Anti-depressants Drugs Flashcards
what group of disorders does depression stem from?
- main: psychoses
- this divides into schizophrenia (thoughts) and affective disorders (mood)
- affective disorders divide into mania and depression
what are the symptoms of emotional/psychological depression?
misery apathy pessimism low self-esteem loss of motivation anhedonia (loss of enjoyment from activities)
what are the biological/somatic symptoms of depression?
slowing of action/thoughts
loss of libido (dopamine)
loss of appetite (serotonin)
sleep disturbances (serotonin)
what are the two types of depression?
unipolar and bipolar depression
simple definition of unipolar depression
(Depressive disorder)
mood swings only in ONE direction
relatively late onset
reactive and endogenous
describe the onset of unipolar and bipolar depression
unipolar- relatively late onset
bipolar- less common and early adult onset
what are the two types of unipolar depression?
i. Reactive depression (most common)
– distorted response to stressful life events, non-familial inheritance.
ii. Endogenous depression
– unrelated to external events, familial pattern.
both respond the same way to the same drug treatments
simple definition of bipolar depression
(Manic depression)
– oscillating between depression and mania
depression is deficit in MA
mania is excess in MA
Strong hereditary tendency.
what kind of drug is used in bipolar depression? why?
lithium
- is a mood stabiliser so the swings between mania and depression are reduced
- impacts secondary messenger mechanisms
- however lithium has a narrow therapeutic window
what is important when giving lithium over a long period?
plasma monitoring needs to occur to avoid toxic effects from chronic use
what does the Monoamine Theory of Depression describe?
Depression is a functional deficit of central MA transmission
(Mania is a functional excess of MA transmission)
Related to Noradrenaline, 5-Hydroxytryptamine (serotonin) (and Dopamine) deficits/excesses
There is good pharmacological evidence to support this theory but biological evidence is inconsistent.
what is the biological evidence against the Monoamine theory?
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:
e.g. downregulation of alpha 2, beta and 5-HT receptors.
what is the impact of TCAs and MAOis on mood?
both increase mood via different methods by essentially making more NA and 5-HT available
also ECT (increase CNS responses to the MAs)
what is the principle action of TCAs?
block NA and 5-HT reuptake
so more remains in the synaptic cleft
what is the principle action of MAOi?
increase the stores of NA and 5-HT
so more is remains/released at the synaptic cleft
name a couple drugs that can reduce mood? how?
methyldopa (antihypertensive)
- inhibits NA synthesis
reserpine (antihypertensive)
- inhibits NA and 5h-HT storage
what is an argument that can be used against the MA theory?
cocaine is not an antidepressant despite its enhanced effect on MAs
what is the cause of the delayed effects of the drugs used in treating depression?
down regulation of MA receptors like beta adrenoceptors and 5 HT2
it may take 2-3 weeks or more to see effects due to changes that have already taken place to NA and 5-HT transmission that have caused adaptive changes in the brain e.g. up or downregulation of receptors
what do recent studies propose to the pathophysiology to depression? i.e. other than Monoamine theory
Could also be due to increased CRH (and thus cortisol) or hippocampal neurodegeneration.
what are the 3 main anti-depressant drugs used to treat depression?
1) TCAs e.g. amitriptyline
2) MAOi e.g. phenelzine, meclobemide
3) SSRI e.g. fluoxetine (prozac)
what is the MoA of TCAs?
Monoamine re-uptake inhibitor so it enhances NA effects as they remain in the cleft
effects on NA=5-HT»_space; DA.
Also acts on other receptors to contribute to the antidepressant effects:
- alpha 2 as antagonist (block pre-synaptic inhibition of NA release)
- mAChR.
- H2 (histamine) receptors.
- 5-HT receptors.
what is the effect of TCAs binding to alpha 2 receptors?
binds to alpha 2 as antagonist
– block pre-synaptic inhibition of NA release so no -ve FB on NA release so more is released
what receptors does TCA bind to?
alpha 2 mAChR. H2 (histamine) receptors. 5-HT2 receptors. beta adrenoceptors
affects monoamine reuptake
what receptors do TCAs down regulate?
TCAs down-regulate beta-adrenoceptors and 5-HT2 receptors.
The time-course of this down-regulation correlates well with the clinical onset of symptom relief.
describe the pharmacokinetics of TCAs
o Oral administration.
o Highly PPB – 90-95% (easily displaced by co-admin drug)
o Hepatic metabolism
– to ACTIVE metabolites
- excreted in the urine (glucuronide conjugates).
o Plasma T1/2 = 10-20 hours – dose once daily.
what are the unwanted effects of TCAs at therapeutic doses?
Atropine-like effects
– anti-PNS effects such as dry mouth, constipation, etc.
Postural hypotension
– due to effects on vasomotor centre.
Sedation
– due to effects on H1 antagonism.
name a TCA and describe it’s structure
amitriptyline
tricyclic molecule of two classes with different groups attached to them
what are the unwanted effects of TCAs due to an acutely toxic dosage?
CNS
– excitement, delirium, seizures –> coma, respiratory depression.
CVS
– cardiac dysrhythmias –> VF & sudden death.
Often used for attempted suicide!
what are the drug interactions TCAs can get into?
- PPB (with co-administered drugs)
- hepatic enzymes (with SSRIs)
- potentiation (alcohol)
- antihypertensives
why does TCA high in PPB increase bioavailability when co-administered with something else?
as it is very 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 (seizure use)
i.e. more it free in the plasma
why do TCAs dependent on hepatic enzymes cause drug interactions?
other drugs e.g oral contraceptives compete with the metabolising hepatic enzymes, so the TCA will remain longer
how does TCA cause potentiation with other drugs?
drugs that potentiate the effects of the CNS depression – e.g. alcohol.
name a MAOi and describe its structure
phenelzine a hydrazine (single ring)
what are the MAO enzymes phenelzine affects?
what do these enzymes break down?
MAO-A breaks down NA & 5-HT mainly
MAO-B: breaks down DA mainly
why does phenelzine affect MAO-A and B?
it is non-selective like most MAOis
there are selective ones
what is the principle action of phenelzine MAOi?
- irreversible binding of MAO enzyme so irreversible inhibition
- MAs like NA can have longer duration of action as they are not metabolised
what is the rapid effect of phenelzine?
increase cytoplasmic (not enhanced release but more leakage) NA, 5-HT due to reduced breakdown so the MA effects are enhanced
what is the cause of the delayed effect of phenelzine?
delayed clinical response due to down-regulation of beta-adrenoceptors and 5-HT2 receptors
– fits with delayed clinical effect.
how can side effects arise from using MAOis?
they also inhibit other enzymes leading to side effects
describe the pharmacokinetic of MAOi
o Oral absorption.
o Short plasma T1/2 (few hours) but a longer DoA so can be give once or twice a day
o Metabolised in the liver, excreted in the urine.
what are the unwanted effects of MAOis?
o Atropine-like effects (anti-PNS effects) – but less so than TCAs. o Postural hypotension (VMC effect) – common. o Sedation – causes seizures in OD. o Weight gain – possibly excessive. o Hepatotoxicity – hydrazines, rare due to reactive group in OD
what are the drug interactions for MAOis?
- Cheese Reaction (tyramine containing foods)
- hypertensives episodes with TCAs
- hyperpyrexia, restlessness, coma and hypotension with pethidine (opioid)
what is the Cheese Reaction?
when MAOis interact with tyramine containing food leading to a hypertensive crisis
what is the mechanism by which tyramine with MAOI causes hypertension?
Cheese reaction:
- tyramine is metabolised by MAO also
- high level of tyramine will compete with NA for MAO
- NA remains longer in the clefts leading to hypertensive episodes
name an MAO-A selective drug
Meclobemide
name an MAO-B selective drug
seliginine (used for PD treatment)
name a reversible MAOi
Meclobemide (RIMA- Reversible inhibitor of MOA-A)
what is the benefit of using a RIMA (Reversible Monamine Oxidase Inhibitor) like meclobemide?
reduced drug interaction
(and reduced duration of action)
there is a less of a Cheese Reaction but possible reduces its efficacy
Meclobemide specifically is MAO-A selective however
name a SSRI
selective serotonin/5-HT reuptake inhibitor
e.g. fluoxetine (tmn Prozac) the most prescribed antidepressant but not the most effective
what is the benefit of using SSRIs in treating depression?
- fewer bad side effects due to fewer receptor interactions
- it is not prone to the Cheese Reaction
- safer in OD
but less effective for severe depression
describe the pharmacokinetic of SSRIs
o Oral administration.
o Plasma T1/2 = 18-24 hours.
o Delayed onset of action – 2-4 weeks.
o Fluoxetine competes with TCAs for hepatic enzymes so avoid co-administration.
what is the drug interaction that fluoxetine can get in?
Fluoxetine (SSRI) competes with TCAs for hepatic enzymes so avoid co-administration.
what are the unwanted effects of SSRIs?
o Nausea, diarrhoea, insomnia, loss of libido.
(Fewer side effects than TCAs/MAOIs)
o Interacts with MAOIs and TCAs – avoid co-administration.
o Increases suicidality in the <18s.
what are some other anti-depressants that can be used?
Venlafaxine
– dose-dependent re-uptake inhibitor (SNRI- Serotonin and Noradrenaline Reuptake inhibitor)
Mertazapine
– alpha 2 receptor antagonist
how is Venlafaxine dose dependent?
in general 5HT>NA>DA
- low dose–> 5HT
- moderate dose –> 5HT and NA
- high dose–> 5HT, NA and DA
what is the effect of mertazapine?
- inhibits negative inhibition of NA release via alpha 2
- therefore Increases NA and 5-HT release.
- useful in SSRI intolerant patients.
