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.

1
GOUT
• Gout is a metabolic disorder of purine
metabolism, characterized by intermittent
attacks of acute pain, swelling and
inflammation.
• It always preceded by hyperuricaemia (6.0mg/dl)
Hyperuricaemia due to excessive amount of uric
acid production or decreased excretion
• Hyperuricaemia - primary or secondary.

• Primary hyperuricaemia classified as

“Overproducers” or “under execrators”

• Primary Hyperuricemia and Secondary Hyperuricemia and Gout with
Gout with No Associated Identifiable Associated Condition
Condition

• Uric acid undersecretion(80%– • develop during course of other diseases

90%) (Leukaemias, lymphomas, chemotherapy)

• Idiopathic • Some drug therapy (Thiazide diuretics,

furosamide, ethacrynic acid)
• Urate overproduction (10%–
20%)
• Some disorders Diabeticketoacidosis, lead
poison, Lymphoproliferative
• HGPRT deficiency diseases, Hemolytic anemias, psoriasis
• PRPP synthetase overactivity
• Dual mechanism
• (Phasphoribosyl pyrophosphate) Obesity, Hypoxemia and hypoperfusion
 Uric acid production and excretion

RNA,DNA

PURINES
PRPP

HYPOXANTHINES
Xanthine oxidase
XANTHINES
Xanthine oxidase

URIC ACID (low water soluble)

Hyperuricemia Gout Deposits of urate crystal Nephrolithiasis

Uric acid freely filtrated through by glomerulus and

Probencid
reabsorbed by tubular fluid
 Pathophysiology of gout
Uricacid

Blood

React with sodium

Sodium crystals (tophi)
Deposited in soft tissues and joints
Inflammation(ry) Indomethacin
Colchicine
Infiltration of granulocytes that phagocytise the urate crystals

Generate free radicals

Free radical damage the tissue
Colchicine
Release of proteolytic enzyme glycoprotein

Release of lysosomal enzymes

Release of lactic acid Colchicine
Destruction of joints More ppt of urate crystals
 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

GOALS:

1. terminate acute attack

2. provide rapid, safe pain/anti-inflammatory relief
3. prevent complications
• destructive arthropathy
• tophi
• renal stones
 Classification of drugs used in gout

ACUTE GOUT :
1. NSAIDS
2. Corticosteroids
3. Colchicine

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 metaphas “spindle poison”
- increases gut motility.
- Antipyretic , respiratory depressant
- Inhibit histamine , Insulin release
- hypertensive at high dose , Increase vasomotor tone
- direct vasoconstrictor
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)

 Corticosteroid
Use when NSAIDS/Cholchicine risky or contraindicated
e.g.,: elderly
hypertensive
peptic ulcer disease
renal impairment
liver impairment
use when • NSAIDS ineffective
Mode 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
– Lacation
– 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.
 Benzbromarone

• It is newer and more potent uricosuric drug

• Used in patients allergic to probenecid or sulfinpyrazone

• It is reversible inhibitor of tubler reabsorption

• Effective dose 60-80mg/day

• With allopurinol more effective

• 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 ?