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PMCOL 200 > 21 Migraines > Flashcards

21 Migraines Flashcards

1
Q

What is the leading cause of disability worldwide, particularly in those under 50?

A

Migraine

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2
Q

What is Migraine?

A

Primary headache disorder characterized by recurring headaches that are moderate to severe, pulsating in nature, last from 2-72 hours

  • Sensitivity to normal sensory input (light, sound, head movement)
  • Sometimes nausea and vomiting
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3
Q

What is an aura?

A
  • Visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision
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4
Q

Aura is thought to be driven by:

A

Aura is thought to be driven by: cortical spreading depression:

  • wave of neuronal depolarization followed by desensitization (depression) that propagates across the cortex
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5
Q

What is cortical spreading depression?

A

Wave of activity that propogates across the cortex (less intense than seizures) but causes mild visual disturbances

  • wave of neuronal depolarization followed by a period of desensitization (because of refractory period) = reduced activity
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6
Q

What specific type of migraine has a strong genetic contribution?

A

Familial hemiplegic migraine

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7
Q

What is familial hemiplegic migraine?

What is the genetic contribution?

A

Migraine that includes weakness of half of the body

  • Genetic:
    • Autosomal dominant inheritance
    • 3 known genetic mutations:
      • P/Q-type Ca2+ channel
      • Na+/K+ATPase
      • Na+ channel subunit
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8
Q

What are three known genetic mutations that cause familial hemiplegic migraine?

A

3 known genetic mutations:

  1. P/Q-type Ca2+ channel
  2. Na+/K+ATPase
  3. Na+ channel subunit

Mutations lower the threshold for cortical spreading depression

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9
Q

What is the largest cranial nerve?

A

Trigeminal nerve

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10
Q

What are the three branches that the peripheral processes of the trigeminal nerve divide into?

What are the 3 main purposes of these branches?

A
  1. Ophthalmic
  2. Maxillary
  3. Mandibular
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11
Q

The trigeminal nerve has peripheral processes that divide into three branches _______, _______ and _______.

These have 3 main purposes:

A

The trigeminal nerve has peripheral processes that divide into three branches opthalmic, Maxillary and Mandibular.

These have 3 main purposes:

  1. Sense pain and temperature in head region (as well as proprioception)
  2. innervates the dura mater (membrane surrounding the brain)
  3. Controls cerebral blood vessels (trigeminovascular system)
    • responsible for bring O2 into the brain
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12
Q

Pain in the head is detected by the ______ branch of the trigeminal nerve innervating the ______ and associated _______

A

Pain in the head is detected by the ophthalmic branch of the trigeminal nerve innervating the dura mater and associated blood vessels

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13
Q

The cause of migraine is still unknown but is thought to be a ________ disease.

Three pieces of evidence for this:

A

The cause of migraine is still unknown but is thought to be a neurovascular ​disease.

Evidence:

  1. During a migraine attack, the extracerebral vessels dilate
  2. Cranial blood vessel stimulation provokes headache
    • eg NO = vasodilation = headache
  3. Vasoconstrictor drugs alleviate headache pain
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14
Q

How is serotonin linked to migraine?

A

Serotonin seems to work by influencing vascular tone in the cerebral region

  • Release of 5-HT (serotonin) leads to vasoconstriction
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15
Q

In between attacks, migraineurs have low levels of _____

A

In between attacks, migraineurs have low levels of 5-HT (serotonin)

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16
Q

During migraine attacks, ____ is released

A

During migraine attacks, serotonin (5-HT) is released

17
Q

Serotonin (5-HT) released from trigeminal nerves can influence vaso_____; people susceptible to migraines have lower levels of _______; and ______ is released during migraine attacks

A

Serotonin (5-HT) released from trigeminal nerves can influence vasoconstriction; people susceptible to migraines have lower levels of serotonin (5-HT); and serotonin (5-HT) is released during migraine attacks

18
Q

What is CGRP and how is it linked to migraine?

A

CGRP = Calcitonin gene-related peptide (CGRP) located in trigeminal peripheral afferents

  • Released from afferents in response to pain (in nociceptors) = leads to vasodilation
    • ​promotes inflammation
  • CGRP elevated in those with migraine suggesting there may be increased signalling of vasodilation
19
Q

Treatment strategies for migraine include both ______ and _______ strategies

A

Treatment strategies for migraine include both prophylactic and abortive strategies

  • Prophylactic: preventative - taken daily to prevent attacks
  • Abortive: Taken once an attack occurs
20
Q

What are some non-pharmacological prophylactic intervention?

A

Identify and avoid/minimize triggers

Common triggers: Caffeine, alcohol, stress, inconsistent sleep, diet, exercise

21
Q

What are three possible pharmacological prophylactic interventions?

A
  1. Beta blockers (propanolol)
    • ​​decrease blood pressure = less pressure on cerebral blood vessels
  2. Anticonvulsants (gabapentin - inhibits Ca2+ channels that can reduce activity to prevent seizures)
    • block pain transmission
  3. Antidepressants (amitriptyline)
    • serotonin reuptake inhibitor SSRI (seen in depression lecture) by blocking SERT
22
Q

What are the most common abortive strategies

A

Non-specific analgesics:

  • aspirin
  • acetaminophen
  • NSAID
  • opioids

Risk of medication overuse headache

23
Q

What is medication overuse headache disorder? Which non-specific analgesic is it mainly associated with?

A

Mainly associated with Opioids (chronic use of opioids can make headaches worse)

  • Headache present on >15 days/month
  • regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache
  • Headache has developed or markedly worsened during medication overuse
24
Q

How does caffeine interact with adenosine receptors?

A

Caffeine is an adenosine receptor antagonist

  • leads to vasoconstriction
  • increases absorption of some analgesics (acetaminophen, ergotamines)
  • Improves migraine treatment during attack
  • may also trigger headaches or result in rebound headache (withdrawal)
25
Q

What is the relationship between caffeine and migraine?

A
  • Caffeine is an adenosine receptor antagonist
  • leads to vasoconstriction
  • increases absorption of some analgesics (acetaminophen, ergotamines)
  • improves migraine treatment during attack
  • may also cause rebound headache (withdrawal) - trigger migraine in those susceptible
26
Q

What were the first developed specific anti-migraine agents?

A

Ergotamines (ergot alkaloids)

27
Q

How do ergotamines work?

A

Agonists for 5HT-1b/d receptors that inhibit neurogenic inflammation (by blocking vasodilation)

  • low degree of receptor selectivity which increases the risk of experiencing drug-induced side effect
  • pKi = -logKi | high pki = high affinity
28
Q

Ergotamine can produce ________, (not only vasoconstriction in brain) often with associated ______ changes and _____ pain in patients with coronary artery disease

A

Ergotamine can produce coronary vasoconstriction, (not only vasoconstriction in brain) often with associated ischaemic changes and anginal pain in patients with coronary artery disease

29
Q

Use of ergotamines is contraindicated in patients with ________, _______, _________, _______

A

Use of ergotamines is contraindicated in patients with peripheral vascular disease, coronary heart disease, uncontrolled hypertension, stroke

30
Q

What is the first line migraine therapy?

A

Triptans (eg sumatriptan)

  • selective 5-HT1b/d agonist
  • two mechanisms
    • vasoconstriction
    • inhibition of trigeminal nerve
  • avoids side effects of ergotamine
31
Q

How do triptans work and provide an example

A
  • Triptans (eg sumatriptan)
  • selective 5-HT1b/d agonist
  • two mechanisms
    1. vasoconstriction
    2. inhibition of trigeminal nerve
  • avoids side effects of ergotamine
    • neglible binding at alpha 1 and alpha 2 receptors
32
Q

What are the pharmacokinetics of Sumatriptan?

  • Absorption and Distribution
    • Bioavailability?
  • Metabolism
    • metabolized by _________ in the liver to __________
    • Half-life around _______
  • Excretion
    • cleared in the ______
A
  • Absorption and Distribution
    • Bioavailability around 14% when taken orally, 96% when given subcutaneously (b/c first pass metabolism)
  • Metabolism
    • metabolized by monoamine oxidase in the liver to indoleacetic acid
    • Half-life around 2 hours
  • Excretion
    • cleared in the urine
33
Q

What enzyme degrades both serotonin and sumatriptan?

A

Monoamine oxidase

34
Q

CGRP peptide is released from the ____________.

What is the goal of CGRP antagonists?

A

CGRP peptide is released from the trigeminal pain afferents and leads to vasodilation

  • CGRP antagonists are meant to reverse the vasodilation implicated in migraine
35
Q

What are two types of migraine treatments that target CGRP peptides?

A
  1. small molecule CGRP antagonists
  2. monoclonal antibodies to CGRP or CGRP receptor
    • basically acts by blocking ability of CGRP to bind to receptor or
    • antibodies bind to receptor and block the agonist from binding
36
Q

What is rimegepant?

A

Rimegepant (nurtek) is a small molecule CGRP receptor antagonist in clinical development

Effective migraine treatment

Less effect on liver aminotransferase levels (safer for longterm use)

37
Q

What are the CGRP antibodies and how do they treat migraines?

A
  • Monoclonal antibodies to either the CGRP receptor or CGRP itself
  • Inhibits CGRP signaling leading to vasoconstriction
38
Q

What are two reasons why drugs might not be approved?

A
  1. Poor bioavailability
  2. side-effects (eg increased aminotransferase in liver indicating liver damage)

PMCOL 200 (30 decks)

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