Allopurinol

Introduction:

Allopurinol is a purine analog. It is also an isomer of hypoxanthine.

Mechanism of action:
Allopurinol inhibits xanthine oxidase enzyme which is required for the synthesis of Uric acid. This enzyme is required when purine is oxidized to Uric acid.

Therapeutic uses:
This is effective in the treatment of gout, which may be due to;
1. Primary hyperuricemia
2. Secondary hyperuricemia (Such as those caused from the use of chemotherapeutic agents or diseases of the kidneys).

It is also effective as an anti-protozoal agent.

Pharmacokinetics:
It is well absorbed (approximately 70-85%) orally. One of its metabolite is alloxanthine (also called as oxypurinol) which is also effective in the inhibition of xanthine oxidase. Allopurinol takes action along with this metabolite.

The plasma half life of allopurinol is 2 hours and that of oxypurinol is 15 hours. The drug and its metabolites are excreted in the urine and feces.

Dosage:
Due to the long half life of oxypurinol the dosage can be maintained at the rate of 1 dose/day. Its initial dose is 100 mg/day.

Adverse effects:
Hypersensitivity reactions such as rashes may occur. GI disturbances such as nausea and diarrhea can also be there.

Interactions:
It may cause an increase of the effect of cyclophosphamide. It may interfere with anti-cancer drugs such as 6-mercaptopurine and the immunosuppressant such as azathioprine.

Colchicine

Introduction:

It is an alkaloid obtained from plant, Colchicum autumnale. It has been found effective in the treatment of acute gout.

Mechanism of action:
It causes the disruption of cellular activities such as movement of granulocytes to the affected area and phagocytosis. It also inhibits the synthesis and release of leukotriene B4.

Action:

It relieves pain. Though it cannot prevent the progression of gout to acute gouty attacks but it is used as a prophylactic drug in this case so helps to keep down pain and frequency of acute attacks. It is now used in combination with probenecid.

Indomethacin is now replacing Colchicine.

Therapeutic Uses:
It is used for the relief of pain and inflammation in acute gout within 12-24 hours.

Pharmacokinetics:
It is absorbed rapidly from GI tract. Its peak plasma level is attained within 2 hours. Its plasma half life is 9 hours. It is recycled in the bile and excreted unchanged in the feces or urine.

Dosage:
The usual dosage of colchicines is 0.6 mg one to three times daily as a prophylaxis of gout.

Adverse effects:
It may cause nausea, vomiting, abdominal pain and diarrhea.
Prolonged administration may cause myopathy, aplastic anemia and alopecia.

Contraindications:
It is contraindicated in pregnancy.

Precautions:
It should be used with caution in hepatic, renal or cardiovascular diseases.

Gout

Purine metabolism is responsible for the production of Sodium urate. When the quantity of Urate in the blood goes up than normal, it may result in gout which may show inflammation and produces more oxygen metabolites in the blood.

Therapeutic strategies:
First of all it is better to use purine free diet i.e. we must use dairy products, fruits and cereals. The sequence, in the diagram, show that most effective medicine in treating gout is that which causes reduced entry of leukocyte into the affected joint which may be achieved by colchicine.

Other ways of therapy include:

1. Disturbing uric acid synthesis with the help of allopurinol.

2. Promoting excretion of uric acid with probenecid or sulfinpyrazone.

3. Use of NSAIDs.

Types of Gout:
There are two types of gout:

1. Acute gout.

2. Chronic gout.

Acute gout:
Causes:
The main causes of acute gout are as follows:

1. Diet which is rich in purine.

2. Kidney diseases.

3. Alcohol consumption.

Treatment:
In this we can use Indomethacin in combination with Aspirin. Indomethacin slows the movement of granulocytes in the area which is affected and aspirin decreases pain and inflammation.

Chronic gout:

Causes:
The main causes of chronic gout are as follows:
1. Genetic defect.
2. Renal deficiency
3. Lesch Nyhan syndrome.
4. Excessive synthesis of uric acid associated with cancer chemotherapy.

Treatment:
In this we can use Uricosuric drugs such as probenecid and sulfinpyrazone and Allopurinol.

Uricosuric drugs (e.g. Probenecid or sulfinpyrazone) promote excretion of uric acid resulting in reduced concentration of uric acid in plasma. It is preferred for patients with normal excretion of uric acid through urine.

Allopurinol selectively inhibits some steps in the middle of the biosynthesis of uric acid. It is preferred for patients with excessive uric acid excretion (which may be due to renal insufficiency).

Anakinra

Introduction:

Anakinra is an IL-1 receptor antagonist.

Action:
The treatment with this drug causes slowing of process of moderate to serious rheumatoid arthritis.

The drug may be used alone or in combination with other drugs.

Administration:
It is administered subcutaneously.

Adverse effects:
It may cause headache, nausea, vomiting and injection site reactions.

Adalimumab

Introduction:

It is a fully human recombinant monoclonal antibody (MAB).

Mechanism of action:
It gets bind to human TNF-α receptor site thus stops endogenous TNF- α activity by preventing its interaction with p55 and p75 cell surface receptors.

Action:
It decreases symptoms of Rheumatoid arthritis and stops erosion of the (bone) structure.

Therapeutic uses:
It is used in Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. (As increased TNF in the synovial fluid cause pain and joint destruction in Rheumatoid arthritis).

Pharmacokinetics:
It is used subcutaneously and its half life is 10-20 days.

Dose and Administration:
Its usual dose is 40 mg every other week. It is used Subcutaneously only.

Adverse effects:
It may cause headache, nausea, rashes and reactions at the site of injection.

Infliximab

Introduction:

It is a chimeric IgGκ monoclonal antibody made up of human (75%) and animals (25%) such as rats and mice.

Mechanism of Action:
Infliximab binds to human TNF-α and as a result neutralize the cytokines.

Action:
It removes the progression of damage or erosion to structure so that patient can perform functions more efficiently.

Pharmacokinetics:
It is administered intravenously and slowly in about 2 hour’s time in doses of 3 mg/kg to 10 mg/kg. Its half life is about 9-10 days. It is distributed equally in vascular compartments.

It is not approved for therapy continuously after 6th week.

Therapeutic uses:
It is used in Rheumatoid arthritis and Crohn’s disease. It has been found that the combination with methotrexate is more effective.

Adverse effects:
It may cause upper respiratory tract infections, nausea and vomiting. The production of anti-infliximab antibodies have also been studied after prolonged use of infliximab. It may cause some of the reactions at the site of infusion such as fever, chill and pruritis.

Leukopenia, neutropenia and thrombocytopenia have also been found.

Etanercept

Introduction:

Etanercept is a biotechnological product as it is genetically engineered fusion protein.
It is composed of:

1. Two identical chains of the recombinant human TNF-receptor p75 monomer.

2. Fc domain of IgG1 (human immunoglobulin).

These two are fused together.

Mechanism of action:

Etanercept binds two molecules of TNF thereby resulting in no binding of TNF to cellular receptors.

Action:
Etanercept, Infliximab and adalimumab decrease the activity of TNF. TNF is important for immunity system and must rest in the rheumatic synovium for the action to take place.

Pharmacokinetics:
It is given subcutaneously, 25 mg, two times a week. Maximum serum concentration is obtained within 72 hours after parenteral administration. Its half life is 4-6 days.

Therapeutic Uses:
Rheumatic and psoriatic arthritis.

Adverse effects:
No important adverse effects have been found.

Contraindications:
In serious type of infections like sepsis, etanercept should not be given to patient.

NOTE:
Etanercept and methotrexate are more effective when used together (than alone) in slowing the

1. Disease process

2. Improvement in function

3. Stoppage of the symptoms.