Mechanism of Action of Cyproheptadine
Cyproheptadine functions as a competitive antagonist at serotonin receptors (particularly 5-HT2A and possibly 5-HT1A), histamine H1 receptors, and possesses anticholinergic properties. 1
Primary Pharmacological Actions
Serotonin Antagonism
- Cyproheptadine competitively blocks serotonin at receptor sites, particularly the 5-HT2A receptors in the central nervous system, which forms the basis for its use as the preferred antidote in severe serotonin syndrome. 2
- The antiserotonergic effects may also occur at 5-HT1A receptors in the midbrain raphe, contributing to its therapeutic effects. 2
- This serotonin antagonism directly reverses excessive serotonergic activity by competing with serotonin for receptor binding sites. 2
Histamine H1 Receptor Antagonism
- Cyproheptadine acts as a first-generation H1-antihistamine, competing with histamine for H1 receptor sites. 1
- This antihistaminic action provides efficacy for allergic-type symptoms and rhinorrhea, with better control of rhinorrhea compared to second-generation antihistamines due to additional anticholinergic effects. 3
Anticholinergic Properties
- The drug possesses anticholinergic effects that contribute to its sedative profile and enhanced control of secretory symptoms. 1
- These anticholinergic properties can cause dry mouth, dry eyes, constipation, urinary retention, and carry risks for narrow-angle glaucoma. 3
Clinical Implications of Mechanism
Life-Saving Application in Serotonin Syndrome
- The American Academy of Pediatrics specifically recommends cyproheptadine over chlorpromazine for severe serotonin syndrome because it directly antagonizes the pathological serotonergic hyperactivity without the risks of increased muscle rigidity, decreased seizure threshold, or worsening of neuroleptic malignant syndrome. 4, 2
- The competitive antagonism at 5-HT2A receptors reverses the clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities characteristic of serotonin syndrome. 2
Sedative Effects
- The combination of antiserotonergic, antihistaminic, and anticholinergic actions produces significant sedation (9-11% incidence), which can impair driving ability and cognitive function, particularly in elderly patients. 3, 5
Pharmacokinetic Considerations
- After oral administration, 40% of radioactivity is excreted in urine with no detectable unchanged drug in patients on chronic dosing, indicating extensive metabolism. 1
- The principal metabolite is a quaternary ammonium glucuronide conjugate of cyproheptadine. 1
- Elimination is diminished in renal insufficiency, requiring dose adjustments. 1
Additional Receptor Activities
- Research has identified N-type calcium channel inhibitory activity, though this is not the primary therapeutic mechanism in clinical use. 6
- The drug demonstrates effects on the hypothalamo-pituitary-adrenal axis through its antiserotonin action, affecting both CNS pathways and peripheral regulatory mechanisms including the adenylate cyclase system. 7