ok

1. Antigout Drugs
1

2. Introduction To Gout
Defination: Gout is metabolic disease in which plasma
urate concentration get increased (hyperuricaemia),
( Normal urate level:3.5 to 7.2 mg/dl).
Gout is a common and complex form of arthritis
that can affect anyone. It's characterized by
sudden, severe attacks of pain, swelling, redness
and tenderness in the joints, often the joint at
the base of the big toe.
2
Ref: https://curearthritis.org/gout/

3. Causes
• Uric acid is product of purine metabolism at low pH (acidic)
has low water solubility. When urate level increases in blood it
gets precipitates and deposits in joints, kidney and cutaneous
tissue which is called as tophy.
• An excess of uric acid, measured in the plasma as sodium urate,
constitutes hyperuricaemia.
• This excess may be caused by an overproduction or under
excretion of urate. It is influenced by genetic and environmental
factors and may be classified as primary (mainly idiopathic) or
secondary.

4. Causes:
4
⚫ Overdrinking of alcoholic beverages, especially beer, or purine-rich
foods.
⚫ Leukaemia's, lymphomas, polycythaemia condition treated with
chemotherapy radiation causes enhanced nucleic acid metabolism
and uric acid production.
An increase in urate production may be caused by excessive
dietary purine intake, certain cancers or their treatment, or,
more rarely, enzyme defects of purine metabolism.

5. PATHOPHYSIOLOGY
The uric acid is a waste product formed from the degradation of purines through the
purines degradation pathway. Purines → xanthine uric acid If there is abnormal
production and/or excretion of uric acid it will cause deposition of Monosodium Urate
Crystals(MUC) in joints and this will initiate the inflammation and cause gout.

6. 9/12/2019 7
* Process of gouty inflammation-
Precipitation of urate crystals in synovial fluid
Start inflammatory response
By producing Chemotactic factors
Migration of granulocytes in to joints
Which phagocytose (engulf) urate crystals
Release glycoprotein
Increases lactic acid production form
inflamed cell
Decreases PH
More urate crystals get precipitate and
affect joint
Release lysosomal
enzyme
Joint destruction
Aggrevates/ Worsen inflammatory condition

8. Antigout drugs
These are the drugs which are used in
treatment of gout condition which are acts
by one of the following mechanism: By
⚫Inhibiting Uric acid synthesis ( Allopurinol).
⚫Increasing Uric acid excretion (Probencid,
Sufinpyazone).
⚫Inhibiting leukocyte migration toward joint
(Colchicine).
⚫Providing general NSAID’s action
(Glucocorticoids).
8

9. Classification
For acute gout: sudden onset of severe inflammation in a small
joint due to precipitating of urate crystal in the joint space.
Drugs used are - NSAID’s, Colchicine, Glucocorticoids.
For chronic gout/ hyperuricaemia: Chronic gout is the
repeated episodes of pain and inflammation. More than one joint
may be affected.
Ex- 1. Uricosurics agent : Probenecid, Sulfinpyrazone,
2. Uricacidsynthesisinhibitor : Allopurinol

10. 1. NSAID’s drugs
1
0
⚫ Various drugs used are indomethacin, naproxen, piroxicam,
diclofenac or etoricoxib given at high and repeated dose to
terminate attack.
⚫ Produces responses slow as compared to colchicine but well
tolerated so more preferred than colchicine.
⚫ Naproxen, piroxicam inhibits chemotactic migration of
leucocytes into the inflamed joint.
⚫ Should be avoid in: GI ulcer, Bleeding or perforation,
Renal insufficiency , Heart failure , Use of oral
anticoagulants

11. MECHANISM OF ACTION
• COX inhibitors cause inhibition of COX enzyme and inhibits conversion of
arachidonic acid into PGG2 later PGG2 to PGH 2, PGI2, PGE2, PGF2α and
PGD2. So inhibits pain sensation-Analgesic action, decreased tissue edema-
Anti inflammatory action.
• Inhibits pain sensation-Analgesic action.
• Reduced capillary permeability, decreased tissue edema-Anti inflammatory
action.
• These release Prostaglandins which are responsible for inflammation, pain
etc.

13. .
Therapeutic uses:
• Acute Gout
Adverse effect:
• Nausea
• Vomiting
• Constipation
• Diarrhea
• Dizziness
• Edema
• Kidney failure
• Ulcers.

14. 2. Colchicine
1
4
⚫ Alkaloid from Colchicum autumnale / autumn crocus found as
antigoute in 1763 and isolated as pure form in 1820.
⚫ Is neither anti-inflammatory or analgesic activity but used
specifically in treatment of gouty inflammation.
⚫ .It does not inhibit the synthesis or promote the excretion of
uric acid, and has no effect on blood uric acid levels.

15. MECHANISM OF ACTION
Colchicine accumulates in white blood cells and affects them in a
variety of ways - decreasing motility, mobilization
(especially chemotaxis), and adhesion.
•Inhibits microtubule polymerization by binding to its constitutive
protein, tubulin. As availability of tubulin is essential to mitosis,
colchicine may inhibit mitosis
•Inhibits activation and migration of neutrophils to sites of
inflammation.
OR
•COLCHICINE: produces its anti-inflammatory effects by
binding to the intracellular protein tubulin ,thereby preventing its
polymerization into microtubules (arresting neutrophil motility)
and leading to the inhibition of leukocyte migration .

16. * Mechanism of action Colchicine:
Start inflammatory
response
By producing
Chemotactic factors
Migration of granulocytes
in to joints
Symptomatic relief for gout
Precipitation of urate
crystals in synovial fluid
Colchicine
Bind to fibrillar protein
tubulin
Depolymerisation
of microtubules
Decreases cell
motility
Prevent
16

17. • PHARMACOKINETICS :
• Absorption: absorbed orally and reaches peak plasma levels
with in 2 hrs.
• Distribution: Uniform.
• Metabolism:Liver
• Elimination: bile-undergoes enterohepatic circulation,
Urine & faeces

18. * Toxicity of Colchicine: High and dose related.
At therapeutic dose: Nausea, vomiting, watery or bloody diarrhoea
and abdominal cramps.
Accumulation of the drug in intestine and inhibition of mitosis .
In overdose: colchicine produces kidney damage, CNS depression,
intestinal bleeding; death is due to muscular
paralysis and respiratory failure.
Chronic therapy: Not recommended because it causes aplastic
anaemia, agranulocytosis and loss of hair.
18

19. 9/12/2019 1
* Drug interaction with other drug: Colchicine shows
1
interaction with;
Sr .
No.
Category of drug Example from class Interaction
1.
Cholesterol drugs
atorvastatin, fluvastatin,
lovastatin, gemfibrozil
Serious muscle
damage.
2. Antiarrhythmic drug. Digoxin,
3.
HIV drugs,
indinavir, atazanavir, nelfinavir,
saquinavir, or ritonavir.
4. Antidepressressants nefazodone.
5.
Antibiotics, clarithromycin or telithromycin
6.
Antifungal drugs ketoconazole or itraconazole.
Increases
concentrationof
colchicine
7.
Calcium channel
blocker
verapamil or diltiazem
stomach pain,
constipation,
diarrhea, nausea, or
vomiting.

20. * Use of Colchicine:
20
1. Treatment of acute gout: Best drug to control an acute attack of
gout, 1 mg orally followed by 0.25 mg 1-3 hourly till control of the
attack.
2.Prophylaxis condition of gout: Colchicine 0.6-1 mg/day prevent
gout attack but now a days NSAID’s are preferred.

21. ADVERSE EFFECTS:
1. diarrhea, Nausea , Vomiting and abdominal pain.
2. Rarely causse hair loss and bone marrow depression
as well as peripheral neuritis and myopathy.

22. 3. Corticosteroid
22
⚫ The use of corticosteroids is often suggested for elderly patients
with chronic tophaceous gout.
⚫ Corticosteroids decrease the pain, swelling, redness and
(inflammation) of gout.
⚫ Intra-articular inj. : those not tolerating
NSAIDs/Colchicine
⚫ But Corticosteroids are used only for patients suffering from renal
failure or peptic ulcer( Bcause NSAID’s are contraindicated).
⚫ Risk of rebound of attack is observed on drug withdrawal.
⚫ Example; Prednisolone 40-60 mg given once a day.

23. URICOSURIC AGENTS
• The uricosuric drugs are anions that are somewhat similar to
urate in structure ,therefore they can compete with uric acid
for transport sites.
• Small doses of uricosuric agents will actually decrease the total
excretion of urate by inhibiting its tubular secretion.
• And at high dosages these same drugs increases uric acid
elimination by unhibiting its proximal tubular reabsorption
• The two most clinically important uricosuric drugs PROBENECID
and SULFINPYRAZONE are organic acids
• The initial phase of therapy with uricosuric drugs is the most
dangerous period, until Uricosuric drugs level build up
sufficiently to fully inhibit uric acid reabsorption as well as
secretion , there may be a temporary increase in uric acid
blood levels that significantlyincreases the risk of an acute
gouty attack

24. • Therefore ,it is wise to begin therapy with the administration of small amts of
colchicine before adding a uricosuric drug to the therapeutic regimen.
• In addition , the initial rise in urinary uric concentrations during uricosuric drug
therapy maya result in renal stone formation.
• PROBENECID:
• Mechanism: Blocks tubular reabsorption of uric acid & enhances urine uric acid
excretion
• Probenecid inhibits Urate Transporters (URAT1) in the apical membrane of the
proximal tubule
• It also inhibits organic acid transporter(OAT)→↑plasma concentration of penicilin
• Dose of probenecid : 0.5 gm orally daily in divided doses, progressing to 1 gm daily
after 1 week.
• It should be given in divided dose with food to reduce adverse GIT effects

25. 4. Probenecid
Uric acid
Reabsorbed by active
transport
⚫ Lipid soluble organic acid developed in 1951.
*Mechanism of action Probenecid:
Probenecid
Active transport
of organic acid
OATP ( organic
anion transporting
polypeptide
receptor)
Block
25
By Blocking
Inhibit
Causes
excretion

26. *Pharmacokinetics:
⚫ Absorption: Rapid orally.
⚫ Distribution: 90% bound to plasma protein
⚫ Metabolism: Liver
⚫ Elimination: Urine.
*Drug interaction with other drug: Probenecid shows
interaction with;
26
Sr .
No.
Category of drug Example from class Interaction
1.
Antibiotics
penicillins, cephalosporins,
sulfonamides,
Inhibits
the urinary
excretion
2. NSAID’s Indomethacin, salicylates
3. Antibiotics
rifampicin. Biliary excretion
4.
Antimicrobial nitrofurantoin
Inhibits tubular
secretion of drug

27. * Toxicity of Probenecid :
Dyspepsia (indigestion).
Rashes and other hypersensitivity .
Toxic doses cause convulsions and respiratory failure.
* Use of Probenecid:
Chronic gout and hyperuricaemia:
⚫ second line or adjunct drug to allopurinol.
⚫ 0.25 g-0.5g BD gradually lower blood urate level along with arthritis,
tophi and other lesions but ineffective during renal insufficiency.
⚫ Plenty of fluids should be given with probenecid to avoid urate
crystallization in urinary tract.
Prolong drug action:
⚫ Probenecid is also used to prolong penicillin or ampicillin action by
enhancing and sustaining their blood levels, e.g. in gonorrhoea, Subacute
bacterial endocarditis (SABE).
27

28. 5. Sulfinpyrazone
⚫ It is a pyrazolone derivative related to phenylbutazone having consistent
uricosuric action.
⚫ Not having anti-inflammatory or analgesic activity but used specifically in
treatment of gouty inflammation.
* Mechanism of action Sulfinpyrazone:
• It inhibits tubular reabsorption of uric acid
• Also inhibits platelet aggregation.
* Pharmacokinetics:
• Absorption: Rapid orally.
• Distribution: 98% bound to plasma protein.
• Elimination: active secretion in proximal tubule Urine.
28

29. * Adverse effect of Sulfinpyrazone:
⚫ Gastric irritation so contraindicated in patients with peptic ulcer.
⚫ Rashes and other hypersensitivity reactions.
⚫ At overdose convulsions, coma, anaemia, jaundice, and ulceration.
* Use of Sulfinpyrazone:
Used in treatment of chronic gout 100-200mg BD
*Drug interaction with other drug: Sulfinpyrazone shows interaction
with;
29
Sr .
No.
Category of drug Example from class Interaction
1.
oral anticoagulant
warfarin
increase the effects
2. tolbutamide
3. Anti asthmatic theophylline worsening asthma
4. Calcium channel
blocker
verapamil
high blood pressure or an irregular
heartbeat.

30. URIC ACID SYNTHESIS INHIBITOR
Allopurinol : is the drug of choice in the treatment of chronic
tophaceous gout and is especially useful in patients whose
treatment is complicated by renal insufficiency.
• it is alternative to increasing uric acid excretion in the
treatment of gout is to reduce its synthesis by inhibiting
xanthine oxidase with allopurinol

31. MOA
• Nucleic acids are converted to xanthine or hypoxanthine and
oxidized to uric acid.
• Allopurinol is contrast to the uricosuric drugs , reduces serum
urate levels through a competitive inhibition of uric acid
synthesis rather than by impairing renal urate re absorption.
• This action is accomplished by inhibiting XANTHINE OXIDASE,
the enzyme involved in the metabolism of hypoxanthine and
xanthine to uric acid.
• After enzyme inhibition , the urinary and blood concentrations
of uric acid are greatly reduced and there is a simultaneous
increase in the excretion of more soluble uric acid precursors,
xanthine and hypoxanthine.

32. 6. Allopurinol
Uric acid
xanthine
⚫ This hypoxanthine analogue was synthesized a purine antimetabolite for
cancer chemotherapy it had no antineoplastic activity.
⚫ It has substrate as well as inhibitor of xanthine oxidase, the enzyme
responsible for uric acid synthesis.
Allopurinol
Hypoxanthine
Alloxanthene
Xanthene oxidase
Xanthene oxidase
Xanthene oxidase
Inhibit both steps
32

33. * Pharmacokinetics:
• Absorption: Rapid orally.(80%)
• Distribution: Not bound to plasma protein.
• Metabolism: During chronic administration inhibit self metabolism.
• Elimination: 1/3 excreted as unchanged form in urine.
*Drug interaction with other drug: Allopurinol shows
interaction with;
33
Sr .
No.
Category of
drug
Example from class Interaction
1.
Anticancer f 6-mercaptopurin & azathioprine
Allopurinol prevent
degradation of all drugs
2. Uricosurics Probenecid kidney or liver disease
3. Anti asthmatic theophylline skin rashes
4.
Haematinics Iron therapy
mobilization of hepatic iron
stores

34. * Adverse effect of Allopurinol:
⚫ Gastrointestinal intolerance , including nausea, vomiting and diarrhea ,
may occur.
⚫ Stevens-Johnson syndrome(serious disorder of the skin and mucous
membranes. painful red or purplish rash)
⚫ Liver damage, cataracts
* Use of Allopurinol:
• In Chronic gout , in which reabsorption of tophi is more rapid than with
uricosuric agents.
• When probenecid or sulfinpyrazone cannot be used because of Adverse
effects or allergic reactions or when they are providing less than optimal
therapeutic effect
• For recurrent renal stones
• In patients with renal functional impairment
34