Newer CNS depressants

Benzodiazepines, second generation

anxiolytics, and antiepileptic drugs
 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
 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
 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.
 Pharmacokinetics
◆ Study administration, absorption and
distribution in Julien, pp. 97 - 103
◆ 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.
 Uses and side effects of
benzodiazepines
◆ Panic attacks and phobias
◆ Alcohol withdrawal and abstinence
◆ Antiepileptic
◆ Dose-related side effects:
◆ Drug-induced brain syndrome
◆ Impaired functioning
◆ Amnesia
◆ Severe interactions with alcohol
 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
 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
 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.
◆ Useful for GAD and anxiety in older people.
◆ Postsynaptic inhibition of adenyl cyclase
◆ Presynaptic inhibition of 5-HT synthesis
 Controversial anti-anxiety
drugs
◆ Triazolam (Halcion)
◆ Flunitrazepam (Rohypnol)
◆ Illegal
in U.S.A.
◆ Produces amnesia
◆ Synergistic with alcohol: “Date-rape drug”
◆ Roughies, roofies, rochas
 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: Fewer side effects
◆ Serotonin (5HT ) agonists, like buspirone
 Antiepileptic drugs, pp. 55-60
◆ 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?