Antirheumatoid and Antigout Drugs notes / Immunosuppressants Agents notes / Bpharma notes

 Antirheumatoid and Antigout Drugs :

Antirheumatoid Drugs :

These are drugs which (except corticosteroids), can suppress the rheumatoid process, bring about a remission and retard disease progression, but do not have nonspecific antiinflammatory or analgesic action. They are used in rheumatoid arthritis (RA) in addition to NSAIDs, and are also referred to as disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs (SAARDs). The onset of benefit with DMARDs takes a few months of regular treatment, and relapses occur at least a few months after cessation of therapy. Recently, some biological agents (antibodies and other proteins) have been added for resistant cases.

Rheumatoid arthritis (RA) is an autoimmune disease in which there is joint inflammation, synovial proliferation and destruction of articular cartilage. Immune complexes composed of IgM activate complement and release cytokines (mainly TNFα and IL-1) which are chemotactic for neutrophils. These inflammatory cells secrete lysosomal enzymes which damage cartilage and erode bone, while PGs produced in the process cause vasodilatation and pain. RA is a chronic progressive, crippling disorder with a waxing and waning course. Multiple small joints of hands and feet are preferentially affected; deformities are produced as the disease progresses. NSAIDs are the first line drugs which afford symptomatic relief in pain, swelling, morning stiffness, immobility, but do not arrest the disease process. 

The goals of drug therapy in RA are:

• Ameliorate pain, swelling and joint stiffness .
• Prevent articular cartilage damage and bony erosions.
• Preserve joint function and prevent deformity.  

Though mild/early cases are still mostly treated with NSAIDs alone, the current recommendation is to add DMARDs as soon as the diagnosis of RA is confirmed. However, use of DMARDs in early/mild RA should be weighed against their potential adverse effects, which may be serious. More than one DMARD may be used concurrently; advanced cases may require 2 or 3 drugs together, because all DMARDs tend to lose effectiveness with time.

Nonbiological drugs :

1. Immunosuppressants (see Ch. 65) :

Methotrexate (Mtx) :

This dihydrofolate reductase inhibitor has prominent immunosuppressant and antiinflammatory property. Beneficial effects in RA are probably related to inhibition of cytokine production, chemotaxis and cell-mediated immune reaction. Proliferation of immune-inflammatory cells is inhibited. Induction of oral low-dose (7.5–15 mg) weekly Mtx regimen has improved acceptability of this drug in RA. Onset of symptom relief is relatively rapid (3–6 weeks), therefore Mtx is preferred for initial treatment. Mtx is now the DMARD of first choice and the standard treatment for most patients, including cases of juvenile RA. Response is more predictable and sustained over long-term. Combination regimens of 2 or 3 DMARDs mostly include Mtx.

Oral bioavailability of Mtx is variable and may be affected by food. Its excretion is hindered in renal disease; therefore, not recommended for such patients. Probenecid and aspirin increase Mtx levels and toxicity. Trimethoprim can add to inhibition of dihydrofolate reductase and depress bone marrow. Oral ulceration and g.i. upset are the major side effects of low dose Mtx regimen.

With prolonged therapy, dose dependent progressive liver damage leading to cirrhosis occurs in some patients, while this is not seen with short courses used for cancer. Incidence of chest infection is increased. Mtx is contraindicated in pregnancy, breast-feeding, liver disease, active infection, leucopenia and peptic ulcer.

NEOTREXATE, BIOTREXATE 2.5 mg tab.

Azathioprine  :

This purine synthase inhibitor acts after getting converted to 6-mercaptopurine by the enzyme thiopurine methyl transferase (TPMT). It is a potent suppressant of cellmediated immunity; appears to selectively affect differentiation and function of T-cells and natural killer cells. It also suppresses inflammation. However, remission is induced in smaller percentage of RA patients and it is less commonly used. Given along with corticosteroids, it has a steroid sparing effect, for which it is primarily used now, especially in cases with systemic manifestations. It is not combined with Mtx.

Dose: 50–150 mg/day; IMURAN; AZORAN, AZOPRINE 50 mg tab.

Immunosuppressants like cyclosporine, chlorambucil, cyclophosphamide are rarely used in RA. These drugs are reserved for cases not responding to other DMARDs.

2. Other immunomodulators :

Sulfasalazine :

It is a compound of sulfapyridine and 5-amino salicylic acid (5- ASA); exerts antiinflammatory activity in the bowel and is useful in ulcerative colitis. In addition, it suppresses the disease in a significant number of RA patients. The mechanism of action is not known. Sulfapyridine split off in the colon by bacterial action and absorbed systemically appears to be the active moiety (contrast ulcerative colitis, in which 5-ASA acting locally in the colon is the active component). Generation of superoxide radicals and cytokine elaboration by inflammatory cells may be suppressed. Efficacy of sulfasalazine in RA is modest and side effects may be unpleasant. Neutropenia/thrombocytopenia occurs in about 5–10% patients; regular blood count monitoring is needed. Hepatitis is possible. Sulfasalazine is used as a second line drug for milder cases or is combined wih Mtx .

Dose: 1–3 g/day in 2–3 divided doses. 

SALAZOPYRIN, SAZO-EN 0.5 g tab.

Hydroxychloroquine/Chloroquine :

These are antimalarial drugs found to induce remission in upto 50% patients of RA, but take 3–6 months. Their advantage is relatively low toxicity, but efficacy is also low; bony erosions are not prevented. Their mechanism of action is not known, however, they have been found to reduce monocyte IL–I, consequently inhibiting B lymphocytes. Antigen processing may be interfered with. Lysosomal stabilization and free radical scavenging are the other proposed mechanisms.

For RA, these drugs have to be given for long periods: accumulate in tissues (especially melanin containing tissue) and produce toxicity, most disturbing of which is retinal damage and corneal opacity. This is less common and reversible in case of hydroxychloroquine, which is preferred over chloroquine. Other adverse effects are rashes, graying of hair, irritable bowel syndrome, myopathy and neuropathy.

Hydroxychloroquine/Chloroquine are employed in milder nonerosive disease, especially when only one or a few joints are involved, or they are combined with Mtx/sulfasalazine. Hydroxychloroquine 400 mg/day for 4–6 weeks, followed by 200 mg/day for maintenance.

ZHQUINE, ZYQ, HCQS 200, 400 mg tab. 

Chloroquine 150 mg (base) per day.

In patients of vitiligo, improvement in skin pigmentation has been noted after few months therapy with hydroxychloroquine, but vitiligo is not an approved use of this drug.