Drug Therapy of Gout

What Is Gout? A medical condition caused by an increase in the level of uric acid >> urate crystals , causing inflammatory responses around some joints of the body ( Gouty arthritis )

Case presentation ( Gouty arthritis) 55 y/o male 12 hours “pain in my big toe & ankle” went to bed last night feeling fine felt as if had broken toe this morning PMH of similar problems in right ankle & left wrist

acute synovitis, ankle & first MTP joints Gout - acute arthritis acute synovitis, ankle & first MTP joints Redness and swelling are noticed around those joints in particular The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

Gout - acute bursitis acute olecranon bursitis Bursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone

Gouty arthritis - characteristics sudden onset middle aged males severe pain distal joints Intense inflammation recurrent episodes influenced by diet ( since uric acid level is influenced by our dietary intake of purines) bony erosions on Xray

Monosodium urate crystals 1-polarized light 2-red compensator These crystals show : 1-needle shape 2-negative birefringence (Birefringence: double streams of light, usually in prisms, etc) Diagnosis is done by taking a biopsy from the synovial fluid and then examined either by:

Crystal-induced inflammation (from gout to gouty arthritis ) crystal deposition (blood stream) hyperuricemia protein binding receptor binding (Synovial joints ) cytokine release influx of PMN’s (Macrophages ) crystals engulfed inflammation PMN is critical component of crystal-induced inflammation

Gouty arthritis - characteristics sudden onset middle aged males severe pain distal joints intense inflammation recurrent episodes influenced by diet bony erosions on Xray Hyperuricemia (always)

Hyperuricemia excretion production hyperuricemia results when production exceeds excretion (either by over production or less excretion )

net uric acid loss results when excretion exceeds production Hyperuricemia production excretion net uric acid loss results when excretion exceeds production

Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals ** could also be in several places in the body

classic location of tophi on helix of ear Gout - tophus classic location of tophi on helix of ear

Gout - X-ray changes DIP (Distal interphalangeal joint) joint destruction phalangeal bone cysts

Gout - X-ray changes bony erosions

Gout - cardinal manifestations arthritis tophi chronic acute & chronic HYPERURICEMIA Nephrolithiasis (Kidney stones) nephropathy *kidneys should be functioning well in order to use classical treatment

Drug therapy of gout Treatment targets either : 1- Decrease Uric Acid Formation 2- Increase Uric Acid Excretion

The Role of Uric Acid in Gout end product of purine metabolism serum uric acid level dependent upon rate of uric acid production efficiency of renal uric acid excretion

Uric acid metabolism cell breakdown dietary intake purine bases hypoxanthine xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid One method of reducing uric acid levels , is inhibition of the enzyme xanthine oxidase xanthine uric acid

Renal handling of uric acid Fate of uric acid in kidneys : Uric acid glomerular filtration tubular reabsorption tubular excretion post-secretory reabsorption net excretion Uric acid Uric acid Uric acid The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys.

The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys Non steroidal anti-inflammatory Drugs are sometimes used in the treatment of Gout ( cause increase in excretion ) Aspirin on the other hand is never used

Gout - problems excessive total body levels of uric acid deposition of monosodium urate crystals in joints & other tissues crystal-induced inflammation

Treating acute gouty arthritis colchicine NSAID’s steroids rest, analgesia, ice, time

Drugs used to treat gout Urate Lowering Drugs For chronic cases Acute Arthritis Drugs steroids NSAID’s colchicine allopurinol probenecid febuxostat? It’s a new drug that’s being developed rest + analgesia + time

Drugs used to treat gout NSAID’s Indomethacin (Indocin) 25 to 50 mg four times daily Naproxen (Naprosyn) 500 mg two times daily Ibuprofen (Motrin) 800 mg four times daily Sulindac (Clinoril) 200 mg two times daily Ketoprofen (Orudis) 75 mg four times daily *Don’t memorize the doses, just the names ** Remember that Aspirin is never used

Colchicine - plant alkaloid colchicum autumnale (autumn crocus or meadow saffron)

Correction for the previous lecture Colchicine is used to prevent the polymerization of the cell’s cytoskeleton by binding to TUBULIN ( not Actin)

Colchicine “only effective in gouty arthritis” ( it only works on the inflammation process , and has nothing to do with uric acid levels .) not an analgesic does not affect renal excretion of uric acid does not alter plasma solubility of uric acid neither raises nor lowers serum uric acid

Colchicine Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules reduces inflammatory response to deposited crystals diminishes PMN phagocytosis of crystals blocks cellular response to deposited crystals

Crystal-induced inflammation crystal deposition hyperuricemia protein binding receptor binding cytokine release influx of PMN’s crystals engulfed inflammation PMN is critical component of crystal-induced inflammation

Colchicine - indications Dose Indication high treatment of acute gouty arthritis low prevention of recurrent gouty arthritis It’s better to use xanthine oxidase inhibitors for

Colchicine - toxicity Associated with high doses : gastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain) hematologic (agranulocytosis, aplastic anemia, thrombocytopenia) muscular weakness adverse effects dose-related & more common when patient has renal or hepatic disease

Gout - colchicine therapy more useful for daily prophylaxis (low dose) prevents recurrent attacks colchicine 0.6 mg qd - bid declining use in acute gout (high dose)

Colchicine - Cancers Promising studies have recently shown that Colchicine could be used for treating tumors HOW ? Since Colchicine prevents the formation of microtubules , this could be useful in limiting the mitotic activity of tumors cell : by preventing the formation of mitotic spindles (microtubules .)

Hyperuricemia - mechanisms excessive production inadequate excretion

net reduction in total body pool of uric acid Urate-lowering drugs block production enhance excretion net reduction in total body pool of uric acid

Gout - urate-lowering therapy Xanthine Oxidase as an example prevents arthritis, tophi & stones by lowering total body pool of uric acid not indicated after first attack initiation of therapy can worsen or bring on acute gouty arthritis no role to play in managing acute gout

Drugs That Block Production of Uric Acid Drug therapy of gout Drugs That Block Production of Uric Acid

Uric acid metabolism cell breakdown dietary intake purine bases hypoxanthine xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid xanthine uric acid

Allopurinol (Zyloprim™) inhibitor of xanthine oxidase effectively blocks formation of uric acid how supplied - 100 mg & 300 mg tablets pregnancy category C **Drugs are characterized according to their effects on pregnancy (fetus) into several categories A,B,C,D,X. A is the safest, X: completely dangerous and should not be given to pregnant women  **benefits from taking the drug must outweigh it’s risks in order for it to be used. allopurinol

Allopurinol - usage indications management of hyperuricemia of gout management of hyperuricemia associated with chemotherapy prevention of recurrent calcium oxalate kidney stones

Allopurinol - common reactions diarrhea, nausea, abnormal liver tests acute attacks of gout rash *Manufactures are obliged to put a special indication on each leaflet ( a BLACK BOX) , that explains the serious side effect for that particular drug e.g Isotretinoin is a highly teratogenic Drug that should have a BLACK BOX **For Allopurinol you might find that BLACK BOX sometimes , because certain people have shown to have allergy for it .

Allopurinol - serious reactions fever, rash, toxic epidermal necrolysis hepatotoxicity, marrow suppression vasculitis drug interactions (ampicillin(antibiotic), thiazides(diuretic ), mercaptopurine, azathioprine(anti-cancer) death

Stevens-Johnson syndrome Another serious side effect , characterized by : Mucocutaenous ulcerations target skin lesions mucous membrane erosions epidermal necrosis with skin detachment Those side effects are treated by systemic corticosteroids

Allopurinol hypersensitivity extremely serious problem prompt recognition required first sign usually skin rash more common with impaired renal function progression to toxic epidermal necrolysis & death

Febuxostat recently approved by FDA (not on market) oral xanthine oxidase inhibitor chemically distinct from allopurinol 94% of patients reached urate < 6.0 mg/dl minimal adverse events can be used in patients with renal disease

PEG-uricase (Polyethelene Glycol) Uricase: enzyme that degrades uric acid  investigational drug PEG-conjugate of recombinant porcine uricase treatment-resistant gout uricase speeds resolution of tophi further research needed

Drugs That Enhance Excretion of Uric Acid Drug therapy of gout Drugs That Enhance Excretion of Uric Acid

Uricosuric therapy probenecid blocks tubular reabsorption of uric acid enhances urine uric acid excretion increases urine uric acid level decreases serum uric acid level

Uricosuric therapy moderately effective increases risk of nephrolithiasis not used in patients with renal disease frequent, but mild, side effects

Uricosuric therapy contra-indications history of nephrolithiasis elevated urine uric acid level existing renal disease less effective in elderly patients

Choosing a urate-lowering drug hyperuricemia excessive production inadequate excretion xanthine oxidase inhibitor uricosuric agent

Refer to the third slide Drug therapy of gout Case Presentation Refer to the third slide

Case presentation - therapy NSAID steroid NSAID colchicine (low-dose) Maintenance dose Anti-inflammatory allopurinol Chronic condition days 1-10 days 11-365 days 365+

Done by Anas Khalil With the help of shaima shahin’s Notes