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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Inebriants

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Benzodiazepines - Inebriant Neurotoxic Poisons

Examples: Alprazolam, brotizolam, chlordiazepoxide, chlorazepate, clobazam, clonazepam, diazepam, estazolam, flunitrazepam, flurazepam, halazepam, lorazepam, lormetazepam, medaz-epam, midazolam, nitrazepam, oxazepam, pinazepam, praz-epam, quazepam, temazepam, triazolam and zolazepam.

Benzodiazepines

Examples

Alprazolam, brotizolam, chlordiazepoxide, chlorazepate, clobazam, clonazepam, diazepam, estazolam, flunitrazepam, flurazepam, halazepam, lorazepam, lormetazepam, medaz-epam, midazolam, nitrazepam, oxazepam, pinazepam, praz-epam, quazepam, temazepam, triazolam and zolazepam.

Uses

·      Anxiety disorders

·      Seizure disorders

·      Insomnia

·      Movement disorders (adjunctive therapy)

·      Mania (adjunctive therapy)

·      Some of these drugs are also used for inducing skeletal muscle relaxation, as pre-anaesthetic medication, and for the treatment of alcohol withdrawal.

Usual Fatal Dose

Uncertain for most benzodiazepines. Even ingestion of up to 2000 mg diazepam has not resulted in death, or for that matter, even serious morbidity. However, several cases of fatality due to triazolam and flunitrazepam overdose have been described.

In general, benzodiazepine metabolism appears to be inhibited by ethanol when given concurrently. Clinically, concomitant administration of high doses of ethanol and benzo-diazepines act to synergistically depress respiration.

Mode of Action

·              Benzodiazepines act by stimulating the GABAb (gamma aminobutyric acid b) receptors, thereby opening up the chloride ion channel in the receptor complex, resulting in the increased conductance of chloride ion across the nerve cell membrane. This lowers the potential difference between the interior and exterior of the cell, blocking the ability of the cell to conduct nerve impulses.

Toxicokinetics

Most benzodiazepines are administered orally or by IV injec-tion. Intramuscular injection may lead to erratic absorption.1 However, lorazepam and midazolam are exceptions to this and can be given IM. Following absorption, all benzodiazepines are bound to plasma proteins to the extent of 70 to 99%, and are metabolised extensively by different microsomal enzyme systems in the liver. Metabolites are invariably as active as the parent compound.

Adverse Effects

·     Weakness, headache, amnesia, vertigo, diplopia, nausea, diarrhoea, and rarely chest pain.

·     Paradoxical effects (disinhibition or dyscontrol reaction) may sometimes occur characterised by restlessness, agita-tion, and hallucinations.

·              Flurazepam has been associated with nightmares and hallucinations.

·     Allergic, hepatotoxic, and haematological reactions are rare. 

Drug Interactions

·              Ethanol has a synergistic effect with benzodiazepines and increases both the rate of absorption as well as associated CNS depression. Similar effect is also seen with concomi- tant administration of phenothiazines and barbiturates.

·              Sodium valproate may cause psychotic reactions when given along with benzodiazepines.

Clinical (Toxic) Features

Benzodiazepines are remarkably safe drugs and rarely produce serious toxic effects even with substantial ingestion. Death is uncommon unless other synergistic drugs have also been ingested. However, newer benzodiazepines such as alprazolam, triazolam, and temazepam are associated with fatalities.

1. Acute Poisoning:

a. Mild—Drowsiness, ataxia, weakness.

b. Moderate to Severe—

–– Vertigo, slurred speech, nystagmus, partial ptosis, lethargy, coma.

––  Hypotension and respiratory depression supervene in potentially lethal ingestions: Respiratory depres-sion is the primary clinical concern in benzodiaz-epine overdose. Overdose may depress respiratory rate and tidal volume and airway protective reflexes.

–– Both miosis and mydriasis have been reported. Nystagmus may also occur.

–– Analysis of acute benzodiazepine overdoses in relation to the incidence of coma indicate that short acting benzodiazepines (midazolam and triazolam) and intermediate acting (flunitrazepam) have a higher acute toxicity, as compared to diazepam, lorazepam and nitrazepam. Flurazepam and temaz-epam may also have greater toxicity.

–– Triazolam, as well as other benzodiazepines, have been implicated in next-day memory impairment/ amnesia in a significant number of patients.

–– Administration of benzodiazepines to a pregnant woman prior to delivery may produce signs of poisoning in the neonate. A condition called “floppy infant syndrome”, characterised by hypotonia that may last several days, may occur following maternal diazepam use.

2. Chronic Poisoning:

Long-term use of benzodiazepines is associated with the development of tolerance. Abrupt cessation provokes a mild withdrawal reaction characterised by anxiety, insomnia, head-ache, tremor, and paraesthesia. Restlessness, encephalopathy, and hallucinations may occur after abrupt withdrawal from high daily doses. Convulsions may occur after a lapse of 3 to 10 days.

Diagnosis

Estimation of plasma levels of benzodiazepines is usually not necessary. Qualitative testing for presence of benzodiazepine is helpful to confirm presence, especially when overdose history is sketchy. Quantitative levels are not usually clinically useful. Blisters of skin (bullae) can occur following overdose with nitrazepam, oxazepam, and temazepam.

Treatment

Acute Poisoning:

·              Decontamination—Ipecac-induced emesis is not recom- mended because of the potential for CNS depression. Stomach wash may be helpful if the patient is seen within 6 to 12 hours after the ingestion. Cuffed endotra- cheal intubation is a prerequisite in comatose patients. Activated charcoal adsorbs benzodiazepines and can be administered in the usual manner.

·              Establish clear airway. Oxygen and assisted ventilation are often necessary.

·              IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults).

·              Correction of hypotension: Begin by infusing 10 to 20 ml/kg of isotonic fluid, and place patient in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central therapy.

·              Forced diuresis and haemodialysis are ineffective.

Antidote—

––Flumazenil is effective in reversing the coma induced by benzodiazepines as well as zolpidem. The effect is however usually short-lived, and flumazenil also has the tendency to induce a withdrawal reaction in benzodiazepine-dependant patients. The mode of action is competitive antago-nism.

––In practice, most patients achieve complete reversal of benzodiazepine effect with a total slow IV dose of just 1 mg. Some investigators suggest that flumazenil is better administered in a series of smaller doses in an incremental manner beginning with 0.2 mg and progressively increasing by 0.1 to 0.2 mg every minute until a cumulative total dose of 3.5 mg is reached. However, resedation occurs within ½ hour to 2 hours (depending on the nature and dose of benzodiazepine ingested), and therefore patients must be carefully monitored and subsequent doses of flumazenil should be adminis-tered as needed. The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of therapeutic value in the event of resedation after initial response.

––Flumazenil has also been reported to reverse cardio-vascular depression secondary to benzodiazepine use.

––Flumazenil does not reverse respiratory depression very well and hence fundamental procedures such as supplemental oxygen, endotracheal intubation, and ventilation must not be neglected.

––Flumazenil is contraindicated in mixed ingestions involving tricyclic antidepressants and drugs which induce seizures, e.g. theophylline, carbamazepine, chloroquine, etc. But there are indications that it may be beneficial in hepatic encephalopathy and ethanol overdose.

–– Flumazenil may cause the following adverse effects: fatigue, nausea, vomiting, hypertension, tachycardia, anxiety, confusion, restlessness, aggression, and rarely convulsions and cardiac arrhythmias.

Chronic Poisoning:

Phenobarbitone-substitution technique is recommended for benzodiazepine withdrawal which employs propran-olol for acute somatic symptoms, while phenobarbitone is used for detoxification.

However the most frequently used method among clinicians is the replacement of a short half-life benzo-diazepine (such as alprazolam) with a long half-life benzodiazepine (such as clonazepam), before initiating a taper and final discontinuation.

Forensic Issues

Ever since the introduction of benzodiazepines in the 1960s, they have become progressively more popular as anxiolytic agents and sedatives, displacing the barbiturates from their previously held top spot. In spite of extensive use worldwide, there have been only a few cases reported involving fatalities, demonstrating the wide margin of safety of benzodiazepines. But complacency must be avoided and the safety profile of these drugs should not be taken for granted, as deaths have been reported in some recent cases even from unexpectedly low doses of certain benzodiazepines. There are also indications that some of the newer benzodiazepines have a slightly smaller margin of safety. This is particularly true with reference to paedi-atric and geriatric patients who are more susceptible to the toxicity of these drugs.

■■  An area of concern with long-term benzodiazepine use is the possibility of behavioural disinhibition which may induce a person to hostile acts, aggressive behaviour, and verbal indecency.

■■  Yet another important issue is with reference to the use of benzodiazepines to deliberately induce amnesia in certain individuals in order to accomplish an immoral act (e.g. date rape). Many of these drugs, particularly flunitrazepam, are capable of causing retrograde amnesia. Flunitrazepam (Rohypnol®; “Roofies”) has become popular as a drug of abuse, often combined with alcohol, marijuana, or cocaine to produce an intense “high”. It has been used as a “date rape” drug, both for its properties of lowering inhibitions and because it can cause retrograde amnesia.

■■While addiction to benzodiazepines is an undeniable possibility among patients on long-term therapy, the abuse potential is much less when compared to most other sedative- hypnotics such as the barbiturates. Withdrawal reactions are also generally less severe and more easily managed. However, abrupt cessation after prolonged use may precipitate tachycardia, hypertension, agitation, hallu-cinations, delirium, and convulsions. Withdrawal syndrome is more likely if the drug has been taken at therapeutic dose for more than four months, higher dosage has been used, the drug is stopped suddenly, or a short acting benzodiazepine has been taken.

■■  Severe dysmorphism, malformations, intrauterine and extrauterine growth retardation, and central nervous system dysfunction have been described in infants born of mothers who used benzodiazepines during pregnancy.

 

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