Cyclic Antidepressant Overdose

Dr. Jordan B. Barnett, MD FACEP

Interim Chairman, Department of Emergency Medicine at Episcopal

Hospital

Overview

• Widely used therapy for major depression

• Third most common cause of drug related death in US throughout 1980s

Pharmacology

• Anticholinger and amine pump blocking properties similar to phenothiazines

• Adrenergic Stimulating affects via blocking uptake of norepinephrine at synapse

• Block sodium channels

• new agents are unicyclic, bicyclic, and tetracyclic

Bioavailability

• slowly absorbed secondary to ionization in the stomach and slowing of peristalsis

• Can remain in gut for 12 hours or more

• Dissolve slowly

• 85-98% plasma bound

• Tissue entry is dependent on lipid solubility and their ionic dissociation at various pH levels

Metabolism

• Demethylation

• hydroxlation

• Glucuronidization

• increased metabolism via enhancement of barbiturates, tobacco, etoh.

• Excreted in bile and enter enterohepatic cycle

Activities of TCAs

• neuronal amine pump in cns blocked, stopping reuptake of norepinephrine and serotonin

• Also block norepinephrine reuptake at the adrenergic synapse outside of cns, leading to adrenergic blockade of cardiovascular system

TCA Pharmacology Cont.

• alpha adrenergic blocking

• anticholinergic

• membrane stabilizing effects similar to quinidine and local anesthetics

• calcium channel blocking effects

Cardiac Complications

• CA block fast sodium channel (responsible for depolarization of conduction tissue

• CAs slow repolarization (QT prolonged)

• Depressed Automaticity

Newer Tricyclics Safer?

• Maprotiline (Ludiomil) is a tetracyclic with more seizures in overdose

• Amoxapine (Asendin) is a metabolite of loxapine with few Cardiovascular effects but a higher incidence of seizures (36%) and Death (15%)

Newer Compounds Safer?

• Trazadone (Desyrel) - unrelated to TCAs and equally effective yet no CNS or Cardiac effects in OD

• Fluoxetine (Prozac) - pure serotonin blocker with little adrenergic activity - rare for CNS or cardiac effects

Signs and Symptoms

• CNS depression

• Anticholinergic toxicity

• Depression of cardiac conduction and contractility

• Disorientation

• Coma, Myoclonus, clonus, seizures

• tachycardia, mydriasis

Toxicity

• Tachycardia, slurred speach, and lethargy are earliest signs

• Coma 35%

• Twitching and myoclonic movements in 40% confused often with seizures and do not respond to dilantin

• Grand mal seizures in 10-20 percent

ECG• ST and T wave changes

• Prolonged QT and QRS interval

• Righward deviation of the QRS axis

• Bundle branch blocks, AV Conduction blocks

• Aberrant conduction

• Ventricular arrhythmias, EMD, Idioventricular rhythms

Sequence of ECG changes

• IV conduction block

• Arrhythmias

• Cardiac condtractility depressed

• bradycardia

Those who die….

• Hypotension

• Conduction blocks

• SVT

• Death usually not due to ventricular arrhythmias!

Treatment

• Prehospital - little can be done

• 25% of cases, patients were alert and awake at first prehospital contact

• All need monitoring, iV line, O2,, constant observation

• NO IPECAC (CNS depression can be rapid)

• Activated charcoal

Mandatory Preventive Care

• Fatal cases can present with only trivial signs of poisoning and develop major toxicity and life threatening complications very quickly

• Gastric Lavage paramount

• Charcoal

• Charcoal every 2 hours to reduce half life from 36 hours to 4 hours

Cathartics

• Recommended

• Yet no effect until patient begins to awaken (Remember- anticholinergic effects!)

Acid-Base Status

• Cardiovascular complications are pH dependent

• Any TCA OD with decreased CNS needs ABGs and Chest xray secondary to pulmonary edema or aspiration pneumonitis

• Maintain pH above 7.4 and a high paO2

ECG AS SOON AS POSSIBLE!• Evaluate QRS duration, axis, rrhythm and

rate

• QRS > 100 ms has a sensitivity for major complications of only 59% and a specificity of 76%

• Looks ofr a negative deflection in lead I and a positive deflection in aVr. This has a positive predictive value of 49% and a negative predictive value of 90%

Other studies needed...

• Sodium (antagonizes CA)

• Potassium (increases toxic effects)

Drug removal

• Peritoneal dialysis or forced diuresis not effective

• Hemoperfusion removes only small quantities

• Fluid loading, alkalinization, pressors are mainstay

Prognosis

• GCS of less than 8 predicts serious complications with a sensitivity of 86% and specificity of 89%.

• A high GCS does not rule out significant ingestion

Treatment of specific complications

• Seizures

• Cardiac depression (hypotension and conduction blocks)

Seizures

• 10% of all cases

• Mortality of 10%Most seizures are brief and benign

• Diazepam

• Phenytoin can cause hypotension and bradycardia and can worsen arrhythmias. Ineffective in 188 human cases. Still widely used, however.

Status Epilepticus

• Often complicated by hyperthermia

• Amoxapine, maprotiline, Despiramine often implicated

• Often requires general anesthesia or paralysis.

• Don’t use succinylcholine since vagal effects - vecuronium safer!

Cardiac Complications

• Avoid physostigimine (Can cause seizures, cholinergic crisis - narrow therapeutic/toxic ratio)

• Alkalinization of blood to ph 7.5. This often abolishes arrhythmias within minutes

How to Alkalinize

• Hyperventilation

• Administration of 1-5 meq/kg of bicarbinate. This, can, however, increase myocardial ischemia

Why is sodium Bicarbinate Effective?

• Sodium reverses blocked membrane channel

• In some studies hypertonic saline as effective as bicarbonate

Cardiac Arrest 2%

• Prolonged CPR and cardiopulmonary bypass has been sucessful in healthy younger patients

• isoproterenol can worsen hypotension and cardiac irritability due to unopposed beta adrenergic effects

• Never use Dobutamine - a Beta adrenergic drug

Disposition and Admission Criteria

• Observe at least 6 hrs

• If any signs or symptoms, admission to monitored bed

• If after 6 hrs only minor signs, such as tachycardia less than 120 or slurred speech with bowel sounds, with signs decreasing, can discharge

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