Anti rheumatoid and Antigout Drugs

 Chapter -15 

Anti rheumatoid and Antigout Drugs

ANTIRHEUMATOID DRUGS

• These are drugs which (except corticosteroids), can suppress the rheumatoid process and bring about a remission, but do not have nonspecific anti-inflammatory 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 a few months after cessation of therapy. Recently, some biologic response modifiers (BRMs) 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. NSAIDs are the first line drugs and 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 

• Prevent deformity and preserve joint function.

• Though mild/early cases are still mostly treated only with NSAIDs, 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.

A. Disease modifying antirheumatic drugs (DMARDs)

1. Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine 
2. Sulfasalazine 
3. Chloroquine or Hydroxychloroquine 
4. Leflunomide 
5. Gold sod. thiomalate, Auranofin 
6. d-Penicillamine

B. Biologic response modifiers (BRMs)

1. TNFα inhibitors: Etanercept, Infliximab, Adalimumab 

2. IL-1 antagonist: Anakinra

C. Adjuvant drugs

Corticosteroids: Prednisolone and others

1. Immunosuppressants

• Methotrexate (MT) This dihydrofolate reductase inhibitor has prominent immunosuppressant and anti-inflammatory property. Beneficial effects in RA are probably related to inhibition of cytokine production, chemotaxis and cell-mediated immune reaction. Induction of oral low-dose (7.5–15 mg) weekly MT regimen has improved acceptability of this drug in RA. Onset of symptom relief is relatively rapid (4–6 weeks), therefore preferred for initial treatment. MT 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.

• Oral bioavailability of MT is variable and may be affected by food. Its excretion is hindered in renal disease: not recommended for such patients. Probenecid and aspirin increase MT levels and toxicity. Trimethoprim can add to inhibition of dihydrofolate reductase and depress bone marrow. Nodulus's, oral ulceration and gig upset are the major side effects of low dose MT regimen. With prolonged therapy, dose dependent progressive liver damage leading to cirrhosis occurs in some patients (this is not seen with short courses used in cancer). Incidence of chest infection is increased. MT is contraindicated in pregnancy, breast-feeding, liver disease, active infection, leucopenia and peptic ulcer

• Azathioprine This purine antimetabolite acts after getting converted to 6-mercaptopurine by the enzyme thiopurine methyl transferase (TPMT). It is a potent suppressant of cell-mediated immunity; appears to selectively affect differentia Tion 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 MT.

2. Sulfasalazine

• It is a compound of sulphapyridine and 5-amino salicylic acid (5-ASA); has anti-inflammatory activity and is primarily used in ulcerative colitis. In addition, it suppresses the disease in significant number of RA patients. The mechanism of action is not known. Sulphapyridine 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 are few, but neutropenia/thrombocytopenia occurs in about 10% patients and hepatitis is possible. It is used as a second line drug for milder cases.

3. Chloroquine and hydroxychloroquine

• These are antimalarial drugs found to induce remission in up to 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 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.

• Chloroquine/hydroxychloroquine are employed in milder nonerosive disease, especially when only one or a few joints are involved, or they are combined with MT/sulfasalazine.

4. Leflunomide

• This immunomodulator inhibits proliferation of activated lymphocytes in patients with active RA. Arthritic symptoms are suppressed and radiological progression of disease is retarded. In clinical trials its efficacy has been rated comparable to Mix and onset of benefit is as fast (4 weeks).

• Leflunomide is rapidly converted in the body to an active metabolite which inhibits dihydroorotate dehydrogenase and pyrimidine synthesis in actively dividing cells. Antibody production by B-cells may be depressed. The active metabolite has a long t½ of 2 weeks; leflunomide, therefore, is given in a loading dose of 100 mg daily for 3 days followed by 20 mg OD

• Adverse effects of leflunomide are diarrhea, headache, nausea, rashes, loss of hair, thrombocytopenia, leucopenia, increased chances of chest infection and raised hepatic transaminases. It is not to be used in children and pregnant/ lactating women. Leflunomide is an alternative to MT or can be added to it, but the combination is more hepatotoxic. Combination with sulfasalazine improves benefit.

5. Gold

• Gold is considered to be the most effective agent for arresting the rheumatoid process and preventing involvement of additional joints. It was the standard DMARD before the advent of low-dose MT regimen. A remission is induced in over half of the patients. It reduces chemotaxis, phagocytosis, macrophage and lysosomal activity, monocyte differentiation and inhibits cell mediated immunity (CMI). Rheumatoid factor levels and ESR are lowered. By an effect on synovial membrane and collagen, it prevents joint destruction; may induce healing of bony erosions. It is effective in psoriatic arthropathy also.

• Gold is heavily bound to plasma and tissue proteins, especially in kidney stays in the body for years.

• Toxicity of parenteral gold salt (hypotension, dermatitis, stomatitis, kidney and liver damage, bone marrow depression) is high. It is rarely used now.

• Auranofin It is an orally active gold compound containing 29% gold, with a bioavailability of 25%. Plasma gold levels and efficacy are lower than with injected gold sod. thiomalate, but it is less toxic. Main adverse effect is diarrhea (30% incidence) and abdominal cramps. Others are pruritus, taste disturbances, mild Anamia and alopecia. Auranofin is used infrequently.

6. d-Penicillamine

• It is a copper chelating agent (see Ch. 66) with a gold-like action in RA, but less efficacious; bony erosions do not heal. It is not favored now because it does not offer any advantage in terms of toxicity, which is similar to that of gold. Loss of taste, systemic lupus and myasthenia gravis are the other adverse effects.

• Penicillamine increases soluble collagen and is the preferred drug for stage II and III scleroderma.

7. Biologic response modifiers

• Recently, several recombinant proteins/monoclonal antibodies that bind and inhibit cytokines, especially TNFα or IL-1 have been produced and found to afford substantial benefit in autoimmune diseases like RA, inflammatory bowel diseases, psoriasis, scleroderma, etc.

• TNFα inhibitors Because TNFα plays a key role in the inflammatory cascade of RA by activating membrane bound receptors (TNFR1 and TNFR2) on the surface of T-cells, macrophages, etc., exogenously administered soluble TNF-receptor protein or antibody can neutralize it and interrupt the reaction. TNF inhibitors mainly suppress macrophage and T-cell function; inflammatory changes in the joint regress and new erosions are slowed. Quicker response than DMARDs has been obtained. Though effective as monotherapy, they are generally added to Mix when response to the latter is not adequate or in rapidly progressing cases. Side effects are few, but susceptibility to opportunistic infections, including tuberculosis and pneumocystis pneumonia is increased. All are very expensive.

• Etanercept: It is a recombinant fusion protein of TN receptor and Fc portion of human IgG1; administered by sic injection 50 mg weekly. Pain, redness, itching and swelling occur at injection site and chest infections may be increased, but immunogenicity is not a clinical problem. 

• Infliximab: It is a chimeral monoclonal antibody which binds and neutralizes TNFα; 3–5 mg/kg is infused i.e., every 4–8 weeks. An acute reaction comprising of fever, chills, urticaria, bronchospasm, rarely anaphylaxis may follow the infusion. Susceptibility to respiratory infections is increased and worsening of CHF has been noted. It is usually combined with Mix which improves the response and decreases antibody formation against infliximab.

• Adalimumab: This recombinant monoclonal anti-TNF antibody is administered sic 40 mg every 2 weeks. Injection site reaction and respiratory infections are the common adverse effects. Combination with Mix is advised to improve the response and decrease antibody formation.

• IL-1 antagonist

• Anakinra: It is a recombinant human IL-1 receptor antagonist. Though clinically less effective than TNF inhibitors, it has been used in cases who have failed on one or more DMARDs.

8. Corticosteroids

• They have potent immunosuppressant and anti-inflammatory activity: can be inducted almost at any stage in RA along with first- or second-line drugs, if potent anti-inflammatory action is required while continuing the NSAID ± DMARD. Symptomatic relief is prompt, but they do not arrest the rheumatoid process, though joint destruction may be slowed, and bony erosions delayed.

• Long-term use of corticosteroids carries serious disadvantages. Therefore, either low dose (5–10 mg prednisolone or equivalent) are used to supplement NSAIDs (once used in this manner, it is difficult to withdraw steroids—exacerbation is precipitated: patient becomes steroid

• dependent), or high doses are employed over short periods in cases with severe systemic manifestations (organ-threatening disease, vasculitis) while the patient awaits response from a remission inducing drug.

• In cases with single or few joint involvements with severe symptoms, intraarticular injection of a soluble glucocorticoid affords relief for several weeks; joint damage may be slowed. However, this procedure should not be repeated before 4–6 months.

DRUGS USED IN GOUT

• Gout It is a metabolic disorder characterized by hyperuricemia (normal plasma urate 1–4 mg/ dl). Uric acid, a product of purine metabolism, has low water solubility, especially at low ph. When blood levels are high, it precipitates and deposits in joints, kidney and subcutaneous tissue (trophy).

Secondary hyperuricemia occurs in:

• Leukemias, lymphomas, polycythemia— especially when treated with chemotherapy or radiation: due to enhanced nucleic acid metabolism and uric acid production

• Drug induced—thiazides, furosemide, pyrazinamide, ethambutol, levodopa, clofibrate reduce uric acid excretion by kidney.

ACUTE GOUT

• Acute gout manifests as sudden onset of severe inflammation in a small joint (commonest is metatarsus-phalangeal joint of great toe) due to precipitation of urate crystals in the joint space. The joint becomes red, swollen and extremely painful: requires immediate treatment.

1. NSAIDs

• One of the strong anti-inflammatory drugs, e.g., indomethacin, naproxen, piroxicam, diclofenac or etoricoxib is given in relatively high and quickly repeated doses. They are quite effective in terminating the attack, but may take 12–24 hours, i.e., response is somewhat slower than with colchicine, but they are generally better tolerated; majority of patients prefer them over colchicine. Their strong anti-inflammatory (not uricosuric) action is responsible for the benefit. Naproxen and piroxicam specifically inhibit chemotactic migration of leucocytes into the inflamed joint. After the attack is over, they may be continued at lower doses for 3–4 weeks while drugs to control hyperuricemia take effect. They are not recommended for long term management due to risk of toxicity

• The NSAIDs have also substituted colchicine for covering up the period of initiation of therapy (6–8 weeks) with allopurinol or uricosurics in chronic gout

2. Colchicine

• It is an alkaloid from Colchicum autumn ale which was used in gout since 1763. The pure alkaloid was isolated in 1820.

• Colchicine is neither analgesic nor anti-inflammatory, but it specifically suppresses gouty inflammation. It does not inhibit the synthesis or promote the excretion of uric acid. Thus, it has no effect on blood uric acid levels.

• An acute attack of gout is started by the precipitation of urate crystals in the synovial fluid. They start an inflammatory response; chemotactic factors are produced → granulocyte migration into the joint; they phagocytose urate crystals and release a glycoprotein which aggravates the inflammation by:

• Increasing lactic acid production from inflammatory cells → local pH is reduced → more urate crystals are precipitated in the affected joint.

• Releasing lysosomal enzymes which cause joint destruction.

Colchicine does not affect phagocytosis of urate crystals but inhibits release of the glycoprotein and the subsequent events. By binding to fibrillar protein tubulin, it inhibits granulocyte migration into the inflamed joint and thus interrupts the vicious cycle. Other actions of colchicine are:

• Antimitotic: causes metaphase arrest by binding to microtubules of mitotic spindle. It was tried for cancer chemotherapy but abandoned due to toxicity. It is used to produce polyploidy in plants. 

• Increases gut motility through neural mechanisms.

• Pharmacokinetics Colchicine is rapidly absorbed orally, partly metabolized in liver and excreted in bile—undergoes enterohepatic circulation; ultimate disposal occurs in urine and farces over many days.

• Toxicity is high and dose related. Nausea, vomiting, watery or bloody diarrhea and abdominal cramps occur as dose limiting adverse effects. Accumulation of the drug in intestine and inhibition of mitosis in its rapid turnover mucosa is responsible for the toxicity. In overdose, colchicine produces kidney damage, CNS depression, intestinal bleeding; death is due to muscular paralysis and respiratory failure. Chronic therapy with colchicine is not recommended because it causes aplastic anemia, agranulocytosis, myopathy and loss of hair.

Use

• Treatment of acute gout Colchicine is the fastest acting drug to control an acute attack of gout; 1 mg orally followed by 0.25 mg 1–3 hourly till control of the attack is achieved (occurs in 4– 12 hour), or till total dose 6 mg is reached, or diarrhea starts. The response is dramatic, so much so that it may be considered diagnostic. However, because of higher toxicity, most physicians prefer using a NSAID. Maintenance doses (0.5–1 mg/day) may be given for 4–8 weeks in which time control of hyperuricemia is achieved with other drugs.

• Prophylaxis Colchicine 0.5–1 mg/day can prevent further attacks of acute gout, but NSAIDs are generally preferred.

3. Corticosteroids

• Intraarticular injection of a soluble steroid suppresses symptoms of acute gout. Crystalline preparations should not be used. It is indicated in refractory cases and those not tolerating NSAIDs/ colchicine.

• Systemic steroids are rarely needed. They are very effective and produce nearly as rapid a response as colchicine but are reserved for patients with renal failure/history of peptic ulcer bleed in whom NSAIDs are contraindicated or for cases not responding to or not tolerating NSAIDs. Prednisolone 40–60 mg may be given in one day, followed by tapering doses over few weeks.

CHRONIC GOUT

• When pain and stiffness persist in a joint between attacks, gout has become chronic. Other cardinal features are hyperuricemia, tophi (chalk-like stones under the skin in pinna, eyelids, nose, around joints and other places) and urate stones in the kidney. Chronic gouty arthritis may cause progressive disability and permanent deformities.

A. URICOSURIC DRUGS

1. Probenecid

It is a highly lipid-soluble organic acid developed in 1951 to inhibit renal tubular secretion of penicillin so that its duration of action could be prolonged. It competitively blocks active transport of organic acids by OATP at all sites; that in renal tubules being the most prominent. This transport is bidirectional: net effect depends on whether secretion or reabsorption of the particular organic acid is quantitatively more important, e.g.:

• Penicillin is predominantly secreted by the proximal tubules; its reabsorption is minimal. Net effect of probenecid is inhibition of excretion; more sustained blood levels are achieved.

• Uric acid is largely reabsorbed by active transport, while less of it is secreted; only 1/10th of filtered load is excreted in urine. Probenecid, therefore, promotes its excretion and reduces its blood level.

Probenecid does not have any other significant pharmacological action; it is neither analgesic nor anti-inflammatory.

Interactions

• In addition to penicillin's, probenecid inhibits the urinary excretion of cephalosporins, sulfonamides, Mix and indomethacin

• It inhibits biliary excretion of rifampicin. Pyrazinamide and ethambutol may interfere with uricosuric action of probenecid

• Probenecid inhibits tubular secretion of nitrofurantoin which may not attain antibacterial concentration in urine.

• Salicylates block uricosuric action of probenecid

Pharmacokinetics Probenecid is completely absorbed orally; 90% plasma protein bound: partly conjugated in liver and excreted by the kidney; plasma t½ is 8–10 hours.

Adverse effects Probenecid is generally well tolerated.

Dyspepsia is the most common side effect (up to 25% incidence with high doses). It should be used cautiously in peptic ulcer patients. Rashes and other hypersensitivity phenomena are rare. Toxic doses cause convulsions and respiratory failure.

Uses

• Chronic gout and hyperuricemia: Probenecid is a second line/adjuvant drug to allopurinol. Started at 0.25 g BD and increased to 0.5 g BD, it gradually lowers blood urate level; arthritis, tophi and other lesions may take months to resolve. Colchicine/NSAID cover is advised during the initial 1–2 months to avoid precipitation of acute gout.

• Probenecid and other uricosurics are ineffective in the presence of renal insufficiency (serum creatinine > 2 mg/dl). Plenty of fluids should be given with probenecid to avoid urate crystallization in urinary tract.

• Probenecid is also used to prolong penicillin or ampicillin action by enhancing and sustaining their blood levels, e.g., in gonorrhea, SABE.

2. Sulfinpyrazone

• It is a pyrazalone derivative related to phenylbutazone having consistent uricosuric action but is neither analgesic nor anti-inflammatory. At the usual therapeutic doses, it inhibits tubular reabsorption of uric acid, but smaller doses can decrease urate excretion as do small doses of probenecid. Its uricosuric action is additive with probenecid but antagonized by salicylates. It inhibits platelet aggregation.

• Pharmacokinetics Sulfinpyrazone is well absorbed orally; 98% plasma protein bound—displacement interactions can occur. Excretion is fairly rapid, mainly by active secretion in proximal tubule. Uricosuric action of a single dose lasts for 6–10 hours. Sulfinpyrazone inhibits metabolism of sulfonylureas and warfarin.

• Adverse effects Gastric irritation is the most common side effect—contraindicated in patients with peptic ulcer. Rashes and other hypersensitivity reactions are uncommon. Unlike phenylbutazone, it does not produce fluid retention or blood dyscrasias.

• Adverse effects Gastric irritation is the most common side effect—contraindicated in patients with peptic ulcer. Rashes and other hypersensitivity reactions are uncommon. Unlike phenylbutazone, it does not produce fluid retention or blood dyscrasias. increase according to response, maximal dose 800 mg/day.

B. URIC ACID SYNTHESIS INHIBITOR

Allopurinol

• This hypoxanthine analogue was synthesized as a purine antimetabolite for cancer chemotherapy. However, it had no antineoplastic activity but was a substrate as well as inhibitor of xanthine oxidase, the enzyme responsible for uric acid syntheses

• Allopurinol itself is a short-acting (t½ 2 hrs.) competitive inhibitor of xanthine oxidase, but its major metabolite alloxanthin (ox purine) is a long acting (t½ 24 hrs) and noncompetitive inhibitor— primarily responsible for uric acid synthesis inhibition in vivo. During allopurinol administration, plasma concentration of uric acid is reduced and that of hypoxanthine and xanthine is somewhat increased. In place of uric acid alone, all 3 ox purines are excreted in urine. Since xanthine and hypoxanthine are more soluble, have a higher renal clearance than that of uric acid and each has its individual solubility, precipitation and crystallization in tissues and urine does not occur.

• Because of raised levels of xanthine and hypoxanthine, some feedback inhibition of de novo purine synthesis and reutilization of metabolically derived purine also occurs.

• Pharmacokinetics About 80% of orally administered allopurinol is absorbed. It is not bound to plasma proteins; metabolized largely to alloxanthin. During chronic medication, it inhibits its own metabolism and about 1/3rd is excreted unchanged, the rest as alloxanthin.

Interactions 

• Allopurinol inhibits the degradation of 6- mercaptopurine and azathioprine: their doses should be reduced to 1/3rd, but not that of thioguanine, because it follows a different metabolic path (S-methylation). 

• Probenecid given with allopurinol has complex interaction; while probenecid shortens t½ of alloxanthin, allopurinol prolongs t½ of probenecid.

• Allopurinol can potentiate warfarin and theophylline by inhibiting their metabolism. (d) A higher incidence of skin rashes has been reported when ampicillin is given to patients on allopurinol.

• Iron therapy is not recommended during allopurinol treatment. The exact nature of interaction is not known, but interference with mobilization of hepatic iron stores is suggested.  

• Adverse effects These are uncommon. Hypersensitivity reaction consisting of rashes, fever, malaise and muscle pain is the most frequent. It subsides on stopping the drug. Renal impairment increases the incidence of rashes and other reactions to allopurinol. Stevens-Johnson syndrome is a rare but serious risk.

• Gastric irritation, headache, nausea and dizziness are infrequent; do not need withdrawal. Liver damage is rare.

• Precautions and contraindications Liberal fluid intake is advocated during allopurinol therapy.

• It is contraindicated in hypersensitive patients, during pregnancy and lactation. It should be cautiously used in the elderly, children and in kidney or liver disease.

• Uses Allopurinol is the first-choice drug in chronic gout. It can be used in both over producers and under accretors of uric acid, particularly more severe cases, with tophi or nephropathy. Uricosurics are infrequently used in India; they are less effective when g. f.r. is low and are inappropriate in stone formers. The two classes of drugs can also be used together when the body load of urate is large.

• With long-term allopurinol therapy, tophi gradually disappear, and nephropathy is halted, even reversed.

• Secondary hyperuricemias due to cancer chemotherapy/radiation/thiazides or other drugs: can be controlled by allopurinol. It can even be used prophylactically in these situations.

• To potentiate 6-mercaptopurine or azathioprine in cancer chemotherapy and immunosuppressant therapy.

Dose: Start with 100 mg OD, gradually increase to maintenance dose of 300 mg/day; maximum 600 mg/day

ZYLORIC 100, 300 mg tabs., ZYLOPRIM, CIPLORIC 100 mg cap.

• Caution Allopurinol as well as uricosurics should not be started during acute attack of gout. During the initial 1–2 months of treatment with these drugs, attacks of acute gout are more common—probably due to fluctuating plasma urate levels favoring intermittent solubilization and recrystallization in joints; cover with NSAIDs/colchicine may be provided.

• Kala-azar Allopurinol inhibits Leishmania by altering its purine metabolism. It is used as adjuvant to sodium stibogluconate in resistant kala-azar cases.