migraine pathophysiology and mechanism of action of sumatriptan

1. -kaxcha medical-
Thailand
Sumatriptan and Migraine
-kaxcha medical-
Thailand

2. Reference: Carlos M., Current Vascular Pharmacology, 2003, 1, 71-84
Fig. (1). Ancient methods attempting to
alleviate or cure headache: Egyptian
papyrus (2500 BC) which describes
bandaging a clay crocodile (with herbs
stuffed into its mouth) to the head of
the sufferer and praying
-kaxcha medical-
Thailand

3. -kaxcha medical-
Thailand
• Exhaustion
(unexplained fatigue)
• Food craving
• Yawning
• Sensitivity to light &
sound
• Neck stiffness
• Constipation & Diarrhea
• Visual
Disturbance
• Numbness
• Nausea & Vomiting
• Throbbing & Drilling
• Inability to Concentrate
• Fatigue
• Depression Mood
• Euphoric Mood
Reference: https://migrainebuddy.com/migraine/2018/9/27/the-stages-of-a-migraine-migraine-attack

4. -kaxcha medical-
Thailand
V1
V2
V3
Brain Trigeminal
Ganglion
PainSkull
Trigeminal
Ganglion
Medulla
Pons
Trigeminal Nucleus
Caudalis

5. -kaxcha medical-
Thailand
Cerebral Cortex
(Gray Matter)

6. -kaxcha medical-
Thailand
Hista
mine
PAR-2Tryptase
Target
CGRPCGRP
Hista
mine
H+
ASIC3 TRP
Stress
Hormone
ยา
หลุด
H2
Receptor
Vasodilation
Vasodilation
H+
Tryptase
Migraine = Neurological Disorder
Reference: Carolina Burgos-Vega et al, Meningeal Afferent Signaling and the Pathophysiology of Migraine, Progress in Molecular Biology and Translational Science, Volume 131, P.537-557, 2015-kaxcha medical-
Thailand

7. -kaxcha medical-
Thailand
Cortical Spreading Depression (CSD)
Olesen and colleagues, which showed that, during aura-like symptoms, slowly spreading oligaemia propagated anteriorly from the occipital pole.
Reference: Turgay Dalkara, Migraine aura pathophysiology: the role of blood vessels and microembolization, Lancet Neurol. Author manuscript; available in PMC 2010 Aug 16.

8. -kaxcha medical-
Thailand
Degranulation
Vasodilation
Depolarization of neurons and glial cells
that spreads across cerebral cortex
Cortical Spreading Depression
(CSD)
Decreased Dural
Blood Flow
Hypoxia
Decrease pHCGRP ASIC 3
Dural Afferent
K+ & Glutamate in Efflux 
Na+ & Ca++ Influx 
Cortical Spreading Depression (CSD)
CSD and Migraine
Reference: Carolina Burgos-Vega et al, Meningeal Afferent Signaling and the Pathophysiology of Migraine, Progress in Molecular Biology and Translational Science, Volume 131,
P.537-557, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412887/, Turgay Dalkara et al, Migraine aura pathophysiology: the role of blood vessels and Microembolisation,
2010

9. -kaxcha medical-
Thailand
TRESK Protein
Gene Mutation of KCNK18
Neuron Cell
TRESK (2 Pore-Potassium Channel Protein)
• ION Channel
• Found in Dorsal root ganglion and Trigeminal ganglia
• Control excitability of TG neuron during inflammation
• Increase threshold of excitability of trigeminal ganglion neurons
• Help prevent or reduce severity of migraine
• Relate to Migraine with Aura
• TRESK Activator: Histamine, Caffeine, Volatile anesthetic
(isoflurane, halothane), Calcium
• TRESK Inhibitor: Cyclosporin, Tacrolimus > Calcinurine inhibitor
induced headache
Calcineurin Ca++
Cyclo
sporin
Tacro
limus
VA
Reference:Ronald G et al, Migraine: Role of the TRESK two-pore potassium channel, 2011

10. -kaxcha medical-
Thailand
Cortical Spreading Depression (CSD)
Genetic Models of Migraine, Familial hemiplegic migraine
Reference: Rob C. G. van de Ven et al, Clinical Implications of Basic Neuroscience Research May 2007, https://jamanetwork.com/journals/jamaneurology/fullarticle/793783

11. -kaxcha medical-
Thailand
CGRPCGRP
Purposed Mechanism for Triptan Effect on Migraine
Reference: https://step1.medbullets.com/neurology/113066/sumatriptan
Sumatriptan 50 mg
(Serotonin Agonist) Vasodilation
-kaxcha medical-
Thailand

12. -kaxcha medical-
Thailand
Pharmacokinetic
• Administered:
- Oral Bioavailability 14% (First Pass Metabolism Effect)
- Onset 30 min
- Time to peak 2-2.5 hours
• Distribution: Vd = 2.4 L/kg, 14-21% bound to plasma proteins
• Metabolism: Via Hepatic (MAO-A) to inactive metabolite
• Excretion: Urine 60%, Feces 40%
• Food has no significant effect on oral 5-HT1 agonist
bioavailability But delays Sumatriptan’s Tmax by approximately
30 minutes
Reference: Sumatriptan Clinical Pharmacokinetics, Andrew K. Scott, Clin. Pharmocokinet. 27 (5): 337·344. 1994
MAO

13. -kaxcha medical-
Thailand
Reference: Lainez MJA. Cephalagia, February 2004Cephalalgia 24 Suppl 2(s2):24-30, Clinical Benefits of Early Triptan Therapy for Migraine
Patient should take the abortive
drugs early in the attack, when
pain is mild, usually less than 1
hour from onset.

14. -kaxcha medical-
Thailand
Brand Generic Name Onset T max T1/2 BA
Imigran
Sumatriptan Fast Acting 2.5 hr 2 hr 14%
Siagran
Relpax Eletriptan Fast Acting 1-2 hr 3.6-5.5 hr 50%
Migraptin
Naratriptan Slow Acting 2-3 hr 5.0-6.3 hr
63% Men
74% WomenAmerge
Maxalt Rizatriptan Fast Acting 1.2 hr 2.0-3.0 hr 45%
Axert Almotriptan Fast Acting 1.4-3.8 hr 3.2-3.7 hr 80%
Zomig Zolmitriptan Fast Acting 2 hr 2.5-3.0 40-48%
Frova Frovatriptan Slow Acting 2.0-4.0 hr 25 24-30%
Reference: Marcelo E. Bigal1 et al, THE TRIPTAN FORMULATIONS A critical evaluation, Arq Neuropsiquiatr 2003;61(2-A):313-320

15. -kaxcha medical-
Thailand
Comparation Sumatriptan Ergotamine
Receptor profile 5HT1B/1D 5HT1, α1 receptor
Efficacy
64% of patient
improved headache symptom
48% of patient
improved headache symptom
Substrate of CYP3A4 No Yes
Vasoconstrictive effect Less Vasoconstrictive effect
Potential vasoconstrictive effect
>>Ergotism<<
Pregnancy category C X
Lactation After 12 hours Not recommend

16. -kaxcha medical-
Thailand
Ergotism:
Peripheral gangrene

17. -kaxcha medical-
Thailand
Treatment Strategy Medication
1. Mild-moderate attack • Acetaminophen then NSAIDs
2. Moderate-severe attack or NSAIDs failure • Start NSAIDs or NSAIDs > Triptan (Triptan ไม่เกิน 9 days/mth ป้องกัน MOH)
3. Refractory Migraine
• Triptans+NSAIDs
• Then D2, Opioids, Ergotamine/caffeine
(Ergotamine/caffeine 0.5-2 mg/time, max 6 mg/day & 10 mg/wk (ไม่เกิน 9 days/mth ป้องกัน MOH),
D2=Prochloperazine, chlorpromazine, Opioid=tramadol, codeine)
4. Vasoconstrictor Unresponsive/Contraindicated
• Acetaminophen, +NSAIDs, +D2, +Opioide, +Steroids
(D2=Prochloperazine, chlorpromazine, Opioid=tramadol, codeine)
5. Menstrual Migraine • Same as Strategy 1&2 + Preventive Treatment: Frovatriptan 2.5 mg, Naratriptan, Zolmitriptan
6. Migraine During Pregnancy
• Acetaminophen, +Opioid (Codeine)
• Sumatriptan+NSAIDs (NSAIDs in 1st Trimester > Spontaneous Abortion)
• Antiemetic > Metoclopramide & Dimenhydrinate
7. Migraine During Lactation
• Same as Strategy 6
• Recommended NSAIDs > Ibuprofen
Reference: Worthington I1, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E, Aube M, Leroux E, Becker WJ; Canadian Headache Society Acute Migraine Treatment Guideline Development
Group. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci. 2013 Sep;40(5 Suppl 3):S1-S80.

18. -kaxcha medical-
Thailand
Headache ≥ 10 Days/mth First Line Second Line
Mild
Acetaminophen, NSAIDs Selective COX2, Opioids
Moderate
Triptan, Triptan + NSAIDs
(Naproxen 500 or Ibuprofen 400 mg)
Ergotamine
Severe
Reference: Basics and Clinical Neuroscience 3, 2556

19. -kaxcha medical-
Thailand
Serotonin Syndrome
Washout >2 Wks
Drug Interaction
MAOI
Vasoconstrictor effects
Washout >24 hr
SNRISSRI
Ergot
Reference: http://www.stepwards.com/?page_id=6549

20. -kaxcha medical-
Thailand
Sulfonamide Group Sumatriptan
Reference: https://ainotes.wikispaces.com/Sulfonamide+Allergy