Pathophysiology and Pharmacology of Migraine

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Questions and Answers

What is the major alkaloid found in ergot alkaloids?

Bromocriptine

Lysergic acid

Ergotamine (correct)

Ergonovine

What adverse effect can result from the GI stimulation by ergot alkaloids?

Drowsiness

Abdominal pain

Constipation

Nausea and vomiting (correct)

Which of the following is a contraindication for the use of ergot alkaloids?

Migraine without aura

Controlled hypertension

Nausea

Uncontrolled hypertension (correct)

What mechanism of action do ergotamine and dihydroergotamine primarily utilize?

Agonize 5-HT1B and 5-HT1D receptors Signup and view all the answers

Which drug is specifically contraindicated with strong CYP3A4 inhibitors?

Ubrogepant Signup and view all the answers

What adverse effect is associated with prolonged vasospasm in patients taking ergot alkaloids?

Gangrene Signup and view all the answers

Which CGRP receptor antagonist is NOT indicated for migraine prophylaxis?

Zavegepant Signup and view all the answers

What role do antiemetics play in the treatment related to ergot alkaloids?

Prevent GI adverse effects Signup and view all the answers

Which of the following is a common combination medication for migraine treatment?

Aspirin, acetaminophen, and caffeine Signup and view all the answers

Which condition is most concerning for the use of ergot alkaloids?

Basilar migraine Signup and view all the answers

What is the mechanism of action of 5-HT agonists in the context of CGRP release during migraines?

They inhibit presynaptic 5-HT1B and 5-HT1D receptors. Signup and view all the answers

Which of the following is a non-antibody antagonist used in the treatment of migraines?

Atogepant Signup and view all the answers

What is the role of eptinezumab in migraine prophylaxis?

It prevents CGRP from binding to its receptor. Signup and view all the answers

Which medication class is NOT mentioned as an FDA approved option for migraine prophylaxis?

Antidepressants Signup and view all the answers

What is the mechanism of action of metoclopramide in treating nausea associated with migraines?

Dopamine receptor blocking. Signup and view all the answers

What is a common adverse reaction associated with metoclopramide when used with triptans?

Serotonin syndrome. Signup and view all the answers

What category of medications includes divalproex and is known to have boxed warnings?

Anticonvulsants Signup and view all the answers

Which medication targets the CGRP receptor directly?

Erenumab Signup and view all the answers

What is a characteristic of humanized monoclonal antibodies against CGRP?

They bind to CGRP to prevent its receptor binding. Signup and view all the answers

Which of the following medications is commonly used off-label for migraine treatment, supported by good evidence?

Amitriptyline Signup and view all the answers

What is the primary characteristic of a primary headache?

It occurs without any identifiable cause. Signup and view all the answers

Which of the following substances is known to be a common trigger for migraines?

Caffeine Signup and view all the answers

What role do serotonin receptors play in migraine pathophysiology?

They mediate neurotransmitter release. Signup and view all the answers

Which phase precedes a migraine with aura?

Premonitory phase Signup and view all the answers

The release of which neuropeptide is primarily involved in the pathophysiology of migraine?

Calcitonin gene-related peptide Signup and view all the answers

Which class of drugs is primarily used as agonists in the treatment of migraines?

5-HT1 receptor agonists Signup and view all the answers

A major side effect of non-selective serotonin receptor agonists is:

Variable adverse effects Signup and view all the answers

What is the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology?

It mediates pain and causes vasodilation. Signup and view all the answers

In patients with coronary artery disease, what is a major concern regarding the use of triptans?

Vasoconstriction of coronary vessels. Signup and view all the answers

Which of the following is a non-pharmacological treatment for migraines?

Acupuncture Signup and view all the answers

Migraine headaches are characterized by which type of pain?

Throbbing or pulsating pain Signup and view all the answers

Which of the following accurately describes the function of serotonin in the gastrointestinal system?

It promotes gastrointestinal tonicity. Signup and view all the answers

What is a common psychological symptom experienced during a migraine?

Euphoria and anxiety Signup and view all the answers

What should be avoided to prevent medication overuse headaches?

Overuse of combination pain relievers Signup and view all the answers

What is the primary function of triptans in migraine treatment?

Rapid relief of migraine symptoms Signup and view all the answers

Which of the following describes the mechanism of action of triptans?

Activation of 5-HT1D and 5-HT1B receptors Signup and view all the answers

Which triptan is considered a 1st generation medication?

Sumatriptan Signup and view all the answers

What is a common adverse drug reaction associated with triptans?

Chest pain possibly due to coronary vasospasm Signup and view all the answers

Which of the following medications should not be administered within 24 hours of triptan administration?

Ergotamine Signup and view all the answers

What is the metabolism route for Eletriptan?

CYP3A4 Signup and view all the answers

Lasmiditan is known for which characteristic compared to triptans?

Lack of vasoconstrictor action Signup and view all the answers

Which condition acts as a contraindication for triptan use?

History of cerebrovascular disease Signup and view all the answers

What is a potential risk associated with the interaction of triptans and SSRIs?

Serotonin syndrome Signup and view all the answers

Which of the following best describes the efficacy of triptans compared to ergot alkaloids?

Triptans have similar efficacy to ergot alkaloids Signup and view all the answers

What should be monitored in patients taking triptans who also use CYP3A4 inhibitors?

Elevated serum levels of triptans Signup and view all the answers

Which adverse drug reaction category most commonly includes muscle weakness with triptan use?

Cardiovascular effects Signup and view all the answers

What defines the pharmacological impact of acute treatments for migraines?

They provide immediate symptom relief during an attack Signup and view all the answers

Which statement about the pharmacokinetics of second-generation triptans is accurate?

They generally have a higher oral bioavailability than first-generation triptans Signup and view all the answers

Study Notes

PHID 1606 - Integrated Sequence VI - Winter Quarter 2024

Course covers Pathophysiology and Pharmacology of Migraine
Recommended reading: Katzung 16th Ed., Chapter 16 (Serotonin; The Ergot Alkaloids), G&G 14th Ed., Chapter 15 (Serotonin), DiPiro 11th Ed., Chapter 78 (Headache Disorders)
Professor: Molly Yao, Ph.D., M.S.
Contact information provided

Learning Objectives

Describe migraine pathophysiology, focusing on serotonin and CGRP effects
Identify serotonin receptor types
Identify and describe different migraine treatment drug classes
Understand and describe mechanisms for migraine drug treatment
List adverse effects, drug interactions, and contraindications for major migraine drugs
Recognize adjunctive antiemetic drugs

Review: Types of Headaches (HA)

Primary Headache: most common (~90%), without underlying cause; subtypes include tension, cluster, and migraine
Secondary Headache: symptomatic of distinct pathology (e.g., tumor, meningitis, head trauma), substance abuse or withdrawal, or overuse of medication (simple analgesics, combination pain relievers, prescription migraine medications (triptans & ergotamine), opioids)

Review: Subtypes of Primary Headaches

Tension type: most common, least studied, pathophysiology unclear; symptoms include bilateral dull, non-pulsatile pressure pain; treatment usually includes OTC analgesics
Cluster: least common, most severe, pathophysiology unclear; symptoms include severe unilateral head pain, occurring in series lasting weeks or months; treatment includes oxygen inhalation, ergots, triptans
Migraine: without aura (common), may have premonitory phase, with aura (classic), HA preceded by neurological symptoms ("aura")

Clinical Presentation of Migraine

Characterized by recurring throbbing or pulsating head pain, often unilateral; frequently interferes with normal function
~12%-79% of migraineurs experience premonitory symptoms (not aura) in hours or days before headache onset
Common neurologic symptoms include phonophobia (sound-sensitivity), photophobia (light-sensitivity), and hyperosmia (smell-sensitivity)
Other symptoms include mood disturbances; autonomic symptoms (polyuria, diarrhea, constipation)
Constitutional symptoms (stiff neck, yawning, thirst, food cravings, anorexia)

Review: Migraine Aura

Aura: ~25% of migraine patients, lasting 5-20 minutes up to 60 minutes; may precede pain by up to 60 minutes
Focal neurological abnormality
Common manifestations: visual symptoms (photopsias, scintillating scotoma, fortification spectrum), sensory symptoms (pins & needles), negative symptoms (blind spot, hemianopsia)
May be characterized by "positive" or "negative" symptoms

Common Triggers

Food: chocolate, alcohol, caffeine withdrawal, fermented/pickled foods, monosodium glutamate, nitrate-containing foods, saccharin/aspartame, tyramine-containing foods
Environmental: glare, flickering lights, high altitude, loud noises, strong smells, tobacco smoke, weather changes
Behavioral/Physiological: insufficient or excessive sleep, fatigue, sexual activity, skipped meals, strenuous physical activity, stress/post-stress

Migraine: Pathophysiology

Brain dysfunction triggers trigeminovascular pain pathway, and sensitizes headache
Activation of trigeminal nerves releases vasoactive neuropeptides (CGRP, neurokinin A, substance P)
Abnormal dural blood vessel dilation and extravasation of plasma causes inflammation, perivascular edema; mechanical stretching associated causes pain
Carotid arteriovenous anastomoses dilation leads to cranial ischemia and hypoxia, perceived as migraine pain
Headache onset is sometimes linked to increases in pulsating of temporal artery

Serotonin (5-HT)

Synthesized from tryptophan
Primarily in GI tract, the majority in the brain stem, and remaining neurons/platelets
Role in CNS (mood, sleep, appetite, temperature, perception of pain, BP, vomiting), and platelets (platelet aggregation)
Role in migraine: vasoconstrictor/vasodilator (except coronary arteries where it vasodilates); inhibits neurotransmitter release; degraded by MAO
Excess 5-HT concurrent with MAO inhibitors causes serotonin syndrome

Serotonin Receptors

Many (15) different subtypes, acting as GPCRs, primarily; 5-HT3 receptors are ligand-gated ion channels
Most migraine drugs act on 5-HT1B/D

Peptide neurotransmitter
Found in peripheral sensory neurons and throughout CNS, including trigeminal complex
Potent vasodilator

Migraine Treatments

Non-Pharmacological

Apply ice to head
Identify and avoid triggers, acupuncture, recommended periods of rest/sleep

Pharmacological (Abortive)

Triptans (1st and 2nd generation): include sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, eletriptan; differing metabolism and other pharmacokinetic/pharmacodynamic effects
Ergots: ergotamine, dihydroergotamine (DHE)
Simple Analgesics: Aspirin, Individual NSAIDs, acetaminophen; and combination products (Excedrin Migraine, Fiorinal, Phrenilin)
CGRP Receptor Antagonists (Non-antibodies): (e.g., ubrogepant, rimegepant, and zavegepant)
CGRP Receptor Antagonists (Antibodies): (e.g., eptinezumab, fremanezumab, and galcanezumab)

Pharmacological Treatments (Prophylactic)

CGRP blockers: Small molecule antagonists such as (Atogepant and Rimegepant), and Blocking antibodies such as (Eptinezumab, Fremanezumab, Galcanezumab, Erenumab)
Others: Propranolol, timolol, topiramate, valproate, divalproex, lisinopril, candesartan, doxepin, amitriptyline

Adjunctive (Antiemetic)

Metoclopramide, Prochlorperazine

Serotonin Syndrome

Clinical Presentation: hyperthermia, hyperreflexia, tremor, clonus, hypertension, hyperactive bowel sounds, diarrhea, mydriasis, agitation, coma; onset within hours
Precipitating Drugs: SSRIs, second-generation antidepressants, MAOIs, linezolid, tramadol, meperidine, fentanyl, ondansetron, sumatriptan, MDMA, LSD, St. John's wort, ginseng
Treatment: discontinue precipitating drugs, first-line therapy: benzodiazepines; consider 5-HT2 blocker

Drug Interactions and Contraindications

Specific interactions exist amongst some migraine treatments
Triptans have interactions with certain other medications and contraindications, including but not limited to, significant cerebrovascular, coronary artery disease and use within 24 hours of other 5-HT or ergotamine-like medications
Ergots have contraindications including pregnancy, uncontrolled HTN, ischemic heart disease, hepatic/renal impairment, sepsis, use within 24 hours of 5-HT or ergotamine medications

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Description

This quiz covers the fundamental aspects of migraine pathophysiology and pharmacology, with a focus on serotonin and CGRP effects. It includes identification of serotonin receptor types and various migraine treatment classes, along with their mechanisms and side effects. Aimed at understanding headache disorders, this quiz is essential for those immersed in health sciences.