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YR2 LCRS Pharmacology > 23. Antidepressants > Flashcards

23. Antidepressants Flashcards

1
Q

what can psychoses be split into?

A

schizophrenia and the affective disorders (mania and depression)

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2
Q

what are the emotional and biological symptoms of depression?

A

EMOTIONAL

  • misery
  • apathy
  • pessimism
  • low self-esteem
  • loss of motivation

BIOLOGICAL

  • slowing of thought and action
  • loss of libido
  • loss of appetite
  • sleep disturbance
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3
Q

what are the 2 main groups of depression?

A

unipolar

bipolar

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4
Q

describe unipolar depression

A
  • mood swings are in the same direction
  • relatively late onset (adulthood)
  • can be split into reactive depression (75%) and endogenous depression (25%)
  • drug treatment available
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5
Q

what is the difference between reactive depression and endogenous depression?

A

reactive depression: depression in response to stressful life events, that is non-familial

endogenous depression: depression that is unrelated to external stresses, with a familial pattern

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6
Q

describe bipolar/manic depression

A
  • oscillating depression and mania (hyper-excitability with symptoms opposite to depression)
  • early adult onset
  • strong hereditary tendency
  • drug treatment (lithium) - a mood-stabilising drug
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7
Q

what is the difference between depression and mania?

A

depression: a functional deficit in central monoamine transmission
mania: a functional excess of central monoamine transmission

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8
Q

describe the monoamine theory of depression

A
  • NA and 5-HT (serotonin) are the 2 monoamines involved
  • there is a delayed onset of clinical effects of anti-depressant drugs
  • the changes in NA and 5-HT are rapid
  • however the clinical effect can take weeks before we see the optimal action of the drug
  • there is a dissociation between the neurochemical change and the antidepressant effect
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9
Q

what is there often down-regulation of in response to anti-depressants? what does this suggest?

A

down-regulation of a2, B, 5-HT receptors

this often correlates with the onset of clinical drug effectiveness so these changes may be responsible for the clinical drug effects

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10
Q

what is seen in chronic depression?

A

hippocampal neurodegeneration

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11
Q

what are the 2 main chemical groups in tri-cyclic antidepressants?

A

dibenzazepines

dibenzcycloheptenes

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12
Q

outline the key features of tri-cyclic antidepressants (TCAs)

A
  • 3-ringed structures
  • neuronal monoamine re-uptake inhibitors
  • prevent reuptake of NA and 5-HT more than dopamine
  • potentiate the action of these monoamines for longer
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13
Q

give an example of a TCA

A

amitriptyline

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14
Q

what other receptor actions do TCAs have?

A

actions on a2 receptors, muscarinic AchRs, histamine receptors, 5-HT receptors

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15
Q

what do TCAs do to a2 receptors?

A

bind to and antagonise these receptors –> enhance the release of NA –> block the inhibitory control over NA –> allow a greater increase of NA into the synaptic cleft

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16
Q

outline the pharmacokinetics of TCAs

A
  • rapid oral absorption
  • highly plasma-protein bound (90-95%)
  • hepatic metabolism: metabolised in the liver which generates active metabolites (weaker) which then undergo renal excretion (as glucoronide conjugates)
  • plasma half life of 10-20hrs (so can be given once a day)
17
Q

what are the unwanted effects of TCAs at therapeutic dose?

A
  • atropine-like effects with amitriptyline: dry mouth, blurred vision, constipation, urinary retention
  • postural hypotension (mediated through the vasomotor centre)
  • sedation (due to H1 antagonism) - patients feel drowsy during the day
18
Q

what are the unwanted effects of TCAs at acute toxicity (overdose)?

A
  • CNS: excitement, delirium, seizures –> coma and respiratory depression
  • CVS: cardiac dysrhythmias –> ventricular fibrillation and sudden death
  • TCAs that are muscarinic antagonists: affect vagal input to the heart
19
Q

how do TCAs interact with other drugs?

A
  • increased TCA effects from co-administration with aspirin and phenytoin (anti-convulsants)
  • warfarin can displace TCAs from their binding sites –> plasma levels of TCA become toxic
  • hepatic microsomal enzymes metabolise TCAs so TCA effects increase if co-administered with drugs that are metabolised by the same enzyme system (neuroleptics and oral contraceptives)
  • potentiation of CNS depressants (e.g. alcohol) with TCAs
  • unpredictable interaction with antihypertensives
20
Q

give an example of a monoamine oxidase inhibitor (MAOI)

A

phenelzine

21
Q

outline the key features of monoamine oxidase inhibitors

A
  • involves monoamine oxidase A (preference for NA and 5-HT) and monoamine oxidase B (preference for dopamine)
  • most drugs are non-selective (inhibit both MAO-A and MAO-B)
  • inhibition is irreversible –> long duration of action
  • down-regulation of b adrenoceptors and 5-HT2 receptors which corresponds with delayed onset of clinical effectiveness
  • not entirely selective –> inhibition of other enzymes
22
Q

what neurochemical changes occur with monoamine oxidase inhibitors? why?

A

rapid increase in cytoplasmic NA and 5-HT

the breakdown of NA and 5-HT is being blocked by MAOIs so there is enhanced activity in the brain

23
Q

describe the chemical structures of MAOIs

A
  • single ring structure

- range of different chemical classes

24
Q

describe the chemical structure of phenelzine

A
  • a hydrazine
  • single ring with a carbon side chain
  • hydrazine functional group on the end which is very reactive
  • functional group forms covalent bonds with the MAO enzyme (irreversible inhibition)
25
Q

outline the pharmacokinetics of MAOIs

A
  • rapid oral absorption
  • taken once a day/every 2 days
  • short plasma half life but longer duration of action due to irreversible inhibition
  • metabolised in the liver and excreted in the urine
26
Q

what are the unwanted effects of MAOIs?

A
  • atropine-like effects (though less than TCAs)
  • postural hypotension (vasomotor mediated effect)
  • sedation with long-term usage (and seizures in overdose)
  • weight gain due to increased appetite
  • hepatotoxicity due to hydrazines (rare)
27
Q

how do MAOIs interact with other drugs?

A
  • tyramine is metabolised by MAOs so if they are inhibited there are problems
  • tyramine is an indirectly acting sympathomimetic amine (activates SNS)
  • MAOIs can react with TCAs to produce hypertensive episodes
  • MAOIs can react with pethidine to cause hyperpyrexia, restlessness, coma and hypotension
28
Q

why must patients taking MAOIs avoid cheese and red wine?

A

they are high in tyramine

tyramine-containing foods + MAOI = hypertensive crisis - throbbing headache, increased blood pressure and intracranial haemorrhage

29
Q

what is moclobemide?

A

a reversible MAO-A inhibitor - selective

it has fewer drug interactions and a shorter duration of action

30
Q

give an example of a selective serotonin reuptake inhibitor (SSRI)

A

fluoxetine - ‘prozac’

31
Q

outline the key features of selective serotonin reuptake inhibitors

A
  • selective 5-HT reuptake inhibition
  • safer in the case of overdose
  • less effective against severe depression
32
Q

outline the pharmacokinetics of SSRIs

A
  • oral administration
  • plasma half life of 18-24hrs (given once a day)
  • delayed onset of action (2-4 weeks before we see optimal anti-depressant action)
  • competes with TCAs for the hepatic enzymes so avoid co-administration
33
Q

describe the chemical structures of SSRIs

A

couple of ring structures with an aliphatic side chain

34
Q

what are the unwanted effected of SSRIs?

A
  • GI side effects (nausea, diarrhoea)
  • insomnia
  • loss of libido
  • can interact with MAOIs so avoid co-administration
  • not effective in all patients/against severe depression
35
Q

name and describe a serotonin and noradrenaline reuptake inhibitor (SNRI)

A

VENLAFAXINE

  • dose-dependent reuptake inhibition of both 5-HT and NA
  • increasing the dose increases NA reuptake inhibition
  • a very high dose can also inhibit the dopamine transporter
  • 2nd line treatment for severe depression
36
Q

name and describe an a2 receptor antagonist

A

MIRTAZAPINE

  • increases NA and 5-HT release in the brain
  • other receptor interactions may contribute to antidepressant activity (histamine antagonism –> sedative)
  • useful in SSRI-intolerant patients

YR2 LCRS Pharmacology (32 decks)

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