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Neurologic & Psych > EXAM #2 Pharmacology Headache Dr. Pond > Flashcards

EXAM #2 Pharmacology Headache Dr. Pond Flashcards

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1
Q

What are the primary forms of headache?

A

-Migraine
-Tension-type
-Cluster

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2
Q

Characteristics of Migraine

A

-unilateral
-pulsatile
-disabling
-N/V
-Photophobia and Phonophobia

-more common in women (3x)

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3
Q

Migraine POUND

A

Pulsatile
One day duration (4-72h)
Unilateral
->start on one side, and may progress to both sides
Nausea, vomitting
Disabling intensity
-> aggravated by or avoidance of movement
->photophobia, phonophobia

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4
Q

Characteristics of Tension-type headache

A

-bilateral
-dull
-hatband pattern

  • more common in women
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5
Q

Characteristics of Cluster Headache

A

-unilateral
-pulsatile
-usually around one eye
-can cause a droopy eyelid
-severe (most severe of the 3 types)
-nasal congestion

-more common in men

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6
Q

What is a secondary headache?

A

Headache secondary to another disease
-infectious
-neoplastic
-drug-induced
-idiopathic

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7
Q

What are the types of migraine?

A

common migraine (without aura)
migraine with aura (aura can be a visual sensation or pattern, omen for the migraine)

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8
Q

Theories of migraine pathogeneisis

A

-dysfunction in brain nuclei involved in the central control of nociception (pain stimuli detection)

-altered cortical excitability (may explain why antiseizure drugs work for migraine)

-cortical spreading depression theory (mouse model): depolarization spreads across the brain (2-3 mm/min followed by depression; the spreading of depression may activate the trigeminovascular system -> causing the aura symptoms

-Neurogenic inflammation: neurons produce neuropeptides -> inflammatory response -> dialtion of trigeminovascular system (blood vessels that go the meninges)

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9
Q

What are the neuopeptides that are thought to cause an inflammatory response and vasodilation to the meninges?

A

-substance P
-neurokinin A
-Calcitonin Gene-Related Peptide (CGRP) - major

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10
Q

Which nerve is involved in the pathophysiology of migraine?

A

Trigeminal nerve (largest cranial nerve, cranial nerve 5)

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11
Q

What controls the output and input of trigeminal nerves?

A

Trigeminal nucleus in the brain stem

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12
Q

What may cause the pain in migrain?

A

Neuropeptides released into

-meninges (causing vasodilation)

-the brain stem -> gets to the thalamus and higher brain center (causing pain, photophobia, and photosonia)

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13
Q

What are Eicosanoids and where are they derived from?

A

-signal molecules

-made by oxidation of fatty acids

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14
Q

Eicosanoids are converted to …. by the enzyme…

A

->Inflammatory stimuli

to Arachidonic acid

by Phospholipase A2 (can be blocked by Corticosteroids - annexin A1)

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15
Q

Which molecules are responsible for inflammation and pain?

A

Prostanoids
-Prostaglandins
-> causes Inflammation, pain, fever

-Prostacyclin (PGI2)
-Thromboxane (TXA2)

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16
Q

Which enzyme converts Arachidonic acid to Prostanoids?

A

Cyclooxygenase (COX-1, COX-2)

blocked by Aspirin, NSAIDs

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17
Q

Which of the COX enzymes is induced and which one is constitutive?

A

COX-1 = constitutive

COX-2 = unducible -> involved in cancer, inflammation, pain

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18
Q

Location of COX-3

A

CNS

-it is a splice variant of COX-1
-not found in humans yet (only in animal models)

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19
Q

Which COX-isoenzymes are blocked by Aspirin?

A

All
COX-1, COX-2

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20
Q

Which COX-isoenzymes are blocked by NSAIDs?

A

Nonselective NSAIDs are fe ibuprofen, naproxen
selective: Celecoxib -> COX-2

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21
Q

What are the symptoms that are relieved by Aspirin and NSAIDs?

A

-Anti-inflammatory
-Analgesic -> Pain
-Antipyretic -> fever

-Antithrombotic (NSAID reversible, Aspirin irreversible)
-Anticancer

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22
Q

How does Acetaminophen work?

A

-not well understood
-weak COX inhibitor in CNS
-> inhibits prostaglandin synthesis in cells with low rate of synthesis and low levels of peroxide

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23
Q

How is Acetaminophen different from an NSAID or
Aspirin?

A

It reduces fever and pain
-but it doesnt have the anti-inflammatory and antithrombotic effect

24
Q

When does Acetaminophen tend to inhibit COX-2?

A

When levels of Arachidonic are low
-> which is in the CNS
-> Acetaminophen works more in the CNS rather than peripheral

25
Q

Which CYP enzymes become active with chronic or high alcohol consumption?

A

MEOS (microsomal ethanol oxidizing systems)
-> Two of them are CYP2E1 and CYP3A4
-alcohol BAC above 0.1%

26
Q

What effect does MEOS have on Acetaminophen?

A

they convert Acetaminophen to toxic intermediates

27
Q

What converts toxic intermediates of Acetaminophen to non-toxic intermediates?

A

Glutathione-conjugation (GSH-conjugation)

28
Q

How does alcohol consumption cause liver toxicity?

A

alcohol depletes Glutathione, which is required to convert toxic intermediates into non-toxic intermediates

-the toxicity is actually seen with a very high acetaminophen dose and very high or chronic alcohol consumption

29
Q

Antidote for Acetaminophen liver toxicity

A

N-acetylcysteine
-> replesnishes glutathione

30
Q

How may Caffeine be involved in pain regulation?

A

-they are Xanthines

MOA:
-inhibit Phosphodiesterase (PDE converts the cAMP to AMP; cAMP is the signal molecule???)

-adenosine receptor antagonist on afferents (nothing to with pain? -> FYI: inhibitory -> the blockage causes a stimulatory effect)
-altering nociceptive pathways by blocking adenosine receptors

-some evidence of COX-inhibition

31
Q

Which NT receptors are involved in migraine?

A

Serotonergic receptors (5-HT-1F) across the brain
-also on trigermnial nerve terminal -> modualting the release of CGRP (neuropeptides causing pain and vasodilation)

32
Q

What is the effect that Serotonin receptors have on the release of CGRP?

A

5-HT receptors have an inhibitory effect
-> activation of the receptor will block the release of the CGRP (inflammatory peptides)

33
Q

MOA of Ergot alkaloids

A

5-HT1B/ 1D / 1F agonist
-vasoconstriction (1B)
-inhibition of CGRP release
-blockage of trigeminal nerve transmission

34
Q

Which form of Ergot alkaloids is a nasal spray, IV, IM, SC?

A

dihydroergotamine

-Ergotamine is sublingual only

35
Q

ADE and BBW of Ergot alkaloids

A

-GI (nausea, diarrhea)
-leg cramps
-serious CV risk and cerebral hemorrhage risks

BBW: serious interaction with CYP3A4 inhibitors and macrolides -> elevates ergot levels - ischemia risk (vasoconstriction)

36
Q

Which of the serotonergic receptors are thogut to cause vasoconstriction of the arterioles of the meninges?

A

1B on arterioles of the meninges

(5-HT-1B)
-> direct vasoconstriction when activated (agonized)
-> CGRP will cause vasodilation when binding on CGRP receptors on the arterioles

37
Q

Which of the serotonergic receptors are thogut to prevent release of neuropeptides (from trigeminal terminals) such as CGRP and cause inflammation?

A

1D/1F on presynaptic receptors
(5-HT-1D or 5-HT-1F)

by agonizing these receptors the release of neuropeptides (such as CGRO) is inhibited and vasodilation is blocked
-also decrease in pain transmission through the brain

38
Q

MOA of Triptans

A

Agonists of 5-HT- receptors (1B/1D/1F)

(5-hydroxytryptamine receptors)

Sumatriptan: is the first and most studied

39
Q

Which Triptan is useful for pateints who suffer from migraine-induced N/V?

A

Zolmitriptan
->it has an intranasal formulation

40
Q

What are the effects of the Triptans?

A

-direct vasoconstriction
-reduced release of the neuropeptides
-reduced pain transmission

41
Q

What are the common side effects of Triptans?

A

-dizziness
-parestheisa (sensation of tingeling)
-abnormal sensation
-rebound headache (when overused)

serious ADE:
-chest pain
-unilateral weakness
-changes in eyesight

42
Q

DDI with Triptans

A

Serotonin syndrome: other serotinon drugs
-MAOIs, Ergots

-CYP 3A4: almotriptan, eletriptan, naratriptan
-CYP 1A2: frovatriptan, zolmitriptan
-CYP 2D6: almotriptan

43
Q

Which drug only targets 5-HT-1F receptors?

A

Lasmiditan

-blocks neuropeptide release on the presynaptic receptor
-but does not cause vasoconstriction of the arteriole on the meninges

44
Q

Which patient population benefits from Lasmitidan?

A

-helpful in patients with CV risk, bc it bypasses the vasoconstriction effect
-Lasmitidan is not quite as effective

45
Q

Which drugs target CGRP receptors?

A

-gepants

Ubrogepant!
Rimegepant!
Olcegepant, Atogepant, Zavegepant

46
Q

MOA OF CGRP receptor antagonist?

A

blocking CGRP receptors on the blood vessels
->preventing vasodilation

blocking CGRP receptors on neurons
->block inflammation and pain transmission

ADE: somnolence, N/V

47
Q

What is the role of CGRP antagonists in therapy?

A

-some used for prophylaxis
-some for acute migrain or both
-cluster headache (similar pathophysiology as migraine)

48
Q

Which drugs are used for migraine prophylaxis?

A

non-selective ß-blockers (propranolol)
-antiepileptics: valproic acid, Topiramate
-Botulinum toxin type A
-Tricyclic antidepressants
-CGRP antibodies (expensive)

49
Q

Why Propranolol - what is their target?

A

Propranol is non-selective -> targeting ß1 and ß2

ß1 causes increased HR and contractility in the heart -> block it to reduce HR and contractility for HTN patients

ß2 causes vasodilation -> block it to reduce pain?
how does vasodilation cause migraine???

50
Q

How are ß-blockers thougt to help with migraine prophylaxis?

A

-Non-selective ß antagonists without intrinsic
sympathomimetic activity

-Blocks ß-mediated vasodilation
-May inhibit ϐ1 receptors in the thalamus
-May inhibit generators of migraine pain
-Inhibit firing of noradrenergic neurons in LC
-Serotonergic modulation

51
Q

How are antiepileptics thought to help with migraine prophylaxis?

A

-preventing hyperexcitability of the cerebral cortex
-> valporic acid, topiramate

52
Q

How does Botulinum toxin A (Botox) thougt to help with migraine prophylaxis?

A

a toxin produced by bacteria -> the toxin is a dichain peptide with a heavy and light chain

-the light chain contains a Zn-containing endopeptidase -> that cleaves synaptosomal protein (SNAP-25) responsible for vesicle docking on the presynaptic neuron
-> no release of neuropeptides (FYI in face-lifting: block of acetlycholine releas which would cause muscle contraction)
“FAILED EXOCYTOSIS”

53
Q

Which protein is cleaved by Botox?

A

SNAP-25

-on of the SNARE proteins that fuse and cause vesicle to bind to the membrane -> NT release into the cleft -> in this case CGRP, neurokinin A, substance P cant be released

54
Q

ADE of Botox

A

BBW: relaxing effect of muscles (blocking ACh) can spread, and swallowing and breathing difficulties can cause death

ADE: headache, respiratory infection, upper eyelid drop, nausea, difficulty swallowing

55
Q

Which monoclonal antibodies block the CGRP receptor?

A

Erenumab

56
Q

Which monoclonal antibodies block the CGRP molecules?

A

-Fremanezumab
-Galcanezumab
-Eptinezumab (IV)

->prevent CGRP from binding to CGRP receptors
->injectables: SC or IV, long-lasting (prophylaxis)

ADE: injection site reaction, hypersensitivity, constipation

Neurologic & Psych (37 decks)

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