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Clinical Pharmacology of A nti-inflammatory Agents. RHEUMATIC DISEASES. Rheumatic diseases (rheumatism) are painful conditions that affect millions. These diseases cause inflammation, swelling, and pain in the joints or muscles.
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RHEUMATIC DISEASES • Rheumatic diseases (rheumatism) are painful conditions that affect millions. These diseases cause inflammation, swelling, and pain in the joints or muscles. • Some rheumatic diseases like osteoarthritis are the result of "wear and tear" to the joints. Other rheumatic diseases, such as rheumatoid arthritis, happen when the immune system goes haywire; the immune system attacks the linings of joints, causing joint pain, swelling, and destruction.
Rheumatoid Arthritis RA is sometimes called a crippling disease. That's because it can result in permanent joint damage and deformity. RA signs and symptoms include: • Joint pain, stiffness, and swelling • Involvement of multiple joints (symmetrical pattern) • Other organ involvement • Joint stiffness, especially in the morning • Fatigue • Fevers • Lumps called rheumatoid nodules To diagnose RA, doctor will ask about medical history and do a physical examination. Also, X-rays and blood tests will likely be taken. One blood test may be for rheumatoid factor; it is positive in 70% to 80% of those with RA.
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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; and second, the slowing or arrest of the tissue-damaging process.
NSAIDs can be classified based on their chemical structure or mechanism of action Salicylates • Aspirin (acetylsalicylic acid) • Diflunisal • Salsalate
NSAIDs Propionic acid derivatives • Ibuprofen • Naproxen • Fenoprofen • Ketoprofen • Flurbiprofen • Oxaprozin Acetic acid derivatives • Indomethacin • Sulindac • Etodolac • Ketorolac • Diclofenac (Safety alert by FDA) • Nabumetone
NSAIDs Enolic acid (Oxicam) derivatives • Piroxicam • Meloxicam • Tenoxicam • Droxicam • Lornoxicam • Isoxicam Fenamic acid derivatives( Fenamates ) • Mefenamic acid • Meclofenamic acid • Flufenamic acid • Tolfenamic acid
NSAIDs Selective COX-2 inhibitors (Coxibs) • Celecoxib (FDA alert) • Rofecoxib (withdrawn from market) - increased cardiovascular thrombotic events • Valdecoxib (withdrawn from market) - increased cardiovascular thrombotic events • Parecoxib FDA withdrawn • Lumiracoxib TGA cancelled registration • Etoricoxib FDA withdrawn • Firocoxib used in dogs and horses Sulphonanilides • Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) Others • Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor
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. Inflammation
The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive 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. Cyclooxygenase isoforms
The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding. Butcelecoxib (Celebrex), blocks COX-2 and has little effect on COX-1, and is therefore further classified as a selective COX-2 inhibitor. Selective COX-2 inhibitors cause less bleeding and fewer ulcers than other NSAIDs.
NSAIDs are generally indicated for the symptomatic relief of the following conditions: • Rheumatoid arthritis • Osteoarthritis • Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome) • Acute gout • Dysmenorrhoea (menstrual pain) • Metastatic bone pain • Headache and migraine • Postoperative pain • Mild-to-moderate pain due to inflammation and tissue injury • Pyrexia (fever) • Ileus • Renal colic • They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth • Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation.
Complications of NSAIDsNSAIDs are safe drugs. However, they have many side effects. The side effects happen more often when they are used over long periods of time, which is common in arthritis patients. Some of the side effects can become very serious. • Central nervous system: Headaches, tinnitus, and dizziness. • Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure. • Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding. • Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. • Hepatic: Abnormal liver function tests and rare liver failure. • Pulmonary: Asthma. • Rashes: All types, pruritus. • Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.
Choice of NSAID • All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for ankylosing spondylitis. • Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin or tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses.
Choice of NSAID (cont’d) • For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive, selective COX-2 inhibitor celecoxib, is probably safest for patients at high risk for gastrointestinal bleeding but may have a higher risk of cardiovascular toxicity. Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for gastrointestinal bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs. • The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.
CORTICOSTEROIDSMost of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors
Glucocorticoids.Anti-Inflammatory and Immunosuppressive effects • Glucocorticoids cause vasoconstriction when applied directly to the skin, possibly by suppressing mast cell degranulation. They also decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells. • The anti-inflammatory and immunosuppressive effects of glucocorticoids are largely due to the actions described above. In humans, complement activation is unaltered, but its effects are inhibited. Antibody production can be reduced by large doses of steroids, although it is unaffected by moderate doses (eg, 20 mg/d of prednisone).
Uses of Corticosteroids • The most commonly used corticosteroids are prednisone,prednisolone, and methylprednisolone. Corticosteroids can be given orally or put directly into the bloodstream through an intravenous needle. They can also be injected directly into an inflamed spot. Corticosteroid cream can be rubbed on the skin. • Corticosteroids are powerful drugs. But they are also highly toxic. Doctors have different opinions about how corticosteroids should be used. • Corticosteroids can't cure a disease. But they do seem to affect the development of some diseases, including rheumatoid arthritis (RA).
Some Commonly Used Natural and Synthetic Corticosteroids for General Use • Short- to medium-acting glucocorticoids: Hydrocortisone (cortisol) Cortisone Prednisone Prednisolone Methylprednisolone
Some Commonly Used Natural and Synthetic Corticosteroids for General Use • Intermediate-acting glucocorticoids Triamcinolone Paramethasone Fluprednisolone • Long-acting glucocorticoids Betamethasone Dexamethasone
Withdrawal • When stop taking corticosteroids, the doses will be slowly reduced over a period of days or weeks. Even if patient has only been taking steroids for a few weeks, he will still need to taper off. Corticosteroid withdrawal can be very difficult for body. In many patients, the disease symptoms become worse. Some people experience a sickness that includes fevers, nausea, vomiting, low blood pressure, and low blood sugar. Others have withdrawal symptoms that include muscle and joint pain, weight loss, fever, and headaches. If patient have problems coming off corticosteroids, doctor will have taper off the drug more slowly. • Different people, and different diseases, react very differently to corticosteroids.
Choosing the right DMARD Current evidence suggests that combinations of DMARDs are more effective, and probably less toxic, than monotherapy.Methotrexate is often used as an anchor drug, combined with hydroxychloroquine, sulfasalazine or leflunomide. An anti-TNF-alpha drug such as etanercept or infliximab may also be used in combination. There is a stronger evidence base for the disease-modifying effects of methotrexate, sulfasalazine, leflunomide and intramuscular gold than for hydroxychloroquine, penicillamine, oral gold, ciclosporin or azathioprine, although these agents do improve symptoms and some objective measures of inflammation. The choice of first agent or combination of agents should be based on a risk/benefit analysis for individual patients.
