Lecture 18: Treatment of Gout and Migraines

Terminate the inflammatory process of an acute attack of gout

NSAIDs

Glucocorticoids - prednisone/prednisolone

Colchicine

Reduce hyperuricemia to prevent the formation of urate deposits and acute attacks of gouty arthritis; long-term prophylaxis

Allopurinol

Febuxostat

Probenecid

Pegloticase

Rasburicase

Anakinra

NSAIDS

First line drug, acute management

MOA: COX 1 and 2 inhibition; NSAIDS also inhibit urate crystal phagocytosis

Naproxen is the primary NSAID used in the treatment of gout

indomethacin, celecoxib also often used

Very effective for inflammation of acute gouty arthritis

Aspirin is contraindicated → decreases urate excretion at low dose

Colchicine

first-line drug, acute management

Uses: reduce pain and inflammation of an acute attack, used prophylactically

MOA: Binds to tubulin; inhibits the assembly of microtubules, esp in leukocytes

Produces its anti-inflammatory effect by inhibiting leukocyte migration and phagocytosis of UA crystals

Has no analgesic effect, no effect on COX enzymes, no effect on urate excretion

Oral (IV: increased toxicity)

Adverse effects: diarrhea, nausea and vomiting, abdominal pain, hair loss, hepatic necrosis

Uricosuric agents Side Effects

large urine volume maintained to minimize possibility of kidney stone formation

Keep urine pH above 6.0 (UA more ionized)

Initial administration could trigger a gouty attack – some agents eliminated by OAT, competing for UA excretion

consider prophylactic colchicine or NSAID

Allopurinol

Preferred for gout

purine derivative which inhibits xanthine oxidase to inhibit uric acid synthesis

Initially, may provoke acute gouty attack (competes with uric acid active transport)

Adverse effects: hypersensitivity (HLA B*5801), nausea, vomiting, vasculitis, agranulocytosis

Used long term

Aluminum hydroxide (antacid) decreases the absorption of allopurinol

Febuxostat

purine derivative which inhibits xanthine oxidase to inhibit uric acid synthesis

history of CV disease have a higher rate of CV death

Probenecid

Inhibits OAT and URAT1 → Reduced urate reabsorption, Increases uric acid excretion

Net reabsorption of uric acid in the proximal tubule is decreased (uricosuric)

Start 2-3 weeks after an acute attack

Adverse effects: nausea, sore gums, loss of appetite, dizziness, headache, vomiting, frequent urination, flushing, hepatic

Decreases excretion of many acidic compounds

Pegloticase

pegylated recombinant form of urate oxidase that converts uric acid to allantoin, a readily excreted metabolite

IV

last resort drug

Prior to treatment:

4 weeks prior: premedicate with methotrexate and folic acid

Screen G6PD deficiency

During treatment: Antihistamines, corticosteroids, methotrexate

Adverse effects: hypersensitivity, nausea, fatigue, constipation

Contraindicated: G6PD deficiency – hemolysis, methemoglobinemia

Migraine Acute Treatment

Seratonin Receptor agonists: Sumatriptan + Lasmiditan

CGRP Antagonists: Ubrogepant and Rimegepant

Ergot Derivatives: Ergotamine + Dihydroergotamine

Migraine Prophylaxis

Erenumab

Atogepant

Rimegepant

Sumatriptan

First line therapy - Symptomatic acute treatment for migraine headache

5-HT1D/1B receptor agonists acting on small peripheral nerves → normalizes CGRP levels

Duration of action shorter than typical migraine, requires additional dose(s)

Can be combined with naproxen

Sumatriptan Side Effects

Mild, altered sensations (tingling, warmth), dizziness, muscle weakness, neck pain

Abdominal pain, bloody diarrhea, and cramping

Coronary artery vasospasm, cardiac arrhythmias, ventricular tachycardia, angina, transient mycoardial ischemia, myocardial infarction and cardiac arrest and death

Cerebral vasospasm resulting in intracranial bleeding, subarachnoid hemorrhage, stroke, seizures, vascular ischemia

Sumatriptan Contraindications

Pregnancy, breast-feeding

Monoamine oxidase inhibitors – serotonin syndrome

Cardiac disease, coronary artery disease, peripheral vascular disease, hypertension, cerebrovascular disease

Diabetes mellitus, renal impairment, epilepsy, tobacco smokers

Lasmiditan

effective agent for migraine (acute attacks)

5-HT1F receptor agonist

lacks vasoconstrictor activity - can be used for patients with relative contraindications to triptans due to CV risk factors

Adverse effects:

dizziness

CNS depression – refrain from driving, operating heavy machinery (8h post admin)

Seratonin syndrome

Ubrogepant

Calcitonin gene-related peptide (CGRP) receptor antagonist

treat the acute symptoms of migraine (w/ nausea and light sensitivity)

Adverse effects: dry mouth, drowsiness, nausea

Metabolized by CYP3A4

Rimegepant

Calcitonin gene-related peptide (CGRP) receptor antagonist

Uses: treat the acute symptoms of migraine and prophylaxis (up to 18 doses/month)

Adverse effects: nausea, abdominal pain

Ergotamine

effective agent for migraine (acute attacks)

most effective if administered early

Caffeine increases absorption

Partial agonist on 5-HT 1B/D receptors on intracranial blood vessels; partial agonist on alpha-1 receptors – powerful vasoconstrictor

Side effects: Vasoconstriction, vasospasms, erythromelalgia, uterine smooth muscle stimulant

Acute: diarrhea, nausea, vomiting, cardiovascular toxicity

Contraindicated in pregnancy (increased risk preeclampsia and constriction of uterine vessels)

Avoid in patients with peripheral vascular disease (atherosclerosis, severe hypertension, ischemic heart disease)

Dihydroergotamine

less vasoconstrictive

Erenumab

migraine prophylaxis in adults

IgG2 human monoclonal antibody; blocks CGRP receptor complex

Injected once/month

Adverse effects: Injection site reactions (pain, erythema, and pruritus)

Avoid use in pt with recent cardiovascular or cerebrovascular ischemic events

Atogepant

migraine prophylaxis in adults

CGRP receptor antagonist

Metabolized by CYP3A4

excreted in renal

Adverse effects: nausea, constipation, fatigue

Metabolized by CYP3A4

Ubrogepant

Atogepant