Headache Drugs Flashcards
How is kallidin formed? Bradykinin?
LMW kinogen –> kallidin via tissue kallikrein
HMW kinogen –> bradykinin via plasma kallikrein
How is kallidin converted to bradykinin?
Aminopeptidase
How is bradykinin formation linked to the clotting cascade?
- XIIa increases the formation of plasma kallikrein
- plasma kallikrein induces conversion of XII –> XIIa
positive feedback loop
By what (2) enzymes are kinins metabolized?
Kininase 1 (carboxypeptidase M/N) converts to active metabolites
Kininase 2 (ACE) converts to inactive metabolites
The prefix “des-arg” denotes?
An active kinin metabolite
Effect of ACEi on bradykinin?
INCREASES Bradykinin by preventing metabolism to inactive compounds via kininase 2 (ACE).
Differences between B1/2 kinin receptors:
+ (2) commonalities
Both are G protein coupled
Both cause ^NO/PG/EDHF
B1: binds active metabolites; present only in damaged tissue
B2: binds native kinins; always expressed
In what three ways do bradykinins induce pain? (3)
- ^ CGRP = Trigeminal vasodilation (migraine***)
- ^ neurokinins
- ^ substance P
How do bradykinins effect
1) microcirculation
2) pulmonary system
3) blood pressure
Microcirculation increased permeability = edema
Bronchospasm
Vasodilation = hypotension
Bradykinins increase prostaglandins.
What are two very common drugs that DECREASE prostaglandins?
What are their MOAs?
NSAIDs: inhibit COX (AA –> PG)
Corticosteroids: increase lipocortin (inhibits PL –> AA)
Kinins:
Classification
+ 3 general effects
Autocoids
Inflammation, pain, vasodilation
Serotonin is stored in platelets.
Why can serotonin be stored without appreciable metabolism?
In what (2) ways does serotonin mediate platelets’ effects?
- Serotonin is metabolized by MAO-A; platelets selectively express MAO-B
- Promotes vasoconstriction + aggregation
Effects of serotonin on CV and GI systems:
What GI system cells release serotonin?
^^ activity in both systems (increased HR; increased motility)
*enterochromaffin cells express serotonin in GI tract
2 Common symptoms assc with serotonin secreting carcinomas:
Diarrhea, abdominal cramping b/c serotonin causes increased GI motility
Urinary metabolite of serotonin?
When is it elevated?
5-hydroxyindolacetic acid (5HIAA)
Increased during active migraine episode
Effects of 5HT1b and 5HT1d receptors?
What drug class selectively targets these serotonin receptors?
For what are they most commonly used?
1d: vasoconstriction of cranial vessels (undoes vasoDilation)
1b: decreased Trigeminal nociception
Triptans select 5HT1b/d; used in acute migraine rescue
What does the pneumonic POUND stand for?
P-pulsatile O- 4-72 hOurs U- unilateral N- nauseating D- debilitating
4 stages seen in migraine attack?
What does the first stage involve?
Prodrome (GI/mood changes)
Aura
Attack
Postdrome
Propranolol/ Atenolol
1) MOA
2) Use in HA treatment
3) Contraindication
B1 AND 2 blockers
Migraine Px
Asthma (B2 = bronchodilator)
Amitriptylline/ Nortryptilline
1) MOA
2) Use in HA treatment
3) Common ADR
4) Contraindication
1) TCAs ( ^NE, 5HT)
2 )Migraine Px especially in patients that w/ frequent HA or trouble sleeping
3) anti-muscarinic fx (dry mouth, constipation, etc)
4) never use in patient with risk of suicide
Levitiracetam drug class?
Anti-epileptic
Valproic Acid, Levitiracetam, Gabapentin, Topirimate
1) Drug Class
2) MOA
3) Use in HA treatment
4) Which is a pregnancy X drug?
1) Anticonvulsants
2) ^ GABA
3) Migraine Px esp in cases of comorbid anxiety/epilepsy
4) never use valproic acid in pregnancy. Strong teratogen.
Verapamil
1) MOA
2) 3 uses
Ca Channel Blocker
HTN; migraine Px; cluster Px
Cyproheptadine
1) MOA
2) Uses (2)
3) Common ADR
1) histamine, serotonin and Ach antagonist
2) Migraine Px and Seasonal allergies
3) sleepiness
How is ketorolac (NSAID) used in the treatment of migraines?
IV administration
Usually in the ER for rescue from severe migraine
What two drugs treat migraine in children?
OTC acetaminophen and ibuprofen
When shouldn’t NSAIDs be used for migraine rescue? Why?
During third trimester of pregnancy
Cause premature closure of the ductus arteriosus + bleeding risk
Ergotamine/dihydroergotamine
1) MOA
2) Use
3) Three ADR/ contraindications
1) non specific serotonin agonist
2) Migraine rescue
3) causes nausea, vasoconstriction, and is pregnancy X
How is ergotamine administered?
Dihydroergotamine?
With what drugs should these never be combined?
Ergotamine = sublingual
Dihydroergotamine = SC/IM/IV, nasal spray
Never administer with triptans or SSRI
In what way are triptans better for migraine rescue than ergots?
Less nausea and vasoconstriction
Triptans should not be combined with what drugs?
SSRIs; ergots –> 5HT STORM!
Rank the t1/2 of: Naratriptan Sumatriptan Zolmitriptan Frovatripran
Sumstriptan + others = short
Frovatriptan = FROever (longest)
Which triptan drug has the highest affinity for the serotonin receptor and is most $$$?
Frovatriptan, also has longest t1/2
Rizatriptan:
1) ROA
2) metabolism
1) sublingual
2) Rapid onset, t1/2= 2hrs
Which of the triptans should be carefully monitored in renal patients (2)? Why?
Naratriptan
Zolmitriptan
*50% drug excreted unchanged via renal system
How are Nara and zolmitriptan metabolized?
P450, but 50% renally excreted unchanged
Two rescue treatments for cluster HA:
O2»_space;»>
Triptans
3 Px treatments for Cluster HA:
Prednisone
Verapamil
Lithium
Tension HA treatment
2 rescue
2 Px
Rescue: NSAIDs and acetaminophen
Px: TCA/ Gabapentin
Acetazolamide and Topirimate may both be used to treat what condition?
What is their mechanism of action?
Treat IIH
Both inhibit carbonic anhydrase and CSF production
When do we need to avoid SSRIs/ Ergots?
When giving triptans
