1. Prepared by: Sumayah Al-Judibi pharmacogonecy Department, College of Pharmacy, King Saud University, Kingdom of Saudi Arabia INTRODUCTION Clinical effect Glutethimide is psychotherapeutic, piperidinedione sedative and hypnotic its main target organ is CNS  coma,fluctuation in depth,hypotention PHYSICO-CHEMICAL Properties oral administration of 500 mg glutethimide peak plasma concentrations of 2.85 to 7.05 ì g/mL achieved within two to six hours. Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue Biological half-life by route of exposure  elimination half-life is 10 to 12 hour may increase in severe poisoning Metabolism Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2-phenylglutarimide this appears to be twice as potent as the parent compound.metabolites are excreted mainly in the urine but also in bile oral administration of 500 mg glutethimide peak plasma concentrations of 2.85 to 7.05 ì g/mL achieved within two to six hours. Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue Biological half-life by route of exposure  elimination half-life is 10 to 12 hour may increase in severe poisoning Metabolism Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2-phenylglutarimide this appears to be twice as potent as the parent compound.metabolites are excreted mainly in the urine but also in bile  oral administration of 500 mg glutethimide peak plasma concentrations of 2.85 to 7.05 ìg/mL achieved within two to six hours. Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue  Biological half-life by route of exposure  elimination half-life is 10 to 12 hour may increase in severe poisoning  Metabolism  Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2- phenylglutarimide this appears to be twice as potent as the parent compound.metabolites are excreted mainly in the urine but also in bile  Mode of action  blocks electron transferin in cellular respiration  Toxicity  In adults, death has been reported after 5 g. The usual lethal dose is 10 to 20 g  Interactions  effects of glutethimide are additive with benzodiazepines, barbiturates, codeine and other CNS depressants. Concomitant administration of antidepressants, antiparkinsonian drugs or other anticholinergic agents may cause additive anticholinergic effects such as urinary retention, exacerbation of glaucoma, or adynamic ileus. Ethanol enhances the effects of glutethimide. Glutethimide induces the hepatic metabolism of some drugs, such as dicoumarol derivatives, vit D  Main adverse effects:nausea, headache, hangover, blurred vision, occasional skin rashes,tendon reflex depressed,slurred speech, blood disorders (megaloblastic anaemia) Osteomalacia peripheral neuropathy and cerebral impairment after prolonged use may also occur dependence, respiration depressed, Bp decrease,pupils dilated.  withdrawal symptom:tremulousness,insomnia, sweating, fever, anxiety, cardiovascular collapse, agitation, delirium,hallucination,disorientation,convulsion,shock.  Sampling and specimen collection :In case of ingestion:Vomitus: total amount,Gastric aspirate: total amount(or gastric lavage: firstportion: 100 mL)  Blood without additives: 10 mL Urine: random specimen: 50 mL  Glutethimide is contraindicated in porphyria. Due to its antimuscarinic actionn, with care to patients with closed-angle glaucoma, prostatic hypertrophy or urinary tract obstruction, and certain cardiac arrhythmias effects of glutethimide  Toxicological analyses and their interpretation :  Glutethimide is psychotherapeutic, piperidinedione sedative and hypnotic its main target organ is CNS  coma,fluctuation in depth,hypotention  lower doses  acute intoxication may cause somnolence,ataxia,  tonic muscle spasm and abnormal reflexes in severe intoxication,  hypotension, hypothermia,shock,coma, respiratory depression and acidosis may occur.  Effects on other organs are usually secondary to coma and shock  ROUTES OF ENTRY  OR  Origin  synthetic  Chemical structure / Glutethimide is Odourless and colourless crystals or white crystalline powder, practically insoluble in water, soluble in ethanol, chloroform,ether, freely soluble in acetone and ethyl acetate, methyl alcohol  USES /Used as an hypnotic in insomnia but rarely as a sedative,glutethimide was initially believed to be almost free from side effects further experience of its toxicity and dependence liability glutethimide has been banned PHYSICO-CHEMICAL Properties Distribution by route of exposure PHARMACOLOGY AND TOXICOLOGY and contraindication  Toxicological analyses and their interpretation  Simple qualitative test /1-Koppanyi-Zwikker test  violet reaction is given by compounds which have >C=O and >NH groups adjacent within a ring (i.e. by glutethimide and by barbiturates).  2-Liebermann's test . A red colouris produced by glutethimide, and by Phenobarbital  3- Mercurous nitrate test  A dark grey / black colour within 2 minutes is given by ring imides or sulphonamides with anadditional ring. The barbiturate reaction is quicker and more intense than that of glutethimide.  4-UV spectrophotometry gives rather more specificity  decline in absorbance at 230 - 235 nm over a time period of some 20 minutes.  5-Immunoassays for barbiturates (e.g. TDx[Abbott Laboratories, AbbottPark, Illinois 60064 USA] or EMIT [Syva- Behring Diagnostics,Cupertino, California 95014 USA]) do notusually have sufficient cross-reactivity torespond to glutethimide (more than 25 ml of the drug required to give positive result)  6-Thin layer chromatography is highly appropriate for identification of glutethimide  Rf of glutethimide is 0.75 on methanol  7-Mercurous nitrate reagent is the most specific, and gives a dark grey response with a sensitivity of approximately 10 ng.  8-the purple response produced by mercuric chloride-diphenylcarbazone reagent,and the positive reaction to Dragendorff or acidified iodoplatinate are also useful but are less characteristic 1)UV spectrophotometry :gives rather more specificity. *Dissolve a portion of material in ethanol to achieve an appropriate instrument response. If necessary, centrifuge or filter the mixture and analyse the clear supernatant. The spectrum in ethanol gives deltamax at 252 nm, 258 nm (A| = 18) and 264 nm. *Glutethimide is unstable at alkaline pH, due to hydrolysis of the glutarimide ring. Adjustment of the pH to >11 (e.g. by addition of 4M NaOH or ammonium hydroxide) to the ethanolic solution of glutethimide results in a characteristic decline in absorbance at 230 - 235 nm over a time period of some 20 minutes. 2)Thin layer chromatography:is highly appropriate for identification of glutethimide, and may be either an in-house system or a commercially-available system such as Toxi-Lab. *The material can be dissolved in an organic solvent such as methanol or dichloromethane and applied directly to the plate. Using silica plates without modifiers and standard systems, the Rf of glutethimide is 0.75 on methanol / concentrated ammonia (100: 1.2), and 0.62 on ethyl acetate / methanol / ammonia (85:15:6). *Several locating reagents can be used. Mercurous nitrate reagent is the most specific, and gives a dark grey response with a sensitivity of approximately 10 ng. However, the purple response produced by mercuric chloride-diphenylcarbazone reagent, and the positive reaction to Dragendorff or acidified iodoplatinate are also useful but are less characteristic). 3)Gas chromatography (advanced qualitative confirmation and advanced quantitative method):*can be used after dissolving the material in a small amount of organic solvent (e.g. 10 mg in 10 mL methanol). *The Retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases. Isothermal analysis may be performed at about 220°C, without the need for derivatization. Flame ionization detection gives adequate sensitivity (2 to 5 ng on column), and nitrogen-phosphorus detection gives additional selectivity. *Mass spectrometry can be applied to the gas chromatographic identification of glutethimide in suspect materials. 4)HPLC (advanced qualitative confirmation and advanced quantitative method ):may be used to identify glutethimide, and most published methods involve reverse phase chromatography with UV detection. *Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785]. *Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin. * Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Additional confirmation of identity may be obtained by performing a full scan analysis on the appropriate portion of the HPLC effluent.