L17: Drugs Used in the Treatment of Generalised Anxiety Disorder

Question 1

What are the symptoms of anxiety disorder?

Answer 1

• verbal complaint
• somatic and autonomic affects - restlesness, agitation, increased sweating, tachycardia
• interference with normal productive activities

Question 2

What causes anxiety anatomically?

Answer 2

Hyperexcitability in amygdala and hippocampus; shared with some other diseases. In anxiety, control is lost, extended release of cortisol.

Question 3

Which axis is responsible for anxiety? Describe it

Answer 3

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.

Question 4

What kind of anxiolytic drugs are used to treat anxiety?

Answer 4

• benzodiazepines
• 5-HT partial agonists
• SSRIs (serotonin selective reuptake inhibitors) - antidepressants
• beta-adrenoreceptor antagonists
• barbiturates

Question 5

What is the chemical structure of benzodiazepines?

Answer 5

• a seven membered ring fused to an aromatic ring
• four main substituent groups can be modified without loss of activity

Question 6

What is the mechanism of action of benzodiazepines?

Answer 6

• 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

Question 7

What are allosteric modulators?

Answer 7

• 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)

Question 8

Where is the binding site of benzodiazepines?

Answer 8

The BDZ binding site lies between adjacent alpha and gamma subunits, meaning both the alpha and gamma subunits confer sensitivity to benzodiazepines.

Question 9

Which combination of GABAa receptors subunits in benzodiazepines sensitive?

Answer 9

only GABAa receptors containing alpha-1, alpha-2, alpha-3 and alpha-5 subunits are BDZ sensitive.

Question 10

What are the other ligands that act at the benzodiazepines binding site?

Answer 10

• 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)

Question 11

What are barbiturates? How do they affect GABA receptors?

Answer 11

• barbiturates enhance GABA action by increasing the Cl- conductance
• main effect: prolong the open time of the channel when activated by GABA (efficacy modulation)

Question 12

Why are barbiturates not used anymore?

Answer 12

• side effects are more severe than for BDZs including respiratory and cardiac depression that can be fatal
• they have high tolerance and dependence problems

Question 13

What is biotransformation?

Answer 13

Active metabolite formation from an active drug, extends therapeutic action.

Question 14

Are benzodiazepines metabolised or biotransformed? How is that helpful?

Answer 14

Extends therapeutic action. Benzodiazepines are biotransformed.

Question 15

What are the pharmacological effects of benzodiazepines?

Answer 15

• 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)

Question 16

Describe pharmacokinetics of benzodiazepines. Where is it absorbed? What does it bind to? Where does it accumulate and why?

Answer 16

• well absorbed from the gut
• bind strongly to plasma proteins
• accumulate in fat due to high lipid solubility

Question 17

Why should treatment of elderly with benzodiazepines should be carefully considered?

Answer 17

• 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

Question 18

What are the toxic effects of an acute overdose of benzodiazepines?

Answer 18

prolonged sleep but little serious depression of respiration or cardiovascular function

Question 19

What are the side effects during therapeutic use of benzodiazepines?

Answer 19

• drowsiness,
• confusion,
• amnesia,
• impaired motor co-ordination

Question 20

What is the tolerance of benzodiazepines?

Answer 20

Pharmacokinetic tolerance is of little importance, as BDZs do not induce hepatic microsomal enzymes. Tissue tolerance does occur - receptor changes

Question 21

What is the dependence of benzodiazepines?

Answer 21

Stopping BDZ treatment after weeks / months leads to increased anxiety and tremor / dizziness

Question 22

What is the receptor that is important in anxiety that responds to 5-HT? What drug showed to alleviate the symptoms of the disorder?

Answer 22

Buspirone acts on 5-HT1a receptors as a partial agonist.

Question 23

How do 5-HT1a receptors act pre-synaptically?

Answer 23

5-HT1A receptors are located pre-synaptically on 5-HT-releasing neurones where they act as inhibitory “autoreceptors” limiting 5-HT release.

Question 24

How do 5-HT1a receptors act post-synaptically?

Answer 24

5-HT1A receptors are also located post-synaptically where they have predominantly inhibitory actions on excitability.

Question 25

How might modulating the 5-HT system act to alleviate anxiety?

Answer 25

• in anxiety, abnormal autoreceptor 5-HT1a receptor expression / function may lead to reduced postsynaptic 5-HT release.
• Buspirone (and SSRIs) normalise this by promoting desensitisation of autoreceptors without apparently affecting post-synaptic receptors

Question 26

How do 5-HT1a partial agonists work? Give an example.

Answer 26

All have a direct effect on 5-HT1a receptors, however they take several days to start working, and even longer to achieve maximal therapeutic effect.
e.g. buspirone

Question 27

Why does it take so long for 5-HT1a partial agonists to work?

Answer 27

• slow effects on autoreceptor function
• neurogenesis?

Question 28

What are the unwanted effects of buspirone (5-HT1a partial agonist)?

Answer 28

• 5-HT1a partial agonists do not induce sedation, motor in co-ordination or withdrawal symptoms
• however, they induce nausea, dizziness, headache and some degree of restlesness

Question 29

What is the effect of beta-adrenoreceptor antagonists?

Answer 29

largely block the peripheral symptoms of anxiety but can cause some drowsiness, used to treat for somatic symptoms

Question 30

How does the senstitivity of benzodiazepines change if alpha-1 subunit of GABAa receptors is mutated?

Answer 30

BDZ’s still have anxiolytic and muscle relaxant effects, but do not have anticonvulsant or hypnotic (sedative) effects

Question 31

Why are alpha-4 and alpha-6 subunits of GABAa receptors insensitive to benzodiazepines?

Answer 31

alpha-4 and alpha-6 subunits have an arginine at position 101. In BDZ-sensitive subunits this is a histidine. The point mutation H101R in BDZ-sensitive alpha subunits renders them BDZ-insensitive without apparently altering GABA sensitivity.