Category Archives: Gastrointestinal

Serotonin (5-HT): receptors, agonists and antagonists

Serotonin (5-HT): receptors, agonists and antagonists

Serotonin (5-hydroxytryptamine, 5HT) is a key mediator in the physiology of mood, vascular function and gastrointestinal motility. This explains the number of therapeutic agents that act targeting the serotonergic system such as: 5-HT3 antagonists, SSRIs and triptans.

This article will focus on the classification of serotonin receptors, as well as drug classes that act on serotonergic transmission. This includes 5-HT agonists, antagonists and medications that modulate 5-HT at the presynaptic level, all of them of very high clinical relevance. Overdose of a combitation of serotonergic agents can lead to serotonin syndrome.

Outline:

Serotonin receptors

serotonin_5ht_receptors

Based on biochemical and pharmacological criteria, serotonin receptors are classified into seven main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated ion channel.

5-HT1 receptors are subdivided into 5-HT1A, 5-HT1B, and 5-HT1D receptors; while 5-HT2 subtypes include 5-HT2A, 5-HT2B, and 5-HT2C.

Drugs acting on serotonergic neurotransmission

serotonin_presynaptic_modulatorsThe figure above depicts how serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation, storage or reuptake.

MAO inhibitors

Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinson’s disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use.

Inhibitors of serotonin storage

They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil.

SNRI

SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentration-dependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective.

SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity.

TCAs

Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response.

Serotonin agonists

serotonin_agonists

Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into:

5-HT1A agonists

Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression.

5-HT1B and 5-HT1D agonists

The “triptans” are a drug class useful as abortive medication for the treatment of  acute migraine headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”.

5-HT2C agonist

Trazodone was previously believed to be a 5-HT2C receptor antagonist. However,  recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific.

5-HT4 agonists

Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity.

Non-selective agonists

Ergotamine activates a more than one subtype of 5-HT receptor, it binds to  5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks.

LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.

serotonin_antagonists

5-HT2 antagonists

Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect.

Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors.  It represents a class of atypical antipsychotic drugs, one key advantage of this group is its reduced incidence of extrapyramidal side effects compared to the classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia.

Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor.

5-HT3 antagonists

This class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV).

References and further reading

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Brunton, L.B., Lazo, J.S., & Parker, K.L. (Eds.). “Goodman & Gilman’s the pharmacological basis of therapeutics“,  11th edition. New York: McGraw-Hill:2005.

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