treatments for anxiety, PTSD and OCD; hypnotics

drug options for GAD

• SSRI

• SNRI

• pregabalin - acts calcium channels

• benzodiazepines for crisis only, short term

• buspirone - 5HT1A partial agonist licenced for anxiety

drug treatments for panic disorder

• SSRI

• tricyclics - imipramine or clomipramine

• benzodiazepines used in short term

• beta blockers but still used for physical symptoms

drug treatments for ocd based on impairment

• moderate impairment

  • CBT or SSRI/ clomipramine

• severe impairment

  • CBT and SSRI/clomipramine

drugs used for PTSD

• SSRI - sertaline or paroxetine or venlafaxine

• antipsychotics may be used if symptoms are severe and other therapies havent worked

what are the 5 binding sites of the GABA-A receptor

• agonist binding site

• picrotoxinin site

• barbiturate

• neurosteroid

• benzodiazepine and beta carboline

barbiturates examples

• amabarbital

• pentobarbital

• thiopental

• phenobarbital

uses of barbiturates

• anxiolytics

• anticonvulsants

• sedatives

• anaesthetics

mechanism of barbiturates

• positive allosteric modulator of GABA-A receptor, prolongs the opening time

• at higher conc directly activate without presence of GABA, and inhibit AMPA receptors, inhibit CNS and NT release

why are barbiturates lethal at overdose

• at higher concentrations direcly activate GABA-A receptors without GABA

• leads to respiratory depression

why did benzodiazepines replace barbiturates

• safer in overdose, if no other drug interactions/alcogol

uses of benzodiazepines

• anxiolytic

• sedative

• muscle relaxant

• amnesic

• anti convulsant

what type of tolerance is seen with benzodiazepines

• oppositional tolerance - effect of drug is conflicting with the response of CNS

dependence of benzodiazepines

• down regulation of GABA-A sensitivity

• increased glutamatergic sensitivity

• strong dependence

sudden withdrawal of benzodiazepiens

• insufficient GABAergic transmission

  • leads to anxiety, insomnia and seizures

spectrum of action of benzodiazepines site ligands

• no natural ligand for BDZ binding site

• inverse agonists/ negative allosteric modulators

• antagonist

• agonist

negative allosteric modulator benzodiazepines

• inverse agonists

• dec action of GABA-A receptors

• cause convulsions, induce anxiety

• DMCM drugs

BDZ antagonists

• bind to same site as diazepam but little effect on GABA alone

• in presence of diazepam, it will block the action

• silent allosteric modulators

• eg flumazenil

BDZ agonist

• potentiates GABA, causes sedation, amnesic effect

• eg diazepam, and z drugs

where is the GABA binding site?

• junction between adjacent subunits of alpha and beta

diazepam binding site

• junction between gamma 2 and alpha subunit

• requires presence of gamma 2 subunit

how does the pharmacology of BDZ site depend on the alpha subunit subtype

if presence of alpha 1,2, 3, 5

• binds clsssic BDZ

if presence of alpha 4,6

• bind Ro

• does not bind classic BDZ

what amino acid allows high affinity for diazepam?

• conserved a105 histidine in alpha 1, 2,3 and 5

what amino acid creates low affinity for diazepam

• presence of arginine in alpha 4,6

do knockout studies of individual subunits work?

• no

• compensatory expression of other subunits

• or letahl to animal

how did knock in experiments prove specific subunits mediate anxiolysis?

• histidine at a105 in alpha 1,2 and 3 was mutated to arginine to give low affinity for diazepam

• sedative amnesic effects due to alpha 1 containing receptors

• anxiolytic effects due to alpha 2 containing

• alpha 2 selective drugs could relieve anxiety without sedation

limitations of a2 selective approach for anxiolytic effect without sedation

• difference in species

• heterogeneity of alpha subunits within a receptor

TPA023B

• zero efficacy at a1 but moderate at a2,3 receptors

• anxiolytic in rodents

• not sedating in animals nut highly sedating in humans

z drugs - hypnotics

• bdz site agonists

• rapid drugs used as sleep aids

• no hangover effect after waking like with BDZ

• only prescribed for 2-3 weeks