Antirheumatics

Treatment of RA 1. Non-steroidal anti-inflammatory drugs (NSAIDs) 2. Glucocorticoids 3. Disease modifying anti-rheumatic drugs - DMARDs - imunosupressive effect - slowly onset of the therapeutic effect - newest - biologic treatment (monoclonal antibodies and solubile receptors ) for example inhibitors of TNF (infliximab, adalimumab; etanercept)

Non-steroidal anti-inflammatory drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs Division according to COX selectivity: Selective inhibitors of COX-1: Acetylsalicylic acid (ASA)- in a dose of 30- 300 mg/day Non-selective inhibitors of COX: Acetylsalicylic acid- in a dose of 500 mg/day or more, ibuprofen, diclofenac, ketoprofen, tiaprofen, indomethacin and many more Preferential inhibitors of COX-2: nimesulide, meloxicam etc. Selective inhibitors of COX-2: celecoxib, rofecoxib, etoricoxib, valdecoxib etc.

Effects of NSAIDs Analgesic effect Antipyretic effect Antiflogistic effect (mainly higher doses) Antiaggregatory effect (not every NSAID, most important is ASA because of irreversible blocade of COX-1- be careful with combination of ASA for anti-aggregation and other NSAIDs- mostly ibuprofen) Other effects- for example reduced incidence of some tumors (for example colorectal carcinoma), uricosuric effekt ...

NSAIDs – one of the most widely used drug groups → their ADRs represent a serious medical / public health / economical problem there are big differences between various NSAIDs in the level risk of particular possible ADRs

Adverse effects of NSAIDs GIT- erosions and ulcers of the gastric mucosa (also in other localisations in the GIT), nausea, vomitus, meteorism, diarrhoea, constipation... (mainly inhibition of COX-1) kidney- reduction of glomerular filtration, retention of Na and fluids, edema, hyperkaliemia, kidney failure, interstitial nephrits... (inhibition of COX-1 and 2) CVS- thrombotic events, increase of blood pressure, heart failure... (mainly COX-2 (mostly in thrombotic events)) CNS- cephalea, weakness, sleap disorders, dizziness, epileptic seizures... other- hepatotoxicity, bleeding, provocation of asthmatic attack, Ray´s syndrom, prolonged childbirth, urticaria, decreased number of white blood cells...

Gastrointestinal ADRs most serious – ↓ production of prostaglandins in the gastric mucosa → peptic ulcer (most often in the stomach and duodenum; the mucosa can get damaged by NSAIDs also in other places in the GIT) roughly 25 % of chronic NSAID users might develop erosions and ulcers, in 2-4 % perforation or bleeding can occure

Kidney ADRs Decreased production of prostanoids → negative effect on the perfusion of the kidneys, glomerular filtration, excretion of sodium and water and on production of renin → circulation overload, oedemas, hypertension ; hyperkalemia ; in severe cases symptoms of acute kidney failure serious complication– interstitial nephritis (immunological reasons) Incidence of kidney ADRs is poughly 18%, severe cases- roughly 1%

Cardiovascular ADRs Increased blood pressure- mostly in hypertensive patients treated with antihypertensives (mainly ACEIs, ARBs, beta blockers), there are big differences between various NSAIDs Development/worsening of heart failure- the risk is highest during the first weeks of treatment, mainly in patients with preexisting congestive heart failure; possibly 19% of all cases of congestive heart failure could be caused (at least partially) by NSAID therapy Thrombotic events- acute myocardial infarction, stroke, thromboembolic disease

NSAIDs Symptomatic treatment Analgetic effect: in several minutes Antiinflammatory effect: in 7-14 days Interindividual variability in response to different drugs Different types of NSAIDs are not combined together

GLUCOCORTICOIDS The most effective symptomatic treatment Their are applied only till DMARDs start to be effective Given is the lowest effective dose and for the shortest time needed Rebound effect!!! (prolonged administration cannot be stopped abruptly

DMARDs = disease-modifying antirheumatic drugs Used nowadays are especially: methotrexate (antagonist of folic acid) – drug of choice sulfasalazine hydroxychloroquine leflunomid If methotrexate not effective, use another DMARDs or combination therapy

DMARDs Biologic treatment Anti TNF: infliximab, adalimumab, certolizumab, golimumab (monoclonal antibodies) etanercept (solubile receptor) Against IL-6 receptor: tocilizumab Against protein CD20 (on B lymphocytes): rituximab Against protein B7 (decrease the activity of T lymphocytes through inhibition of their interaction with antigen presenting cells): abatacept

Treatment of OA Rapid acting drugs Slowly acting drugs 1. Analgetic drugs Paracetamol, metamizol Nonsteroidal antiinflammatory drugs Weak opioids – tramadol 2. Topical transdermal treatment NSAID (diclofenac, ketoprofen) Irritants (capsaicin, menthol) 3. Steroid antiflogistic drugs (corticoids) intra-articular administration triamcinolone, betametazone avoid frequent administration Slowly acting drugs chondroprotectives 1. Disease modifying drugs (DMOAD)? Glucosaminsulphate Chondroitinsulphate Hyaluronic acid No proven agents that reverse osteoarthritis (alternative to pharmacotherapy in advanced stages of the disease is surgery).