Tricyclic antidepressants poisoning

2.  They have been employed in drug therapy since the late 1950s.
 Tricyclic antidepressants (TCAs) were one of the most important causes of
mortality resulting from poisoning until 1993 and still continue to be a
major cause of death from self-poisoning.
 TCAs remain widely prescribed for depression and an increasing number of
other indications including anxiety disorders, attention deficit disorder,
pediatric enuresis, and chronic pain syndromes.
 Referred as “ tri cyclic ” compounds –three rings.

3.  Life threatening ,high risk for suicide. Involve multiple ingestions –ethanol ,
diazepam, codeine
 Tricyclic antidepressants (TCAs) are very toxic by ingestion. Due to
both accidental and deliberate overdoses.
 Overdose of greater than 15 mg/kg can result in severe, life-threatening
poisoning.
 Toxicity due to rapid absorption , tight binding to plasma proteins , low
therapeutic margins.

4.  They are highly protein bound. have a large volume of distribution.
 a long half life of elimination that generally exceeds 24 hours and in the case of
amitriptyline is 31 to 46 hours.
 The ingestion of large quantities of tricyclics in self poisoning causes altered
pharmacokinetics.
 Gastrointestinal absorption may be delayed because of inhibition of gastric emptying.
 significant enterohepatic recirculation prolongs the final elimination.
 The amount of unbound tricyclic may also increase if the overdose causes respiratory
depression resulting in an acidosis, which reduces protein binding
PHARMACOKINETICS

6.  Toxicity is due to a combination of anticholinergic effects at autonomic nerve endings in
the brain; blockade of cardiac sodium channels; and blockade of α 1- adrenergic
receptors.
TCAs are metabolized by the liver and excreted by the kidney. They are highly protein-
bound and the amount of unbound (i.e. active) TCA increases in acidosis.
The anticholinergic action prevents re-uptake of norepinephrine into nerve terminals at
noradrenergic and serotonergic sites. This can result in urinary retention, dilated pupils,
pyrexia, confusion, convulsions, and a dry mouth.
Blockade of cardiac sodium channels causes prolongation of the PR, QRS, and QT
intervals on the ECG.
Blockade of α 1 -adrenergic receptors results in vasodilatation which leads to hypotension
and reflex tachycardia.
MACHANISM

8. CNS CARDIOVASCULAR ANTICHOLNERGIC
HYPOTHERMIA
VENTRICULAR RATE ≥120
BEATS/MIN MYDRIASIS
RESPIRATORY DEPRESSION ARRHYTHMIAS BLURRED VISION
SEIZURES BUNDLE BRANCH BLOCK TACHYCARDIA
ABNORMAL TENDON
REFLEXES
CARDIAC ARREST URINARY RETENTION
AGITATION HYPOTENSION VASODILATION
DISORIENTATION CIRCULATORY COLLAPSE DECREASED GI MOTALITY
MYOCLONIC JERKS DECREASED BRONCHIAL
SECRATION
COMA, PYRAMIDAL SIGNS DRY MUCUS MEMBERANE AND
SKIN
CLINICAL FEATURES OF TCA POISONING

9. TCA OVERDOSE
 The cardiovascular toxicity, which is the most common cause of morbidity and mortality from TCAs, is related
to their sodium channel blockade and α-adrenergic blockade.
 TCAs bind to and inhibit the movement of sodium ions into the fast sodium channel thereby slowing
depolarization in the His-Purkinje system and ventricular myocytes. This results in slowed cardiac conduction
by slowing the propagation of ventricular depolarization which is manifested as a prolonged QRS on the ECG.
 Specifically, TCAs inhibit outward potassium current by blocking potassium channels, which ultimately results
in prolongation of the QT interval.
 Sinus tachycardia is the most common cardiac disturbance seen following TCA overdose. Competitive
blockade at muscarinic receptors plays a primarily role.
 although norepinephrine reuptake inhibition also contributes to the tachycardia and hypertension.

10.  prolonged blockade can cause depletion of norepinephrine from the presynaptic nerve terminal, and inhibition
of α1-adrenergic receptors which results in the subsequent development of refractory hypotension and
bradycardia in cases of serious overdose.
 This hypotension can be exacerbated by hypoxia, acidosis, and volume-depletion.
 Neurologic effects of TCAs, including agitation and delirium, primarily result from CNS blockade of
muscarinic receptors.
 By impairing sweating heat dissipation is reduced and this can result in a fever, especially if seizures occur.

11. CLINICAL MANIFESTATIONS
 Clinical symptoms of antidepressant toxicity often progress rapidly and unpredictably, and, many times,
patients present asymptomatically or minimally symptomatic and progress to life threatening cardiovascular
and neurologic toxicity within an hour.
a) Cardiovascular effects
Hypertension (early) ,
Hypotension ,
Dysarrhythmia,
Delayed conduction,
Long QT

12. b) Nervous system
 Early manifestations include altered mental status, delirium, psychotic behavior, and agitation, and
hallucinations. These symptoms can later proceed rapidly to coma.
 Drowsiness, slurred speech, sedation (H1 block)
 Seizures are usually generalized and often occur within 1-2 hours of ingestion.
 Seizures occurs in 4% of patients with overdose and in 14% of fatal cases
 Tricyclic antidepressant toxicity can be caused by either an acute ingestion or a chronic ingestion.
 Toxicity secondary to chronic ingestions usually presents with symptomatology that is an exaggeration of the
usual side effects of tricyclics.

13. TREATMENT OF TCA POISONING
— as with all poisoning an ABCDE approach and supportive therapy . It
should be instituted. Any hypoxia should be corrected with supplemental oxygen and patients who are
hypercapnic should receive assisted ventilation. Often correction of hypoxia, hypercapnea, and fluid
resuscitation will be sufficient to correct the acidosis and any arrhythmias.
— should be considered if the
patient presents within 1 hour of ingestion and is able to protect
their airway.
— is indicated if the patient has a metabolic acidosis which persists
despite correction of hypoxia and fluid resuscitation. Rapid correction is required if the patient is acidotic
with a prolonged QRS or QT. The dose of sodium bicarbonate is 50 mmol (50 ml of 8.4 % ), which may
need repeating, aiming for pH 7.5. Even in the absence of acidosis, alkalinization with sodium bicarbonate
should be considered in patients with:
o QRS > 120 ms.
o Arrhythmias.
o Hypotension resistant to fluid resuscitation.

14. Alkalinization by sodium bicarbonate reduces TCA toxicity by increasing protein binding, thereby reducing the
available active substrate; antagonising cardiac sodium channel blockade; and improving myocardial contractility by
correcting the acidosis.
 Benzodiazepines — are used to control convulsions (e.g. lorazepam 4 mg IV) or sedate agitated patients.
Phenytoin is contraindicated in TCA overdose because it also blocks sodium channels and increases the risk of
cardiac arrhythmias.
 Arrhythmias — are best treated with correction of hypoxia and acidosis. Class Ia (quinidine, procainamide) and Ic
(flecanide, propafenone) anti-arrhythmics are contra-indicated because they may worsen sodium channel
blockade and exacerbate arrhythmias.
 Hypotension — should be treated with intravenous fluids and correction of acidosis with sodium bicarbonate. If
hypotension persists despite this then lipid emulsion may be considered. Inotropes may be required for resistant
hypotension. Glucagon is also a treatment option for severe hypotension, heart failure, or cardiogenic shock.
 Cardiac arrest — may respond to prolonged resuscitation and efforts should be continued for at least 1 hour.

15.  Anti-Imipramine antibodies.
 Titrations with Fab.
 Anti -TCA monoclonal antibody.
 Combination of Anti -TCA Fab and Sodium bicarbonate.
ANTIDOTE
DISCHARGE CRITERIA
 Observed for 6 hrs.
 If no abnormality in vital functions , discharged after a
final dose of charcoal.
 Persistent Tachycardia should be evaluated

16.  TCA toxicity is due to a combination of anticholinergic effects at autonomic nerve endings and in the brain;
blockade of cardiac sodium channels; and blockade of α 1 adrenergic receptors.
 Clinical features include:
• Anticholinergic
• Cardiovascular — hypotension, sinus tachycardia, prolonged PR, QRS and QT, atrioventricular block.
• CNS — drowsiness, ataxia, divergent squint, hyperreflexia, hypertonia, extensor plantars, seizures, coma, and
respiratory depression.
 Indications for sodium bicarbonate include:
• Persistent acidosis despite correction of hypoxia and fluid resuscitation.
• QRS > 120 ms.
• Arrhythmias.
• Hypotension resistant to fluid resuscitation.
Lipid emulsion, inotropes, and/or glucagon may be required for resistant hypotension.
KEY POINT