34. Serotonin, serotonin receptor agonists and antagonists

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-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

NSAIDs like paracetamol, aspirin, ibuprofen, diclofenac and triptans like sumatriptan and zolmitriptan are important here. 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 zolmitriptan, 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

Betablockers like propranolol and metoprolol, and pizotifen are important here. Methysergide can also be used but can cause retroperitoneal fibrosis and is therefore not preferred.

Injecting botulinum toxin into the trigeminal nerves is also used to prevent migraines.

Indications:

Reducing the frequency of migraine episodes. Beta blockers are the first-line treatment.

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.


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