Prepared by: Sumayah Al-JudibiPrepared by: Sumayah Al-Judibi

pharmacogonecy Department, College of Pharmacy, King Saud University, Kingdom of Saudi Arabia

INTRODUCTIONINTRODUCTION

Clinical effectClinical effect

Glutethimide is psychotherapeutic, piperidinedione sedative and hypnotic its main target organ is CNS coma ,fluctuation in depth,hypotentionPHYSICO-CHEMICAL Properties

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

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

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

PHYSICO-CHEMICAL

Properties

Distribution by route of exposure Distribution by route of exposure

PHARMACOLOGY AND TOXICOLOGY and contraindication

PHARMACOLOGY AND TOXICOLOGY and contraindication

Toxicological analyses and their

interpretation

Toxicological analyses and their

interpretation

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 characteristic1)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.