Migraine- Khan

What are the 2 types of migraines?

1. HA with aura (what is aura? pt. sees spots, feels pins/needles, weakness, aphasia)

2. HA without aura

What are the 2 phases to the VASCULAR component of migraines?

1st phase: VASOCONSTRICTION (cerebral vasoconstriction and ischemia)

2nd phase: VASODILATION (cerebral vasodilation and pain)

During the 1st phase of a migraine, _________________ is released from CNS neurons and platelets.

serotonin

The NEURO component of migraines includes activation of WHAT system?

trigeminal nerve system (carries pain signals from blood vessels and meninges surrounds brain relayed through trigeminal nucleus (brainstem)—> thalamus+ sensory cortex)

What transmitters are released during pain signaling?

• CGRP

• glutamate

• substance P and K

• serotonin

What is CGRP and what is it’s role in migraines?

• CGRP= calcitonin-gene related peptide

• deals with vasodilation and inflammation

CGRP produces its effects through what receptors?

G protein coupled calcitonin-like receptor and RAMP1

What effect does serotonin in migraines?

• vaso__________

• may inhibit _____________ and ____________ activity

• effects ________ muscle to…

• vasoconstrictor

• may inhibit calcium channels and glutamate/ CGRP activity

• effects smooth muscle —> enhances platelet aggregation, NT in the CNS

What serotonin receptors are involved in migraines? What type of receptor are they?

5-HT_1B and 5-HT_1D —> GPCRs

Describe the biosynthesis of serotonin:

_________________—>_______________—> serotonin

What enzymes are involved?

• L-tryptophan—> 5-hydroxytryptophan—> serotonin

• enzymes: tryptophan hydroxylase, aromatic AA decarboxylase

What’s the difference between prophylaxis and abortive drugs for migraine treatment?

• FYIIIIIIIII (for understanding)

• Prophylaxis: reduce frequency and severity of attacks

• Abortive: used for reversing, aborting attacks, reducing pain and others

What drugs are used for migraine PROPHYLAXIS tx?

• tricyclic antidepressants

• anticonvulsants

• antihypertensives

• CGRP antagonists

• CGRP antibodies

What drugs are used for migraine ABORTIVE tx?

• Serotonin agonists (-triptans, -ditans)

• Ergot derivatives

• NSAIDs

• CGRP receptor antagonists

Preferred tricyclic antidepressant for migraine prophylaxis?

amitriptyline

What anticonvulsants can be used for migraine prophylaxis?

• valproic acid/ divalproex

• topiramate

BBW of valproic acid/ divalproex?

BBW for hepatotoxicity and teratogenicity (neural tube defects, Cat X)

What antihypertensives are preferred for migraine prophylaxis? alternatives?

• preferred: b-blockers (propranolol, metoprolol)

• alternatives: lisinopril, verapamil

List of the CGRP antagonists used for migraine prophylaxis and abortive tx?

• atogepant- only prophylaxis

• rimegepant- both

• ubrogepant- only abortive

What antibodies are used for migraine prophylaxis? what is their target?

• eptinezumab

• galcanezumab

• fremanezumab

• erenumab

• target: CGRP antibodies

List the “-triptans”

• more of an FYI, not technically in SG

• sumatriptan

• zolmitriptan

• naratriptan

• rizatriptan

• eletriptan

• frovatriptan

• almotriptan

Triptans are ____________ agonists.

a. histamine

b. CGRP

c. serotonin

d. glutamate

c.

What are the 2 MOAs of the “-triptans” (ex: sumatriptan)?

• results?

1. activates 5-HT_1D/1B receptors in cerebral blood vessels

   • results: produces VASOCONSTRICTION, inhibits vasodilation to the HA

2. stimulates presynaptic 5-HT_1D/1B receptors

   • results: inhibits release of pro-inflammatory neuropeptides that cause vasodilation, inflammation, and pain

What are the warnings and precautions of the triptans?

• warning: rare but serious CV events (ischemia, MI, arrhythmias)

• precaution: increased risk of serotonin syndrome

What 2 triptans have a SLOWER onset and LONGER duration of action compared to the others form the class?

Frovatriptan and naratriptan

What are the ADRs and CONTRAINDICATIONS of the triptans?

• ADRs

  • Paresthesia (tingle/numb)

  • seizure (suma)

  • tightness of pressure in neck and chest

  • route specific ADRs

• C/Is

  • CV—> IHD, uncontrolled HTN, PVD, angina, arteriosclerosis

  • Cerebrovascular—> TIA, stroke

  • SEVERE liver/ kidney disease

  • concurrent MAOI therapy within 2 weeks (suma, riza, zolmi)

What is serotonin syndrome?

What are the 3 major categories?

List the symptoms for each category?

• Serotonin syndrome—> triad of symptoms

  1. cognitive: agitation, confusion, hypomania, insomnia, hallucinations

  2. neuromuscular, sweating, fever, diarrhea

  3. somatic/neuromuscular: tremor, hyperreflexia, rigidity, akathisia

WHAT ARE THE 3 IMPORTANT REGIONS in the SAR of triptans?

1. Core (indole)—> required for activity

2. Group at position 3—> required (substituted amines preferred), may influence at metabolism

3. Group at position 5—> enhance activity/selectivity

How do modifications at position 3 and 5 do to the activity of triptans?

• mod at pos 3: sub of alkyl amines prolongs duration of action

• mod at pos 5: sub or addition of heterocycles enhances bioavailability

List the drugs that are ergot derivatives:

• ergotamine

• dihydroergotamine

List the receptors that ergot derivatives MAY act on:

• a-adrenergic receptors (antagonists/partial agonists)

• 5-HT receptors (partial agonists)

• dopamine receptors (partial agonists)

What are the symptoms of chronic ergot toxicity

“Saint Anthony’s Fire”—> Painful convulsions, mania/psychosis, hallucinations, n/v, vasoconstriction/gangrene

What are the contraindications and precautions with ergot derivatives?

• SAME C/I as triptans (vascular disease, severe renal/hepatic disease)

• C/I with strong CYP3A4 inhibits (life-threatening peripheral ischemia)

• PREGNANCY X (avoid)

• avoid with other vasoconstrictors

What is the chemical difference between ergotamine and dihydroergotamine?

identical except for double bond placement

What is the ROA of each of the ergot derivatives?

• ergo: oral tablet, suppository

• dihydroergo: IM, SQ, IV, or nasal

CYP___ is involved in the metabolized of ergot derivatives.

3A4

What is the role of caffeine in Cafergot (brand name of Ergotamine)?

caffeine enhances absorption (remember low oral bioavailability)

What OTC agents can be used for prophylactic and abortive therapy in migraines? examples?

NSAIDs and APAP

(ex: aspirin, ibuprofen, naproxen)

What is the only NSAID that’s an OTC product that has an indication for migraines?

Excedrin migraine

How is Lasmiditan different from the triptans?

• Lasmiditan—> selective 5-HT_1F agonists and does NOT cause vasoconstriction

• Triptans—> 5-HT_1D/1B agonists and causes vasoconstriction and inhibits release of pro-inflammatory neuropeptides