Sedatives

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Caution surrounding Psychotropics

Effect size of antidepressants for anxiety = 1.2

Effect size of antidepressants for depression = 0.7

 

Introduction

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Types of Sedatives

Likely the most common sedative family worldwide is the benzodiazepines (BZPs). In general population in Canada, 8% have used benzos in the past year; 2% have used them for over a year.

 

BZPs differ from each other primarily regarding speed of onset and duration.

• diazepam (Valium) - most rapid onset, long acting (lipophilic)
• lorazepam (Ativan) - rapid onset, long acting
• alprazolam (Xanax) - fast onset, short-acting, fast offset
  • interdose withdrawal leads to feelings of anxiety and high dependency
• clonazepam (Klonopin) - intermediate
• midazolam (Versed) - fast-acting
• triazolam - short
• oprazolam - short
• fluorazepam - long (t1/2 of 100 hours)
• chlordiazepoxide

Other sedatives include barbituates and buspirone.

 

 

 

Uses

should be given for at most weeks or months due to potential for dependence and side effects.

• generalized anxiety disorder (at beginning of treatment)
• phobias
• panic disorder
• insomnia
• chemotherapy-induced vomiting
• treatment of epilepsy
• as a component of anesthesia (amnesic)
• procedural sedation
• cessation of seizure
• alcohol withdrawal
• muscle spasms

 

 

Side Effects

• sedation
• dizziness, weakness, ataxia
• psychomotor impairment
• cognitive impairment
• anterograde amnesia (used in cancer centres to prevent negative associations from forming
• nausea, slight hypotnesion
• personality changes in less tha 1%, but disinhibition can lead to rage etc
• loss of coordination
• increased traffic accidents

long term use can result in cognitive decreases

 

 

Adverse Drug Reactions

• enhanced toxicity of other CNS depressants, ie alcohol, TCAs, barbiturates

Overdose: give flumazinil

 

Interactions

There are varying effects of alcohol on benzo concentrations.

Synergistic pharmacological interactions occur.

 

 

Overuse, misuse, abuse

People with the below risk factors should be prescribed BZPs extremely carefully, if at all, given the risk of abuse:

• multiple drug abuse
• alcohol abuse
• chronic pain disorders
• severe personality disorders

Specific drugs also carry increased risk for abuse, due to rapid onset/offset and euphoriant effects. These include:

• triazolam: rapid onset/offset, euphoriant
• alprazolam: rapid offset, significant withdrawal effects
• diazepam: most rapid onset, euphoriant

 

 

Withdrawal

 

Symptoms of BZD withdrawal syndrome:

• insomnia
• anxiety
• GI distress
• diaphoresis
• tremor
• GI distress
• lethargy
• dizziness
• headache
• increased sensory acuity (hearing, visual)
• zappy feelings in your fingers
• seizure
• psychosis
• delirium

 

risk factors:

• short acting agents
• dose and duration
• rate of discontinuation
• panic disorder or severe Axis II disorder
• concomitant alcohol/substance abuse

lose dose: tachycardia, hypertension, insomnia

high dose: seizures, psychosis

 

Stopping Treatment

Tapering often takes place over months, with a 10% reduction in dose per week. It may be challenging to assess whether symptoms are related to anxiety or to the taper.

 

To stop treatment, in general you should taper off with all psychotropics.

Go really slow at the end of the taper (asymptotic)

get patient involved in drafting the schedule

have a treatment plan for break-through emergence of symptoms (PRNs)

switch to long-acting BZP prior to taper (ie clonazapam or diazepam)

 

Benzo agonists

facilitate GABA action: zolpidem, zaleplon, eszopiclone

antagonists: used in overdose: flumazenil

inverse agonists: act as negative allosteric modulators of GABA receptors

 

 

Mechanism of action

Benzodiazepines bind to chloride channels in neurons, causing conformational changes that increase GABA binding and subsequent chloride channel opening. This leads to hyperpolarization and inhibits CNS activity.

 

 

 

Pharmacokinetics

down-regulation of GABAA receptors occurs a lot

acts on the GABA_A receptor

 

onset	hypnotic utility abuse potential
lipophilicity	duration of effect onset/offset of effect
half-life	dosing frequency risk of accumulation withdrawal syndrome
hepatic metabolism	specific populations: elderly, hepatic impairment

 

Phase I capacity decreases with age, meaning half life will be increased in the elderly.

Non-phase I metabilized drugs: lorazepam, o, tamazapam

 

 

Buspirone

A sedative-hypnotic

 

Uses

• have anti-anxiety effetcs without sedative, euphoric, hypnotic, or psychomotor effects
• can take more than a week for anxiety to get better; with peak effect at 4-6 weeks
• can't be used PRN
• minimal potential for abuse
• doesn't potentiate effects of alcohol or TCAs
• can be combined with antidepressants to augment their effect

Mechanism

• 5-HT 1A receptor agonist
• also DA D2 receptor
• buspirone metabolite inhibits α2, leading to increased NE release

adverse effects

• nausea, headache, dizziness, tension, restlessness, insomnia
• tachycardia, palpations, nervousness, gi distress, paresthesia

contraindications

• haloperidol, MAOIs

 

• Barbiturates are a powerful sedative and hypnotic drug class that are infrequently used these days.
• Barbiturates were the first generation of sedative drugs. Due to their lethality, hey are therefore not used any more, except before and during medical/surgical procedures.
• Increasing the dose leads to sedation, hypnosis, anesthesia, and finally coma and death.
• Barbiturates increase the duration of GABA channel opening and high levels may act as GABA agonists.

 

 

Resources and References

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