Mechanism of Action of Tricyclic Antidepressants (TCAs)

Introduction

Tricyclic antidepressants (TCAs) are one of the oldest classes of antidepressant medications. Although largely replaced by SSRIs due to their improved safety profiles, TCAs are still widely used for treatment-resistant depression, neuropathic pain, and other off-label conditions. They work by inhibiting the reuptake of norepinephrine and serotonin, thereby increasing the levels of these neurotransmitters in the synaptic cleft.

Common TCAs include:

• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Clomipramine
• Doxepin

These drugs are frequently covered in USMLE, GPAT, NCLEX, and NEET-PG pharmacology sections.

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Stepwise Mechanism of Action of TCAs

1. Inhibition of reuptake transporters
   TCAs inhibit both the norepinephrine transporter (NET) and the serotonin transporter (SERT) on presynaptic neurons.
2. Increased synaptic levels of NE and 5-HT
   This inhibition leads to an accumulation of norepinephrine (NE) and serotonin (5-HT) in the synaptic cleft.
3. Enhanced postsynaptic neurotransmission
   The increased availability of NE and 5-HT leads to improved neurotransmission, which contributes to mood elevation.
4. Delayed therapeutic response
   Like SSRIs, TCAs exhibit a delayed clinical effect, typically seen after 2–4 weeks, due to neuroadaptive changes in receptor sensitivity.
5. Additional receptor blockade
   TCAs also block muscarinic (anticholinergic), histaminergic (H1), and alpha-1 adrenergic receptors, contributing to both therapeutic and adverse effects.

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Pharmacokinetic Parameters of TCAs

Drug	Half-life	Metabolism	CYP Interaction	Excretion
Amitriptyline	~10–28 hours	Hepatic (CYP2D6)	Strong CYP2D6 substrate	Renal
Nortriptyline	~18–44 hours	Hepatic	Moderate	Renal
Imipramine	~12–25 hours	Hepatic (CYP2D6)	Moderate	Renal
Desipramine	~15–24 hours	Hepatic	Moderate	Renal

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Clinical Uses of TCAs

• Major depressive disorder (MDD)
• Neuropathic pain (e.g., diabetic neuropathy)
• Migraine prophylaxis
• Chronic tension-type headaches
• Nocturnal enuresis (imipramine)
• Obsessive-compulsive disorder (clomipramine)
• Insomnia (off-label)
• Fibromyalgia

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Adverse Effects of TCAs

• Sedation – due to H1 blockade
• Dry mouth, blurred vision, constipation, urinary retention – anticholinergic effects
• Orthostatic hypotension – alpha-1 blockade
• Weight gain – H1 and 5-HT receptor modulation
• Sexual dysfunction
• Arrhythmias and QT prolongation – sodium channel blockade
• Seizures – especially with overdose
• High lethality in overdose – caution in suicidal patients

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Comparative Analysis: TCAs vs SSRIs

Feature	TCAs	SSRIs
Reuptake inhibition	NE + 5-HT	Selective for 5-HT
Receptor blocking	Muscarinic, alpha-1, H1	Minimal
Sedation	Common	Less common
Cardiovascular risk	High (arrhythmias)	Low
Overdose safety	Dangerous	Safer

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Practice MCQs

Q1. TCAs primarily work by inhibiting:
a. Monoamine oxidase
b. Dopamine reuptake
c. Serotonin and norepinephrine reuptake ✅
d. GABA reuptake

Q2. Which TCA is commonly used in OCD?
a. Amitriptyline
b. Clomipramine ✅
c. Nortriptyline
d. Desipramine

Q3. TCA overdose can lead to:
a. Hepatitis
b. QT prolongation and arrhythmia ✅
c. Parkinsonism
d. Pancreatitis

Q4. Common anticholinergic side effect of TCAs is:
a. Polyuria
b. Diarrhea
c. Dry mouth ✅
d. Tinnitus

Q5. Which receptor blockade causes orthostatic hypotension with TCAs?
a. D2 receptor
b. H1 receptor
c. Muscarinic receptor
d. Alpha-1 adrenergic receptor ✅

Q6. Amitriptyline is useful in:
a. Acute psychosis
b. Migraine prophylaxis ✅
c. Schizophrenia
d. ADHD

Q7. Which TCA is a metabolite of amitriptyline?
a. Imipramine
b. Nortriptyline ✅
c. Clomipramine
d. Desipramine

Q8. Why should TCAs be used cautiously in cardiac patients?
a. Cause bradycardia
b. Cause AV block
c. Block sodium channels and prolong QT ✅
d. Increase renin secretion

Q9. Which symptom is LEAST likely with TCAs?
a. Sedation
b. Constipation
c. Insomnia ✅
d. Blurred vision

Q10. Which CYP enzyme metabolizes many TCAs?
a. CYP3A4
b. CYP2E1
c. CYP2D6 ✅
d. CYP1A2

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FAQs

Q1: Are TCAs first-line drugs today?
No. Due to their adverse effect profile and overdose risk, they are usually reserved for treatment-resistant cases.

Q2: Can TCAs cause seizures?
Yes. Especially in high doses or overdose situations.

Q3: Why are TCAs dangerous in overdose?
Because of cardiotoxicity, arrhythmias, and CNS effects. Even a 2-week supply can be lethal.

Q4: Do TCAs cause weight gain?
Yes, especially amitriptyline and doxepin due to histaminergic and serotonergic modulation.

Q5: Can TCAs be used in children?
Not commonly. Imipramine may be used for nocturnal enuresis in select pediatric cases.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK538173/