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Anxiolytics

• caution

 

Caution surrounding Psychotropics

Effect size of antidepressants for anxiety = 1.2

Effect size of antidepressants for depression = 0.7

 

 

Benzos are very common sedatives. In general population, 8% have used benzos in the past year; 2% have used them for over a year.

 

• types
• uses
• side effects
• adverse drug reactions
• potential for abuse
• withdrawal
• mechanism of action
• pharmacokinetics

 

Types of benzodiazepines

The big difference of benzodiazepines is length of action.

 

• 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

down-regulation of GABAA receptors occurs a lot

acts on the GABA_A receptor

 

 

 

Uses

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

 

• anxiety
• specific and social phobias
• panic disorder
• insomnia (quick acting is best)
• phobias
• chemotherapy-induced vomiting
• treatment of epilepsy
• as a component of anesthesia (amnesic)
• can be used to end seizures
• alcohol withdrawal
• muscle spasms
• as a diagnostic aid (not sure how)

 

 

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 factors:
  • multiple drug abuse
  • alcohol drug abuse
  • need for large doses
  • recent abrupt BZP d/c
• drug factors:
  • rapid onset, offset
  • euphoriant effects

specific tricky drugs:

• 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

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

 

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.