Leflunomide

Leflunomide is a drug that causes modification of the immune system while undergoing treatment (this modification or alteration is a part of the treatment so that is why it is also called as immunomodulatory agent) and disease modifying anti-rheumatic agent.


Mechanism of action:
Leflunomide causes inhibition of:

1. Multiplication or propagation of T cells

2. Production of autoantibodies by B cells.

Leflunomide inhibit the enzyme Dihydroorotate dehydrogenase (DHODH). This causes Uridine 5’-monophosphate (UMP) not to be produced.

UMP is essential in two ways:

1. It is an important component of RNA synthesis.

2. It is pioneer in making nucleotide which is composed of thymidine, which is required for DNA synthesis.

As a result there is a cell arrest.

Action:

It is a reversible inhibitor of DHODH. It helps to reduce pain and inflammation and along with this function it also helps to reduce the decay or erosion cause to the bones or any other body parts due to inflammation.

It can be used alone or in combination with other drugs like methotrexate.

Pharmacokinetics:
It is well absorbed orally. Its half life is 13-19 days. The binding of this drug to serum albumin is about more than 85%. It is excreted both through biliary and renal excretion. It readily converts to metabolites and the metabolites are excreted in the urine and feces.

The metabolite which is still effective goes back to do some work. Cholestyramine enhances leflunomide excretion.

Adverse effects:
It may cause headache, diarrhea (loose bowels) and nausea. Alopecia, Weight loss or weight gain and allergic reactions like skin rash are its rare side affects.

Contraindications:
It is contraindicated in pregnancy.

Precautions:
As this drug may cause an increase in liver enzyme level so it must be used with caution in liver diseases.

Methotrexate

It is thought that methotrexate is the cornerstone of the therapy for the patients, who have not responded well to other NSAIDs in severe rheumatoid arthritis or psoriatic arthritis.


Action:
As this is an immunosuppressant, this may be responsible for its effectiveness in reducing arthritis which according to some experts is an autoimmune disease.

Methotrexate slows the decay within moving joints, which may be due to the inhibition of thymidylate synthetase and some other related enzymes.

Pharmacokinetics:
The drug is found to be absorbed about 65%-75% after oral administration. Its serum half life is about 6-9 hours.

It has been found that methotrexate shows response usually sooner than the other agents i.e. it may be within 3 to 6 weeks of treatment.

Dosage:
Small doses are effective for the treatment of Arthritis than those needed for the treatment of cancer as this drug is also useful for the treatment of cancer. The dose is reduced to once a week administration.

Adverse Effects:
In small doses it may cause mucosal ulceration and nausea. Some of the following adverse effects may also be seen:

1. Cytopenia

2. Liver cirrhosis (it is particularly dose related)

3. Pneumonia like syndrome (hypersensitivity lung reaction)

Disease modifying anti-rheumatic agents

Disease modifying anti-rheumatic drugs (DMARDs) or slow acting anti-rheumatic drugs (SAARDs)


1. Slow the course of the disease and can induce remission.

2. Reduce or prevent the joint damage.

Drugs to be choosen:
Many experts start therapy with the conventional drugs i.e. methotrexate or hydroxychloroquine. But if these do not work properly then they go to the newer agents i.e. anakinra, adalimumab, leflunomide, and infliximab. Often it is also prescribed that the combination therapy is more effective.

Acetaminophen

Action:

It inhibits prostaglandin synthesis in CNS (so analgesic and anti-pyretic) but has less effect on COX so (weak anti-inflammatory).

Therapeutic Uses:
It is used as analgesic and anti-pyretic. It is analgesic /anti-pyretic of choice for children with viral infections or chicken pox.

Drug interactions:
It does not antagonize the uricosuric agent (probenecid) and so may be used in patients with gout who are taking this drug.

Pharmacokinetics:
Rapidly absorbed from GI tract. 1st pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. It is conjugated in the liver to form inactive glucoronidated or sulfated metabolites. It is excreted in the urine.

Adverse effects:
It may cause skin and minor allergic reactions. Prolonged use may cause renal tubular necrosis and hypoglycemic coma.

Celecoxib

Action:

Inhibition of COX-2 by celecoxib is time dependent and reversible.

Pharmacokinetics:
It is readily absorbed orally. Its peak concentration is approximately 3 hours. It is metabolized in the liver by cytochrome P450 (CYP2C9). It is excreted in feces and urine. Its half life is 11 hours, so its dose is adjusted according to once a day.

Adverse Effects:
It may cause abdominal pain, Diarrhea, Dyspepsia and Kidney toxicity may also occur.

Drug interactions:
It inhibits CYP2D6 and so can elevate levels of ß-blockers, anti-depressants and anti-psychotic drugs.

Fluconozole, fluvastatin and zafirlukast may increase serum level of celecoxib.

Precautions:

It should be avoided in patients;

- with chronic renal insufficiency

- Severe heart disease

- Volume depletion

- Hepatic failure

COX-2 selective NSAIDs

COX-2 is better in providing space for inhibitors than COX-1.


Uses:
It is used as a pain reliever.
Adverse effects:
It may cause renal insufficiency and hypertension.

Diflunisal

It is diflurophenyl derivative of salicylic acid.


Action:
3-4 times more potent than aspirin but cannot be used as antipyretic.

Pharmacokinetics:
It is not metabolized to salicylate and therefore cannot cause salicylate intoxication. It cannot enter CNS, so cannot relieve fever.