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LCRS Pharma > Anti-depressants Drugs > Flashcards

Anti-depressants Drugs Flashcards

1
Q

what group of disorders does depression stem from?

A
  • main: psychoses
  • this divides into schizophrenia (thoughts) and affective disorders (mood)
  • affective disorders divide into mania and depression
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2
Q

what are the symptoms of emotional/psychological depression?

A 
misery
apathy
pessimism
low self-esteem
loss of motivation
anhedonia (loss of enjoyment from activities)
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3
Q

what are the biological/somatic symptoms of depression?

A

slowing of action/thoughts
loss of libido (dopamine)
loss of appetite (serotonin)
sleep disturbances (serotonin)

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4
Q

what are the two types of depression?

A

unipolar and bipolar depression

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5
Q

simple definition of unipolar depression

A

(Depressive disorder)
mood swings only in ONE direction

relatively late onset
reactive and endogenous

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6
Q

describe the onset of unipolar and bipolar depression

A

unipolar- relatively late onset

bipolar- less common and early adult onset

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7
Q

what are the two types of unipolar depression?

A

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

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8
Q

simple definition of bipolar depression

A

(Manic depression)
– oscillating between depression and mania
depression is deficit in MA
mania is excess in MA

Strong hereditary tendency.

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9
Q

what kind of drug is used in bipolar depression? why?

A

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
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10
Q

what is important when giving lithium over a long period?

A

plasma monitoring needs to occur to avoid toxic effects from chronic use

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11
Q

what does the Monoamine Theory of Depression describe?

A

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.

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12
Q

what is the biological evidence against the Monoamine theory?

A

 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.

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13
Q

what is the impact of TCAs and MAOis on mood?

A

both increase mood via different methods by essentially making more NA and 5-HT available

also ECT (increase CNS responses to the MAs)

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14
Q

what is the principle action of TCAs?

A

block NA and 5-HT reuptake

so more remains in the synaptic cleft

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15
Q

what is the principle action of MAOi?

A

increase the stores of NA and 5-HT

so more is remains/released at the synaptic cleft

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16
Q

name a couple drugs that can reduce mood? how?

A

methyldopa (antihypertensive)
- inhibits NA synthesis

reserpine (antihypertensive)
- inhibits NA and 5h-HT storage

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17
Q

what is an argument that can be used against the MA theory?

A

cocaine is not an antidepressant despite its enhanced effect on MAs

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18
Q

what is the cause of the delayed effects of the drugs used in treating depression?

A

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

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19
Q

what do recent studies propose to the pathophysiology to depression? i.e. other than Monoamine theory

A

Could also be due to increased CRH (and thus cortisol) or hippocampal neurodegeneration.

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20
Q

what are the 3 main anti-depressant drugs used to treat depression?

A

1) TCAs e.g. amitriptyline
2) MAOi e.g. phenelzine, meclobemide
3) SSRI e.g. fluoxetine (prozac)

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21
Q

what is the MoA of TCAs?

A

Monoamine re-uptake inhibitor so it enhances NA effects as they remain in the cleft

effects on NA=5-HT&raquo_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.
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22
Q

what is the effect of TCAs binding to alpha 2 receptors?

A

binds to alpha 2 as antagonist

– block pre-synaptic inhibition of NA release so no -ve FB on NA release so more is released

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23
Q

what receptors does TCA bind to?

A 
alpha 2 
 mAChR.
 H2 (histamine) receptors.
 5-HT2 receptors.
 beta adrenoceptors

affects monoamine reuptake

24
Q

what receptors do TCAs down regulate?

A

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.

25
Q

describe the pharmacokinetics of TCAs

A

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.

26
Q

what are the unwanted effects of TCAs at therapeutic doses?

A

 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.

27
Q

name a TCA and describe it’s structure

A

amitriptyline

tricyclic molecule of two classes with different groups attached to them

28
Q

what are the unwanted effects of TCAs due to an acutely toxic dosage?

A

 CNS
– excitement, delirium, seizures –> coma, respiratory depression.
 CVS
– cardiac dysrhythmias –> VF & sudden death.

Often used for attempted suicide!

29
Q

what are the drug interactions TCAs can get into?

A
  • PPB (with co-administered drugs)
  • hepatic enzymes (with SSRIs)
  • potentiation (alcohol)
  • antihypertensives
30
Q

why does TCA high in PPB increase bioavailability when co-administered with something else?

A

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

31
Q

why do TCAs dependent on hepatic enzymes cause drug interactions?

A

other drugs e.g oral contraceptives compete with the metabolising hepatic enzymes, so the TCA will remain longer

32
Q

how does TCA cause potentiation with other drugs?

A

drugs that potentiate the effects of the CNS depression – e.g. alcohol.

33
Q

name a MAOi and describe its structure

A 
phenelzine 
a hydrazine (single ring)
34
Q

what are the MAO enzymes phenelzine affects?

what do these enzymes break down?

A

MAO-A breaks down NA & 5-HT mainly

MAO-B: breaks down DA mainly

35
Q

why does phenelzine affect MAO-A and B?

A

it is non-selective like most MAOis

there are selective ones

36
Q

what is the principle action of phenelzine MAOi?

A
  • irreversible binding of MAO enzyme so irreversible inhibition
  • MAs like NA can have longer duration of action as they are not metabolised
37
Q

what is the rapid effect of phenelzine?

A

increase cytoplasmic (not enhanced release but more leakage) NA, 5-HT due to reduced breakdown so the MA effects are enhanced

38
Q

what is the cause of the delayed effect of phenelzine?

A

delayed clinical response due to down-regulation of beta-adrenoceptors and 5-HT2 receptors

– fits with delayed clinical effect.

39
Q

how can side effects arise from using MAOis?

A

they also inhibit other enzymes leading to side effects

40
Q

describe the pharmacokinetic of MAOi

A

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.

41
Q

what are the unwanted effects of MAOis?

A 
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
42
Q

what are the drug interactions for MAOis?

A
  • Cheese Reaction (tyramine containing foods)
  • hypertensives episodes with TCAs
  • hyperpyrexia, restlessness, coma and hypotension with pethidine (opioid)
43
Q

what is the Cheese Reaction?

A

when MAOis interact with tyramine containing food leading to a hypertensive crisis

44
Q

what is the mechanism by which tyramine with MAOI causes hypertension?

A

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
45
Q

name an MAO-A selective drug

A

Meclobemide

46
Q

name an MAO-B selective drug

A

seliginine (used for PD treatment)

47
Q

name a reversible MAOi

A

Meclobemide (RIMA- Reversible inhibitor of MOA-A)

48
Q

what is the benefit of using a RIMA (Reversible Monamine Oxidase Inhibitor) like meclobemide?

A

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

49
Q

name a SSRI

A

selective serotonin/5-HT reuptake inhibitor

e.g. fluoxetine (tmn Prozac) the most prescribed antidepressant but not the most effective

50
Q

what is the benefit of using SSRIs in treating depression?

A
  • 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

51
Q

describe the pharmacokinetic of SSRIs

A

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.

52
Q

what is the drug interaction that fluoxetine can get in?

A

Fluoxetine (SSRI) competes with TCAs for hepatic enzymes so avoid co-administration.

53
Q

what are the unwanted effects of SSRIs?

A

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.

54
Q

what are some other anti-depressants that can be used?

A

Venlafaxine
– dose-dependent re-uptake inhibitor (SNRI- Serotonin and Noradrenaline Reuptake inhibitor)

Mertazapine
– alpha 2 receptor antagonist

55
Q

how is Venlafaxine dose dependent?

A

in general 5HT>NA>DA

  • low dose–> 5HT
  • moderate dose –> 5HT and NA
  • high dose–> 5HT, NA and DA
56
Q

what is the effect of mertazapine?

A
  • inhibits negative inhibition of NA release via alpha 2
  • therefore Increases NA and 5-HT release.
  • useful in SSRI intolerant patients.

LCRS Pharma (32 decks)

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