Chapter 163 – Sedative Hypnotics
Barbituates
Pathophysiology

Binds to barbituate receptor on GABA receptor → opening of Clchannel opening the channel → influx of Cl-. ↑ intracelluar Cl- →
membrane hyperpolarization with ↓ depolarization d/t ↑
stabilization. Activity is independent of GABA.

↓ response to acetylcholine at autonomic synapses (muscarinic
receptors and ganglionic receptors) and NMJ (nicrotinic receptors)
Pharmacology

Absorption: Well absorbed, but may have ↓ absorption d/t ↓
peristalsis in overdose

Distribution: 50% protein bound

Metabolism: Variable duration of action – ultra-short acting
(immediate onset, duration = minutes) through long acting (onset
1 hr, duration 10-12 hrs) Shorter acting agents are metabolized by
the liver to inactive metabolites, whereas long acting agents have ↓
metabolism and are excreted unchanged

Elimination: 25% of long acting (phenobarbitol) is excreted
unchanged in the urine
Clinical
CNS
HEENT
Resp
CVS
Metab
Presentation
drowsiness, slurred speech, ataxia → coma; may have decorticate or decerebrate posturing; silent EEG
unreactive pupils
respiratory depression (centrally mediated), non-cardiogenic pulmonary edema
hypotension (↓ peripheral sympathetic activity)
hypothermia with short-acting agents
Management
ABCs: Pts may require intubation + mechanical ventilation until toxicity subsides. Hypotension is usually mild and responds
to fluids
Decontamination: MDAC is recommended for phenobarbital and may be beneficial in other significant overdoses that ↓ GI
motility.
Specific treatment: No specific antidote. Treatment is mainly supportive.
Enhance elimnation: Hemodialysis or hemoperfusion can be used in the setting of renal failure, refractory hemodynamic
instability or failure to improve with more conservative management
Disposition
Onset of symptoms is generally within 1 hr, so pts who are asymptomatic after 6 hrs of observation can be discharged.
Benzodiazepines
Pathophysiology

Binds to Cl- channel on membrane → ↑ GABA activity with ↑ frequency of opening, with subsequent ↑ intracellular
Cl-. This results in hyperpolarization of the cell. Activity is GABA dependant.

Three receptors, with variable distribution in the CNS and PNS produce different clinical effects
Agents
Short acting (t1/2 = 1.5 – 3 hrs): midazolam
Intermediate (t1/2 = 3 – 20 hrs): oxazepam, temazepam, lorazepam
Long (t1/2 > 24 hrs): clonazepam, diazepam, chlordiazepoxide
Pharmacology

Absorption: PO doses are well absorbed. IM lorazepam and midzolam also have predictable absorption.

Distribution: Highly protein bound. Readily cross the blood-brain barrier

Metabolism/Elimination: Metabolism occurs in the liver. Some are directly conjugated while others are metabolically
converted by cytochrome P450. The longer acting agents (diazepam, diazepoxide) have active metabolites.
Clinical Presentation
CNS
CNS depression (spectrum from drowsiness → coma)
CVS
Resp
Mild hypotension (uncommon unless combined with narcotic)
High PO doses or IV dosing → respiratory depression. (↑ when combined with narcotic)
Management
ABCs: Standard ACLS protocol
Decontamination: Not useful
Specific Treatments:

Flumazenil: Non-specific benzodiazepine receptor antagonist. Improves sedation, but does not always reverse
respiratory depression. Dose: 0.2 mg then 0.3 mg then 0.5 mg q 1 min until total = 3 mg. Risk of cardiac
dysrhythmias + seizures associated with use, particularly in the setting of multi-drug toxicity.
Enhance Elimnation: HD & HP not effective
Disposition: Pts who are asymptomatic 4-6 hrs post-ingestion can be discharged
Flunitrazepam
Therapeutic Use: insomnia, pre-op sedation (illegal in the US and Canada)
Mechanism of Action: High-affinity binding to benzodiazepine receptors
Clinical Effects: ↓ LOC, although pts rouse with noxious stimulation. Symptoms may last up to 48 hrs.
Diagnosis: Urine contains metabolites up to 72 hrs after ingestion
Buspirone
Therapeutic Use: general anxiety disorder
Mechanism of Action: Partial 5HT agonist + DA antagonist
Clinical Effects: May cause lethargy at very high doses, but typically minimal effects
Chloral Hydrate
Therapeutic Use: sedation, particularly in children
Mechanism of Action: Metabolite has a barbituate-like effect on the GABA receptor
Pharmacology: Rapidly absorbed from the GI tract and metabolized by ADH → active metabolite (trichloroethanol)
Clinical
CNS
HEENT
Resp
CVS
GI
Presentation
↓ LOC
Pear-like odour
Respiratory depression
↓ myocardial contractility, ↓ refractory period, ↑ catecholamine sensitivity, hypotension
GI irritation: nausea, vomiting, esophagitis, gastritis
Management
ABCs: Treat dysrhythmias and ectopy with β blockers.
Decontamination: Rapid absorbed, so not effective
Specific Management: Supportive care
Enhanced Elimination: Hemodialysis or hemoperfusion are effective pts who remain unstable after β blockade
Gamma Hydroybutyrate
Uses: Muscle building/fat burning (GHB); sedation (GHB); industrial solvent (GBL & 1,4-butanediol)
Pharmacology

GHB binds to GHB receptors in the hippocampus, striatum and cortex. Binding → ↑ DA synthesis, but ↓ release,
leading to ↑ concentration of pre-synaptic DA. At higher levels of GHB, DA release occurs.

Also binds to GABAA receptors
Pharmacokinetics

Absorption: Rapidly absorbed from the GI tract with peak levels 20 – 60 minutes post-ingestion and symptoms
within 15 minutes

Distribution: Readily crosses the BBB

Metabolism/Elimination:
◦ GHB: T1/2 is 30 minutes, but is longer with toxic dosing.
◦ 1,2-butanediol: Metabolized by ADH to GHB. EtOH competitively inhibits GHB metabolism, resulting in late
development of toxicity. This is associated with ↑ mortality
◦
GBL: Rapidly metabolized to GHB by hepatic and plasma lactonases
Clinical Presentation
CNS
↓ LOC + apnea alternating with period of aggitation and combativeness
HEENT Miosis +/- nystagmus
Resp
Periodic respiratory depression
GI
Emesis
Pts generally wake up within 3-4 hrs and recover completely within 8 hrs.
Management
ABCs: May require medication for intubation despite apparent coma
Specific treatment: Supportive care
Benzodiazepine Withdrawal
Onset: Onset of symptoms depends on the t1/2 of the drug being used. Withdrawal is more common with shorter acting
benzodiazepines and with use > 4 months.
Clincal Presentation: Anxiety, depression, insomina, sympathomimetic symptoms → delirium, seizures, hallicinations
Management: Long-acting benzodiazepines with slow taper
Barbituate Withdrawal
Similar to benzodiazepine withdrawal.
GHB Withdrawal
Onset: Physiologic withdrawal can occur within hrs of last dose in pts with chronic GHB use.
Clinical Presentation: Symptoms range from anxiety and tremour → hallucinations, delirium and autonomic instability
Management: Benzodiazepines may be ineffective d/t ↓ GABA levels, whereas barbituates act independently of GABA and are
generally effective