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What is Arthritis? There are 127 different kinds of

arthritis!

Rheumatoid arthritis: Severe inflammation that involves many joints and moves beyond musculoskeletal system.

Gout: Very painful form of arthritis characterized by the formation of uric acid crystals and severe inflammation.

Osteoarthritis: progressive degeneration of joint cartilage. Minor degree of inflammation.

GOUT

• Gout is a metabolic disorder of purine metabolism, characterized by intermittent attacks of acute pain, swelling and inflammation.

• It always preceded by hyperuricaemia

Hyper uricaemia 6.8mg/dl

• Excessive amount of uric acid production

• Decreased excretion

• Or both

• Primary Hyperuricemia and Gout

• Uricacid under excretion 80–90%

• Urate over production (10–20%)

• Purine intake shell fish , Red meat

• Idiopathic

• PRPP synthetase over activity

Secondary Hyperuricemia and Gout Identifiable Associated Condition

• develop during course of other diseases (lymphomas, chemotherapy, CKD) cell death

• Some drug therapy (Thiazide diuretics, furosamide, ethacrynic acid, Aspirin)

• Some disorders Diabetic ketoacidosis, lead poison, Lymphoproliferative diseases, Hemolytic anemias, psoriasis

• Dual mechanism Obesity and hypo perfusion to joint

Uric acid production and excretion

RNA,DNA

PURINES

HYPOXANTHINES

XANTHINES

URIC ACID (low water soluble)

Uric acid freely filtrated through by glomerulus and reabsorbed by tubular fluid

Xanthine oxidase

Xanthine oxidase

Probencid

PRPP

Hyperuricemia Gout Deposits of urate crystal

Pathophysiology of goutUricacid

Blood

React with sodium Sodium crystals (tophi)

Deposited in soft tissues and joints

Inflammation(ry)

Infiltration of granulocytes that phagocytise the urate crystals

Generate free radicalsFree radical damage the tissue

Release of proteolytic enzyme glycoprotein Release of lactic acid

More ppt of urate crystals

Indomethacin

Colchicine

Colchicine

ColchicineRelease of lysosomal enzymesDestruction of joints

Symptoms

• Acute joint pain• Swelling in the joints• Skin may be in red colour and shiny appearance • Formation of tyophi

Cause and risk factors

• Hereditary factors 40-50 age• Consumption of alcohol spe..Beer• Excessive consumption of red meat, internal organs • Trauma to joints

Diagnosis

• Joint fluid aspiration • Blood test (Serum uric acid levels) • X-rays

Acute gout

• Painful arthritic attack of sudden onset.• Usually occurring at night or in early morning• Arthritic pain worsen progressively• Generally involves one or few joints• Most common site of initial attack metatarsophalangeal

joint.• Other sites ankle, heel, knee, wrist, elbow and fingers.

Chronic gout

• Frequency of attacks increases, continuous

deposit leads to damage joints and chronic pain

• Patients may develop large subacutenous tophi (Stones) in pinna of external ear, eyelids, nose and around joints

• The ureate crystals in kidney leads renal disease.

• Articular cartilage may be destroyed result in joint deformities

GOUT - TREATMENT

1. terminate acute attack2. provide rapid, safe pain/anti-inflammatory relief3. prevent complications

• destructive arthropathy• tophi• renal stones

GOALS:

Classification of drugs used in gout CAPS

ACUTE GOUT : 1. Colchicine2. Corticosteroids3. NSAIDS

CHRONIC GOUT:• Inhibit uric acid synthesis:- Allopurinol, febuxostate

(Urostatic)• Increase uric acid excretion:- Probencid, Sulphinpyrazole

(Urosuric)

Colchicine

• Alkaloid from colchium autumnale. (1973)

• Neither analgesic nor anti inflammatory, but specific

for gouty inflammation.

• It is only effective in prophylaxis of acute gout

• It has no effect on synthesis or promote excretion • MOA• Colchicine binds to intracellular protein ‘Tubulin’ and

causes depolymerisation and disappearance of microtubules in granulocytes & Inhibit granulocyte migration so dec phagocytic activity

• Colchicine inhibit glycoprotein release– Other actions-

- arrest of mitosis in metaphase “spindle poison” - increases gut motility.

- Antipyretic , respiratory depressant

- Inhibit histamine , Insulin release

- hypertensive at high dose, Increase vasomotor tone

Uses Colchicine preferred in pts without confirmed diagnosis of

gout.

Acute gout-1mg orally followed by 0.25 mg 3 hrly till control. EHC 3-7days With safer alternatives NSAIDs use of Colchicine have declined

ADR:- diarrhoea, vomiting, abdominal pain.

Acute toxicity - bloody diarrhoea, throat pain, respiratory depression, haematuria.

Chornic toxicity- agranulocytosis, peripheral neuritis and myopathy, renal tubular necrosis.

NSAIDs• Strong anti inflammatory drugs• Use in patients without contraindication• Use maximum dose/potent NSAID

e.g., Indomethacin 50 mg po t.i.d. Diclofenac 50 mg po t.i.d. Ketorolac 10 mg q4-6hrsr, Napoxen, Piroxicam

• continue until pain/inflammation absent for 48 hours• MOA: inhibit urate crystal phagocytosis and chemotatic

migration of leukocytes into inflammed joints.• NSAIDs are not recommended for long term.

• (Salicylates are not used , have tendency to raise uric acid)

CorticosteroidUse when NSAIDS/Cholchicine risky or contraindicated

e.g.,: elderlyhypertensivepeptic ulcer diseaserenal impairmentliver impairment

use when • NSAIDS ineffectiveMode of administration – • intra articular - Depomedrol 40-80 mg with lidocaine.• Oral Prednisone 30-40 mg qd for 3-4 days, taper by 5 mg

every 2-3 days & stop over 1-2 wks

Drugs for chronic gout• Uric acid synthesis inhibitors:- Allopurinol

(Xanthine oxidase inhibitor)

• Hypoxanthine Xanthine Uric acid

Xanthine oxidase-

Allopurinol

• Allopurinol prevents the synthesis of uric acid by inhibiting the enzyme Xanthine oxidase, result reduce plasma ureate levels.

• Inc. xanthine, hypoxanthines are excreted through urine

• Allopurinol short acting competitive inhibitor

• Metabolite alloxanthine is long acting t1/2 24hr.

• Start low 50-100 mg qd• Increase by 50-100mg every 2-3 weeks according to

symptoms – “Average” dose 300 mg daily– lower dose if renal/hepatic insufficiency– higher dose in non-responders– prophylactic colchicine until allopurinol dose stable

• Indications: • Chronic gout• In patients 24 hrs urinary acid excretion exceeds 1.1g• For recurrent renal ureate stones.

Allopurinol side effects

• GI upset, alopecia, cataract.

• Allopurinol Hypersensitivity: Pruritic papular skin rash, fever, hepatitis,

eosinophilia, renal impairment

• CI:- – Chidrens– Elderly patients– Pregnancy– Lactation– Liver and kidney diseases.

Allopurinol drug interactions

• Allopurinol prolong ½ life of Vidarabine, Cyclosporin drugs and increase toxicity

• Dec. metabolism of 6-mercaptopurine, Azothiaprine inc. its effects.

• Interferes with the mobilization of hepatic iron stores - heamtonic should be avoided during allopurinol therapy.

Uricosuric drugs: (probencid)

• Highly lipid soluble benzoic acid.

• It blocks reabsorption of urate in proximal tubule by blocking transport (Bidirectional transport)

• PK: Dose dependent t1/2 life

• Dose -250- 500mg b.d. with plenty of fluids, alkalinization of urine.

Uses : chronic gout along with NSAIDs / colchicine for initial 1-2 months.

Sulfinpyrazone

• It is a Pyrazolone derivaties related to Phenylbutazone.

• Inhibits tubular reabsorption of uric acid at therapeutic doses.

• Its action is additive with probenecid.• Use -chronic gout• Dose :100-200mg BD gradually increase

according to the response.

• It is newer and more potent uricosuric drug

• Used in patients allergic to probenecid or sulfinpyrazone

• It is reversible inhibitor of tubuler reabsorption

• Effective dose 60-80mg/day

• With allopurinol more effective

Benzbromarone

• A 56yrs old male awake in the night with sudden severe pain in his first metatarsophalangeal joint which lasted for a week. Over the next few months, he had similar acute episode of pain in his ankles and knees, as well as his big toe. The GP suspected gout and referred him to specialist

• What treatment should be GP institute for the acute attacks prior to the specialist diagnosis?

• what test could the rheumatologist do to confirm the suspected diagnosis?

• What is the cause of gout?• Which drugs act for acute attacks?• What would you prescribe for prophylaxis to

reduce recurrent attacks ?

360umol/L or 6mg/dl