22. Anti-depressants Flashcards
What 2 types can psychoses be split into?
- Schizophrenia (disorder of thought processes)
* Affective disorders (disorders of mood - mania + depression)
What is the most common affective disorder?
Depression
What are the emotional symptoms of depression?
- Misery
- Apathy
- Pessimism
- Loss of motivation
- Anhedonia (inability to feel pleasure)
What are the biological symptoms of depression?
- Slowing of thought and action
- Loss of libido
- Loss of appetite
- Sleep disturbance
What are the 2 main groups of depression?
Unipolar (depressive disorder) and bipolar (manic depression)
Describe unipolar depression
- Mood swings in the same direction
- Late onset (adulthood)
- Can be reactive (75%) or endogenous (25%)
- Reactive: in response to stressful life events (non-familial)
- Endogenous: unrelated to external stresses (familial pattern)
Describe bipolar depression
- Oscillating depression and mania
- Less common than unipolar depression
- Early adult onset
- Strong hereditary tendency
What is the drug treatment for bipolar depression?
Lithium - not conventional antidepressant, more mood-stabilising
Summarise the monoamine theory of depression
- Depression - functional deficit of central monoamine transmission
- Mania - functional excess of central monoamine transmission
- NA + 5-HT (serotonin) are the two monoamines involved
- Based on pharmacological evidence - biochemical evidence in inconsistant
How quickly is an effect seen in the use of anti-depressant drugs?
- Changes in the monoamines is rapid
- However, the clinical effects can take weeks
- Dissociation between the neurochemical change and antidepressant effect
What receptors change in response to anti-depressants and how quickly does the change occur?
Down-regulation of α2, β and 5HT receptors
• Correlates with the onset of clinical drug effectiveness
• Therefore, this may be responsible for the clinical drug effects
How is the HPA (hypothalamic-pituitary-adrenal) axis involved in depression?
- CRH (corticotropin-releasing hormone) levels increased in depressed patients
- CRH stimulates the pituitary synthesis of ACTH
What is seen in the hippocampus in chronic depression?
Hippocampal neurodegeneration
What are the 2 main chemical groups of tri-cyclic antidepressants?
Dibenzazepines and dibenzocycloheptenes
How do tri-cyclic antidepressants work?
- Neuronal monoamine re-uptake inhibitors
- Prevent reuptake of NA and 5-HT more than dopamine
- Also act on α2 receptors, muscarinic AChRs, histamine receptors and 5-HT receptors - some of these actions are important but some contribute to the side-effects
(3 ringed structures)
What happens if TCAs bind to and antagonise alpha 2 receptors?
- Block inhibitory control over NA
* Enhance release of NA into synaptic cleft
What effect do TCAs have on β-adrenoceptors and 5-HT receptors?
- Down-regulation
* Could cause the delayed onset of the anti-depressant
Describe the absorption and protein binding of TCAs?
- Rapid oral absorption
* Highly protein bound (90-95%)
How are TCAs metabolised and what is the half life?
- Hepatic metabolism - generates active metabolites
- Renal excretion as glucuronide conjugates
- Half-life: 10-20 hours
What are the unwanted effects of TCAs at a therapeutic dosage?
- Atropine-like effects - dry mouth, blurred vision, constipation, urinary retention (TCAs have muscarinic antagonist activities)
- Postural hypotension - central effect
- Sedation - due to H1 antagonism
What are the unwanted effects of TCAs at acute toxicity?
CNS - excitement, delirium, seizures, coma, respiratory depression
CVS - dysrhythmias, ventricular fibrillation, sudden death
Outline the drug interactions of TCAs
Plasma protein binding
• Increased TCA effects when co-administered with aspirin and phenytoin
• Warfarin can displace TCAs from their binding sites - toxic levels of TCA
Hepatic microsomal enzymes
• These metabolise TCAs
• If drugs are metabolised by the same enzyme (e.g. oral contraceptives), TCA effect increases
- Potentiation of CNS depressants (alcohol) with TCAs
- Interaction with antihypertensives
Describe the action of monoamine oxidase inhibitors
- Most are non-selective - can inhibit MAO-A and MAO-B
- May result in the inhibition of other enzymes
- Inhibition is irreversible - long duration of action
- Rapid increase in cytoplasmic NA and 5-HT
- Down-regulation of β-adrenoreceptors and 5-HT receptors
Which monoamines does MAO-A and MAO-B have a preference for?
MAO-A - NA and 5-HT
MAO-B - DA
