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Sunday, August 10, 2025

CGRP inhibitors


Overview
CGRP inhibitors are a newer class of drugs developed for the prevention and treatment of migraine and, in some cases, episodic cluster headache. CGRP is a neuropeptide widely distributed in the central and peripheral nervous system. It plays a critical role in migraine pathophysiology by promoting vasodilation, neurogenic inflammation, and pain transmission. CGRP inhibitors target either the CGRP ligand itself or the CGRP receptor, reducing migraine frequency and severity.

Mechanism of Action

  • CGRP ligand binders: Monoclonal antibodies (mAbs) that attach to circulating CGRP, preventing it from binding to receptors (e.g., fremanezumab, galcanezumab, eptinezumab).

  • CGRP receptor blockers:

    • Monoclonal antibodies (erenumab) that block the CGRP receptor.

    • Small-molecule antagonists (“gepants”) – ubrogepant, rimegepant, atogepant – which block the receptor and are effective for acute treatment or prevention.

  • By blocking CGRP signaling, these agents decrease migraine-associated vasodilation and nociceptive transmission in the trigeminovascular system.

Available Agents and Indications

  1. Monoclonal Antibodies (mAbs) – Preventive Migraine Therapy

    • Erenumab – CGRP receptor mAb

    • Fremanezumab – CGRP ligand mAb

    • Galcanezumab – CGRP ligand mAb (also approved for episodic cluster headache)

    • Eptinezumab – CGRP ligand mAb (IV formulation)

  2. Small-Molecule CGRP Receptor Antagonists (Gepants)

    • Acute Migraine Treatment: Ubrogepant, Rimegepant

    • Preventive: Atogepant; Rimegepant (also approved for prevention)

Therapeutic Uses

  • Migraine prophylaxis in adults with episodic or chronic migraine

  • Acute migraine treatment (gepants) in adults with or without aura

  • Episodic cluster headache prevention (galcanezumab in some regions)

  • Alternative for patients with inadequate response or contraindications to traditional migraine preventives (e.g., beta-blockers, anticonvulsants)

Dosing and Administration

  • mAbs: Administered subcutaneously monthly or quarterly (eptinezumab is IV every 3 months)

  • Gepants: Oral tablets; ubrogepant and rimegepant for acute use; atogepant and rimegepant for prevention with once-daily or alternate-day dosing depending on the drug

Contraindications

  • Hypersensitivity to the active substance or formulation components

  • Limited safety data in pregnancy and breastfeeding; generally avoided unless benefits outweigh risks

Precautions

  • Long-term cardiovascular safety is still under surveillance, but no major signal of increased CV risk in trials

  • Monitor for constipation with erenumab

  • Use cautiously in severe hepatic or renal impairment for gepants (dose adjustments may be required)

Adverse Effects

  • mAbs: Injection site reactions, constipation (erenumab), muscle cramps/spasms, hypersensitivity reactions (rare, including anaphylaxis)

  • Gepants: Nausea, somnolence, dry mouth, rare hypersensitivity reactions

  • Serious adverse events are rare; most are mild-to-moderate and transient

Drug Interactions

  • mAbs: Minimal CYP metabolism; low potential for drug–drug interactions

  • Gepants: Metabolized by CYP3A4 – strong inhibitors (ketoconazole, clarithromycin) increase levels; strong inducers (rifampicin, carbamazepine) reduce levels; avoid coadministration with potent inhibitors/inducers without adjustment




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