17 - Antidepressants

Question 1

What are MAOIs? How long is their wash-out period?

Answer 1

• Irreversible inhibitors of MAO A and B

- 2 weeks before new enzyme is synthesized

Question 2

How many phases of MAOI overdose?

Answer 2

4

Question 3

Phase 1 of MAOI overdose

Answer 3

• Asymptomatic (latent) period
• Up to 6-12 h
• Monitor for 24h post-ingestion

Question 4

Phase 2 of MAOI overdose

Answer 4

• Neuromuscular excitation and sympathetic hyperactivity
• Hypertension, hyperreflexia, hyperthermia
• Tremor, myoclonus, seizures, agitation, rigidity

Question 5

Phase 3 of MAOI overdose

Answer 5

• CNS depression and possible CV collapse

- Hypotension

Question 6

Phase 4 of MAOI overdose

Answer 6

Secondary complications for survivors

Question 7

MAOI overdose tx

Answer 7

• Severe hypertension -> tx w/ short-acting antihypertensive
• Arrhythmias -> standard anti-arrhythmic
• Hypotension -> direct acting vasopressors (not indirect); start low
• Charcoal
• Hyperthermia -> treat aggressively
• Rigidity -> BZDs, dantrolene (muscle relaxant) to prevent rhabdomyolysis

Question 8

Foods to avoid w/ MAOIs

Answer 8

• Cheese (all aged)
• Alcoholic beverages -> red wine, sherry, cognac, beer
• Fish -> smoked, caviar
• Meat -> fermented, salami, some sausage

Question 9

Describe the MAOI-cheese reaction

Answer 9

• Hypertensive crisis from indirect acting amines
• • Direct acting don’t require MAO for their metabolism
• • Catabolized by COMT
• Tyramine = indirect acting amine
• Peripheral effects as it doesn’t cross BBB
• Causes NE release from peripheral noradrenergic neurons
• Normally, little absorbed
• • Dietary amine metabolized by GI MAO-A

Question 10

What do TCAs block in the brain?

Answer 10

• Block serotonin and NE reuptake

- Block histamine, muscarinic, and alpha-adrenergic receptors

Question 11

Cardiac effects of TCAs at usual doses

Answer 11

• Hypertension, tachycardia
• Slowed cardiac conduction
• Antiarrhythmic properties
• Orthostatic hypotension

Question 12

Px at high risk for TCA cardiac adverse events

Answer 12

• Elderly
• CV disease
• Drug interactions (increased levels)
• Overdose cases

Question 13

Central anticholinergic effects of TCAs

Answer 13

• Agitation
• Hallucinations
• Confusion
• Sedation
• Coma, seizures

Question 14

Peripheral anticholinergic effects of TCAs

Answer 14

• Hypertension, tachycardia, hyperthermia
• Mydriasis
• Dry, flushed skin
• Decreased GI motility
• Urinary retention

Question 15

CV effects of TCAs at toxic doses

Answer 15

• Intraventricular conduction delay (QRS prolongation)
• Sinus tachycardia
• Ventricular arrhythmias
• Hypotension

Question 16

CNS effects of TCAs at toxic doses

Answer 16

• Coma
• Delirium
• Myoclonus
• Seizures

Question 17

Other effects of TCAs at toxic doses

Answer 17

• Hyperthermia
• Ileus
• Urinary retention

Question 18

Risk factors that increase risk of TCA toxicity

Answer 18

• Pre-existing heart condition
• Electrolyte abnormalities
• Hepatic insufficiency
• Stimulant drug use
• Multiple drugs that increase QT interval
• Increased dose

Question 19

TCA overdose – general management

Answer 19

• *Treat symptomatically
• Airway if needed, IV-line, cardiac monitoring, EKG
• Decreased LOC => O2, dextrose, naloxone, thiamine, ABGs
• Stomach lavage
• Charcoal 50-100 g + cathartic
• Usually 10-20 mg/kg is considered life-threatening (limit Rx to 1 g if suicidal)
• Sx from as little as 3-4 times daily dose

Question 20

What is the most common cause of death in TCA overdose?

Answer 20

Refractory hypotension (due to vasodilation or impaired cardiac contractility)

Question 21

Tx of TCA induced orthostatic hypotension

Answer 21

• Intravascular volume expansion
• Sodium bicarbonate, vasopressors (NE) or inotropes (dopamine)
• Correct hyperthermia, acidosis, seizures

Question 22

Tx of TCA induced CNS toxicity

Answer 22

• Confusion, agitation, hallucinations -> supportive therapy and BZDs
• Coma, myoclonus -> coma usually resolves in 24 h
• Seizures -> usually brief but often occur immediately before cardiac arrest
• • Acidemia from seizures may predispose to arrhythmias
• • Usually responsive to IV BZDs (midazolam infusion)
• • Refractory -> barbiturates or propofol
• • Phenytoin no longer recommended (b/c proarrhythmic w/ limited efficacy)

Question 23

What is the most common mechanism of TCA associated death?

Answer 23

Myocardial depression, ventricular tachycardia, or ventricular fibrillation

Question 24

What is a predictor of arrhythmias?

Answer 24

QRS duration > 0.10 s

Question 25

____ can reduce arrhythmias and hypotension caused by TCAs

Answer 25

Sodium bicarbonate

Question 26

Can anti-arrhythmics be given to TCA-induced arrhythmias?

Answer 26

No, b/c pro-arrhythmic

Question 27

What can be used to treat TCA cardiotoxicity?

Answer 27

Lipid emulsion b/c TCAs are highly lipophilic

Question 28

TCA overdose – length of tx

Answer 28

- Anti-cholinergic effects after a large ingestion may result in slow absorption - Asymptomatic w/ normal ECG x 6 h w/ only tx GI decontamination -> not likely to develop toxic effects - If symptomatic w/ altered mental status, seizures, or cardiac dysrhythmias -> monitor in ICU x 12-24 h after all sx resolved and all supportive interventions are d/c - If parameters remain normal then psychiatry to evaluate

Question 29

Venlafaxine safety

Answer 29

- In general, safety profile good - Recent data indicated that may not be as safe as SSRIs; closer to TCAs - Rare reports of conduction disturbances - Potentially may increase QRS; pro-arrhythmic in overdose or poor metabolizers - Blood pressure increases - - Dose dependent response - - Usually reversible upon d/c - - Risk greater w/ increased age

Question 30

Symptoms of venlafaxine overdose?

Answer 30

- Overdoses reported --> seizures, hypotension, sinus tachycardia - Serotonin syndrome - - Drug interactions w/ serotonergic agents (MAOIs, SSRIs)

Question 31

When is venlafaxine contraindicated?

Answer 31

- Relatively contraindicated in px w/ high risk of overdoses and/ or pre-existing seizures and cardiac disease - Watch in subjects who are poor CYP2D6 metabolizers, or concomitant drugs that inhibit CYP2D6

Question 32

Desvenlafaxine safety

Answer 32

- Minor effects w/ mild hypertension and tachycardia | - Risk of seizures or serotonin toxicity is low

Question 33

Signs and symptoms of duloxetine overdose

Answer 33

- Somnolence - Serotonin syndrome - Seizures - Vomiting

Question 34

SSRIs toxic effects and tx

Answer 34

- Tremor, sinus tachycardia, N/V/D, seizures, serotonin syndrome - Mild bradycardia may occur in OD - Lower incidence of mortality vs. TCAs - Tx = charcoal + supportive care

Question 35

Causes of serotonin syndrome

Answer 35

- Drugs that inhibit breakdown of 5-HT -> MAOIs - Drugs that block re-uptake of 5-HT -> SSRIs, venlafaxine, trazodone, clomipramine, dextromethorphan, meperidine, pentazocine, cocaine - Drugs that are 5-HT precursors or agonists -> lithium, buspirone, L-tryptophan, LSD, psilocybin - Drugs that enhance 5-HT release -> MDMA

Question 36

Tx of serotonin syndrome

Answer 36

- Supportive care - Neuromuscular sx -> BZDs - Increased temp -> Tylenol, cooling blankets - Severe rigidity -> dantrolene - Severe sx -> cyproheptadine 4 mg PO q4h; 5-HT antagonism; watch anticholinergic and antihistaminic properties

Question 37

Cognitive sx of serotonin syndrome

Answer 37

- Agitation | - Mental status changes (confusion, hypomania)

Question 38

Autonomic dysfunction sx of serotonin syndrome

Answer 38

- Diaphoresis - Diarrhea - Fever - Shivering

Question 39

Neuromuscular sx of serotonin syndrome

Answer 39

- Incoordination - Myoclonus - Tremor - Hyperreflexia

Question 40

Citalopram and cardiac toxicity

Answer 40

- Dose related QT prolongation - High risk in metabolic disturbance and pre-existing cardiac disease - Potential increased risk of Torsades de Pointes - Maximum dose = 40 mg/day - - 20 mg in elderly or hepatic impairment

Question 41

Bupropion safety

Answer 41

- May cause sinus tachycardia but not usually associated w/ conduction abnormalities - Study in depressed cardiac px -> no significant effect on heart (conduction, arrhythmias, hypotension, pulse) - XL product = delayed onset seizures - - Must monitor for longer time

Question 42

Mirtazapine safety

Answer 42

- Increased 5-HT and NE + serotonin blocker - Mild-moderate anticholinergic - Antihistamine effects * *Watch for serotonergic and anticholinergic effects in overdose - Case series -> no cardiac effects, no QTc prolongation