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wikitox:2.1.11.9.1_methyprylon [2018/09/01 09:00] (current)
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 +====== Methprylon ======
 +
 +===== GENERAL =====
 +
 +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 Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the [[:​wikitox:​benzodiazepines|]]. In relatively small doses, the older agents can cause a profound, prolonged and occasionally cyclical coma, respiratory depression and death (especially when [[:​wikitox:​3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|cardiac arrhythmias]] accompany the toxic profile). Toxicity is even more severe with sedative coingestants,​ especially [[:​wikitox:​3.5.1_alcohol|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.
 +
 +===== TOXIC DOSE =====
 +
 +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.
 +
 +Doses of more than 6 g methyprylon usually produce prolonged coma frequently accompanied by haemodynamic,​ respiratory and hepatic dysfunction (13). Although a dose of 6 g has been fatal in one patient (67), others have recovered after ingestion of up to 30 g (68).
 +
 +===== TOXICOKINETICS / TOXICODYNAMICS =====
 +
 +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.
 +
 +Therapeutic effects are produced by plasma concentrations of 10 mg/L (13). Although toxic plasma concentrations have not been clearly defined, concentrations in excess of 30 mg/L are associated with stupor (68) or coma (103) and concentrations over 100 mg/L are said to be potentially lethal (13). Nevertheless,​ a patient who survived their coma was reported with peak concentrations of methyprylon of 168 mg/L (104). The elimination half-life of methyprylon was 50 h, suggesting concentration dependent elimination (104). This was confirmed in another study, which showed the decline in the concentration of plasma methyprylon was nonlinear between 66 and 30 mg/L and linear at concentrations less than 30 mg/L(105). The patient regained consciousness when the methyprylon concentration fell below 43 mg/L. Serial measurements in a 14-year-old girl after an overdose also showed much longer half-lives than the usually reported four hours (106).
 +
 +===== PATHOPHYSIOLOGY =====
 +
 +The mechanism of the CNS depressant effects of methyprylon is unknown. Habituation,​ dependence and tolerance may occur, similar to that seen with barbiturates (13).
 +
 +===== CLINICAL PRESENTATION =====
 +
 +==== Acute overdose ====
 +
 +Methyprylon poisoning produces CNS depression with respiratory depression, nystagmus, pupillary abnormalities,​ dysarthria, drowsiness, confusion and coma (105;220) accompanied by hypotension (68) and hypothermia or hyperpyrexia (221). ST segment and T-wave changes on ECG have been ascribed to methyprylon overdose (221).
 +
 +==== Acute withdrawal ====
 +
 +Withdrawal from central nervous system depressants is dealt with in more detail in the [[:​wikitox:​management_of_alcohol_and_drug_withdrawal|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).
 +
 +
 +==== Adverse reactions ====
 +
 +Frequently reported central nervous system disturbances are headache, dizziness, drowsiness and vertigo. However, nightmares, anxiety, excitation, depression, ataxia and incoordination have been described. Gastrointestinal complaints such as nausea, vomiting, heartburn and changes in bowel habit are also well recognised. In addition, methyprylon may precipitate allergic disorders, pruritus and skin eruptions (13).
 +
 +===== DIAGNOSTIC TESTS =====
 +
 +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 [[:​wikitox:​3.4.15_rhabdomyolysis|rhabdomyolysis]]. Core body temperature should be assessed as hypothermia is common. Chest X-ray is helpful to assess for [[:​wikitox:​non_cardiogenic_pulmonary_oedema|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.
 +
 +
 +==== Postmortem considerations ====
 +
 +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.
 +
 +===== TREATMENT =====
 +
 +==== Overview ====
 +
 +Oral [[:​wikitox:​3.2.2.2.3_activated_charcoal|activated charcoal]] within 1 hour of ingestion may be of some value in poisoning with the other drugs in this monograph. More aggressive respiratory and cardiovascular support will be required for the older agents. [[:​wikitox:​non_cardiogenic_pulmonary_oedema|Non-cardiogenic pulmonary oedema]] should be managed along conventional lines. In the face of continuing hypotension not responding to [[:​wikitox:​3.4.8_fluid_resuscitation|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.
 +
 +
 +==== Elimination enhancement ====
 +
 +Principles of [[:​wikitox:​3.2.3_enhance_elimination_techniques|elimination enhancement]] are discussed in the Treatment monograph.
 +
 +Methyprylon may have greater elimination during [[:​wikitox:​3.2.3.1_extracorporeal_removal|extracorporeal elimination]] than ethchlorvynol,​ glutethimide or methaqualone (277). Methyprylon poisoning has been managed with a variety of extracorporeal techniques (68;​106;​281;​292–296) but it is unclear whether there is likely to be a consistent response with a significant effect on outcome.
 +
 +
 +==== Monitoring ====
 +
 +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.
 +
 +===== REFERENCES =====
 +
 +(1) Smith AJ, Whyte IM. New drugs for old: an issue for debate? Med J Aust 1988; 149(11–12):​581-582
 +
 +(13) Dollery CT. Therapeutic drugs. CD_ROM DATABASE Release 1.0 ed. London: Churchill Livingstone,​ 1999
 +
 +(14) Tiller JW, Burrows GD, O'​Sullivan BT. Buspirone overdose. Med J Aust 1989; 150(1):54. (15) Goetz CM, Krenzelok EP, Lopez G, Borys D. Buspirone toxicity: A prospective study. Ann Emerg Med 1990; 19:630
 +
 +(16) Napoliello MJ, Domantay AG. Buspirone: a worldwide update. Br J Psychiatry Suppl 1991;​(12):​40–44
 +
 +(17) Cantor CH. Substances involved in fatal drug overdoses in Brisbane, 1979-1987. Acta Psychiatr Scand Suppl 1989; 354:69–71
 +
 +(18) Buckley NA, Whyte IM, Dawson AH, McManus PR, Ferguson NW. Correlations between prescriptions and drugs taken in self-poisoning. Implications for prescribers and drug regulation. Med J Aust 1995; 162(4):​194–197
 +
 +(19) Pershad J, Palmisano P, Nichols M. Chloral hydrate: the good and the bad. Pediatr Emerg Care 1999; 15(6):​432–435
 +
 +(20) Lipshitz M, Marino BL, Sanders ST. Chloral hydrate side effects in young children: causes and management. Heart Lung 1993; 22(5):​408–414. (21) Laptook AR, Rosenfeld CR. Chloral hydrate toxicity in a preterm infant. Pediatr Pharmacol (New York) 1984; 4(3):​161–165
 +
 +(22) Seger D, Schwartz G. Chloral hydrate: a dangerous sedative for overdose patients? Pediatr Emerg Care 1994; 10(6):​349–350
 +
 +(23) Granoff DM, McDaniel DB, Borkowf SP. Cardiorespiratory arrest following aspiration of chloral hydrate. Am J Dis Child 1971; 122(2):​170–171
 +
 +(24) Baselt RC, Cravey RH. Chloral hydrate. Disposition of toxic drugs and chemicals in man. Chicago: Year Book Medical Publishers, Inc., 1989: 144–147
 +
 +(25) Sing K, Erickson T, Amitai Y, Hryhorczuk D. Chloral hydrate toxicity from oral and intravenous administration. J Toxicol Clin Toxicol 1996; 34(1):​101–106
 +
 +26) Fetu D, Carel N, Fossier T, Motreff C. [Chloral hydrate poisoning]. Ann Fr Anesth Reanim 1994; 13(5):​745–748
 +
 +(27) Jonville AP, Mesny J, Quillet L, Soyez C, Autret E, Breteau M. [Accidental chloral hydrate poisoning]. J Toxicol Clin Exp 1991; 11(6):​337–341
 +
 +(28) Donovan KL, Fisher DJ. Reversal of chloral hydrate overdose with flumazenil. BMJ 1989; 298(6682):​1253
 +
 +(29) Brown AM, Cade JF. Cardiac arrhythmias after chloral hydrate overdose. Med J Aust 1980; 1(1):​28–29
 +
 +(30) Vellar ID, Richardson JP, Doyle JC, Keating M. Gastric necrosis: a rare complication of chloral hydrate intoxication. Br J Surg 1972; 59(4):​317–319
 +
 +(31) Gleich GJ, Mongan ES, Vaules DW. Esophageal stricture following chloral hydrate poisoning. JAMA 1967; 201(4):​266-267
 +
 +(32) Stalker NE, Gambertoglio JG, Fukumitsu CJ, Naughton JL, Benet LZ. Acute massive chloral hydrate intoxication treated with hemodialysis:​ a clinical pharmacokinetic analysis. J Clin Pharmacol 1978; 18(2–3):​136–142
 +
 +(33) Ludwigs U, Divino Filho JC, Magnusson A, Berg A. Suicidal chloral hydrate poisoning. J Toxicol Clin Toxicol 1996; 34(1):​97–99
 +
 +(34) Gerretsen M, de Groot G, van Heijst AN, Maes RA. Chloral hydrate poisoning: its mechanism and therapy. Vet Hum Toxicol 1979; 21 Suppl:​53–56
 +
 +(35) Gauillard J, Cheref S, Vacherontrystram MN, Martin JC. [Chloral hydrate: a hypnotic best forgotten?​]. Encephale 2002; 28(3 Pt 1):​200–204
 +
 +(36) Jastak JT, Pallasch T. Death after chloral hydrate sedation: report of case. J Am Dent Assoc1988; 116(3):​345–348
 +
 +(37) King K, England JF. Chloral hydrate (Noctec) overdose. Med J Aust 1983; 2(6):260. (38) Millhouse J, Davies DM, Wraith SR. Chronic ethchlorvynol intoxication. Lancet 1966; 2(7475):​1251–1252
 +
 +(39) Flemenbaum A, Gunby B. Ethchlorvynol (Placidyl) abuse and withdrawal (review of clinical picture and report of 2 cases). Dis Nerv Syst 1971; 32(3):​188–192
 +
 +(67) Reidt WU. Fatal poisoning with methyprylon (Noludar), a nonbarbiturate sedative. N Engl J Med 1956; 255:​231–232
 +
 +(68) Xanthaky G, Freireich AW, Matusiak W, Lukash L. Hemodialysis in methyprylon poisoning. JAMA 1966; 198(11):​1212–1213
 +
 +(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
 +
 +(104) Bridges RR, Peat MA. Gas-liquid chromatographic analysis of methyprylon and its major metabolite (2,​4-dioxo-3,​3-diethyl-t-methyl-1,​2,​3,​4-tetrahydropyridine) in an overdose case. J Anal Toxicol 1979; 3:21–25
 +
 +(105) Contos DA, Dixon KF, Guthrie RM, Gerber N, Mays DC. Nonlinear elimination of methyprylon (Noludar) in an overdosed patient: correlation of clinical effects with plasma concentration. J Pharm Sci 1991; 80(8):​768–771
 +
 +(106) Pancorbo AS, Palagi PA, Piecoro JJ, Wilson HD. Hemodialysis in methyprylon overdose. Some pharmacokinetic considerations. JAMA 1977; 237(5):​470–471
 +
 +(220) Durakovic Z, Dujmic S, Dujmic L, Plavsic F. [Methyprylon poisoning]. Arh Hig Rada Toksikol1985;​ 36(2):​195–199
 +
 +(221) Pellegrino ED, Henderson RR. Clinical toxicity of methyprylon (Noludar). Case report and review of twenty three cases. J Med Soc N J 1957; 54:​515–518
 +
 +(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
 +
 +(277) Gwilt PR, Perrier D. Plasma protein binding and distribution characteristics of drugs as indices of their hemodialyzability. Clin Pharmacol Ther 1978; 24(2):​154–161
 +
 +(281) Koffler A, Bernstein M, LaSette A, Massry SG. Fixed-bed charcoal hemoperfusion. Treatment of drug overdose. Arch Intern Med 1978; 138(11):​1691–1694
 +
 +(292) el Badry A, Hassaballa A, el Ayadi A. Treatment of a non-barbiturate hypnotic poisoning-methyprylon- by extra-corporeal haemodialysis. Dtsch Zahnarztl Z 1966; 21(3):​605–607
 +
 +(293) Yudis M, Swartz C, Onesti G, Ramirez O, Snyder D, Brest A. Hemodialysis for methyprylon (Noludar) poisoning. Ann Intern Med 1968; 68(6):​1301–1304
 +
 +(294) Chang TM, Coffey JF, Lister C, Taroy E, Stark A. Methaqualone,​ methyprylon,​ and glutethimide clearance by the ACAC microcapsule artificial kidney: in vitro and in patients with acute intoxication. Trans Am Soc Artif Intern Organs 1973; 19:87–91
 +
 +(295) Polin RA, Henry D, Pippinger CE. Peritoneal dialysis for severe methyprylon intoxication. J Pediatr 1977; 90(5):​831–833
 +
 +(296) Collins JM. Peritoneal dialysis for methyprylon intoxication. J Pediatr 1978; 92(3):​519–520
 +
  
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