Ch 149 – Antidepressants
Tricyclic Antidepressants
Pharmacokinetics

Absorption: Rapidly absorbed from the GI tract with peak levels at 2-4 hrs

Distribution: Protein bound and lipophilic with high Vd

Metabolism/Elimination: Hepatic metabolism with long elimination half-life (up to 72 hrs)
Mechanism for TCA Toxicity
1. High doses of medications in un-acclimatized individuals.
2. Combination of TCA with medications that have similar actions (eg. antihistamines; antipsychotics)
3. Subset of the population metabolizes TCAs slowly, leading to toxic levels with therapeutic doses
4. Interaction with drugs that ↓ the metabolism of TCAs
5. Some TCAs are available as mixed formulas (with benzodiazepines or antipsychotics) so they have
additional potential for toxicity.
6. Pts with underlying cardiac or seizure disorders are at ↑ risk for toxicity.
7. TCAs can potentiate a serotonin syndrome when combined with SSRIs.
General Classes
Secondary Amines (NDP): nortriptyline, protriptyline, desipramine
Tertiary Amines: amitriptyline, clomipramine, doxepin, imipraimne, trimipramine
Other: cyclobenzaprine (no anti-depressant properties but similar structure & toxic effects)
Therapeutic Mechanism of Action

Inhibition of amine reuptake (norepinephrine; serotonin)

Antagonism of post-synapitc serotonin receptors
TCA Toxicity: Seven Key Mechanisms
Effect
Antihistaminic Effects
Antimuscarinic Effects
Inhibition of αadrenergic receptors
Inhibition of Amine
Uptake
Mechanism
Binds to peripheral +
central histamine receptors.
Competitive inhibition of
Ach at periph + central
muscarinic receptors.
Inhibition of post-synaptic
central + periph αadrenergic receptors, esp
α1 receptors
Inhibition of reuptake of
norepinephrine & serotonin.
Clinical Findings
Sedation
Management
Central: agitation →
delirium; confusion,
amnesia, hallucinations,
slurred speech, ataxia,
sedation, coma
Physostigmine inhibits
acetylchoinesterase and can
reverse symptoms.
Unfortunately it is associated
with asystole and thus is not
used in the tx of TCA toxicity.
Peripheral: dilated pupils,
blurred vision, tachycardia,
hyperthermia, hypertension,
↓ oral secretions, dry skin,
ileus, urinary retentions, ↑
tone, tremors
Sedations, orthostatic
hypotension + reflex
tachycardia, pupillary
constriction
Norepinephrine:
Early sympathomimetic
effects, +/- cardiac
arrhythmias.
Serotonin: hyperreflexia,
myoclonus.
Serotonin syndrome, esp if
taken in combination with
SSRIs or SNRIs
Effect
Sodium Channel
Blockade
Mechanism
Inhibition of Na influx
through voltage dependent
Na channel during phase 0
of depolarization.
Clinical Findings
Delayed depolarization &
conduction abnormalitites –
worse with ↓ Na, acidosis &
↑ HR.
Management
Alkalinization (pH 7.50 – 7.55)
and ↑ serum Na helps
overcome the Na channel
blockade. This is achieved
with NaHCO3- .
Typical EKG changes:
prolonged PR
prolonged QRS
RAD in terminal 40
ms… terminal R wave
in aVR & S wave in lead
I
+/- bradycardia
ectopy
Potassium Channel
Antagonist
GABA-A Receptor
Antagonist
Block of myocardial
potassium channels
resulting in ↓ K efflux
during repolarization.
Antagonism of the GABA-A
receptor (binds to
picrotoxin site)
Decreased myocardial
contractility.
Prolonged repolarization → ↑
QT. This rarely leads to
toursades as the typical
tachycardia of TCA overdose
is protective.
Generalized seizures
GABA-A agonists such as
benzodiazepines &
barbiturates are most
effective.
Dosages: narrow therapeutic spectrum

Typical doses are 1-5 mg/kg

Doses > 5 mg/kg can produce sx of toxicity

Doses > 10 mg/kg typically produce life-threatening sx
Levels:



No generally available in the ED
Therapeutic: < 300 ng/mL
Toxicity can occur at any level about this
Pts with levels > 1000 ng/mL are at ↑ risk of seizures and cardiac toxicity
Clinical Features
System
CNS
H/N
Cardiac
Respiratory
GI
MSK
GU
Mild
Moderate
altered LOC* esp drowsiness, confusion
ataxia
slurred speech
hyper-reflexia
dry mucous membranes
sinus tachycardia
mild hypertension
Severe
coma
seizures +/- status epilepticus
conduction delays
SVT
hypotension
PVCs
ventricular tachycardias
respiratory depression
ileus
↑ tone
urinary retention
* Most common symptom.
Diagnosis
1. Blood levels: Quantitative levels are not typically available on an emergency basis. Qualitative
levels can usually be obtained. False positive qualitative tests occurs with:
a. diphenhydramine
b. carbamazepine
c. cyclobenzaprine
d. cyproheptadine
2.
e. phenothiazines
EKG: Abnormalities are common but may not be present during the 1st 6 hrs after ingestion
therefore a normal EKG during that time may not r/o toxicity.
After 6 hrs, however, EKGs changes do not develop. Look for
characteristic findings:
a. Sinus tachycardia (due to muscarinic cholinergic
Selective Serotonin
stimulation)
Reuptake Inhibitors
b. ↑ PR, QRS > 100 ms, (d/t Na channel blockade)
c. Terminal RAD (last 40 ms) in AVR: Look for positive
Fluoxetine
terminal QRS deflection, R wave > 3 mm or R/S ≥ 0.7
Fluvoxetine
d. Brugada-like pattern: ↑ ST in V1-V3 and RBBB pattern
Paroxetine
(d/t Na channel blockade)
Sertraline
e. ↑ QT (due to K channel blockade)
Citalopram
Escitalopram
In the setting of acute TCA overdose: (Boehnert. NJEM. 1985)

QRS > 100 ms: 1/3rd of pts developed seizures

QRS > 160 ms: ½ of pts developed ventricular
dysrhythmias
The absence of RAD, QRS prolongation > 100 ms, QT prolongation and sinus tachycardia had an
NPV of 100% in one study. (Niemann. Am J Cardio. 1986)
Management
1. Stabilization & Monitoring:
a. ABCs
b. Continuous cardiac monitoring + serial EKGs
c. IV access
d. ABG if symptomatic (to determine pH)
e. Foley catheter & NG in pts with muscarinic symptoms (urinary retention + ileus)
2. Decontamination: Gastric lavage may be effective within 2 hrs of ingestions. AC is indicated, and
MDAC can be considered.
3. NaHCO3- Therapy
a. Indications:
i. QRS > 100 ms
ii. Terminal RAD > 120º
iii. Refractory hypotension
iv. Ventricular dysrhythmias
b. Dosage:
i. 1-2 mEq/kg bolus until clinical improvement or pH b/n 7.50 – 7.55
ii. Infusions of 150 mEq in 1 L D5W @ 2-3 cc/kg/hr are used to maintenance.
c. Complications: Alkalinization results in hypokalemia. Electrolytes should be monitored
carefully. IV potassium should be administered as required to maintain normal potassium
levels. If Na HCO3- → problems with volume overload, consider hypertonic saline or
hyperventilation instead.
4. Seizures: Expect self-limited generalized seizures.
a. Treat with benzodiazepines
b. Dilantin has no role
c. Do NOT use physostigmine – associated with cardiac arrest
5. Altered LOC: All patients with altered LOC receive a trial of O2, naloxone, dextrose & thiamine. In
pts with suspected mixed benzo + TCA toxicity, flumazenil should not be given as it can lead to
seizures. Agitation is common. Benzodiazepines are useful to manage this.
6. Hypotension: Initially, this can be treated with 10 cc/kg NS boluses. If BP does not improve,
HCO3- should be used. If pressors are necessary, norepinephrine is the 1st choice b/c it will
compete with the TCA at the α receptor level. Dopamine does not work as well.
7. Dysrhythmias:
a. Asymptomatic patients with sinus tachycardia, ↑ PR & QT intervals or 1st degree block do
not need intervention.
b. Pts with more significant cardiac findings or symptoms should be treated with HCO3-.
c.
Pts with ventricular dysrhythmias should be treated with HCO3-. The 2nd line treatment is
lidocaine (Class Ib). Class Ia & Ic antiarrhythmic agents, β-blockers, CCAs and class III
antiarrhythmic agents are contraindicated in TCA overdose.
Disposition

Patients who are asymptomatic 6 hrs after ingestion do not require further observation for toxicity.

Symptomatic patients can be discharged once they are asymptomatic for 12 – 24 hrs.
Selective Serotonin Reuptake Inhibitors
Therapeutic Mechanism of Action
Preferentially block the reuptake of serotonin into the pre-synaptic nerve terminal. Since serotinerigic
neurons are concentrated in the mainly in the GI tract with the remainder in the CNS, these are the systems
affected by their use.
Pharmacokinetics

Absorption: Rapidly absorbed with peak levels at 3-5 hrs

Distribution: Protein bound + lipophilic with high Vd

Metabolism/Eliminatoin: Hepatic metabolism. Citalopram, escitalopram and fluoxetine have the
longest half lives. These drugs have active metabolites.
Clinical Presentation
SSRI Overdose
CNS
Lethargy and sedation, seizures (rarely)
CVS
QTc prolongation, which may be delayed upt o 24 hrs with ecitalopram and citalopram
GI
Nausea and vomiting
Serotonin Syndrome
See below
Management

ABCs: r/o TCA using EKG (QRS < 100 ms)

Decontamination: Consider AC – often not necessary given benign nature of ingestion. No role for
HD or HP d/t lg Vd.

Supportive management: hydration, cardiac monitoring x 6 hrs (24 hrs if citalopram or
escitalopram)
Disposition
Discharge after 6 hrs of monitoring if asymptomatic, unless citalopram or escitalopram ingestion.
Serontonin Syndrome
Etiology
Increased 5HT can occur through a number of different mechanisms:

↑ 5HT production: busprione, lithium, tryptophan, VPA

↑ 5HT release: ectasy, mirtazepine

↓ 5HT reuptake: SSRIs, some narcotics (meperidine, dextromethorphan), trazodone, venlafaxine,
cocaine

↓ 5HT breakdown: MAOi, clonazepam
Clinically, the most common cause is combining two agents by not allowing appropriate washout time
between antidepressants or inadvertently adding a medication with serotonergic activity.
Clinical Presentation
↑ 5HT levels → excess stimulation of type Ia 5HT receptor. Symtoms usually occur within hrs of exposure
(vs days in NMS)
CNS
Altered LOC (either agitation or somnolence)
PNS
HN
CVS
GI
Metab
Derm
MSK
Hyper-reflexia and ↑ tone (esp lower extremities), tremour
Nystagmus
Labile BP, tachycardia (d/t autonomic instability)
Diarrhea
Hyperthermia
Diaphoresis
muscle rigidity
Management

ABCs

Decontamination: discontinue drug(s)

Supportive management: Benzos + passive +/- active cooling for hyperthermia

Antidote: Cyproheptadine has anti-serotonergic activity and can be used in pts with severe toxicity.
It has anticholinergic activity, which may worsen hyperthermia.
Disposition
Symptomatic pts generally require admission for observation x 24 hrs (minimum)
Monoamine Oxidase Inhibitors
Therapeutic Mechanism of Action
The MAO-isoenzymes MAO-A & MAO-B inactivate direct acting (epinephrine, NE, 5HT) and indirect acting
(tyramine) biogenic amines. MAOi’s have 4 major effects:

Inhibition of MAO

↑ amphetamine and methamphetamine activity

Eventual depletion of pre-synaptic NE stores b/c MAOi’s enter the neuron and displace stored NE
from vesicles

Inhibition of pyridoxine (vitamin B6) containing enzymes
Pharmacokinetics

Absorption: Well absorbed with peak levels at 0.5-2.5 hours

Distribution: Protein bound with lg volume of distribution

Elimination: Primary hepatic metabolism (small amt excreted unchanged in the urine)
Clinical Presentation
The clinical course of MAOi toxicity can occur in three settings:
Setting
Overdose
Food/Drug
Interactions
MAOi/Drug
Interactions
Clinical Presentation
1. Asymptomatic or latent phase (12- 24 hrs)
2. Neuromuscular and cardiovascular excitation (d/t ↑ NE,
epi and 5HT levels)
3. ↓ LOC, hypotension and cardiovascular collapse (? d/t
catecholamine depletion)
4. Complications of phase 3
Sympathetic signs & symptoms
Examples of foods:

Aged cheese

Smoked or pickled meat or fish

Red wine

Pasturized pale beer
Sympathetic storm or serontonin syndrome
May develop hypotension and cardiovascular collapse in
more severe cases
Agents:
↑ 5HT: SSRIs, Li, MDMA, cocaine, meperidine,
dextromethorphan, buspirone, cocaine
↑ NE/Epi: cocaine, sympathomimetics
Special Considerations
Reversible MAOi’s (moclobemide) do not
have significant toxicity compared to
irreversible ones
Rapid onset of symptoms b/c ingested
tyramine → ↑ rls of biogenic amines
from the adrenal medulla
Symptoms are short lived b/c tyramine
has a short duration of action
Onset of symptoms minutes to hours
afterdrug exposure.
Reaction may go on for hours to days,
depending on the t½ of the drug
Management - Overdose

ABCs: Avoid β blockers and CCBs b/c of the risk of hypotension and bradycardia. There is also a
concern that β blockade may lead to ↑ vasoconstriction d/t unopposed peripheral α stimulation



Decontamination: Typically delayed onset, so decontamination not effective
Supportive Management:
o Hyperthermia: treat agitation + cooling
o Agitation: benzodiazepines
o Hypertension: short-acting direct arterial vasodilators (nitroprusside, nitroglycerin,
phentolamine)
o Hypotension: Fluids + direct acting vasopressor (NE)
Enhanced Elimination: HD and HF not effective
Management – Food/Drug Interaction

If hypertensive urgency or emergency, oral α blocker or nifedipine (dihydroperidine) if not normally
hypertensive.

IV phentolamine (α blocker) or other direct vasodilators can be used for more exact titration of BP
Disposition

Any pts with suspected overdose should be admitted for observation x 24 hrs b/c symptoms are
often delayed.

Pts with a food/drug or drug/drug interaction should be monitored for 6 hrs prior to d/c if
asymptomatic.
Buproprion (Zyban, Wellbutrin)
Therapeutic Mechanism of Action
Inhibits DA reuptake → ↑ DA neurotransmission. It also ↓’s NE reuptake, to a lesser extent.
Pharmacokinetics

Absorption: Well absorbed with peak levels at 2 hrs

Distribution: Lipophilic and protein bound with lg Vd

Metabolism/Elimination: Active metabolites with t½ > 20 hrs. Hepatic metabolism.
Clinical Presentation
CNS
Seizures*, agitation, tremor, drowsiness, confusion
CVS
Tachycardia
GI
vomiting
* Seizures occur with OD and supratherapeutic doses. Usually self-limited, but may develop status
epilepticus.
Management

ABCs: No special considerations

Decontamination: Avoid AC b/c of risk of seizures with airway compromise

Supportive management: Treat seizure with benzodiazepines

Enhanced Elimination: HF, HP and forced dieresis not effective
Disposition

Observe pts with immediate-release ingestion x 8 hrs

Observe pts with sustained-release ingestion x 12 hrs
Trazodone
Therapeutic Mechanism of Action

Inhibition of 5HT activity (typically used for sedation or as a treatment adjunct rather than as a
stand-alone antidepressant)
Pathophysiology
Other effects of trazodone include:

Peripheral α1 blockade → hypotension

↓ NE reuptake

Post-synaptic 5HT blockade
Pharmacokinetics

Absorption: Well absorbed with peak concentrations in 1-2 hrs

Distribution: Protein bound

Metabolism/Elimination: Hepatic metabolism. t½ = 6 hrs
Clinical Presentation
Hypotension (orthostatic or generalized) is the primary symptom
Management
Supportive
Venlafaxine (Effexor)
Therapeutic Mechanism of Action
Blocks reuptake of 5HT (and to a lesser extent DA and NE).
Pathophysiology

Dose-dependent Na blockade

Active metabolite also blocks 5HT, DA and NE reuptake
Pharmacokinetics

Absorption: Rapidly absorbed with peak concentration at 2hrs. XR preparation peaks at 6-7 hrs

Distribution: Lg Vd

Metabolism: Hepatic metabolism → active metabolite with long t½
Clinical Presentation
CNS
seizures, somnolence
CVS
tachycardia, ↑ QTc, ↑ QRS, hemodynamic collapse
Management
Supportive. May discharge if asymptomatic 6 hrs post-ingestion
Mirtazapine
Therapeutic Mechanism of Action

Blocks pre-synaptic α2 receptors → ↑ release of NE and 5-HT.

Blocks 5-HT2 and 5-HT3 receptors → More targeted CNS effects with ↓ GI side effects
Pathophysiology

↑ synaptic 5-HT can lead to serotonin syndrome

α1 blockade → vasodilation with hypotension and tachycardia

H1 and muscarinic blockade → anticholinergic symptoms
Pharmacokinetics

Absorption: Rapidly absorbed with peak levels 2 hrs after dosing

Distribution: Highly protein bound

Metabolism: Hepatic metabolism with active metabolites. T½ of metabolites is 19 hrs. T½ of
mirtazapine is 20-40 hrs.
Clinical Presentation
CNS
↓ LOC, confusion, anxiety, no seizures
CVS
Mild hypotension + tachycardia, no EKG changes
Management
Supportive