Phamacotherapy of

Gout
Dr.Rathnakar U.P.
MD.DIH.PGDHM
Gout
Metabolic disorder preceded by hyperuricemia
Precipitation of sodim urate crystals in the
tissues ⇛inflammatory response
. . .
 Exces Sodiu
s uric m
acid

Accumulate Sodiu
s in Soft m
tissue urate
 Secondary Hyperuricemia

Leukemias, lymphomas,
Polycythemias when treated with
radiation/chemotherapy

Drug induced: thiazides, frusemide,

ethacrynic acid, ethambutol,
Pyrazinamide. Ethanol, clofibrate

Diabetic ketoacidosis, lead

poisoning, psoriasis
Hperuricemia MSU crystals Phagocytosed by
deposited synoviocytes
In joints

•Release infl.mediators
•[PG,Lysozomal enzymes.IL-1]

•Phagocytosed by •PMN migrate to joint

• Macrophages •Phagocytose MSU
•RELEASES A GLYCOPROTEIN

Sequenc Amplifies inflammation

e of Lowers pH
events
At
Further precipitation of urates
mol.level
Clinical presentation of gout
Acute Chronic
Gout Tophaceous
Gout
 Diagnosis
 Definitive diagnosis
 IN synovial fluid or
Tophaceous material
 Demonstration of MSU
crystals

 Polarized microscopy,
 Synovial Fluid Findings
Needle shaped
crystals of
monosodium urate
monohydrate
Engulfed by
neutrophils
 Drugs used in Gout
Classification

Drugs used for acute gout:

NSAIDS
Colchicine
Corticosteroids
Drugs used for chronic gout:
Uricosurics: Probenecid, Sulfinpyrazone
Uric acid Synthesis inhibitor: Allopurinol
NSAIDs
Indomethacin, naproxen, piroxicam,
diclofenac potassium
Except aspirin, salicylates & tolmetin
Inhibit urate crystal phagocytosis &
migration of leukocytes → inflamed
joint
Not recommended for long term use
Indomethacin:
50mg QID→ 25mg QID
 Drugs used in Gout
Classification

Drugs used for acute gout:

NSAIDS
Colchicine

Drugs used for chronic gout:

 Obtained from
Colchicine Colchicum
autumnale
No
analgesic/anti-
inflammatory
action
No effect on
blood uric acid
levels
Hperuricemia MSU crystals Phagocytosed by
deposited synoviocytes
In joints

•Release infl.mediators
•[PG,Lysozomal enzymes.IL-1]

•Phagocytosed by •PMN migrate to joint

• Macrophages •Phagocytose MSU
•RELEASES A GLYCOPROTEIN

Amplifies inflammation
Lowers pH
Sequen
ce of Further precipitation of urates
events
 Colchicine---MOA
Inhibits release of glycoprotein
Binds to‘tubulin’ →
depolymerisation/disappearance of
microtubules prevents migration of
granulocytes
Other actions
Antimitotic-Metaphase arrest
Increases gut motility
Spindle poisons:
Mebendazole
Colchicine
Griseofulvin
Vinca Alkaloids
Paclitaxel

Mitotic spindle is essential for

equal partitioning of DNA
during cell division
 Pharmacokinetics
Rapid oral absorption
Partly metabolized in liver
Excreted in bile-
enterohepatic circulation
Ultimately excreted in urine
& faeces
Gout-Colchicine
Acute:
1mg→0.25 mg 3 h till
controlled or diarrhoea starts
Dramatic response-Diagnostic

Prophylactic: 0.5 mg/day

 Other uses
Familial mediterranean fever
Primary biliary cirrhosis
Sarcoid arthritis

ADE
Diarrhoea(bloody), pain abdomen & vomiting
Respiratory depression, throat pain,
haematuria & oliguria
Agranulocytosis, peripheral neuritis &
myopathy
 Nausea

G.I.Disturbances

ADE OF COLCHICINE Diarrhoea

Agranulocytosis

Alopecia
 Drugs used in Gout
Classification

Drugs used for acute gout:

NSAIDS
Colchicine
Corticosteroids
Drugs used for chronic gout:
 Corticosteroids
Intraarticular injection of Soluble
steroids
Crystalline preparations should not be
used
Indicated in
Refractory cases
Intolerance to NSAIDs or Colchicine
Systemic steroids- Prednisolone-
reserved for severe cases
 Drugs used in Gout
Classification

Drugs used for acute gout:

NSAIDS
Colchicine
Corticosteroids
Drugs used for chronic gout:
Uricosurics: Probenecid, Sulfinpyrazone
Uric acid Synthesis inhibitor: Allopurinol
 URATE LOWERING TREATMENT

Who to treat?
1. Tophi
2. Gouty athropathy
3. Radiographic changes of gout
4. Multiple joint involvement
5. Nephrolithiasis
 Probenecid
Competitive inhibition of active
transport of organic acids at all sites
especially at renal tubules
Penicillin ⇨predominantly secreted;
minimal absorption
Net effect⇨ probenecid inhibits secretion
⇨⇪blood levels
Uric acid⇨ largely reabsorbed
Net effect⇛ Probenecid promotes
excretion ⇨⇩blood levels
 Probenecid Probenecid
[Decreases plasma concn of UA] [Increases concn of penicillins]

URIC ACID TRANSPORTER PENICILLIN

[Absorption] [Excretion]

Lumen

Renal tubule
 Pharmacokinetics
Complete oral absorption
90% plasma protein bound
Conjugated in liver &
excreted in urine
Plasma t1/2 = 8-10 hrs
 Drug interactions
Probenecid Inhibits: Excretion of
Penicillins,
Cephalosporins,
Sulfonamides,
Methotrexate,Indomethacin

Inhibits Biliary excretion

of Rifampin
Inhibits Secretion of
nitrofurantoin
⇛fails to attain anti
 Uses: Probenecid
1. Chronic gout:
With plenty of water + alkalinisation of
urine:
To prevent crystallization of excess
urate in urinary tract
Life long treatment is often required
Not to be started during acute attack;
dealt with NSAIDs
No use if kidney is damaged
2. Also in Secondary hyperuricemia
3. Prolong action of Penicillin/Ampicillin
 Sulfinpyrazone
Uricosuric drug
Inhibits tubular reabsorption of
uric acid
Uricosuric action: additive with
Probenecid
 Antagonised by salicylates
Inhibits platelet aggregation
 Benzbromarone
Newer, more potent uricosuric drug
Used in
patients allergic or refractory to
probenecid or sulfinpyrazone
Patients with renal insufficiency
Reversible inhibitor of tubular
reabsorption of uric acid
ADE: Fulminant liver failure
 Drugs used in Gout
Classification

Drugs used for acute gout:

NSAIDS
Colchicine
Corticosteroids
Drugs used for chronic gout:
Uricosurics: Probenecid, Sulfinpyrazone
Uric acid Synthesis inhibitor: Allopurinol
 Hypoxanthine
Allopurinol

Xanthine Xanthine
oxidase oxidase

Xanthine
Alloxanthine
Xanthine
oxidase

Uric acid
Allopurinol
 Pharmacokinetics
80% orally absorbed
Not bound to plasma
proteins
Metabolized largely to
Alloxanthine
Chronic use: inhibits its
own metabolism
 Drug interactions of
Allopurinol
Inhibits degradation of 6-
mercaptopurine & azathioprine
Probenecid shortens t1/2 of
alloxanthine
Allopurinol prolongs t1/2 of
probenecid
Potentiates warfarin & theophylline
Ampicillin + Allopurinol ⇨⇪ rashes
Iron therapy is not recommended
Allopurinol
Adverse effects:
Hypersensitivity reactions:
rashes, fever, malaise &
muscle pain; STEVENS
JOHNSON SYNDROME
Gastric irritation,
headache, nausea &
dizziness

Allopurinol
Contraindications:
• Hypersensitive
• Pregnant & lactating mothers
• Elderly & children
• Liver & kidney disease
Allopurinol
Other uses:
Secondary hyperuricemia
To potentiate 6-
mercaptopurine or
Azathioprine
Kala-azar: inhibits
Leishmania by altering purine
metabolism
 Rasburicase
Recombinant urate-
oxidase
Produced by a
genetically modified
Saccharomyces
cerevisiae strain
Lowers urate levels
more effectively than
allopurinol
Rasburicase
Indicated for
 With anti cancer therapy in
children

Adverse efffects:
Hemolysis in -(G6PD)-
deficient patients,
methemoglobinemia, acute
renal failure, and
 SJS
allopurinol, diclofenac, fluconazole,
valdecoxib, penicillins, barbiturates,
sulfonamides, phenytoin, azithromycin,
lamotrigine, nevirapine, ibuprofen[8],
ethosuximide, carbamazepine
Choi, H. K. et. al. Ann Intern Med 2005;143:499-516
Gout
What is gout-Purine metabolism
Inflammation of joints
MOA of inflammation
Drugs—Acute and chronic