Migraine Flashcards
What are migraines
Primary headache disorder characterized by recurring headaches, pulsating nature, and last from 2-72 hours
What are the effects of migraines
Sensitivity to normal sensory input (light, sound, head movement)
Sometimes nausea and vomiting
What is a migriane aura
Occurs in 20% of migraines, signs of a migraine before it hits
Visual disturbance made up of flashing lights or zigzag lines across field of vision
Theorized mechanism behind migraine aura
Though to be driven by cortical spreading depression
Wave of neuronal depolarization followed by desensitization (depression, caused by hyperpolarization), that propagates across the cortex
How can cortical spreading depression be monitored
Measuring blood flow
Blood flow increase in an area means higher neuronal activity
Look for progression of excitation followed by depression
AKA high blood flow followed by low blood flow
What affects rate of headaches
Genetic contributions: Familial hemiplegic migraines (Migraines that run in the family)
Headaches also occur more in women than men specifically after puberty (hormones?)
What kind of inheritance is Familial Hemiplegic Migraines
Autosomal (one copy of gene is enough to cause disease in offspring)
What genetic mutations are associated with FHM?
P/Q-type calcium channel
Na+/K+ ATPase
Na+ channel subunit
Lowers the threshold for cortical spreading depression and makes it easier to achieve depolarization
What is the largest cranial nerve
Trigeminal nerve
What are the three branches of the trigeminal
Ophthalmic
Maxillary
Mandibular
What are the purposes of the trigeminal nerve
Sense pain and temperature in the head region
Innervate the dura mater
Control cerebral blood vessels (Trigeminovascular system)
Dura mater
Membrane that surrounds the brain
What causes headache pains
Pain caused by organs around the brain (Dura mater and trigeminal nerve)
No nociceptors on the brain so brain itself can not feel pain
What is the mechanism behind headaches
Pain in head detected by ophthalmic branch of the trigeminal nerve
Innervates the dura mater and corresponding blood vessels
Vasodilation = Migraine
Why are migraines considered to be a neurovascular disease
Extracerebral vessels dillate during migraine attack
Cranial blood vessel stimulation (causes vasodilation) provokes headache
Vasoconstrictor drugs alleviate pain
What is the relation between serotonin and migraines?
Release of 5-HT leads to vasoconstriction
Low-5HT levels in migraines between attacks
In response to a migraine 5-HT is released during an attack to counterbalance the lack of 5-HT and cause vasoconstriction to end the migraine
CGRP
Calcitonin gene-related peptide is located in trigeminal peripheral afferents
It is released by afferents in response to pain and leads to vasodilation
Causes migraines
CGRP is elevated in those with migraines
Prophylactic treatments
Taken daily to prevent attacks
Abortive treatments
Taken once an attack occurs
What are the two prophylactic treatment strategies against migraines
Non-pharmacological intervention: Identify triggers
Pharmacological interventions:
Beta-blockers (decrease blood pressure)
Anticonvulsants (Block pain transmission) Antidepressants (serotonin reuptake inhibitor, allows accumulation of serotonin)
What the abortive treatment strategies against migraines
Non-specific analgesics (Asprin, acetaminophen, NSAID, opioids)
Risk of medication overuse headache
Overuse of opioids will cause greater headaches later on
Caffeine and Migraines
Adenosine receptor (located on blood vessal) antagonist
Leads to vasoconstriction
Increases absorption of analgesics like acetaminophen and ergotamines
Improves migraine treatment during attack
Rebound vasodilation when caffeine wears off can trigger headaches
Ergotasmines
Ergot alkaloid (LSD)
Agonists for 5HT-1b/d receptors
Inhibits neurogenic inflammation through vasoconstriction
Issues of ergotasmines
Low degree of receptor selectivity, increased side effects
Coronary vasoconstriction
Patients with heart diseases should not take drug
Pharmacokinetics of ergotamines (absorption)
Large first-pass metabolism, leads to low bioavailability when taken orally (<1%)
Caffeine can improve rate and extent of absorption
Pharmacokinetics of ergotamines (Metabolism)
Metabolized by liver by poorly defined enzymes
Half-life 2 hours
Pharmacokinetics of ergotamines (Excretion)
Excreted in bile
Examples of a Triptans
Sumatriptan
Sumatriptan
First line migraine therapy
Selective for 5-HT 1b/d agonist
Vasoconstriction and inhibition of trigeminal nerve
Avoids the side effects of ergotamine
Pharmacokinetics of sumatriptan (Absorption)
Bioavailability is around 14% when taken orally
96% when taken subcutaneously (avoids first pass metabolism)
Pharmacokinetics of sumatriptan (Metabolism)
Metabolized by monoamine oxidase in the liver, converted into indoleacetic acid
Half-life is around 2 hours
Pharmacokinetics of sumatriptan (Excretion)
Cleared in the urine
What kind of CGPR Antagonists are used?
Small molecule CGRP antagonists
Sits in binding pocket
Monoclonal antibodies to CGRP or CGRP receptors
Binds on to receptor and sterically inhibits binding to CGRP
Rimegepant
(Nurtek)
CGRP receptor antagonists
Effective migraine treatment with less side effects
Less effect on liver aminotransferase levels (safer for long-term use)
Good bioavailability
CGRP Antibodies
Monoclonal antibodies that bind to either CGRP receptors or to CGRP
Inhibits CGRP signalling leading to vasoconstriction
Monoclonal
Produced antibodies that act like natural antibodies
