Anxiolytics and Hypnotics.

Pharmacological strategies for anxiety

• SSRIs/ SNRIs

• Benzodiazepines

• Buspirone

• Pregabalin

• Beta blocker.

Acute, event, trigger specific anxiety.

Treated with a benzodiazepine with half-life matched to clinical need.

GAD treatment

SSRISs are 1st line.

Escitalopram (eg: Lexapro), sertraline (eg: Zoloft), fluoxetine (eg: Prozac)

• Can also be used to treat panic disorder, social anxiety, PTSD.

• Affects plus or minus 3% of population over 18

• Women twice as likely to be affected

• Often co-ccurs with other disorders eg: panic disorder.

CNS effects of benzodiazepines.

• reduced anxiety

• sleep at higher doses

• lower muscle tone, muscle relaxation

• reduced seizures, anticonvulsant

• Reduced memory formation; anterograde amnesia.

Rapid anxiolytic effect - drug reaches brain and allosteric modulation of GABA A occurs - inhibition changes immediately.

GABA A receptor.

• Pentamer

• 19 subunits cloned. 19 potential

• 5 subunits required for a functional channel/

• Most common subunits are a1B2gamma2.

• Each receptor contains 2 alpha, 2 beta and 1 gamma.

• Ion channel is selectively permeable to Chloride. — hyper polarisation results.

Different binding site on receptor for GABA A and benzodiazepine.

Receptor has both PAM and NAM.

Benzodiazepine = PAM. Positive Allosteric Modulators.

Short duration. half life less than 6 hours.

Triazolam. Hypnotic.

Short. 12-18 hours.

Lorazepam. Hypnotic/ anxiolytic.

Medium. 24hrs.

Alprazolam. Anxiolytic/ hypnotic.

Long 24-48hrs

Diazepam. Anxiolytic/ anticonvulsant

Active metabolites result and these themselves are active and have prolonged effects. Can get accumulation so have to be careful, especially with older people who have a slower metabolic action.

Drug that ends in lam or pam is a benzodiazepine.

Benzodiazepine safety

• Much safer

• Flumazenil antagonises the benzodiazepine site. Antidote to overdose.

• Enhanced CNS inhibition as a side effect: Drowsiness, amnesia, impaired coordination, ‘hangover effect’

• Often relatively safe in overdose.

• Excessive CNS suppression can send someone to respiratory block.

Drug that drives: Tolerance

Drug alters the body. Homeostatic response of the body.

Benzodiazepines drive tolerance and so they drive dependence.

Benzodiazepines used for alcohol withdrawal.

Anxiolysis

A minimal level of sedation that relaxes a person while keeping them awake, fully conscious, and able to answer questions or follow instructions.

Buspirone.

Partial agonist of 5-HT 1A. (receptor referred to as an auto receptor) (auto receptor has a negative feedback loop- turns off its own release)

Adaptive serotonergic effects.

Timing: Between benzos and SSRIs, days to two or 3 weeks.

Pregabalin and gabapentin.

Structurally related to GABA.

Do not act as GABA receptors.

Bind alpha2sigma subunit of voltage-gated Ca2+ channels.

Primary pharmacological target is calcium channels, they block them. Ca channels are presynaptic, trigger exocytosis. these drugs decrease overall activity, release.

Barbiturates (pentobarbital)

Can kill someone in overdoes through respiratory suppression.

Hypnotics. Uses.

Benzodiazepines

Z-drugs, eg: Zolpidem. Preferential action at a1-containing GABA A receptors; storing hypnotic action with relatively weak anxiolysis.

Zolpidem.

• Illustrates how GABA A receptor subunit composition can influence drug effects.

• Zolpidem preferentially binds to the alpha 1 subunit.

• This produces less anxiolytic and muscle-relaxant activity than a typical benzodiazepine such as diazepam, which acts more broadly across α1, α2, α3 and α5-containing receptors.

• Useful for insomnia rather than broad anxiolytic, anticonvulsant or muscle-relaxant actions.

Hamilton Anxiety Rating Scale (HAM-A)

0-17: Mild

18-24: Moderate

25-30: Severe.