L 16 Migraines and Gout Flashcards
What is the mechanism of injury in Gout?
Uric acid is poorly soluble in water and therefore precipitates out in the form of crystals. This happens especially in the joints. Synoviocytes in the joint phagocytose the crystals and secrete cytokines that attract PMNs and macrophages which release inflammatory mediators and cause inflammation through PG’s, IL-1, LTB4
What is the general goal in treating gout?
The goal is to prevent and reduce the inflammation that is causing the symptoms. This is done by preventing phagocytosis of crystals and preventing the formation of PGs and other mediators of inflammation.
Treatment strategy for acute gout attacks
1) NSAID’s to reduce the inflammation and to help with the pain
2) Colchicine
Long term treatment strategies for gout
Uricosuric agents: to increase excretion
Xanthine Oxidase inhibitors to reduce the amount of uric acid produced
Enzymes that convert uric acid to allantoin
Glucocorticoids to reduce the inflammatory mediators
Colchicine
Used for treatment of acute gouty attacks
Has no analgesic and no COX effects
Binds to tubulin and prevents microtubule formation which prevents phagocytosis
Also prevents LTB4 formation which prevents chemotaxis for leukocyte migration
Takes 12-24 hours for effect because must wait for already present mediators and cytokines to be metabolized.
Major side effect is diarrhea
Uricosuric agents
Used for the long term maintenance of gout.
Mechanism: work like ASA in that they block the acid transporters in the kidney. Initially, may cause a gout attack by decreasing uric acid secretion, but once drug levels reach steady state, they block the active transport reuptake of filtered acid and cause increased excretion.
Can also cause kidney stones.
Do not give this drug during an active attack, but after acute case has passed. Also, give Colchicine prophylactically to reduce chance of causing gout attack while dosing up.
Primary side effect is GI irritation. Has many drug interactions because it blocks the reuptake of acid from the kidneys.
Probenacid
Uricosuric agent
Can decrease excretion of acidic agents
Where does uric acid come from?
Purines in nucleic acids are broken down and produce uric acid.
Purine => Hypoxanthine => Xanthine (by xanthine oxidase) => uric acid
Purines come from anything that you eat that contains nucleic acids. Red meat has lots, mutton has more. But plants and anything with cells and nuclei have it.
Allopurinol
Inhibits the synthesis of uric acid by competitively binding to xanthine oxidase and then its metabolite irreversibly binds the enzyme do disable it.
It is similar enough to uric acid that it can compete for transport in the kidney and cause a gout attack so colchicine prophylaxis may be necessary.
Febuxostat
Xanthine oxidase inhibitor used for long term treatment of gout
Similar in action to Allopurinal
Drug interactions of Allopurinol and Febuxostat
Aluminum Hydroxide decreases the absorption of allopurinol
Increases the effects of chemotherapeutic mercaptopurines 6-MP and azathioprine
Inhibits activation of fluorouracil (5-fu) reducing it’s therapeutic effects
Rasburicase
Recombinant form of urate oxidase from an animal. Can therefore only be used once.
Mechanism: breaks down uric acid into allantoin which can be excreted by the kidneys.
Patients with hematologic and solid tumors can have tumor lysis syndrome from rapid killing of cancer cells => hyperuricemia
Hypersensitivity can be a problem because it is not a human enzyme
Pegloticase (Krystexxa)
Mammalian urate oxidase enzyme converts uric acid into allantoin which is easily excreted by the kidney
Briefly describe the 3 basic types of headaches
Migraine: unilateral, pulsating/throbbing, may have aura, light and sound intolerance, nausea/vomiting, more common in females, lasts 2-72 hours, responds to -triptan medications
Cluster: males>females, often onset at night, behind the eye, sharp pain, lasts up to 90 minutes
Tension: onset from stress, females>males, lasts 30min-7days, bilateral like a band around the head, dull persistent ache
Underlying cause of migraines
Thought to be due to initially reduced blood flow to posterior part of the brain, followed by vasodilation and release of neuroactive molecules like substance P => pain
