ECG Manifestations of TCA TOXICITY

 #️⃣ TCA TOXICITY: EMERGENCY MANAGEMENT

💊 MECHANISMS OF TOXICITY

1️⃣ Sodium Channel Blockade → Wide QRS, VT/VF

2️⃣ Alpha-1 Antagonism → Hypotension

3️⃣ Anticholinergic → “Hot as a hare, dry as a bone”

4️⃣ GABA Antagonism → Seizures

📊 ECG FINDINGS

• QRS Duration Predicts Risk:

•100ms: 33% seizure risk

•160ms: 50% arrhythmia risk

• aVR Clues:

•R wave ≥3mm

•R/S ratio >0.7

⚠️ ANTIDOTES & CONTRAINDICATIONS

• Sodium Bicarbonate (1-2 mEq/kg):

•For QRS >100ms or arrhythmias

•Mechanism: Alkalemia → ↑ sodium channel recovery

• Avoid:

•Phenytoin (worsens sodium blockade)

•Class Ia/Ic antiarrhythmics

🚨 RESUSCITATION PRIORITIES

1️⃣ ABCs:

•Intubate early (rapid clinical decline)

2️⃣ Decontaminate:

•Activated charcoal (if <1h post-ingestion)

3️⃣ Seizures:

•Benzodiazepines (diazepam/lorazepam)

4️⃣ Hypotension:

•NS bolus + norepinephrine

📌 CLINICAL PEARLS

• “30-50 rule”: QRS >100ms → ICU admission

• ECG Monitoring: Continue until QRS narrows (<100ms) for 24h

• Deadly Dose: 10-20 mg/kg (1-2g in adults)

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Tricyclic Antidepressants (TCAs): A Deep Dive into Mechanisms, Uses, Electrophysiology, and Toxicity

Tricyclic antidepressants (TCAs) remain one of the most fascinating drug classes in clinical medicine. Although newer antidepressants have largely replaced them for routine psychiatric care, TCAs continue to hold an important place in pharmacology, cardiology, pain medicine, and in toxicology—often for the worst reasons, as TCA overdose is one of the most dangerous ingestions in emergency medicine.

TCAs are powerful, multi-mechanistic drugs. Their benefits and their dangers come from the same pharmacologic actions. To understand their clinical significance, it’s essential to explore how they work, where they act, and why toxicity can so quickly become life-threatening.

This article explores TCAs in great depth—humanized, readable, and designed to help clinicians, trainees, and healthcare workers connect electrocardiographic findings with real cellular physiology.

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1. Overview: What Are TCAs?

TCAs are older antidepressant medications introduced in the 1950s. They share a 3-ring (tricyclic) chemical structure, which gives the class its name. Although originally developed for major depressive disorder, TCAs have broad pharmacologic profiles and numerous clinical applications today.

Common TCAs

Amitriptyline

Nortriptyline

Imipramine

Desipramine

Doxepin

Clomipramine

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2. Mechanism of Action — Why TCAs Affect So Many Systems

Unlike “cleaner” modern antidepressants (SSRIs/SNRIs), TCAs hit multiple receptors and ion channels simultaneously. Their therapeutic effect comes primarily from monoamine reuptake inhibition, but most of their side effects and toxicity stem from other receptor interactions.

Let’s break this down:

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2.1 Inhibition of Biogenic Amine Reuptake

TCAs block:

Norepinephrine transporter (NET)

Serotonin transporter (SERT)

This leads to increased synaptic levels of norepinephrine and serotonin—hence the antidepressant effect.

Clinical impact

Mood elevation

Improved energy

Treatment of neuropathic pain (via descending inhibitory monoamine pathways)

This is the “good” part of TCAs.

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2.2 Anticholinergic (Antimuscarinic) Effects

TCAs strongly antagonize muscarinic receptors.

Effects

Tachycardia

Dry mouth

Blurred vision

Urinary retention

Constipation

Hyperthermia in severe toxicity

These effects make TCAs poorly tolerated and dangerous in overdose.

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2.3 Sodium Channel Blockade (Quinidine-like effect)

This is the most clinically dangerous mechanism.

TCAs block fast sodium channels in:

Cardiac myocytes

His-Purkinje system

Neurons

Electrophysiologic impact

Prolonged phase 0 depolarization

Widened QRS complex

Slowed conduction → re-entry → ventricular arrhythmias

Risk of seizures (neuronal Na+ channel blockade)

This mechanism explains ECG abnormalities and cardiotoxicity.

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2.4 Alpha-1 Adrenergic Receptor Blockade

TCAs block peripheral alpha-1 receptors → vasodilation.

Results:

Hypotension

Orthostatic dizziness

Reflex tachycardia

In overdose, this becomes profound and resistant to fluids.

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2.5 Antihistamine (H1) Blockade

TCAs antagonize H1 receptors causing:

Sedation

Weight gain

Potentiation of CNS depression

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2.6 GABA Antagonism

TCAs weakly inhibit GABA-A receptors.

Result:

Increased risk of seizures, especially in overdose

Lowered seizure threshold even at therapeutic doses in some patients

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3. Electrophysiology: Why TCAs Are So Dangerous for the Heart

TCA toxicity is essentially sodium channel blockade toxicity.

Key ECG finding: Widened QRS

QRS Duration Clinical Meaning

< 100 ms Generally low risk

> 100 ms ~33% risk of seizures

> 160 ms ~50% risk of ventricular arrhythmias

This correlation is one of the most reliable in toxicology.

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3.1 Terminal R Wave in aVR — The Signature of TCA Toxicity

A terminal R wave in aVR suggests sodium channel blockade in the rightward vectors of the heart.

Diagnostic clues:

R wave > 3 mm in aVR

R/S ratio > 0.7 in aVR

Why this happens: TCAs slow conduction through the His-Purkinje fibers and shift terminal depolarization forces toward the right upper quadrant (aVR direction).

This is a hallmark ECG sign of TCA overdose and helps distinguish it from other wide-complex etiologies.

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4. Clinical Indications of TCAs

Although less commonly used for depression now, TCAs remain highly valuable for a range of conditions.

Psychiatric

Major depressive disorder (second-line)

OCD (especially clomipramine)

Pain Medicine

Neuropathic pain

Diabetic neuropathy

Post-herpetic neuralgia

Fibromyalgia (occasionally)

Neurology

Migraine prophylaxis

Chronic tension-type headache

GI Disorders

IBS (low-dose amitriptyline for visceral pain modulation)

Sleep Disorders

Low-dose doxepin for insomnia

TCAs are powerful but require careful prescribing.

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5. Toxicity: Why TCA Overdose Is a Medical Emergency

TCAs are one of the most dangerous medications to overdose on because:

They have narrow therapeutic windows

They rapidly cause life-threatening cardiac arrhythmias

They cause seizures, coma, hypotension, and acidosis

Early symptoms

Agitation

Drowsiness

Dry mouth

Tachycardia

Neurological toxicity

Confusion

Hallucinations

Seizures (often early)

Coma

Cardiac toxicity (life-threatening)

Sinus tachycardia

Wide QRS

Ventricular tachycardia

Hypotension from vasodilation + myocardial depression

Cardiac arrest

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6. Why Acidosis Worsens TCA Toxicity

Acidosis increases the unbound fraction of TCAs → increases toxicity.

Also, acidic pH enhances sodium channel blockade, worsening:

QRS widening

Arrhythmias

Neurologic instability

This is why sodium bicarbonate therapy is the cornerstone of treatment.

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7. Management of TCA Toxicity — Life-Saving Interventions

TCA overdose is a clinical diagnosis. Treat immediately—don’t wait for levels.

1. Airway and Supportive Care

Early intubation for agitation or seizures

Avoid flumazenil

2. Activated Charcoal

If patient is alert and within 1–2 hours of ingestion.

3. Benzodiazepines (Diazepam or Lorazepam)

Preferred for seizures.

Phenytoin is contraindicated

→ It blocks sodium channels and worsens QRS widening.

4. Sodium Bicarbonate (Mainstay of therapy)

Indications:

QRS > 100 ms

Seizures

Ventricular arrhythmias

Hypotension

Mechanisms:

Alkalinizes blood → reduces TCA binding to sodium channels

Increases sodium gradient → improves conduction

Narrows QRS

5. Fluids + Vasopressors

Hypotension often requires:

Normal saline

Norepinephrine (preferred)

6. Lipid Emulsion Therapy

Consider in severe, refractory cardiotoxicity.

7. Avoid

Class Ia/III antiarrhythmics

Beta-blockers

Calcium channel blockers

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8. Long-Term Considerations

Patients who survive severe TCA overdose may experience:

Cognitive changes

Severe anticholinergic rebound

Mood destabilization

Psychiatric evaluation is essential before discharge.

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Conclusion

Tricyclic antidepressants are remarkable medications—powerful, useful, and incredibly dangerous in overdose. Their wide-ranging effects stem from a complex pharmacologic profile that touches nearly every major receptor group: muscarinic, histaminergic, adrenergic, serotonergic, and voltage-gated sodium channels.

Understanding TCA physiology—particularly their electrophysiologic impact—is essential for anyone working in emergency medicine, cardiology, psychiatry, or pharmacology. Recognizing ECG findings such as QRS widening and a terminal R in aVR can be lifesaving, and prompt administration of sodium bicarbonate remains the cornerstone of management.

TCA toxicity highlights an important truth in medicine:

The more powerful the drug, the more respect it demands.

Thanks.