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Pharm > Anti-depressants > Flashcards

Anti-depressants Flashcards

1
Q

Categorise psychosis

A

Schizophrenia (disorder of thought process)

Affective disorders (disorder of mood)

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2
Q

Categorise affective disorders

A

Mania

Depression

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3
Q

Symptoms of clinical depression

A

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
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4
Q

2 main types of depression

A

1) Unipolar depression/depressive disorder

2) Bipolar depression /manic depression

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5
Q

Outline unipolar depression

Categorise it in terms of cause

A

Mood swings in same direction

Reactive (75%):

  • Stressful life events
  • Non-familial

Endogenous:

  • Unrelated to external stress
  • Familial
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6
Q

What is the onset of unipolar

A

Relatively late onset

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7
Q

Differentiate treatment for reactive and endogenous depression

A

Same drugs

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8
Q

Outline bipolar/manic depression

A

Oscillating depression/mania

Strong hereditary tendency

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9
Q

What is the onset of bipolar depression

A

Less common; Early adult onset

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10
Q

Drug treatment for bipolar

Action of what drug can affect drug used in treatment of bipolar disorder

A

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

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11
Q

Outline the monoamine theory of depression

A

Depression = functional deficit of central MA transmission;

Mania = functional excess

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12
Q

What are the mono-amines

A

NA & 5-HT

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13
Q

What is pharmacological evidence of the monoamine theory of depression

A

That various compounds which increase or decrease monoamine concentration in the synapse improve and worsen mood respectively

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14
Q

Outline the action of tricyclic antidepressants overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

Block NA & 5-HT reuptake and enhance synaptic levels of these

Improve mood

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15
Q

Outline the action of MAO inhibitors overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

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

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16
Q

Outline the action of reserpine overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

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)

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17
Q

Outline the action of a-methyltyrosine overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

Inhibits NA synthesis

Mood ↓ Calming of manic patients

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18
Q

Outline the action of methyldopa overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

Inhibits NA synthesis

Worsens mood

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19
Q

Outline the action of ECT overall, and the effect on mood

This is pharmacological evidence of the monoamine theory of depression

A

Increases CNS responses to NA and 5-HT

Improves mood

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20
Q

Give an example of a TCA

A

Amitriptyline

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21
Q

Give e piece of pharmacological evidence that might count against the monoamine theory of depression

Give a possible explanation

A

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)

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22
Q

T/F amphetamine supports the monoamine theory of depression

A

Not really

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23
Q

Give biochemical evidence of the monoamine theory of depression

A

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

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24
Q

T/F the onset of the clinical effects antidepressant drugs is delayed because the effects on NA and 5-HT take a while

A

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

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25
Q

What is thought to be the mechanism of action of anti-depressant drugs which icnrease 5-HT and NA inthe synapse

A

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

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26
Q

As well as monoamine theory, what else might be related to cause of depression

A

HPA axis increase in CRH

Hippocampal degeneration in chronic severe depression (which can be reduced with the current antidepressant drugs!)

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27
Q

Give an example of a TCA

A

Amitryptiline

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28
Q

Structures of TCAs

A

Dibenzazepines

Dibenzcycloheptenes

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29
Q

What type of molecule is amitryptiline

A

Dibenzcycloheptenes with aliphatic side chain on the central ring

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30
Q

Mechanism of action of TCAs

A

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

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31
Q

T/F TCAs bind to NA receptors on the presynaptic membrane to prevent NA reuptake equally to 5-HT receptors

A

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)

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32
Q

What could be other mechanism of action of TCAs

A

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

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33
Q

What is the effect of TCAs on a2 receptors

A

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

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34
Q

Outline the adaptive changes TCAs cause

A

Delayed down-regulation of β-adrenoceptors & 5-HT2 receptors

This may coincide with the delayed onset of action of these drugs

35
Q

Where is the absorption of TCAs

A

Rapid oral absorption

36
Q

How are TCAs foud in the plasma

A

90-95% plasma protein bound

37
Q

Outline metabolism of TCAs

A

Hepatic 1st pass metabolism

Active metabolites that are more weakly active but can act on the NA and 5-HT reuptake proteins

38
Q

Outlinee excretion of TCAs

A

renal excretion (glucuronide conjugates)

39
Q

What is the plasma half time of TCAs

A

Plasma t1/2 (10-20 hrs)

40
Q

Unwanted effects of TCAs at therapeutic dose

A

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

41
Q

Why to TCAs give atropine like side effects

A

Because they have antagonistic effects on muscarinic acetycholine receptors

42
Q

What are atropine like effects

A

Blurred vision
Dry mouth
Urinary retention
Constipation

43
Q

Why could the histamine receptor related side effects of TCAs be useful

A

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)

44
Q

Unwanted effects of TCAs at toxic dose

A

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

45
Q

Drug interactions of TCAs

A

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

46
Q

State drugs which compete with TCAs for PPB

A

Aspirin and phenytoin and warfarin so can push TCA level to toxic free level

47
Q

State drugs which compete with TCAs for hepatic microsomal enzyme

A

Microsome is referring to the rER

Neuroleptics
Oral contraceptives
Steroids

So have to be careful when prescriping anti-pschotics with antidepressants

48
Q

What is the problem with alcohol and TCAs

A

Both causing CNS depression (TCA through droswiness due to H1 antagonism)

problems with suicide cos they might be drunk first

49
Q

How could TCAs affect BP with antihypertensives

A

Could increase or decrease BP

50
Q

Give an example of monoamine oxidase inhibitors

A

Phenelzine

51
Q

What are the two types of MAO

A

MAO A: preferentially breaks down NA and 5-HT

MAO B: preferentially breaks down DA

Both break down both

52
Q

What are MAOIs

What is their MOA

A

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

53
Q

What type of enzyme inhibiors are MAOIs

A

IRREVERSIBLE –> long d.o.a

54
Q

Structures of MAOIS

A

Single ring structure with aliphatic side chain

55
Q

Why does phenelzine bind irreversibly

A

It has hydrazine NN group whcih is highly reactive and binds covalently to MAO enzymes A and B

56
Q

What are the rapid and delayed effects of MAOIs

A

Rapid effects : increased cytoplasmic NA & 5-HT

Delayed effect: down-regulation of beta adrenoceptors and 5-HT2 receptors

57
Q

Differentiate MOA of MAOIs and TCAs

A

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

58
Q

Outline absorption of MAOIs

A

Rapid oral absorption

59
Q

Half life of MAOIs

A

few hours

60
Q

T/F MAOIs need to be taken quite regularly because their t1/2 is only a few hours

A

F… because they irreversibly bind enzymes, they have long d.o.a despite their relatively short plasma half life

THIS IS A KEY POINT

61
Q

Where are MAOIs metabolised and excfreted

A

Metabolised in liver; excreted in urine

62
Q

What are the unwanted effects of MAOIs

A

Atropine - like effects (< TCAs)

Postural hypotension (common)

Sedation (Seizures in o.d.)

Weight gain (possibly excessive) Think MAObeseI

Hepatotoxicity (reactive hydrazine group; rare)

63
Q

T.F the atropine like effects of MAOIs are caused by the same thing as TCAs but they arent as bad

A

T…
both caused by antagonism action on mAChR

But worse with TCA

64
Q

Compare severity of side effects vs drug interactions with MAOIs and TCAs

A

MAOI side effects not as bad

but the drug interactions worse

65
Q

Drug interaction with MAOIs

A

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

66
Q

Why can cheese reaction occur with MAOIs but not in notmal people

A

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

67
Q

What is the cause of the hyperprexia,restlessness, coma & hypotension that comes with co-administering MAOI and pethidine

A

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

68
Q

What is moclobemide. Benefit and cost

A

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)

69
Q

Give example of SSRI

A

e.g. Fluoxetine and citalopram

70
Q

What is SSRI mecahnism of action

A

Selective 5-HT re-uptake inhibition not on NA

71
Q

What is the structure of SSRI

A

Not significant

72
Q

What is the benefit of SSRI compare to TCA and MAOIs

But what is the problem

A

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

73
Q

Administration of SSRIs

A

Oral

74
Q

What is the plasma t1/2

A

Plasma t1/2 (18-24 hrs)

75
Q

Onset of action of SSRIs

A

Delayed onset of action (2-4 weeks)

76
Q

Why is coadministration of fluoexetne and TCA avoided

vs

why is coadministration of MAOI and TCA acoided

A

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

TCA and MAOI avoided due to hypertension

77
Q

Side effects of SSRI

A

Nausea (10%), diarrhoea, insomnia & loss of libido (30%)

78
Q

Drug interactions of SSRI

A

Interact with MAOIs (avoid co-administration).. due to additive effect

And TCA for hepatic enzymes

79
Q

What is most prescrbed antidepressant drug

A

Fluoxetine (‘Prozac’): currently most prescribed antidepressant drug

80
Q

Atypical antidepressants

A

Venlafaxine and mirtazapine

81
Q

How does venlafaxine work

A

Dose-dependent Reuptake inhibitors

With increasing dose, reduces uptake of:

5HT > NA&raquo_space; DA (SNRI)

2nd Line treatment for severe depression

82
Q

What are the SNRIs

A

Seratonin and NA reuptake inhibitor venlafaxine

83
Q

How does mirtazapin work

A

α2 Receptor antagonist

↑ NA & 5HT release

Other R interactions (sedative)

Useful in SSRI-intolerant patients

Pharm (33 decks)

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