Download Tricyclic Antidepressants

Tricyclic Antidepressants
PHARMACOLOGY —
TCAs have several important cellular effects, including:
 Inhibition of presynaptic neurotransmitter reuptake (norepinephrine and serotonin)
 Blockade of cardiac fast sodium channels
 Antagonism of central and peripheral muscarinic acetylcholine receptors
 Antagonism of peripheral alpha-1 adrenergic receptors
 Antagonism of histamine (H1) receptors
 Antagonism of CNS gamma-aminobutyric acid (GABA) A receptors
Therapeutic doses of TCAs are rapidly absorbed from the gastrointestinal tract, reaching maximal plasma
concentrations within two to eight hours.
Following overdose, antimuscarinic effects may delay gastric emptying and absorption, significantly prolonging the
time to peak plasma concentration.
TCAs are lipophilic and have a large volume of distribution (Vd).
The plasma fraction of drug is usually highly bound to alpha-1 acid glycoprotein.
The combination of a large Vd and protein binding means that forced diuresis, dialysis, and hemoperfusion have no
role in the management of TCA overdose.
TCAs are primarily metabolized by the liver. Some drugs of this class have active metabolites, which may persist for 12
to 24 hours.
Half-life varies according to drug and ranges from 7 to 58 hours, but can be prolonged in overdose.
Seventy percent of the total dose is excreted via the kidney as inactive metabolites; the remainder is excreted via the
biliary system.
Enterohepatic recirculation can delay final elimination of a large fraction of the drug, prolonging absorption and
potentially increasing toxicity following overdose
CLINICAL FEATURES
Presenting signs of TCA overdose typically include CNS sedation (from antihistaminic effects), but may also include
confusion, delirium, or hallucinations. Arrhythmias, cardiac conduction delays, hypotension, and anticholinergic
toxicity (hyperthermia, flushing, dilated pupils, intestinal ileus, urinary retention, and sinus tachycardia)
Cardiac toxicity
Cardiac conduction abnormalities occur because TCAs inhibit the fast sodium channels in the His-Purkinje system as
well as the atrial and ventricular myocardium. This decreases conduction velocity, increases the duration of
repolarization, and prolongs absolute refractory periods.
Sinus tachycardia is common in overdose, likely as a result of anticholinergic (vagolytic) effects of the drug and a reflex
tachycardia due to hemodynamic decompensation.
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ECG changes in TCA overdose
Prolongation of the QRS >100 msec
Abnormal morphology of the QRS (eg, deep, slurred S wave in leads I and AVL)
Abnormal size and ratio of the R and S waves in lead AVR: R wave in AVR >3 mm; R to S ratio in AVR >0.7.
Management
 Isotonic saline to address hypotension.
 Sodium bicarbonate to address other cardiovascular toxicities - The benefit of sodium bicarbonate is probably due
to both an increase in serum pH and the increase in extracellular sodium. The increase in serum pH favors the
neutral form of the drug, making it less available to bind to sodium channels. Increasing the extracellular sodium
concentration increases the electrochemical gradient across cardiac cell membranes, potentially attenuating the
TCA-induced blockade of rapid sodium channel
 Alpha adrenergic vasopressors to address hypotension refractory to aggressive fluid resuscitation and bicarbonate
infusion.
 Antiepileptic therapy — Benzodiazepines remain the treatment of choice for TCA-induced seizures