≪ View Page

Differences

This shows you the differences between two versions of the page.

Link to this comparison view

Both sides previous revisionPrevious revision
Next revision		Previous revision
wikitox:benzodiazepines [2025/02/18 17:28] – kharriswikitox:benzodiazepines [2025/02/24 21:39] (current) – kharris
Line 3: Line 3:
 ===== Overview ===== ===== Overview =====
  
-Isoniazid is used to treat mycobacterial infections, including Mycobacterium tuberculosis. Due to its specific and therefore limited use, overdose is uncommon.+Benzodiazepines are widely used drugs for their sedative, anxiolytic and anticonvulsant effects. They have high risk of abuse and dependence.
  
-The hallmarks of toxicity are seizures, coma and metabolic acidosis. Pyridoxine, given in a dose proportional to the ingested dose of isoniazid, is used as an antidote.+Many benzodiazepine drugs are available including alprazolam, bromazepam, clobazam, clonazepam, diazepam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam and temazepam. 
 + 
 +Newer illicit designer benzodiazepines are frequently used recreationally. They are commonly sold as ‘Xanax’ (a brand name for alprazolam) but usually contain agents such as etizolam, clonazolam, or flubromazolam. 
 + 
 +Overdose causes sedation, but except for alprazolam, which has higher potency, or when taken in combination with other sedatives, rarely leads to coma. Supportive care in normally or that is required until symptoms resolve. 
 + 
 +The z-drugs, zolpidem and zopiclone, have similar effects to benzodiazepines in overdose and can be managed similarly.
  
 ===== Mechanism of Toxic Effects ===== ===== Mechanism of Toxic Effects =====
  
-The toxicity of isoniazid results from functional pyridoxine toxicity. This occurs through two mechanisms 1) Isoniazid metabolites inhibiting the action of pyridoxine phosphokinase, which converts pyridoxine to its active form and 2) Isoniazid directly combining with pyridoxal phosphate, forming inactive hydrazone.+Benzodiazepines bind to the benzodiazepine receptor, which modifies the gamma amino benzoic acid (GABA) chloride channel complex. Benzodiazepines enhance the effects of the inhibitory neurotransmitter GABA, thus central nervous system depression occurs. Benzodiazepines also cause muscle relaxation and are anticonvulsant. 
 + 
 +Zolpidem is a potent agonist at GABAA receptors but only those containing the alpha1 subunit (corresponding to the benzodiazepine (BZ)1. 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.
  
-Functional pyridoxine deficiency leads to deficiency of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), resulting in seizures.+Zopiclone is a potent agonist at binding sites that belong to the GABAA receptor-benzodiazepine receptor-chloride ion channel complex, but which are not the benzodiazepine specific sites.
  
-Isoniazid also acts as a weak monoamine oxidase inhibitor (MAOi) and has potential to cause serotonin toxicity (if taken with another serotonergic agent) and tyramine reactions.+Zolpidem and zopiclone cause sedation but have little muscle relaxant or anticonvulsant properties.
  
 ===== Risk Assessment ===== ===== Risk Assessment =====
  
-Severe toxicity has been reported with ingestion of greater than 20mg/kg and are common with ingestions over 6g.+Predicting the clinical effect from the ingested dose of these agents can be difficult due to significant variations in a patient’s tolerance. Patients naïve to these drugs may get significant sedation with only a few tablets, whereas those who are tolerant may get minimal symptoms from much larger ingestions. 
 + 
 +Increased effects should be expected with alprazolam, which has increased potency compared to other agents in this class and when there is co-ingestion with other sedative agents. The elderly and very young are also at increased risk.
  
 ===== Kinetics in Overdose ===== ===== Kinetics in Overdose =====
Line 23: Line 33:
 ==== Absorption ==== ==== Absorption ====
  
-Isoniazid is well absorbed with a high bioavailability (90%). In therapeutic use, peak plasma concentrations occur at 1-2 hours post ingestion.+All benzodiazepines are lipid soluble drugs that are absorbed fairly rapidly. The rate of absorption is an important variable in determining the clinical effects with more rapid rises in serum concentrations leading to greater depth of sedation. The extent of absorption of these drugs is high.
  
 ==== Distribution ==== ==== Distribution ====
  
-Isoniazid has good tissue penetration with a volume of distribution of 0.7-0.8L/kg. Protein binding is low.+All are highly protein bound and have volumes of distributions of about 1 L/kg. They distribute well into the central nervous system.
  
 ==== Metabolism-Elimination ==== ==== Metabolism-Elimination ====
  
-Metabolism is primarily hepatic, predominantly by cytochrome CYP2E1. The rate of metabolism varies depending on if the patient is a slow (common in those of Asian and Scandinavian descent) or fast acetylator (common in those of African and Caucasian descent).+All benzodiazepines are hepatically metabolised with renal clearance accounting for less than 5%. The half-life of these drugs varies widely and many have active metabolites.
  
-Elimination if primarily via the kidneys. The elimination half life ranges from 1-4 hours but can be prolonged in slow acetylators.+Despite this variation those with a shorter half-life (e.g. temazepam) and those with a longer half-life (e.g. diazepam, clonazepam) have very similar spectrums of clinical toxicity. This results from development of tolerance. It is actually the development of tolerance to the benzodiazepines (during the period of high levels following overdose) that determines the recovery of consciousness rather than the clearance of the drug.
  
 ---- ----
Line 39: Line 49:
 ===== Clinical Effects ===== ===== Clinical Effects =====
  
-Acute toxicity results in seizures, coma and metabolic acidosis, generally occurring within 2 hours of ingestion.+The clinical effects of benzodiazepine poisoning are due entirely to central nervous system depression.
  
-In patients presenting with seizures, coma or unexplained metabolic acidosis, who have a history of tuberculosis (or have contact with those with tuberculosis) isoniazid toxicity should be considered.+Severe poisonings may develop hypothermia, bradycardia, and hypotension; however, this is unusual. Respiratory depression and depression of consciousness may lead to aspiration pneumonia. Deep coma is unusual. Most patients are stuporous or still responsive to painful stimuli unless they have co-ingested other sedating drugs.
  
 ---- ----
Line 47: Line 57:
 ===== Investigations ===== ===== Investigations =====
  
-• Bloods gas analysis – looking for metabolic acidosis\\ +There are no specific investigations for those with benzodiazepine toxicity, and those with mild toxicity may not require any investigations. 
-• Serum creatine kinase – likely to be elevated in the setting of seizures\\ + 
-• Renal and liver panels+In those with more significant toxicity it may be useful to check blood glucose, renal function and electrolytes and an ECG.
  
 ---- ----
Line 57: Line 67:
 ==== Supportive ==== ==== Supportive ====
  
-Patients who have compromise of airway or breathing, secondary to coma on refractory seizures, should be intubated and ventilated.+Supportive care is the mainstay of management. Patients with more severe toxicity leading to compromised airway or breathing, should be intubated and ventilated.
  
-Ensure adequate intravenous hydration to patients with seizures especially if they have evidence of rhabdomyolysis. +Sedated patients should have intravenous fluids to maintain hydration and consideration of thromboprophylaxis and pressure cares.
- +
-First line management of seizures is with pyridoxine (see below), if this is unavailable, or if seizures are refractory, then treat with an intravenous benzodiazepine, and rapidly escalate to a barbiturate if unresponsive to benzodiazepines.+
  
 ==== Decontamination ==== ==== Decontamination ====
  
-Offer activated charcoal to all patient presenting within 2 hours of an intentional overdose of isoniazid. If the patient is intubated this can be given by nasogastric or orogastric tube.+Given the rapid onset of effects and expected positive outcome with supportive care, gastrointestinal decontamination is not suggested.
  
 ==== Enhanced Elimination ==== ==== Enhanced Elimination ====
  
-Isoniazid is dialysable, but its use as a treatment should be considered second line, after antidotal treatment with pyridoxine. +There is no role for enhanced elimination
- +
-Consider haemodialysis if:\\ +
-• Seizures or metabolic acidosis are refractory to pyridoxine\\ +
-• Seizures or metabolic acidosis with inadequate supplies of pyridoxine+
  
 ==== Antidotes ==== ==== Antidotes ====
  
-Intravenous pyridoxine (vitamin B6) is indicated for isoniazid toxicity complicated by seizures or metabolic acidosis. Give:+Flumazenil is a benzodiazepine antagonist, that also reverses the effects of the z-drugs. Whilst it can be used both therapeutically and diagnostically, its use is generally discouraged, especially in those regularly using benzodiazepines.
  
-**In those ingesting 5g or less of isoniazid:\\ +In patients with benzodiazepine dependence, it can lead to withdrawal including seizures. It has also been shown to prevent the in-dose tolerance that is responsible for patients waking post overdose, and therefore can potentially prolong toxicity.
-Pyridoxine in a gram for gram dose with the ingested dose of isoniazid (i.e. if 3g of isoniazid has been ingested, give 3g intravenous Pyridoxine). **+
  
-**In those ingesting >5g or with an unknown dose:\\ +Use of flumazenil should only be considered in the following circumstances (assuming the patient does not have benzodiazepine dependence):
-Pyridoxine 5g.**+
  
-Infuse the required dose at a rate of 500mg/minute. If seizures stop during infusion, give the remainder of the infusion over 4hr. Dose can be repeated at 30 minutes if seizures or metabolic acidosis do not resolve.+  * To avoid intubation in the very old or young children 
 +  * Reversal of procedural sedation 
 +  * Where there is compromised airway or ventilation and intubation is not available
  
-Intravenous pyridoxine is not always readily available (or an adequate dose may not be available). In this situation an oral dose of pyridoxine equivalent to the ingested dose of isoniazid can be given, noting that if activated charcoal has been given the bioavailability of this will be reduced.+**Use: \\ Flumazenil 0.1 – 0.2 mg intravenously (Child: 5mcg/kg max 0.2mg). Repeat every minute until desired effect. Max dose 2mg**
  
-Pyridoxine is cleared by dialysis, so the dose will have to be adjusted in patients who are being dialysed – discuss with a clinical toxicologist.+The half-life of flumazenil (45-60min) is shorter than many benzodiazepines so re-sedation may occur. If this is the case then re-bolus the patient as per the dosing above and start an infusion at 2/3 the bolus dose needed per hour, titrate to effect (if increasing the rate, first bolus until desired clinic effect achieved and add the required bolus dose to the ongoing hourly rate).
  
 ---- ----
Line 95: Line 99:
 ===== Observation and Disposition ===== ===== Observation and Disposition =====
  
-Observe asymptomatic patients following acute isoniazid overdose for 12 hours post ingestion. +Asymptomatic patients should be observed for at least 4 hours post ingestion for the onset of toxicity.
- +
-Patients who develop severe isoniazid toxicity (seizures, coma, metabolic acidosis) require management in an intensive care unit.+
  
-Given the risk of tyramine reactions, at discharge, patients should be advised to follow a tyramine-free diet for 3 days.+If flumazenil is given, then patients need observation for at least for hours post the last dose to ensure that re-sedation does not occur.
  
 ---- ----
Line 105: Line 107:
 ===== Further Reading ===== ===== Further Reading =====
  
-  - Bateman DN, Page CB. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. Br J Clin Pharmacol 2016;81(3):437–45. {{:wikitox:brit_j_clinical_pharma_-_2015_-_bateman_-_antidotes_to_coumarins_isoniazid_methotrexate_and_thyroxine_toxins_that_work.pdf|PDF}} +  - Buckley NA, Dawson AH, Whyte IM, O’Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ 1995;310(6974):219–21. {{:wikitox:relative_toxicity_of_benzodiaz.pdf|PDF}} 
-  - Dilrukshi M, Ratnayake CAP, Gnanathasan CA. Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report. BMC Res Notes 2017;10(1):370. {{:wikitox:oralpyridoxinecansubstituteforiv.pdf|PDF}} +  - Isbister GK, O’Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004;58(1):88–95. {{:wikitox:alprazolam_is_relatively_more_toxic_than_other_benzodiazepines_in_overdose.pdf|PDF}} 
-  - Morrow LE, Wear RE, Schuller D, Malesker M. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy 2006;26(10):1529–32. {{:wikitox:pharmacotherapy_-_2012_-_morrow_-_acute_isoniazid_toxicity_and_the_need_for_adequate_pyridoxine_supplies.pdf|PDF}} +  - Moosmann B, King LA, Auwarter V. Designer benzodiazepines: A new challenge. World Psychiatry 2015;14(2):248. {{:wikitox:designerbenzodiazepines.pdf|PDF}} 
-  - Mowry JB, Shepherd G, Hoffman RS, Lavergne V, Gosselin S, Nolin TD, et al. Extracorporeal treatments for isoniazid poisoning: Systematic review and recommendations from the EXTRIP workgroup. Pharmacotherapy 2021;41(5):463-78. [[https://www.extrip-workgroup.org/_files/ugd/4654ea_8119b35b017d499c857acba44af1af18.pdf|EXTRIP]] +  - Penninga EI, Graudal N, Ladekarl MB, Jurgens G. Adverse events associated with flumazenil treatment for the management of suspected benzodiazepine intoxication–a systematic review with meta-analyses of randomised trials. Basic Clin Pharmacol Toxicol 2016;118(1):37–44. {{:wikitox:adverse_events_associated_with_flumazenil_treatment_for_the_management_of.pdf|PDF}} 
-  - Skinner K, Saiao A, Mostafa A, Soderstrom J, Medley G, Roberts MS, et al. Isoniazid poisoning: Pharmacokinetics and effect of hemodialysis in a massive ingestion. Hemodial Int 2015;19(4):E37–40. {{:wikitox:hemodialysis_international_-_2015_-_skinner_-_isoniazid_poisoning_pharmacokinetics_and_effect_of_hemodialysis_in_a_massive.pdf|PDF}} +  - Ingum J, Bjorklund R, Volden R, Morland J. Development of acute tolerance after oral doses of diazepam and flunitrazepam. Psychopharmacol 1994; 113(3–4): 304–10. {{:wikitox:acutetolerancebenzodiazepines.pdf|PDF}}
-  - Wason S, Lacouture PG, Lovejoy FH Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246(10):1102–4. {{:wikitox:singlehighdosepyridoxine.pdf|PDF}}+