L17: Drugs Used in the Treatment of Generalised Anxiety Disorder Flashcards
What are the symptoms of anxiety disorder?
- verbal complaint
- somatic and autonomic affects - restlesness, agitation, increased sweating, tachycardia
- interference with normal productive activities
What causes anxiety anatomically?
Hyperexcitability in amygdala and hippocampus; shared with some other diseases. In anxiety, control is lost, extended release of cortisol.
Which axis is responsible for anxiety? Describe it
Hypothalamic-pituitary-adrenal (HPA axis) activated as part of the stress (fear) response.
- The amygdala and hippocampus regulate the release of corticotrophin releasing factor (CRF) from the hypothalamus.
- CRF stimulates cortisol production in the adrenal gland.
- The hippocampus exerts inhibitory influence on CRF release while the amygdala exerts an excitatory effect.
- Dysregulation of hippocampal and/or amygdala function may, therefore, result in abnormal regulation of the HPA axis.
What kind of anxiolytic drugs are used to treat anxiety?
- benzodiazepines
- 5-HT partial agonists
- SSRIs (serotonin selective reuptake inhibitors) - antidepressants
- beta-adrenoreceptor antagonists
- barbiturates
What is the chemical structure of benzodiazepines?
- a seven membered ring fused to an aromatic ring
- four main substituent groups can be modified without loss of activity
What is the mechanism of action of benzodiazepines?
- BDZ binding shows a close but not exact correlation with the location of GABAa receptors.
- BDZ bind to a site on the GABAa receptor distinct from the GABA binding site (2 GABA binding sites at interface between alpha and beta subunits)
- BDZs enhance GABA action by increasing the chloride ion conductance
- Benzodiazepines are positive allosteric modulators of the GABAa receptor
- they do not open the Cl- channel but act allosterically to enhance GABA affinity
- BDZs increase the number of open channels without altering the individual channel conductance or open time
What are allosteric modulators?
- alter the action of an agonist by binding to an accessory site
- no effect in absence of agonist
- they can increase affinity (altering GABA binding) or efficacy (alter channel activation/gating)
Where is the binding site of benzodiazepines?
The BDZ binding site lies between adjacent alpha and gamma subunits, meaning both the alpha and gamma subunits confer sensitivity to benzodiazepines.
Which combination of GABAa receptors subunits in benzodiazepines sensitive?
only GABAa receptors containing alpha-1, alpha-2, alpha-3 and alpha-5 subunits are BDZ sensitive.
What are the other ligands that act at the benzodiazepines binding site?
- competitive antagonists (neutral allosteric modulators): block the effects of BDZs (e.g. flumazenil)
- Inverse agonists (negative allosteric modulators): lead to reduction of affinity. Some ligands have been shown to bind to the BDZ site but have the opposite actions, i.e. induce anxiety (anxiogenic)
What are barbiturates? How do they affect GABA receptors?
- barbiturates enhance GABA action by increasing the Cl- conductance
- main effect: prolong the open time of the channel when activated by GABA (efficacy modulation)
Why are barbiturates not used anymore?
- side effects are more severe than for BDZs including respiratory and cardiac depression that can be fatal
- they have high tolerance and dependence problems
What is biotransformation?
Active metabolite formation from an active drug, extends therapeutic action.
Are benzodiazepines metabolised or biotransformed? How is that helpful?
Extends therapeutic action. Benzodiazepines are biotransformed.
What are the pharmacological effects of benzodiazepines?
- reduction of anxiety and aggression - anxiolytics
- sedation and induction of sleep - hypnotics and pre-operative sedation
- reduction in muscle tone and co-ordination - muscle relaxants
- anticonvulsant effects
- useful in acute alcohol withdrawal (allosteric modulator)
- amnestic (useful in general anaesthesia)
Describe pharmacokinetics of benzodiazepines. Where is it absorbed? What does it bind to? Where does it accumulate and why?
- well absorbed from the gut
- bind strongly to plasma proteins
- accumulate in fat due to high lipid solubility
Why should treatment of elderly with benzodiazepines should be carefully considered?
- the activity of hepatic microsomal enzymes (CYP) decreases with age
- a greater proportion of body mass is fat in the elderly
- these lead to an increase in the half-life, as metabolism is decreased and more is sequestered by fat reserves
What are the toxic effects of an acute overdose of benzodiazepines?
prolonged sleep but little serious depression of respiration or cardiovascular function
What are the side effects during therapeutic use of benzodiazepines?
- drowsiness,
- confusion,
- amnesia,
- impaired motor co-ordination
What is the tolerance of benzodiazepines?
Pharmacokinetic tolerance is of little importance, as BDZs do not induce hepatic microsomal enzymes. Tissue tolerance does occur - receptor changes
What is the dependence of benzodiazepines?
Stopping BDZ treatment after weeks / months leads to increased anxiety and tremor / dizziness
What is the receptor that is important in anxiety that responds to 5-HT? What drug showed to alleviate the symptoms of the disorder?
Buspirone acts on 5-HT1a receptors as a partial agonist.
How do 5-HT1a receptors act pre-synaptically?
5-HT1A receptors are located pre-synaptically on 5-HT-releasing neurones where they act as inhibitory “autoreceptors” limiting 5-HT release.
How do 5-HT1a receptors act post-synaptically?
5-HT1A receptors are also located post-synaptically where they have predominantly inhibitory actions on excitability.
