23. Antidepressants Flashcards
what can psychoses be split into?
schizophrenia and the affective disorders (mania and depression)
what are the emotional and biological symptoms of depression?
EMOTIONAL
- misery
- apathy
- pessimism
- low self-esteem
- loss of motivation
BIOLOGICAL
- slowing of thought and action
- loss of libido
- loss of appetite
- sleep disturbance
what are the 2 main groups of depression?
unipolar
bipolar
describe unipolar depression
- mood swings are in the same direction
- relatively late onset (adulthood)
- can be split into reactive depression (75%) and endogenous depression (25%)
- drug treatment available
what is the difference between reactive depression and endogenous depression?
reactive depression: depression in response to stressful life events, that is non-familial
endogenous depression: depression that is unrelated to external stresses, with a familial pattern
describe bipolar/manic depression
- oscillating depression and mania (hyper-excitability with symptoms opposite to depression)
- early adult onset
- strong hereditary tendency
- drug treatment (lithium) - a mood-stabilising drug
what is the difference between depression and mania?
depression: a functional deficit in central monoamine transmission
mania: a functional excess of central monoamine transmission
describe the monoamine theory of depression
- NA and 5-HT (serotonin) are the 2 monoamines involved
- there is a delayed onset of clinical effects of anti-depressant drugs
- the changes in NA and 5-HT are rapid
- however the clinical effect can take weeks before we see the optimal action of the drug
- there is a dissociation between the neurochemical change and the antidepressant effect
what is there often down-regulation of in response to anti-depressants? what does this suggest?
down-regulation of a2, B, 5-HT receptors
this often correlates with the onset of clinical drug effectiveness so these changes may be responsible for the clinical drug effects
what is seen in chronic depression?
hippocampal neurodegeneration
what are the 2 main chemical groups in tri-cyclic antidepressants?
dibenzazepines
dibenzcycloheptenes
outline the key features of tri-cyclic antidepressants (TCAs)
- 3-ringed structures
- neuronal monoamine re-uptake inhibitors
- prevent reuptake of NA and 5-HT more than dopamine
- potentiate the action of these monoamines for longer
give an example of a TCA
amitriptyline
what other receptor actions do TCAs have?
actions on a2 receptors, muscarinic AchRs, histamine receptors, 5-HT receptors
what do TCAs do to a2 receptors?
bind to and antagonise these receptors –> enhance the release of NA –> block the inhibitory control over NA –> allow a greater increase of NA into the synaptic cleft
outline the pharmacokinetics of TCAs
- rapid oral absorption
- highly plasma-protein bound (90-95%)
- hepatic metabolism: metabolised in the liver which generates active metabolites (weaker) which then undergo renal excretion (as glucoronide conjugates)
- plasma half life of 10-20hrs (so can be given once a day)
what are the unwanted effects of TCAs at therapeutic dose?
- atropine-like effects with amitriptyline: dry mouth, blurred vision, constipation, urinary retention
- postural hypotension (mediated through the vasomotor centre)
- sedation (due to H1 antagonism) - patients feel drowsy during the day
what are the unwanted effects of TCAs at acute toxicity (overdose)?
- CNS: excitement, delirium, seizures –> coma and respiratory depression
- CVS: cardiac dysrhythmias –> ventricular fibrillation and sudden death
- TCAs that are muscarinic antagonists: affect vagal input to the heart
how do TCAs interact with other drugs?
- increased TCA effects from co-administration with aspirin and phenytoin (anti-convulsants)
- warfarin can displace TCAs from their binding sites –> plasma levels of TCA become toxic
- hepatic microsomal enzymes metabolise TCAs so TCA effects increase if co-administered with drugs that are metabolised by the same enzyme system (neuroleptics and oral contraceptives)
- potentiation of CNS depressants (e.g. alcohol) with TCAs
- unpredictable interaction with antihypertensives
give an example of a monoamine oxidase inhibitor (MAOI)
phenelzine
outline the key features of monoamine oxidase inhibitors
- involves monoamine oxidase A (preference for NA and 5-HT) and monoamine oxidase B (preference for dopamine)
- most drugs are non-selective (inhibit both MAO-A and MAO-B)
- inhibition is irreversible –> long duration of action
- down-regulation of b adrenoceptors and 5-HT2 receptors which corresponds with delayed onset of clinical effectiveness
- not entirely selective –> inhibition of other enzymes
what neurochemical changes occur with monoamine oxidase inhibitors? why?
rapid increase in cytoplasmic NA and 5-HT
the breakdown of NA and 5-HT is being blocked by MAOIs so there is enhanced activity in the brain
describe the chemical structures of MAOIs
- single ring structure
- range of different chemical classes
describe the chemical structure of phenelzine
- a hydrazine
- single ring with a carbon side chain
- hydrazine functional group on the end which is very reactive
- functional group forms covalent bonds with the MAO enzyme (irreversible inhibition)
