Ali Jaber, Ph.D. MS in Pharmacy MS in Pharmaceutical Chemistry

Transcription

1 Nonsteroidal antiinflammatory drugs (NSAID) Ali Jaber, Ph.D. MS in Pharmacy MS in Pharmaceutical Chemistry

2 The inflammatory response occurs in vascularised tissues in response to injury. It is part of the innate nonspecific immune response. Inflammatory responses require activation of leukocytes: neutrophils, eosinophils, basophils,mast cells, monocytes, and lymphocytes,

3 Ex Inflammatory stimulus (+) Phospholipids In Phospholipase A 2 Arachidonic acid Cyclooxy genase (COX) 5-lipoxygenase 15-lipoxygenase Endoperoxides Leucotrienes Lipoxins PGs TxA 2

4 PROSTANOIDS (PGs & Txs) PGI 2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: vasodilatation inhibition of platelet aggregation TxA 2 is found in the platelets. Main effects: platelet aggregation vasoconstriction

5 PGE 2 causes: inhibition of gastric acid secretion contraction of pregnant uterus contraction of GI smooth muscles PGF 2α main effects: contraction of bronchi contraction of miometrium

6 Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. It exists in 3 isoforms: COX-1 (constitutive) acts in physiological conditions. COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 (in brain).

7 Essential of Medical Pharmacology 5 st Ed. (2003)

8 COX inhibitors NSAIDs Nonselective COX-1/COX-2 inhibitors COX-2 inhibitors Selective (coxibs) Preferential COX-3 inhibitors Antipyretic analgesics

9 Nonselective COX-1/COX-2 inhibitors (Classical NSAIDs) Salicylates Phenylacetates Indolacetates Enolates De rivatives Fenamates of acid Propionates Butylpyrazolidindiones Pyrazolones

10 Nonselective COX-1/COX-2 inhibitors Acetylsalicylic acid (Aspirin ) Paracetamol (Panadol) Diclofenac (Voltaren) Indometacin Piroxicam (Brexin) Meloxicam (Mobic) Ibuprofen (Brufen) Ketoprofen (Profenid)

11 Beneficial actions of NSAIDs due to prostanoid synthesis inhibition 1. Analgesia prevention of pain nerve ending sensitization 2. Antipyresis connected with influence of thermoregulatory centre in the hypothalamus 3. Antiinflammatory action mainly antiexudative effect 4. Antithrombotic action in very low daily doses 5. Closure of ductus arteriosus

12 Shared toxicities of NSAIDs due to prostanoid synthesis inhibition 1. Gastric mucosal damage connected with PGE inhibition 2. Bleeding: inhibition of platelet function (TxA 2 synthesis) 3. Limitation of renal blood flow Na + and water retention 4. Delay / prolongation of labour connected with PGF 2α inhibition 5. Asthma and anaphylactoid reactions connected with PGF 2α inhibition

13 Lüllmann, Color Atlas of Pharmacology 2 nd Ed. (2000)

14 Aspirin (Bayer, 1899) As analgesic for headache,pulled muscle, neuralgias. As antipyretic in fever of any origin. However, paracetamol is preferred Acute rheumatic fever. Aspirin is the first drug of choice. Other drugs substitute Aspirin only when it fails or in severe cases. Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal is effective in most cases. Since large doses of Aspirin are poorly tolerated for a long time, the new NSAIDs (diclofenac, ibuprofen, etc.) in depot form are preferred.

15 Aspirin therapy in children with rheumatoid arthritis has been found to raise serum concentration transaminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association between salicylate therapy and Reye s syndrome, a rare form of hepatic encephalopathy seen in children, having viral infection (varicella, influenza), has been noted. Aspirin should not be given to children under 15 years unless specifically indicated, e.g. for juvenile arthritis (paracetamol is preferred). Postmyocardial infarction and poststroke patients. By inhibiting platelet aggregation in low doses (100 mg daily) Aspirin decreases the incidence of reinfarction.

16 Arachidonic acid Cyclooxygenase (COX) Endoperoxides (-) >1 g/24 h Aspirin Thromboxane A 2 synthase (-) 100 mg/24 h PGs TxA 2

17 Drug interactions with NSAIDs Drugs Result Diuretics Decrease diuresis Beta-blockers Decrease antihypertensive effect ACE inhibitors Decrease antihypertensive effect Anticoagulants Increase of GI bleeding Sulfonylurea Increase hypoglycemic risk Cyclosporine Increase nephrotoxicity GCS Increase of GI bleeding Alcohol Increase of GI bleeding

18 Ibuprofen (Brufen) Oral ibuprofen is often prescribed in lower doses at which it has analgesic but not antiinflammatory efficacy. A topical cream preparation is absorbed into fascia and muscle. A liquid gel preparation of ibuprofen provides prompt relief in postsurgical dental pain.

19 Ketoprofen (Profenid) The effectiveness of ketoprofen at dosages of mg/d is equivalent to that of other NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, gout, dysmenorrhea, and other painful conditions. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs. Its major adverse effects are on the GIT and the CNS.

20 Indometacin Is a potent nonselective COX inhibitor and may also inhibit phospholipase, reduce neutrophil migration, and decrease T cell and B cell proliferation. Indications: juvenile rheumatoid arthritis, gout and post episiotomy pain. Side effects: A high incidence (up to 50%) of GI and CNS side effects is produced: GI bleeding, diarrhoea, frontal headache, mental confusion, etc.

21 Diclofenac (Voltaren) Diclofenac in rectal suppository form can be considered a drug of choice for analgesia and postoperative nausea. It is also available for intramuscular and oral administration Indications: All moderate pain Side effects occur in approximately 20%: GI distress and occult bleeding, gastric ulceration. A preparation combining diclofenac and misoprostol (PGE 1 ) decreases upper GI ulceration but may result in diarrhoea.

22 Piroxicam, (Feldene) Its long half-life permits once-daily dosing. Piroxicam can be used for the usual rheumatic indications. Side effects: Toxicity includes GI symptoms (20% of patients), dizziness, tinnitus, headache, rash. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered. This risk is as much as 10 times higher with piroxicam than with other NSAIDs.

23 COX-2 inhibitors (1) Selective COX-2 inhibitors (Coxibs) Celecoxib (celebrex) Etoricoxib (Arcoxia) (2) Preferential COX-2 inhibitors Meloxicam(Mobic) Nimesulide(Aulin)

24 Inhibiting activity rate (COX-2/COX-1) Aspirin Indometacin Meloxicam ,8 Classical NSAIDs (Preferential COX-2 inhibitor)

25 Coxibs are selective COX-2 inhibitors. They exert antiinflammatory, analgesic, and antipyretic action with low ulcerogenic potential. Coxibs can cause infertility. They have prothrombotic cardiovascular risk. The ulcerogenic potential of preferential COX-2 inhibitors Meloxicam (Mobic), and Nimesulide (Aulin ) is significant.

26 Celecoxib (Celebrex)is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, Side effects: celecoxib may cause rashes. It does not affect platelet aggregation at usual doses.

27 Etoricoxib (Arcoxia) is a second-generation COX-2-selective inhibitor Indications: treatment of the symptoms of osteoarthritis, rheumatoid arthritis and for the relief of acute musculoskeletal pain Etoricoxib has similar efficacy to traditional NSAIDs for osteoarthritis, acute gouty arthritis, and primary dysmenorrhea and has a GI safety profile similar to other coxibs.

28 Meloxicam (Mobic) It has been shown to preferentially inhibit COX-2 over COX-1 It is not as selective as the other coxibs and may be considered preferentially" selective rather than highly selective. Indications: treatment of osteoarthritis and rheumatoid arthritis. Side effects: are similar to those of other NSAIDs.

29 Comparative action between COX-1/COX-2 COX-2 COX inhibitors inhibitors inhibitors 1. Analgesic action (+) (+) (+) 2. Antipyretic action (+) (+) 3. Antiinflammatory action (+) (+) (+) 4. Antiplatelet aggregatory (+) (-) 5. Gastric mucosal damage (+) (+) (+) (+) 6. Renal salt / water retention (+) (+) 7. Delay/prolongation of labor 8. Infertility (+) (+) (-) (+) (+) (+) 9. Ductus arteriosus closure (+)? 10. Aspirin-like asthma 11. Cardiotoxicity (+) (-)? (+) (+)

30 Bextra (Valdecoxib): Pfizer (penalty!) Many severe side effects Infertility (> PGF 2α ) Thrombosis (< PGI 2 ; > TxA 2 )

31 NONOPIOID ANALGESICS (1) Anilides Paracetamol tabl. 500 mg (Acetaminophen USAN) Propacetamol (prodrug) (2) Pyrazolones Metamizole (Analgin tabl. 500 mg) (3) COX-1/COX-2 inhibitors Aspirin, Diclofenac, Ibuprofen, Naproxen etc. (4) COX-2 inhibitors COX-3 inhibitors (antipyretic analgesics) NSAIDs in low doses

32 Pathogenesis of pain Lüllmann, Color Atlas of Pharmacology 2 nd Ed. (2000)

33 Acetaminophen (USAN) (Paracetamol INN) Efferalgan Panadol ParacetaMAX Propacetamol is a prodrug. It converts into paracetamol. Acetylsalicylic acid Aspirin Aspegic lisinate (Metamizole INN) Analgin Proalgin Lüllmann, Color Atlas of Pharmacology 2nd Ed. (2000)

34 Paracetamol (Panadol, Efferelgan) paracetamol lacks antiinflammatory properties. Indications: mild to moderate pain: headache, myalgia,postpartum pain. paracetamol is the preferred drug in children as antipyretic and analgesic Side effects: hepatotoxcity most of all Acute paracetamol poisoning occurs especially in small children who have low hepatic glucuronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in adult) is taken, serious toxicity can occur. The letal dose is 250 mg/kg