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Gout and Gout and HyperuricaemiaHyperuricaemia

Prepared by : Farjana Rahman

B.Pharm, Southeast UniversityM.Pharm, East West University, Bangladesh

IntroductionIntroduction

Gout is characterized biochemically as a disorder of uric acid metabolism and clinically by hyperuricaemia and

recurrent attacks of acute arthritis. Gouty arthritis is most frequently seen as an acute inflammation primarily in the

large toe, instep, ankle, or heel,less often in the knee or elbow.

Most hyperuricemic persons are asymptomatic betweenacute attacks.Uric acid stones may form in the lumen of the urinary tract, and progressive renal failure often occurs in the later stages of untreated Gout.

► Urate: end product of purine metabolism

► Gout: deposition of monosodium urate crystals in tissues

► Hyperuricemia: serum urate > urate solubility (> 6.8 mg/dl)

Pathways of uric acid

But in…► leukemia►myeloid metaplasia► lymphoma► Polycythemia► And in rapid weight loss (dieting)

Breakdown of cellular nucleoprotein is increased

Excess formation of uric acid

MaleMale Postmenopausal Postmenopausal

femalefemale Old aged peopleOld aged people HypertensionHypertension Pharmaceuticals:Pharmaceuticals:

Diuretics, ASA, Diuretics, ASA, cyclosporinecyclosporine

TransplantTransplant Alcohol intakeAlcohol intake

Highest with beerHighest with beer

Not increased Not increased with winewith wine

High BMI High BMI (obesity)(obesity)

Diet high in meat Diet high in meat & seafood& seafood

Complications

• Arthritis• Tophi• Urinary Calculi• Gouty Nephropathy

It is essential to identify the condition early to avoid the complications that result from a prolonged elevated uricaemia.

Clinical Manifestations

• Asymptomatic hyperuricemia

• Acute gouty arthritis

• Chronic gout

• Chronic tophaeceous gout

• Advanced Gout & Complications

Acute Gouty Flares

• Abrupt onset of severe joint inflammation, often nocturnal; Warmth, swelling, erythema, &

• pain;Possibly fever• Untreated? Resolves in 3-10 days• 90% 1st attacks are monoarticular• 50% are podagra

90% of gout patients eventually have podagra :1st MTP joint

Sites of Acute Gouty Flares

Fig: Acute Attack of Gout (MTP) joint

Can occur in other joints, bursa & tendons

Flares Intervals

• Silent tissue deposition & Hidden Damage may also occur in gouty attack

Advanced Gout

• Chronic Arthritis• Polyarticular acute flares with upper

extremities more involved

Solid urate deposits in tissues

Irregular & destructive

Investigation,Diagnosis & Treatment

Investigation

• The diagnosis of acute gout can only be made through examination of synovial fluid aspirated from the inflamed joint

• Sudden onset of acute inflammatory monoarthritis, particularly in the foot or ankle, should always raise the suspicion of gout

Investigation [cont..]• In 10% of patients acute gouty arthritis is

polyarticular• Hyperuricaemia alone is not diagnostic of gout

as many hyper-patients with acute gout have a normal serum uric acid concentration

• The diagnosis of gout is thus confirmed only by microscopic examination of synovial fluid aspirated from the affected joint

Diagnosis

• The differential diagnosis in acute gouty arthritis must include septic arthritis

• Patients with commonly present with acute swelling and tenderness of the joint with a fever

Diagnosis [Cont..]

• Patients with joint sepsis are usually more ill and have other systemic signs of infection such as a swinging fever and severe malaise

• Large joint are most frequently infected, and the joint is hot

Diagnosing [Cont..]

X-raysX-raysSynovial fluid analysis (Polarized Light Microscopy)Synovial fluid analysis (Polarized Light Microscopy)

The Gold standardCrystals intracellular during attacksNeedle & rod shapesStrong negative birefringence

X-raysX-rays Synovial fluid Synovial fluid analysisanalysis

Treatment• Initial treatment of gout and its

associated hyperuricemia must involve therapy directed toward terminating painful inflammatory process that is a prominent feature of acute gouty arthritis.

• A variety of nonsteroidal antiinflammatory compounds (e.g.,indomethacin, oxyphenbutazone, ibuprofen, naproxen, sulindac) can be administered either alone or in combination with colchicine, a relatively specific agent for use acute gouty attacks.

Clinically used drugs ( for gout and hyperuracemia)Pain reliver•Colchicine • NSAIDs (indomethacin, ibuprofen & naproxen )•Azapropazone•Corticosteroids•Narcotic Pain RelieversImproves uric acid removal•Probenecid•SulfinpyrazoneBlock uric acid production•Allopurinol•Phenylbutazone•OxyphenbutazoneNew drugs •Febuxostat•Rasburicase•pegloticase

Adverse Effects

Colchicine

-gastrointestinal diarrhea, nausea, vomiting, hemorrhagiccolitis, occurs in 70-80% of patients on oral therapy, less frequent

with IV therapy but may see with high doses -bone marrow depression: cumulative toxicity-renal dysfunction: toxic side effect seen after large doses,Hematuria , oliguria .-necrosis of soft tissue after extravasation : do not give IM/SQ

Corticosteroids -may include thinning bones, poor wound healing and a decreased

ability to fight infection.

Adverse Effects (continue……)NSAIDs( Indomethacin, Ibuprofen and

Naproxen)-nausea, vomiting , diarrhea constipation ,

decreased appetite, rash, dizziness , headache, and drowsiness.

-NSAIDs may also cause fluid retention, leading to edema.

-The most serious side effects are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery.

Adverse Effects (continue….)

Probenecid -hypersensitivity: rashes +/- fever, anaphylaxis-gastrointestinal: take with food or milk- stomach pain and kidney stones.

Sulfinpyrazone -hypersensitivity reactions (uncommon) rash, may cause

bronchoconstriction in patients with ASA intolerance, contraindicated in patients allergic to phenylbutazone / pyrazoles

-gastrointestinal irritation: take with food or milk

Adverse Effects (continue……)

Allopurinol -hypersensitivity rash-usually occurs within 1st 5 weeks with ampicillin

treatment -severe hypersensitivity more common in pts

with impaired renal function-gastrointestinal: nausea, vomiting, abdominal

pain -hepatomegaly/nephritis: may be manifestation

of a hypersensitivity reaction

Drug interactionColchicine penicillin, or other beta-lactams,clarithromycin, erythromycin, cyclosporine, verapamil NSAIDs Lithim, methotrexate and warfarin

Probenecidsulfonamides and sulfonylureas , methotrexaterifampin , penicillin antibiotics , salicylates (large doses

(>2 gms) inhibit the uricosuric effect of probenecid )

Drug interaction (continue……)Sulfinpyrazone -salicylates -warfarin Allopurinol -asthma drugs (aminophylline, theophylline)

azathioprine, -"blood thinners" (e.g., warfarin), chlorpropamide,

cyclosporine, mercaptopurine, -"water pills" (e.g., thiazide diuretics such as

hydrochlorothiazide).-ampicillin-ACE inhibitors

Drug interaction (continue……)Corticosteroids-Anticoagulants-Anticonvulsants -Anti-diabetic -Antifungals -Bronchodilators-Digoxin - HIV protease inhibitors-Liver vaccines- Macrolides- Methotrexate- Nonsteroidal anti-inflammatory drugs-Rifampicin -Diuretics -Ephedrine

Case Study-1

A 45 years old asymptomatic aircrew reported for periodic medical examination. Except for being overweight (BMI: 27kg/m2), the general and systemic examination was within normal limits. The routine laboratory investigations revealed a serum uric acid of 8.8 mg/dl. The individual denied consumption of alcohol/ medication and had no symptoms referable to joints. The various issues involved in the aeromedical decision making in this aircrew are as follows -

a) Does he require medication for his condition? b)What are the underlying pathology and the prognosis? c) What life style and preventive therapy will you suggest

to this aircrew?

a) Does he require medication for his condition

• The serum uric acid level in the body is a function of balance between the breakdown of purine and the rate of urate excretion.

• The normal serum uric acid as measured by automated enzymatic (uricase) method is less than 7.0 mg/dl for adult male and any value more than 7.0 mg/dl is considered to represent hyperuricemia.

• As the air crew has a creatinine level more than the normal level (8.8 mg/dl), Yess, he needs some pharmacological treatment.

b) What are the underlying pathology and the prognosis?

• The laboratory investigations can be divided in to the following heads:

1. Test directed towards establishing the diagnosis (a) Serum uric acid (b) Joint aspiration and demonstration of strongly

birefringent needle shaped intra and extracellular crystals in cases of gout.

2. Test directed towards the pathophysiology - 24 hours urinary uric acid estimation: Excretion of >800

mg of uric acid per 24hr on a regular diet suggests overproduction of purine as the etiology. It is also useful in assessing the risk of stone formation. and in deciding whether to start uricosuric therapy or not.

b) What are the underlying pathology and the prognosis?

3. Tests directed towards establishing the etiology (a) Complete blood counts: for hemolytic anemia or hematological

malignancies (b) Liver function test: base line liver function is required before initiation

of allopurinol therapy. It also aids in the detection of metabolic disorders. (c) Blood sugars: for underlying diabetes mellitus and glycogen storage

disorders. (d) Renal function test and serum electrolytes: for underlying renal

disease and acidosis (e) Serum calcium and phosphate: for hyperparathyroidism, sarcoidosis

and myeloma. (f) Thyroid stimulating hormone: to rule out hypothyroidism.4. Radiological evaluation Radiological feature of advanced chronic gouty arthritis includes soft tissue

masses, cystic changes and well-defined erosions with sclerotic margins and overhanging bony edges.

c) What life style and preventive therapy will you suggest to this aircrew?

Life StyleLife Style

c) What life style and preventive therapy will you suggest to this aircrew? (Cont.)

a) High protein diet is associated with increase urinary uric acid excretion and may reduce the serum uric acid level. The amount of red meat and seafood however has to be reduced. Diet should include, consumption of more of low fat dairy product and complex carbohydrate which helps in reducing the serum uric acid levels.

Preventive therapyPreventive therapy

b) Purine rich vegetables (peas, lentils, spinach, mushroom, cauliflower) may not affect serum uric acid to desirable extent and hence purine restricted diet is rarely necessary. Vitamin C in dosages of 500mg/ day has mild urate lowering effect.

(c) High-fructose corn syrup containing foods and drinks increase blood urate levels and are hence not recommended to be consumed. Coffee may decrease the risk of gout attacks .

(d) Alcohol increases the urate levels by increasing the production of uric acid as well as by impairing its excretion. Beer with its high purine content causes more elevation of serum urate levels than wine.

Preventive therapy (Cont.)Preventive therapy (Cont.)

Case Study- 2

• A 52-year-old male presented with severe pain in his wrists and right big toe, which was accompanied by inflammation and erythema of the joints. The patient had previously been diagnosed with acute gouty arthritis approximately 7 years ago, but had not experienced another acute attack since his original diagnosis. He had been taking simvastatin 40 mg nightly for hyperlipidemia for 7 years, 20 mg lisinopril daily for hypertension for 10 years, and hydrochlorothiazide 25 mg, also for hypertension, which was recently added two months ago. The patient had been steadily gaining weight over the last few years and was now about 50 lbs overweight. He stated that he drinks about a six pack of beer every day.

Nonpharmacological Treatment• Gout is influenced by numerous factors, including overeating,

obesity, alcohol abuse, hyperlipidemia, and insulin resistance syndrome.

• A low purine and protein diet along with alcohol restriction, weight loss through caloric restriction, and management of associated disease, may be extremely beneficial.

• Also, since patients with gout are at an increased risk for developing nephrolithiasis, health care providers should emphasize the importance of increasing fluid intake and decreasing salt consumption.

• In addition, joint rest and local application of ice may be beneficial.

Pharmacological Treatment• Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the

primary therapy for acute gouty arthritis for patients without complications or contraindications.

• Although ketoprofen and ibuprofen are often used, the FDA currently has approved only three NSAIDs for treatment of acute gouty arthritis: indomethacin, naproxen, and sulindac.

• The most important determinant of therapeutic success is probably not which NSAID is selected, but rather how soon NSAID therapy is initiated.

• In patients with contraindications to NSAIDs, Colchicine is a highly effective alternative treatment. Colchicine, which has been used for gout for a rather long time, interferes with the migration of neutrophils to the inflammation site, inhibiting the underlying inflammatory cascade.

• Corticosteroids can also be used for acute gouty arthritis but generally are reserved as the last treatment option because of their associated short- and long-term side effects.

• Corticosteroids can either be injected into the involved intraarticular joints or administered systemically. Because rapid removal of corticosteroids can precipitate a rebound attack, steroid withdrawal should be done gradually.

Question And

Answering