Pharmacotherapy of HAs-french Flashcards
Medication overuse HA can result from _______
overuse of analgesics in tx of migraine or tension headache
Medication overuse HA is defined as a dull or migraine-like HA that occurs at least ____ days/month
15 days/month
Ex’s of Risks for developing medication overuse HA:
-highest risk associated with which medication clas?
-lowest risk assoc. with ?
1 in 25 over use pain meds–> 1 in 4 of these –>MOH
High risk: butalbital combos, ASA-acetaminophen-caffeine, opioids
Moderate: -triptans, ergot alkaloids
Low: NSAIDs
Preventative measures for medication overuse HA
- Restrict drug use (per attack - per week - per month)
- Initiate prophylactic therapy as necessary
Describe the Simplified Pathophysiology of Migraine(with or without aura)
Trigeminal Neurovascular Dysfunction–>
- Trigeminal Neurovascular Activation–>
- Release of Vasoactive Peptides (CGRP)–>
- Neuroinflammation (including PG release)
- Vasodilation of Pial and Dural Vessels–> Mod to severe pain***
Target of NSAID analgesics–>
COX-2 inhibitors
Target of triptans-ergot alkaloids=
5HT 1B-1D agonists
Role of Spreading Cortical Depression= (describe)
=self-propagating wave of neuronal and glial depolarization hypothesized to:
–Cause the aura of migraine
–Activate trigeminal afferents
–Alter BBB permeability via changes in metalloproteinases
Role of Trigeminovascular System=
sensory neurons that project to cerebral and pial vessels and to dura mater
–Activation releases vasoactive peptides (SP-CGRP)–> Neurogenic inflammation–> Vasodilation and plasma protein extravasation
________ has role in prolongation and intensification of migraine pain (sensitization)
Inflammation
Role of Sensitization: likely responsible for many migraine clinical symptoms
–list ex’s of some of these clinical sx
Throbbing quality of pain
Worsening of pain with coughing-bending-sudden head movements
Hyperalgesia
Allodynia
Role of Serotonin (5-HT):
agonists of 5HT receptors are an important component in ____ treatment
**Acute–BUT role in generation of migraine unclear
slide 8
?
Neurotransmitter in diffuse CNS systems that has a role in migraine pathophysiology and is a primary target for pharmacotherapy:
?
serotonin
Pt with severe HA symptoms presents to the ED–> with N/V:
-treatment?
-SC sumatriptan
IV metaclopramide (or prochlorperazine)
+diphenhydramine for **dystonia ADRs
Which of the following would be a reasonable choice for initial treatment of a mild migraine attack without nausea or vomiting in a 28-year-old nonpregnant woman?
- Acetaminophen
- Butalbital/acetaminophen/caffeine
- Oxycodone/acetaminophen
- Ergotamine
A. acetaminophen or an NSAID
The drug of choice for treatment of moderate to severe migraine is:
- Aspirin
- A triptan
- An ergot
- Onabotulinum toxin A
triptan
“Triptans” (5HT1B/D Agonists) - Sumatriptan:
-MOA in migraine? (3 things)
- Cerebral vasoconstriction –> reverse dilation-induced HA
- Inhibit neuropeptide release–> DECREASES vasodilation, pain, neuroinflammation
Prevent activation of pain fibers in trigeminal nerves
T/F: do triptans differ in onset and duration?
YES.
-sumatriptan: onset=30-60 min, and 3-4 hr duration
Orally administered short-acting triptans have an onset of action of about:
- 5-10 minutes
- 15-30 minutes
- 30-60 minutes
- 60-90 minutes
30-60 min
Which of the following triptan formulations has the fastest onset of action?
- Almotriptan tablets
- Naratriptan tablets
- Zolmitriptan nasal spray
- Frovatriptan tablets
Zolmitriptan nasal spray (10-15 min)
Compared to oral sumatriptan, the subcutaneous formulations:
?
Triptans: ADRs?
(are they well tolerated?
- Generally well tolerated if no CVS conditions and 24 hr limits observed - **pregnancy category C
- Paresthesias, flushing, dizziness, drowsiness, chest tightness (increased with sumatriptan)
- **Rarely: coronary vasospasm, angina, MI, arrhythmia, stroke, death
Triptans: DDIs
-Additive vasoconstriction with ________
-ergot alkaloids
-
Triptans: DDIs
-Increased risk of serotonin syndrome** with ______ - risk very much less with SNRIs-SSRIs
MAOIs
-**Neuromuscular effects (clonus), ANS changes, mental status changes (agitation, delirium, hypervigilance
“Ditans” (5HT1F Agonists): Lasmiditan
-MOA in migraines?
-5HT1F Agonist
–>Similar to triptans, but selective agonist activity on 5HT1F receptors
Unlike triptans, use is NOT contraindicated in patients with vascular disease
No direct comparisons with triptans or “gepants”
“Ditans” (5HT1F Agonists) - Lasmiditan
- Absorption?
- metabolism?
Absorption: given orally reaches a Tmax at 1.8 hrs
Metabolism: Via hepatic and extra-hepatic enzymes primarily by non-CYP enzymes - half-life ~ 6 hours
Lasmiditan ADRs are _______ related
-list ex’s of ADRs?
**incidence is dose-related
CNS-related S/E MC: dizziness, sedation and paresthesias
- Label warning against driving or operating machinery for at least 8 hours after taking drug
- Decreases in heart rate have occurred – use with caution with other HR-lowering drugs
Lasmiditan: DDIs ?
-caution in concomitant used of _______
- alcohol or other CNS depressants
- Use with other serotonergic drugs may increase risk for serotonin syndrome
“Gepants” (CGRP Receptor Antagonists)
Urbegepant - Rimegepant: MOA in migraines?
- ->Small molecule antagonists that bind to calcitonin gene-related peptide (CGRP) receptor
- -CGRP is a neuropeptide widely distributed but especially common in trigeminal ganglia
- -Potent vasodilator and pain-signaling transmitter
Are geptants more effective than triptans?
NO, they are less effective than triptans, BUT they can be used in Pts with vascular disease
–Rimegepant is also approved for migraine prevention given every other day
“Gepants” (CGRP Receptor Antagonists)–>Urbegepant/ Rimegepant
- Given orally–> they begin reducing migraine pain within _____ min
- half-life?
-60 min
Half-life: rimegepant ~ 11 hours – urbogepant ~ 6 hours
Metabolized by CYP3A4 – avoid use with inhibitors or inducers; also P-glycoprotein substrate
“Gepants” (CGRP Receptor Antagonists)–>Urbegepant/ Rimegepant
-ADRs?
generally well-tolerated
Nausea and somnolence in less than 5% of patients
-NOT associated with medication overuse headache
Ergot Alkaloids - Ergotamine-DHE
MOA in Migraine?
=5HT1B/D Agonist
- Similar to triptans, somewhat less effective, affect multiple receptors
- **More toxic - NOT first-line
- Try if no response to triptans, prolonged attacks, or frequent recurrence
Pharmacokinetics: Ergotamine
oral absorption?
Ergotamine: Oral (INCREASED absorption w/caffeine) - SL - PR; long duration
Dihydroergotamine: Intranasal-parenteral; rapid and reliable onset
Ergot Alkaloids: ADRs?
- Nausea / vomiting (give w/antiemetic), diarrhea, cramps, paresthesias
- Serious effects: vascular occlusion and gangrene (strict dosage limits)
- **Mediated via α1 adrenergic vasoconstriction
Ergot Alkaloids: DDIs ?
-SEVERE peripheral ischemia can occur if used with _______
non-selective (β1-β2) beta-blockers
Which of the following statements is true?
- The combination of ergotamine and caffeine is safer and more effective than a triptan for acute treatment of migraine
- Patients who do not respond to a triptan alone should take both a triptan and an ergot
- Dihydroergotamine may be effective in some patients who do not respond to a triptan
- All of the above
-Dihydroergotamine may be effective in some patients who do not respond to a triptan
A 35-year-old woman with severe episodic migraine attacks with nausea and vomiting asks about switching from sumatriptan oral tablets to the nasal spray formulation. You should tell her that:
- Intranasal sumatriptan generally starts relieving pain in about 10-15 minutes
- Intranasal sumatriptan can have an unpleasant taste
- Sumatriptan nasal spray is partially absorbed in the GI tract, and absorption of the drug could be reduced in patients with vomiting
- All of the above
ALL the above
Which of the following drugs should not be used for treatment of migraine in patients with vascular disease?
Lasmiditan Zolmitriptan Ubrogepant Ibuprofen All of the above
Zolmitriptan??
Non-Opioid Analgesics[tNSAIDs)
-list Ex’s
-Acetaminophen-Celecoxib-Aspirin]
NSAIDs MOA in migraines?
**Inhibition of COX-2
Interrupts neuroinflammatory pathway initiated by release of CGRP (Calcitonin Gene-Related Peptide)
May be sufficient for migraines of mild-moderate intensity
Therapy for migraine prevention would be considered if:
Headaches are severe
Headaches don’t respond to opioid therapy
Patient cannot tolerate NSAIDs
Patient has a contraindication to acute vasoconstrictor therapy
Headaches last longer than 2 hours
Headaches are disabling
??
NSAIDs:
-which form is used most often>
Oral route used most commonly – indomethacin available as suppository
Durations of action range from 4-6 to 8-12 hours
Non-Opioid Analgesics (tNSAIDs): ADRs?
which Pts should avoid them?
Generally well tolerated
–Should be avoided in patients with acute gastritis, peptic ulcer disease, renal insufficiency, or bleeding disorders
Non-Opioid Analgesics (tNSAIDs): DDIs?
-increased bleeding risk in Pts receiving _______
antiplatelet agents (clopidogrel-prasugrel) or anticoagulants (warfarin)
Isometheptene MOA: ?
Elicits sympathomimetic effect; constricts dilated cerebral/cranial arterioles
Dichloralphenazone MOA?
Elicits mild sedative effect; reduces emotional response to painful stimulus
Acetaminophen MOA?
Inhibits prostaglandin synthesis in CNS - decreases sensitization
When are prophylactic meds indicated for Pts suffering from migraines?
-If migraines are severe, frequent (> 4/month), long lasting (> 12 h), or disabling**
Drug factors that may indicated the need for a Pt to be started on Prophylactic meds for migraines
Failure or overuse of acute therapies
Contraindications to vasoconstrictor therapies
Occurrence of adverse drug events
Prophylactic Management of Migraines: MOA
- which meds are TOC?
- how much time is needed before effects are seen?
no single medication as treatment of choice
**Generally requires 3-4 weeks for benefit
Trial of 4-6 weeks recommended before switching
Migraines may improve independent of treatment - consider slow taper off if good control
Therapy for migraine prevention would be considered if:
Headaches are severe
Headaches don’t respond to opioid therapy
Patient cannot tolerate NSAIDs
Patient has a contraindication to acute vasoconstrictor therapy
Headaches last longer than 2 hours
Headaches are disabling
?
For migraine prevention, beta blockers should be used with caution or not be used at all in patients who have:
Asthma
Depression (comorbidity - may be aggravated)
Decompensated heart failure
All of the above
All of the above
What role does BP have in migraine tx?
BP treatment appears to reduce the overall prevalence of headaches –> likely to be effective for migraines also
which BBs are approved for prophylactic tx of migraines?
Beta blockers - **propranolol-timolol FDA-approved for prophylaxis (metoprolol-atenolol-nadolol also used)
- BBs are commonly used for continuous prophylaxis
- **Propranolol reduces frequency and severity of migraine in 60-80% of patients
- Less enthusiasm for use in patients >60 yo or smokers
Which CCB can be used for migraine prophylaxis tx?
verapamil, diltiazem, nifedipine
**Verapamil MC used, evidence for effectiveness is limited
ACEIs [lisinopril] / ARBs [candesartan]–> Small studies show decrease in migraine frequency
which TCAs are approved for tx of migraines?
- **Amitriptyline, venlafaxine (SNRI), nortriptyline
- Postulated mechanism in migraine is uncertain
- [?] Enhancement of monoamine neurotransmission in brain pain pathways
- Can prevent migraine in some Pts and may be given concurrently with other prophylactic meds
About what percentage of patients achieve a ≥ 50% reduction in migraine headache frequency when taking topiramate or valproate for migraine prevention?
20%
50%
75%
90%
50%
which anticonvulsants are FDA approved for migraine proph?
**Valproate and topiramate – FDA approved for migraine prophylaxis (gabapentin also effective)
- Postulated mechanism in migraine is uncertain - [?] alteration of neuronal transmission in CNS
- Reduce migraine frequency by > 50% in 50% of patients - similar to propranolol
Erenumab (Aimovig®) - new in 2018
-MOA?
=Human monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) receptor
-CGRP is a neuropeptide widely distributed but especially common in trigeminal ganglia
–Potent vasodilator and pain-signaling transmitter
-*Once-monthly SC injection reduces migraine frequency - may be effective when other therapies failed
Erenumab (Aimovig®):
-Adverse effects?
similar to placebo
Injection site reactions (5-6%) - constipation (1-3%)
Long-term efficacy and safety unknown, esp. in patients with cardiac risk factors
A 31-year-old woman with a history of frequent severe migraine attacks has been taking valproate for 3 years for migraine prevention. She tells you that she is planning to become pregnant in the near future. You should:
- Increase her dose of valproate because serum levels of the drug decrease significantly during pregnancy
- Switch her to topiramate because it is safer for use during pregnancy
- Switch her to dihydroergotamine nasal spray taken once weekly during pregnancy
- Discontinue valproate because it can cause congenital malformations
Discontinue valproate because it can cause congenital malformations
Botulinum Toxin Type A (Botox®):
-can this be used for migraine tx?
**Recent evidence trials supports use in chronic migraine if ≥ 15 HA days per month, lasting at least 4 hours
-2nd line agent, high cost
Botulinum Toxin Type A (Botox®): Adverse effects?
Headache, neck pain
Generalized muscle weakness, drooping eyelids
Category C in pregnancy
Nonsteroidal Anti-inflammatory Drugs (NSAIDs):
- Ex’s for migraine tx?
- used for _______
Naproxen and flurbiprofen
-**Short-term prevention of migraine (e.g., menstrual migraine), as well as for aborting acute attacks
Methysergide (limited availability in U.S.): what is the MOA?
Serotonin receptor antagonist - 5HT2 blocker
Blocks serotonin-mediated vasoconstriction that initiates the migraine attack
Role in refractory migraine with high attack frequency
Effective, but side effects and insidious toxicity limit use (reserved for severe cases if other drugs not effective)
Agents that can be used for migraine headache prophylaxis include:
Amitriptyline Botulinum toxin type A Sumatriptan Lisinopril Verapamil Dihydroergotamine Ibuprofen Diphenhydramine Valproic acid
Amitriptyline?
