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 Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the benzodiazepines.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.

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).

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).

The mechanism of the CNS depressant effects of methyprylon is unknown. Habituation, dependence and tolerance may occur, similar to that seen with barbiturates (13).

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).

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).

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).

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.

Oral 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. 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.

Methyprylon may have greater elimination during 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.

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.

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