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Tricyclic Antidepressants

Tricyclic Antidepressants: Mechanism of action and side effects Tricyclic Antidepressants (TCAs) -tryptylines (e.g. amitriptyline, nortriptyline), -pramines (e.g. clomipramine, imipramine), doxepin Competitive inhibition of excitatory muscarinic acetylcholine (ACh) receptors (primary neurotransmitter at neuromuscular junctions) Blockage of sodium channels in cardiac muscle cells ↓ Cortical neuronal firing ↓ Parasympathetic activity ↓ Depolarization of cardiac cells Exact mechanism unknown ↓ Smooth muscle contractions QT interval prolongation Arrythmias ↓ Bladder contractions Urinary retention Competitive inhibition of alpha-1 receptors on vascular smooth muscle throughout the body Blockage of serotonin (5-HT) & norepinephrine (NE) transporters on presynaptic neurons Competitive inhibition of histamine (H1) receptors throughout the body, especially in sleep-wake regions of the CNS (eg. thalamus & cortex) Exact mechanism unknown ↓ Blood vessel constriction Orthostatic hypotension ↓ Regulation of sympathetic activity Transient cerebral hypoperfusion ↑ Heart rate & cardiac contractility Dizziness ↓ Gut motility ↓ Saliva production Constipation Xerostomia (dry mouth) ↑ Levels of 5-HT & NE at synaptic cleft ↓ H1-induced depolarization in cerebral cortex ↓ Regulation of food intake (exact mechanism unknown) Diaphoresis (excessive sweating) Sedation ↓ Satiety signalling ↑ Neurotransmission in mood-regulating brain areas (e.g., limbic system) ↓ N-methyl-D-aspartate (NMDA) receptor depolarization of cortical neurons Weight gain ↑ Appetite Antidepressant effect (eg. ↑ mood & ↑ self worthiness) Author: Emily Cox Reviewers: Sara Cho, Luiza Radu, Emily J. Doucette, Susan Poon* Confusion * MD at time of publication Published Sept 16, 2025 on www.thecalgaryguide.com Legend: Exact mechanism unknown ↓ Pupillary dilation Paradoxical sweating Blurred vision Anticholinergic side effects Pathophysiology Mechanism Pharmacologic effect Adverse effect