Anti-depressants Flashcards
Psychoses can be subdivided into what? How does depression come under psychoses?
Psychoses = Schizophrenia or Affective/mood disorders
Affective/mood disorders = Mania or depression
List the Emotional (Psychological) and Biological (somatic) of depression.
Emotional (Psychological): Misery, apathy, pessimism Low self-esteem Loss of motivation Anhedonia (= inability to feel pleasure in normally pleasurable activities)
Biological (Somatic):
Slowing of thought & action
Loss of libido
Loss of appetite, sleep disturbance
Describe Unipolar depression/depressive disorder. State and distinguish between its two subtypes.
- Mood swings in same direction
- Relatively late onset
- All types of unipolar depression respond in the same way to the same drug treatments.
- Reactive depression:
- stressful life events
- non-familial inheritance - Endogenous depression:
- unrelated to external stresses
- familial pattern
Describe Bipolar depression /manic depression. Evaluate the treatment of lithium for bipolar depression.
- Oscillating depression/mania
- Less common
- Early adult onset.
- Strong hereditary tendency.
- Drug treatment includes Lithium – can stabilise the swings between mania and depression but lithium has a narrow therapeutic window.
The Monoamine theory of depression states that what?
Depression is a functional deficit of central monoamine transmission whereas Mania is a functional excess of monoamine transmission.
i.e. Related to NA and 5-HT (serotonin) deficits/excesses.
Summarise two pieces of biological evidence inconsistent with the monoamine theory
Biological evidence:
A reduction in NA metabolites is not concurrent with a worse depression.
Delayed onset of the clinical effect of drugs (a few weeks sometimes) – possibly due to adaptive changes and not MA theory i.e. there is a downregulation of receptors.
Could also be due to increased CRH (and thus cortisol) or hippocampal neurodegeneration.
Explain why there is good pharmacological evidence to support the monoamine theory by stating the mechanism of action of different drugs and the resulting effect on mood. Tricyclic antidepressants MAO inhibitors Reserpine α-Methyltyrosine Methyldopa Electroconvulsive therapy (ECT)
Pharmacological evidence:
Tricyclic antidepressants: Block NA & 5-HT reuptake
Mood ↑
MAO inhibitors: Increase stores of NA & 5-HT
Mood ↑
Reserpine: Inhibits NA & 5-HT storage
Mood ↓
α-Methyltyrosine: Inhibits NA synthesis
Mood ↓ (Calming of manic patients)
Methyldopa: Inhibits NA synthesis
Mood ↓
Electroconvulsive therapy (ECT)
Increases CNS responses to NA & 5-HT
Mood ↑
State the primary mechanism of action of TCAs and the result of this action. What receptors do they also act on?
Monoamine (NA and 5-HT) re-uptake inhibitor => *delayed down-regulation of β-adrenoceptors & 5-HT2 receptors
Also acts on:
- α2 adrenoceptors (block pre-synaptic inhibition of NA release)
- mAChRs
- histamine receptors
- 5-HT
*The time-course of this down-regulation correlates well with the delayed clinical onset of symptom relief.
Summarise the pharmacokinetics of TCAs
- ROA, transportation in blood, metabolism, excretion, plasma half-life
Give an example of a TCA
- Oral administration.
- Highly PPB – 90-95%.
- Hepatic metabolism to produce ACTIVE metabolites
- Excreted in the urine as glucuronide conjugates
- Plasma T1/2 = 10-20 hours
E.g. Amitriptyline
What are the unwanted effects of TCAs at therapeutic doses and at toxic doses (overdosing)?
At therapeutic doses:
Atropine/anti-PNS like effects
Postural hypotension – due to effects on vasomotor centre.
Sedation – due to effects on H1 antagonism.
Acute toxicity (overdose):
CNS – excitement, delirium, seizures leading to coma and respiratory depression.
CVS – cardiac dysrhythmias leading to ventricular fibrillation & sudden death.
Often used for attempted suicide!
State/describe how TCAs may interact with co-administered drugs
As TCAs are highly plasma protein bound there can be a massive increase of bioavailability if co-administered with something that displaces it from the plasma proteins – e.g. aspirin, phenytoin.
Drugs (e.g. neuroleptics, oral contraceptives) that compete with TCAs for the same metabolising hepatic microsomal enzymes => increased effects of TCAs since its metabolism is slowed down
TCAs potentiate CNS depressants e.g. alcohol.
TCA interacts with antihypertensive drugs
Monoamine oxidase enzymes (MAO-A and MAO-B) break down which monoamines.
MAO enzymes:
MAO-A breaks down NA & 5-HT
MAO-B: breaks down DA
Describe the selectivity of MAOIs and their duration of action.
State the rapid effects of MOAIs and explain the delayed clinical response.
- Most are non-selective MAOIs (selegiline is MAO-B specific)
- Irreversible inhibition leads to a long duration of action.
Rapid effects – increase cytoplasmic NA and 5-HT due to their impaired breakdown
Delayed clinical response due to down-regulation of b-adrenoceptors and 5-HT2 receptors – again, fits with delayed clinical effect.
- Inhibits other enzymes – leads to side effects.
Summarise the pharmacokinetics of MOAIs
- ROA, metabolism, excretion, plasma half-life
Give an example of a monoamine oxidase inhibitor.
- Oral absorption.
- Short plasma T1/2 but a longer DoA.
- Metabolised in the liver, excreted in the urine.
e.g. Phenelzine
Summarise the unwanted effects of MOAIs
- Atropine-like effects (anti-PNS effects) – but less so than TCAs.
- Postural hypotension
- Sedation (causes seizures in overdose)
- Weight gain
- Hepatotoxicity
