Antidepressants

Question 1

What are the classifications of psychoses?

Answer 1

Psychoses:

• Schizophrenia - disorder of thought process
• Affective disorders - disorder of mood
  1) Mania
  2) Depression

Question 2

List some psychological symptoms of clinical depression?

Answer 2

Misery, apathy, pessimism

Low self-esteem

Loss of motivation

Anhedonia - inability to feel pleasure in normally pleasurable activities.

Question 3

List some biological (somatic) symptoms of depression?

Answer 3

Slowing of thought and action

Loss of libido

Loss of appetite

Sleep disturbance

Question 4

Describe unipolar depression/depressive disorder?

Answer 4

• Mood swings in same direction
• Relatively late onset
• Drug treatment - same class of drugs for both reactive and endogenous depression.

Unipolar depression can be split into:

Reactive depression (75% of unipolar depression)

1) stressful life events    2) non-familial

Endogenous depression (25%)

1) unrelated to external stresses    2) familial pattern

Question 5

Describe bipolar depression/manic depression?

Answer 5

• Oscillating depression/mania
• Less common; Early adult onset
• Strong hereditary tendency - genetic link with bipolar depression
• Drug treatment (Lithium - mood stabiliser, restricts swings between the depression and manic phase.) Taken orally - complex intracellular mechanism. Narrow therapeutic range - you must monitor plasma level of lithium.

Question 6

What is the monoamine theory of depression?

Answer 6

Depression = functional deficit of central MA transmission.
Mania = functional excess of MA transmission.

Both of these MA: Noradrenaline and serotonin (5-HT)

There is pharamacological evidence supporting the MA hypothesis of depression. However the biochemical evidence is inconsistent.

There is a delayed onset of clinical effect of drugs (adaptive changes) - This delay seems to correlate with the down-regulation of: a2, b, 5HT receptors.

Question 7

What is the pharmacological evidence supporting the MA theory of depression?

Answer 7

Tricyclic antidepressants - block NA and 5-HT reuptake = increases mood

MAO inhibitors increases stores of NA and 5-HT = increases mood

Methyldopa - inhibits NA synthesis = decreases mood

See slide 5

Question 8

Give an example of a TCA and describe their method of action?

Answer 8

Example: Amitriptyline

Neuronal monoamine re-uptake inhibitors. Inhibits the reuptake of NA and 5-HT

Other receptor actions?

	- α2 - TCAs are alpha 2 antagonist. Meaning that it reduces the negative feedback leading to a more extensive release of NA. 
	- mAChRs (block these - atropine like effects)
	- histamine - drowsiness caused by H1 receptor blocking
	- 5-HT

Delayed down-regulation of β-adrenoceptors and 5-HT2 receptors

See slide 7 for diagram

Question 9

Describe the pharmacokinetics of TCAs?

Answer 9

Rapid oral absorption

Highly PPB (90 - 95%)

Hepatic metabolism - active metabolites generated- renal excretion (glucuronide conjugates)

Plasma t1/2 (10-20 hrs)

Question 10

What are the unwanted effects of TCAs at a therapeutic dose?

Answer 10

Atropine - like effects (amitriptyline). Since they can antagonise muscarinic receptors.

Postural hypotension (vasomotor centre)

Sedation (H1 receptors antagonism)

Question 11

What are the unwanted effects of TCAs at acute toxicity (O.D)

Answer 11

CNS: excitement, delirium, seizures –> coma, respiratory depression

CVS: cardiac dysrhythmias –> ventricular fibrillation/sudden death

Care - attempted suicide

Question 12

What are the drug interactions of TCAs?

Answer 12

Many!

PPB: increases TCA effects (aspirin, compete with TCA to PPB, phenytoin) Displacement of TCA from PPB resulting in more free TCAs.

Hepatic microsomal enzymes: increases TCA effects (neuroleptics; oral contraceptives)

Potentiation of CNS depressants (alcohol) - Alcohol effect on top of the TCAs.

Antihypertensive drugs (monitor closely) - there are increases and drops in BP

Question 13

Give an example of a MAO inhibitor and describe their method of action?

Answer 13

Example: Phenelzine.
Single ring structure with long side chains.

There are two types of MAO: MAO-A (DO, NA and 5-HT) and MAO-B (dopamine)

Most are non-selective MAO inhibitors.

Irreversible inhibition –> long d.o.a.

Rapid effects : increases cytoplasmic NA and 5-HT. The increase in cytoplasmic NA results in leakage into the synaptic cleft.

Delayed effects:

 1) clinical response
2) down-regulation of β-adrenoceptors and 5-HT2 receptors

Inhibition of other enzymes

Question 14

Describe the pharmacokinetics of MAOI

Answer 14

Rapid oral absorption

Short plasma t1/2 (few hrs) but longer d.o.a.

Metabolised in liver; excreted in urine

Question 15

What are the unwanted effects of MAOI?

Answer 15

Atropine - like effects (< TCAs)

Postural hypotension (common)

Sedation (Seizures in o.d.)

Weight gain (possibly excessive)

Hepatotoxicity (hydrazines; rare)

Question 16

What are the drug interactions of MAOI?

Answer 16

Can cause serious problems

1) ‘Cheese reaction’: Tyramine-containing foods + MAOI –> hypertensive crisis (throbbing headache, increase bp, intracranial haemorrhage) Tyramine binds to NA transporter and pushes NA out into the pre-synaptic cleft has a sympathomimetic effect.
2) MAOIs + TCAs –> hypertensive episodes (avoid)
3) MAOIs + pethidine –> hyperpyrexia, restlessness, coma and hypotension. Caused by the interaction with the metabolism of pethidine

Moclobemide: reversible MAO-A inhibitor (RIMA). ↓ Drug interactions ↓ duration of action.

Question 17

Give an example of an SSRIs and its method of action?

Answer 17

Example: Fluoxetine

Selective 5-HT re-uptake inhibition

Less troublesome side-effects; safer in overdose, fewer atropine like side effective, less cheese reaction

But less effective against severe depression

Question 18

What are the pharmacokinetics of SSRIs?

Answer 18

oral administration

Plasma t1/2 (18-24 hrs) - dosing once a day

Delayed onset of action (2-4 weeks)

Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration)

Question 19

What are the unwanted effects of SSRIs?

Answer 19

Fewer than TCAs/MAOIs as a result Fluoxetine (‘Prozac’): currently most prescribed antidepressant drug

1) Nausea, diarrhoea, insomnia and loss of libido
2) Interact with MAOIs (avoid co-administration)

Question 20

Describe venlafaxine

Answer 20

Dose-dependent Reuptake inhibitor - if you increase the dose you get the addition of these effects below.
5HT > NA&raquo_space; DA (SNRI)

2nd Line treatment for severe depression

Question 21

Describe Mirtazapine

Answer 21

α2 Receptor antagonist

↑ NA and 5HT release

Other receptor interactions (sedative)

Useful in SSRI-intolerant patients