15 - Benzodiazepines

Question 1

What are some GABAergic sedative-hypnotic drugs?

Answer 1

• Chloral hydrate
• Meprobamate
• Barbiturates
• Benzodiazepines
• Z-drugs

Question 2

Briefly describe chloral hydrate and meprobamate

Answer 2

• Used historically for anxiolysis and sedation
• 3 chloral hydrate products still marketed in Canada
• Meprobamate and its pro-drug (carisoprodol) unavailable in Canada
• Narrow therapeutic index compared to future GABAergic drug classes

Question 3

Are barbiturates still used today?

Answer 3

• Secobarbital/ amobarbital/ thiopental used for procedural sedation and anesthesia
• Phenobarbital used for status epilepticus, refractory epilepsy

Question 4

Can BZD overdose alone be fatal?

Answer 4

Rarely

Question 5

Predisposing factors to BZD overdose

Answer 5

• Age
• Hepatic impairment
• COPD

Question 6

Mild CNS sx of BZD

Answer 6

• Drowsiness or lethargy

- May appear w/in 30-60 mins of ingestion

Question 7

Moderate CNS sx of BZD

Answer 7

• Slurred speech
• Amnesia and ataxia
• May appear shortly thereafter

Question 8

Severe CNS sz of BZD

Answer 8

• Stupor or coma
• May occur hours after large ingestions alone or sooner if polydrug overdose
• Usually accompanied by hypothermia, hyporeflexia, miosis

Question 9

Rare paradoxical reactions to BZD

Answer 9

• Agitation

- Aggression w/ confusion (more common in elderly, especially if previous dementia)

Question 10

Rank barbiturates, BZDs, and Z-drugs based on effect on respiration

Answer 10

Barbiturates > BZDs >/ Z-drugs

Question 11

Respiratory depression ____ CNS depression

Answer 11

• Parallels

- Ex: pt in stupor or coma more likely to be hypo-ventilated than pt w/ slurred speech or ataxia

Question 12

Does level of CNS depression predict level of respiratory depression?

Answer 12

• Not always

- Pt in coma may have normal vital signs

Question 13

What can increase the risk of respiratory depression with BZDs?

Answer 13

• Respiratory disease
• Elderly
• Concomitant opioid use

Question 14

What is considered hypoventilation?

Answer 14

< 12 breaths/min for adults

Question 15

CVD effects from BZDs and Z-drugs

Answer 15

• Negligible effects generally
• May produce significant postural hypotension or bradycardia in at-risk px
• CV collapse rare but may occur w/ large combined alcohol or opioid overdose

Question 16

Management of BZD overdose

Answer 16

• Emergency and supportive measures
• • Protect airways, assist ventilation
• • Treat coma, hypotension, and hypothermia
• Decontamination
• • Activated charcoal for poly-drug OD (limited utility in mono-drug overdose due to aspiration risk)
• • Urinary alkalinisation for barbiturates (especially phenobarbital)

Question 17

Antidote for BZD overdose

Answer 17

Flumazenil (controversial)

Question 18

What is flumazenil?

Answer 18

• Competitive antagonist of BZ receptor
• Reverses BZD (and Z-drug) induced CNS depression
• Can induce BZD withdrawal
• Re-sedation common after 1-2 hours (like naloxone)

Question 19

When is flumazenil used?

Answer 19

Ideal for BZD naive px w/ BZ only overdose

Question 20

Dose of flumazenil

Answer 20

• 0.1-0.2 mg IV over 30 seconds

- Subsequent doses of 0.3 mg and 0.5 mg at 1 min interval up to 3 mg total

Question 21

Flumazenil contraindications

Answer 21

• Pt is physically dependent (withdrawal)
• Pt receiving BZ for control of seizure disorder
• Pre-existing cardiac arrhythmia or high-risk of arrhythmia
• Co-ingestion of agents causing seizure (theophylline, TCAs, etc.)
• Increased intracranial pressure
• Unreliable/ unavailable hx (w/ a mono overdose b/c rarely fatal; would potentially be putting pt at more risk)

Question 22

Ideal scenario for flumazenil use

Answer 22

• Pure BZD overdose in non-tolerant individual who has:
• • CNS depression
• • Normal vital signs, including SaO2
• • Normal EKG
• • Otherwise normal neurologic exam

Question 23

BZD chronic use issues

Answer 23

• Long term use of BZD has NOT been associated w/ cumulative toxicity or organ damage
• Tolerance and dependence during continuous use and withdrawal after cessation of drug use are common clinical consequences
• Female gender and older age are strong predictors of long-term use
• Inappropriate use is often “long-term” use BUT “long-term” use alone is not necessarily inappropriate use

Question 24

Treating BZD dependency

Answer 24

• Pharmacotherapy substitutions include (among others):
• • Longer acting BZD (ie: diazepam)
• • Pregabalin
• • Carbamazepine
• • Melatonin
• • Flumazenil (patch?)
• *Gradual dose reduction +/- behavioural or psychological interventions
• Determine gradual dose reduction regimens specific to pt
• • Switch to long-acting BZD not usually required