34. Serotonin, serotonin receptor agonists and antagonists

Page created on June 15, 2019. Last updated on January 7, 2022 at 22:05

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-HT_1B and 5-HT_1D agonists. They vasoconstrict meningeal vessels and modulate pain sensation in the trigeminal ganglion.

Ergotamine is also a 5-HT_1B and 5-HT_1D 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.