Anxiety and Depression

Question 1

Benzodiazepines

• What are they mainly prescribed fro?
• Why did they first get used?
• Why are they used less now?

Answer 1

• Insomnia and Anxiety
• They were advantageous over barbiturates due to safety in overdose
• The continuous use of drugs can lead to unpleasant withdrawal effects - it is reccommended a 2-4 week limit on the duration of BDZ use

Question 2

How do Benzodiazepines work?

Answer 2

Act on GABA-A (ligand gate chloride channel) - BDZ’s are allosteric modulators - on their own they have no effect on neuronal excitability. Their effect only appears in presence of GABA and they potentiate the effect of GABA by increasing its affinity for its Alpha-subunit binding site. (GABA binds to the Beta-subunit)

Question 3

What is significant about alpha 1 containing BDZ’s? What is the most commonly occuring combination?

Answer 3

40% alpha1/B2/Y2.
Receptors contailong alpha 1 (or BZ1 receptors) habe been shown to mediate sedative effects hence use for insomnia.
“alpha-1 sparing” drugs still have same anxiolutic effect - but a knock out of alpha 1 is lethal. (Knabl et al 2008)

Question 4

What is the target site for SSRI’s?

What is significant about it homology?

Answer 4

5-HT transporter in the plasma membrane

It’s 70-80% similar to to the transporters for NA and DA

Question 5

What does the target of SSRI’s normally do?

Answer 5

5-HT transporters normally co-transport 2 sodiums and one Cl with each 5-HT molecule with the countertransport of one K ion.

Question 6

Which TCA inhibits the serotonin re-uptake trasnporter more than the noradrenaline?

What drug favours inhibition of NA reuptake?

Are other TCA’s selective?

Answer 6

Clomipramine

Nortriptyline

No - other than this they are relatively non selective for either 5-HT or NA.

Question 7

What is the mechanism of action of fluoxetine?

Answer 7

Potent 5-HT(2) antagonist as well as being an SSRI.

Question 8

Do SSRI’s have additional actions?

Answer 8

Mirtazepine and Mianserin block Noradrenaline alpha-2 receptors - these are autoreceptors found on 5-HT and NA nerves that function to inhibit the release of teh respective transmitters
This mechanism of action may contribute to the antidepressant activity of the drugs.

Question 9

Name 6 SSRI’s

Answer 9

Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline

Question 10

Name 7 TCA’s

Answer 10

Clomipramine
Amitriptyline (broken down to Nortriptyline)
Dosulepin
Doxepin
Imipramine
Iofepramine
Trimipramine

Question 11

Name a Non TCA serotonin and noradrenaline re-uptake inhbitor

Answer 11

Venflaxine

Question 12

Name a Non-TCA noradrenaline reptake inhibitor

Answer 12

Reboxetine

Question 13

Name 3 atypical antidepressants and their actions

Answer 13

A-2 adrenoreceptor antagonist - mianserin
A2/5HT2A antagonist - mirtazepine
5HT2c antagonist - agomelatine

Don’t block 5HT or NA but have antidepressant effects

Question 14

Name a reversible and 3 irreversible MAO inhibitors?

Answer 14

Reversible - moclobemide

Irreversible - Phenelzine, Isocarboxetine, tranylcypromine

Question 15

Why are SSRI’s more popular?

Why were non TCA’s developed?

What are the side effects of SSRI’s?

Answer 15

SSRI’s have milder side effects compared to TCA’s. In particular they lack of antimuscarinic effects and cardotoxic effects in over-dosage. Non TCA’s were devloped in the hope they may lack these negative side effects.

Question 16

How do MAO inhibitors work? What do they metabolise?

Whats the draw back?

Answer 16

MAO is a mitocondrial enzyme existing in two isoforms: MAO-A has noradrenaline and 5HT as preferred substrates. MAO-B has substrate preferences in the reverse direction. Both metabolism dopamine.

Unfortunately - they have a toxic interaction with sympathomimetic amines such as tyramine (found in certain food stuffs) and ephedrine found in some membranes. - these are substrates for both forms of the enzyme?

Question 17

Why is tyramine a problem to MAOI;s?

Answer 17

Both forms of MAO are found in the intestine and the liver and prevent tyramine in foodstuffs from exerting ANY pharmacological effects by metabolising it during its first pass through the enteric or hepatice circulation.

After MAO is inhibited, the sympateomimetic effects of tyramine are caused by displacement of NA from binding sites in symapthetic nerve terminals.

Normally NA displaced by tyramine would be inactivated by MAO but after inactivation this doesn’t happen.

The most dangerous effect is a massive rise in blood pressure.

Question 18

Why is moclobemide the preferred MAOI?

Answer 18

It’s selective for MAO-A - so leaves the MAO-B form available to metabolise tyramine.

It is also reversible and competes with tyramine for active s