Clonazepam is also used to treat panic disorder including agoraphobia in adults. J Ann Toxicol ; The cornerstone of treatment in benzodiazepine BZD overdoses is good supportive care and monitoring. J Psychiatry Neurosci ; BZD are very rarely fatal in overdoses, and the altered mental status from BZD overdose greatly increases the risk of aspiration following oral charcoal dosing.
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In addition to those patients on long-term BZD use, flumazenil should not be used in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, co-ingestion of BZD and tricyclic antidepressant or other proconvulsant, or even a possible ingestion of a proconvulsant. Antidotes for toxicological emergencies: Am J Health Syst Pharm. Drug Abuse Warning Network, April 4, ; Accessed: Characteristics of alprazolam-related deaths compiled by a centralized state medical examiner.
Circumstances and toxicology of sudden or unnatural deaths involving alprazolam. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. Treatment of patients with substance use disorders, second edition. Basic Clin Pharmacol Toxicol. Treatment of benzodiazepine overdose with flumazenil. J Toxicol Clin Toxicol. Michael J Burns, MD is a member of the following medical societies: David C Lee, MD is a member of the following medical societies: American Society of Health-System Pharmacists.
Sign Up It's Free! If you log out, you will be required to enter your username and password the next time you visit. Share Email Print Feedback Close. Approach Considerations As with any overdose, the first step is to assess the patient's airway, breathing, and circulation and to address these rapidly as needed. Prehospital Care Prehospital care for patients who have overdosed on benzodiazepines BZDs includes the following: Rapid glucose determination finger stick and administration of D50 if necessary.
What would you like to print? If examination is delayed, the body is refrigerated as soon as possible. Specimens taken at examination are also refrigerated immediately. Postmortem blood is generally not frozen because freezing breaks up cells, and this interferes with the analysis. Whole blood is used; the blood is not centrifuged because postmortem blood is generally hemolysed and does not separate well into cells and serum. Screening usually takes place within 2 days and determination of positive cases within 1 or 2 weeks.
Analysis takes place immediately after extraction. Olanzapine is unstable in blood specimens, and because drug levels in liver are generally much higher and less susceptible to postmortem change, they are more useful for interpretation. The analysis methods used in the Toxicology Laboratory of the medical examiner of Alberta are as follows similar principles are employed in other toxicology laboratories.
Internal standard was added clozapine was used as internal standard for olanzapine quantification until replaced by analog LY The basified specimen was then extracted with 1-chlorobutane 8 mL. The organic fraction was extracted with dilute sulphuric acid 3 mL, 0. The aqueous acid layer was retained and neutralized with sodium hydroxide 0. The chlorobutane was separated, concentrated under nitrogen and injected onto the gas chromatograph GC with nitrogen—phosphorus detection NPD.
The same process was used for sheep blood-based calibrators and controls. All chemicals were reagent grade or better, and solvents were distilled in-glass. Specimens with concentrations exceeding this range were diluted appropriately and re-analyzed. Assays using clozapine as internal standard tended to give quadratic rather than linear calibration curves, but with acceptable correlations typically 0.
Under these conditions, olanzapine eluted at approximately 5. Olanzapine extracts are unstable if exposed to air overnight and were analyzed immediately after extraction. For the qualitative analysis, postmortem blood and urine specimens when available were screened by a panel of immunoassays ELISA, fluorescence polarization immunoassay and radioimmunoassay ; they were screened for volatiles including ethanol by headspace GC and for acidic, neutral and basic solvent extracts by GC with NPD, electron capture detection ECD and mass spectroscopic detection MSD.
Of the 29 toxicology cases with recorded olanzapine levels, 11 were reported in the literature Table 1 , 15 by medical examiners Table 2 , Table 3 and 1 in the Canadian Adverse Drug Reaction Monitoring Programme Table 3. In addition, 2 other cases from the literature were deemed relevant and are discussed, although no olanzapine levels were available. Elian 21 and Stevens et al 22 reported a case each 1, 2 involving the suicidal ingestion of mg of olanzapine. Anderson and Kuwahara 18 identified olanzapine in 35 cases where the cause of death was not immediately apparent or a toxicology screen had been specifically requested.
In most cases, the cause of death was attributed to other drugs including multiple drug intoxication , the decedent's actions or the circumstances involved. Although these levels were equal to or greater than accepted therapeutic levels, 2 cases 3, 4 specifically indicated olanzapine toxicity. Of 11 deaths ascribed to natural causes, significant cardiovascular disease was noted in 8 age range 22—32 yr.
Gerber and Cawthon 23 attributed 2 deaths to olanzapine in a 5-month period from December — 1 was a suicide 5 and the other believed to be due to direct toxicity in a year-old man 6 who had been taking 30 mg olanzapine daily for 8 months before he died autopsy findings included coronary artery disease and a nonsignificant blood concentration of risperidone. Two deaths were attributed to olanzapine toxicity — 1 was a year-old man with a history of seizure disorder 7 and the other believed to be direct toxicity was a year-old man purportedly taking 70 mg of olanzapine daily 8.
In their annual report, 7 fatal exposures involving olanzapine were described 6 from acute intentional overdose ; 25 3 cases appeared to involve olanzapine alone, but blood levels were available in 1 case only Of the other 2 cases, 1 was a year-old man who died, despite active intervention, of cerebral hemorrhage with hypotension and hyperpyrexia; blood results included hyperglycemia, hypokalemia and elevated creatine phosphokinase. No details were available on the other case attributed to olanzapine toxicity these 2 cases are included in the total.
Of the TESS cases involving coingestants, 1 was a year-old man who was taking olanzapine 10 mg twice daily and developed hyperpyrexia, refractory hypotension and bleeding after taking a mg paroxetine tablet; he died despite intervention. Wong et al 26 reported 5 cases in which cause of death was ascribed to pulmonary embolus, arteriosclerotic heart disease, injuries due to suicide and undetermined sudden death 2 cases. Thus, a total of 13 deaths in which olanzapine appeared to significantly contribute, either in combined toxicity or as the principal cause of toxicity, were identified from the literature.
Of the 27 cases from the Alberta medical examiner in which olanzapine was detected, 6 were attributed to olanzapine toxicity. In the other cases, drugs other than olanzapine predominated, except for 1 case in which olanzapine was the only drug detected, but death was due to diabetic ketoacidosis, and another case in which death was due to atherosclerotic coronary artery disease. Five of those examined were found to have significant atherosclerosis, which was determined to be the cause of death.
One case involved hypertension, and 2 of those who died had diabetes. Saskatchewan records drug overdose as cause of death but not the offending drug; Nova Scotia does not have a computerized database; Newfoundland and Prince Edward Island had no cases on record. Six cases 18—23 involved concomitant drugs; in 3 cases, olanzapine 24—26 was the only drug. Cardiovascular disease and diabetes were reported in 1 case 19 , and obesity, asthma and breast carcinoma were reported in 1 case The Canadian Adverse Drug Reaction Monitoring Program Newsletter of July 27 advised that olanzapine was reported as a suspected drug in 22 deaths, including 8 involving suicide or overdose and 14 due to a variety of causes e.
Malignant hyperpyrexia was reported as the cause of death in an overdose of olanzapine mg and diphenhydramine 20 mg. The cause of death was not determined in 1 case in which olanzapine was added to an existing regimen of loxapine, nor in 1 case of a patient with hypertension, chronic obstructive pulmonary disease, adrenal insufficiency and irritable bowel syndrome with a kg weight gain in 2 years who was taking multiple medications.
Of note, all information provided by the Health Product Safety Information Division is subject to the caveat that data are unpublished and received from a variety of sources; thus, cause and effect relations have not been established. From medical examiners' reports and the Canadian Adverse Drug Reaction Monitoring Program, there were 16 cases in which olanzapine was identified as the principal cause of toxicity or contributory in combined toxicity.
Given the limitations of autopsy material, a causal relation cannot be inferred from the data presented. Nonetheless, there are potentially 29 cases in which acute olanzapine toxicity appears to have contributed to death. These numbers are definitely small when compared with the number of prescriptions for olanzapine, but it is likely that data for many cases not just involving olanzapine are not readily accessible and therefore represent underestimates of the total numbers of possible drug-related toxicity cases.
The findings have clinical relevance, but the significance, particularly for olanzapine, is unclear given the lack of comparative data at this point. The inherent difficulties in collecting these data include lack of computerized databases, toxicology findings not systematically recorded by drug, and cause of death not recorded as an overdose. Interpretation of postmortem concentrations of new drugs is particularly difficult because no postmortem database exists and perimortem details are usually unavailable.
Postmortem concentrations are usually compared with therapeutic or pharmacokinetic data because this is the only information available and, consequently, high concentrations are interpreted as consistent with overdose. Furthermore, the number of cases detected is not only a function of the frequency of drug use in that particular jurisdiction but also of the analytical procedures used by the investigating laboratory.
However, risperidone and pimozide are not detected by the screening procedures used in most postmortem toxicology laboratories, and their overdose occurrence is thus likely to be under-reported. The relative safety of the atypical antipsychotics has been comprehensively reviewed elsewhere. Also, a review of inquiries to the UK National Poisons Information Service over 9 months revealed no fatalities after overdoses of atypical antipsychotics.
However, the outcome of treated overdoses in hospital settings likely differs from outcomes for individuals who do not receive active intervention, and, as the authors comment, patients who die outside of hospital are unlikely to be revealed by inquiries to a poison centre. Gardner et al 31 reported rapid recovery with the use of activated charcoal in a year-old woman from an overdose of mg of olanzapine that was associated with initial tachypnea, tachycardia, unstable blood pressure and hypoxemia.
The findings of this review suggest an adverse outcome for patients often with pre-existing undetected physical pathology such as cardiovascular disease who take overdoses of multiple medications and do not receive intervention. Olanzapine has a high volume of distribution i. After death, significant redistribution from liver to central blood specimens occurs, and the higher range of olanzapine concentrations in postmortem blood is consistently observed independent of any assay differences.
Higher concentrations are also observed in central heart blood specimens than in peripheral femoral blood specimens. Postmortem olanzapine blood concentrations may not represent true antemortem or perimortem levels and should be interpreted cautiously. In only 1 case of our series 17 was an antemortem specimen available for comparison. The patient died approximately 2 hours after admission to hospital, and the postmortem olanzapine heart blood concentration was elevated 5-fold over the antemortem level.
Thus, because of olanzapine's instability in blood, sample concentrations should be measured as soon as possible after death. Compounds with a heterocyclic sulfur atom, such as chlorpromazine and perphenazine, are readily oxidized to sulfoxides and sulfones and are unstable in liver homogenates; 34 olanzapine may be similarly subject to in vitro degradation.
The significant variation in blood concentrations of olanzapine in clinical practice makes it difficult to interpret postmortem findings. Olanzapine is extensively metabolized in the liver, 39 and an impairment of enzyme-mediated metabolism may lead to variable blood concentrations. However, the existence of multiple pathways for olanzapine metabolism suggests that an alteration of one route of metabolism may not necessarily result in significant change in the clearance of olanzapine in vivo.
In many overdose situations, there is often limited information concerning concomitant medications that were recently prescribed but not necessarily taken at the time of overdose. Furthermore, in clinical practice, antipsychotics are frequently taken in conjunction with other drugs and at greater than recommended doses. Although the specific pathophysiology remains undetermined at this time, it has been suggested that the most likely mechanism of death in an overdose of olanzapine involves cardiac toxicity at the cellular membrane level.
Sudden death is more common in patients with psychiatric problems, particularly those receiving antipsychotic drugs. An analysis of 85 fatal intoxications found that pimozide and olanzapine were less likely to be associated with death in overdose than prothipendyl and chlorprothixene, 45 which is surprising given pimozide's known cardiotoxicity. Similarly, diabetes mellitus and obesity both additional risk factors for cardiovascular disease are more prevalent in patients with schizophrenia, and an increased risk of these disorders has been reported in patients taking olanzapine.
In summary, although olanzapine has been associated with toxicity in certain overdose situations, evidence of any direct relation remains limited. The adverse consequences of overdose are compounded in psychiatric populations because of frequent, yet often undiagnosed or untreated physical illnesses, complex polypharmacy with high doses of psychotropic drugs and delayed or absent interventions. Infrequent, serious adverse effects can occur, and early signal detection and effective notification processes are crucial when they do occur.
It is recommended that similar toxicology data reviews be conducted for commonly prescribed psychotropic drugs. None declared for Dr. Pierre Chue, 3rd Floor, St. National Center for Biotechnology Information , U. Journal List J Psychiatry Neurosci v. Pierre Chue and Peter Singer. This article has been cited by other articles in PMC.Organophosphate Poisoning