Miscellaneous Anxiolytics, Sedatives and Hypnotics


DRUGS INCLUDED


  • Buspirone
  • Chloral hydrate
  • Ethchlorvynol
  • Glutethimide
  • Hexapropymate
  • Meprobamate
  • Methaqualone
  • Methyprylon
  • Zolpidem
  • Zopiclone

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 Most are older drugs (chloral hydrate was synthesized in 1832) that have been superseded in clinical practice by the benzodiazepines but two (zolpidem and zopiclone) are newer non-benzodiazepine agents with effects on the gamma-amino-butyric acid A [GABA(A)] receptor that have been developed in the hope of less dependence producing potential. Buspirone is unusual in this group being an anxiolytic that is a partial agonist at serotonin 5HT1A receptors. 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 as in chloral hydrate). 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).

Acute overdose toxicity and risk of death has been observed disproportionately with chloral hydrate but death has been reported after overdose with all the older agents. Zopiclone and zolpidem appear less toxic in overdose with a profile more similar to the benzodiazepines and produce mild to moderate CNS depression in most cases although deaths have been recorded after overdose with both agents. Buspirone has a risk of serotonin toxicity when combined with other serotonergic agents but little intrinsic toxicity otherwise although a death in combination with alprazolam, diltiazem, alcohol and cocaine has been reported.

STRUCTURE AND CLASSIFICATION/USES


There is no consistent structural relationship amongst these agents (see Table 1 and Figure )

Table 1. Structural classification of miscellaneous anxiolytics, sedatives and hypnotics (see also Figure)
media type=


MW, molecular weight
N/A, Not available
*From Flanagan RJ. Guidelines for the interpretation of analytical toxicology results and unit of measurement conversion factors. Ann Clin Biochem 1998;35 ( Pt 2):261-7
**As trichloroethanol

Indications include anxiety and insomnia (see Table 2). Buspirone may have some benefit in dopamine induced movement disorders (2) and tardive dyskinesia (3) although it can produce movement disorders of its own (4).

Table 2. Typical therapeutic doses of miscellaneous anxiolytics, sedatives and hypnotics for their primary indication (13;122;230)
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NR, not reported

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.

Buspirone

Serotonin toxicity has been seen when therapeutic doses of buspirone have been combined with serotonin uptake inhibitors (5-8), monoamine oxidase inhibitors (9;10) and possibly on its own (11) although it has been used successfully to treat serotonin uptake inhibitor adverse effects (12). Daily doses as high as 375 mg have been administered to healthy male volunteers; near this dosage, nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress occurred (13). Doses up to 2400 mg daily were administered during early trials where akathisia, tremor, and rigidity were observed (14). Deliberate self-poisoning with 250 mg (14) and up to 300 mg (15) resulted in drowsiness in about one half of patients. One fatality followed ingestion of 450 mg of buspirone with other drugs (alprazolam, diltiazem, alcohol, and cocaine) (16).

Chloral hydrate

Chloral hydrate was by far the most commonly implicated single compound in fatal overdoses in Brisbane, Australia between 1979 and 1987 (17) and had one of the highest odds ratios for death from deliberate self-poisoning when adjusted for prescription numbers (58.1; 95% CI, 18.1-187) (18).

Doses of 80 to 100 mg/kg have been given to children (< 5 years old) with sedation as the only effect (19). Paradoxical excitement occurred in 18% of children receiving a mean dose 87 mg/kg as pre-medication (20). A preterm infant developed severe chloral hydrate toxicity after its therapeutic administration as an adjunct to the treatment of hyaline membrane disease (21). Therapeutic doses of chloral hydrate may produce arrhythmias when used to sedate children with stimulant ingestions (22). A 2-year old had a respirator arrest after aspiration of 250 mg of chloral hydrate but survived (23). More than 1.5 to 2.0 g of chloral hydrate has produced excessive sedation in children and adults (19). Toxic effects of lethargy and ataxia are seen in adults at doses of 2 – 3 g (13) although tolerant individuals have been know to consume up to 25 g per day without mishap (24).

Two cases of intravenous administration of a therapeutic dose of oral chloral hydrate resulted in central nervous system depression and minimal local effects at the injection site (25). Ingestion of 219 mg/kg of chloral hydrate resulted in transient bigeminy, ingestion of up to 960 mg/kg caused torsades de pointes and ventricular fibrillation (25).

The intentional ingestion of 5 g of chloral hydrate by a 67-yr-old man resulted in cardiac arrhythmia including tachyarrhythmia and polymorphic ventricular extrasystoles (26). A 42-year-old woman had an accidental overdose of chloral hydrate due to repeated dosing of a therapeutic dose of chloral syrup for insomnia. The total ingestion was estimated at 8 g. There was mild CNS depression with ventricular bigeminy (27). An adult who ingested 10 g of chloral hydrate became unconscious with respiratory depression and hypotension (28). Doses of 10 to 37.5 g (29) and 38 g (19) were associated with severe toxicity (coma and arrhythmia) but ultimate survival.

Gastric perforation and gastrointestinal hemorrhage with later gastroesophageal stricture formation have been reported after doses of 30 g (30) and 18 g (31). Coma and signs of cardiac toxicity appeared 2 hours after ingestion of approximately 38 g of chloral hydrate (32). A 29-year-old male was admitted after ingestion of 70 g of chloral hydrate. He was hypotensive, hypothermic and profoundly unconscious but survived (33).

The minimum lethal dose of chloral hydrate for an adult is unclear and has been variously quoted as 3 g (24), 4 g (34) or 5 – 10 g (13;35). A young healthy female died after taking a therapeutic dose of chloral hydrate syrup before surgery to extract third molars (36). Forty grams of chloral hydrate resulted in the death of a 33-year-old woman (34) and 35 grams resulted in the death of a 35-year-old woman (37).

Ethchlorvynol

Chronic abusers may ingest up to 4 g/day with only minor symptoms (38), however, death has been seen after acute ingestion of only 2.5 g alone (39) or in combination with alcohol (40). Deep coma occurred after ingestion of 12.5 g of the drug (41). Severe noncardiogenic pulmonary edema occurred following the intravenous injection of 25 to 40 mg/kg of ethchlorvynol (42;43).

While death has been reported after ingestion of 5 g (44) and up to 49.5 grams of ethchlorvynol (45), survival of doses from 25 to 45 g has been reported (45).

Glutethimide

Six of 63 patients hospitalized with glutethimide overdose died including all three aged 60 years or older. Age was the major identifiable determinant of survival, regardless of other factors. An ingested dose of 10 g or more was almost always associated with deep coma (46).

Relatively small doses (2.5 and 5 g) have been associated with bleeding, liver failure and, in one case, acute renal failure (47).The acute ingestion of at least 15 grams of glutethimide resulted in cyclic and, sometimes, unilateral clinical findings that were reflected in the EEG. Complete clinical recovery resulted with supportive care (48).

Minimum lethal dose for an adult has been estimated as 5 g (49) although ingestion of 75 g has been survived (50).

Hexapropymate

Coma with respiratory depression has been reported following doses as small as 3.6 g (51). Doses of 8 g or more appear to involve an increased risk of serious cardiovascular disorders (hypotension, shock) (52). A 28 year old man who ingested 16 g became deeply comatose, was treated supportively, and survived (53). Ingestions of 20 g and 40 g recovered with supportive care (54). A 20 year old man who ingested 9.2 g died in 12 hours,(55) and a 32 year old man who ingested 40 g lapsed into a deep coma before he died on the third day after overdose (56).

Meprobamate

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).

Methaqualone

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).

Methyprylon

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).

Zolpidem

Zolpidem, in therapeutic doses, has been implicated in psychotic reactions characterized by auditory and visual hallucinations as well as delusional thinking (69). In a large series (344 cases) of zolpidem overdose in adults, ingested doses of zolpidem ranged between 10 and 1400 mg. Drowsiness occurred at doses of 140 to 440 mg; coma or respiratory failure were rare (70). In a series of 54 single-drug poisonings with zolpidem in adults, only mild symptoms were observed up to 600 mg. Patients mainly suffered from somnolence. Only one patient became comatose after ingestion of 600 mg zolpidem. On the other hand, in combined intoxications with other CNS active drugs or ethanol a zolpidem dose as low as 100 – 150 mg induced coma in some patients, even if the amount of the additionally ingested drugs in itself would not have caused a comatose state (71). In a 44-year old male an overdose of 200 mg of zolpidem alone resulted in coma (GCS of 7) and respiratory failure (72). In a series of 12 pediatric ingestions, one child had no effect with 2.5 mg. As little as 5 mg caused symptoms with minor outcome in six unintentional ingestions (5 – 30 mg). Minor to moderate symptoms were reported 1-4 h after intentional ingestions (12.5 – 150 mg). (73)


Zopiclone

After a therapeutic dose of zopiclone (7.5 mg), alcohol enhanced and prolonged the effect without modifying plasma concentrations (74).

Transient first degree AV heart block occurred after ingestion of 127.5 mg of zopiclone (in combination with piperazine) (75). Sleepiness was the only feature after an oral ingestion of 300 mg of the drug (76).

A 72-year-old man being treated for lung cancer ingested 90 mg of zopiclone in a suicide attempt and died between 4 and 10 h after the ingestion (77). A combined ingestion of alcohol and 150 mg of zopiclone resulted in the death of a 29-year old woman (78). A 72-year-old woman with poor respiratory function due to bronchogenic carcinoma died after ingesting 200 to 350 mg of zopiclone (79).

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. Pharmacokinetics (where known) of these agents are shown in Table 3.

Table 3. Pharmacokinetics of the miscellaneous anxiolytics, sedatives and hypnotics (13;122)
media type=
NR, not reported

*Pharmacokinetics in the dog (301)

Buspirone

Little or no information is available on the toxicokinetics/ toxicodynamics of buspirone.

Chloral hydrate

After a single oral dose of 1000 mg, mean peak trichloroethanol concentration in blood was 8.0 mg/L (range 2 – 12) at 1 h (80) with an elimination half-life of 8 –12 h (13). In chloral hydrate intoxication, there may be delayed absorption and some slowing of metabolism (81). Two hours after ingestion of 38g in a 38-year old female, the plasma concentration of trichloroethanol was 330 mg/L and the half-life was 35 hours (32).

Ethchlorvynol

Mean peak serum concentration after 500 mg of ethchlorvynol was 6.5 mg/L at 1 h (82). Chronic abusers may ingest up to 4 g/day with steady state serum concentrations of up to 37 mg/L (38). Initial serum concentrations were reported at 70 mg/L in a somnolent yet totally conscious adult with evidence of tolerance (83).

Admission ethchlorvynol blood concentrations in a series of 38 overdose cases ranged from 3 to 46 mg/L in ethchlorvynol alone ingestions and from 3 to 75 mg/L when taken in combination with other agents (84). In pure ingestions, ethchlorvynol concentrations greater than 19 mg/L were usually associated with dysarthria, mydriasis, nystagmus, and tachycardia; when concentrations exceeded 38 mg/L, coma, areflexia, hypotension, and respiratory depression were generally noted as well (84).

Although serial estimations of ethchlorvynol can allow calculation of when the patient will achieve “therapeutic” concentrations (85) there can be a marked lack of correlation between concentrations of the drug and clinical status (86). In a series of nonfatal (51) and fatal (38) ingestions involving ethchlorvynol over a 14-year period (1975 through 1988), the concentrations in the (nonfatal) pure and mixed ingestions were similar (3 – 115 mg/L) and were little different to the concentrations in the fatal cases (5 – 258 mg/L) (87). Concentrations of 8 (45;86), 22 (45) and 85 mg/L (45) have been associated with coma in nontolerant individuals.

Glutethimide

A single dose of 500 mg results in a mean peak concentration of 4.3 mg/L (range 2.9 – 7.1) (88). Balance disturbances, psychomotor retardation and changes in consciousness with temporary excitation were observed with a concentration of 5 mg/L in the blood (89).

Some evidence for concentration dependent toxicity was found in a series of 70 cases of glutethimide overdose (90). Mild features were seen with concentrations in the range 5 – 56 mg/L (mean 27), moderate toxicity was seen with concentrations between 22 and 78 mg/L (mean 45) and severe toxicity when the concentrations were 15 – 120 mg/L (mean 50) (90). Blood concentrations and clinical findings were evaluated in twenty-six nonfatal and twelve fatal intoxications involving the combination of glutethimide and codeine ("loads") (91). The mean glutethimide concentration was 10 ± 5 mg/L for nonfatal cases (range 2 – 18 mg/L) and 13.9 ± 6.6 mg/L for fatal cases (range 4.6 – 26.4 mg/L). Six patients with serum glutethimide concentrations of 10 mg/L or greater were comatose (91). In another study of 63 cases, a plasma concentration exceeding 30 mg/L was almost always associated with deep coma (46).

Normal plasma half-lives of glutethimide and the relatively small amounts in urine of unchanged drug and unconjugated metabolites indicated that drug elimination is not markedly impaired in intoxicated patients (92).

Hexapropymate

A serum hexapropymate concentration of = 5.5 mg/L has been regarded as non-toxic (54). In a study of 6 patients treated on 8 occasions, maximum serum concentrations varied from 7.6 to 72.5 mg/L with no relationship between concentration and severity of clinical symptoms (54). Detailed analysis of the drug elimination in one patient showed a terminal elimination half-life of 21 hours, suggesting delayed absorption or dose dependent elimination (54).

Meprobamate

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.

Methaqualone

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).

Methyprylon

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).

Zolpidem

After a single 20 mg oral dose peak plasma concentrations of 0.192 to 0.324 mg/L occur 0.75 to 2.6 hours post dose (107). Zolpidem was identified in the blood of 29 subjects arrested for impaired driving (108). Zolpidem concentrations ranged from 0.05 to 1.4 mg/L (mean 0.29 mg/L). In the subjects where zolpidem was present with other drugs and/or alcohol, symptoms reported included slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus (108). In five separate cases, where zolpidem was the only drug detected (0.08 – 1.40 mg/L, mean 0.65 mg/L), signs of impairment included slow and slurred speech, slow reflexes, disorientation, lack of balance and coordination, and "blacking out" (108). After ingestion of 300 mg of zolpidem, an initial plasma concentration of > 0.5 mg/L was reported in a comatose patient (109).

Zopiclone

The disposition of the enantiomers of zopiclone was investigated after oral administration of a single dose of 15 mg of a racemic mixture (twice the usual therapeutic dose) in 12 adult Caucasian volunteers. Determination of concentrations of zopiclone enantiomers in plasma showed that zopiclone pharmacokinetics is stereoselective with peak concentrations of 0.0873 and 0.044 mg/L for (+)-zopiclone and (-)-zopiclone, respectively (110).

After zopiclone 7.5 mg, alcohol enhanced and prolonged the effects without modifying plasma concentration (74). After oral ingestion of 300 mg of zopiclone, the plasma concentration was 1.6 mg/L at 4.5 h after the dose and the elimination half-life was 3.5 h (76).

PATHOPHYSIOLOGY


Buspirone

Buspirone is a partial agonist at the 5-HT1A receptor. 5-HT1A receptor sites are located on both presynaptic and postsynaptic neurons. The net effect of the binding of buspirone to these 5-HT1A receptors is a reduction in serotonergic activity (implying greater effect on pre-synaptic autoreceptors than post-synaptic heteroceptors) (13). Buspirone has a direct antagonist effect on the presynaptic dopamine receptor, thus increasing dopaminergic transmission; it does not interact directly with noradrenergic receptors but decreased serotonergic activity may lead to a secondary increase in noradrenergic activity (13). Buspirone does not interact directly with either the benzodiazepine-GABA receptor complex or with GABA receptors (111), but there is some evidence that buspirone enhances benzodiazepine receptor binding in vivo (112). Nevertheless, benzodiazepine antagonists (e.g. flumazenil) do not reverse buspirone effects (113) and buspirone is ineffective in ameliorating features of benzodiazepine withdrawal in man (114). There is evidence for the development of tolerance to some of the effects of buspirone that does not seem to be due to a change in the binding properties of the 5HT1A receptor itself but may be due to a change in its coupling mechanism (115). The abuse liability of buspirone appears lower than that of the benzodiazepines (116).

Chloral hydrate

The sedative effects of chloral hydrate are attributed to its metabolite trichloroethanol but the mechanism of action is unknown (35). The parent compound is quite irritant and caustic to mucosal surfaces (30). Trichloroethanol mediated enhanced automaticity of supraventricular and ventricular pacemaker cells (117) with increased myocardial irritability to circulating catecholamines (118) is believed to be the mechanism of the cardiac arrhythmias. Tolerance to the sedative effects appears rapidly and prominently with a high potential for abuse/dependence and a major withdrawal syndrome (13).

Ethchlorvynol

Intravenous ethchlorvynol interferes with the integrity of endothelial cells in the lung to create gaps between the cells and resultant reversible pulmonary edema (119;120). The mechanism of the CNS depression is unknown. Tolerance, dependence and a withdrawal syndrome occur (39;121). Like the barbiturates, it can precipitate acute intermittent porphyria in susceptible individuals (122).

Glutethimide

The mechanism of action of the central nervous system depression effects of glutethimide is unclear although there is evidence of weak enhancement of GABA binding with inhibition of diazepam binding (123). Glutethimide also has some anticholinergic activity. The contribution to glutethimide toxicity of its metabolite, 4-hydroxy-2-ethyl-2-phenylglutarimide (4-hydroxyglutethimide), is unclear with some supporting evidence for a significant contribution (124) but other evidence of lack of correlation with clinical effect (125). There is also the potentially confounding issue of rapid (4 – 6 h) tolerance developing to parent drug and/or its metabolites as occurs with benzodiazepines (126). There is evidence for toxic activity of the alpha-phenyl-gamma-butyrolactone metabolite (127) but its contribution to the clinical picture is unknown. Tolerance, dependence and a withdrawal syndrome occur (128;129) particularly when combined with codeine (“loads”) (130-132). Glutethimide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients (122).

Hexapropymate

The mechanism of the CNS depressant effects of hexapropymate is unknown. There are no reports of tolerance, abuse or dependence, however, it is likely the drug has a high potential for these effects. Hexapropymate is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in vitro systems (122).

Meprobamate

Meprobamate has a CNS depressant effect similar to that of the 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).

Methaqualone

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).

Methyprylon

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

Zolpidem

The GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex is discussed in the benzodiazepine monograph. The channel is not homogenous and can be assembled from multiple different combinations of alpha, beta and gamma sub-units (140). Zolpidem is a potent agonist at GABA(A) receptors but only those containing the alpha1 subunit (corresponding to the benzodiazepine (BZ)1 or omega1 subtype); it is not effective at receptors containing the alpha5 subunit (corresponding to one type of BZ2 or omega2 receptors) (141;142). It is this selectivity for BZ1 receptors that is thought to explain its greater potency as a sedative-hypnotic and lesser activity as a muscle relaxant and anticonvulsant (142;143). The sedative-hypnotic effects are antagonized by flumazenil (144). It has been proposed that zolpidem lacks benzodiazepine-like side-effects, having minimal abuse and dependence potential. Nevertheless, there is a considerable number of zolpidem dependence case reports in the literature (145;146) and a withdrawal syndrome including seizures (147) exists. Zolpidem has recently been classified as a psychotropic at risk of abuse in Europe (148).

Zopiclone

Zopiclone is a potent agonist at binding sites that belong to the GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex but which are not the benzodiazepine specific sites. The GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex is discussed in the benzodiazepine monograph. Zopiclone either acts on a site distinct from that of benzodiazepines or induces conformational changes different from those induced by benzodiazepines (149). It is possible that zopiclone acts via the mitochondrial benzodiazepine receptor which can result in allosteric modulation of GABA(A) receptor function (150). Zopiclone has no effect on other brain receptors such as the GABA receptor itself, dopamine receptors, serotonin or noradrenergic receptors (151). The sedative-hypnotic effects are antagonized by flumazenil (107). As with zolpidem, initial suggestions were that there was little or no potential for tolerance, abuse or dependence, however, it is clear that all can occur (145;152) and that a withdrawal syndrome including delirium (153) exists.

PREGNANCY AND LACTATION


The U.S. FDA and Australian ADEC pregnancy risk categories (where known) are shown in Table 4 along with distribution into breast milk. In several cases there are no data on distribution into breast milk, but small amounts of drug would be expected. For those where information is available only small amounts appear in breast milk and only for chloral hydrate is there likely to be significant concern for the child.

Table 4. U.S. FDA Risk Category and Breast Milk Distribution of the miscellaneous anxiolytics, sedatives and hypnotics
media type=
NR, not reported

*Appendix provides definitions of U.S. FDA pregnancy categories

ADEC, Australian Drug Evaluation Committee (see Appendix)

CLINICAL PRESENTATION


ACUTE OVERDOSE

Buspirone

Only mild toxicity is to be expected even after very large doses of buspirone. Nausea, vomiting, dizziness, drowsiness (15), miosis and gastric distress may occur at lower doses (13) while akathisia, tremor and rigidity may occur at higher doses (14). Combined overdose with a serotonergic agent may produce features of serotonin toxicity (5-10). There is one case of buspirone overdose that resulted in a generalized tonic clonic seizure approximately 36 hours after ingestion (154). A combined overdose with fluvoxamine resulted in prolonged bradycardia (155). Death from buspirone alone has not been reported.

Chloral hydrate

The acrid pear-like odor of chloral hydrate on the breath is distinctive and disagreeable (13;156). Typical presentation of a significant chloral hydrate ingestions is with CNS depression, which rapidly progresses to profound unconsciousness with hypotension (33;118) and hypothermia (33). Patients are often found already in coma (157) with respiratory failure (33;157) or frank cardiorespiratory arrest (118;157). Death, if it occurs in this context, is usually due to the effects of cerebral hypoxia (157).

Mortality is increased if cardiac arrhythmias are present. These manifest as supraventricular and ventricular tachyarrhythmias (29;117;158;159). The ventricular arrhythmias vary from extrasystoles which may be polymorphic (26), to polymorphic ventricular tachycardia (160), torsades de pointes (25;161) and ventricular fibrillation (25). These arrhythmias also occur in children (162-164).

The arrhythmias may be precipitated by catecholamines used to treat the hypotension (33;118) and can also occur when chloral hydrate is used to treat agitation due to stimulants (22) or when flumazenil is used to reverse the sedation (165). In one case report, reversible symptomatic myocardial ischaemia of 4 h duration was attributed to chloral hydrate overdose (166).

The caustic effect of chloral hydrate can result in gastro-esophageal necrosis (30), with or without perforation (167) and subsequent stricture formation (31).

Ethchlorvynol

Ethchlorvynol has a characteristic pungent, aromatic, “vinyl-like” odor (156). Severe poisoning produces a deep, often prolonged (86), coma with hypotension, respiratory depression and hypothermia (45). The coma is deep enough to result in pressure necrosis and rhabdomyolysis (168) and may be accompanied by flexor or extensor posturing (169) and acute urinary retention (170). In a series of 11 ethchlorvynol alone overdose cases, the most common physical findings were depressed level of consciousness (10 cases), dysarthria (7), mydriasis (6), nystagmus (6), areflexia (4), tachycardia (4), and hypotension, ataxia and respiratory depression (2 cases each) (84). In a series of 7 patients who ingested the drug, all were severely neurologically depressed; 3 were haemodynamically unstable and 1 developed noncardiogenic pulmonary edema 40 h after admission (43).

Intravenous injection of ethchlorvynol reproducibly causes a severe noncardiogenic pulmonary edema (42;43).

Glutethimide

Coma after glutethimide ingestion is common, often very deep and may be cyclical (48) due to delayed absorption related to its anticholinergic effects. Hypotension (46) can occur and features of anticholinergic toxicity are common. Hypothermia can occur, particularly in combined overdose with other sedative-hypnotics (171) as can occasional hyperthermia (172). Mortality is high in glutethimide poisoning (173) with the elderly at an even higher risk for fatal outcome (46). In 63 patients hospitalized with glutethimide poisoning, assisted ventilation was required in 59% of cases, and 32% developed hypotension (46). In a series of 26 non-fatal cases, depressed level of consciousness was the most common abnormal physical finding (24 cases); 18 patients were lethargic but rousable with non-painful stimulation and 6 were comatose (91). Glutethimide overdose has been associated with skin lesions resembling those seen in barbiturate poisoning (174;175) and with pressure necrosis and rhabdomyolysis (176).

Occasionally, unilateral neurological findings have been noted in papillary responses (177) and on EEG (48) and cerebellar degeneration has been reported (178).

There is a single case report of methemoglobinaemia (179) and isolated reports of bleeding and hepatic and renal injury (47) although it is unclear what contribution hypoperfusion had to the organ injury.

Seizures attributed to hypocalcaemia have been seen after misuse of glutethimide (180) but it is unclear what contribution there was of glutethimide withdrawal.

Hexapropymate

Prolonged, deep coma (53;56) with respiratory depression (51) and hypotension (52) is the usual picture in significant hexapropymate poisoning. Death can occur in as little as 12 hours (55). In a series of 8 presentations after hexapropymate overdose, initial symptoms included coma, hypotension, hypothermia, and hypoventilation (54). Maximum coma depth (Glasgow coma score) was 3 to 5 in 5 out of 8 events and on 7 occasions assisted ventilation was required (for 12 hours or more in 5 events) (54).

Meprobamate

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 hospitalized 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 rhabdomyolysis (195;196) with subsequent contractures (197) and noncardiogenic pulmonary edema has been reported (198;199). Rare complications include acute pancreatitis (200) and esophageal 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).

Methaqualone

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 edema (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).

Methyprylon

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).

Zolpidem

Zolpidem in overdose generally produces mild CNS depression with drowsiness, slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus (108) Occasionally more severe CNS depression occurs with development of a profound but short-lasting coma (72;109), associated with pin-point pupils (109) and respiratory depression (72;109;222) especially if other drugs or ethanol are ingested (71) or in cases of chronic hepatic or respiratory insufficiency (223). Pulmonary edema occurs in fatal cases (224).

In a large series of 244 cases of intentional acute overdoses, half of the patients ingested other substances (psychotropic drugs and alcohol) concomitantly (70). Signs of intoxication were observed in two thirds of the population but could be attributed to zolpidem in only 105 cases with drowsiness (N 89), vomiting (N 7), coma (N 4) or respiratory failure (N 1). There were no electrocardiographic abnormalities that appeared to be directly related to zolpidem and symptoms of intoxication rapidly remitted in 91% of cases (70).

In a series of 91 well documented cases of acute zolpidem intoxication there were 54 single-drug poisonings with zolpidem. Of these, only one patient became comatose. On the other hand, in combined intoxications with other CNS active drugs or ethanol, coma was more common even if the amount of the additionally ingested drugs in itself would not have caused a comatose state (71).

In a series of 12 pediatric zolpidem exposures, in ten cases onset of symptoms was within 10 to 60 min (mean 31.6 min). The duration of symptoms in the unintentional cases ranged from less than 60 min up to 4 h (mean 2.4 h) and 6 – 10 h (mean 7.5 h) in the intentional exposures (73).

Zopiclone

Drowsiness (76), lethargy and ataxia are the principal effects reported in zopiclone overdose (13). Rarely, coma may occur (225). In a death due to respiratory failure after zopiclone overdose it was postulated that hypoventilation due CNS depression occurred (79). Similar to benzodiazepines, coma may be due to flow limitation and obstructive apnoea via an increase in upper airway resistance and work of breathing (226). There is a single case report of first-degree heart block after zopiclone poisoning (75).

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


Buspirone

Common adverse affects include dizziness, light-headedness, headache, nausea, nervousness and excitement. Rare adverse effects include tachycardia, palpitations, chest pain, confusion, drowsiness, dry mouth, sweating, dystonia, akathisia, tardive dyskinesia, serotonin toxicity and angioedema (230).

Chloral hydrate

Chloral hydrate has an unpleasant taste and is corrosive to skin and mucous membranes unless well diluted. The most frequent adverse effect is gastric irritation; abdominal distension and flatulence may also occur. CNS effects such as drowsiness, light-headedness, ataxia, headache, and paradoxical excitement, hallucinations, nightmares, delirium, and confusion (sometimes with paranoia) occur occasionally (122). Paradoxical excitement can occur after therapeutic use of chloral hydrate in up to 18% of children (20).

Ethchlorvynol

Side-effects of ethchlorvynol include gastrointestinal disturbances, dizziness, headache, unwanted sedation and other symptoms of CNS depression such as ataxia, facial numbness, blurred vision, and hypotension. Hypersensitivity reactions include skin rashes, urticaria, and occasionally, thrombocytopenia and cholestatic jaundice. Idiosyncratic reactions include excitement, severe muscular weakness, and syncope without marked hypotension (122).

Glutethimide

Side-effects of glutethimide include nausea, headache, blurred vision, unwanted sedation and other CNS effects such as ataxia, impaired memory, and paradoxical excitement, and occasional skin rashes. Acute hypersensitivity reactions, blood disorders, and exfoliative dermatitis have been reported in rare instances (122).

Hexapropymate

Little or no information is available on the side-effect profile of hexapropymate but unwanted sedation and other symptoms of CNS depression are likely. Thrombocytopenic purpura related to hexapropymate has been reported (231).

Meprobamate

Drowsiness is the most frequent side-effect of meprobamate. Other effects include nausea, vomiting, diarrhea, paresthaesia, 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. Erythaema multiforme or Stevens-Johnson syndrome and exfoliative or bullous dermatitis have been reported (122).

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

Methaqualone

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 possible of agranulocytosis due to methaqualone has been suggested (235). Drug-induced gout has been reported with methaqualone (236).

Methyprylon

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 recognized. In addition, methyprylon may precipitate allergic disorders, pruritus and skin eruptions (13).

Zolpidem

The most common adverse effects occurring in clinical trials were dizziness and light-headedness (5.2%), somnolence (5.2%), headache (3%), and gastrointestinal disturbance (3.6%) (13). Memory disturbance (anterograde amnesia), nightmares, nocturnal restlessness, depressive syndrome, episodes of confusion, perceptual disturbances or diplopia, tremor, unsteady gait, and falls have been observed rarely in long-term clinical trials (237). More recently, zolpidem has been implicated in psychotic reactions characterized by auditory and visual hallucinations as well as delusional thinking (69;238).

Zopiclone

The most commonly recorded adverse effect during controlled clinical trials is a mild metallic or bitter after-taste (13). Less commonly, mild gastrointestinal disturbances including nausea and vomiting or minor mental disturbances such as irritability, confusion and depressed mood have occurred. Allergic and allied manifestations (urticaria and various rashes) have only very rarely been observed (13).

DIAGNOSTIC TESTS


Routine quantitative drug estimation is not readily available for any of these agents and not indicated for routine management. Chloral hydrate is radio-opaque and large amounts may be seen plainly on X-ray film of the abdomen (239).

Mortality is closely related to the development of cardiac arrhythmias so an electrocardiograph and cardiac monitoring are mandatory in chloral hydrate poisoning. 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 noncardiogenic pulmonary edema 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.

Eosphago-gastroscopy may be indicated after large chloral hydrate ingestions to assess mucosal damage and potential for stricture formation. If bezoar formation in meprobamate poisoning is considered to be contributing to continuing toxicity, eosphago-gastroscopy could be considered.

Post-mortem Considerations


For many drugs, there is a post-mortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artefactual 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 post-mortem blood samples is unknown (240). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is standardized amongst forensic pathologists.

Chloral hydrate

In 14 deaths due to overdose of chloral hydrate, postmortem blood concentration of trichloroethanol averaged 119 mg/L (range 20 to 240 mg/L) (241). In 4 cases with ingestions of 15 – 30 g, postmortem blood trichloroethanol concentrations averaged 265 mg/L (range 100 – 640) (242). Fatalities have been associated with trichloroethanol concentrations > 250 mg/L (243;244). A death due to chloral hydrate alone had trichloroethanol measured in blood (127 mg/L), urine (128 mg/L) and stomach contents (25 mg total) (245). The blood trichloroethanol concentration found in a case where laboratory grade chloral hydrate was ingested was 1700 mg/L (244).

In a case in which the death of a 2-year-old male child was the result of an acute intoxication with chloral hydrate, lidocaine and nitrous oxide, trichloroethanol concentrations were: plasma, 79.0 mg/L; urine, 31.0 mg/L; gastric contents, 454.0 mg/L; bile, 111.0 mg/L; vitreous, 40.2 mg/L; cerebrospinal fluid (CSF), 68.3 mg/L; and liver, 164 mg/kg (246).

Perimortal fixation of the gastrointestinal mucosa was found in a 34-year-old man who died of chloral hydrate overdose (trichloroethanol blood concentration was 52 mg/L) (247). This phenomenon of perimortal fixation is a useful indication for the forensic pathologist and should direct the suspicion to oral poisoning (247).

Ethchlorvynol

In 13 deaths due to ethchlorvynol, postmortem blood concentrations averaged 199 mg/L (range 14 – 400) (241). Even after embalming, a high concentration of ethchlorvynol (112 mg/L) was able to be identified in the bile (248).

Glutethimide

In 11 fatal cases, blood concentration averaged 45 mg/L (range 10 – 97) (242). Death has been associated with a mean blood glutethimide concentration in excess of 40 mg/L (103). Blood concentrations were evaluated in twelve fatal intoxications involving the combination of glutethimide and codeine ("loads"). The mean glutethimide concentration was 13.9 ± 6.6 mg/L for fatal cases (range 4.6 – 26.4 mg/L). The mean codeine concentration for fatal intoxications was 1.21 +/- 1.17 mg/L (range 0.13-4.32 mg/L) (91).

Meprobamate

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). Post mortem 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).

Methyprylon

Death has been associated with a mean blood methyprylon concentration of 117 mg/L (103). Postmortem blood concentrations were reported as 53 – 66 mg/L (mean 59) in 4 fatal cases (250).

Zolpidem

In a case of acute zolpidem overdose, postmortem analysis revealed: blood (subclavian), 4.5 mg/L; blood (iliac), 7.7 mg/L; vitreous humor, 1.6 mg/L; bile, 8.9 mg/L; urine, 1.2 mg/L; liver, 22.6 mg/kg; and gastric contents, 42 mg (224). In a second case involving a 58-year old female, zolpidem concentrations were as follows: blood (iliac), 1.6 mg/L; vitreous humor, 0.52 mg/L; bile, 2.6 mg/L; liver, 12 mg/kg; and gastric contents, 0.9 mg (224). The blood/vitreous humor ratios of zolpidem were 2.81 (subclavian) and 4.81 (iliac) in the first case and 3.08 (iliac) in the second case. These ratios, along with the sampling times of blood and vitreous humor for both cases, do not conclusively indicate the presence or absence of postmortem drug redistribution of zolpidem (224). The following concentrations of zolpidem: blood, 7.9 mg/L and urine, 4.1 mg/L were found in an elderly woman (251).

After the death of a 39-year old obese male, zolpidem was present at concentrations of 2.91, 1.40, and 2.13 mg/L in the heart blood, peripheral blood, and urine, respectively. The liver had zolpidem present at a concentration of 4.74 mg/kg, and the gastric contents had a total of 172 mg zolpidem. Additional drugs present included hydrocodone and morphine (unconjugated) at 0.16 and 0.04 mg/L, respectively. The cause of death was determined to be multiple drug intoxication (252). In a fatality due to ingestion of zolpidem and acepromazine, zolpidem and acepromazine blood concentrations were 3.29 and 2.40 mg/L, respectively (253). In a case described as a fatal overdose of zolpidem, a 68-year-old female ingested at least 300 mg of zolpidem and toxicological analyses revealed blood concentrations of 4.1, 19.3 and 2.3 mg/L of zolpidem, meprobamate and carisoprodol, respectively (254).

Zopiclone

A 29-year-old female weighing 64 kg had cardiac blood ethanol 153 mg% and zopiclone blood concentrations in the range 0.9 – 2.0 mg/L in 10 distinct sampling sites. The authors concluded that zopiclone showed little preferential concentration in solid organs and consequently has relatively stable postmortem blood concentrations, with little drug redistribution artifacts (78). In two cases of death due to the ingestion of zopiclone, quantitative determinations of zopiclone yielded 1.4 – 3.9 mg/L in the blood, 0.81 and 8.7 mg/kg in the liver and 13.5 and 133 mg in the stomach contents (255).

A 72-year-old woman with respiratory debilitation due to bronchogenic carcinoma overdosed herself with probably 200 to 350 mg of zopiclone and zopiclone was found to be 1.9 mg/L in postmortem femoral blood (79). A 72-year-old man who ingested 90 mg of zopiclone in a suicide attempt, died between 4 and 10 h after the ingestion and zopiclone, quantitated by GC-MS in the femoral blood, cardiac blood, vitreous humor, urine and bile was found to be 0.254, 0.408, 0.094, 7.33 and 114.7 mg/L, respectively (77). A fatality, attributed to a suicidal ingestion of zopiclone and subsequent death by drowning, demonstrated a testicular tissue concentration of 2.2 mg/kg of zopiclone (256).

In a suicide case involving multiple psychoactive drugs, toxicological analysis demonstrated 44.9 mg/L of zopiclone, 12.8 mg/L of phenobarbital, 10.9 mg/L of chlorpromazine, and 4.8 mg/L of promethazine in the gastric contents; 0.5 mg/L of zopiclone, 8.6 mg/L of phenobarbital, 0.2 mg/L of chlorpromazine and 0.3 mg/L of promethazine in the serum; and 43.0 mg/L of zopiclone, 8.1 mg/L of phenobarbital, 1.3 mg/L of chlorpromazine and 1.3 mg/L of promethazine in the urine. On the basis of these findings, the cause of death was considered to be multiple drug poisoning but zopiclone was considered primarily responsible for her death (257).

TREATMENT


Overview

Oral activated charcoal is unlikely to be of value in pure buspirone, zolpidem or zopiclone poisoning. It may be given to patients who have recently (within 1 hour) ingested these drugs with other drugs that may benefit from decontamination. Oral activated charcoal within 1 hour of ingestion may be of some value in poisoning with the other drugs in this chapter. Given the caustic nature of chloral hydrate, gastric lavage is not indicated. Glutethimide has significant enterohepatic recirculation, thus repeated doses of charcoal may be of benefit (258). The use of 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.

The preferred treatment for buspirone, zolpidem or zopiclone poisoning is entirely supportive with IV access and fluids and maintenance of the airway and ventilation if required. More aggressive respiratory and cardiovascular support will be required for the older agents. Noncardiogenic pulmonary edema should be managed along conventional lines (see Chapter 33). In the face of continuing hypotension not responding to fluid resuscitation, inotropic agents may be required (see Chapter 37). Adrenergic inotropes should be used with caution, if at all, in chloral hydrate poisoning because of the risk or precipitating an arrhythmia.

Chloral hydrate induced arrhythmias are frequently life-threatening and often resistant to conventional antiarrhythmics (29;158-160). There is good case evidence for the routine use of an intravenous beta-blocker (propranolol or esmolol) in these patients (25;29;158-160).

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 24 – 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 sedation after chloral hydrate with flumazenil (28) but ventricular arrhythmias have been precipitated by flumazenil in this context (165) and its use cannot be recommended. There is also one report of reversal of CNS depression by flumazenil after carisoprodol (which is metabolized to meprobamate) (261).

Flumazenil will rapidly and effectively reverse sedation due to zolpidem or zopiclone. However, by analogy with the benzodiazepines, patients are likely to wake from their sedation or coma because of the rapid development of tolerance (126) rather than from clearance of the drug. The administration of a benzodiazepine antagonist such as flumazenil in the presence of a benzodiazepine prevents of the development of tolerance (262). This could theoretically result in a prolongation of the effect of the benzodiazepine manifesting as a prolonged requirement for the antagonist and hospital length of stay. This has been seen after diazepam overdose treated with flumazenil (263;264) while, in contrast, a much shorter duration of symptoms was seen with similar doses managed before the availability of an antagonist (265). For routine management of uncomplicated zolpidem or zopiclone overdose there is no indication for the use of flumazenil.

Flumazenil (0.1-2.0 mg IV) has been given to unconscious patients where the drug ingested is unknown (266;267) although this remains controversial (268). Flumazenil should only be given if there is no evidence of proconvulsant/proarrhythmic drug ingestion as the removal of the effects of benzodiazepines or other similar drugs that have been coingested may lead to seizures, cardiac arrest or death. (165;269-276)

Enhancement of Elimination

Principles of elimination enhancement are discussed in the Treatment monograph. Based on their volumes of distribution and plasma protein binding (277), there is no indication for extracorporeal techniques in buspirone, zolpidem or zopiclone poisoning and there are no reports of their use in these poisonings.

Similarly, although there are numerous case reports of the use of a variety of techniques in ethchlorvynol (278-281), glutethimide (50;282-285) and methaqualone (101;281;286) poisoning, there is unlikely to be any significant additional elimination of these drugs with these techniques. This has been supported by more detailed studies indicating that removal of ethchlorvynol from the overdosed patient by haemoperfusion is limited by extensive distribution into and slow redistribution from body tissues (287). In a separate study, patients intoxicated with ethchlorvynol and 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). A series of 31 cases (291) and another of 70 cases (90) of glutethimide overdose also showed that patients can be successfully managed without extracorporeal elimination. Given the quality of supportive care that can be provided in centers capable of performing these techniques, there does not seem to be any indication to use extracorporeal elimination in ethchlorvynol, glutethimide or methaqualone poisoning.

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.

For chloral hydrate and meprobamate, which have 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. There is good evidence that elimination half-lives can be significantly reduced for trichloroethanol by haemodialysis (32;81;297), resin haemoperfusion (298) and combined haemoperfusion and haemodialysis (33). In all these cases there was clinical improvement coincident with the procedure but it is unknown whether the same outcome would have been achieved with conservative therapy.

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 chloral hydrate, continuous cardiac monitoring until the patient is clearly awake is mandatory. 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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