CPTP3.3: Neuropharmacology of antidepressants Flashcards
What is the monoamine theory of depression?
It states that depression is due to a deficit in central monoamine (5-HT and NA) neurotransmission.
What are classes of antidepressants which block 5-HT/NA reuptake?
- TCA’s (tricyclic antidepressants)
- SSRI’s
- SNRI’s (5-HT and NA reuptake inhibitors) and NARI’s (noradrenaline reuptake inhibitors)
How do TCA’s work?
Block reuptake of NA and 5-HT which will prolong the effects of the neurotransmitters
What are examples of TCA’s?
Amitriptyline; imipramine; lofepramine
What are the clinical limitations of TCA’s?
- Delayed onset in actions (2-3 weeks before being therapeutically active)
- Usually non-selective, so interact with other postsynaptic receptors like:
m1-receptor antagonism -> cholinergic side effects like dried mouth, blurred vision, constipation, urinary retention
H1-receptor antagonism-> sedation, weight gain
alpha-1 adrenoreceptor antagonism: postural hypotension
Hence, patient will feel worse before they get better as side effects are immediate and therapeutic effects are delayed -> poor compliance and poor overall therapeutic efficacy
- Also cardiotoxic and potentially fatal in OD
When are TCA’s used?
- For treatment of severe, treatment resistant depression
2. Cheap
When are TCA’s not used?
- Elderly and young patients as they’re more sensitive to side effects
- Cardiac patients (cardiotoxicity)
- Drivers/workers (sedation)
- Suicidal patients (overdose)
What are 2nd generation antidepressants?
Selective for 5-HT and NA transporters and do not have affinity for postsynaptic receptors -> fewer side effects (better adverse side effect profile than TCA’s)
e.g. SSRI/SNRI/NARI
What are the side effects of SSRI’s?
- Precipitate anxiety
- Nausea
- Sexual dysfunction (impotence)
- GI (nausea, constipation)
- Weight gain
- Drug interactions with other antidepressants
- Cytochrome P450 inhibition (liver toxicity)
Main difference between TCA’s and SSRI’s?
SSRIs have a better adverse side effect profile than TCAs
Explain how monoamine oxidase (MAO) works.
MAO metabolises transmitter outside the vesicles that was transported into the vesicle by VMAT2.
What do MAO inhibitors do?
They block MAO which will lead to:
- Decreased intraneuronal breakdown
- Increased vesicle content
- Increased transmitter release
What are the two types (isoforms) of MAO’s?
- MAO(A) breaks down 5HT and NA
2. MAO(B) breaks down DA
What is the difference between older MAOIs and newer MAOIs?
Older ones block both isoforms irreversably which can lead to stimulant effects and OD fatality
How can MAOIs cause hypertension?
Diet in amines can lead to production of NA, which is usually broken down by MAO(A) but MAOIs prevent this from happening -> hypertension
Explain the serotonin syndrome (toxicity).
When switching between SSRIs and MAOIs, half lives of drugs should be examined as drug interactions can cause confusion hypertensive crisis and hyperthermia due to too high levels of 5HT
Give an example of an SSRI/SNRI/NARI
Fluoxetine/venlafaxine/reboxetine
What are atypical antidepressants?
They have affinity for a range of monoamine transporters and receptors
Give examples of atypical antidepressants.
- Mirtazepine
- Nefazodone
- Mianserin
Why do antidepressants have a delayed onset of action? There are 2 hypotheses - explain them.
1) 5-HT1A autoreceptors mediate inhibitory neurotransmission and when there is an acute increase of 5HT, 5-HT1A autoreceptors are activated which inhibits transmission of 5HT by inhibiting terminal release as well. After repeated dosing, 5-HT1A autoreceptors are desensitised and firing and terminal release is restored which leads to increased levels of synaptic 5-HT levels
2) 5HT is a trophic factor and antidepressants cause increases in 5HT and increased 5HT causes synaptic remodelling which takes time
