Anti-depressants Flashcards
Categorise psychosis
Schizophrenia (disorder of thought process)
Affective disorders (disorder of mood)
Categorise affective disorders
Mania
Depression
Symptoms of clinical depression
Emotional
(Psycho-logical):
- Misery, apathy, pessimism
- Low self-esteem
- Loss of motivation
- Anhedonia (inability to enjoy activities)
Biological (Somatic): -Slowing of thought & action -Loss of libido -Loss of appetite, sleep disturbance
2 main types of depression
1) Unipolar depression/depressive disorder
2) Bipolar depression /manic depression
Outline unipolar depression
Categorise it in terms of cause
Mood swings in same direction
Reactive (75%):
- Stressful life events
- Non-familial
Endogenous:
- Unrelated to external stress
- Familial
What is the onset of unipolar
Relatively late onset
Differentiate treatment for reactive and endogenous depression
Same drugs
Outline bipolar/manic depression
Oscillating depression/mania
Strong hereditary tendency
What is the onset of bipolar depression
Less common; Early adult onset
Drug treatment for bipolar
Action of what drug can affect drug used in treatment of bipolar disorder
Lithium…. mood stabiliser
Orally (lithium carbonate)
Change in intracellular second messanger:
Involves change in IP3 (reduced) and cAMP
Small therapeutic window (like digoxin)- check plasma levels
Diuretics increase the action
Acute overodose–> confusion and convulsions and arrhythmia
Outline the monoamine theory of depression
Depression = functional deficit of central MA transmission;
Mania = functional excess
What are the mono-amines
NA & 5-HT
What is pharmacological evidence of the monoamine theory of depression
That various compounds which increase or decrease monoamine concentration in the synapse improve and worsen mood respectively
Outline the action of tricyclic antidepressants overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Block NA & 5-HT reuptake and enhance synaptic levels of these
Improve mood
Outline the action of MAO inhibitors overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Increase stores of NA & 5-HT in the cytoplasm of the presynaptic terminal (less in vesicles)
Increases synaptic level of NA and 5-HT
Improves mood
Outline the action of reserpine overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Inhibits NA & 5-HT storage in the presynaptic terminals
Was used as antihypertenstive (but patients taking it got depressed) because they reduced NA in the SNS
Worsens mood (used in lots of animal studies of depression)
Outline the action of a-methyltyrosine overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Inhibits NA synthesis
Mood ↓ Calming of manic patients
Outline the action of methyldopa overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Inhibits NA synthesis
Worsens mood
Outline the action of ECT overall, and the effect on mood
This is pharmacological evidence of the monoamine theory of depression
Increases CNS responses to NA and 5-HT
Improves mood
Give an example of a TCA
Amitriptyline
Give e piece of pharmacological evidence that might count against the monoamine theory of depression
Give a possible explanation
Amphetamines normally gets taken up into the presynaptic nerve terminal and causes NA release
Should be mood enhancing according to theory, but they are not so aren’t used as antidepressants
Might be because in cinically depressed patients there are dysfunctional pre-synaptic nerve terminals (i.e. the amphetamine cannot bind to its target sites within the nerve terminal and cause NA release)
T/F amphetamine supports the monoamine theory of depression
Not really
Give biochemical evidence of the monoamine theory of depression
That clinically depressed patients have lower levels of NA and 5-HT metabolites in their urine implying they don’t have as much monoamine
But the severity of depression is not linked to how monoamine levels ar
T/F the onset of the clinical effects antidepressant drugs is delayed because the effects on NA and 5-HT take a while
F…
THERE IS DELAYED ONSET
But not because of the NA and 5-HT
The levels of these are increased quickly,
it’s because the benefits of these drugs is linked to another mechanism
What is thought to be the mechanism of action of anti-depressant drugs which icnrease 5-HT and NA inthe synapse
The delayed clinical onset with these drugs coincides with the downregulation of a2, b and 5HT receptors
This might be the clinical effect rather than just increased levels of the chemicals
As well as monoamine theory, what else might be related to cause of depression
HPA axis increase in CRH
Hippocampal degeneration in chronic severe depression (which can be reduced with the current antidepressant drugs!)
Give an example of a TCA
Amitryptiline
Structures of TCAs
Dibenzazepines
Dibenzcycloheptenes
What type of molecule is amitryptiline
Dibenzcycloheptenes with aliphatic side chain on the central ring
Mechanism of action of TCAs
NA = 5-HT
NA is inactivaated mainly by reuptake 1
The TCAs get into the brain and then they block the carrier molecules which move 5HT and NA back into the presynaptic nerve terminal
This enhances the levels of these monoamines in the synapse
There are different carriers for each monoamine and on different nerve terminals, but they are both blocked equally by TCAs
T/F TCAs bind to NA receptors on the presynaptic membrane to prevent NA reuptake equally to 5-HT receptors
FALSE FALSE FALSE
THEY BIND TO REUPTAKE PROTEINS ON THE PRESYNAPTIC MEMBRANE, THESE ARE NOT RECEPTORS THESE ARE CARRIER MOLECULES
(however they do also inhibit a2 receptors which does increase NA release due to loss of negative feedback)
What could be other mechanism of action of TCAs
Action on receptors (i.e. not just the reuptake CARRIER MOLECULES that they block, but possibly also receptors, presynaptic and post synaptic)
Antaganonism of:
- α2
and various actions on
- mAChRs
- histamine
- 5-HT
Might be cause of side effects
What is the effect of TCAs on a2 receptors
They are a2 antagonists
a2 present on presynaptic nerve terminal and negatively feedsback for NA release, reduces release
So TCA reduces the negative feedback and increases NA release
Outline the adaptive changes TCAs cause
Delayed down-regulation of β-adrenoceptors & 5-HT2 receptors
This may coincide with the delayed onset of action of these drugs
Where is the absorption of TCAs
Rapid oral absorption
How are TCAs foud in the plasma
90-95% plasma protein bound
Outline metabolism of TCAs
Hepatic 1st pass metabolism
Active metabolites that are more weakly active but can act on the NA and 5-HT reuptake proteins
Outlinee excretion of TCAs
renal excretion (glucuronide conjugates)
What is the plasma half time of TCAs
Plasma t1/2 (10-20 hrs)
Unwanted effects of TCAs at therapeutic dose
Atropine - like effects e.g. dry mouth, constipation, blurry vision (amitriptyline, Musc. antagonism)
Postural hypotension (central- vasomotor centre)
Sedation (H1 antagonism)… leads to potentiation of alcohol depressive effect
Why to TCAs give atropine like side effects
Because they have antagonistic effects on muscarinic acetycholine receptors
What are atropine like effects
Blurred vision
Dry mouth
Urinary retention
Constipation
Why could the histamine receptor related side effects of TCAs be useful
H1 antagonists (drowsy, so sedative)
This can help if you get patients to take last thing at night before they go to sleep
helps with the insomnia symptom of depression (but some sedation might carry on)
Unwanted effects of TCAs at toxic dose
CNS: excitement, delirium, convulsive seizures –> coma, respiratory depression
CVS: cardiac dysrhythmias –> ventricular fibrillation/sudden death
Patients on these drugs can attempt suicude due to these toxicity
Drug interactions of TCAs
Many
PPB: TCA effects can be increased to toxic levels by drugs which compete for PPB
Hepatic microsomal enzymes metabolise lots of drugs and if taking another drug metabolised by this system it can slow metabolism of TCAs and increase to toxic dose in plasma
Potentiation of CNS depressants - ALCOHOL
Antihypertensives
State drugs which compete with TCAs for PPB
Aspirin and phenytoin and warfarin so can push TCA level to toxic free level
State drugs which compete with TCAs for hepatic microsomal enzyme
Microsome is referring to the rER
Neuroleptics
Oral contraceptives
Steroids
So have to be careful when prescriping anti-pschotics with antidepressants
What is the problem with alcohol and TCAs
Both causing CNS depression (TCA through droswiness due to H1 antagonism)
problems with suicide cos they might be drunk first
How could TCAs affect BP with antihypertensives
Could increase or decrease BP
Give an example of monoamine oxidase inhibitors
Phenelzine
What are the two types of MAO
MAO A: preferentially breaks down NA and 5-HT
MAO B: preferentially breaks down DA
Both break down both
What are MAOIs
What is their MOA
Monoamine oxidase inhibitors
non-selective MAO inhibitors i.e. not selective for MAO A or B
Inhibiting ENZYMES unlike TCAs which were inhibiting CARRIER PROTEINS
These enzymes are present in the cytoplasm of the presynaptic nerve terminal of 5-HT neurons and NA neurons
Inhibiting them increases MA in the cytoplasm, and then this causes leakage into the synaptic cleft
What type of enzyme inhibiors are MAOIs
IRREVERSIBLE –> long d.o.a
Structures of MAOIS
Single ring structure with aliphatic side chain
Why does phenelzine bind irreversibly
It has hydrazine NN group whcih is highly reactive and binds covalently to MAO enzymes A and B
What are the rapid and delayed effects of MAOIs
Rapid effects : increased cytoplasmic NA & 5-HT
Delayed effect: down-regulation of beta adrenoceptors and 5-HT2 receptors
Differentiate MOA of MAOIs and TCAs
Both increase MA in the synapse.
TCAs by MA reuptake inhibition
MAOIs by inhibiting enzyme which breaks down MAs
Both have their clinical effects by downregulatin of beta adrenoceptros and 5-HT receptors though
Outline absorption of MAOIs
Rapid oral absorption
Half life of MAOIs
few hours
T/F MAOIs need to be taken quite regularly because their t1/2 is only a few hours
F… because they irreversibly bind enzymes, they have long d.o.a despite their relatively short plasma half life
THIS IS A KEY POINT
Where are MAOIs metabolised and excfreted
Metabolised in liver; excreted in urine
What are the unwanted effects of MAOIs
Atropine - like effects (< TCAs)
Postural hypotension (common)
Sedation (Seizures in o.d.)
Weight gain (possibly excessive) Think MAObeseI
Hepatotoxicity (reactive hydrazine group; rare)
T.F the atropine like effects of MAOIs are caused by the same thing as TCAs but they arent as bad
T…
both caused by antagonism action on mAChR
But worse with TCA
Compare severity of side effects vs drug interactions with MAOIs and TCAs
MAOI side effects not as bad
but the drug interactions worse
Drug interaction with MAOIs
Cheese reaction Tyramine (=sympathomimetic drug like amphetamine) containing foods+MAOI can lead to hypertensive crisis (throbbing headache, increasing bp, intracranial haemorrahage)
MAOI + TCAs leads to HTN epidodes
MAOIs + pethidine (=opioid) –> hyperpyrexia, restelessness, coma and hypotension
Why can cheese reaction occur with MAOIs but not in notmal people
MAO is present in gut wall too and breaks down any tyramine
Tyramine basically acts like amphetamine and causes release of NA into the synaptic cleft
Normally all tyramine is broken down completely by the MAO and doesn’t get into blood
If taking MAOI for depresion it won’t be broken down, can get into blood and into CNS and have sympathomimejtc effect
What is the cause of the hyperprexia,restlessness, coma & hypotension that comes with co-administering MAOI and pethidine
MAOIs also block the enzyme which breaks down this opioid
Thereore the opioid gets broken down by different enzyme which causes metabolites that have these effects
What is moclobemide. Benefit and cost
reversible MAO-A inhibitor (RIMA). ↓ Drug interactions BUT ↓ doa so need to give 2-3 times per day
Less cheese reacton too
(think of be mid(n)e and rima)
Give example of SSRI
e.g. Fluoxetine and citalopram
What is SSRI mecahnism of action
Selective 5-HT re-uptake inhibition not on NA
What is the structure of SSRI
Not significant
What is the benefit of SSRI compare to TCA and MAOIs
But what is the problem
Less troublesome side effects (no cheese reaction(although strictly this is interaction), less atropine like side effects); safer in o.d.
But less effective vs severe depression
Administration of SSRIs
Oral
What is the plasma t1/2
Plasma t1/2 (18-24 hrs)
Onset of action of SSRIs
Delayed onset of action (2-4 weeks)
Why is coadministration of fluoexetne and TCA avoided
vs
why is coadministration of MAOI and TCA acoided
Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration)
TCA and MAOI avoided due to hypertension
Side effects of SSRI
Nausea (10%), diarrhoea, insomnia & loss of libido (30%)
Drug interactions of SSRI
Interact with MAOIs (avoid co-administration).. due to additive effect
And TCA for hepatic enzymes
What is most prescrbed antidepressant drug
Fluoxetine (‘Prozac’): currently most prescribed antidepressant drug
Atypical antidepressants
Venlafaxine and mirtazapine
How does venlafaxine work
Dose-dependent Reuptake inhibitors
With increasing dose, reduces uptake of:
5HT > NA»_space; DA (SNRI)
2nd Line treatment for severe depression
What are the SNRIs
Seratonin and NA reuptake inhibitor venlafaxine
How does mirtazapin work
α2 Receptor antagonist
↑ NA & 5HT release
Other R interactions (sedative)
Useful in SSRI-intolerant patients
