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ACEM Primary Written > Psychiatry: Pharmacology - Antidepressants > Flashcards

Psychiatry: Pharmacology - Antidepressants Flashcards

1
Q

Describe the monoamine hypothesis of depression. What is this model based on?

A

Decreased functional amine-dependent synaptic transmission in depression
Based on the observation that all currently available antidepressants enhance synaptic availability of 5HT, NA, DA, or a combination

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2
Q

Describe the neurotrophic hypothesis of depression. What is this model based on?

A

Nerve growth factors are critical in regulation of neuroplasticity, resilience and neurogenesis: depression caused by loss of neurotrophic support
Based on observation that brain-derived neurotrophic factor (BDNF) is upregulated by effective antidepressants

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3
Q

Describe the neuroendocrine hypothesis of depression

A

HPA axis dysregulation occurs in depression (e.g. upregulation of stress response: increased cortisol, ACTH)

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4
Q

Describe the integrated model of depression (monoamine, neuroendocrine and neurotrophic hypotheses)

A

Monoamines and hormones probably upregulate BDNF and other neurotrophic factors, explaining the delay in response to treatment

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5
Q

Six classes of antidepressants with examples

A
  1. SSRIs (e.g. fluoxetine, sertraline, citalopram)
  2. SNRIs (e.g. venlafaxine, duloxetine)
  3. TCAs (e.g. imipramine, amitriptyline, nortriptyline)
  4. MAOIs (e.g. moclobemide, seleginine)
  5. 5HT2 antagonists (e.g. trazodone, nefazodone)
  6. Tetracyclics and unicyclics (e.g. bupropion, mirtazapine)
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6
Q

Five shared pharmacokinetic characteristics of antidepressants

A
  1. Relatively rapid oral absorption
  2. Achieve peak plasma levels within 2-3hrs
  3. Highly protein-bound
  4. Hepatically metabolised
  5. Renally cleared
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7
Q

Five indications for SSRIs

A
  1. Depression
  2. Anxiety
  3. OCD
  4. PMDD
  5. Bulimia nervosa
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8
Q

Mechanism of action of SSRIs

A

Allosterically inhibit SERT (bind at site other than 5HT binding site) with ~80% of activity inhibited at therapeutic doses

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9
Q

Pharmacokinetics of SSRIs (using fluoxetine as an example)

A

Absorption: oral bioavailability of fluoxetine 78%
Distribution: high lipid solubility, crosses BBB, high Vd, high protein binding
Metabolism: fluoxetine unique from other SSRIs -> is hepatically metabolised to active metabolite norfluoxetine which has a long t1/2 (7-9 days)
Excretion: 80% in urine

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10
Q

Seven adverse effects of SSRIs

A
  1. GI upset (most common)
  2. Loss of libido and sexual dysfunction
  3. Headaches
  4. Insomnia or hypersomnia
  5. Weight gain (especially with paroxetine)
  6. Discontinuation syndrome seen in drugs with short t1/2 (e.g. paroxetine, sertraline): paraesthesias, dizziness
  7. Risk of serotonin syndrome in combination with MAOI (or other drugs that increase synaptic 5HT)
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11
Q

What is the clinical relevance of fluoxetine’s active metabolite norfluoxetine?

A

Long t1/2 (7-9 days)
Fluoxetine must be discontinued >/= 4 weeks prior to commencing MAOI to minimise risk of serotonin syndrome

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12
Q

What are some of the drug interactions seen with SSRIs?

A

Inhibits CYP2D6 (paroxetine, fluoxetine): increases TCAs, fleicanide, risperidone, B-blockers
Inhibits CYP3A4 (fluvoxamine): increases TCAs, glucocorticoids, carbamazepine, CCBs
In combination with MAOI can cause serotonin syndrome

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13
Q

Which SSRIs are not enzyme inhibitors?

A

Citalopram and escitalopram

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14
Q

For what disorders are SNRIs indicated?

A
  1. Depression
  2. Pain disorders (e.g. neuropathies, fibromyalgia)
  3. GAD
  4. Stress urinary incontinence
  5. Vasomotor symptoms or menopause
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15
Q

What is the mechanism of action of SNRIs?

A

Bind SERT and NET to inhibit both 5HT and NA reuptake

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16
Q

What is unique about venlafaxine and desvenlafaxine?

A

Low protein binding (30%)

17
Q

What are the adverse effects of SNRIs?

A

Many shared with SSRIs, including discontinuation syndrome
Additional risk of noradrenergic effects: hypertension, tachycardia, CNS activation (insomnia, anxiety, agitation)

18
Q

What drug interactions are seen with SNRIs?

A

Relatively few compared with SSRIs
Risk of serotonin syndrome with MAOIs

19
Q

Six indications for TCAs

A
  1. Depression
  2. Anxiety
  3. Post herpetic neuralgia
  4. Neuropathic pain
  5. Enuresis
  6. Insomnia
20
Q

Mechanism of action of TCAs

A

Inhibits SERT, NET and range of receptors (a1, muscarinic, H1, 5HT2, Na+ channels)

Ratio of inhibition varies between different drugs:
- Amitriptyline: SERT&raquo_space; NET
- Imipramine: highly anticholinergic, SERT = NET
- Desipramine: less anticholinergic, NET > SERT

21
Q

Describe the pharmacokinetics of TCAs

A

Absorption: well-absorbed (except amitriptyline, which is incompletely absorbed and undergoes first-pass metabolism)
Distribution: high protein-binding and lipid solubility, high Vd
Metabolism: hepatic via CYP2D6 (levels increased with CYP2D6 inhibitors), long t1/2, amitriptyline produces active metabolite nortriptyline
Elimination: urine 60% (5% unchanged), bile, faeces

22
Q

Six adverse effects of TCAs

A
  1. Anticholinergic: dry mouth, constipation, urinary retention, delirium, hyperthermia, blurred vision
  2. Alpha blockade: orthostatic hypotension
  3. Antihistamine: weight gain, sedation
  4. Arrhythmias: act as class 1A (Na+ channel blockade -> prolongs AP) at therapeutic doses, risk of arrhythmias at higher doses
  5. Sexual dysfunction
  6. Discontinuation syndrome: cholinergic rebound, flu-like symptoms
23
Q

Drug interactions seen with TCAs

A

CYP2D6 inhibitors increase levels
Any drugs with additive effects (e.g. antihistamines, a-blockers)

24
Q

What is the potentially lethal dose of TCAs?

A

> 1.5g

25
Q

Describe the clinical presentation of TCA overdose

A

Anticholinergic syndrome: mydriasis, dry mouth, confusion, hyperthermia, tachycardia
Na+ channel blockade: slowed conduction, widened QRS, decreased contractility, arrhythmias (AV block, VT, TdP)
Alpha blockade: vasodilation, hypotension

26
Q

How is TCA overdose treated?

A

NaHCO3 to displace TCA from cardiac Na+ channels
Mg2+ and amiodarone in TdP
Gastric lavage and activated charcoal
Airway support with O2
Diazepam for seizures
Physostigmine if refractory to above measures

27
Q

Mechanism of action of MAOIs

A

Bind MAO-A and MAO-B (most irreversibly and non-selectively) to inhibit monoamine degradation -> increases presynaptic stores -> increases release

28
Q

Describe the pharmacokinetics of MAOIs

A

Absorption: well-absorbed from GIT but tendency for extensive first-pass metabolism which reduces oral bioavailability
Metabolism: hepatic
Elimination: in urine

29
Q

Six adverse effects of MAOIs

A
  1. Orthostatic hypotension
  2. Weight gain
  3. Sexual dysfunction
  4. Amphetamine-like properties: activation, insomnia, restlessness
  5. Discontinuation syndrome: delirium
  6. Multiple drug and food interactions
30
Q

Describe 9 drug interactions seen with MAOIs

A
  1. Serotonergic drugs (e.g. SSRIs, SNRIs, TCAs): serotonin syndrome
  2. Tyramine (e.g. in aged cheese, tap beer, soy, sausages): malignant HTN with risk of sequelae
  3. Sympathomimetics (e.g. pseudoephedrine, phenylpropanolamine): malignant HTN
  4. Drugs metabolised by pseudocholinesterase (e.g. suxamethonium, ester LAs): increased duration of action (inhibits pseudocholinesterase)
  5. Antihistamines: potentiates effects
  6. Anti-Parkinson drugs: potentiates effects
  7. Antihypertensives: potentiates effects
  8. Hypoglycaemics: potentiates effects
  9. Sedatives: potentiates effects
31
Q

Describe the clinical presentation seen with MAOI overdose

A
  1. Autonomic instability
  2. Hyperadrenergic symptoms
  3. Psychosis, delirium
  4. Fever
  5. Seizures

ACEM Primary Written (150 decks)

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