Amitriptyline is a tricyclic antidepressant indicated in the treatment of depressive illness, either endogenous or psychotic, and to relieve depression associated anxiety. The non-FDA-approved indications are anxiety, post-traumatic stress disorder, insomnia, chronic pain (diabetic neuropathy, fibromyalgia), irritable bowel syndrome, interstitial cystitis (bladder pain syndrome), migraine prophylaxis, postherpetic neuralgia, and sialorrhea. The three-ring central structure, along with a side chain, is the basic structure of tricyclic antidepressants. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. Amitriptyline by blocking the reuptake of both serotonin and norepinephrine neurotransmitters. In adrenergic neurons, norepinephrine is synthesized from tyrosine and stored in synaptic vesicles. Once an action potential arrives at the nerve terminal, calcium channels open, causing the influx of calcium in the cytosol. Calcium then triggers the release of neurotransmitters stored in synaptic vesicles via exocytosis. The norepinephrine is released into the synapse and acts on α1, β1 and β2receptors which contribute to mood improvements. The norepinephrine in the synapse is rapidly taken up by the norepinephrine reuptake transporter on the presynaptic neuron, and is recycled. Amitriptyline inhibits these reuptake transporters on adrenergic neurons, thereby increasing norepinephrine concentration in the synapse. This allows more stimulation of adrenergic needed to improve depressive moods. The most commonly encountered side effects of amitriptyline include weight gain, gastrointestinal symptoms like constipation, xerostomia, dizziness, headache, and somnolence.

Amitriptyline Norepinephrine Reuptake Inhibitor Pathway References