Treatment of Headache

Question 1

Bradykinin and Kallidin

Answer 1

kinins are autocoids that induce inflammation, pain, and vasodilation

Question 2

Synthesis of kinins

Answer 2

Kininogens –> Kvllikrein –> Kinins

Kininogens are precursors of kinins

Kallikreins are serine proteases that cleave kininogens into kinins

Question 3

High Molecular Weight Kininogen

Answer 3

cleaved by plasma kallikrein into bradykinin

Question 4

Low Molecular Weight Kininogen

Answer 4

cleaved by tissue kallikrein into kallidin

kallidin then cleaved by aminopeptidase into bradykinin

Question 5

Positive Feedback Loop of Kinin forming system

Answer 5

Auto activation of factor XII
Factor XII activates Plasma Kallikrein
Plasma Kallikrein converts HMWK to Bradykinin
Plasma Kallikrein activates factor XII

Question 6

Carboxypeptidase N and M

Answer 6

metallopeptidases that cleave kinins into active kinin metabolites

Question 7

ACE

Answer 7

hydrolyzes bradykinin into active products

ACE inhibitors increase bradykinin

Question 8

Kinin Receptors

Answer 8

B1 and B2 are GPCRs; activation stimulate increase in synthesis of prostaglandins, NO, and EDGF
B1 activated by bradykinin and kinin active metabolites: induced by tissue damage and inflammation
B2 activated by native bradykinin and kallidin: expressed in most tissue

Question 9

NSAIDs

Answer 9

reduce bradykinin and kallidin induced increases in PG production by inhibiting COX

Question 10

Corticosteroids

Answer 10

reduce bradykinin and kallidin induced PG production by stimulating increases in Lipocortin (phospholipase A2 inhibitor)

Question 11

Effects of Kinins

Answer 11

pain: induce excitation of sensory neurons, inducing release of neuropeptides, substance P, neurokinins and CGRP
inflammation: increase permeability of microcirculation, promote edema
respiration: induce bronchospasms
cardiovascular: induce vasodilation and lower BP

Question 12

CGRP

Answer 12

the most potent vasodilator peptide in the trigeminal system

Question 13

Serotonin

Answer 13

not synthesized by platelets, but taken up and stored by them
promote platelet aggregation and vasoconstriction, positive inotropic and chronotropic
inactivated by MAO-A (platelets only possess MAO-B)
Urinary metabolite = 5-HIAA

Question 14

Enterochromaffin cells

Answer 14

release 5-HT in response to vagal stimulation and stretching with food

Question 15

5-HT1D receptors

Answer 15

induce vasoconstriction of cranial blood vessels

Question 16

5-HT1B receptors

Answer 16

autoreceptor activation of it inhibits nociceptive trigeminal afferents

Question 17

Triptans

Answer 17

5-HT1B/1D agonists that control/reverse acute migraines

Question 18

Prophylactic Treatment of Migraines

Answer 18

Beta Blockers
TCAs
Anticonvulsants
Calcium Channel Blockers
Cyproheptadine

Question 19

Beta Blockers

Answer 19

Propranolol and Atenolol
3 weeks to be effective
Mechanism unclear
Side Effects: reduced energy, tiredness
Don't use in patients with asthma

Question 20

TCAs

Answer 20

Amitriptyline and Nortriptyline

Side Effects: significant antimuscarinic, weight gain, tiredness

Question 21

Anticonvulsants

Answer 21

Valproic Acid, Topiramate, Gabapentin, & Levetiracetam
Increase in GABA signaling

Don’t use valproic acid if pregnant because teratogenicity
Side Effects: drowsy, anorexia, nausea, ataxia, alopecia, liver toxicity, tremor

Question 22

Calcium Channel Blockers

Answer 22

Verapamil
reduces incidence of migraine
Side Effects: negative inotropic and hypotension

Question 23

Cyproheptadine

Answer 23

potent antagonist of histamine, acetylcholine, and serotonin

Side Effects: high incidence of CNS depression and sleepiness

Question 24

Rescue/Abortive Agents for Migraine

Answer 24

NSAIDs
Ergot Alkaloids
Triptans

Question 25

Ergot Alkaloids

Answer 25

Ergotamine and Dihydroergotamine
Use: moderate to severe migraine attacks
combine it with an antiemetic to curve nausea
Mechanisms: agonist effects at 5-HT1
Ergotamine - Sublingual
Dihydroergotamine - Nasal, SC/IM/IV
Side Effects: Nausea, Vomiting, Vasoconstriction
Contraindications: Pregnancy, Peripheral Vascular Disease, Ischemic Heart Disease, DO NOT USE WITH TRIPTANS

Question 26

Triptans

Answer 26

Sumatriptan, Rizatriptan, Zolmitriptan, Naratriptan, Frovatriptan
significantly less nausea and vasoconstriction compared to Ergot
Selective 5-HT1B/D receptor agonist
Side Effects: Headache recurrence, tingling, paresthesias, dizziness, flushing, neck pain, drowsiness
Contraindications: Ergot within 24 hours, peripheral vascular disease, ischemic heart disease, SSRIs (would lead to serotonin syndrome)

Question 27

Sumtriptan

Answer 27

prototype, short onset, short duration, SC/PO/nasal spray, relief within 1 hour, half life 2 hours
PO>Nasal>SC onset of action
low bioavailability, short half life

Question 28

Naratriptan and Zolmitriptan

Answer 28

PO onset 1 hour, lipophilic, greater bioavailability, more effective, longer duration, P450 metabolism, 50% excreted unchanged, lower the dose in renal dysfunction

Question 29

Frovatriptan and Rizatriptan

Answer 29

Frova - Longest acting, half life = 24 hours, highest affinity for 5HT1B receptor, slower onset
Riza - sublingual, fastest onset, less nausea, half life 2 hours, metabolism MAO

Question 30

Acute Treatment for Cluster Headache

Answer 30

Oxygen, Triptans (rapid onset)

Question 31

Prophylaxis for Cluster Headaches

Answer 31

High Dose prednisone, Calcium channel blockers

Question 32

Abortive Medications for Tension Headaches

Answer 32

Acetaminophen and NSAIDs

Prophylaxis - TCAs and Gabapentin

Question 33

Treatment of Idiopathic Intracranial Hypertension

Answer 33

Acetazolamine and Topiramate which are carbonic anhydrase inhibitors to reduce CSF production