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Pharmacology > L13 Antidepressant Drugs > Flashcards

L13 Antidepressant Drugs Flashcards

1
Q
  1. What is depression?
  2. what is mania/hypomania?
  3. What are they associated with?
  4. When is depression diagnosed?
A
  1. the pathological state of sadness
  2. pathological state of happiness
  3. loss of appetite, weight loss, sleep disturbance, suicidal thoughts
  4. presence of depressed mood or loss of interest, plus four other symptoms, for at least two weeks
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2
Q

Outline Mood Disorders as a group

A

Can be split into

Psychotic

  • Bipolar affective disorder - Mania/Hypomanic episodes, depressive episodes
  • Psychotic Depression

Non-Psychotic Depression

Dysthymia (depressive personality)

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3
Q

Depressive Illness - Epidemiology

  1. Who is most at risk
  2. What is the annual prevalence?
  3. What is the lifetime risk?
  4. What is the lifetime suicide risk?
A
  1. Females (twice that of males)
  2. 6%
  3. 25%
  4. 6% (15% for those hospitalised)
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4
Q

What are the factors in depressive illness?

A
  • Social
  • Personality
  • Biological

Depressive illness is a multi-factorial disorder but in more severely ill it is clear that neurochemical disturbance is the most important factor

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5
Q

Depression - Aetiology

  1. What is the Original Amine Hypothesis of Depressive Illness
A
  1. Depressive illness induced by amine depleting
    agents, Depressive illness alleviated by agents which elevate amine levels

Depressive illness associated with reduced amine
activity (serotonin and noradrenaline, dopamine less important)

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6
Q

What is the evidence for serotonin abnormalities in depressive illness?

A

Reserpine depletes brain 5-HT and causes depression

Effective antidepressants augment 5-HT function

Depressed patients have reduced CSF 5HIAA

Depressed patients have reduced serotonin uptake in platelets

Increased serotonin receptors (5HT-2) in post mortem (depressed) brain tissue

Reduced prolactin response to a 5-HT agonist eg fenfluramine

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7
Q

What is the evidence for noradrenaline abnormalities in depressive illness?

A

Reserpine depletes brain NA and causes depression

Effective antidepressants augment NA function

Depressed patients have reduced CSF MHGP

Changes in receptor sensitivity follow time-course of clinical response

Blunted growth hormone response to clonidine

Raised plasma noradrenaline

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8
Q

What are the roles of serotonin and noradrenalin?

A

Pain perception

Vasoconstriction

Urethral sphincter contraction

Bladder wall relaxation

Gastrointestinal motility

Pilomotor contraction

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9
Q

What is depression associated with on a NT level?

A

Depression is associated with an imbalance of 5-HT and NA in the brain and spinal cord (CNS)

Evidence overall is for reduced 5-HT function and dysregulation of the NA system

Not known which is the primary abnormality

There are also disturbances of the corticosteroid system which could be primary or secondary to above

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10
Q
  1. What is the NA source?
  2. What is the 5-HT source?
A
  1. Locus Coeruleus
  2. Nucleus Raphe Magnus
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11
Q

How Antidepressants Work

  1. What is their main action?
  2. What are their two principle modes of action?
  3. What can most of the important clinical actions of antidepressant drugs not be fully accounted for on the basis of “synaptic pharmacology?
A
  1. act to increase the availability of 5-HT and NA at the synapse
  2. inhibition of re-uptake of amines inhibition of monoamine oxidase
  3. Many drugs require long term administration to be effective.

Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse.

That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role (drug-induced neural plasticity).

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12
Q

What is the

  1. Acute Synaptic Pharmacology of antidepressants?
  2. Chronic Synpatic Pharmaology of antidepressants?
A
  1. Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor
  2. Down regulation of the post-synaptic receptors

Alteration of second messenger systems

Alteration of protein synthesis

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13
Q

Antidepressants

When do these occur?

  1. Synpatic effects
  2. Side Effects
  3. Therapeutic Effect
A
  1. Hours to days
  2. Hours to days
  3. 1-6 weeks
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14
Q

History of Antidepressants

A

Greek theory of “humours”

Later religious explanations-witchcraft

Rise of the asylums (19th century)

1938 ECT-first effective antidepressant

First antidepressant drugs 1957 -iproniazid -imipramine

1980’s-explosion of specific antidepressant treatments

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15
Q

What are the main groups of Antidepressant drugs?

A
  • Monoamine Oxidase Inhibitors - MAOIs
  • Monoamine Uptake Inhibitors
    • ​Non-selective - TRICYCLICS - TCA
    • Selective -
      • Serotonin Selective SSRI
      • ​Noradrenaline NARI
      • Mixed Serotonin and Noradrenaline Reuptake SNRI
  • Others - Tryptophan, Mirtazapine
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16
Q

Outline the Receptor Affinities of the Main Antidepressant Groups

A

Receptors = NA, 5HT, M, H, A

TCAs- all

SSRIs- 5HT

SNRIs - NA and 5HT

NARIs- NA

17
Q

Inhibition of radioligand and binding to human monoamine uptake transporters (Ki, nM)1

What do these ratio’s indicate?

A

Which drugs exibit particularly high 5HT:NA ratios?

  • Chlorimipramine (TCA) (135.7)
  • Fluoxetine (SSRI) (296.3)

Some are broad, some are selective

18
Q

Tricyclic antidepressants (TCAs)

  1. What are the effects of TCAs?
  2. Give an example of a TCA
  3. Outline the pharmacokinetics
  4. How are they excreted?
  5. What should the dose be commenced at?
  6. Why are they no longer first line?
A
  1. therapeutic inhibition of reuptake of noradrenaline and serotonin anticholinergic antihistaminergic -peripheral antiadrenergic quinidine like effects on heart
  2. Amitriptyline, Clomipramine, Dothiepin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine
  3. Good absorption, Large “first pass metabolism”, Highly protein bound
  4. Mostly in the liver
  5. 1/3-1/2 daily dose, can be given once daily
  6. Toxc in overdose: dothiepin and amitriptyline-hence no longer first line (lofepramine is relatively safe in OD and almost free of anticholinergic side effects)
19
Q

Amitriptyline (TCAs)

  1. What are the indications for it’s use?
  2. What is it’s half life?
  3. What is an appropiate dose?
  4. Name the main adverse effects?
A
  1. depression, panic disorder, nocturnal enuresis in children, neuralgia
  2. Half-life 9-25 hours (active metabolite nortriptyline)
  3. 150-200 mg per day (depression); NE 10-20 mg (7-10yrs) & 25-50 mg (11-16 yrs); neuralgia low doses
    • Sedation, often with hangover
    • Postural hypotension
    • Tachycardia/QT prolongation/arrhythmias (esp in OD)
    • Anticholinergic effects-dry mouth, blurred vision, glaucoma, constipation, urinary retention
    • Tremor
    • Headache
    • Mania
    • Sexual difficulties
    • Cholestatic jaundice
    • Blood dyscrasias
    • Lowers epileptic threshold
20
Q

What are the cardiac side effects of TCAs? (tricyclic antidepressants?)

What monitoring is required?

A

Cardiac conduction delay

Anti-arrhythmic at therapeutic doses

Arrhythmigenic at toxic doses

Minimal effects on cardiac output

  • Monitoring ECG parameters:

nQRS - >30% above baseline

21
Q

Amitriptyline

What are the major drug interactions?

A

SSRI’S (except citalopram)-increased plasma levels of TCAs

Alcohol (increased sedation)

Antimuscarinics-increased risk of antimuscarinic SEs

Antipsychotics-increased risk of antimuscarinic SEs and ventricular arrhythmias (especially pimozide/thioridazine/clozapine)

MAOI’s (increased risk hypertension/CNS excitation)

Directly acting sympathomimetics eg adrenaline in local anaesthetics

Hypotensive drugs eg clonidine; adrenergic neurone blockers (guanethidine)

Pharmacokinetic -warfarin (protein binding) - Cimetidine-increased plasma levels of TCAs (enzyme inhibition) -barbiturates and tobacco (enzyme induction)

22
Q

Clomipramine (TCA)

  1. What are the indications?
  2. What is it’s half life?
A
  1. depression, phobic and obsessional states, adjunctive treatment of cataplexy associated with narcolepsy
  2. Half-life 19-37 hours (active metabolite desmethyl-clomipramine)
23
Q

SSRI Antidepressants

  1. Give an example
  2. What are the indications?
  3. What are the benefits
  4. What are the main side-effects?
A
  1. Citalopram, Escitalopram, Fluoxetine (prozac), Fluvoxamine, Paroxetine, Sertraline
  2. depressive illness, phobic disorders, panic disorder, generalised anxiety disorder, obsessive compulsive disorder
  3. Dosing is easier, Safe in overdose, No significant cardiac side-effects (but May cause weight loss, Non-sedative (therefore not immediately helpful with disturbed sleep)
  4. Nausea/dyspepsia/abdominal pain/diarrohoea/constipation, Hypersensivitity reactions, Headache, Agitation, Sexual difficulties
24
Q

SSRI Antidepressants

  1. What are the specific problems?
  2. What are the symptoms of Serotonin Syndrome?
A
  1. Hyponatraemia -more common in elderly -possibly due to inappropriate secretion of ADH -seen with all ADs but more common with SSRIs

Use in under 18 year olds -fluoxetine approved, others to be avoided -use with extreme caution -monitor for suicidality and hostility

2.

Restlessness

Diaphoresis

Tremor

Shivering

Myoclonus

Confusion

Convulsions

Death

25
Q

MAOI Antidepressants

  1. What do they do?
  2. What are the two types of MAO in the body?
  3. What are the two types of inhibitors?
A
  1. increase synaptic amine levels by inhibiting Monoamine Oxidase enzyme
  2. -MAO-A breaks down serotonin and noradrenaline -MAO-B breaks down dopamine
  3. -irreversible (destroys MAO, more likely to cause “cheese reaction”) -reversible
26
Q

MAOI Antidepressants

  1. Name an MAOI
    1. Irreversible, non-selective
    2. reversible, selective
  2. What are these depressants used for?
  3. What are the main side effects?
  4. What interactions should be avoided?
A
  1. MAOI
    1. Isocarboxazid Phenelzine Tranylcypromine (most dangerous)
    2. moclobemide (RIMA) (cheese reactions unlikely)
  2. used for “neurotic” or “atypical” depression
  3. -hypotension –cheese reaction -oedema -abnormal liver function -anticholinergic effects -agitation
  4. Avoid with other antidepressants, indirect-acting sympathomimetics (present in many cold preparations and decongestants eg ephedrine, phenylpropanolamine), levodopa, 5HT IA agonists and opiates (esp pethidine)
27
Q

MAOI Antidepressants

What is the ‘Cheese Reaction’

What is required to avoid this?

Which foods should be avoided?

A

Rare fatalities when MAOI’s combined with foods containing tyramine (an indirectly acting sympathomimetic) - because of depressor effect-may cause a dangerous rise in BP

Restrictive diet required (unpopular with patients)-freshness is key, the more “convenience” the better-avoid food that is stale or “going off”

  • Dairy products (hard and soft cheese, cheese spreads)
  • Fruit and vegetables (broad bean pods, avocada and banana skins)
  • Game, meat and fish (pickled/salted/dried herrings, hung or badly stored meat)
  • Meat products (stored liver pate, salami, pastrami)
  • Pizzas (gourmet unsafe, chain store safe)
  • Soy and soybean (including soy sauce)
  • Yeast and meat extracts (“Oxo”, “Marmite”, “Bovril”)
  • Alcohol (esp Chianti, home brew, real ale, red wines)
  • Dealcoholised drinks
28
Q

Outline the OTHER Antidepressant Drugs

(won’t be exam questions, focus on main groups)

A
  • Mianserin (blocks inhibitory alpha 2 autoreceptors)
  • Mirtazapine (Alpha-2-noradrenergic antagonist)
  • Nefazodone (mixed SSRI and 5HT receptor antagonist)
  • Reboxetine (NARI)
  • Trazodone (antagonist at 5HT2 receptors)
  • Venlafaxine (SNRI)
29
Q

St John’s Wort (Hypericum perforatum)

  1. How does it act?
    1. What is it used for?
  2. It is generally well tolerated, but what may some SE be?
  3. What interactions can it have?
A
  1. MAO inhibition, reuptake inhibition of serotonin and noradrenaline, upregulation of serotonin receptors all demonstrated
    1. Unlicensed, May be effective for mild depression
  2. dry mouth, nausea, constipation, fatigue, dizziness, headache, restlessness
  3. -important drugs metabolised more rapidly eg carbamazepine - increased serotonergic effect when combined with an SSRI-avoid -increased viral load in HIV -unwanted pregnancy when on OCP -reduced effect of warfarin
30
Q

What are the general issues when treating depressive illness?

A

Antidepressants have been shown to be effective in depressive illness

More minor forms of illness less responsive

Regular reviews increase compliance

Antidepressants take several weeks to work

Antidepressants are not addictive

Avoid combining antidepressants (esp MAOI’s)-seek specialist advice

31
Q

Antidepressants

  1. What does choice of antidepressant depend upon?
  2. What is the usual order of choice?
  3. What is the duration of treatment?
  4. How long should they be withdrawn over?
A
  1. side-effect profile risk of overdose (ensure adequate dose also) previous response safety in relation to age and health
  2. SSRI/SNRI/TCA
    • ​​If one episode, continue treatment for 4-6 months
  • If recurrent longer term prophylaxis (several years) should be considered​
    4. over 1-2 weeks to avoid withdrawal effects
32
Q

How should the following be treated?

  1. Psychotic Depression
  2. Resistant Depression
A
  1. Combination of antiP and antidepressant (better than either alone) and Electroconvulsive Therapy
  2. Try augmentation eg antidepressant plus lithium carbonate (mood stabiliser), B-blocker; thyroxine. Try ECT (can also be useful if condition is life-threatening)
33
Q

What is Electroconvulsive Therapy?

A

No absolute contraindications to use, may be lifesaving

No evidence of brain damage or permanent intellectual impairment

Risk of death is similar to that of general anaesthesia for minor surgical procedures (2 deaths per 100,000 treatments)

Main side effects: muscle pain, headache, short term memory loss

34
Q

What psychological therapies may be effective in mild/moderate depression?

A

Cognitive therapy Interpersonal therapy Problem solving

However are not effective in more severe depression

Pharmacology (26 decks)

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