====== Meprobamate ======

===== 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 Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the [[:wikitox:benzodiazepines|]].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.

Meprobamate was implicated in 50 (6.5%) of 773 admissions to Massachusetts General Hospital due to psychotropic drug overdose between 1962 and 1975. Estimated doses ingested were as high as 40 g. Two patients died, one of whom ingested an estimated 12 to 20 g of meprobamate apparently with no other drugs (57).

A 36-year-old female was deeply comatose after ingestion of 40 gm of meprobamate and survived (58). Four hours after an overdose of 30 – 40 g, a patient presented deeply unconscious, hypotensive and in respiratory failure (59). Ingestion of 72 g of meprobamate was complicated by shock ascribed to cardiac failure and vasodilatation (60). After an ingestion of 100 g, haemodynamic compromise with profound hypotension was present (61).

Death has resulted from the ingestion of 3.6 g of meprobamate alone (62). A series of 12 fatal cases involved doses of 16 – 40 g (63).

===== 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.

There may be significant differences in arterial versus venous plasma concentrations with meprobamate (93). A single 400 mg dose produces a mean peak venous concentration of 7.7 mg/L at 2 h (94). Analysis of single psychoactive drug cases and single-drug-plus-ethanol cases showed that, in the presence of ethanol, the toxic blood concentration of meprobamate was decreased by an average of 50% (95).

Light coma occurred in a series of patients with plasma concentrations of 60 – 120 mg/L while deep coma was associated with concentrations of 100 – 240 mg/L (96). Coma, hypotension and hypothermia occurred in four cases of severe meprobamate intoxication with maximal plasma concentrations of 176, 180, 190 and 203 mg/L (97). All patients survived without sequelae including one patient resuscitated from cardiac arrest. Four hours after an overdose of meprobamate (30 – 40 g), a patient with a serum meprobamate concentration of 500 mg/L was deeply unconscious, hypotensive and in respiratory failure (59). Eight hours after ingestion of 100 g of meprobamate, the plasma concentration was 460 mg/L and the patient was profoundly hypotensive (61). Twenty five hours after admission after a meprobamate overdose, deep coma and cerebral electrical silence (flat line EEG) were observed at a time when the meprobamate plasma concentration was 250 mg/L (98). The patient recovery was uneventful.

===== PATHOPHYSIOLOGY =====

Meprobamate has a CNS depressant effect similar to that of the [[:wikitox:barbiturates|]] but the mechanism of action is unknown. It has no effect on the GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex. It has some skeletal muscle relaxant effect (133). Peripheral vasodilatation appears to be the cause of significant hypotension and shock with little evidence of myocardial dysfunction except when hypothermia is present (134). Meprobamate use can result in psychological and physical dependence with a barbiturate-type withdrawal syndrome (13). Like the barbiturates, it can precipitate acute intermittent porphyria in susceptible individuals (13).

===== CLINICAL PRESENTATION =====

==== Acute overdose ====

Meprobamate toxicity is primarily CNS depression with rapid onset of deep coma (58;181;182) and respiratory failure (59). Hypotension of varying degrees (61;183;184) up to and including cardiogenic shock(60;185) is common and worsens the prognosis (186;187). Hypothermia may be severe (188;189) and, if present, worsens the hypotension (134).

In an unselected group of 1125 consecutively hospitalised self-poisonings in Oslo, the complication rate was highest in poisonings with opiates (60.7%), meprobamate (37.5%) and antihistamines (30.0%) (190). Meprobamate poisoning is still a problem in France with a significant frequency (5.5% of presentations) and is the most frequently involved in fatal pharmaceutical overdoses (15.3%) (191). Meprobamate was implicated in 50 (6.5%) of 773 admissions to Massachusetts General Hospital due to psychotropic drug overdose between 1962 and 1975. In 25 cases deep coma (grade 3 or 4 (192)) was reached; 23 patients became hypotensive, and 16 required assisted ventilation Two patients died (57). In four cases of severe meprobamate intoxication, the clinical course was complicated by coma, hypotension, and hypothermia in all patients (97). As with all cases of prolonged coma, pulmonary embolism is a potential risk (193).

The coma may be so profound that the issue of brain death is raised. EEGs in this context may show an isoelectric trace even though subsequent recovery may be complete (98;194).

Ischaemic muscle injury may result in [[:wikitox:3.4.15_rhabdomyolysis|rhabdomyolysis]] (195;196) with subsequent contractures (197) and noncardiogenic pulmonary oedema has been reported (198;199). Rare complications include acute pancreatitis (200) and oesophageal spasm (201).

Large oral ingestions of meprobamate may result in tablet clumping and bezoar formation (202;203). As with many sedative drug overdoses, delirium during recovery is not uncommon and may be contributed to by withdrawal in dependent patients (204).

==== 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 ====

Drowsiness is the most frequent side-effect of meprobamate. Other effects include nausea, vomiting, diarrhea, parasthaesia, weakness, and CNS effects such as headache, paradoxical excitement, dizziness, ataxia, and disturbances of vision (122). There may be hypotension, tachycardia, and cardiac arrhythmias. Hypersensitivity reactions occur occasionally. These may be limited to skin rashes, urticaria, and purpura or may be more severe with angioedema, bronchospasm or anuria. Erythema multiforme or Stevens-Johnson syndrome and exfoliative or bullous dermatitis have been reported (122).

Blood disorders including agranulocytosis, eosinophilia, leukopenia, thrombocytopenia, and aplastic anaemia have occasionally been reported (122).

===== 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.

In a series of 12 fatal cases involving doses of 16–40 g, the blood concentration averaged 226 mg/L (range 142–346) (63). In another series of 16 deaths attributed solely to meprobamate, the mean blood concentration was 95 mg/L (range 35 – 240) (242). Death has been associated with a mean blood meprobamate concentration of 205 mg/L (103). Postmortem concentrations have ranged from 41 to 397 mg/l (mean = 182) (191).

In a death where the blood concentration was 204.6 mg/L, the maximum concentration was found in the heart (708 mg/kg) suggesting postmortem redistribution (62). In a case of suicidal overdose of meprobamate and sparteine, the blood concentrations of meprobamate and sparteine were found to be 88.2 and 40.4 mg/L, respectively (249).


===== 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. The use of [[:wikitox:3.2.2.2.3.1_repeated_doses_of_activated_charcoal|repeated oral activated charcoal]] administration has been reported to shorten half-life in two patients who presented with acute meprobamate ingestions (259) but whether this changed outcome is unclear.

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.

==== Antidotes ====

The use of flumazenil is dealt with in more detail in benzodiazepines. There is one report of reversal of CNS depression by flumazenil after carisoprodol (which is metabolized to meprobamate) (261).

==== Elimination enhancement ====

Principles of [[:wikitox:3.2.3_enhance_elimination_techniques|elimination enhancement]] are discussed in the Treatment monograph.

For meprobamate, which has relatively low plasma protein binding and volumes of distribution of less than or near 1 L/kg, there is likely to be a relatively high elimination rate with extracorporeal techniques. It has been estimated that one haemodialysis and/or haemoperfusion allows the removal of an average of 7–17% of ingested meprobamate (299). Significant reduction in meprobamate elimination half-life has been demonstrated with charcoal and resin haemoperfusion (97) and continuous arteriovenous haemoperfusion (CAVHP) (300) indicating a possible role for these techniques.

==== 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.

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