Alright, let’s geek out hard on the gepants—these small-molecule CGRP receptor antagonists that finally ditched the hepatotoxicity baggage of the first-gen olcegepant/telcagepant era. We’re talking high-affinity, canonical CGRP receptor blockade (not AMY1 cross-reactivity dominant), interrupting trigeminovascular activation, dural vasodilation, and central sensitization without vasoconstriction. Perfect for your migraine patients with CV risk factors where triptans are a no-go. I’ll hit the four clinically relevant ones: rimegepant, atogepant, ubrogepant, and zavegepant. All data current as of late 2025—no signal for serious hepatotoxicity across the class in post-marketing registries. Shared Mechanism : Competitive antagonists at the CGRP receptor (CLR/RAMP1 heterodimer). Ki in the picomolar range (atogepant ~15-26 pM, highest affinity; others low nanomolar). They blunt CGRP-mediated cAMP elevation in trigeminal ganglia, inhibit neurogenic inflammation, and dampen pain transmission at TCC and higher centers. No direct vascular constriction—huge win over triptans. All primarily CYP3A4 substrates (strong inhibitors/inducers are clinical headaches), minimal renal clearance. Now, molecule by molecule. Rimegepant (Nurtec ODT) – MOA : High selectivity for canonical CGRP receptor; some AMY1 affinity but ~100-fold less. ODT formulation bypasses first-pass a bit for faster onset. – Half-life : ~11 hours (longest oral gepant)—this enables dual use. – Indications : Acute treatment of migraine with/without aura (75 mg ODT PRN, max 75 mg/24h; can repeat if needed but official limit one dose/day). Also preventive for episodic migraine (75 mg every other day)—only gepant with both labels. Real-world data through 2025 shows sustained efficacy at 52 weeks without MOH risk. – Side effects : Cleanest profile. Nausea ~2-4%, somnolence <2%. Hypersensitivity (rash, dyspnea) rare but labeled. No hepatotox signal in long-term extension trials. Mild CYP3A4 interactions—avoid with strong inhibitors. Atogepant (Qulipta) – MOA : Highest potency among orals (Ki 15-26 pM), tight binding, excellent receptor occupancy at trough with daily dosing. Minimal off-target (AMY1 affinity >>100-fold lower). – Half-life : ~11 hours, steady-state receptor blockade >90% at 60 mg QD. – Indications : Only purely preventive oral gepant—episodic (and now expanded to chronic in some regions post-2024 data) migraine in adults. Doses 10/30/60 mg QD; 60 mg for higher burden. Phase 3/advance trials show ~4-5 fewer migraine days/month vs placebo. – Side effects : Constipation 5-10% (dose-dependent, magnesium antagonism at gut?), nausea 5-8%, fatigue ~4%. Weight gain rare. Transaminase bumps transient and <3x ULN in <1%. No clinically apparent liver injury in registries. Ubrogepant (Ubrelvy) – MOA : Solid CGRP receptor antagonist, slightly lower affinity than atogepant/rimegepant but rapid onset. Some cross to AMY1 but not driving efficacy. – Half-life : 5-7 hours—shortest oral, so pure acute player. – Indications : Acute only—with/without aura. 50 or 100 mg PRN; optional second 50 mg after 2h (max 200 mg/24h). Pain freedom at 2h ~20% vs ~12% placebo; comparable to high-dose rimegepant but faster redosing flexibility. – Side effects : Nausea 2-5%, somnolence 2-4%, dry mouth ~2%. Lowest constipation rate in class. Again, no hepatotox beyond background. Zavegepant (Zavzpret) – MOA : Same receptor blockade but intranasal—bypasses GI/hepatic first-pass entirely, direct mucosal absorption to trigeminal terminals. Fastest Tmax (~30 min). Only non-oral gepant. – Half-life : ~6-8 hours (estimates vary; nasal kinetics differ). – Indications : Acute treatment only—with/without aura. 10 mg single spray one nostril PRN (max one dose/24h). Phase 3: pain freedom 2h ~24%, slightly edges orals in speed for some patients. Great for nausea/vomiting when PO impossible. – Side effects : Dysgeusia/ageusia 15-20% (bitter metallic—patients hate it but transient), nasal discomfort 5-10%, throat irritation. Nausea low because non-oral. No systemic hepatotox worries amplified. Bottom line for your practice: These are vascular-safe, low-side-effect tools. Acute hierarchy often ubro/zavegepant for speed, rimegepant for versatility. Preventive: atogepant daily or rimegepant QOD. Combo with mAbs safe per 2025 consensus—no tachyphylaxis or rebound. Watch CYP3A4, counsel on taste for zavegepant, and monitor constipation on atogepant. Class is transformative for refractory or CV-comorbid migraineurs. Questions on dosing nuances or trial endpoints?