Anesthesia Pharmacology: Serotonin Pharmacology
Effects mediated through serotonin receptors:
At least seven major 5 HT subtypes identified:
Most subtypes are G protein coupled.
At least one subtype is a ligand-gated ion channel.
Coupling mechanism; comments
Raphe nuclei, hippocampus
↓cAMP, potassium channels:partially selective agonist: 8-OH-DPAT
↓cAMP,partially selective agonist: sumatriptan (Imitrex)
Area postrema, sensory and enteric nerves
Receptor: Na+-K+ ion channel: partially selective antagonists ondansetron (Zofran), granisetron (Kytril), tropisetron
CNS, ,smooth muscle
↑cAMP; partially selective agonists: metoclopramide (Reglan)
Direct effects: Serotonin causes contraction, acting through 5-HT2 receptors.
Serotonin promotes vasoconstriction except:
In skeletal muscle vasculature where vasodilation occurs and
In the heart where vascular endothelial cell-dependent vasodilation occurs.
Serotonin-mediated reflex bradycardia results from 5-HT3 activation of at chemoreceptor nerve endings.
Serotonin-induced vasoconstriction is especially pronounced on pulmonary and renal vasculature.
Venoconstriction with subsequent increased capillary filling causes flushing following serotonin administration.
Serotonin causes a small direct positive inotropic (increased force of heart contraction) and positive chronotropic (increased heart rate) cardiac effects.
Subendocardial fibroplasia associated with prolonged elevation of serotonin in the blood (e.g. in carcinoid syndrome) may result in myocardial space for electrical or valve malfunction.
Serotonin induces platelet aggregation by activation of platelet surface 5-HT2 receptors.
Serotonin causes contraction of gastrointestinal smooth muscle with both increased tone and increased peristalsis.
These effects are 5-HT2 receptor mediated and are due to both:
Direct effect on smooth muscle receptors and
Stimulation of enteric ganglia cells.
Serotonin activation of 5-HT4 receptor results in increased acetylcholine release which in turn increase GI motility, as is therefore described as "prokinetic"
An example of the effect is seen in carcinoid tumor where serotonin overproduction results in severe diarrhea.
Serotonin stimulates itch and pain sensory nerve endings.
Serotonin also activates chemosensitive nerve endings in coronary vessels
5-HT3 receptor activation on these chemosensitive vagal nerve endings causes chemoreceptor reflex, known as the Bezold-Jarisch reflex.
Reflex response is characterized by significant negative chronotropic ( i.e. reduced heart rate or bradycardic response) with hypotension.
The bradycardia is likely mediated by the vagus nerve since the response is blocked by the anticholinergic, antimuscarinic drug, atropine.
Other agents that activate chemoreceptor reflex include:
Nicotinic cholinergic receptor agonists and
Some cardiac glycosides
5-HT3 receptor activation in the gastrointestinal tract and in the medullary vomiting center is associated with the vomiting reflex.
This system is important in vomiting caused by chemotherapeutic (anticancer) drugs.
Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.