Anti-gout Drugs

Question 1

Gout

Answer 1

It is a metabolic disorder characterized by hyperuricemia.

The normal plasma urate levels should be of 2-6mg/dl.

Uric acid is a product of purine metabolism and has low water solubility especially at low pH.

When plasma urate levels are increased, it gets precipitated and deposited in joints, kidneys (may cause nephritis) and Subcutaneous tissue ( may cause hypersensitivity reactions).

Causes
1. Overdrinking of alcoholic beverages
2. Eating purines rich foods
3. Leukemias, lymphomas and polycythemia conditions especially when they are treated with chemotherapy or radiation it causes increased nucleic acid metabolism causing increased uric acid production.
4. Drugs like furosemide, ethambutol, clofibrate, pyrazinaminde and levodopa decreases the excretion of uric acid by kidneys and produces gout.

Question 2

Classification of Anti-gout drugs.

Answer 2

According to the mechanism of action
1. Inhibition of uric acid synthesis
- Allopurinol
2. Promotion of uric acid excretion
- probenecid
- Sulfapyrazone
3. Inhibiting migration of leukocytes towards joints
- colchicine
4. Providing general NSAIDs action
- glucocorticoids

According to the condition of gout
1. Acute gout :-
It is a painful condition that mostly affects only one joint.
It is a sudden onset of severe inflammation in small joints (mostly metarso-phalangeal joints of great toe) due to the precipitation of urate crystal in the joint space.
Requires immediate treatment.
- NSAIDs
- colchicine
- glucocorticoids
2. Chronic gout :-
It is a repeated episode of pain and inflammation and it affects more than one joint.
Other important features of chronic gout are :- hyperuricemia, tophi and urate crystals in kidneys.
Uricosuric drugs:-
- probenecid
- Sulfapyrazone
Uric acid synthesis inhibitors:-
- Allopurinol
- Febuxostat

Question 3

NSAIDs

Answer 3

• Various drugs like indomethacin, piroxicam, diclofenac, etoricoxib and naproxen are used.

• They are given at high and repeated doses to terminate the attack.

• They produce the response slowly as compared to colchicine but they are well tolerated.

• Naproxen and Piroxicam inhibits the chemotactic migration of leukocytes into inflammed joints.

• But they are not recommended for long term management due to their risk of toxicity.

Question 4

Colchicine

Answer 4

Colchicine is an alkaloidal drug obtained from Colchium Autumnale or Autum crotus.

It is neither analgesic or anti-inflammatory but it specifically suppresses gouty inflammation.

Process of gouty inflammation
An acute attack of gout is started by — precipitation of urate crystals in synovial fluid — They get engulfed by synovial cells and starts inflammatory response — by producing chemotactic factors (primarily WBC) — migration of granules to joint — which phagocytose urate crystals — releases glycoproteins which further worsens the inflammation by
i. Increasing lactic acid production by the inflammed cells — decrease in pH — more urate crystals get precipitated in the affected joint.
ii. Releases lysosomal enzyme — joint destruction — aggravates or worsens the inflammatory condition.

Mechanism of action
• colchicine do not affect phagocytosis of urate crystals but it inhibits the release of chemotactic factors and glycoproteins, suppressing the further events.
• Colchicine binds to fibrillar proteins i.e tubulin — depolymerization of microtubules — decreases the cell motility — prevents migration of granulocytes to joint
(precipitation of urate crystals in synovial fluid — starts inflammatory response — by producing chemotactic factors)
— gives symptomatic relief of gout.

Other actions
Anti-mitotic:-
It binds to microtubules of mitotic spindle and causes metaphase arrest which is used in cancer chemotherapy but abandoned due to its toxicity. It is used in the polyploidy of plants.
Gut action:-
It increases gut motility through the neural mechanism.

Toxicity
• toxicity is high and dose related.
• Nausea, vomiting, bloody or watery diarrhoea and abdominal cramps are the dose limiting adverse effects.
• Accumulation of drug in intestine and inhibition of mitosis are responsible for toxicity.
• At overdose, it causes CNS depression, kidney damage, intestinal bleeding and death due to muscular paralysis and respiratory failure.
• In chronic therapy, it causes Aplastic Anaemia, Agranulocytosis, myopathy and loss of hair.

Pharmacokinetics
• rapidly absorbed orally
• partly metabolized in the liver
• excreted through bile, feces and urine.

Drug interactions
• when colchicine is taken with
1. Cholesterol drugs like genfibrozil, Atrovastatin, fluvostatin, lovostatin
2. HIV drugs like indinavir, nelfinavir, atazanavir, saquinavir
3. Anti-arrhythmic drugs like digoxin
4. Antibiotics like clarithromycin, telithromycin
5. Anti-depressants like nefazodone
Because they cause severe muscle damage
• colchicine shouldn’t be given with Antifungal drugs like ketoconazole, itraconazole- because it increases the concentration of colchicine.
• colchicine shouldn’t be given with Calcium channel blockers like verapamil and diltiazem because it causes nausea, vomiting, stomach pain, diarrhoea and constipation.

Uses
• acute gout
• prophylaxis of gout