NSAIDS & Drugs in Rheumatoid Arthritis (RA)

Transcription

1 NSAIDS & Drugs in Rheumatoid Arthritis (RA)

2 RA is a chronic progressive inflammation of joint lining with an autoimmune background against synovial membranes that can lead to joint destruction Affects approximately 1% of world population Causes pain, swelling, stiffness and loss of function in the joints Generally occurs in a symmetrical pattern and it is polyarticular > 3 joints May also attack other tissues like skin, lungs, eyes, and blood vessels

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4 Small joints of hands and feet are affected first, larger joints later It begins during the most productive years (30 60 yrs) Occurs much more frequently in women than in men (women:men=3:1) Causes are not yet known, however infectious agents, such as viruses and bacteria, may trigger RA in people with an inherited tendency to develop the disease

5 Management of RA: Goals - Relieve pain - Reduce swelling - Slow down or help prevent joint damage - Increase ability to function - Improve sense of well-being

6 Approaches in the management of RA: General - Exercise - Stress reduction Drugs Surgery In some cases, surgery (joint replacement and tendon reconstruction), two types of surgery available to patients with severe joint damage

7 Drugs in RA Research efforts focus on developing drugs that can reduce inflammation and slow or stop progression of the disease with few side effects Reagents that blunt inflammation but don t have effects on disease progression: - Nonsteroidal anti-inflammatory drugs (NSAIDs) - Steroids (Cortisone, Hydrocortisone, Prednisone)

8 Disease Modifying Anti-Rheumatic Drugs (DMARDs): Broad Acting: Methotrexate Hydroxychloroquin Azathoprine Cyclophosphamide Cyclosporin More selective biologics: TNF antagonists Intravenous Immunoglobulin (IV Ig)

9 1. Steroidal 2. Nonsteroidal - Aspirin - Newer NSAID s Antiinflammatory drugs 3. Disease modifying antirheumatic drugs (DMARD s)

10 Cell membrane phospholipids NSAID S Phospholipase A 2 Arachidonic acid Lipoxygenase Cyclooxygenase ( PG synthase ) 5-HPESE PGD, PGH 2, PGG 2 v (PS) p (TS) LTB 4, LTC 4, LTD 4 ( SRS-A ) PGE 2 PGF 2α PGE 1 PGI 2 TXA 2

11 Lipoxygenase: Present in lungs; WBC s and platelets Cyclooxygenase (COX) Present in all tissues COX 1 : present mainly in kidneys; stomach and platelets COX 2 : present in other tissues

12 PG- synthesis inhibitors - Phospholipase inhibitors Glucocorticoids (cortisol; cortisol synthetic analogs) Phenothiazines Antimalarial drugs Local anaesthetics

13 - COX-inhibitors NSAID s a. Non-selective (inhibit COX 1 & COX 2 ) Aspirin; Diclofenac (Na +, K + ); Indomethacin, Iboprofen; Naproxen...etc b. Selective (inhibit selectively COX 2 ) Meloxicam; Celecoxib; Rofecoxib; Etoricoxib; Etodolac; Valdecoxib; Nabumetone etc

14 - Thromboxane synthase inhibitors Dazoxiben, Hydralazine, Diazoxide - Leukotriene synthesis inhibitors * Lipoxygenase inhibitors Zileuton * Leukotriene antagonists Zafirlucast; Montelucast...

15 NSAID s Inflammatory process involves enzymes (collagenases; hyaluronidase ); biologically derived oxidants generated by neutrophils and macrophages; coagulation system; fibrinolytic and complement systems and many mediators (prostaglandins; kinins; leukotrienes etc)

16 Available NSAID s Aspirin Choline salicylates Magnesium; Na + salicylate Meclofenamate Mefenamic acid Etodolac

17 Diclofenac (Na + ; K + ) Ibuprofen Celecoxib Fenoprofen Valdecoxib Ketoprofen Meloxicam Naproxen Azapropazone Ketorolac *** Acetaminophen (paracetamol)

18 NSAID s pharmacokinetics - Orally, some parenterally effective - Differ in potency and are highly bound to plasma proteins - Have small AVD - Have similar efficacy and even toxicities - t 1/2 and duration of action differ according to available dosage forms

19 NSAID s general effects - Analgesia Effective in mild to moderate pain (headache, toothache, backache, dysmenorrhea...etc) Highly effective analgesics associated with relatively fewer side effects Unlike narcotic analgesics, they do not lead to addiction In patients with RA they provide symptomatic relief, improved function but no change in disease progression

20 The choice of a particular NSAID depends on: Availability; cost; pharmacokinetic properties & side effect profile NSAID s undergo great variation among pts with respect to their analgesic and side effects It is common that in many cases switching from one NSAID to another could be to the side of the pt (e.g. one NSAID leading to a side effect could not be observed with another)

21 - Antiinflammatory effect - Antipyretic effect - Antiplatelet effect (significant with Aspirin, not significant with selective COX 2 inhibitors) - Patency of ductus arteriosus Maintained by PG s (Indomethacin has been used successfully to close it) - Prolongation of labor and gestation (possible use in premature labor) - Contraceptive effect especially with selective COX 2 inhibitors (inhibit ovulation)

22 Acetyl salicylic acid (Aspirin) Actions: - Analgesic Effective in mild to moderate pain - Antipyretic - Antiinflammatory - Antiplatelet, aspirin leads to irreversible inhibition of platelet COX and reversible inhibition of vascular COX

23 Aspirin clinical uses: - Minor pain (headache, toothache, backache) Dose mg - Rheumatoid arthritis; dose 900 mg - Rheumatic fever; dose 3-5 g/day - Antiplatelet (many doses were evaluated, 81 mg, 100mg and 300mg daily or every other day)

24 Aspirin is available in nearly all dosage forms, oral & parenteral Aspirin side effects: - Gastric irritation - Bleeding and anemia - Bronchoconstriction Aspirin toxic effects: Salicylism (dizziness, tinnitus, nausea and vomiting and reversible deafness)

25 Aspirin contraindications: - Peptic ulcer disease - Bronchial asthma - Reye s syndrome ** Buffered aspirin Aspirin MOA: Inhibition of prostaglandin synthesis Aspirin doesn t lead to addiction

26 Acetaminophen (Paracetamol) Analgesic and antipyretic MOA: Inhibition of prostaglandin synthesis centrally Has no antiinflammatory or antiplatelet activity Not contraindicated in patients with peptic ulcer or bronchial asthma

27 Paracetamol is not contraindicated during pregnancy or in patients with Reye s syndrome Large doses > 10g liver damage Management of toxicity: - Gastric lavage - NaHCO 3 - Specific antidote: N-Aceylcysteine (Mucomyst ) I.V

28 Sulfate Paracetamol Glucuronide MFO Toxic metabolites Glutathione None toxic metabolites DNA adduct Irreversible liver damage

29 NSAId s side and toxic effects: I. PG-synthesis inhibition related - GIT bleeding and ulceration (commonest) Most severe with Piroxicam, Naproxen and Azapropazone - Prolonged bleeding time, GIT blood loss (antiplatelet effect) - Delayed parturition

30 Cont. NSAID s side and toxic effects - Allergic reactions (bronchospasm, urticaria..) - Renal effects (Na + & H 2 O retention, BP, hyperkalemia, renal failure ) II. PG-synthesis inhibition unrelated - Hepatotoxicity - CNS effects (headache, dizziness, tinnitus, deafness, drowsiness, nervousness...)

31 Cont. NSAID s side and toxic effects - Dermal effects - Retinal and visual disturbances - Nephropathy (renal papillary necrosis, acute interstitial nephritis, acute renal failure...) Nephropathy is more common with combined analgesic therapy and chronic use (analgesic nephropathy)

32 NSAID s most important drug-drug interactions: + Warfarin bleeding + 4-quinolone antibacterial agents convulsions + Phenytoin; Sulfonylurea phenytoin and sulfonylurea toxicity + Methotrexate excretion of methotrexate toxicity + Indomethacin + ACE inhibitors or K + sparing diuretics hyperkalemia

33 Steroids Low-dose prednisone ( 10 mg qd) May substitute for NSAID Used as bridge therapy If used long term, consider prophylactic treatment for osteoporosis Intra-articular steroids (prednisone; prednisolone; hydrocortisone; triamcinolone...) Useful for flares

34 Steroids have: - Antiinflammatory effects; mechanisms: Inhibition of prostaglandins & leucotreines Inhibit neutrophil and macrophage function Inhibition of platelet activation factor (PAF) - Inhibition of tissue necrosis factor or receptor (TNF; TNR) - Inhibition of nitric oxide reductase...

35 - Immunosupressant effects; mechanisms: initial processing of Ag Ab formation effectiveness of T-lymphocytes lymphocyte induction & proliferation lymphoid tissue including leukemic lymphocytes (antileukemic effect)...

36 Steroids side effects: - Suppression of hypothalamic-pituitary-adrenal axis - Osteoporosis - Aldosterone-like activity - Hyperglycemia - GIT ulceration - CNS manifestations - Cataract...

37 Disease modifying drugs (DMARDs) Overall MOA is unclear but found to improve or reverse joint damage or course of the disease and at least prevent or delay late complications These drugs need frequent monitoring Blood, liver, lung, and kidney are frequent sites of adverse effects Interval of laboratory testing varies with the drug 4 to 8 week intervals are commonly needed Most patients need to be seen 3 to 6 times a year

38 Minocycline An infectious etiology of RA has long been postulated, but not proved Despite insufficient evidence for the infectious nature of this disorder, several antibacterials, such as sulfa compounds, tetracyclines and rifampicin, have been investigated in the treatment of RA Minocycline significantly improved the clinical parameters of RA activity, the ESR and patients had fewer erosions

39 - In general minocycline has a modest effect and may work best when given early in the disease course or in patients with a mild disease - Major side effects to minocycline include: GIT adverse effects, dizziness, rash and headaches Less common adverse effects were intracranial hypertension, pneumonitis, persistent skin and mucosal hyperpigmentation, lupus-like syndrome and acute hepatic injury

40 Sulfasalazine, hydroxychloroquine Moderate effect, low cost, improve joint damage Sulfasalazine is an immunosuppressive medicine. It helps to suppress overactivity of the immune system in RA. It can help to reduce pain and swelling by limiting inflammation. Hydroxychloroquine interferes with antigen presentation and the activation of the immune response by increasing the ph within macrophage phagolysosomes Major side effects are GIT disturbances

41 Deep Intramuscular gold - Slow onset, decreases progression, rare remission, requires close monitoring - Gold has immunosuppressant effect and affects lysosomal membranes and inactivates lysosomal enzymes within the synoviocyte - Side effects include: Allergy, mouth ulcers and glossitis, BMD, hepatic and renal damage...

42 Immunosuppressive drugs Methotrexate - Most effective single DMARD; good benefit-to-risk ratio - It is the current 'gold standard' of rheumatoid arthritis treatment - It has the highest rate of continued long-term treatment, maintaining efficacy without excessive toxicity - Can be used alone or in combination - Methotrexate is proven to slow radiographic progression of disease, but it takes 6-8 weeks for the onset of benefit

43 - Methotrexate mechanism of action Methotrexate is a folic acid antagonist cytotoxic drug. By binding to dihydrofolate reductase, methotrexate interferes with DNA synthesis and cell replication. Suppresses the immune system - Common adverse effects include nausea, mouth ulcers, reversible alopecia, rash, and increased rheumatoid nodule formation. Rarer adverse effects include bone marrow suppression and hepatic fibrosis/cirrhosis

44 Azathioprine - Slow onset, reasonably effective, high risk to benefit ratio - An immunosuppressant affects proliferating cells, such as the T cells and B cells of the immune system used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues - It inhibits the synthesis of DNA - Side effects include anemia, severe leukopenia and high risk of developing certain types of cancers (e.g., leukemia, lymphoma, skin cancer)

45 Cyclophosphamide - Effective for vasculitis, less so for arthritis - A potent immunosuppressant, used in the management of rheumatoid disorders and autoimmune nephritis - Its effects and side effects are due to a metabolite - Major side effects include hemorrhagic cystitis with hematuria mainly due to the metabolite known as acrolein, thus it is co-administered with N-acetylcystein or 2- mercaptoethanesulfonate (MESNA). Both are thiols that neutralize acrolein - Other toxic effects include nausea, vomiting, bone marrow depression (BMD)

46 Cyclosporine - An immunosuppressant drug widely used in organ transplantation and approved to be used in RA - Side effects can include nephrotoxicity, gingival hyperplasia, convulsions, peptic ulcers, fever, pancreatitis, vomiting, diarrhea, hepatotoxicity, burning sensations at finger tips and an increased vulnerability to opportunistic fungal and viral infections

47 Combined therapy a. Methotrexate (MTX) + hydroxychlorquin + sulfasalazine Superior to one or 2 drug therapy (better improvement) with no greater side effects b. Prednisone with sulfasalazine and low-dose methotrexate (Superior to sulfasalazine alone in early disease) c. Methotrexate + hydroxychloroquine or methotrexate + cyclosporine May have additive beneficial effects compared to each drug alone

48 80 % response Or improvement 40 3 drugs 2 drugs MTX

49 Newer DMARD s - Leflunomide The newest of the commonly used DMARDs Has comparable clinical and radiographic efficacy to methotrexate and sulfasalazine Good to patients in whom methotrexate is ineffective or inappropriate It is a Pyrimidine inhibitor, primarily inhibits replication of activated lymphocytes by blocking the de novo synthesis of pyrimidines and hence DNA It also has a weak antiinflammatory action

50 Effects and side effects to Leflunomide are similar to methotrexate Orally effective for the treatment of active rheumatoid arthritis It reduces the signs, symptoms, and joint damage caused by rheumatoid arthritis and also improves physical function

51 Biological therapy A major advance in the treatment of RA has been the development of biological therapies, in particular drugs directed against the pro-inflammatory cytokine TNF; Etanercept, a recombinant soluble TNF-Fc fusion protein, and Infliximab, an anti- TNF monoclonal antibody, are approved for the treatment of refractory RA Major disadvantages include : parenteral administration (SC, IV) and cost

52 - Etanercept A protein produced by recombinant DNA, blocks or inhibits TNF Has rapid onset, given SC once or twice/week Quite effective in refractory RA patients alone and in combination with methotrexate Also effective in psoriatic arthritis and ankylosing spondylitis Could lead to injection site reactions (redness, itching, pain, or swelling), long-term effects unknown, expensive

53 - Infliximab A monoclonal antibody against tumor necrosis factor alpha (TNF-α) used to treat autoimmune diseases (of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis) It promotes complement activation and antibodymediated cellular cytotoxicity of inflammatory cells It is given in an IV infusion

54 Infliximab side effects include: - Allergic reactions - Serious infections - Liver toxicity - Reactivation of TB & hepatitis B - Drug-induced lupus - Serious blood disorders; - Lymphoma...

55 IV Immunoglobulins IV Ig can improve the symptoms and improve the functional capability of RA patients. This effect is associated with a partial modulation of serum concentrations of inflammatory cytokines and with a late decrease in soluble interleukin-2 receptor (sil-2r) which is correlated with the late reduction in disease activity Ig s are usually given in IV infusion; generally well tolerated and side effects are usually mild and occur early during the infusion. The commonest are flu-like symptoms with myalgia, fever, headache, nausea and vomiting