Benzodiazipines

Flumazenil REF: Harrison’s 17th ed Table e 35-4

See APPENDIX-42 for list of “Antidotes”

“Specific antidote for benzodiazepine poisoning is flumazenil”

Diazepam generates active metabolites, has slow elimination and tends to accumulate with regular use.

Lorazepam, Oxazepam and Temazepam do not produce active metabolites and are relatively safer in elderly patients and in those with liver disease.

These agents should be used in preference to diazepam.

Ref: Essentials of Pharmacology By K D Tripathi, 5th Edtion, Page 364.

Ans. is ‘c’ i.e., Triazolam

o Midazolam (slightly shorter acting than triazolam) and triazolam are shortest acting BZDs.

Ans. is ‘d’ i.e., Temazepam

BZDs with significant anticonvulsant property are diazepam, clonazepam, nitrazepam, lorazepam and flurazepam.

Ans. is ‘d’ i.e., Flumazenil

o Flumazenil is a benzodiazepene analogue which competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant effects respectively.

o It also antagonizes the action of Zolpidem, Zopiclone and Zopeplon as these drugs also act on BZD site.

Ans. is ‘b’ i.e., Diazepam antagonist

Ans. is ‘b’ i.e., Oral Diazepan 6 hrly

Ans. C: Alprazolam

Alprazolam is approved for the short-term treatment of panic disorder, with or without agoraphobia. Alprazolam is very effective in the short-term symptomatic relief of moderate to severe anxiety, essential tremor, and panic attacks.

Alprazolam is indicated for the management of anxiety disorders or the short-term relief of symptoms of anxiety. Alprazolam is recommended for the short-term treatment of severe acute anxiety.

Alprazolam is sometimes prescribed for anxiety with associated depression.

The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors. Other benzodiazepines are not known to have antidepressant activity.

Ans. B: Flumazenil

Decontamination

– Gastric lavage is not recommended but may be considered if the presence of a lethal co-ingestant is suspected and the patient presents within 1 hour of ingestion.

–  Single-dose activated charcoal is recommended for GI decontamination in patients with protected airway who present within 4 hours of ingestion.

• Respiratory depression may be treated with assisted ventilation.
• Flumazenil

– Flumazenil is a competitive BZD receptor antagonist and should be used cautiously because it has potential to precipitate BZD withdrawal in chronic users, resulting in seizures.

–  Flumazenil administration is contraindicated in mixed overdoses (e.g., TCAs) because BZD reversal can precipitate seizures and cardiac arrhythmias.

– Ideal indication for flumazenil use is isolated BZD overdose, particularly if overdose is iatrogenic in nature.

Ans. Flumazenil

Ans. is ‘d’ i.e., Coronary dilatation

Mechanism of action of benzodiazepines (BZDs)

• Benzodiazepines act preferentially on midbrain ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental function).
• Muscle relaxation is produced by action on medulla.
• Ataxia is due to action on cerebellum.
• BZDs acts on GABA_A receptors.
• GABA_,,_, receptor has 5 subunits a / p, p, a / y.
• GABA binding site is on p. subunit, while BZDs binding site is on a / y subunit.
• BZDs receptor increase the conductance of Cl- channel.
• BZDs do not themselves increase Cl- conductance, i.e. they have only GABA facilitatory but no GABA mimetic action. (Barbiturates have both GABA facilitatory and GABA mimetic actions).

Effect on CNS

• In contrast to barbiturates, BZDs are not general depressant, but exert relatively selective anxiolytic, hypnotic, muscle relaxant and anticonvulsant effects.
• The antianxiety action of BZDs is not dependent on their sedative property —› with chronic administration relief of anxiety is maintained, but drowsiness wanes off due to development of tolerance.
• Stage 2 sleep is increased, while REM, Stage 3 & 4 sleep are decreased.
• Nitrazepam is the only benzodiazepine, which increases REM sleep.
• Clonazepan and diazepam have more marked muscle relaxant property.
• Clonazepam, diazepam, nitrazepam and flurazepam have more prominent anticonvulsant activity than other BZDs.
• Diazepam (but not other BZDs) has analgesic action.
• Diazepam produces short lasting coronary dilatation on i.v. injection.
• Diazepam decreases nocturnal gastric secretion and prevents stress ulcers.

Ans. is `c’ i.e., Beta carboline

Ans. is i.e., Naloxone-Datura

The antidote for datura poisoning is physostigmine (not naloxone). Naloxone is an opioid antagonist medication used to block or reverse the effects of opioid drugs.

Deferoxamine is the antidote for iron poisoning, flumazenil is the antidote for BZDs poisoning and Dimercaprol is used to treat arsenic, gold, or mercury poisoning. It is also used together with another medicine called edetate disodium (EDTA) to treat lead poisoning.

Ans. b. Retrograde amnesia

At the time of peak concentration in plasma, hypnotic doses of benzodiazepines (midazolam) can be expected to cause varying degrees of lightheadedness, lassitude, increased reaction time, motor incoordination, impairment of mental and motor functions, confusion, and anterograde amnesia.”

Midazolam:

• It causes anterograde amnesia^Q
• Tolerance and tachyphylaxis may occur, particularly with longer-term infusions^Q(Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med. 1998;26(5): 947-56)
• Benzodiazepine withdrawal syndrome has also been associated with high dose/ long-term midazolam infusions^Q
• Compared with propofol infusions, midazolam infusions have been associated with a decreased occurrence of hypotension° but a more variable time course for recovery of function after the cessation of the infusion.

Ans. is ‘b’ i.e., Midazolam

• Ajay Yadav 4^th/e p. 85] o Midazolam is the shortest acting benzodiazipine.
• It is 3 times more potent than diazepam.
• Midazolam is now very commonly used BZD in intraoperative period.
• Advantages of midazolam over diazepam are :
• Water based preparation, so injection is painless.
• Elimination half life is 2-3 hours, so can be safely used for day care procedures.
• Reversal with flumezanil is complete (no resedation).
• Disadvantages are that decrease in BP and peripheral vascularresistance, respiratory depression and incidence of apnea are higher and more profound than diazepam

Ans. is ‘a’ i.e., Flumazenil

Ans. D.  i.e., Temazepam 

• BZD’s with significant anticonvulsant properties are diazepam, clonazepam, nitrazepam, lorazepam, and flurazepam. 

Ans. is ‘c’ i.e., Triazolam