5-HT3 antagonist
Encyclopedia
The 5-HT3 antagonists are a class of medication
s that act as receptor antagonist
s at the 5-HT3 receptor
, a subtype of serotonin
receptor
found in terminals of the vagus nerve
and in certain areas of the brain.
With the notable exception of alosetron
and cilansetron
, which are used in the treatment of irritable bowel syndrome
, all 5-HT3 antagonists are antiemetic
s, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy
and are considered the gold standard for this purpose.
The 5-HT3 antagonists may be identified by the suffix –setron, and are classified under code A04AA
of the WHO
's Anatomical Therapeutic Chemical Classification System
.
proposed the existence of two serotonin receptor subtypes, the M and D receptors (thus named because their function could be blocked by morphine
and Dibenzyline
respectively), in a landmark paper. The 5-HT3 receptor was later found to correspond to the M receptor. In the 1970s, John Fozard proved that metoclopramide
and cocaine
were weak antagonists at the 5-HT3 (5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT3 receptor antagonist. The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.
While Fozard was investigating cocaine analogues, workers at Sandoz
identified the potent, selective 5-HT3 receptor antagonist ICS 205-930 from which the first marketed selective 5-HT3 receptor antagonists ondansetron and granisetron
were developed, and approved in 1991 and 1993 respectively. Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997. A new and improved 5-HT3 receptor antagonist, named palonosetron, was approved in 2003.
The development of selective 5-HT3 receptor antagonists was a dramatic improvement in the treatment
of nausea and vomiting. Ondansetron, granisetron, dolasetron and palonosetron are currently approved in the United States, and form the cornerstone of therapy for the control of acute emesis with chemotherapy agents with moderate to high emetogenic potential.
were first introduced in the early 1990s, and they have become the most widely used antiemetic drugs in chemotherapy
. They have also been proven safe and effective for treatment of postoperative nausea and vomiting. Serotonin (5-HT) is found widely distributed throughout the gut
and the central nervous system
. In the gut, 5-HT is found mostly in mucosal enterochromaffin cells
. Enterochromaffin cells are sensory transducers that release 5-HT to activate intrinsic (via 5-HT1P and 5-HT4 receptors) and extrinsic (via 5-HT3 receptors) primary afferent nerves. Chemotherapeutic drugs for malignant disorders that cause vomiting have been found to cause release of large amounts of serotonin from enterochromaffin cells in the gut, serotonin acts on 5-HT3 receptors in the gut and brain stem.
afferents
, the solitary tract nucleus (STN), and the area postrema itself. Serotonin
is released by the enterochromaffin cells
of the small intestine
in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. The 5-HT3 receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT3 receptors. The highest concentration of 5-HT3 receptors in the central nervous system
(CNS
) are found in the STN and chemoreceptor trigger zone
(CTZ), and 5-HT3 antagonists may also suppress vomiting and nausea by acting at these sites.
When patients undergo chemotherapy, serotonin is released from enterochromaffin cells by the cytotoxicity, the selective 5-HT3 receptor antagonists prevent the ability of serotonin to activate and sensitize gastrointestinal vagal-nerve terminals to other emetogenic substances released.
and peripheral
nervous systems. The rapidly activating, desensitizing, inward current is predominantly carried by sodium
and potassium
ions. 5-HT3 receptors have a negligible permeability to anions.
The 5-HT3 receptor consists of five subunits that may be the same (homopentameric 5-HT3A receptors) or different (heteropentameric receptors, usually consisting of 5-HT3A and 5-HT3B receptor subunits).
The subunits surround a central ion channel
in a pseudo-symmetric manner (Fig.1). Each subunit comprises an extracellular
N-terminal domain, four transmembrane domains (M1-M4) connected by intracellular (M1-M2 and M3-M4) and extracellular loops (M2-M3) and an extracellular
C-terminus (Fig.1). The extracellular domain is the site of action of agonists and competitive antagonists because of ligand binding and the transmembrane domain controls the movement of ions across the cell membrane
. The human subunits 5-HT3A and 5-HT3B have been isolated and as well as sharing 41% amino acid
sequence identity the location of their genes
are in close proximity on the long arm of chromosome
11. The 5-HT3C, 5-HT3D and 5-HT3E subunits have not been isolated.
Genes
that code for the subunits of the 5-HT3 receptor have been identified. HTR3A
and HTR3B
for the 5-HT3A and 5-HT3B subunits and in addition HTR3C
, HTR3D
and HTR3E
genes
encoding 5-HT3C, 5-HT3D and 5-HT3E subunits. The latter three tend to show peripherally restricted pattern of expression, with high levels in the gut
. In human duodenum
and stomach
, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A and 5-HT3B. There is some evidence to suggest that the 5-HT3 receptor subunits are an important contribution to the effectiveness of these compounds. In patients treated with chemotherapeutic drugs, certain polymorphism
of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of antiemetic drug efficacy. HTR3C
and HTR3E
do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological
role for these additional subunits has yet to be identified.
Experiments have shown evidence that the ligand-binding site is located at the interface of two adjacent subunits. The ligand binding site is formed by three loops (A-C) from the principal ligand binding subunit (principal face) and three β-strands (D-F) from the adjacent subunit (complementary face). The amino acid residue E129 on loop A faces into the binding pocket and forms a critical hydrogen bond with the hydroxyl group of 5-HT. Loop B contains W183, a critical tryptophan
ligand binding residue that contributes to a cation-π interaction between the pi electron
density of tryptophan and the primary amine of 5-HT. Loop C residues have been considered as candidates for the differing pharmacology
of rodent
and human
5-HT3 receptors because of their divergence between species. The most important aromatic residue within loop C is probably Y234 that lies opposite to the loop B tryptophan
in the ligand binding pocket and is involved in ligand binding. Loops D and F are in fact β-strands not loops. W90 in loop D is critical for ligand binding and antagonists may directly contact R92. The azabicyclic ring of the competitive antagonist
granisetron is located close to R92 and the aromatic rings lie close to W90. Loop E residues Y143, G148, E149, V150, Q151, N152, Y153 and K154 may be important for granisetron binding. The structure of loop F has yet to be clarified but W195 and D204 seem to be critical for ligand binding. The results of several studies suggest that the orientation of granisetron (a 5-HT3 receptor antagonist )in the 5-HT3 receptor binding pocket is with its aromatic rings between Trp-183 and Tyr-234 and its azabicyclic ring between Trp-90 and Phe-226.(Fig.2)
Chemical structures of the first generation 5-HT3 receptor antagonist can be categorized to three main classes
The first-generation 5-HT3 receptor antagonist (ondansetron, dolasetron
, granisetron, and tropisetron
) have been the most important drugs in antiemetic therapy for emetogenic chemotherapy
. They are especially effective in treating acute emesis, occurring in the first 24 hours following chemotherapy
.
A newer drug palonosetron
is a pharmacologically distinct and highly selective, second generation 5-HT3 receptor antagonist. Palonosetron
has two stereogenic centers and exists as four stereoisomers.
Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).
The pharmacophore
of 5-HT3receptors consists of three components: a carbonyl-containing linking moiety, aromatic/heteroaromatic ring, and a basic center. The carbonyl
group is coplanar to the aromatic ring. 5-HT3 receptor antagonists are more likely to bind in their protonated form. Docking of a range of antagonists into a homology model of the 5-HT3 receptor binding site shows a reasonably good agreement with the pharmacophore
model and supports the observed differences between species. Studies of granisetron in the binding pocket revealed that the aromatic rings of granisetron lie between W183 and Y234 and the azabiciclic ring between W90 and F226. In this study another energetically favorable location of granisetron was identified, closer to the membrane, on a position that could be a part of a binding/unbinding pathway for the ligand. A similarly located alternative binding site for granisetron has since been identified in another study of the 5-HT3 receptor.
5-HT3 receptor antagonists share the same pharmacophore
. An aromatic moiety (preferably indole), a linking acyl group capable of hydrogen bonding interactions, and a basic amine
(nitrogen
) can be regarded as the key pharmacophoric
elements of the known 5-HT3receptor antagonists. There are steric limitations of the aromatic binding site and although two hydrogen-bonding interactions are possible on the heterocyclic linking group (oxadiazole capable of accepting two hydrogen bonds), only one is essential for high affinity. An optimal environment of the basic nitrogen is when its constrained within an azabicyclin system with the highes affinity observed for systems with nitrogen at the bridgehead position and secondary amines being more potent. The 5-HT3 receptor can only accommodate small substituents on the charged amine, a methyl group being optimal. The optimal distance between the aromatic binding site and the basic amine is 8,4-8,9 Å and it is best if a two-carbon linkage separates the oxadiazole and the nitrogen. An increasing substitution of R increases affinity. The most potent antagonists of 5-HT3 receptors have a 6-membered aromatic ring, and they usually have 6,5 heterocyclic rings. No correlation has been found between the lipophilicity of compounds and the 5-HT3 receptor affinities. Since most of the known 5-HT3 antagonists are ester or amide derivatives they are potentially susceptible to hydrolysis, which could be avoided by incorporating H-bond acceptors within a 5-membered heteroaromatic ring.
Structure-activity relationship (SAR) studies of LGIC receptor ligands are valuable to investigate their structure and function. An antagonist
-like molecule with low intrinsic activity (ia) decreases the frequency of channel-opening and the permeability of ions. Small lipophilic C5 (R1) (see fig. 7) substituents afford compounds with potent antagonism which indicates that the C5 substituent may fit in a narrow, hydrophobic groove of the binding region in the receptor. It seems that the amino acid residues that interact with the C7 (R2) substituents have little to do with ligand binding but play a big role in ion channel gating. Sterically bulky substituents show a greater interaction with the gating amino acid
residues and favor the open conformation af the ion channel because of sterical repulsion.
Ondansetron is a racemate but the stereochemistry
of the asymmetric
carbon
atom
is not an important factor in the 5-HT3 receptor interaction. Annelation of the 1,7-positions of the indole nucleus of ondansetron results in increased affinity for the receptor
.
A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 8). The carbonyl
group is responsible for a strong interaction with the receptor and contributes significantly to the binding process. This carbonyl group is completely coplanar with the adjacent aromatic ring, indicating that the receptor-bound conformation corresponds to one of the most stable conformations of this group in the flexible compounds.
, they have different chemical structure
s and exhibit differences in affinity for the receptor
, dose response and duration of effect. Also they are metabolized in different ways, that is different components of the cytochrome P450 (CYP) system are predominate in the metabolism
of the antagonists.
The 5-HT3 receptor antagonist have similar activity. However patients who are resistant to one antagonist
might benefit from another, possibly because the drugs are metabolized differently. A correlation exists between the number of active CYP 2D6 alleles and the number of vomiting episodes by patients who receive treatment with cisplatin
and ondansetron or tropisetron
. Patients with multiple alleles tend to be unresponsive to the antiemetic
drug and vice versa.
(CINV), especially that caused by highly emetogenic drugs such as cisplatin
; when used for this purpose, they may be given alone or, more frequently, with a glucocorticoid
, usually dexamethasone
. They are usually given intravenously
, shortly before administration of the chemotherapeutic agent, although some authors have argued that oral administration may be preferred.
The concomitant administration of a NK1 receptor antagonist
, such as aprepitant
, significantly
increases the efficacy of 5-HT3 antagonists in preventing both acute and delayed CINV.
The 5-HT3 antagonists are also indicated in the prevention and treatment of radiation-induced
nausea and vomiting (RINV), when needed, and postoperative nausea and vomiting
(PONV). Although they are more effective at controlling CINV—where they stop symptoms altogether in up to 70% of people, and reduce them in the remaining 30%—, they are just as effective as other agents for PONV.
Current evidence suggests that 5-HT3 antagonists are ineffective in controlling motion sickness
. A randomized, placebo-controlled trial
of ondansetron to treat motion sickness in air ambulance
personnel showed subjective improvement, but it was not statistically significant
.
carried out in 2000 found ondansetron to be useful in treating antipsychotic
-induced tardive dyskinesia
in people with schizophrenia
.
The study's patients also showed significant
improvement in the disease's symptoms; a later double-blind
, randomized controlled trial
also found ondansetron to significantly improve schizophrenia symptoms when used as an adjunct to haloperidol
, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.
Alosetron
and cilansetron
—the latter being developed by Solvay
—are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, and is only available through a restrictive program to patients who meet certain requirements.
Certain prokinetic drugs such as cisapride
, renzapride
and metoclopramide
, although not 5-HT3 antagonists proper, possess some weak antagonist effect at the 5-HT3 receptor. Galanolactone
, a diterpenoid
found in ginger
, is a 5-HT3 antagonist and is believed to at least partially mediate the anti-emetic activity of this plant. Mirtazapine
(trade name Remeron) is a tetracyclic antidepressant with 5-HT3 antagonist effects and strong anti-emetic properties. Studies show mirtazapine as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations. Mirtazapine has also been used in the treatment of the motility disorder gastroparesis
due to its anti-emetic effects. Olanzapine
(trade name Zyprexa), an atypical antipsychotic
with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.
related to the use of 5-HT3 antagonists; the most common are constipation
or diarrhea
, headache
, and dizziness
. Unlike antihistamine
s with antiemetic properties such as cyclizine
, 5-HT3 antagonists do not produce sedation
, nor do they cause extrapyramidal effects, as phenothiazine
s (such as prochlorperazine
) sometimes do.
All 5-HT3 antagonists have been associated with asymptomatic electrocardiogram
changes, such as prolongation of the PT and QTc intervals and certain arrhythmias. The clinical significance of these side effects is unknown.
by various isoenzymes of the cytochrome P450 system. They do not, however, inhibit
or induce
these enzymes.
of the vagus nerve
, which send signals directly to the brain's vomiting center in the medulla oblongata
, and in the chemoreceptor trigger zone
of the brain, which receives "input" from nausea-inducing agents in the bloodstream and communicates with the vomiting center. By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways that lead to vomiting.
The 5-HT3 antagonists are greatly selective, and have little affinity for other receptors, such as dopamine
, histamine
and muscarinic acetylcholine receptor
s.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
s that act as receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s at the 5-HT3 receptor
5-HT3 receptor
The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
, a subtype of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
found in terminals of the vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
and in certain areas of the brain.
With the notable exception of alosetron
Alosetron
Alosetron is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome in women only. It is currently marketed by Prometheus Laboratories Inc...
and cilansetron
Cilansetron
Cilansetron is a drug that is a 5HT-3 antagonist currently under trial phase in the EU and US it is manufactured by Solvay Pharmaceuticals INC....
, which are used in the treatment of irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
, all 5-HT3 antagonists are antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
s, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and are considered the gold standard for this purpose.
The 5-HT3 antagonists may be identified by the suffix –setron, and are classified under code A04AA
ATC code A04
-A04AA Serotonin antagonists:-A04AA Serotonin antagonists:-A04AA Serotonin antagonists::A04AA01 Ondansetron:A04AA02 Granisetron:A04AA03 Tropisetron:A04AA04 Dolasetron:A04AA05 Palonosetron-A04AD Other antiemetics::A04AD01 Scopolamine...
of the WHO
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
's Anatomical Therapeutic Chemical Classification System
Anatomical Therapeutic Chemical Classification System
The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. It is controlled by the WHO Collaborating Centre for Drug Statistics Methodology , and was first published in 1976....
.
History
The history of the 5-HT3 receptor antagonists began in 1957, when J.H. Gaddum and Zuleika P. Picarelli at the University of EdinburghUniversity of Edinburgh
The University of Edinburgh, founded in 1583, is a public research university located in Edinburgh, the capital of Scotland, and a UNESCO World Heritage Site. The university is deeply embedded in the fabric of the city, with many of the buildings in the historic Old Town belonging to the university...
proposed the existence of two serotonin receptor subtypes, the M and D receptors (thus named because their function could be blocked by morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
and Dibenzyline
Phenoxybenzamine
Phenoxybenzamine is a non-selective, irreversible alpha antagonist.-Uses:It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma...
respectively), in a landmark paper. The 5-HT3 receptor was later found to correspond to the M receptor. In the 1970s, John Fozard proved that metoclopramide
Metoclopramide
Metoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...
and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
were weak antagonists at the 5-HT3 (5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT3 receptor antagonist. The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.
While Fozard was investigating cocaine analogues, workers at Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
identified the potent, selective 5-HT3 receptor antagonist ICS 205-930 from which the first marketed selective 5-HT3 receptor antagonists ondansetron and granisetron
Granisetron
Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect...
were developed, and approved in 1991 and 1993 respectively. Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997. A new and improved 5-HT3 receptor antagonist, named palonosetron, was approved in 2003.
The development of selective 5-HT3 receptor antagonists was a dramatic improvement in the treatment
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of nausea and vomiting. Ondansetron, granisetron, dolasetron and palonosetron are currently approved in the United States, and form the cornerstone of therapy for the control of acute emesis with chemotherapy agents with moderate to high emetogenic potential.
Development
5-HT3 receptor antagonists or serotonin antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
were first introduced in the early 1990s, and they have become the most widely used antiemetic drugs in chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. They have also been proven safe and effective for treatment of postoperative nausea and vomiting. Serotonin (5-HT) is found widely distributed throughout the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
and the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. In the gut, 5-HT is found mostly in mucosal enterochromaffin cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Enterochromaffin cells are sensory transducers that release 5-HT to activate intrinsic (via 5-HT1P and 5-HT4 receptors) and extrinsic (via 5-HT3 receptors) primary afferent nerves. Chemotherapeutic drugs for malignant disorders that cause vomiting have been found to cause release of large amounts of serotonin from enterochromaffin cells in the gut, serotonin acts on 5-HT3 receptors in the gut and brain stem.
Mechanism of action
The 5-HT3 receptors are present in several critical sites involved in emesis, including vagalVagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
afferents
Afferent nerve
In the nervous system, afferent neurons , carry nerve impulses from receptors or sense organs towards the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons...
, the solitary tract nucleus (STN), and the area postrema itself. Serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
is released by the enterochromaffin cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. The 5-HT3 receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT3 receptors. The highest concentration of 5-HT3 receptors in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
) are found in the STN and chemoreceptor trigger zone
Chemoreceptor trigger zone
The chemoreceptor trigger zone , is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier...
(CTZ), and 5-HT3 antagonists may also suppress vomiting and nausea by acting at these sites.
When patients undergo chemotherapy, serotonin is released from enterochromaffin cells by the cytotoxicity, the selective 5-HT3 receptor antagonists prevent the ability of serotonin to activate and sensitize gastrointestinal vagal-nerve terminals to other emetogenic substances released.
The 5-HT3 receptor
The 5-HT3 (5-HT3) receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT (serotonin) receptors which are G protein-coupled receptors. This ion channel is cation-selective and mediates neuronal depolarization and excitation within the centralCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
nervous systems. The rapidly activating, desensitizing, inward current is predominantly carried by sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
ions. 5-HT3 receptors have a negligible permeability to anions.
The 5-HT3 receptor consists of five subunits that may be the same (homopentameric 5-HT3A receptors) or different (heteropentameric receptors, usually consisting of 5-HT3A and 5-HT3B receptor subunits).
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
in a pseudo-symmetric manner (Fig.1). Each subunit comprises an extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
N-terminal domain, four transmembrane domains (M1-M4) connected by intracellular (M1-M2 and M3-M4) and extracellular loops (M2-M3) and an extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
C-terminus (Fig.1). The extracellular domain is the site of action of agonists and competitive antagonists because of ligand binding and the transmembrane domain controls the movement of ions across the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. The human subunits 5-HT3A and 5-HT3B have been isolated and as well as sharing 41% amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence identity the location of their genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
are in close proximity on the long arm of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
11. The 5-HT3C, 5-HT3D and 5-HT3E subunits have not been isolated.
Genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
that code for the subunits of the 5-HT3 receptor have been identified. HTR3A
HTR3A
5-hydroxytryptamine receptor 3A is a protein that in humans is encoded by the HTR3A gene....
and HTR3B
HTR3B
5-hydroxytryptamine receptor 3B, also known as HTR3B, is a human gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor....
for the 5-HT3A and 5-HT3B subunits and in addition HTR3C
HTR3C
5-hydroxytryptamine receptor 3C is a protein that in humans is encoded by the HTR3C gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor....
, HTR3D
HTR3D
5-hydroxytryptamine receptor 3D is a protein that in humans is encoded by the HTR3D gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor.-External links:...
and HTR3E
HTR3E
5-hydroxytryptamine receptor 3E is a protein that in humans is encoded by the HTR3E gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor....
genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
encoding 5-HT3C, 5-HT3D and 5-HT3E subunits. The latter three tend to show peripherally restricted pattern of expression, with high levels in the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
. In human duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A and 5-HT3B. There is some evidence to suggest that the 5-HT3 receptor subunits are an important contribution to the effectiveness of these compounds. In patients treated with chemotherapeutic drugs, certain polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of antiemetic drug efficacy. HTR3C
HTR3C
5-hydroxytryptamine receptor 3C is a protein that in humans is encoded by the HTR3C gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor....
and HTR3E
HTR3E
5-hydroxytryptamine receptor 3E is a protein that in humans is encoded by the HTR3E gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor....
do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological
Pathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
role for these additional subunits has yet to be identified.
The 5-HT3 receptor ligand binding site
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
ligand binding residue that contributes to a cation-π interaction between the pi electron
Electron
The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...
density of tryptophan and the primary amine of 5-HT. Loop C residues have been considered as candidates for the differing pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
of rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
and human
Human
Humans are the only living species in the Homo genus...
5-HT3 receptors because of their divergence between species. The most important aromatic residue within loop C is probably Y234 that lies opposite to the loop B tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
in the ligand binding pocket and is involved in ligand binding. Loops D and F are in fact β-strands not loops. W90 in loop D is critical for ligand binding and antagonists may directly contact R92. The azabicyclic ring of the competitive antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
granisetron is located close to R92 and the aromatic rings lie close to W90. Loop E residues Y143, G148, E149, V150, Q151, N152, Y153 and K154 may be important for granisetron binding. The structure of loop F has yet to be clarified but W195 and D204 seem to be critical for ligand binding. The results of several studies suggest that the orientation of granisetron (a 5-HT3 receptor antagonist )in the 5-HT3 receptor binding pocket is with its aromatic rings between Trp-183 and Tyr-234 and its azabicyclic ring between Trp-90 and Phe-226.(Fig.2)
| 5-HT3 receptor antagonists | Binding affinity (Kd, Ki, K50) | Species |
|---|---|---|
| Tropisetron | 11nM | Human |
| Granisetron | 1,44 nM | Human |
| Ondansetron | 4,9 nM | Human |
| Palonosetron | 31,6 nM | Rat cerebral cortex, Rabbit ileal myenteric plexus, Guinea-pig ileal plexus |
| Dolasetron | 20,03 nM | NG 108-15 |
| Metoclopramide (non-selective) | 355 nM | Human |
| Cocaine | 2,45-83 nM | Rat-Rabbit |
The 5-HT3 receptor antagonists structure
- CarbazoleCarbazoleCarbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene ring fused on either side of a five-membered nitrogen-containing ring...
derivatives (ondansetron) - Indazoles (Granisetron)
- Indoles (TropisetronTropisetronTropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...
and DolasetronDolasetronDolasetron is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when...
)
The first-generation 5-HT3 receptor antagonist (ondansetron, dolasetron
Dolasetron
Dolasetron is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when...
, granisetron, and tropisetron
Tropisetron
Tropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...
) have been the most important drugs in antiemetic therapy for emetogenic chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. They are especially effective in treating acute emesis, occurring in the first 24 hours following chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
A newer drug palonosetron
Palonosetron
Palonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting...
is a pharmacologically distinct and highly selective, second generation 5-HT3 receptor antagonist. Palonosetron
Palonosetron
Palonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting...
has two stereogenic centers and exists as four stereoisomers.
Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).
The 5-HT3 receptor antagonists pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
of 5-HT3receptors consists of three components: a carbonyl-containing linking moiety, aromatic/heteroaromatic ring, and a basic center. The carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group is coplanar to the aromatic ring. 5-HT3 receptor antagonists are more likely to bind in their protonated form. Docking of a range of antagonists into a homology model of the 5-HT3 receptor binding site shows a reasonably good agreement with the pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
model and supports the observed differences between species. Studies of granisetron in the binding pocket revealed that the aromatic rings of granisetron lie between W183 and Y234 and the azabiciclic ring between W90 and F226. In this study another energetically favorable location of granisetron was identified, closer to the membrane, on a position that could be a part of a binding/unbinding pathway for the ligand. A similarly located alternative binding site for granisetron has since been identified in another study of the 5-HT3 receptor.
Structure-activity relationship (SAR)
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
. An aromatic moiety (preferably indole), a linking acyl group capable of hydrogen bonding interactions, and a basic amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
(nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
) can be regarded as the key pharmacophoric
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
elements of the known 5-HT3receptor antagonists. There are steric limitations of the aromatic binding site and although two hydrogen-bonding interactions are possible on the heterocyclic linking group (oxadiazole capable of accepting two hydrogen bonds), only one is essential for high affinity. An optimal environment of the basic nitrogen is when its constrained within an azabicyclin system with the highes affinity observed for systems with nitrogen at the bridgehead position and secondary amines being more potent. The 5-HT3 receptor can only accommodate small substituents on the charged amine, a methyl group being optimal. The optimal distance between the aromatic binding site and the basic amine is 8,4-8,9 Å and it is best if a two-carbon linkage separates the oxadiazole and the nitrogen. An increasing substitution of R increases affinity. The most potent antagonists of 5-HT3 receptors have a 6-membered aromatic ring, and they usually have 6,5 heterocyclic rings. No correlation has been found between the lipophilicity of compounds and the 5-HT3 receptor affinities. Since most of the known 5-HT3 antagonists are ester or amide derivatives they are potentially susceptible to hydrolysis, which could be avoided by incorporating H-bond acceptors within a 5-membered heteroaromatic ring.
Structure-activity relationship (SAR) studies of LGIC receptor ligands are valuable to investigate their structure and function. An antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
-like molecule with low intrinsic activity (ia) decreases the frequency of channel-opening and the permeability of ions. Small lipophilic C5 (R1) (see fig. 7) substituents afford compounds with potent antagonism which indicates that the C5 substituent may fit in a narrow, hydrophobic groove of the binding region in the receptor. It seems that the amino acid residues that interact with the C7 (R2) substituents have little to do with ligand binding but play a big role in ion channel gating. Sterically bulky substituents show a greater interaction with the gating amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues and favor the open conformation af the ion channel because of sterical repulsion.
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
of the asymmetric
Asymmetric
Something which is asymmetric displays asymmetry. Specific uses of the term may include:*Asymmetric relation for information on such relations in mathematics and set theory*Asymmetric warfare for information and theories of modern war...
carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
atom
Atom
The atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
is not an important factor in the 5-HT3 receptor interaction. Annelation of the 1,7-positions of the indole nucleus of ondansetron results in increased affinity for the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
.
A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 8). The carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group is responsible for a strong interaction with the receptor and contributes significantly to the binding process. This carbonyl group is completely coplanar with the adjacent aromatic ring, indicating that the receptor-bound conformation corresponds to one of the most stable conformations of this group in the flexible compounds.
Comparative pharmacology of 5-HT3 antagonists
Despite that the 5-HT3 receptor antagonist share their mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
, they have different chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
s and exhibit differences in affinity for the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, dose response and duration of effect. Also they are metabolized in different ways, that is different components of the cytochrome P450 (CYP) system are predominate in the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of the antagonists.
The 5-HT3 receptor antagonist have similar activity. However patients who are resistant to one antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
might benefit from another, possibly because the drugs are metabolized differently. A correlation exists between the number of active CYP 2D6 alleles and the number of vomiting episodes by patients who receive treatment with cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
and ondansetron or tropisetron
Tropisetron
Tropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...
. Patients with multiple alleles tend to be unresponsive to the antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
drug and vice versa.
| Drug | Chemical nature |
Receptor antagonist Receptor antagonist A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses... s |
T1/2 (h) | Metabolism Metabolism Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories... |
Dose Dose (biochemistry) A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement... |
|---|---|---|---|---|---|
| Ondansetron Ondansetron Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves... |
Carbazole Carbazole Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene ring fused on either side of a five-membered nitrogen-containing ring... derivative |
5-HT3 receptor antagonist and weak 5-HT4 antagonist Antagonist An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend... |
3.9 hours | CYP1A1 CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.-Function:... /2 CYP1A2 Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body... , CYP2D6 CYP2D6 Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds... , CYP 3A3/4 CYP3A4 Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... /5 CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:... |
0.15 mg/kg |
| Granisetron Granisetron Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect... |
Indazole Indazole Indazole, also called benzpyrazole or isoindazone, is a heterocyclic aromatic organic compound.Indazole derivatives display a broad variety of biological activities.... |
5-HT3 receptor antagonist | 9-11.6 hours | CYP3A3/4 CYP3A4 Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... /5 CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:... |
10 µg/kg |
| Dolasetron Dolasetron Dolasetron is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when... |
Indole Indole Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an... |
5-HT3 receptor antagonist | 7–9 hours | CYP 3A3/4 CYP3A4 Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... /5 CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:... , CYP2D6 CYP2D6 Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds... |
0.6–3 mg/kg |
| Palonosetron Palonosetron Palonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting... |
Isoquinoline Isoquinoline Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline... |
5-HT3 receptor antagonist; highest affinity for 5-HT3 receptor in this class | 40 hours | CYP1A2 CYP1A2 Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body... , CYP2D6 CYP2D6 Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds... , CYP3A3/4 CYP3A4 Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... /5 CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:... |
0.25 mg x 1 dose |
| Ramosetron Ramosetron Ramosetron is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting. Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”. In India it is marketed under the brand name of "IBset".It is only licensed for use in Japan and... |
Benzimidazole Benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in... derivative |
5-HT3 receptor antagonist | 5.8 hours | 300 µg/kg | |
| Tropisetron Tropisetron Tropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg... |
Indole Indole Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an... |
5-HT3 receptor antagonist | 5.6 hours | CYP 3A3/4 CYP3A4 Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... /5 CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:... , CYP2D6 CYP2D6 Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds... |
200 µg/kg |
Therapeutic uses
5-HT3 antagonists are most effective in the prevention and treatment of chemotherapy-induced nausea and vomitingChemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea...
(CINV), especially that caused by highly emetogenic drugs such as cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
; when used for this purpose, they may be given alone or, more frequently, with a glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
, usually dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. They are usually given intravenously
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
, shortly before administration of the chemotherapeutic agent, although some authors have argued that oral administration may be preferred.
The concomitant administration of a NK1 receptor antagonist
NK1 receptor antagonist
Neurokinin 1 antagonists are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. The discovery of neurokinin 1 receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.An example of...
, such as aprepitant
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
, significantly
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
increases the efficacy of 5-HT3 antagonists in preventing both acute and delayed CINV.
The 5-HT3 antagonists are also indicated in the prevention and treatment of radiation-induced
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
nausea and vomiting (RINV), when needed, and postoperative nausea and vomiting
Postoperative nausea and vomiting
Postoperative nausea and vomiting is an unpleasant complication affecting about a third of the 10% of the population undergoing general anaesthesia each year. This equates to about two million people in the United Kingdom annually.-Impact:...
(PONV). Although they are more effective at controlling CINV—where they stop symptoms altogether in up to 70% of people, and reduce them in the remaining 30%—, they are just as effective as other agents for PONV.
Current evidence suggests that 5-HT3 antagonists are ineffective in controlling motion sickness
Motion sickness
Motion sickness or kinetosis, also known as travel sickness, is a condition in which a disagreement exists between visually perceived movement and the vestibular system's sense of movement...
. A randomized, placebo-controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
of ondansetron to treat motion sickness in air ambulance
Air ambulance
An air ambulance is an aircraft used for emergency medical assistance in situations where either a traditional ambulance cannot reach the scene easily or quickly enough, or the patient needs to be transported over a distance or terrain that makes air transportation the most practical transport....
personnel showed subjective improvement, but it was not statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
.
Investigational
A small, open-label trialOpen-label trial
An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....
carried out in 2000 found ondansetron to be useful in treating antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
-induced tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
in people with schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
.
The study's patients also showed significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
improvement in the disease's symptoms; a later double-blind
Double-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
, randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
also found ondansetron to significantly improve schizophrenia symptoms when used as an adjunct to haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.
Available agents
- OndansetronOndansetronOndansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
(trade name Zofran in most countries) was the first 5-HT3 antagonist, developed by Glaxo around 1984. Its efficacy was first established in 1987, in animal models, and it was extensively studied over the following years. Ondansetron was approved by the U.S. Food and Drug AdministrationFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1991, and has since become available in several other countries, including the UK, Ireland, Australia, Canada, France and Brazil. As of 2008, ondansetron and granisetron are the only 5-HT3 antagonists available as a generic drugGeneric drugA generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
in the United States. Ondansetron may be given several times daily, depending on the severity of symptoms. - TropisetronTropisetronTropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...
(trade name Navoban) was also first described in 1984. It is available in several countries, such as the UK, Australia and France, but not in the United States. The effects of tropisetron last up to 24 hours, so it only requires once-daily administration. - GranisetronGranisetronGranisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect...
(trade name Kytril) was developed around 1988. It is available in the U.S., UK, Australia and other countries. Clinical trialClinical trialClinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s suggest that it is more effective than other 5-HT3 antagonists in preventing delayed CINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy). It is taken once daily. - DolasetronDolasetronDolasetron is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when...
(U.S. trade name Anzemet) was first mentioned in the literature in 1989. It is a prodrugProdrugA prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, and most of its effects are due to its active metabolite, hydrodolasetron, which is formed in the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by the enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
carbonyl reductaseCarbonyl reductase (NADPH)In enzymology, a carbonyl reductase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are R-CHOH-R' and NADP+, whereas its 3 products are R-CO-R', NADPH, and H+....
. Dolasetron was approved by the FDA in 1997, and is also administered once daily. - PalonosetronPalonosetronPalonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting...
(trade name Aloxi) is the newest 5-HT3 antagonist to become available in the U.S. market. It is an isoquinolineIsoquinolineIsoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline...
derivative, and is effective in preventing delayed CINV. Palonosetron was approved by the FDA in 2003, initially for intravenous useIntravenous therapyIntravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
. An oral formulation was approved on August 22, 2008 for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as IV use against delayed CINV. - RamosetronRamosetronRamosetron is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting. Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”. In India it is marketed under the brand name of "IBset".It is only licensed for use in Japan and...
(trade name Nasea) is only available in Japan and certain Southeast AsiaSoutheast AsiaSoutheast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
n countries as of 2008. It has higher affinity for the 5-HT3 receptor than the older 5-HT3 antagonists, and maintains its effects over two days; it is therefore significantlyStatistical significanceIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
more effective for delayed CINV. In animal studies, ramosetron was also effective against irritable bowel syndromeIrritable bowel syndromeIrritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
-like symptoms.
Alosetron
Alosetron
Alosetron is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome in women only. It is currently marketed by Prometheus Laboratories Inc...
and cilansetron
Cilansetron
Cilansetron is a drug that is a 5HT-3 antagonist currently under trial phase in the EU and US it is manufactured by Solvay Pharmaceuticals INC....
—the latter being developed by Solvay
Solvay (company)
Solvay S.A. is a Belgian chemical company with its head office in Ixelles, Brussels, Belgium. It was founded in 1863 by Ernest Solvay to produce sodium carbonate by the solvay process. Since then the company has diversified to two major sectors of activity: chemicals and plastics...
—are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, and is only available through a restrictive program to patients who meet certain requirements.
Certain prokinetic drugs such as cisapride
Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
, renzapride
Renzapride
Renzapride is a gastroprokinetic agent and antiemetic which acts as a full 5-HT4 full agonist and 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors, though it is unlikely that these properties contribute to its therapeutic...
and metoclopramide
Metoclopramide
Metoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...
, although not 5-HT3 antagonists proper, possess some weak antagonist effect at the 5-HT3 receptor. Galanolactone
Galanolactone
Galanolactone is a diterpenoid lactone first isolated from ginger. It is known to be present in acetone extracts of ginger, and appears to be an antagonist at 5-HT3 receptors....
, a diterpenoid
Terpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
found in ginger
Ginger
Ginger is the rhizome of the plant Zingiber officinale, consumed as a delicacy, medicine, or spice. It lends its name to its genus and family . Other notable members of this plant family are turmeric, cardamom, and galangal....
, is a 5-HT3 antagonist and is believed to at least partially mediate the anti-emetic activity of this plant. Mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(trade name Remeron) is a tetracyclic antidepressant with 5-HT3 antagonist effects and strong anti-emetic properties. Studies show mirtazapine as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations. Mirtazapine has also been used in the treatment of the motility disorder gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
due to its anti-emetic effects. Olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
(trade name Zyprexa), an atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.
Adverse effects
There are few side effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
related to the use of 5-HT3 antagonists; the most common are constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
or diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, and dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
. Unlike antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s with antiemetic properties such as cyclizine
Cyclizine
Cyclizine is an antihistamine drug used to treat nausea, vomiting and dizziness associated with motion sickness, vertigo and post-operatively following administration of general anaesthesia and opioids.-Indications:...
, 5-HT3 antagonists do not produce sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, nor do they cause extrapyramidal effects, as phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
s (such as prochlorperazine
Prochlorperazine
Prochlorperazine is a dopamine receptor antagonist that belongs to the phenothiazine class of antipsychotic agents that are used for the antiemetic treatment of nausea and vertigo. It is also a highly-potent typical antipsychotic, 10-20x more potent than chlorpromazine...
) sometimes do.
All 5-HT3 antagonists have been associated with asymptomatic electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
changes, such as prolongation of the PT and QTc intervals and certain arrhythmias. The clinical significance of these side effects is unknown.
Pharmacokinetics
All 5-HT3 antagonists are well-absorbed and effective after oral administration, and all are metabolized in the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by various isoenzymes of the cytochrome P450 system. They do not, however, inhibit
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
or induce
Enzyme induction and inhibition
Enzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
these enzymes.
Mechanism of action
As their name implies, 5-HT3 antagonists prevent serotonin from binding to 5-HT3 receptors. Such receptors are present mostly on the ends of afferent branchesAfferent nerve
In the nervous system, afferent neurons , carry nerve impulses from receptors or sense organs towards the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons...
of the vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
, which send signals directly to the brain's vomiting center in the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
, and in the chemoreceptor trigger zone
Chemoreceptor trigger zone
The chemoreceptor trigger zone , is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier...
of the brain, which receives "input" from nausea-inducing agents in the bloodstream and communicates with the vomiting center. By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways that lead to vomiting.
The 5-HT3 antagonists are greatly selective, and have little affinity for other receptors, such as dopamine
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
, histamine
Histamine receptor
The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
and muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s.