Newer CNS depressants

1
Newer CNS depressants

• Benzodiazepines, second generation anxiolytics,
  and antiepileptic drugs

2
Use of benzodiazepines

• Not for chronic anxiety disorders
• Not for the elderly
• Not for depression
• For short-term treatment of stress-related
  anxiety
• Acute situational grief
• Acute stress reactions
• Short-term anxiety-induced insomnia

3
Pharmacodynamics

• GABAA receptor interactions
• Benzodiazepine agonists, eg. diazepam
• Benzodiazepine antagonists, eg. flumazenil
• Chloride ion channels and fast IPSPs
• GABAB receptor interactions
• Presynaptic for several neurotransmitters
• Potassium ion channels and late IPSPs
• Baclofen, a muscle relaxant and antispastic

4
Localized pharmacodynamics

• Low-dose antianxiety effects hippocampus and
  amygdala
• Mental confusion and amnesia hippocampus and
  cerebral cortex
• Sedative-hypnotic effects cerebral cortex
• Different benzodiazepines have different relative
  effects, perhaps due to multiple subtypes of
  GABAA receptors.

5
Pharmacokinetics

• Study administration, absorption and distribution
  in textbook.
• Metabolism is unusual
• Intermediate metabolites may be psychoactive.
• Intermediate metabolites may be long-lasting.
• Elderly patients have difficulty metabolizing
  long-acting benzodiazepines, leading to profound
  dementia. May take 60 days to clear.

6
Uses and side effects of benzodiazepines

• Panic attacks and phobias alprazolam (Xanax)
• Alcohol withdrawal and abstinence
• Antiepileptic
• Dose-related side effects
• Drug-induced brain syndrome
• Impaired functioning
• Amnesia
• Severe interactions with alcohol

7
Benzodiazepine miscellany

• Fetal effects have been reported for BDZ taken in
  the first trimester, but other research disputes
  the claim.
• If abused, BDZs are part of polydrug abuse,
  complicating flumazenil antagonistic effects
• GABAA antagonists may enhance learning by
  facilitating cortical and hippocampal cholinergic
  activity
• GABAB antagonists may enhance cognition and
  counter depression

8
Second generation anxiolytics

• Zolpidem (Ambien, 1993) Not a BDZ, it is a
  specific agonist at GABAA1 receptors.
• Rapid uptake and short elimination half-life make
  it an effective insomnia treatment
• Little interference with normal sleep cycle
• Safe, and high doses trigger vomiting
• High doses produce problems in older people
• Flumazenil antagonizes zolpidem

9
Second generation anxiolytics

• Buspirone (BuSpar) A weak agonist of 5-HT1A
  receptors, so no crossing or synergy with other
  CNS depressants
• Buspirone is also antidepressant
• No sedation, little amnesia or confusion
• Very slow development of main effect several
  weeks tid. Minimal abuse, withdrawal symptoms.
• Useful for GAD and anxiety in older people.
• Postsynaptic inhibition of adenyl cyclase
• Presynaptic inhibition of 5-HT synthesis
• Remember grapefruit juice effect on buspirone

10
Controversial anti-anxiety drugs

• Triazolam (Halcion)
• Flunitrazepam (Rohypnol)
• Illegal in U.S.A.
• Produces amnesia
• Synergistic with alcohol Date-rape drug
• Roughies, roofies, rochas

11
Future directions in anxiety control

• Find partial agonists of BDZ receptors
• Abecarnil, used for GAD
• Find drugs which act on different receptor
  subtypes, like Zolpidem
• Alpidem acts on GABA A1 and GABA A3 sites
• Imidazenil has fewer side effects
• Nonhormonal neurosteroids (epalons) as GABAA
  agonists Ganaxolone
• Serotonin (5HT1A) agonists, like buspirone
  gepirone, alnespirone, ipsapirone

12
Antiepileptic drugs

• Epileptic seizures, foci/lesions, and kindling
• Sodium channel blocking
• carbamazepine, phenytoin (Dilantin)
• lamotrigine, valproate/valproic acid
• GABA agonism
• reduce metabolism of GABA
• facilitate GABA release gabapentin
• Enhance GABA action benzodiazepines, valproic
  acid

13
Other uses of antiepileptics

• Kindling may be part of a set of psychiatric
  disorders characterized by impulse control
  difficulty.
• Bipolar Disorder and mania
• Conduct Disorder
• Borderline Personality Disorder
• Panic Disorder
• Intermittent Explosive Disorder
• Antiepileptic drugs are sometimes helpful.

14
Antiepileptic drugs

• Identify the three main groups of antiepileptic
  drugs.
• In which group would you place carbamazepine and
  valproic acid?
• Construct a timeline of the drug treatment of
  seizure disorders, starting with bromide.
• How do antiepileptic drugs relate to specific
  psychological disorders?
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