NSAIDs, Antipyretics, Antigout drugs Department of Pharmacology MU Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slides is against the law. • Analgesics-antipyretics (A-A) drugs against fever and pain • Nonsteroidal antiinflammatory drugs (NSAIDs) - against inflammation, fever and pain A-A and NSAIDs overlap partially • Antigout drugs – gout therapy Mechanism of action • all of them have similar mechanism of action– inhibition of eicosanoids synthesis (with higher or lower selectivity and strength) • NSAIDs differ in the strength of COX1/COX2 inhibition and the incidence of typical AE (ulcer disease, bleeding) Cyclooxygenases • COX-1 – constitutive – prostanoids involved in physiological processes (gastroprotective effects, platelet activities) • COX-2 – inducible – activity enhanced by proinflammatory factors (IL-1, IL-2, TNF-, oncogenes,..) – prostanoids → inflammation, fever, pain • COX-3 ? – central mechanism of analgesic and antipyretic effect (localization: heart + CNS) Classification by COX1/COX2 inhibition 1. Nonspecific inhibitors • ASA, ibuprofen, diclofenac, … 2. Preferential inhibitors of COX-2 • meloxicam, nimesulid 3. Specific inhibitors of COX-2 • coxibs Classification 1. Salicylic acid derivatives 2. Aniline derivatives 3. Propionic acid derivatives 4. Pyrazolones 5. Acetic acid derivatives 6. Oxicams 7. Coxibs 8. Other 1. Salicylates Effects: • analgesic • antiinflammatory • antipyretic • antirheumatic • antiaggregation → inhibition of platelet function NSAIDs: • ASA (acetylsalicylic acid) • sodium salicylate • cholinsalicylate Therapy of inflammatory bowel desease: • sulfasalazine → sulfapyridine + 5-aminosalicylic acid • mesalazine Salicylic acid derivatives – drugs Acetylsalicylic acid • efficiency standard of AA and NSAIDs • selective inhibitor of COX1 (100-200 : 1) • irreversible acetylation of COX-1 active centre • pharmacokinetics: – weak acid, complete and rapid absorption in stomach and proximal part of intestine – salicylic acid (SA) is product of metabolisation – T1/2 ASA 15-20 min, T1/2 SA 30 hrs depending to dose – 80-95% binding to plasma proteins, elimination and exkretion via kidneys – higher doses – risk of cumulation in a body Usual dosages • antipyretic 500 mg • analgesic 500 mg (4 - 6 hrs) • anti-phlogistic, -rheumatic, -uratic 3,6 – 4 g/day • antiaggregative 30 –100 mg • total daily dose 4 g/day ASA – adverse effects • salicylism (d.) – hearing impairment, tinnitus, deafness, vertigo • allergy - itching, rash, anaphylaxis,… • aspirin-induced asthma - LT • GIT - nausea, dyspepsia, bleeding, ulcer disease • „analgetic“ nephropathy – reversible decrease of glomerular filtration • increased bleeding CAVE • pregnancy- differs in trimesters • children- Rey‘s syndrome • elders- more sensitive to AE ASA interactions • anticoagulants • NSAIDs and other analgesics (except of opioids) • other – valproate, sulfonylureas – competition on plasma proteins – increase of efficacy – SSRI – potentiate ASA antiaggregative effect (citalopram, fluoxetine) – glucocorticoids decrease ASA plasma levels, but increase the risk of GIT bleeding and ulceration ASA - contraindications • hemophilia and other diseases influencing blood coagulation • administration prior to surgery • gastroduodenal ulcers, gastritis • children to 12 years – Rey‘s syndrome (hyperpyrexia, acidosis, seizures, vomiting, psichiatric disorders, hepatopathy) • pregnancy (only temporary) • asthma, allergy, nasal polyps 2. Aniline derivatives Paracetamol (=acetaminophen) • analgesic, antipyretic, is not antiinflammatory active • does not influence blood coagulation or uric acid levels • mechanism of action is unclear: – central mechanism due to COX-3 inhibition – indirect effect on 5-HT3 spinal receptors – elevates PGG2 to PGH2conversion in peripheral tissues – influencing the endocannabinoid and vanillin system and Ca2+ channels Usual doses • comparable effect to ASA, but better tolerance • drug of choice to  fever and pain in children younger than 12 years • pain in adults – 300 to 500 mg every 3-4 hrs – 650 mg every 4 to 6 hrs – 1000 mg every 6 hrs • total daily dose up to 4 g Pharmacokinetics: • p.o. good absorbtion, maximum in 30-60 min, low plasma protein binding, hepatic metabolism • production of hepatotoxic mtb. – binding to gluthathione • overdose (10 – 15 g) → antidote N-acetylcysteine AE, CI: • allergy • hepatotoxicity after ↑ doses • comorbidities: – alcohol addiction – nephropathy – hepatopathy 3. Pyrazolones Propyphenazone • in combinations (with paracetamole and caffein) • AE: GIT intolerations, rash, bronchospasm, hematopoetic disorders Metamizole • analgetic, antipyretic + spasmolytics effect • combined with spasmolytics (pitofenone, fenpiverine) • AE: rare but serious - the most serious are agranulocytosis and pancytopenia 4. Propionic acid derivatives Ibuprofen • good analgesic and antiinflammatory effect • used often for acute pain therapy • low AE incidence, well tolerated NSAID, indicated for children Ketoprofen • phototoxicity Dexketoprofen Naproxen • longer T1/2 (12-15 hrs) • low gastro- and cardiovascular toxicity compared to other NSAIDs Tiaprofenic acid • good penetration to synovial fluid → joints diseases Flurbiprofen 4. Propionic acid derivatives 5. Acetic acid derivatives Diclophenac • antiinflammatory, analgesic, weak antipyretic ef. • bioavailability 30-70% • short biological halftime → retarded DDF • more AE than ASA, less than indomethacin – mild: cephalgia, insomnia, GIT disorders, photosensitivity – significant risk of cardiovascular AE Aceclofenac 5. Acetic acid derivatives Indomethacin • very strong nonselective COX inhibitor • toxic → short-time treatment of acute states • urikosuric effects→ used in gout attacks • AE in 30 % of pacients – GIT, cephalgia, depression, confusion, hallucinations, hematoxicity, cartilages destruction 6. Oxicams • high plasma protein binding (interactions!) • long biological halftime (once daily dosing) • different COX affinity Meloxicam • COX-2 more selective • lower AE incidence Locnoxicam • nonselective COX inhibitor • low occurence of GIT adverse effect Piroxicam • nonselective COX inhibitor, high toxicity 7. Coxibs • 100 x more selective to COX-2 (specific COX-2 inhibitors) – lower AE in GIT – do not influence thrombocyte aggregation or renal perfusion • good analgesic effect, not suitable for treatment of acute or transient pain → effect is progressing slowly • prescription and indication restrictions • I: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis • AE: increase of thrombembolisms (myocardial infarction, strokes) after chronic use Celecoxib Parecoxib – only inj. Etoricoxib Pharmacokinetics: • after p.o. administration good absorption from GIT, but not too fast, max levels reach in 2-4 hours • fat diet slows down absorption 7. Coxibs 8. Other Nimesulide • preferential inhibitor of COX-2 • inhibits enzymes destroys cartilage (elastases, collagenases), due to occurrence of AE, indication of treatment of painful osteoarthritis has been taken • is not the first choice medicine in any of indications • PK: lipophilic, short elimination half-life (1,5-5 hrs), analgesia up to 12 hrs • AE: hepatotoxicity (max duration of therapy 15 days) Adverse effects • because of COX-1 inhibition: – GIT -  cytoprotective PGE2, PGI2  erosions, ulcerations – thrombocytes -  TXA2: inhibition of thrombocytes aggregation  increased bleeding – PGE2, PGI2 regulation of renal functions  renal failure –  LT production induces in predisposed people bronchoconstriction  asthma attack – uterus -  PGE/F: inhibition of constriction  prolongation and complications during delivery • coxibs: – thromboembolic cardiovascular and cerebrovascular complications Prevention of AE • dose reduction or DDF change • combination with protective drugs – proton pump inhibitors (lansoprazole, omeprazole) – prostaglandine analogues (misoprostol) – H2 antihistamines (ranitidine, famotidine) • think about preferential or specific COX-2 inhibitors NSAIDs for local aplication • ketoprofen, ibuprofen, naproxen, indomethacin, diclophenac, nimesulide, piroxicam • flurbiprofen (lozenges), choline salicylate (oral gel) • DDF: creams, gels, solutions (sprays), patches, lozenges • AE: hypersensitivity reaction, phototoxic reaction Treatment of gout Drugs 1. Acute gout attack – strong anti-inflammatory action – pain-killers – inhibition of leucocyte migration to the joint 2. Hyperuricemia therapy / prevention of gout attack – increase of uric acid excretion – block of synthesis + diet Treatment of acute gout attack • NSAIDs – higher doses (i.m., p.o., p.r.) – some have preferably uricosuric effect – indometacine, diclofenac, piroxicam • colchicine – alcaloid obtained from Colchicum autumnale – p.o. every 2-4 hrs – mitotic poison, inhibits phagocytosis and leukocyte migration – AE: severe diarrhea – rehydratation! • glucocorticoids – local adm. (i.a.) – triamcinolone – systemic (p.o., i.m., i.v.) – prednison, methylprednisolon • canakinumab – IL-1 inhibitor, human monoclonal antibody – patients who do not tolerate NSAIDs and GC – s.c. aplication Chronic treatment of gout 1. Uricosurics • inhibit reabsorption of uric acid in primary tubulus Lesinurad • only in combination with xantin oxidase inhibitors Probenecide • sometimes used with antibiotics or antivirotics to make them stay longer in the body • Not registered in Czech Rep. 2. Antiuratics • inhibit syntesis of urine acid by inhibition xantin oxidase (XO) Allopurinol • isomer of hypoxanthin, competitive inhibition of xanthin oxidase • inhibits de novo syntesis of purines • not combine with cytostatics of purine structure (azathioprin, 6mercaptopurin) – allopurinol  their toxicity! • AE: usually well tolerated, most common: – rash, GIT intoleration, hypersensitive reaction hypoxanthin xanthin uric acid XO XO Febuxostat • MA: non-purine inhibitor of xantinoxidase • clinical trials proved higher efficacy than allopurinol • AE: gout attacts, liver function abnormalities, diarrhoea, nausea, headache Pegloticase (recombinant uricase) • MA: transforms uric acid to alantoin with better solubility • AE: anaphylactic shock, reaction to infusion, gout attacts at the beginning of therapy • i.v. aplication (only to inpatient)