Anxiolytics

Question 1

Categories of drugs used in tx of Anxiety

Answer 1

• Antidepressants (most common)
  
  • SSRIs - SNRIs
• Benzodiazepines (sedative-hypnotic agent)
• Busprione
• Barbiturates (sedative-hypnotic agent)

Question 2

(General) MOA of sedative-hypnotic drugs

Answer 2

• graded dose-dependent depressant effects

1. augment GABA neuronal inhibition and/or
2. inhibit glutamate neuronal excitation

• sedatve drugs = decreasing activity, moderating excitement, calming
• hypnotic drugs = produce drowsiness, facilitate onset/maintenance of sleep that resembles natural sleep

Question 3

Pharmacodynamics/dosing of barbituates vs. benzodiazepines

Answer 3

• Barbiturates: Increase in dose above that needed for hypnosis-sleep ==> general anesthesia -==> depression of respiratory and vasomotor centers ==> coma and death
• Benzodiazepines: Non-linear/less steep dose-response relationship ==> greater dosage increments are required to achieve CNS depression more profound than hypnosis-sleep - consistent with their greater margin of safety

Question 4

Benzodiazepines: MOA

Answer 4

• facilitate action of GABA @ GABA_A receptor-chloride channel complex
  
  • ==> increased GABA channel opening ==> increased Cl^-flow into cells ==> hyperpolarization ==> decreased neuronal excitability
• Benzodiazepines intensify effect of GABA

Question 5

Barbituates: MOA

Answer 5

• facilitate action of GABA @ GABA_A receptor-chloride channel complex
• barbiturates prolong the effect of GABA @ therapeutic levels (requires presence of GABA)
• @ high concentration: barbiturates interact directly w/GABA receptor (GABA not required)
• ALSO barbiturates depress excitatory NTs (glutamate)
• MOA ==> greater CNS depression + full surgical anesthesia ==> lower safety margin

Question 6

GABA channel subunits and clinical relevance

Answer 6

• GABA receptors with α1 subunits = @ cortex
  
  • receptors appear to mediate sedative (sleep), amnestic, and anticonvulsant actions of benzodiazepines
• GABA receptors with α2/α5 subunits = @ limbic system / and brain stem
  
  • receptors appear to mediate myorelaxant, motor impairing, anxiolytic, and ethanol-potentiating effects of benzodiazepines

Question 7

Benzodiazepines vs. “Z-drugs”

Answer 7

• Benzodiazepines
  
  • bind to GABA-chloride channels with both α1 and α2/α5 subunits
  • ==> both sleep and anxiolysis
• “Z-drugs” (zolpidem, zaleplon, eszopiclone)
  
  • not benzodiazepines structurally
  • bind only to GABA-chloride channels with α1 subunits
  • ==> sleep without anxiolysis (reduced potential for dependence)

Question 8

Clinical indications of phenobarbital

Answer 8

• e.g. of barbituate that inhibits spread of seizures in cortical neurons @ doses that don’t cause severe sedation

Question 9

Clinical indications of diazepam/lorazepam

Answer 9

• e.g. of benzodiazepines
• drugs of choice in status epilepticus

Question 10

General pharmacologic effects of benzodiazepines/barbituates

Answer 10

• anxiolysis
• anticonvulsant effects
• muscle relaxation
  
  • requires high doses, acoompanies by significant CNS depression
• hypnosis (sleep)
• anesthesia (short-acting barbiturates)
  
  • NOT benzodiazepines
• ==> tolerance
• ==> psychologic and physical dependence

Question 11

Benzodiazepines: absorption/distribution

Answer 11

• absorption
  
  • oral
    
    • rapid: diazepam, alprazolam, triazolam
    • slow: oxazepam, temazepam
  • IM = used for faster onset/if oral not possible
    
    • Lorazepam
• distribution = lipid soluble ==> enters CNS rapidly

Question 12

Benzodiazepines: metabolism

Answer 12

• metabolism of most drugs = CYP450 enzymes @ liver
• many phase I metabolites are active w/longer half-lives than parent compounds
  
  • ==> accumulation of metabolites
  • e.g. diazepam
• others metabolized to active compounds but quickly conjugate
  
  • ==> short-lived effects
  • e.g. alprazolam
• others metabolized directly to inactive form w/out P450 enzymes
  
  • ==> shorter half-lives
  • GOOD CHOICE @ elderly or hepatic dysfxn
  • e.g. lorazepam
  • e.g. oxazepam

Question 13

Tx for GAD & Panic disorder

Answer 13

• GAD
  
  • SSRIs
  • SNRIs
• Panic disorder
  
  • Acute: high potency BDZs (alprazolam, clonazepam)
  • SSRIs

Question 14

Tx for Social Phobia, OCD, PTSD

Answer 14

• Social Phobia
  
  • Generalized: SSRI, SNRI
  • Performance: Beta-blockers, high-potency BDZs (alprazolam, clonazepam)
• OCD
  
  • CBT
  • SSRIs, SNRIs
• PTSD
  
  • CBT
  • SSRIs

Question 15

Benzodiazepine use in axiety disorders (based on pharmacokinetic properties)

Answer 15

• Oral onset: Most rapid with alprazolam or diazepam for situational anxiety
• IM absorption: Lorazepam, rapid and reliable
• Elimination half-life
  
  • Agents with short-intermediate t_1/2 (oxazepam, alprazolam, lorazepam) preferred in the elderly or in presence of hepatic disorder
  • Agents with longer t_1/2 (diazepam or chlordiazepoxide) may be dosed at bedtime if both hypnotic and daytime anxiolytic activity desired

Question 16

Characteristics of buspirone

Answer 16

• Buspirone is an alternative as an anxiolytic
• Not a benzodiazepine, but a 5HT1A partial agonist located presynaptically on nerve terminals
• NO sedation (or additive CNS depression), anticonvulsant, or myorelaxant action
• Requires 2 weeks for onset of anxiolytic effect and 4-6 weeks for maximal efficacy (thus it is more useful and effective in chronic anxiety). Less patient acceptance.
• Must be administered on routine schedule (not on prn basis)
• Side effects include dizziness, nausea, headache