Submitted by: Panganiban, Victor Pasamante, Jane Angele Pascua, Ayvee Pascual, Marie Jiselle Plete, Mark Gregor

Pua, Minnie Abigail

PRPP--5-phosphoribosyl-1-pyrophosphate synthetase HPRT--hypoxanthine guanine phosphoribosyl transferase). APRT adenine phosphoribosyl transferase; PNP purine nucleotide phosphorylase

Can be due to inability to regulate the production of purine nucleotides Biochemical hallmark
Increased uric acid

Marked by transient attacks of acute arthritis

Due to crystallization of urates in joints

Leads to chronic GA and (+) tophi

Tophi large aggregates of urate crystal +

surrounding inflammatory reaction

Primary 90%
Overproduction of uric acid Diet unknown enzyme defects Known enzyme defect (eg. Partial HGPRT deficiency) Reduced excretion of uric acid with normal

production

Secondary 10%
Overproduction of uric acid with increased urinary

excretion
Increased nucleic acid turnover ( leukemias and neoplasms) Inborn errors of metabolism ( complete HGPRT deficiency)

Reduced excretion of uric acid with normal

production
Chronic renal disease

serum uric acid concentration above 7 mg per dL (420 mol per L). This concentration is also the limit of solubility for monosodium urate in plasma. At levels of 8 mg per dL (480 mol per L) or greater, monosodium urate is more likely to precipitate in tissues.

Often, some precipitating event such as an: > infection > surgery, > the stress of hospitalization > a stubbed toe > a heavy drinking binge can cause inflammation.

Urate nephropathy 3 types can occur:

Acute uric acid nephropathy Chronic urate nephropathy Nephrolithiasis

Acute
Precipitation of urate crystals in collecting duct Obstruction of nephrons/ acute renal failure Most common for leukemia/lymphoma pxs

undergoing chemotherapy
Death of tumor cells nucleic acids are broken down to uric acid

chronic
Tophi formation in kidney (+) arterial and arteriolar thickening due to

hypertension

nephrolithiasis

Precipitation of Monosodium urate (MSU)

Solubility of MSU modulated by temp
Lower temp = less soluble

Intra-articular conc of urate & cations

Crystallization dependent on: Presence of nucleating agents

Insoluble collagen fibers, chondroitin sulfate, proteoglycans, cartilage fragments

Synovial fluid is a poorer solvent for MSU compared to plasma

Joint fluid easily supersaturated Specifically - peripheral joints (toes and ankles)

Attack starts with trauma or unknown event

Causing release of crystal in the synovial fluid Cascading event initiates, intensifies, & sustains a

powerful inflammatory response (hallmark of acute attack)

MSU crystals are phagocytosed

Synoviocytes secrete inflammatory mediators

Hyperuricemia
NORMAL: 6mg/dL women 6.8 mg/dL-male

Lifestyle -consumption of alcohol -sugar, meat and seafood -sedentary lifestyle also increases the risk of developing the diseases Medical conditions -Metabolic Syndrome - Leukemia

Gout -there are high levels of uric acid circulating in the blood, (urate crystals to settle in the tissues of the joints).

COMMON SITE OF URATE CRYSTALS DEPOSITION:

Gout monosodium urate -most common form of crystal -induced arthritis -the deposition of crystals in and around: joints and tendons articular cartilage of joints tendons surrounding tissues.
2

>3 White blood cells

(mistaking the urate crystals for a foreign invader)

> hallmarks of a GOUT ATTACK

(redness, swelling, and pain )

Asymptomatic (acute inflammatory reaction /acute gout) slow destruction of the involved repeated attacks (chronic gout).

but may also affect the:

( heel, Ankle, hand, Wrist, elbow.)

4It

most commonly affects the

METATARSALPHALENGEAL jt.

-At the base of the BIG TOE known as PODAGRA- 75 % -Due to lower temp.

-stone-like deposits >joints, ligaments, and tendons, leading to permanent joint deformity and decreased motion. -leading to permanent joint deformity and decreased motion -can also cause kidney stones, also called renal calculi or uroliths

People with long-standing hyperuricemia can form tophi

6

usually hard non painful deposits. associated with arthritis due to bone erosion.

asymptomatic stage
shows no external manifestations.

acute stage
uric acid crystals are deposited in the joint spaces

leads to a sudden onset of intense pain and swelling in the

joints, which also may be warm and very tender an acute attack commonly occurs at night and can be triggered by stressful events, alcohol or drugs, or the presence of another illness.

Symptoms include:
high level of uric acid in the bloodstream

sustained uric acid crystals - synovial fluids around the movable joints. joints - start aching suddenly and swell up; feel hot and tender skin - appears red, shiny and bruised; may also start to peel off. movement of the joint becomes painful

intercritical stage symptom-less hiatus between gout attacks period between acute attacks person does not have any symptoms and has normal joint function. chronic stage most disabling stage of gout and usually develops over a long period (10 years) the disease has caused permanent damage to the affected joints and sometimes to the kidneys. characterized by more frequent polyarticular, gout attacks, kidney stones or tophi.

Symptoms include: extensive deposition of urates on the cartilages ear, tendons and other soft tissues of the body. sores that exude white pus may form - skin over the urate deposits. joints become stiff and almost immovable. unbearable, crushing pains accompany this condition. can lead to decreased kidney function and kidney stones

Gout

metabolic disorder excessive concentration of uric acid in the blood deposition of sodium urate in the joints extremities, and notoriously the great toe. chalky deposits --- tophi

Pseudogout

type of inflammation of joints deposition of calcium pyrophosphate in and around the joints. "false gout"

caused by crystals in a joint causes arthritis cause calcification of cartilage arthritis of pseudogout is diagnosed by detecting typical crystals in joint fluid treatment is directed at the inflammation associated with other illnesses

Synovial fluid/Arthrocentesis

-more reliable method of diagnosis -based upon the identification of monosodium urate (MSU) crystals in the synovial fluid.

Blood test -used to measure levels of uric acid in the blood. -not a reliable method

X-rays

- may show tophi-crystals deposits and bone (repeated inflammations)

-

monitoring the effects of chronic gout on the joints.

affected joints often show the joints to be normal so may not help in the diagnosis.

a. Diet:
( X )Avoid High in purines: > Total alcohol intake was strongly associated with an increased risk of gout (beer and liquor were particularly strong factors). > Fructose in soft drinks also increases the risk of gout. > shellfish > organ meats( liver, brains, kidneys, and sweetbreads) > Researchers have reported ( x ) - in general, that meat or seafood consumption increases the risk of gout attacks, ( + ) - while dairy food consumption seemed to reduce the risk. -Protein intake or purine-rich vegetable consumption was not associated with an increased risk of gout

Foods moderately high in purines include: anchovies grouse mutton veal bacon liver salmon turkey kidneys partridge trout goose haddock pheasant scallops

Foods very high in purines include: hearts herring mussels yeast smelt sardines Sweetbreads

b. WEIGHT REDUCTION -a regular aerobic exercise program c. MEDICATION

ANTIGOUT PREPARATIONS (M04)

primary: Probenecid Sulfinpyrazone Benzbromarone Isobromindione Uricosurics secondary: Amlodipine Atorvastatin Fenofibrate Guaifenesin Losartan purine analogues: Allopurinol# Oxypurinol Tisopurine Xanthine oxidase inhibitors other: Febuxostat Inositols (Phytic acid, Myoinositol)

Mitotic inhibitors Colchicine

Cinchophen NSAIDs except aspirin Sevelamer Urate oxidase (Rasburicase, Pegloticase)

Other

1.

PAIN RELIEVERS- to manage the pain

ACETAMINOPHEN (TYLENOL)

( X )AVOID:

> ASPIRIN

2. ANTIINFLAMMATORY AGENTS such as NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS), COLCHICINE, AND

CORTICOSTEROIDSinflammation

are used to decrease joint

Steroids - Glucocorticoids

inhibits neutrophil motility and activity, leading to net antiinflammatory effect.

inhibits the deposition of uric acid (urate)

inhibiting the oxidation of glucose enhanced by a low pH in the tissues, reducing the production of lactic acid in leukocytes

is a non-steroidal anti-inflammatory drug (NSAID) highly selective COX-2 inhibitor and primarily inhibits this isoform of cyclooxygenase inhibits COX-2 without affecting COX-1. COX-1 is involved in synthesis of prostaglandins and thromboxane ,

isoform 2 of cyclo-oxigenase enzyme (COX-2) reduces the generation of prostaglandins (PGs) from arachidonic acid

(aka "COXIB"), showed less marked activity on type 1 cycloxigenase compared to traditional.

3. MEDICATIONS MANAGING THE CHRONIC UNDERLYING

METABOLIC DERANGEMENT THAT CAUSES HYPERURICEMIA AND GOUT

a.

PROBENECID
-It is primarily used in treating gout and hyperuricemia, increases uric acid excretion in the urine

-the OAT binds to probenecid instead of to uric acid, preventing the reabsorption of uric acid

PROBENECID

is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia. competitively inhibits the renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects

enzyme inhibitor, inhibiting xanthine oxidase >xanthine oxidase- is responsible for the successive oxidation of hypoxanthine and xanthine resulting in the production of uric acid, the product of human purine

>inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, converted to closely related purine ribotides adenosine and guanosine monophosphates
> Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis

This medication, also known as (Zyloprim)Allopurinol, is used for the treatment and prevention of gout attacks and certain types of kidney stones. It is also used to treat elevated uric acid levels in the blood and urine, which can occur in patients receiving chemotherapy for the treatment of leukemia, lymphoma and other types of cancer. If left untreated, high uric acid levels in patients receiving cancer chemotherapy can cause kidney stones and kidney failure.