Pharm 23 - Antidepressants

Question 1

Psychoses can be split into schizophrenia and affective disorders. What are the types of affective disorders

Answer 1

Mania and depression

affective disorders = feelings, behaviour, mood

Question 2

What is schizophrenia

Answer 2

Disorder of thought process

Question 3

What are the biological symptoms of depression

Answer 3

Slowing of thought and action
Loss of libido
Loss of appetite, sleep disturbance

Question 4

What are the features of unipolar depression/depressive disorder

Answer 4

1. Mood swings in same direction
2. Late onset (more common)
3. 2 types: reactive depression (75% - stressful life events, non-hereditary) and endogenous depression (25% - unrelated to external stresses, familial pattern)

Question 5

What are the features of bipolar depression/manic depression?

Answer 5

1. Oscillation between depression and mania (hyper excitability)
2. Early adult onset (less common)
3. Strong hereditary tendency
4. Different treatment unipolar depression - Li = mood stabiliser

Question 6

Describe the monoamine theory of depression

MA = NA / 5-HT

Pharm evidence supports but not biochemical

Answer 6

Depression = functional deficit of central MA transmission

Mania = functional excess of central MA transmission

Question 7

What is usually the response to antidepressants

Answer 7

1. Downregulation of a2, B, 5-HT receptors

Question 8

What are the classes of antidepressants

Answer 8

1. TCAs
2. MAO inhibitors (MAOI)
3. SSRIs

Question 9

Give an example of a TCA

Answer 9

Amitriptyline

Question 10

How do TCAs work

Answer 10

1. Inhibit neuronal monoamine reuptake (NA and 5-HT more than Dopamine) - so more NA/5-HT in synapses for longer —> potentiates effects of neurotransmitters
2. TCA also antagonise a2 receptors
3. TCA also have effects on mAChR, histamine-Rs, 5-HT-Rs

Question 11

TCAs cause delayed downregulation of which receptors?

Answer 11

B-adrenoreceptors and 5-HT2 receptors

Question 12

Describe the pharmacokinetics of TCAs

Answer 12

1. Rapid oral absorption
2. Highly PPB (90-95%)
3. Hepatic metabolism produces active metabolites
4. Quite long t1/2 - 10-20 hours

Question 13

How are the active TCA metabolites excreted

Answer 13

Excreted via the kidney as glucuronide conjugates

Question 14

At therapeutic dose, what are the side effects of TCAs?

Answer 14

1. Atropine-like effects (dry mouth, constipation, bladder dysfunction)
2. Postural hypotension
3. Sedation/drowsy (H1 antagonism)

Question 15

What are the symptoms of acute toxicity due to OD on TCA (TCA commonly used for suicide)

Answer 15

CNS - excitement, delirium, seizures —> coma, respiratory depression

CVS - cardiac dysrhythmias —> ventricular fibrillation/sudden death

Question 16

Give 4 drug interactions of TCAs

Answer 16

1. Aspirin - aspirin displaces TCAs from plasma proteins - free TCA rises into toxic ranges
2. If TCAs given alongside drugs (neuroleptics, oral contraceptives) that are metabolised by same hepatic metabolic enzymes -TCA conc rises as less TCA metabolism
3. TCA can potentiate CNS depressants
4. TCA may affect antihypertensives

Question 17

Give an example of a MAOI

Answer 17

Phenelzine

Question 18

What does MAO-A break down

Answer 18

NA and 5-HT

Question 19

What does MAO-B break down

Answer 19

Dopamine

Question 20

Why do most MAOIs have a long duration of action

Answer 20

Irreversible, Non selective inhibition

MAOIs also inhibit other enzymes

Question 21

Describe the structure of MAOIs

Answer 21

Single-ring structure

Question 22

What are the 2 main groups of TCAs

Answer 22

Dibenzazepines and dibenzocycloheptenes (3 tings w/ 2 benzene rings)

Question 23

What are the rapid effects of MAOIs

Answer 23

Increased cytoplasmic NA and 5-HT (in nerve terminals)

Question 24

What are the delayed effects of MAOIs

Answer 24

Clinical response and down regulation of B-adrenoreceptors and 5-HT2-Rs

Question 25

Describe the pharmacokinetics of MAOIs

Answer 25

1. Rapid oral absorption 2. Short t1/2 - BUT longer DOA due to irreversible inhibition 3. Metabolised in liver and excreted in urine

Question 26

What are the side effects of MAOIs

Answer 26

1. Atropine like effects (less than TCAs) 2. Postural hypotension 3. Sedation (seizures in OD) 4. Weight gain (linked w increased appetite) 5. Hepatotoxicity

Question 27

What are the serious drug reactions

Answer 27

1. Cheese reaction - Tyramine containing foods + MAOI causes less tyramine broken down by MAO-A/B = more plasma tyramine which can cause a hypertensive crisis 2. MAOIs and TCAs --> hypertensive episodes 3. MAOIs and pethidine --> hyperpyrexia, restlessness, coma and hypotension

Question 28

What does tyramine do?

Answer 28

Indirectly activates SNS by inducing NA release from terminals

Question 29

Give an example of a reversible MAOI

Answer 29

Moclobemide - used for depression as fewer drug interactions but reduced DOA

Question 30

Give an example of a SSRI

Answer 30

Fluoxetine (Prozac) - most prescribed current antidepressant

Question 31

What is the mechanism of Prozac (SSRI)

Answer 31

Selective 5-HT reuptake inhibitor - but less effective against severe depression

Question 32

Describe the pharmacokinetics of SSRIs

Answer 32

1. Oral administration 2. Long plasma t1/2 - 18-24 hrs 3. Delayed onset of action (2-4 weeks) 4. Fluoxetine competes w/ TCAs for hepatic enzymes (avoid co-administration)

Question 33

What are the side effects of SSRIs

Answer 33

1. Fewer than TCAs/MAOI --> less troublesome SEs and safer in OD 2. Nausea, diarrhoea, insomnia and loss of libido 3. Interact w/ MAOIs so avoid coadmin

Question 34

Name 2 other antidepressants

Answer 34

1. Venlafaxine - Dose dependent reuptake inhibitor (SNRI - Serotinin and NA reuptake inhibitor) 2. Mirtazapine - a2 receptor antagonist - inhibit negative feedback - causing increased NA and 5-HT release. Also reacts w/ histamines etc causing a sedative effect

Question 35

When is mirtazapine useful

Answer 35

In patients who are intolerant to SSRI