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.

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

Gout - acute arthritis

acute synovitis, ankle & first MTP

joints

The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

Redness and swelling are noticed around those joints in particular

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

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:

These crystals show :

Crystal-induced inflammation (from gout to gouty arthritis )

PMN is critical

component of crystal-induced

inflammation

crystal deposition

(blood stream)

hyperuricemia

protein binding

receptor binding

(Synovial joints )

cytokine release

influx of PMN’s

(Macrophages )

crystals engulfed

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

productio

n

excretion

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

excretion )

Hyperuricemia

productionexcretion

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

Gout - tophus

classic location of tophi on helix

of ear

Gout - X-ray changesDIP (Distal interphalangeal joint) joint destructionphalangeal bone cysts

Gout - X-ray changes

bony erosions

acute &

chronic

chronic

Gout - cardinal manifestations

Nephrolithiasis

(Kidney stones)

nephropathy

arthritis tophi

HYPERURICEMIA

*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

Uric acid metabolism

cell breakdown

dietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

One method of reducing uric acid levels , is inhibition of the enzyme xanthine oxidase

Renal handling of uric acid

•glomerular filtration

•tubular reabsorption

•tubular excretion

•post-secretory reabsorption

•net excretion

Fate of uric acid in kidneys :Uric acid

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

allopurinol

probenecid

febuxostat?

steroids

NSAID’s

colchicine

Acute Arthritis Drugs

Urate Lowering Drugs

For chronic cases

rest + analgesia + time

It’s a new drug that’s being developed

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

Drugs used to treat gout

*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

PMN is critical

component of crystal-induced

inflammation

crystal deposition

hyperuricemia

protein binding

receptor binding

cytokine release

influx of PMN’s

crystals engulfed

inflammation

Colchicine - indications

Dose Indication

hightreatment of acute gouty arthritis

lowprevention of recurrent gouty arthritis

It’s better to use xanthine oxidase inhibitors for

Colchicine - toxicity

• gastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain)

• hematologic (agranulocytosis, aplastic anemia, thrombocytopenia)

• muscular weaknessadverse effects dose-related & more common

when patient has renal or hepatic disease

Associated with high doses :

Gout - colchicine therapy

• more useful for daily prophylaxis (low dose)prevents recurrent attackscolchicine 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

hyperuricemia

excessive production

inadequate excretion

Urate-lowering drugs

net reduction in total body pool of uric acid

block production

enhance excretion

Gout - urate-lowering therapy

• 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

Xanthine Oxidase as an example

Drug therapy of gout

Drugs That Block Production of Uric Acid

Uric acid metabolism

cell breakdown

dietary intake

purine bases

hypoxanthine

xanthine

uric acid

xanthine oxidase

catalyzes hypoxanthine to xanthine & xanthine to

uric acid

Allopurinol (Zyloprim™)

• inhibitor of xanthine oxidase• effectively blocks formation of uric

acid• how supplied - 100 mg & 300 mg

tablets• pregnancy category C

allopurinol**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 - 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

Mucocutaenous ulcerations

target skin lesions

mucous membrane erosions

epidermal necrosis with skin detachment

Another serious side effect , characterized by :

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

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-indicationshistory of nephrolithiasiselevated urine uric acid levelexisting renal disease

• less effective in elderly patients

Choosing a urate-lowering drug

hyperuricemia

excessive production

inadequate excretion

xanthine

oxidase inhibito

r

uricosuric agent

Drug therapy of gout

Case Presentation

Refer to the third slide

Case presentation - therapy

NSAID

steroid

colchicine (low-dose)

allopurinol

NSAID

days 1-10 days 11-365 days 365+

Anti-inflammatory

Maintenance dose

Chronic condition

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