Pharmacology 22 - Antidepressant Drugs Flashcards
List symptoms of depression
Emotional (psychological)
- Misery, apathy, pessimism
- Low self-esteem
- Loss of motivation
- Anhedonia (loss of the ability to enjoy activities)
Biological (somatic)
- Slowing of thought and action
- Loss of libido
- Loss of appetite
- Sleep disturbance
List characteristics of unipolar depression/ depressive disorder.
List the types.
- Mood swings in same direction
- Relatively late onset
- Reactive depression (distorted reaction to stressful life events, non-familial) 75%
- Endogenous depression (unrelated to external stresses, familial pattern) 25%
List characteristics of bipolar depression/ manic depression?
- Oscillating depression/mania
- Less common; Early adult onset
- Strong hereditary tendency
- Treated with lithium (mood stabiliser, first line drug, influences intracellular second mechanisms reducing cAMP - narrow therapeutic window)
Describe the monoamine theory of depression
- Depression is due to a functional deficit of central monoamine transmission, while mania is due to functional excess
- Changes in central noradrenaline and 5-HT (serotonin) transmission
- Based on pharmacological evidence, biological evidence is inconsistent (eg. changes in receptor populations, monoamine metabolites)
- Delayed onset of clinical effect of drugs due to adaptive changes (eg. downregulation of adrenoceptors and 5-HT receptors)
- Down regulation of a2, beta, 5HT receptors
List pharmacological evidence supporting the monoamine hypothesis of depression
- Tricyclic antidepressants block NA and 5-HT reuptake, and increase mood
- Monoamine oxidase inhibitors increase stores of NA and 5-HT, and increase mood
- Reserpine inhibits NA and 5-HT storage in the brain and decreases mood
- a-Methyltyrosine inhibits NA synthesis and calms manic patients
- Methyldopa inhibts NA synthesis and decreases mood
- ECT increases CNS respose to NA and 5-HT and improves mood
- However cocaine prevents NA reuptake and does not affect depression
Give an example of a TCA
Amitriptyline
Describe the mechanism of action of TCAs
- 3 ring structures
- Neuronal monoamine re-uptake inhibitors
- NA and 5-HT
- Also antagonise a2 receptors (enhancing release of NA and 5-HT), as well as interacting with mAChRs, histamine and 5-HT
- Delayed down-regulation of beta-adrenoceptors and 5-HT2 receptors
Describe pharmacokinetics of TCAs
- Rapid oral absorption
- Highly plasma protein binding (90-95%)
- Hepatic metabolism to active metabolites, renal excretion of glucoronide conjugates
- Plasma half life 10-20 hours
List unwanted effects of TCAs at therapeutic dosage
- Atropine like effects (amitriptyline - dry mouth, dry skin, blurred vision due to inhibiting muscarinic receptors)
- Postural hypotension (vasomotor centre)
- Sedation (H1 antagonism)
List unwanted effects of TCAs in acute toxicity (overdose)
- CNS excitement, delirium, seizures resulting in coma and respiratory depression
- Cardiac dysrhythmias leading to ventricular fibrillation/ sudden death
- Therefore, take care for attempted suicide
List drug interactions of TCAs
- Aspirin and phenytoin increase TCA effects, as they displace TCA from plasma proteins
- Neuroleptics and oral contraceptives increase TCA effects, as they use the same hepatic microsomal enzymes (therefore TCA is metabolised more slowly)
- Potentiation of CNS depressants (alcohol - sedation)
- Antihypertensive drugs (unpredictable - might go up or down)
Describe the mechanism of action of monoamine oxidase inhibitors
- MAO-A preferentially breaks down NA and 5HT
- MAO-B preferentially breaks down DA
- Most inhibitors are non-selective
- Irreversible inhibition therefore long duration of action
- Rapid effect of increasing cytoplasmic NA and 5-HT (via slowing breakdown)
- Delayed effects include clinical response (2-3 weeks) due to downregulation of beta adrenoceptors and 5-HT2 receptors
- Inhibition of other enzymes
Describe pharmacokinetics of MAO inhibitors
- Rapid oral absorption
- Short plasma half life (a few hours) but longer duration of action
- Metabolised in liver and excreted in urine
List unwanted effects of MAO inhibitors
- Atropine like effects (less marked than TCAs)
- Postural hypotension (common)
- Sedation (seizures in overdose)
- Weight gain
- Hepatotoxicity (rare)
List drug interactions of MAO inhibitors
- Tyramine (intrinsically active sympathomimetic which increases release of noradrenaline) containing foods + MAOI results in hypertensive crisis (throbbing headache, increase in BP and intracranial haemorrhage - cheese reaction due to lack of tyramine breakdown)
- MAOIs and TCAs result in hypertensive episodes
- MAOIs and pethidine result in hyperpyrexia, restlessness, coma and hypotension
What is moclobemide?
Reversible MAO-A inhibitor (RIMA), with decreased drug interactions and decreased duration of action, so must be taken more regularly
Give and example of a SSRI
Fluoxetine (Prozac)
Describe the mechanism of action of fluoxetine
- Selective 5-HT re-uptake inhibition
- Less troublesome side-effects so safer in overdose
- Less effective in severe depression
Describe pharmacokinetics of SSRIs
- Oral administration
- Plasma half life 18-24 hours (taken once a day)
- Delayed onset of action (2-4 weeks)
- Fluoxetine compretes with TCAs for hepatic enzymes, so avoid co-administration
List unwanted effects of SSRIs
- Fewer than TCAs/ MAOIs
- Nausea, diarrhoea, insomnia, loss of libido
- Interact with MAOIs (avoid co administration)
What is the most prescribed antidepressant drug?
Fluoxetine (SSRI - trade name prozac)
What is venlafaxine?
- Dose dependent reuptake inhibitor
- 5HT > NA»_space; DA (higher doses affect NA/dopamine too)
- 2nd line treatment for severe depression
- More expensive than fluoxetine
What is mirtazapine?
- a2 receptor antagonist
- Increase NA and 5HT release
- Other receptor interactions (sedative)
- Useful in SSRI-intolerant patients
Describe classification of depression
- Psychoses are split into schitzophrenia and affective disorders (disorders of mood)
- Affective disorders are split into mania and depression
What are the two types of depression?
- Unipolar depression/ depressive disorder
- Bipolar depression/ manic depression
Give an example of a monoamine oxidase inhibitor
Phenelzine
When is ECT used?
- Last resort
- Used in black depression
- Electrical stimulation of the temporal lobe for short bursts
- Suxamethonium (short acting) taken initially to prevent patients harming themselves/ seizure
