Antidepressants

Question 1

Mechanism of SSRIs

Answer 1

Block the reuptake of serotonin so that more remains in the synaptic cleft.

Question 2

Half lives of SSRIs

Answer 2

Fluoxetine - long (2-3 days)

paroxetine, sertraline, citalopram, escitalopram, fluvoxamine - short (20-30 hours)

Question 3

Which SSRIs cause long QTc?

Answer 3

Citalopram, escitalopram

Question 4

Pharmacokinetics of SSRIs

Answer 4

Slowly absorbed, peak plasma levels after 4-8 hours.

Elimination primarily hepatic.

Question 5

Drug interactions of SSRIs

Answer 5

o With MAOIs – provokes serotonin syndrome (agitation, hyperpyrexia, rigidity, myoclonus, coma and death).
o Caution with lithium and tryptophan
o Tramadol, linezolid also implicated in serotonin syndrome.
o Can inhibit some CYP450 enzymes, increasing levels of other drugs.

Question 6

ADRs of SSRIs

Answer 6

o GI – nausea, loss of appetite, dyspepsia, bloating, diarrhoea, constipation.
o Headache, insomnia, day time somnolence, agitation, tremor, restlessness, fatigue.
o Associated with seizures and mania.
o Extrapyramidal side effects
o Sweating
o Sexual dysfunction – ejaculatory delay, anorgasmia
o Increased risk of bleeding (aspirin, NSAIDs)
o Suicidal ideation, risk of self-harm, particularly in children and adolescents.

Question 7

SSRI overdose

Answer 7

Generally safe

Question 8

TCA examples

Answer 8

• Amitriptyline, nortriptyline, imipramine, dothiepin (most cardiotoxic)
• Clomipramine has mainly 5-HT effects and is used in the treatment of OCD. It is the most potent in the class.
• Lofepramine has mainly NA effects and is the least cardiotoxic.
• Inhibit reuptake of NA and 5-HT. Also have actions on histamine H1, adrenergic Alpha 1, anticholinergic.

Question 9

TCA pharmacokinetics

Answer 9

o Well absorbed
o Plasma levels peak 2-4 hours after ingestion.
o Subject to first pass metabolism
o Widely distributed in the body
o Half-life is suitable for once daily dosing
o Metabolised in the liver by hydroxylation and demethylation.

Question 10

TCA uses

Answer 10

Used less for depression now, more for neuropathic pain.

Question 11

TCA ADRs

Answer 11

o Autonomic effects – dry mouth, disturbance of accommodation, micturition difficulties leading to urinary retention, constipation, postural hypotension, tachycardia, increased sweating, worsening of glaucoma. Nortriptyline and lofepramine have fewer of these side effects.
o Psychiatric effects – tiredness and drowsiness with amitriptyline, insomnia with desipramine and lofepramine. May provoke mania in patients with bipolar.
o Cardiovascular effects – tachycardia and hypotension. Prolonged PR and QTc intervals, ST depression, flattened T waves. Ventricular arrhythmias and heart block occur rarely.
o Neurological effects – fine tremor, incoordination, headache, muscle twitching, epileptic seizures in predisposed patients, rarely peripheral neuropathy.
o Other – allergic skin rashes, cholestatic jaundice, rarely agranulocytosis. Weight gain and sexual dysfunction are common.
o Withdrawal – sudden cessation can be followed by nausea, anxiety, sweating, GI symptoms and insomnia.

Question 12

TCA toxicity

Answer 12

cardiovascular – VF, conduction disturbances, low BP. Respiratory – respiratory depression

Question 13

SNRIs background

Answer 13

• Inhibit reuptake of 5-HT and NA, so work in a similar way to TCAs.
• Less anticholinergic and sedative as doesn’t inhibit neurotransmitter receptors (unlike TCAs)
• Second line treatment in depression and anxiety

Question 14

Venlafaxine

Answer 14

o SNRI
Well absorbed, plasma peak at 1.5-2 hours
o Half-life 3-7 hours
o Metabolised to desmethylvenlafaxine, which has similar pharmacodynamic properties but a half-life of 8-13 hours
o Can have once daily dosing with a slow release preparation.
o Show to be as effective as SSRIs and TCAs
o Side effect profile is like that of SSRIs
o More toxic than SSRIs in overdose
o Fewer effect on CYP450

Question 15

Duloxetine

Answer 15

o Well absorbed, plasma peak at about 6 hours.
o Half-life about 12 hours
o Some CYP450 inhibition
o Also used in urinary incontinence and neuropathic pain.

Question 16

SNRI ADRs

Answer 16

o Nausea, dry mouth, dizziness,
o Sexual dysfunction
o Hypotension and hypertension

Question 17

Example of a NARI

Answer 17

reboxetine -rarely prescribed

Question 18

example of a NASSA

Answer 18

• Mirtazepine – weak NA receptor reuptake inhibitor, antihistamine, alpha 1 and alpha 2 blocker. Side effects of weight gain, increased appetite, sedation.
• Can be combined with SSRIs and SNRIs

Question 19

MAOIs

Answer 19

• First antidepressants, now rarely used.
• There are two types of MAO, A and B.
• Block intracellular breakdown of dopamine, 5-HT, NA, thyramine.
• “Cheese reaction” – prevent breakdown of dietary tyramine – hypertensive crisis. Strict dietary restrictions are necessary.
• Phenelzine, isocarboxid and tranylcypromine bind irreversibly to MAO A and MAO B.
• Moclobemide has less of a tyramine reaction. Specific to MAO A.
• May have particular value in treating atypical depression and bipolar depression.
• Side effects – dry mouth, micturition difficulty, postural hypotension, confusion, mania, headache, dizziness, tremor, paraesthesia of extremities, constipation, oedema of ankles.
• Sudden withdrawal can cause anxiety and dysphoria.

Question 20

5-HT2 receptor antagonists

Answer 20

• Agomelatine – melatonin receptor agonist, selective serotonin antagonist