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Poisoning monographs

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 Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the benzodiazepines.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

In a series of chronic drug users, mild toxicity (slurred speech, ataxia, drowsiness and nystagmus) appeared after cumulative doses of 300 – 4900 mg of methaqualone (64). Deep coma (unresponsive to pain) occurred after an estimated ingestion of greater than 4.5 g of methaqualone (65). A 23-year-old man was admitted after ingestion of 4 – 5 g. On admission he was somnolent and poorly responsive to painful stimuli and later became deeply comatose. He recovered completely (66).


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 250 mg oral dose produced a mean peak concentration of 2.2 mg/L (range 1.0 – 4.0) (99). Concentrations greater than 8 mg/L have been associated with unconsciousness (100); concentrations in overdose have ranged from 2 to 230 mg/L (101). A mean serum methaqualone concentration of 5 ± 3 mg/L (mean ± SD) was seen in a series of 60 poisonings (102). Serum methaqualone concentrations showed no significant correlation with the physical findings, except that concentrations >= 9 mg/L were always associated with a depressed level of consciousness, whether or not other drugs were present (102).


The mechanism of action of is unclear but there is evidence at least some of its actions are related to effects at the flumazenil-sensitive benzodiazepine recognition site(s) of the GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex (135). Serotonin appears to play a facilitatory role in the anticonvulsant activity of methaqualone (136). The physical dependence picture on methaqualone is closer to that of benzodiazepines than barbiturates and alcohol(137). Methaqualone has been withdrawn from the market in many countries because of problems with abuse (122;138;139).


Acute overdose

In a series of sixty cases of methaqualone ingestion from 1977 through 1980 there was a depressed level of consciousness that, in general, responded to a brief period of observation and supportive care (102).

More severe methaqualone overdose can produce early CNS excitation (66) (occasionally), followed by CNS depression with coma (205) which may be profound (65) and accompanied by convulsions (206) and hypotension (207). Necrosis of pressure areas can occur (208). If CNS excitement is present, delirium (209) or even a schizophreniform psychosis (210), increased limb reflexes (66), myoclonus (66;211) and positive pyramidal signs (66) may be present. The muscular hyperactivity may be so severe as to require drug paralysis for control (212). Flexor or extensor posturing may appear as an early and transient feature (169). Ocular movements may be absent (169) or show alternating skew deviation (roving eye movements) (213). Signs may occasionally be unilateral (209). Respiratory insufficiency (214), including apnoea (215), and noncardiogenic pulmonary oedema (66;216), which can be unilateral (217) may occur.

There is one case report of hemorrhagic complications possibly due to methaqualone-induced thrombocytopenia (218) and/or platelet dysfunction (219).

Acute 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).

Adverse reactions

Unwanted sedation and other symptoms of CNS depression are recognised adverse effects of methaqualone. Peripheral neuropathies are a significant problem (232). Fixed drug eruptions (233) and erythema multiforme (234) are reported. Platelet aggregation can be impaired with consequent bleeding disorder (219) and the possiblility of agranulocytosis due to methaqualone has been suggested (235). Drug-induced gout has been reported with methaqualone (236).


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.

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.



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.

Elimination enhancement

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 methaqualone poisoning (101;281;286), there is unlikely to be any significant additional elimination of this drug with these techniques. In a study patients intoxicated with methaqualone did not improve with charcoal haemoperfusion(288). Methaqualone, in addition, could not be eliminated sufficiently well in animal trials of charcoal haemoperfusion (289) and a large series (116 patients) showed that patients could indeed be managed conservatively (290). 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 methaqualone 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.


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(215) Johnstone RE, Manitsas GT, Smith EJ. Apnea following methaqualone ingestion. Report of a case. Ohio State Med J 1971; 67(11):1018–1020

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(218) Trese M. Retinal hemorrhage caused by overdose of methaqualone (Quaalude). Am J Ophthalmol 1981; 91(2):201–203

(219) Mills DG. Effects of methaqualone on blood platelet function. Clin Pharmacol Ther 1978; 23(6):685–691

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

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