Disease-Modifying Antirheumatic Drugs part 2

Methotrexate

Methotrexate is now considered the DMARD of first choice to treat rheumatoid arthritis and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy.

Mechanism of Action

Methotrexate's principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis.

Pharmacokinetics

The drug is approximately 70% absorbed after oral administration. It is metabolized to a less active hydroxylated metabolite, and both the parent compound and the metabolite are polyglutamated within cells, where they stay for prolonged periods. Methotrexate's serum half-life is usually only 6–9 hours, although it may be as long as 24 hours in some individuals. Methotrexate's concentration is increased in the presence of hydroxychloroquine, which can reduce the clearance or increase the tubular reabsorption of methotrexate. This drug is excreted principally in the urine, but up to 30% may be excreted in bile.

Indications

Although the most common methotrexate dosing regimen for the treatment of rheumatoid arthritis is 15–25 mg weekly, there is an increased effect up to 30–35 mg weekly. The drug decreases the rate of appearance of new erosions. Evidence supports its use in juvenile chronic arthritis, and it has been used in psoriasis, psoriatic arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, Wegener's granulomatosis, giant cell arteritis, systemic lupus erythematosus, and vasculitis.

Adverse Effects

Nausea and mucosal ulcers are the most common toxicities. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum methotrexate concentrations, and liver biopsy follow-up is only recommended every 5 years. A rare hypersensitivity-like lung reaction with acute shortness of breath is documented, as are pseudolymphomatous reactions. The incidence of gastrointestinal and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate. This drug is contraindicated in pregnancy.

Mycophenolate Mofetil

Mechanism of Action

Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug. The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits T-cell lymphocyte proliferation; downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1

Indications

MMF is effective for the treatment of renal disease due to systemic lupus erythematosus and may be useful in vasculitis and Wegener's granulomatosis. Although MMF is occasionally used at a dosage of 2 g/d to treat rheumatoid arthritis, there are no well-controlled data regarding its efficacy in this disease.

Rituximab

Mechanism of Action

Rituximab is a chimeric monoclonal antibody that targets CD20 B lymphocytes. This depletion takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of B lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral B cells although this depletion neither correlates with efficacy nor with toxicity.

Rituximab has shown benefit in the treatment of rheumatoid arthritis refractory to anti-TNF agents. It has been approved for the treatment of active rheumatoid arthritis when combined with methotrexate.

Pharmacokinetics

Rituximab is given as two intravenous infusions of 1000 mg, separated by 2 weeks. It may be repeated every 6–9 months, as needed. Repeated courses remain effective. Pretreatment with glucocorticoids given intravenously 30 minutes prior to infusion (usually 100 mg of methylprednisolone) decreases the incidence and severity of infusion reactions.

Indications

Rituximab is indicated for the treatment of moderately to severely active rheumatoid arthritis in combination with methotrexate in patients with an inadequate response to one or more TNF- antagonists.

Adverse Effects

About 30% of patients develop rashes with the first 1000 mg treatment; this incidence decreases to about 10% with the second infusion and progressively decreases with each course of therapy thereafter. These rashes do not usually require discontinuation of therapy although urticarial or anaphylactoid reactions, of course, preclude further therapy. Immunoglobulins (particularly IgG and IgM) may decrease with repeated courses of therapy and infections can occur, although they do not seem directly associated with the decreases in immunoglobulins. Rituximab has not been associated with activation of tuberculosis, nor with the occurrence of lymphomas or other tumors. Other adverse effects, eg, cardiovascular events, are rare.

Sulfasalazine

Mechanism of Action

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression of T-cell responses to concanavalin and inhibition of in vitro B-cell proliferation have also been documented. In vitro studies have shown that sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by monocytes or macrophages, eg, interleukins-1, -6, and -12, and TNF- . These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis.

Pharmacokinetics

Only 10–20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid. Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine's half-life is 6–17 hours.

Indications

Sulfasalazine is effective in rheumatoid arthritis and reduces radiologic disease progression. It has been used in juvenile chronic arthritis and in ankylosing spondylitis and its associated uveitis. The usual regimen is 2–3 g/d.

Adverse Effects

Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemoglobinemia also occur, but rarely. Neutropenia occurs in 1–5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic.

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Disease-Modifying Antirheumatic Drugs

DMARDs

Careful clinical and epidemiologic studies have shown that rheumatoid arthritis is an immunologic disease that causes significant systemic effects which shorten life in addition to the joint disease that reduces mobility and quality of life. NSAIDs offer mainly symptomatic relief; they reduce inflammation and the pain it causes and often preserve function, but they have little effect on the progression of bone and cartilage destruction. Interest has therefore centered on finding treatments that might arrest—or at least slow—this progression by modifying the disease itself. The effects of disease-modifying therapies may take 6 weeks to 6 months to become evident although some biologics are effective within 2 weeks; generally, they are slow-acting compared with NSAIDs.

These therapies include methotrexate, a T-cell-modulating biologic (abatacept), azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, a B-cell cytotoxic agent (rituximab), sulfasalazine, and the TNF- -blocking agents. These drugs comprise both biologically derived and nonbiologic agents and will be listed alphabetically, independent of origin. Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy.

Abatacept

Mechanism of Action

Abatacept is a costimulation modulator that inhibits the activation of T cells. After a T cell has engaged an antigen-presenting cell (APC), a signal is produced by CD28 on the T cell that interacts with CD80 or CD86 on the APC, leading to T-cell activation. Abatacept (which contains the endogenous ligand CTLA-4) binds to CD80 and 86, thereby inhibiting the binding to CD28 and preventing the activation of T cells.

Pharmacokinetics

Abatacept is given as an intravenous infusion in three initial doses (day 0, week 2, and week 4), followed by monthly infusions. The dose is based on body weight, with patients weighing less than 60 kg receiving 500 mg, those 60–100 kg receiving 750 mg, and those more than 100 kg receiving 1000 mg. Dosing regimens in any adult group can be increased if needed. The terminal serum half-life is 13–16 days. Coadministration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance.

Indications

Abatacept can be used as monotherapy or in combination with other DMARDs in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to other DMARDs. It reduces the clinical signs and symptoms of rheumatoid arthritis, including slowing of radiographic progression. It is also being tested in early rheumatoid arthritis.

Adverse Effects

There is a slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory tract. Concomitant use with TNF- antagonists is not recommended due to the increased incidence of serious infection with this combination. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Anti-abatacept antibody formation is infrequent (< 5%) and has no effect on clinical outcomes. The incidence of malignancies is similar to placebo with the exception of a possible increase in lymphomas. The role of abatacept in this increase is unknown.

Azathioprine

Mechanism of Action

Azathioprine acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses inosinic acid synthesis, B-cell and T-cell function, immunoglobulin production, and interleukin-2 secretion.

Pharmacokinetics

The metabolism of azathioprine is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dosage is not adjusted.

Indications

Azathioprine is approved for use in rheumatoid arthritis and is used at a dosage of 2 mg/kg/d. Controlled trials show efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus erythematosus, and Behçet's disease.

Adverse Effects

Azathioprine's toxicity includes bone marrow suppression, gastrointestinal disturbances, and some increase in infection risk, lymphomas may be increased with azathioprine use. Rarely, fever, rash, and hepatotoxicity signal acute allergic reactions.

Chloroquine & Hydroxychloroquine

Mechanism of Action

Chloroquine and hydroxychloroquine are used mainly in malaria and in the rheumatic diseases. The mechanism of the anti-inflammatory action of these drugs in rheumatic diseases is unclear. The following mechanisms have been proposed: suppression of T-lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals.

Pharmacokinetics

Antimalarials are rapidly absorbed and 50% protein-bound in the plasma. They are very extensively tissue-bound, particularly in melanin-containing tissues such as the eyes. The drugs are deaminated in the liver and have blood elimination half-lives of up to 45 days.

Indications

Antimalarials are approved for rheumatoid arthritis, but they are not considered very effective DMARDs. Dose-response and serum concentration-response relationships have been documented for hydroxychloroquine and dose-loading may increase rate of response. Although antimalarials improve symptoms, there is no evidence that these compounds alter bony damage in rheumatoid arthritis at their usual dosages (up to 6.4 mg/kg/d for hydroxychloroquine or 200 mg/d for chloroquine). It usually takes 3–6 months to obtain a response. Antimalarials are often used in the treatment of the skin manifestations, serositis, and joint pains of systemic lupus erythematosus, and they have been used in Sjögren's syndrome.

Adverse Effects

Although ocular toxicity may occur at dosages greater than 250 mg/d for chloroquine and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely occurs at lower doses. Nevertheless, ophthalmologic monitoring every 6–12 months is advised. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. These drugs appear to be relatively safe in pregnancy.

Cyclophosphamide

Mechanism of Action

Cyclophosphamide's major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and B-cell function by 30–40%; T-cell suppression correlates with clinical response in the rheumatic diseases

Indications

Cyclophosphamide is active against rheumatoid arthritis when given orally at dosages of 2 mg/kg/d but not when given intravenously. It is used regularly to treat systemic lupus erythematosus, vasculitis, Wegener's granulomatosis, and other severe rheumatic diseases.

Cyclosporine

Mechanism of Action

Through regulation of gene transcription, cyclosporine inhibits interleukin-1 and interleukin-2 receptor production and secondarily inhibits macrophage–T-cell interaction and T-cell responsiveness. T-cell-dependent B-cell function is also affected.

Pharmacokinetics

Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20–30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3A and consequently is subject to a large number of drug interactions.

Indications

Cyclosporine is approved for use in rheumatoid arthritis and retards the appearance of new bony erosions. Its usual dosage is 3–5 mg/kg/d divided into two doses. Anecdotal reports suggest that it may be useful in systemic lupus erythematosus, polymyositis and dermatomyositis, Wegener's granulomatosis, and juvenile chronic arthritis.

Adverse Effects

Cyclosporine has significant nephrotoxicity, and its toxicity can be increased by drug interactions with diltiazem, potassium-sparing diuretics, and other drugs inhibiting CYP3A. Serum creatinine should be closely monitored. Other toxicities include hypertension, hyperkalemia, hepatotoxicity, gingival hyperplasia, and hirsutism.

Leflunomide

Mechanism of Action

Leflunomide undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite, A77-1726. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G₁ phase of cell growth. Consequently, leflunomide inhibits T-cell proliferation and production of autoantibodies by B cells. Secondary effects include increases of interleukin-10 receptor mRNA, decreased interleukin-8 receptor type A mRNA, and decreased TNF- –dependent nuclear factor kappa B (NF- B) activation.

Pharmacokinetics

Leflunomide is completely absorbed and has a mean plasma half-life of 19 days. A77-1726, the active metabolite of leflunomide, is thought to have approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.

Indications

Leflunomide is as effective as methotrexate in rheumatoid arthritis, including inhibition of bony damage. In one study, combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone.

Adverse Effects

Diarrhea occurs in approximately 25% of patients given leflunomide, although only about 3–5% discontinue the drug because of this effect. Elevation in liver enzymes also occurs. Both effects can be reduced by decreasing the dose of leflunomide. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocytopenia occur rarely. This drug is contraindicated in pregnancy.

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Drugs to treat inflamation

Nonselective COX Inhibitors:

Diclofenac

Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor.

Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs.

A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered for preemptive analgesia and postoperative nausea. In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration.

Diflunisal

Although diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety. Diflunisal is subject to capacity-limited metabolism, with serum half-lives at various dosages approximating that of salicylates. In rheumatoid arthritis the recommended dose is 500–1000 mg daily in two divided doses. It is claimed to be particularly effective for cancer pain with bone metastases and for pain control in dental (third molar) surgery. A 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.

Because its clearance depends on renal function as well as hepatic metabolism, diflunisal's dosage should be limited in patients with significant renal impairment.

Etodolac

Etodolac is a racemic acetic acid derivative with an intermediate half-life. Etodolac does not undergo chiral inversion in the body. The dosage of etodolac is 200–400 mg three to four times daily.

Flurbiprofen

Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)(–) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor- (TNF- ) and nitric oxide synthesis. Hepatic metabolism is extensive; its (R)(+) and (S)(–) enantiomers are metabolized differently, and it does not undergo chiral conversion. It does demonstrate enterohepatic circulation.

Flurbiprofen is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat.

Although its adverse effect profile is similar to that of other NSAIDs in most ways, flurbiprofen is also associated rarely with cogwheel rigidity, ataxia, tremor, and myoclonus.

Ibuprofen

Ibuprofen is a simple derivative of phenylpropionic acid . In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.

Oral ibuprofen is often prescribed in lower doses (< 2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names.

Ibuprofen is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. The oral and intravenous routes are equally effective for this indication. A topical cream preparation appears to be absorbed into fascia and muscle; an (S)(–) formulation has been tested. Ibuprofen cream was more effective than placebo cream in the treatment of primary knee osteoarthritis. A liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain.

In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention. The drug is relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. Aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported. Interaction with anticoagulants is uncommon. The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. Common adverse effects are listed on page 624; rare hematologic effects include agranulocytosis and aplastic anemia.

Indomethacin

Indomethacin, introduced in 1963, is an indole derivative. It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation.

It differs somewhat from other NSAIDs in its indications and toxicities.

Indomethacin was particularly popular for gout and ankylosing spondylitis. In addition, it has been used to accelerate closure of patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many other conditions, including Sweet's syndrome, juvenile rheumatoid arthritis, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty.

An ophthalmic preparation seems to be efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome.

At usual doses, indomethacin has the common side effects listed above. At higher doses, at least a third of patients have reactions to indomethacin requiring discontinuance. The gastrointestinal effects may include pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Rarely, psychosis with hallucinations has been reported. Serious hematologic reactions have been noted, including thrombocytopenia and aplastic anemia. Renal papillary necrosis has also been observed. A number of interactions with other drugs have been reported. Probenecid prolongs indomethacin's half-life by inhibiting both renal and biliary clearance.

Ketoprofen

Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.

The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs in clinical efficacy. Its major adverse effects are on the gastrointestinal tract and the central nervous system (see common adverse effects above).

Ketorolac

Ketorolac is an NSAID promoted for systemic use mainly as an analgesic, not as an anti-inflammatory drug (although it has typical NSAID properties). The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously, but an oral dose formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. An ophthalmic preparation is available for ocular inflammatory conditions. Toxicities are similar to those of other NSAIDs, although renal toxicity may be more common with chronic use.

Nabumetone

Nabumetone is the only nonacid NSAID in current use; it is converted to the active acetic acid derivative in the body. It is given as a ketone prodrug that resembles naproxen in structure. Its half-life of more than 24 hours permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve.

Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach than some other NSAIDs when given at a dosage of 1000 mg/d. Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID. Like naproxen, nabumetone has been reported to cause pseudoporphyria and photosensitivity in some patients. Other adverse effects mirror those of other NSAIDs.

Naproxen

Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer. Naproxen's free fraction is significantly higher in women than in men, but half-life is similar in both sexes. Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. A topical preparation and an ophthalmic solution are also available.

The incidence of upper gastrointestinal bleeding in over-the-counter use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common NSAID-associated adverse effects have been noted.

Oxaprozin

Oxaprozin is another propionic acid derivative NSAID, its major difference from the other members of this subgroup is a very long half-life (50–60 hours), although oxaprozin does not undergo enterohepatic circulation. It is mildly uricosuric, making it potentially more useful in gout than some other NSAIDs. The drug has the same benefits and risks that are associated with other NSAIDs.

Piroxicam

Piroxicam, an oxicam, is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life permits once-daily dosing.

Piroxicam can be used for the usual rheumatic indications. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered. Epidemiologic studies suggest that this risk is as much as 9.5 times higher with piroxicam than with other NSAIDs (see common adverse effects above).

Sulindac

Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to 12–16 hours.

In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. It appears to inhibit the occurrence of gastrointestinal cancer in rats. The latter effect may be caused by the sulfone rather than the sulfide.

Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferases; it is also sometimes associated with cholestatic liver damage, which disappears when the drug is stopped.

Tolmetin

Tolmetin is a nonselective COX inhibitor with a short half-life (1–2 hours)and is not often used. Its efficacy and toxicity profiles are similar to those of other NSAIDs with the following exceptions: it is ineffective (for unknown reasons) in the treatment of gout, and it may cause (rarely) thrombocytopenic purpura.

Also see the table

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Drugs to treat inflamation

COX-2 Selective Inhibitors:

COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active "housekeeping" COX-1 isozyme found in the gastrointestinal tract, kidneys, and platelets. Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects similar to those of nonselective NSAIDs but with an approximate halving of gastrointestinal adverse effects. Likewise, COX-2 inhibitors at usual doses have been shown to have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect. Unfortunately, because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market.

Celecoxib:

Celecoxib is a selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1.

Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above.

Meloxicam:

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A₂, even at supratherapeutic doses its blockade of thromboxane A₂ does not reach levels that result in decreased in vivo platelet function (see common adverse effects above).

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Salicylates

Aspirin:

Aspirin's long use and availability without prescription diminishes its glamour compared with that of the newer NSAIDs. Aspirin is now rarely used as an anti-inflammatory medication and will be reviewed only in terms of its anti platelets effect (ie, doses of 81–325 mg once daily).

Pharmacokinetics:

Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5. The salicylates are rapidly absorbed from the stomach and upper small intestine yielding a peak plasma salicylate level within 1–2 hours. Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood. Salicylate is nonlinearly bound to albumin. Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.

Mechanisms of Action:

Aspirin irreversibly inhibits platelet COX so that aspirin's antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours.

Clinical Uses:

Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting.

Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.

Adverse Effects:

In addition to the common side effects listed above, aspirin's main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. Hepatotoxicity, asthma, rashes, gastrointestinal bleeding, and renal toxicity rarely if ever occur at antithrombotic doses.

The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia.

Nonacetylated Salicylates:

These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, although they may be less effective analgesics than aspirin. Because they are much less effective than aspirin as COX inhibitors and they do not inhibit platelet aggregation, they may be preferable when COX inhibition is undesirable such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction.

The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements.

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Nonsteroidal Anti-Inflammatory Drugs

Introduction:

Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects, but it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process.

Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin's efficacy and decrease its toxicity.

Chemistry & Pharmacokinetics

The NSAIDs are grouped in several chemical classes. This chemical diversity yields a broad range of pharmacokinetic characteristics. Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.

Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly protein-bound (~98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).

All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.

Summary of some NSAIDs is given below:

Properties of Aspirin and Some Other Nonsteroidal Anti-Inflammatory Drugs.

Drug  Half-Life (hours)  Urinary Excretion of Unchanged Drug  Recommended Anti-inflammatory Dosage  Aspirin 0.25 < 2% 1200–1500 mg tid Salicylate1   2–19 2–30% See footnote 2 Celecoxib 11 27%3   100–200 mg bid Diclofenac 1.1 < 1% 50–75 mg qid Diflunisal 13 3–9% 500 mg bid Etodolac 6.5 < 1% 200–300 mg qid Fenoprofen 2.5 30% 600 mg qid Flurbiprofen 3.8 < 1% 300 mg tid Ibuprofen 2 < 1% 600 mg qid Indomethacin 4–5 16% 50–70 mg tid Ketoprofen 1.8 < 1% 70 mg tid Ketorolac 4–10 58% 10 mg qid4   Meloxicam 20 Data not found 7.5–15 mg qd Nabumetone5   26 1% 1000–2000 mg qd6   Naproxen 14 < 1% 375 mg bid Oxaprozin 58 1–4% 1200–1800 mg qd6   Piroxicam 57 4–10% 20 mg qd6   Sulindac 8 7% 200 mg bid Tolmetin 1 7% 400 mg qid

Pharmacodynamics :

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins. Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors.

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse the vasodilation of inflammation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants and can be associated with gastrointestinal ulcers and bleeds as well, although as a group the newer agents tend to cause less gastrointestinal irritation than aspirin. Nephrotoxicity has been observed for all of the drugs for which extensive experience has been reported. Nephrotoxicity is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity can also occur with any NSAID. Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate and other DMARDs—they alter the course of any arthritic disorder. Several NSAIDs (including aspirin) appear to reduce the incidence of colon cancer when taken chronically. Several large epidemiologic studies have shown a 50% reduction in relative risk when the drugs are taken for 5 years or longer. The mechanism for this protective effect is unclear. The NSAIDs have a number of commonalities. Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout). Adverse effects are generally quite similar for all of the NSAIDs: 1.      Central nervous system: Headaches, tinnitus, and dizziness. 2.      Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure. 3.      Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding. 4.      Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5.      Hepatic: Abnormal liver function tests and rare liver failure. 6.      Pulmonary: Asthma. 7.      Rashes: All types, pruritus. 8.      Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.

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Therapeutic Strategies

Therapeutic Strategies

The treatment of patients with inflammation involves two primary goals: 

• first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient

• second, the slowing or arrest of the tissue-damaging process. 

Reduction of inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.

The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. Although there are increasing data that low-dose corticosteroids have disease-modifying properties, the toxicity associated with chronic corticosteroid therapy usually limits their use. The glucocorticoids continue to have a significant role in the long-term treatment of arthritis.

Another important group of agents is characterized as disease-modifying antirheumatic drugs (DMARDs). They decrease inflammation, usually improve symptoms, and slow the bone damage associated with rheumatoid arthritis. They are thought to affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications.

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The Immune Response

What is immune response?

The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process. Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response. One of the most important conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. 

The cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. 

The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability.

Cyclooxygenase enzyme has two isoforms (COX-1 and COX-2)

• COX-1 isoform tends to be homeostatic in function, while 

• COX-2 is induced during inflammation and tends to facilitate the inflammatory response. 

On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy.

Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes produces oxygen-derived free radicals. Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.

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