BENZODIAZEPINES

1. Sedative-hypnotic

1. Binds to the benzodiazepine site of the GABA-A receptor.
   • Main function is to increase the efficiency of GABAergic synaptic inhibition.
   • Facilitates increased frequency (c.f. barbiturates, that increase duration) of the opening of chloride channel.
   • Benzodiazepines are unable to open the channel itself. (c.f. barbiturates, which can open the channels themselves at higher doses)

1. PO, IV, IM, PR

1. Lipid soluble drug
2. Very strongly bound to plasma proteins.

1. Refer to the diagram above for benzodiazepine metabolism. The asterisks indicate active metabolites. Note that diazepam is metabolized to desmethymdiazepam, which is active.
2. Lorazepam has no active metabolite.
3. Note that hepatic metabolism accounts for clearance of all benzodiazepines.
   • Most BZDs will undergo phase I reaction, catalyzed by CYP450 systems. The metabolites are then conjugated to form glucuronides and excreted.
   • However, many phase I metabolites are pharmacologically active, e.g. desmethyldiazepam. This means that the T ½ of diazepam is 40 hours.
   • Triazolam is metabolized to its α-hydroxy metabolites that do have activity, but they are rapidly conjugated.
   • Note that the metabolism of diazepam, midazolam and alprazolam may be induced/inhibited by other drugs.
4. In patients who are elderly and have severe disease, these drugs may have longer elimination half-lives.

In summary, BZDs undergo phase I and phase II reactions in the liver and are excreted by the kidneys. Liver disease affects T ½ but renal disease does not.

1. Renal

1. Can be used in ED to treat status epilepticus
2. Procedural sedation
3. Aids induction prior to intubation
4. Alcohol withdrawal (Delirium tremens)
5. Other – muscle relaxation, sedative hypnotic in agitated patient, post intubation sedation.

1. Elderly and those with pre-existing hepatic disease.

1. Inhibitors of CYP 450 (e.g. amiodarone, cimetidine and antibiotics) may increase duration.
2. Inducers will reduce duration of action.
3. Additive toxicity (CVS and respiratory depression) with opioids.
4. Also additive toxicity with alcohol and other typical anti-psychotics (Esp. the phenothiazines)
5. It is antagonized by flumazenil

1. Extension of its pharmacologic properties
   • Oversedation, leading to respiratory depression (especially in patients with pre-existing pulmonary disease). It is a dose related inhibition of the respiratory centre.
   • CVS Depression (especially in patients who are hypovolemic/CCF/pre-existing CVS disease) due to inhibition of vasomotor centers.
   • CVS collapse is possible.
   • Effects more marked with IV use.
2. Tolerance (more drug needed to produce same effect)
   • Cross tolerance occurs with EtoH
   • May be due to down-regulation of BZD receptor
3. Dependence, both physiological and psychological
   • Characterized by anxiety, insomnia, CNS excitability and seizures in severe cases.
   • Higher dose/drugs with short T ½ and abrupt cessation leads to withdrawal symptoms.

1. For status: 0.15mg/kg IV; or 10mg PR and repeat in 10 minutes.

1. Flumazenil is the direct antidote
   • It is a competitive antagonist of benzodiazepines at the BZD receptor. It also reduces GABA binding. This leads to reduced chloride entry into the cell, and therefore reduced hyperpolarization and increased excitability.
   • Indications for flumazenil: a) avoid intubation after BZD overdose; b) reversal of BZD after procedural sedation; and c) diagnostic tool.
   • Adverse effects as follows:
     • Very short T ½ (duration of action is 1-3 hours) and therefore may need repeated dosing.
     • Unpredictable effect on antagonism of respiratory depression (that is, giving flumazenil may not reverse respiratory effects of BZDs)
     • Risk of precipitating seizures in mixed OD
     • Risk of precipitating withdrawal symptoms
     • Risk of precipitating seizures in a patient taking BZDs for epilepsy.
   • Due to unpredictable effect on antagonism, ongoing CVS/respiratory monitoring is required when used.