Antidepressants Flashcards
What are the classifications of psychoses?
Psychoses:
- Schizophrenia - disorder of thought process
- Affective disorders - disorder of mood
1) Mania
2) Depression
List some psychological symptoms of clinical depression?
Misery, apathy, pessimism
Low self-esteem
Loss of motivation
Anhedonia - inability to feel pleasure in normally pleasurable activities.
List some biological (somatic) symptoms of depression?
Slowing of thought and action
Loss of libido
Loss of appetite
Sleep disturbance
Describe unipolar depression/depressive disorder?
- 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
Describe bipolar depression/manic depression?
- 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.
What is the monoamine theory of depression?
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.
What is the pharmacological evidence supporting the MA theory of depression?
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
Give an example of a TCA and describe their method of action?
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
Describe the pharmacokinetics of TCAs?
Rapid oral absorption
Highly PPB (90 - 95%)
Hepatic metabolism - active metabolites generated- renal excretion (glucuronide conjugates)
Plasma t1/2 (10-20 hrs)
What are the unwanted effects of TCAs at a therapeutic dose?
Atropine - like effects (amitriptyline). Since they can antagonise muscarinic receptors.
Postural hypotension (vasomotor centre)
Sedation (H1 receptors antagonism)
What are the unwanted effects of TCAs at acute toxicity (O.D)
CNS: excitement, delirium, seizures –> coma, respiratory depression
CVS: cardiac dysrhythmias –> ventricular fibrillation/sudden death
Care - attempted suicide
What are the drug interactions of TCAs?
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
Give an example of a MAO inhibitor and describe their method of action?
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
Describe the pharmacokinetics of MAOI
Rapid oral absorption
Short plasma t1/2 (few hrs) but longer d.o.a.
Metabolised in liver; excreted in urine
What are the unwanted effects of MAOI?
Atropine - like effects (< TCAs)
Postural hypotension (common)
Sedation (Seizures in o.d.)
Weight gain (possibly excessive)
Hepatotoxicity (hydrazines; rare)
What are the drug interactions of MAOI?
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.
Give an example of an SSRIs and its method of action?
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
What are the pharmacokinetics of SSRIs?
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)
What are the unwanted effects of SSRIs?
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)
Describe venlafaxine
Dose-dependent Reuptake inhibitor - if you increase the dose you get the addition of these effects below.
5HT > NA»_space; DA (SNRI)
2nd Line treatment for severe depression
Describe Mirtazapine
α2 Receptor antagonist
↑ NA and 5HT release
Other receptor interactions (sedative)
Useful in SSRI-intolerant patients
