Pharmacology of HA/Migraines - BANKS

Learning Objectives

1. Know and understand path-has of migraine HA

2. Know understand MOA of pharm agents for treatment and prevention of Migraines

3. 
   

Migraine Pathophysiology

1. Trigeminovascular system is the anatomical/physiological SUBSTRATE of migraines

2. Nociceptive transmission (PAIN) originates from activation/sensitizing of 1st order TGeminal neurons that have cell bodies in Tgeminal ganglion and afferent fibers innervate meninges and its vessels (PAIN transmission comes from activation of Tgeminal neurons in ganglion/afferent fibers that innervate meninges and vessels)

3. Ascending pain transmission from Tgeminal ganglion reaches brainstem —→ activates 2nd order Tgeminal neurons such as spinal Tgeminal nucleus

4. Activation of 3rd order Tgeminal neurons in thalamus —→ relay pain information to somatosensory cortex + other cortical areas —→ RESULT = FEELINGS/PERCEPTION OF PAIN

5. Release of Vasoactive peptides leading to dilation of intracranial arteries

   1. peptides

      1. CGRP

      2. PACAP-38

      3. Glutamate // NO // Substance P // Vasoactive intestinal peptide

Easier:

1. 1st order Tgeminal neurons in meninges/vessels transmit ASCENDING Pain signal

2. Pain signal ascends and reaches 2nd order Tgeinal neurons (such as spinal Tgeminal nucleus)

3. 3rd order Tgeminal neurons activated in thalamus —→ relay pain to somatosensory/cortical areas. —→ feelings of pain

4. Release of VASOACTIVE peptides

Migraine Phases/Progression

1. Prodrome

2. Aura (visual/sensory symptoms)

3. Headache and associated phase of migraine attack

4. Postdrome

PAHP

Acute abortive agents in Migraines

1. 5HT 1B/1D/1F Agonists —> (Triptans)

2. Selective 5HT1F agonists

   1. “Ditans”

5HT 1B/1D/1F Agonists (Triptans) MOA

1. Blocks release of CGRP and Substance P at presynaptic 5HT 1B, 1D, and 1F receptors

2. Constricts menial, dural, cerebral and pill vessels via activation of 5HT1B receptors

What are points about the 5HT1B receptors?

1. G-alpha - i (GPCR) receptor protein unit

2. Located presynaptically on trigeminal ganglia and nerves

3. Expressed on vascular smooth muscle (pill, menial, extra cranial vessels)

“Before”

What are points about the 5HT1D receptors?

1. G-alpha - i (GPCR) receptor protein unit

2. Localized in trigeminal ganglia and trigeminal nerves

3. Inhibit release of CGRP in spinal trigeminal neurons

What are points about the 5HT1F receptors?

1. G-alpha - i (GPCR) receptor protein unit

2. Located on glutaminergic neurons in trigeminal ganglion and nucleus caudal and other cortical areas

3. Located on cerebral blood vessels, but exert no vasoconstrictive effect

“Freak Glutaminergic/Caudal”

3 ways acute abortive agents work in migraines

1. Vascular

   1. Selectiveconstriction of intracranial blood vessels

2. Neurogenic

   1. decrease Tgeminal nerve activation and vasoactive neuropeptide release

3. Central

   1. decrease CT release from activated Tgeminal nerves in brainstem

5HT 1B/1D/1F Agonists (Triptans) ADVERSE EFFECTS

• Rare, but may cause chest pain due to coronary artery constriction, mimicking angina

• Rare, but potential Myocardial Infarction (MI)

Selective 5HT1F Agonists MOA

1. Lasmiditan

2. Inhibits dural plasma protein extravasation

3. Inhibits trigeminal nucleus caudalis stimulation

4. Should not induce vasoconstriction

Ergot Alkaloids - Dihydroergotamine points

Adverse effects —→ Similar to Triptans

1. more generalized ad sustained vasoconstrictor effects

2. Overuse syndrome + rebound HA

3. Pregnancy category X

MOA:

1. Similar to triptans

2. Activates 5HT1A, 2A, 2C

3. Activates D1/D2 receptors

Examples:

• Dihydroergotamine mesylate nasal spray (Trudhesa)

Other acute Agents - CGRP

CGRP receptor antagonists

1. Ubrogepant

2. Rimegepant

3. Atogepant

4. Zavegepant

• Should not induce vasoconstriction

What is the CGRP receptor?

G protein couple receptor composed of a calcitonin-like receptor and receptor activity-modifying protein (RAMP1)

Non specific acute agents for migraine

1. Aspirin

2. Acetaminophen

3. NSAIDs (ibuprofen, naproxen, diclofenac, etc)

   1. Celecoxib oral solution

      1. AE’s —→ standard GI bleeding for NSAIDs and CV thrombotic events risk

4. Caffeine

   1. Adenosine receptor antagonist

5. Butoprhanol (Stall)

   1. Mu opioid receptor partial agonist

Preventative agents in Migraines Part 1

1. Beta-antagonists

   1. Propranolol, Metoprolol, Timolol

   2. MOA

      1. B2 mediated inhibition of NO synthase

      2. Inhibit Glutamie NMDA receptors

      3. Stabilize neuronal membranes

2. Topiramate

   1. MOA

      1. blocks voltage-dependent L and N sodium channels

      2. increases GABA and inhibits Glutamate

      3. AE’s —→ Reduced appetite / Pregnancy category D

3. Sodium Valproate/Divalproex

   1. MOA

      1. increases GABA

      2. Anti-nociceptive activity at Tgeminal nucleus

      3. AE’s —→ TERATOGENIC

Preventative agents in Migraines Part 2

1. Onabotulinum Toxin

   1. MOA (hypothesis)

      1. Decreased synaptic vesicle release of ACh by blocking the synaptosomal nerve-associated protein 25 (SNAP-25) —→ reduces Tgeminal nerve pathway

      2. Modulates neuro inflammation by inhibiting release of Substance P, glutamate, CGRP

      3. Diminishes central sensitization by altering TRPV1, TRPV2, TRPA1

2. CGRP receptor Antibodies

   1. Erenumab // Galcanezmab // Eptinezumab // Fremanezumab

   2. MOA

      1. CGRP receptor IgG2 monoclonal antibody

      2. Should NOT induce vasoconstriction

What drug is in the pipeline for Migraines?

Pituitary adenylate cyclase activating polypeptide (PACAP-38)