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Benzodiazepines

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Types

  • 1:4 benzodiazepines eg chlordiazepoxide, midazolam
  • 1:5 eg clobazam

Pharmacology

  • benzodiazepine receptors associated with GABA chloride channel complex (GABAA receptor). GABA agonists cause opening of the Cl channel.
  • benzodiazepine receptor is a modulating unit, modifying the response to GABA. BZ agonists enhance submaximal responses to GABA (cannot enhance maximal responses). Has no direct action on the Cl channel.
  • GABA increases BZ binding
  • 2 types of receptor: Stimulation of BZ1 receptor results in hypnotic effects while BZ2 receptors mediate anticonvulsant effects
  • probably also a peripheral BZ receptor
  • BZ receptors found in cerebral cortex, limbic system, cerebellar cortex and spinal cord
  • increasing doses of benzodiazepines increase receptor occupancy, producing a progressive spectrum of effect from anxiolysis and anticonvulsant effects to amnesia, sedation and eventually hypnosis and anaesthesia.
  • flumazenil when given in increasing doses progressively reverses these effects without any change in the pharmacokinetics of the agonist drug.
  • thiopentone and neurosteroids also act on GABA-Cl channel complex
  • anxiolytic effect probably mediated by 5-HT receptors in limbic system
  • an endogenous ligand probably exists but has yet to be identified (some patients in hepatic coma can be wakened by flumazenil)

Pharmacokinetics

Diazepam

Administration

  • PO/IV/IM
    • more reliably absorbed following oral than IM admin: may be due to precipitation in the muscle
    • IM injection of diazemuls very painful
    • peak plasma levels 1 hr after oral admin
    • in social concentrations (10%) alcohol slows absorption. High concentrations (50%) increase uptake
    • oral abs of all orally administered benzodiazepines increased by concurrent metoclopramide; speeds gastric transit; and decreased by factors that decrease gastric emptying eg presence of food, aluminium antacids, opioids. Increase in gastric pH (eg following administration of H2 blockers) decreases ionization and therefore speeds absorption but overall aluminium antacids decrease rather than increase speed of absorption.

Protein binding

  • high (95%)
  • response to all benzodiazepines enhanced in hypoalbuminaemic patients. Thought that this may be related to plasma binding

Distribution and elimination

  • all benzodiazepines: 2 compartment model with usual initial distribution phase to vessel-rich tissues with subsequent re-distribution to muscle and fat
  • elimination phase dependent on hepatic metabolism
  • diazepam appears to undergo enterohepatic recirculation with second plasma peak occurring 4-6 hrs after initial administration. This may be associated with re-sedation. Not uncommon for there also to be an additional peak at 10-12 hrs, although this only seen when very large doses are given (eg 1 mg/kg)
  • oxidized in liver to active metabolites including desmethyldiazepam which has a half-life of over 100 hrs
  • hepatic extraction ratio is low
  • benzodiazepine oxidation appears to be a "susceptible pathway" and may be impaired in patients with liver disease and in some elderly patients
  • inhibited by hepatic enzyme inhibitors (eg cimetidine, isoniazid and certain oestrogens contained in oral contraceptives)

Placental transfer

  • being very lipophilic all benzodiazepines cross placental barrier rapidly
  • diazepam levels are higher in infants than in mothers following single dose and levels fall more slowly in neonate

Midazolam

Administration

  • only available in injectable form.

Protein binding

  • high.

Distribution and elimination

  • shorter duration of action than diazepam because of rapid re-distribution
  • hydroxylated by hepatic microsomal enzymes and then conjugated with glucuronic acid before renal excretion; high extraction ratio and therefore metabolism is dependent on liver blood flow as well as the factors affecting diazepam metabolism
  • elimination half-life may be increased unpredictably in the critically ill, particularly septic patients with impaired hepatic blood flow
  • hydroxymidazolam is active metabolite but has a similar or shorter elimination t1/2 than parent drug
  • imidazole ring opens up - changes from water to lipid soluble at pH > 4
  • metabolism inhibited by inhibitors of cytochrome P450 system (eg propofol, diltiazem, erythromycin)

Placental transfer

  • probably slower than diazepam

Lorazepam

Administration

  • PO - less rapidly absorbed with peak plasma levels after up to 2 hrs
  • IM- absorption from IM injection site similar to that following oral admin
  • IV
    • Diluted in propylene glycol
      • may be unstable in solution
      • can precipitate in IV catheters and tubing, necessitating dedicated infusion line
      • toxicity may be occur with large doses or prolonged infusions
        • acute renal failure
        • lactic acidosis
        • hyperosmolar state

Protein binding

  • high

Distribution and elimination

  • less  lipid soluble than diazepam and therefore has slower onset of action
  • hepatic conjugation
    • this metabolic pathway is more resistant to the effects of cirrhosis and hepatic failure. As a result lorazepam may be preferable to diazepam or midazolam if a benzodiazepine has to be used in a patient with liver failure
  • no active metabolites

Placental transfer

  • less marked than with diazepam

Pharmacodynamics

CNS

  • dose related depression
  • large IV doses can be used to induce anaesthesia but may take 2-5 mins and wide inter-individual variation in response
  • amnesia: has not been reported with oral medication with the exception of lorazepam. With diazepam there is a brief but intense period of amnesia after IV injection which has largely passed by 20-30 min.
  • all possess anti-convulsant action. Lorazepam may be more effective than the combination of diazepam and phenytoin in the treatment of status epilepticus
  • anti-hallucinatory effects
  • hypnotic
  • no analgesic activity
  • sexual hallucinations

CVS

  • even in large IV doses tend not to depress CVS and any depressant effect far smaller than that associated with other induction agents. Lorazepam causes less hypotension than midazolam
  • fall in SVR
  • when used for cardioversion associated with fewer VEs than barbiturates. Combined with minimal CVS depression makes them drugs of choice for this procedure
  • tachycardia probably a response to vasodilatation
  • minimal changes in coronary and cerebral blood flow. Slight decrease in cerebral perfusion pressure due to slight fall in aortic pressure. Like other anaesthetics decrease renal blood flow and function. Lowers liver blood flow in parallel with small decreases in cardiac output

RS

  • in normal oral doses given for hypnotic or anxiolytic effect no evidence of respiratory depression
  • IV: sensitivity to CO2 is lost as loss of consciousness occurs. Effect of a normal induction dose can vary from no detectable respiratory depression to apnoea. Normal effect is a slight decrease in tidal volume; may be compensated for by an increase in respiratory rate. Not only shifts CO2 response curve to the right but also flattens slope
  • in COAD patients depressant effect may be greater

Endocrine

  • midazolam infusion blunts ACTH response to surgery
  • very high concentrations of midazolam and diazepam and their metabolites suppress bovine adrenal cortisol synthesis in vitro

ICU sedation

Midazolam

  • satisfactory hypnotic in patients who are also receiving analgesia
  • in patients with multiorgan dysfunction unpredictable half-life may be a problem
  • may impair verbal contact and cooperation, particularly during weaning, because of potent amnesic properties. Attempts to control agitated patients with larger doses results in over-sedation
  • protective effect against cerebral ischaemic damage

Diazepam & lorazepam

  • can be given as intermittent boluses but administration by infusion limited by long t1/2
  • enteral lorazepam may be particularly useful in patients in patients requiring prolonged sedation

Flumazenil

Pharmacokinetics

  • admin: IV/PO but 84% first-pass metabolism. IM injection may be painful
  • after IV dose, distributed throughout the body within 5 mins. Maximal brain levels 5-8 mins after injection
  • 99.8% metabolized in the liver
  • t1/2 0.7-1.3 hrs
  • plasma protein binding approx 40%

Clinical use

  • reversal of benzodiazepine sedation. NB may wear off before benzodiazepine agonist
  • specific reversal of the central effects of benzodiazepines in patients in ITU to allow return of spontaneous respiration and consciousness

Contraindications

  • patients known to be hypersensitive to benzodiazepines
  • epileptic patients after prolonged administration of benzodiazepines
  • reversal of anaesthesia in the presence of neuromuscular blockade

Caution in:

  • chronic benzodiazepine users, especially those with raised ICP following a head injury. Increase in ICP has been reported in patients with head injury following reversal of sedation
  • patients who have taken other drugs (esp. tricyclics) in addition to benzodiazepines, in whom the convulsive effects of other drugs are no longer suppressed by the benzodiazepine and who may therefore fit. Ventricular arrhythmias have followed use in mixed drug overdoses

Use following benzodiazepine overdose

  • in ICU can obviate need for assisted ventilation even after severe benzodiazepine OD. However unless there is rapid access to a toxicology lab one can seldom be confident about the exact drugs that have been ingested by an unconscious patient. In patients who have also taken tricyclics the risk of convulsions after flumazenil is considerable and may outweigh the benefit of giving the drug
  • benzodiazepines remarkably safe in OD if taken alone and rapid reversal of sedation is rarely necessary or cost-effective. For these reasons flumazenil is licensed for use after benzodiazepine OD only if the patient is so severely poisoned as to require admission to ICU

Dosage

  • reversal of midazolam sedation: 0.005-0.01 mg/kg. Titrate in increments of 0.1-0.2 mg. Resedation is possible but unlikely in this situation if the flumazenil is given as the midazolam effect is waning
  • if used to antagonize effect of OD, or after prolonged use or use of a longer-acting drug, infusion may be more appropriate: 100-400 mcg/hr

Further reading

Liu LL, Gropper MA. Postoperative analgesia and sedation in the adult intensive care unit. A guide to drug selection. Drugs, 2003;63(8):755-67


© Charles Gomersall December 1999, October 2003


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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