age was the major identifiable determinant of survival, regardless of other factors. An ingested dose of 10 g or more was almost always associated with deep coma (46).

Relatively small doses (2.5 and 5 g) have been associated with bleeding, liver failure and, in one case, acute renal failure (47).The acute ingestion of at least 15 grams of glutethimide resulted in cyclic and, sometimes, unilateral clinical findings that were reflected in the EEG. Complete clinical recovery resulted with supportive care (48).

Minimum lethal dose for an adult has been estimated as 5 g (49) although ingestion of 75 g has been survived (50).

In most cases, it is the development of tolerance to sedative-hypnotics that determines the recovery of consciousness after overdose rather than the clearance of the drug. In general, because of tolerance and the active metabolites of these drugs, there is a poor correlation between concentration and effect.

A single dose of 500 mg resulted in a mean peak concentration of 4.3 mg/L (range 2.9 – 7.1) (88). Balance disturbances, psychomotor retardation and changes in consciousness with temporary excitation were observed with a concentration of 5 mg/L in the blood (89).

Some evidence for concentration dependent toxicity was found in a series of 70 cases of glutethimide overdose (90). Mild features were seen with concentrations in the range 5 – 56 mg/L (mean 27), moderate toxicity was seen with concentrations between 22 and 78 mg/L (mean 45) and severe toxicity when the concentrations were 15 – 120 mg/L (mean 50) (90). Blood concentrations and clinical findings were evaluated in twenty-six nonfatal and twelve fatal intoxications involving the combination of glutethimide and codeine (“loads”) (91). The mean glutethimide concentration was 10 ± 5 mg/L for nonfatal cases (range 2 – 18 mg/L) and 13.9 ± 6.6 mg/L for fatal cases (range 4.6 – 26.4 mg/L). Six patients with serum glutethimide concentrations of 10 mg/L or greater were comatose (91). In another study of 63 cases, a plasma concentration exceeding 30 mg/L was almost always associated with deep coma (46).

Normal plasma half-lives of glutethimide and the relatively small amounts in urine of unchanged drug and unconjugated metabolites indicated that drug elimination is not markedly impaired in intoxicated patient (92).

The mechanism of action of the central nervous system depression effects of glutethimide is unclear although there is evidence of weak enhancement of GABA binding with inhibition of diazepam binding (123). Glutethimide also has some anticholinergic activity. The contribution to glutethimide toxicity of its metabolite, 4-hydroxy-2-ethyl-2-phenylglutarimide(4-hydroxyglutethimide), is unclear with some supporting evidence for a significant contribution(124) but other evidence of lack of correlation with clinical effect (125). There is also the potentially confounding issue of rapid (4–6 h) tolerance developing to parent drug and/or its metabolites as occurs with benzodiazepines (126). There is evidence for toxic activity of the alpha-phenyl-gamma-butyrolactone metabolite (127) but its contribution to the clinical picture is unknown. Tolerance, dependence and a withdrawal syndrome occur(128;129) particularly when combined with codeine (“loads”) (130-132). Glutethimide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients (122).

Coma after glutethimide ingestion is common, often very deep and may be cyclical (48) due to delayed absorption related to its anticholinergic effects. Hypotension (46) can occur and features of anticholinergic toxicity are common. Hypothermia can occur, particularly in combined overdose with other sedative-hypnotics (171) as can occasional hyperthermia (172). Mortality is high in glutethimide poisoning (173) with the elderly at an even higher risk for fatal outcome (46). In 63 patients hospitalised with glutethimide poisoning, assisted ventilation was required in 59% of cases, and 32% developed hypotension (46). In a series of 26 non-fatal cases, depressed level of consciousness was the most common abnormal physical finding (24 cases); 18 patients were lethargic but rousable with non-painful stimulation and 6 were comatose (91). Glutethimide overdose has been associated with skin lesions resembling those seen in barbiturate poisoning (174;175) and with pressure necrosis and rhabdomyolysis (176).

Occasionally, unilateral neurological findings have been noted in papillary responses (177) and on EEG (48) and cerebellar degeneration has been reported (178).

There is a single case report of methaemoglobinaemia (179) and isolated reports of bleeding and hepatic and renal injury (47) although it is unclear what contribution hypoperfusion had to the organ injury.

Seizures attributed to hypocalcaemia have been seen after misuse of glutethimide (180) but it is unclear what contribution there was of glutethimide withdrawal.

Withdrawal from central nervous system depressants is dealt with in more detail in the drug withdrawal monograph. Suddenly stopping treatment in dependent people may produce withdrawal symptoms and signs including anxiety, dysphoria, irritability, insomnia, nightmares, sweating, memory impairment, hallucinations, hypertension, tachycardia, psychosis, tremors and seizures (227). The withdrawal syndromes associated with the older agents are similar to those associated with barbiturates (228); they are severe and likely to be associated with life-threatening events such as seizures. Acute withdrawal from sedative-hypnotics may present solely as a confusional state due to non-convulsive status epilepticus (toxic ictal delirium) which can easily be missed (229).

Side-effects of glutethimide include nausea, headache, blurred vision, unwanted sedation and other CNS effects such as ataxia, impaired memory and paradoxical excitement, and occasional skin rashes. Acute hypersensitivity reactions, blood disorders, and exfoliative dermatitis have been reported in rare instances(122).

Routine quantitative drug estimation is not readily available for any of these agents and not indicated for routine management. Hepatic and renal function tests are indicated. Measurement of creatine kinase in cases of coma will help in the assessment of rhabdomyolysis. Core body temperature should be assessed as hypothermia is common. Chest X-ray is helpful to assess for non-cardiogenic pulmonary oedema in a patient with oxygen desaturation. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

For many drugs, there is a postmortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artifactual elevation of drug concentrations in blood (postmortem redistribution). Highest drug concentrations are found in central vessels such as pulmonary artery and vein, and lowest concentrations are found in peripheral vessels such as subclavian and femoral veins. This creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of postmortem blood samples is unknown (240). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is now standardised amongst forensic pathologists.

In 11 fatal cases, blood concentration averaged 45 mg/L (range 10–97) (242). Death has been associated with a mean blood glutethimide concentration in excess of 40 mg/L (103). Blood concentrations were evaluated in twelve fatal intoxications involving the combination of glutethimide and codeine (“loads”). The mean glutethimide concentration was 13.9 ± 6.6 mg/L for fatal cases (range 4.6–26.4 mg/L). The mean codeine concentration for fatal intoxications was 1.21 ± 1.17 mg/L (range 0.13–4.32 mg/L) (91).

Oral activated charcoal within 1 hour of ingestion may be of some value in poisoning with the other drugs in this monograph. Glutethimide has significant enterohepatic recirculation, thus repeated doses of charcoal may be of benefit (258).

More aggressive respiratory and cardiovascular support will be required for the older agents. Non-cardiogenic pulmonary oedema should be managed along conventional lines. In the face of continuing hypotension not responding to fluid resuscitation, inotropic agents may be required.

Patients with a significant sedative drug overdose should be advised not to drive until potential interference with psychomotor performance has resolved (260). For overdose of most of these agents this will be at least 48 hours after discharge.

Principles of elimination enhancement are discussed in the Treatment monograph.

Although there are numerous case reports of the use of a variety of techniques in ethchlorvynol poisoning (278–281), there is unlikely to be any significant additional elimination of this drug with these techniques. A series of 31 cases (291) and another of 70 cases (90) of glutethimide overdose also showed that patients can be successfully managed without extracorporeal elimination. Given the quality of supportive care that can be provided in centres capable of performing these techniques, there does not seem to be any indication to use extracorporeal elimination in glutethimide poisoning.

Routine observation of vital signs, especially GCS airway patency and blood pressure, is indicated. For the older agents, continuous arterial blood pressure monitoring should be considered. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

(1) Smith AJ, Whyte IM. New drugs for old: an issue for debate? Med J Aust 1988; 149(11–12):581-582

(46) Greenblatt DJ, Allen MD, Harmatz JS, Noel BJ, Shader RI. Correlates of outcome following acute glutethimide overdosage. J Forensic Sci 1979; 24(1):76–86

(47) Krell I, Jordan T, Queck G, Wolf E. [A contribution to acute glutethimide (Elrodorm) intoxication]. Z Gesamte Inn Med 1975; 30(2):81–83

(48) Myers RR, Stockard JJ. Neurologic and electroencephalographic correlates in glutethimide intoxication. Clin Pharmacol Ther 1975; 17(2):212–220

(49) Baselt RC, Cravey RH. Glutethimide. Disposition of toxic drugs and chemicals in man. Chicago: Year Book Medical Publishers, Inc., 1989: 379–383

(50) Rosenbaum JL, Kramer MS, Raja R. Resin hemoperfusion for acute drug intoxication. Arch Intern Med 1976; 136(3):263–266

(88) Curry SH, Gordon JS, Riddall D, Simpson P, Binns TB, Rondel RK et al. Disposition of glutethimide in man. Clin Pharmacol Ther 1971; 12(5):849–857

(89) Mankowski W, Krupinski B, Skret K. [Suicidal attempts with old (currently unused) drug]. Przegl Lek 2002; 59(4–5):390–391

(90) Chazan JA, Garella S. Glutethimide intoxication. A prospective study of 70 patients treated conservatively without hemodialysis. Arch Intern Med 1971; 128(2):215–219

(91) Bailey DN, Shaw RF. Blood concentrations and clinical findings in nonfatal and fatal intoxications involving glutethimide and codeine. J Toxicol Clin Toxicol 1985; 23(7–8):557–570

(92) Kennedy KA, Ambre JJ, Fischer LJ. A selected ion monitoring method for glutethimide and six metabolites: application to blood and urine from humans intoxicated with glutethimide. Biomed Mass Spectrom 1978; 5(12):679–685

(103) Bailey DN, Shaw RF. Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations in nonfatal and fatal intoxications involving a single drug. J Toxicol Clin Toxicol 1983; 20(2):133–145

(122) Sweetman S. Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic ed. expires 03/2003 Greenwood Village, Colorado: MICROMEDEX, 2003

(123) Skerritt JH, Johnston GA. Interactions of some anaesthetic, convulsant, and anticonvulsant drugs at GABA-benzodiazepine receptor-ionophore complexes in rat brain synaptosomal membranes. Neurochem Res 1983; 8(10):1351–1362

(124) Hansen AR, Kennedy KA, Ambre JJ, Fischer LJ. Glutethimide poisoning. A metabolite contributes to morbidity and mortality. N Engl J Med 1975; 292(5):250–252

(125) Curry SC, Hubbard JM, Gerkin R, Selden B, Ryan PJ, Meinhart R et al. Lack of correlation between plasma 4-hydroxyglutethimide and severity of coma in acute glutethimide poisoning. A case report and brief review of the literature. Med Toxicol Adverse Drug Exp 1987; 2(4):309–316

(126) Ingum J, Bjorklund R, Volden R, Morland J. Development of acute tolerance after oral doses of diazepam and flunitrazepam. Psychopharmacology (Berl) 1994; 113(3–4):304–310

(127) Andresen BD, Davis FT, Templeton JL, Panzik HL, Hammer RH. Toxicity of alpha-phenyl-gamma-butyrolactone, a metabolite of glutethimide in human urine. Res Commun Chem Pathol Pharmacol 1977; 18(3):439–451

(128) Jones AH, Mayberry JF. Chronic glutethimide abuse. Br J Clin Pract 1986; 40(5):213. (129) Bauer MS, Fus AF, Hanich RF, Ross RJ. Glutethimide intoxication and withdrawal. Am J Psychiatry 1988; 145(4):530–531

(130) DiGiacomo JN, King CL. Codeine and glutethimide addiction. Int J Addict 1970; 5(2):279–285

(131) Sramek JJ, Khajawall A. “Loads”. N Engl J Med 1981; 305(4):231. (132) Loghin F, Popa DS, Socaciu C. Influence of glutethimide on rat brain mononucleotides by sub-chronic codeine treatment. J Cell Mol Med 2001; 5(4):409–416

(171) Fell RH, Dendy PR. Severe hypothermia and respiratory arrest in diazepam and glutethimide intoxication. Anaesthesia 1968; 23(4):636–640

(172) Schleissner LA. Glutethimide intoxication with prolonged coma and hyperpyrexia treated with methylphenidate. Calif Med 1966; 105(1):41–44

(173) Kovacs T, Pall D, Abafalvi Z, Karanyi Z, Worum F, Matyus J et al. [Acute toxicological cases during a ten-year period in our clinic]. Orv Hetil 2002; 143(2):71–76

(174) Burdon JG, Cade JF. “Barbiturate burns” caused by glutethimide. Med J Aust 1979; 1(3):101–102

(175) Leavell UW, Jr., Coyer JR, Taylor RJ. Dermographism and erythematous lines in glutethimide overdose. Arch Dermatol 1972; 106(5):724–725

(176) Penn AS, Rowland LP, Fraser DW. Drugs, coma, and myoglobinuria. Arch Neurol 1972; 26(4):336–343

(177) Brown DG, Hammill JF. Glutethimide poisoning: unilateral pupillary abnormalities. N Engl J Med 1971; 285(14):806

(178) Valsamis MP, Mancall E. Toxic cerebellar degeneration. Hum Pathol 1973; 4(4):513–520

(179) Filippini L. [Methemoglobinemia in Doriden poisoning]. Schweiz Med Wochenschr 1965; 95(47):1618–1619

(180) Pedersen JG, Kristensen IH. [Hypocalcemic seizures after misuse of glutethimide (Doriden)]. Ugeskr Laeger 1976; 138(20):1202–1204

(227) Benzodiazepines. In: Rossi S, Vitry A, Hurley E, Abbott F, Goldsworthy S, editors. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2002

(228) Coupey SM. Barbiturates. [Review] [13 refs]. Pediatr Rev 1997; 18(8):260–264

(229) van Sweden B, Mellerio F. Toxic ictal delirium. Biol Psychiatry 1989; 25(4):449–458

(240) Pounder DJ, Jones GR. Post-mortem drug redistribution–a toxicological nightmare. Forensic Sci Int 1990; 45(3):253–263

(242) Baselt RC, Cravey RH. A compendium of therapeutic and toxic concentrations of toxicologically significant drugs in human biofluids. Analytical Toxicology 1977; 1:81–103