Table of Contents
Page created on June 15, 2019. Last updated on December 18, 2024 at 16:57
Serotonin
Serotonin or 5-hydroxytryptamine (5-HT) is an important central and peripheral neurotransmitter as well as a local hormone. 90% of serotonin in the body is found in the neuroendocrine enterochromaffin cells in the GI tract, where they function as a local hormone. It’s also found in platelets and in serotonergic neurons.
Synthesis and metabolism:
Serotonin is synthesised in two steps. Tryptophan is converted into 5-hydroxytryptophane, which is then converted into 5-hydroxytryptamine by aromatic acid decarboxylase.
Serotonin is metabolised also in two steps; first by monoamine oxidase A (MAO-A) and then by aldehyde dehydrogenase (ALDH).
Serotonin receptors:
The following serotonin receptors are most important:
Type | Subtypes | Signal | Potential | Tissue |
5-HT1 |
A, B, C, D, E, F | Gi-coupled. cAMP ↓ | Inhibitory | CNS, blood vessels |
5-HT2 |
A, B, C |
Gq-coupled, IP3 ↑ |
Excitatory |
CNS, PNS, blood vessels, GI, platelets |
5-HT3 |
– |
Ligand-gated Na+, K+ channel |
Excitatory |
CNS, PNS, GI |
5-HT4 | – | Gs-coupled, cAMP ↑ | Excitatory |
CNS, ENS |
Drugs related to serotonin
Many drugs are serotonin receptor agonists or antagonists, or in other ways interact with serotonergic transmission.
Serotonin agonists:
Drug class | Drug names | Indications | Agonized serotonin receptor |
Anxiolytic |
Buspirone | Anxiety | 5-HT1A |
Triptans |
Sumatriptan, almotriptan | Migraine episodes | 5-HT1B, 5-HT1D |
Recreational drugs |
LSD, psilocybin | “Wanna do drugs?” |
5-HT1A, 5-HT2A, 5-HT2C |
– | (Lorcaserin) | Obesity |
5-HT2C |
Prokinetic drugs | Metoclopramide, prucalopride | GERD, gastroparesis |
5-HT4 |
Serotonin antagonists:
Drug class | Drug names | Indications | Antagonized serotonin receptor |
– |
Cyproheptadine | Serotonin syndrome | 5-HT1A, 5-HT2A |
Atypical antipsychotics |
Clozapine, olanzapine | Schizophrenia, bipolar disorder | 5-HT2A, 5-HT2C |
– | Pizotifen | Migraine prophylaxis |
5-HT2 |
Antiemetics | Ondansetron, granisetron | Chemotherapy, radiotherapy |
5-HT3 |
Drugs acting on serotonergic neurons:
Drug class | Drug names | Indications | Mechanism of action |
SSRIs |
Fluoxetine, paroxetine | Depression | Inhibit serotonin reuptake |
SNRIs |
Venlafaxine, duloxetine | Depression |
Inhibit serotonin and norepinephrine reuptake |
MAO-A inhibitors | Moclobemide | Depression |
Inhibit serotonin breakdown |
Serotonin syndrome
Serotonin syndrome is a life-threatening condition caused by serotonergic overactivity. It can be caused by any drug that increases serotonin levels.
Etiology:
- MAO inhibitors
- SSRIs
- SNRIs
- Tricyclic antidepressants
- MDMA
The risk is especially increased if two or more serotoninergic drugs are combined.
Clinical features:
Neuromuscular excitability, autonomic dysfunction, altered mental status. Hyperthermia.
Treatment:
Withdrawal of the causative drug. Administration of cyproheptadine, a serotoninergic antagonist. External cooling.
Migraine
Migraine is characterised by recurring episodes of typically unilateral, localized headaches. They are frequently accompanied by nausea, vomiting and sensitivity to light and sound. They are sometimes preceded by an aura, which are transient neurologic symptoms like seeing flashing lights or paresis.
The pathomechanism is not well understood.
Treatment of migraine involves two components:
- Abortive therapy – drugs taken to improve symptoms of an episode
- NSAIDs
- Triptans
- (Ergotamine)
- Prophylactic therapy – drugs taken to prevent episodes from occurring
- Beta blockers
- Pizotifen
- Botulinum toxin
Antiemetics like metoclopramide and ondansetron can be useful to treat nausea.
Abortive therapy of migraine
Compounds:
- NSAIDs
- Paracetamol
- Aspirin
- Ibuprofen
- Diclofenac
- Triptans
- Sumatriptan
- Almotriptan
- Ergotamine
Ergotamine can also be used but its usefulness is severely limited by its severe side effects.
Indications:
Terminating or reducing pain of a migraine. NSAIDs are preferred for moderate attacks, and triptans + NSAIDs are preferred for severe attacks.
Mechanism of action:
The triptans, including sumatriptan and almotriptan, are selective 5-HT1B and 5-HT1D agonists. They vasoconstrict meningeal vessels and modulate pain sensation in the trigeminal ganglion.
Ergotamine is also a 5-HT1B and 5-HT1D agonist, with the same mechanism of action as the triptans.
Dosing:
Rapidly absorbed preparations like a suppository or effervescent tablets that are dissolved in water are preferred.
Contraindications:
Triptans and ergotamine should never be given simultaneously.
Side effects:
Ergotamine:
- Damage to the foetus
- Nausea, vomiting
- Severe peripheral vasoconstriction (including the coronaries) with possibility of gangrene
Triptans:
- Paraesthesia
- Temporary blood pressure increase
Prophylactic therapy of migraine
Compounds:
- Beta blockers
- Metoprolol
- Propranolol
- Tricyclic antidepressants
- Amitryptiline
- Anti-epileptics
- Topiramate
- Valproate
- Calcium channel blockers
- Verapamil
- CGRP antagonists
- Erenumab
- Serotonin antagonists
- Pizotifen
All of the mentioned can be used as first-line, depending on the comorbidities of the patients. If there are none, beta blockers are preferred.
Injecting botulinum toxin into the trigeminal nerves is also used to prevent migraines.
Indications:
Reducing the frequency and severity of migraine episodes.
Mechanism of action:
Beta blockers prevents migraine episodes by unknown mechanisms. They probably cause vasoconstriction of cerebral vessels.
Pizotifen is a 5-HT2 receptor antagonist which also causes vasoconstriction of cerebral vessels.
CGRP has a role in mediating migraine pain.
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