Benzodiazepines (BZ) PDF

Sedative Hypnotics Benzodiazepines (BZ) Dr. Isam Elhassan Specialist of Forensic Medicine & Clinical Toxicology Benzodiazepines (BZ) Benzodiazepines are the most commonly prescribed psychotropic drug. They are generally felt to have high therapeutic indices, which a...

Sedative Hypnotics Benzodiazepines (BZ) Dr. Isam Elhassan Specialist of Forensic Medicine & Clinical Toxicology Benzodiazepines (BZ) Benzodiazepines are the most commonly prescribed psychotropic drug. They are generally felt to have high therapeutic indices, which allowed them to replace barbiturates and other more toxic agents as first-line anxiolytics and hypnotics. Chronic use of BZ may lead to tolerance and dependence. Benzodiazepines (BZ) Common benzodiazepines Diazepam [valium] Lorazepam [ativan] Flunitrazepam [Rohipnol] Bromazepam [Calmipam] Clonazepam [Rivotrill] Midazolam [Dormicum]  Benzodiazepines (BZ) Classification according to duration of action Ultrashort (< 6h) Short (12 – 18h) Medium (24h) Long (24 – 48h) Triazolam Lorazepam Alprazolam Diazepam Midazolam Oxazepam Nitrazepam Clonazepam Temazepam Chlorzepate Chlordiazepoxide flurazepam  Benzodiazepines (BZ) pharmacokinetics Absorption  Oral: - well absorbed - chlorazepate (prodrug) gastric Nordazepam HCL (active & rapidly absorbed)  IV: - Midazolam as IV anathesia - Diazepam as IV anasthesia & anticonvulsant  IM: - Slow absorption - lorazepam may be used in status epilepticus when IV is difficult Benzodiazepines (BZ) pharmacokinetics Distribution All over the body – passes BBB & placental barrier Redistributed & gradually accumulate in body fat Highly bound to plasma protein Benzodiazepines (BZ) pharmacokinetics Metabolism most of them – oxidation producing active metabolites followed by conjugation with glucuronic acid Some of them – conjugate directly with glucuronic acid producing inactive metabolites (as Nitrazepam/Clonazepam) Benzodiazepines (BZ) pharmacokinetics excretion In urine after conjugation with glucuronic acid Benzodiazepines (BZ) Mechanism of action BZ exert their effects through high affinity binding to BZ receptors that located at the alpha subunit of the GABAA receptors. The net effect of BZ on GABAA receptors is to increase the frequency of opening at the GABAA chloride channel  Benzodiazepines (BZ) toxicity C.P: CNS depression is the main presentation of BZ overdose ( less than Barbiturate) Drowsiness, stupor, ataxia and low grade coma Profound coma significant hypotension, respiratory depression or hypothermia is extremely uncommon in isolated BZ overdoses Death from isolated BZ overdose is rare NB: BZ overdose is generally safer than Barbiturate Benzodiazepines (BZ) toxicity Investigations  Routine investigations:  CBC  Electrolytes  ABG  RFT  Specific investigation:  Serum BZ concentrations using GCMS or immunoassays. Benzodiazepines (BZ) toxicity Treatment I. Supportive [ABCs] see general toxicology II. GIT Decontamination III. Elimination of the poison from blood Benzodiazepines (BZ) toxicity Treatment I. Supportive [ABCs] Care of coma and vital functions Endotracheal intubations, airway and assisted ventilation if necessary Shock control (IV fluids and dobutamine) Warming with blanket. Coma cocktail (naloxone, thiamine and glucose) ? Antibiotics for pneumonias Benzodiazepines (BZ) toxicity Treatment II. GIT Decontamination a. Emesis : if the patient is alert and gag reflex is present b. Gastric Lavage with cuffed endotracheal tube [up to 12 hrs post ingestion due to decreased GIT motility] c. Activated charcoal. d. Multiple — dose activated charcoal [MDAC]: in (long — acting). e. Cathartics (e.g. sorbitol)  Benzodiazepines (BZ) toxicity Treatment III. Elimination of the poison from blood Forced alkaline diuersis: [see general toxicology] for long acting barbiturates [excreted by kidneys] N.B other barbiturates have limited renal excretion [metabolized mainly by liver]. Hemodialysis and hemoperfusion: Have been successfully utilized in barbiturate overdoses with refractory hypotension and dense coma. Hemodialysis and hemoperfusion should be reserved for extreme cases where prolonged coma is anticipated.  Benzodiazepines (BZ) toxicity Treatment IV- Antidotes Specific antidote: * Flumazenil [Anexatel] Action : Flumazentil is a competitive BZ receptor antagonist , thus antagonizes the action of benzodiazepines advantage: Effective within minutes in treating isolated BZ overdose. d- Disadvantage: - Not used in combined toxicity [BZ+ drugs causing seizures] Thank you