Serotonine lecture

Anti-Migraine and Anti-Emetic Agents

Serotonin (5-HT) Agents

  • Zolmitriptan
    • A selective agonist for 5-HT1B and 5-HT1D receptors.
  • Lasmiditan
    • Primarily acts as a 5-HT1F receptor agonist.
  • Ubrelvy (Ubrogepant)
    • Mechanism involves disruption of CGRP (Calcitonin Gene-Related Peptide).
  • Palonosetron
    • A 5-HT3 antagonist used as an anti-emetic.
  • Nabilone
    • A cannabinoid used in treatment options.
  • Aprepitant
    • A neurokinin antagonist utilized in chemotherapy-induced nausea and vomiting (CINV).

Serotonin (5-HT) Overview

  • 5-Hydroxytryptamine (5-HT):
    • First identified in the 1940s.
    • Functions:
    • Role in mood regulation: anxiety, depression, schizophrenia.
    • Involvement in drug abuse and sleep regulation.
    • Connection to hallucinations and cardiovascular disorders.
    • Regulates appetite.
  • Signal-Target Interactions:
    • Operates through G protein-coupled receptors (GPCRs), inclusive of several serotonin receptor subtypes.

Biosynthesis

  • Biosynthesis of Serotonin involves the following:
    • Tryptophan Hydroxylase converts tryptophan to 5-hydroxytryptophan (5-HTP).
    • Aromatic amino acid decarboxylase then converts 5-HTP to serotonin (5-HT).
    • Metabolism of 5-HT includes:
    • Monoamine Oxidase (MAO) breaks down serotonin.
    • The transformation leads to formation of key metabolites including melatonin and 5-hydroxyindole-3-acetic acid.

Serotonergic Neurotransmission

  • Neurotransmission Steps:
    • Stored serotonin (5-HT) is released and interacts with postsynaptic receptors.
    • Diffusion or metabolism afterward.

Anti-Emetic Agents

Categories of Anti-Emetic Agents

  • 5-HT3 Antagonists
    • Include Ondansetron (Zofran), Dolasetron (Anzemet), Granisetron, and Palonosetron.
  • Neurokinin Antagonists
    • Aprepitant introduced in late 1990s for chemotherapy nausea.
  • Mixed Receptor Antagonists
    • Metoclopramide: dopamine antagonist with weak 5-HT3 antagonism.
  • Cannabinoid Agonists
    • Include THC and synthetic cannabinoids.

5-HT3 Antagonists Overview

  • Ondansetron (Zofran)
    • Developed in 1984 as a potent antiemetic.
    • Used primarily following chemotherapy, half-life of 3-4 hours, primarily metabolized by CYP3A4 and CYP2D6.
    • Associated with side effects like dizziness, headache, constipation.

Timeline of 5-HT3 Receptor Antagonists

  • Highlights FDA approvals of key agents from 1984 onward:
    • Ondansetron: 1984
    • Granisetron: 1991 (injection), 1993 (solution)
    • Dolasetron: 2001
    • Palonosetron: 2008 (oral formulation for CINV).

Mechanism of Action and Metabolism

  • Dolasetron:
    • Has a long half-life of 4-9 hours, excellent bioavailability as a metabolite; limited side effects.
  • Granisetron:
    • Half-life of 6 hours, FDA approved for extended release.
  • Palonosetron:
    • First-in-class for treatment of acute CINV, substantial metabolic stability.

Cannabinoid Agonists

  • Mechanism: Cannabinoids inhibit neurotransmission via CB1 and CB2 receptors, contributing to antiemetic effects.
  • Examples of Cannabinoid Agents:
    • Tetrahydrocannabinol (THC): Principal psychoactive element of cannabis.
    • Dronabinol: CLogP of 7.24 (important for BBB permeability).
    • Nabilone: CLogP of 5.66, used for nausea relief.

Anti-Migraine Agents

Overview of Migraine

  • Migraine Phases: Involves phases of neurological disturbances known as aura, leading to headache. Migraine headaches can be classified as:
    • Classical (with aura) vs. Common (without aura).
    • Duration: 4 to 72 hours, associated with nausea and sensitivities.

Triptans Overview

  • Mechanism of Action: Triptans are serotonin receptor agonists that mimic serotonin activity, resulting in vasoconstriction and blockage of neuropeptide release.
  • Examples of Triptans:
    • Sumatriptan (Imitrex): First approved in 1992, subcutaneous injection and nasal sprays are quicker acting, half-life = 2.5 hours.
    • Zolmitriptan (Zomig): Improved bioavailability, half-life = 3-4 hours, metabolized by CYP1A2 to a potent active metabolite.
    • Naratriptan (Amerge): Lower incidence of side effects, exhibits gentle action.
    • Rizatriptan (Maxalt): Fast-acting triptan, half-life = 2-3 hours, needs caution when co-administered with MAO inhibitors.
    • Almotriptan (Axert): Highly bioavailable, rapidly absorbed, favorable side effect profile.
    • Frovatriptan (Frova): Longest half-life, highest receptor selectivity, thus limiting side effects.
Common Side Effects of Triptans
  • Nausea, dry mouth, dizziness associated with the use of triptans.
  • Contraindications include patients with cardiovascular issues due to potential vasoconstrictive side effects.