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Yr 2 LCRS - Pharm > 23 - Anti-Depressants > Flashcards

23 - Anti-Depressants Flashcards

1
Q

What are the different psychoses?

A

PSYCHOSES

  • SCHIZOPHRENIA
  • AFFECTIVE DISORDERS
    • Mania
    • Depression (more common)
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2
Q

What are the emotional (psychological) symptoms of depression?

A

Misery

Apathy

Pessimism

Low self-esteem

Loss of motivation

Anhedonia (inability to feel pleasure at normally pleasurable activities)

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3
Q

What is anhedonia?

A

Inability to feel pleasure in normally pleasurable activities.

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4
Q

What are the biological (somatic) symptoms of depression?

A

Slowing of thought & action

Loss of libido

Loss of appetite

Sleep disturbance

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5
Q

What is unipolar depression (depressive disorder)?

A

Mood swings in same direction (same direction as symptoms classical to depression)

Relatively late onset

Can be split into two forms:

Reactive depression

  • stressful life events
  • non-familial (no genetic link)
  • more common than endogenous depression

Endogenous depression

  • unrelated to external stresses
  • familial pattern (potential genetic link)

Drug treatment

  • Use the same drugs for both forms of unipolar depression
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6
Q

What is the difference between schizophrenia and affective disorders?

A

Schizophrenia

  • disorder of thought processes

Affective Disorders

  • disorders of mood
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7
Q

What are the two forms of depression?

A

Unipolar Depression (Depressive Disorder)

Bipolar Depression (Manic Depression)

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8
Q

What percentage of the population experience depression?

A

5-10% of the population experience depression over the course of their lifetime

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9
Q

What is bipolar depression (manic depression)?

A

Symptoms oscillate between depression and mania

Mania are symptoms essentially opposite to those of depression

Less common

Early adult onset

Strong hereditary tendency

Drug treatment

  • Lithium is first-line treatment
  • Not strictly an anti-depressant
  • Lithium is actually a mood-stabiliser
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10
Q

What is the Monoamine Theory of Depression?

A

Schlidkraut (1965)

Main biochemical theory of depression

Depression is due to a function deficit of central monoamine transmission

  • functional deficit of NA & 5-HT systems in the brain

Mania is due to a functional excess of monoamine transmission

Evidence

  • pharmacological is supportive of the theory
  • biochemical is inconsistent

Delayed onset of clinical effect of drugs

  • may be due to a downregulation of receptors
  • downregulation of alpha2, beta, 5HT receptors
  • adaptive changes

General conclusions remain firm

New potential theories:

  • HPA axis (increased CRH levels?)
  • Hippocampal neurodegeneration?
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11
Q

Define the differences between depression and mania according to the Monoamine Theory of Depression

A

Depression = functional deficit of central MA transmission

Mania = functional excess

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12
Q

How does lithium work?

A

Taken orally as lithium carbonate

MOA: Change in intracellular second messengers including IP3 and cAMP

Has a narrow therapeutic window

  • can be below therapeutic level or too high and toxic very easily
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13
Q

Outline the pharmacological evidence supporting the monoamine theory of depression

A

TCAs

  • block NA and 5-HT reuptake
  • therefore, they increase NA and 5-HT in synapse
  • they are mood elevating drugs
  • therefore, decreased NA and 5-HT must lower mood

etc.

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14
Q

List the different classes of antidepressant drugs

A

Tricyclic Antidepressants (TCAs)

Monoamine Oxidase Inhibitors (MAOIs)

Selective Serotonin Reuptake Inhibitors (SSRIs)

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15
Q

Give an example of a TCA

A

Amitriptyline

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16
Q

Describe the structure of TCAs

A

Structure:

  • All either dibenzazepines or dibenzocycloheptenes
  • 3 ring structures (tricyclic)
  • Aliphatic side chain on amitriptyline
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17
Q

Give an example of some biochemical evidence that is not supportive of the monoamine theory of depression

A

Amphetamines increase NA in synapse

However, they do not improve mood in depression

Therefore, not supportive of the monoamine theory of depression

However, it may be that in clinical depression, nerve terminals are not functioning correctly so NA cannot have its normal effect

18
Q

Outline the mechanism of action of TCAs

A

Neuronal Monoamine Re-Uptake Inhibitors

Inhibit NA re-uptake

Also inhibit 5-HT reuptake in equal amounts to NA

This is at central neurones

This is mainly via reuptake 1 for NA

Acting on protein carriers not receptors

Enhance NA and 5-HT synaptic concentrations in the brain

Delayed down-regulation of beta-adrenoreceptors and 5-HT2 receptors

  • these adaptive changes underlie the onset of therapeutic action of anti-depressant drugs

There is also evidence that TCAs act on receptors including:

  • alpha-2
  • mAChRs
  • histamine
  • 5-HT

This could contribute to its anti-depressant action

19
Q

How does this additional action of TCAs on alpha 2 receptors contribute to their anti-depressant actions?

A

TCAs = Alpha-2 Antagonists

Alpha 2 receptors tend to be located pre-synaptically

If too much NA is released, it feeds back to alpha 2 receptors

This decreases NA release

Therefore, if TCAs reduce this negative feedback, NA will be increased in the synapse

20
Q

Outline the pharmacokinetics of TCAs

A

Rapid oral absorption

Highly Plasma Protein Bound = 90 - 95%

Hepatic metabolism

  • often generate active metabolites
  • renal excretion (glucuronide conjugates)

Plasma t1/2 = 10-20 hrs

  • means patient can take them once a day
21
Q

What are the unwanted effects of the TCAs?

A

AT THERAPEUTIC DOSAGE

Atropine-Like Effects

  • paticularly with amitriptyline
  • can antagonise muscarinic ACh receptorss
  • lead to dry mouth, blurred vision, urinary tension, constipation

Postural Hypotension

  • due to central action on vasomotor centre in brainstem

Sedation

  • H1 antagonism
  • H1 receptors often cause drowsiness

ACUTE TOXICITY (O.D.)

CNS TOXICITY

  • excitement
  • delirium
  • convulsive seizures
  • can lead to coma
  • can lead to respiratory depression

CVS

  • cardiac dysrhythmias
  • can lead to ventricular fibrillation
  • can lead to sudden death

N.B. COMMONLY USED FOR ATTEMPTED SUICIDE BY O.D. FOR TCAs

22
Q

Outline the drug interactions of TCAs

A

TCAS HAVE MANY DRUG INTERACTIONS

Highly Plasma Protein Bound

  • can increase TCA effects if other drugs are competing for the plasma proteins
  • could push TCAs up to toxic level
  • e.g. aspirin, warfarin or phenytoin may compete with TCAs

Metabolised By Hepatic Microsomal Enzymes

  • any other drug which uses this system will compete with TCAs
  • could cause level of TCAs to rise too much
  • increase TCA effects
  • neuroleptics and oral contraceptives can do this

Potentiate of CNS Depressants

  • if alcohol and TCAs are taken together, TCAs potentiate depressant effect of alcohol

Interfere with Antihypertensive Drugs

  • monitor closely
  • can increase or decrease blood pressure
  • this is in people with hypertension
23
Q

Give an example of a MAOI

A

Phenelzine

24
Q

What are the two forms of MAO?

A

Two main forms of MAO:

MAO-A

  • mainly metabolises NA & 5-HT

MAO-B

  • mainly metabolises dopamine
25
Q

Outline the mechanism of action of MAOIs

A

Most are non-selective MAOIs

  • inhibit MAO-A and MAO-B

Irreversible inhibition (Phenelzene)

  • causes long duration of action

Rapid effects

  • increase cytoplasmic NA & 5-HT
  • leakage into synaptic cleft

Delayed effects

  • clinical response
  • down-regulation of β-adrenoceptors & 5-HT2 receptors

Inhibition of other enzymes

  • not 100% selective to MAOs
26
Q

Describe the structures of MAOIs

A

Single ring structure

Aliphatic side-chain

Phenelzene

  • irreversibly blocks enzyme
  • due to hydrosine side chain which is highly reactive
  • binds covalently to MAOs
27
Q

Outline the pharmacokinetics of MAOIs

A

Rapid oral absorption

Short plasma t1/2

  • few hours
  • but longer duration of action due to irreversible blocking of enzymes

Metabolised in liver

Excreted in urine

28
Q

Outline the unwanted effects of MAOIs

A

Atropine - Like Effects

  • act on muscarinic ACh receptors
  • however, less severe effects than TCAs

Postural Hypotension

  • common
  • mediated in brainstem

Sedation

  • convulsive seizures in overdose

Weight Gain

  • possibly excessive

Hepatotoxicity

  • hydrazines
  • rare
29
Q

Outline the drug interactions of MAOIs

A

‘Cheese Reaction’

  • Tyramine-containing foods + MAOI
  • Tyramine is indirectly sympathetic acting (sympathomimetic substance)
  • Tyramine binds to NA transporter, goes into NA neurone and pushes NA into synaptic cleft in brain
  • Tyramine is broken down by MAOs
  • If give with MAOIs, they have nothing breaking down tyramine
  • leads to hypertensive crisis
    • throbbing headache
    • b.p.
    • intracranial haemorrhage
  • must avoid certain foods
    • cheese
    • game
    • red wine
    • yeast extracts

MAOIs + TCAs

  • hypertensive episodes
  • avoid

MAOIs + Pethidine

  • Pethidine is an opioid in obs and gynae
  • Inhibition of the system that normally metabolises pethidine
  • hyperpyrexia
  • restlessness
  • coma
  • hypotension.
30
Q

What is Moclobemide?

A

MOCLOBEMIDE

Reversible MAO-A Inhibitor (RIMA)

  • therefore more selective than normal MAOIs

Decreases normal MAOI drug interactions

  • beneficial

Decreased duration of action

  • have to be taken more than normal MAOIs
31
Q

Give an example of an SSRI

A

Fluoxetine (Prozac)

Currently the most prescribed anti-depressant drug

32
Q

Outline the mechanism of action of SSRIs

A

Selective 5-HT re-uptake inhibition

  • reduce 5-HT reuptake
  • no effect on NA

Less troublesome side-effects

  • less atropine side effects
  • less ‘cheese-effect’

Safer in overdose

But less effective in severe depression

33
Q

Describe the structures of SSRIs

A
34
Q

Outline the pharmacokinetics of SSRIs

A

p.o.administration

Plasma t1/2

  • 18-24 hrs

Delayed onset of action

  • 2-4 weeks

Hepatic metabolism

  • Fluoxetine competes with TCAs for hepatic enzymes
  • Avoid co-administration with TCAs

•

35
Q

What are the unwanted effects of SSRIs?

A

Fewer side effects than TCAs/MAOIs

  • Nausea
  • Diarrhoea
  • Insomnia
  • Loss of Libido
36
Q

What are the drug interactions of SSRIs?

A

Interact with MAOIs

  • Avoid co-administration with MAOIs

Interact with TCAs

  • Hepatic metabolism
  • Fluoxetine competes with TCAs for hepatic enzyme
  • Avoid co-administration with TCAs
37
Q

What is Venlafaxine?

A

Dose-Dependent Reuptake Inhibitor

SNRI = Serotonin and Noradrenaline Reuptake Inhibitor

5HT > NA >> DA

  • NA reuptake effects with higher dose
  • Dopamine reuptake effects with a very high dose

2nd line treatment for severe depression

38
Q

What is Mirtazapine?

A

α2 Receptor Antagonist

Increases NA & 5HT release

  • inhibit alpha 2 negative feedback

Other H1 receptor interactions

  • can cause sedation

Useful in SSRI-intolerant patients

39
Q

Largely, how to tricyclic antidepressant drugs work?

A

Inhibition of central NA and 5HT reuptake

40
Q

What is the ‘cheese reaction’ most likely to be caused by?

A

Monoamine Oxidase Inhibitors (MAOIs)

Yr 2 LCRS - Pharm (44 decks)

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