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Slide 1-

Assoc. Prof. I. Lambev www.medpharm-sofia.eu COX inhibitors Nonsteroidal anti- inflammatory drugs Nonopioid analgesics
Slide 2-

The clinical features of inflammation have been recognized since ancient times as swelling, redness, pain, and heat. The underlying mechanisms which produce these symptoms are complex, involving many different cells and cell products. A normal inflammatory response is essential to fight infections and is part of the repair mechanism and removal of debris following tissue damage. Inflammation can also cause disease, due to damage of healthy tissue. This may occur if the response is over- vigorous, or persists longer than is necessary. Additionally, some conditions have a previously unrecognized inflammatory component, e.g. atherosclerosis.
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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, although not all cell types need be involved in an inflammatory episode. The cells migrate to the area of tissue damage from the systemic circulation and become activated.
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Inflammatory disease Acute respiratory distress syndrome Bronchial asthma Atherosclerosis Glomerulonephritis Inflammatory bowel disease Osteoarthritis Psoriasis Rheumatoid arthritis Sarcoidosis Inflammatory cell infiltrate Neutrophil Eosinophil,T cell, monocyte, basophil T cell, monocyte Monocyte,T cell, neutrophil Monocyte, neutrophil,T cell, eosinophil Monocyte, neutrophil T cell, neutrophil Monocyte, neutrophil T cell, monocyte Diseases with a chronic inflammatory component
Slide 5-

Inflammatory mediators Activated leukocytes at a site of inflammation release compounds which enhance the inflammatory response mainly cytokines and eicosanoids (arachidonic acid metabolites). But the complexity of the response is indicated by the range of many mediators: complement products, kinins (bradykinin) and the contact system (coagulation factors XI and XII, pre-kallikrein, high molecular weight kininogen); nitric oxide and vasoactive amines (histamine, serotonin and adenosine); activated forms of oxygen; platelet activating factor (PAF); metalloproteinases (collagenases, gelatinases, and proteoglycanase), etc.
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Cytokines (ILs, TNFs, IFNs, CSFs, etc.) are peptides regulating cell growth, differentiation, and activation, and some have therapeutic value: IL-1 plays a part in the sepsis syndrome and rheumatoid arthritis, and successful blockade of its receptor offers a therapeutic approach for these conditions. • TNFα is similar to IL-1. Agents that block him, e.g. etanercept, infliximab are finding their place among Disease modifying antirheumatic drugs.
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The main cell and inflammatory cytokines in chronic inflammatory diseases Clinical Pharmacology – 9th Ed. (2003)
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Eicosanoids (prostaglandins, thromboxanes, leukotrienes, lipoxins) is the name given to a group of 20-carbon unsaturated fatty acids, derived principally from arachidonic acid in cell walls. They are short-lived, extremely potent, and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on manipulation of their biosynthesis that most current antiinflammatory therapy is based. Their biosynthetic paths appear in the next slides.
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(+) Phospholipase A2 Phospholipids Arachidonic acid 5-lipoxygenase Leucotrienes Cyclooxy genase (COX) Endoperoxides PGs TxA2 15-lipoxygenase Lipoxins Inflammatory stimulus Ex In
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PGI2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: vasodilatation inhibition of platelet aggregation TxA2 is found in the platelets. Main effects: platelet aggregation vasoconstriction PROSTANOIDS (PGs & Txs)
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PGE2 causes: inhibition of gastric acid secretion contraction of pregnant uterus contraction of GI smooth muscles PGF2α – main effects: contraction of bronchi contraction of miometrium
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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).
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Essential of Medical Pharmacology – 5st Ed. (2003)
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COX-2 inhibitors Selective (coxibs) Preferential COX-3 inhibitors Antipyretic analgesics Nonselective COX-1/COX-2 inhibitors NSAIDs COX inhibitors
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Nonselective COX-1/COX-2 inhibitors (Classical NSAIDs) Salicylates Phenylacetates Indolacetates Enolates Fenamates Propionates Butylpyrazolidindiones Pyrazolones De rivatives of acid
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DERIVATIVES OF ACIDS Salicylates Acetylsalicylic acid (Aspirin®, 1899), Diflunisal Methyl salicylate (revulsive drug) Phenylacetates: Acelcofenac, Diclofenac Indolacetates: Indometacin, Sulindac Enolates (oxicams) Piroxicam, Piroxicam beta-cyclodextrin (prodrug), Lornoxicam, Tenoxicam Propionates Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen OTHERS (with less application) Pyrazolones: Phenazone, Propyphenazone, etc. Pyrazolidinediones: Oxyphenbutazone, Phenylbutazone Nonselective COX-1/COX-2 inhibitors
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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
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Shared toxicities of NSAIDs due to prostanoid synthesis inhibition 1. Gastric mucosal damage connected with PGE inhibition 2. Bleeding: inhibition of platelet function (TxA2 synthesis) 3. Limitation of renal blood flow Na+ and water retention 4. Delay / prolongation of labour connected with PGF2α inhibition 5. Asthma and anaphylactoid reactions connected with PGF2α inhibition
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Mechanisms by which NSAIDs may induce mucosal injury Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Metabolism of Aspirin Basic & Clinical Pharmacology – 10th Ed. (2007)
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Salicylic acid Aspirin (1899) Cortex Salicis albae
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Effects of NSAIDs 1. Analgesic and antipyretic action Aspirin is a weaker analgesic than morphine-type drugs Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine Aspirin relieves inflammatory, tissue injury related, connective tissue and integumental pain but is rela- tively ineffective in severe visceral and ischemic pain. The analgesic action is mainly due to obtunding perip- heral pain receptors and prevention of PG mediated sensitization of nerve endings. A central subcortical action, raising threshold to pain perception also contri- butes. No sedation, tolerance, and dependence are produced.
Slide 26-

Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (swea- ting, cutaneous vasodilation), but does not decrease heat production. 2. Antiinflammatory action is exerted at high daily doses of Aspirin (3 to 6 g). Clinical symptoms of inflam- mation are suppressed, but prolongation of the under- lying disease in rheumatoid arthritis, rheumatic fever, and osteoarthritis is not affect. 3. Inhibition of platelet aggregation in low doses (75–100 mg/24 h Aspirin). 4. Metabolic effects of Aspirin and other NSAIDs are significant only at antiinflammatory doses. Cellular metabolism is increased, especially in skeletal muscles, due to uncoupling of oxidative phosphorylation as a
Slide 27-

result of increased heat production. There is increased utilization of glucose and blood sugar may decrease (specially in diabetics) and liver glycogen is depleted. However, hyperglycemia is often seen at toxic doses: this is due to central sympathetic stimulation and release of adrenaline and GCS. Chronic use of large doses cause negative nitrogen balance by increased conversion of protein to carbohydrate. Plasma free fatty and cholesterol are reduced. 5. Respirations. At antiinflammatory doses respiration is stimulated by peripheral (increased CO2 production) and central (increased sensitivity of respiratory centre to CO2) action. Hyperventilation is prominent in salicy- late poisoning. Further raise in the salicylate level causes respiratory depression and failure, and death.
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6. Acid-base and electrolyte balance. Antiinflammatory doses produce significant changes. Initially respiratory stimulation predominates and tends to wash out CO2 despite increased production and the result is respiratory alkalosis, which is compensated by increased renal excretion of HCO3- (with accompanying Na+, K+, and water). Most adults treated with 4–6 g/daily of Aspirin stay in a state of compensated respiratory alkalosis. Still higher doses cause respiratory depression with CO2 retention, while excess CO2 production continues to develop respiratory acidosis. To this are added dis- sociated salicylic acid as well as metabolic acid (because there is rebound depression). It develops uncompensated metabolic acidosis. Dehydration occurs in poisoning due to increased water loss in urine.
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7. CVS. Larger doses of Aspirin increase cardiac output to meet increased peripheral oxygen demand and cause direct vasodilatation. Toxic doses depress vaso- motor centre: BP falls. Because of increased cardiac work as well as sodium and water retention, CHF my develop if the heart reserves are low. 8. GIT. Aspirin and its metabolite salicylic acid irritate gastric mucosa and cause epigastralgia, nausea, and vomiting. In higher doses it also stimulates CTZ. Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This “ion trapping” in the gastric mucosal cell enhances gastric toxicity.
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Further, Aspirin partial contact with gastric mucosa promotes local back diffusion of acid, respectively focal necrosis of mucosal cells and capillaries, acute ulcers, erosive gastritis, congestio, and microscopic haemorrhages. The occult blood loss in stools is increased with any dose of Aspirin, averaging 5 ml/24 h at antinflammatory doses. Soluble Aspirin tablets containing calcium carbonat + citric acid and other buffered preparations have less gastric toxicity.
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Alcohol increasis GI toxicity of NSAIDs. 9. Urate excretion. Aspirin in high dose reduces renal tubular excretion of urate (both substances are trans- ported by the same mechanism).
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Uses of Aspirin® (Bayer, 1899) As analgesic (300 to 600 mg during 6 to 8 h) for head- ache, backache, pulled muscle, toothache, neuralgias. As antipyretic in fever of any origin in the same doses as for analglesia. However, paracetamol and metamizole are safer, and generally preferred. Acute rheumatic fever. Aspirin is the first drug of choice. Other drugs substitute Aspirin only when it fails or in severe cases. Antirheumatic doses are 75 to 100 mg/kg/24 h (resp. 4–6 g daily) in the first weeks. 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.
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Aspirin therapy in children with rheumatoid arthritis has been found to raise serum concentration trans- aminases, 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.
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Arachidonic acid Cyclooxygenase (COX) Endoperoxides PGs TxA2 (-) Aspirin Thromboxane A2 synthase (-) 100 mg/24 h >1 g/24 h
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Drug interactions with NSAIDs
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Ibuprofen is a derivative of phenylpropionic acid. In doses of 2.4 g daily it is is equivalent to 4 g of Aspirin in anti-inflammatory effect. Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at which it has analgesic but not antiinflammatory efficacy. It is available in low dose forms under several trade names (e. g. Nurofen® – film-tabl. 400 mg). A topical cream preparation is absorbed into fascia and muscle. A liquid gel preparation of ibuprofen provides prompt relief in postsurgical dental pain. In comparison with indometacin, ibuprofen decreases urine output less and also causes less fluid retention. It is effective in closing ductus arteriosus in preterm infants, with much the same efficacy as indometacin.
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Chemical structures of the propionic acid derivatives (propionates)
Slide 39-

Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)(-) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect TNF-α and NO synthesis. Hepatic metabolism is extensive. It does demonstrate enterohepatic circulation. The efficacy of flurbiprofen at dosages of 200–400 mg/d is compa- rable to that of Aspirin and other NSAIDs for patients with rheumatoid arthritis, ankylosing spondylitis, gout, and osteoarthritis. Flurbiprofen i.v. is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. Its adverse effect profile is similar to other NSAIDs.
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Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life. The effectiveness of ketoprofen at dosages of 100–300 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. Phenylbutazone is a derivative of pyrazolidinedione with a high GI toxicity. It is rarely used now.
Slide 41-

Indometacin is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indometacin's half-life by inhibiting both renal and biliary clearance. Indometacin is indicated for use in juvenile rheumatoid arthritis, gout and ankylosing spondylitis, postepisio- tomy pain, etc. It has been used to treat patent ductus arteriosus. An ophthalmic preparation seems to be efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indometacin oral rinse. A high incidence (up to 50%) of GI and CNS side effects is produced: GI bleeding, diarrhoea, frontal headache, mental confusion, etc.
Slide 42-

Diclofenac is a phenylacetic acid derivative. A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. 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 (Voltaren® and Feloran® – SR tablet: 100 mg/24 h). Side effects occur in approximately 20%: GI distress and occult bleeding, gastric ulceration. A preparation combining diclofenac and misoprostol (PGE1) decrea- ses upper GI ulceration but may result in diarrhoea.
Slide 43-

Piroxicam, an oxicam (enolate derivative), is a nonselective COX-1/COX-2 inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life permits once-daily dosing. Piroxicam can be used for the usual rheumatic indications. 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.
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COX-2 inhibitors (1) Selective COX-2 inhibitors (Coxibs) Celecoxib Etoricoxib Parecoxib (2) Preferential COX-2 inhibitors Meloxicam Nimesulide Nabumetone
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Inhibiting activity rate (COX-2/COX-1) Aspirin Indometacin Meloxicam 155 60 0,8 (Preferential COX-2 inhibitor) Classical NSAIDs
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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, Nabumetone, and Nimesulide (Aulin®) is significant. Etoricoxib Parecoxib
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Celecoxib is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin – would be expected of a drug metabolized via CYP 2C9.
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Etoricoxib is a second-generation COX-2-selective inhibitor with the highest selectivity ratio of any coxibs. It is extensively metabolized by hepatic CYP450 enzy- mes followed by renal excretion and has an elimination t1/2 of 22 h. Etoricoxib is approved in the UK for the treatment of the symptoms of osteoarthritis (60 mg once daily) and rheumatoid arthritis (90 mg once daily), acute gouty arthritis (120 mg once daily), and for the relief of acute musculoskeletal pain (60 mg once daily). Ninety mg daily of etoricoxib has superior efficacy com- pared with 500 mg of naproxen twice daily in the treat- ment of rheumatoid arthritis over 12 weeks. Etoricoxib has similar efficacy to traditional NSAIDs for osteo- arthritis, acute gouty arthritis, and primary dysmenor- rhea and has a GI safety profile similar to other coxibs.
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Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs and may be considered “ preferentially" selective rather than “highly” selective. The drug has been approved for the treatment of osteoarthritis and rheumatoid arthritis. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Other toxicities are similar to those of other NSAIDs.
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OUT OF DATE Many severe side effects Infertility (> PGF2α) Thrombosis (< PGI2; > TxA2) Bextra® (Valdecoxib): Pfizer (penalty!) OUT OF DATE
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COX-3 inhibitors (antipyretic analgesics) NSAIDs in low doses 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
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Pathogenesis of pain Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Acetaminophen (USAN) (Paracetamol – INN) Efferalgan® Panadol® ParacetaMAX® Propacetamol is a prodrug. It converts into paracetamol. Acetylsalicylic acid Aspirin® Aspegic® lisinate Dipyrione (BAN) (Metamizole – INN) Analgin® Proalgin® Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Slide 55-

Paracetamol Although equivalent to Aspirin as an effective analgesic and antipyretic agent, paracetamol differs in that it lacks antiinflam- matory properties. It does not affect uric acid levels and lacks platelet-inhibiting properties. The drug is useful in mild to moderate pain: headache, myalgia, postpartum pain. Paracetamol alone is inadequate therapy for inflammatory conditions such as rheuma- toid arthritis, although it may be used as an analgesic adjunct to antiinflammatory therapy. For mild analge- sia, paracetamol is the preferred drug in patients aller- gic to Aspirin or when salicylates are poorly tolerated. It is preferable to Aspirin in patients with hemophilia or a history of peptic ulcer and bronchospasm. It is preferred to Aspirin in children with viral infections.
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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. N-acetyl-p-benzoquinoneimine (NABQI) is a highly reactive arylating metabolite of paracetamol which detoxicated by conjugation with glutathione. When a very large doses of paracetamol are taken, the glucuroconjugation capacity is saturated, more NABQI is formed, hepatic glutathione is depleted and NABQI binds covalently to proteins in liver cells (and renal tubules) causing necrosis. In chronic alcoholics even 5-6 g/d taken for a few days can result in hepatotoxicity because ethanol induces CYP 2E2, that metabolizes paracetamol, to NABQI. Treatment needs activated charcoal, given orally or through the tube to prevent GI absorption, and acetylcysteine (150 mg/g by i.v. infusion).
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Metabolism of paracetamol to hepatotoxic metabolites (NABQI etc.) (GSH – glutathione; SG – glutathione moiety) Daily dose > 7.5 g: hepatotoxicity and nephrotoxicity NABQI NB: Acetylcysteine and GSH contain –SH groups. Basic & Clinical Pharmacology – 10th Ed. (2007)
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Rang et al. Pharmacology – 6th Ed. (2007)
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Metamizole (Analgin® – tabl. 500 mg, Dipyron) is a derivative of pyrazolone. It is a potent and promptly acting analgesic, antipyretic, and spasmolytic but has poor antiinflammatory and not uricosuric activity. Analgin can be given orally, i.m. as well as i.v. (very slowly). Pain at the i.m. injection site and rarely abscess can occur. Occasionally an i.v. injection produces fall in BP. Few cases of agranulocytosis were reported and metamizole was banned in the USA and some European country. However, it has been extensively used in Bulgaria and many other European country, as well as in India and Russia. Adverse reaction data collected over four decades shows that the risk of serious toxicity with metamizole is very low than with Aspirin or many other NSAIDs.
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Pathophysiologic events in a gouty joint Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymor- phonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macro- phage release of inflammatory mediators. (PG – prostaglandin; IL-1 – interleukin-1; LTB4 – leukotriene B4) GOUT Basic & Clinical Pharmacology – 10th Ed. (2007)
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DRUGS IN GOUT (1) Acute goat Colchicine Diclofenac, Indometacin, Naproxen, Phenylbutazone, Piroxiam (2) Chronic gout Uricostatics (xantine oxidase inhibitors) Allopurinol, Febuxostat Uricosurics Benzbromarone, Probenecide Sulfinpyrazone Uricolytics: Uricase, Rasburicase Drug combinations Harpagin® (allopurinol & benzbromarone)
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Inhibition of uric acid synthesis by allopurinol Basic & Clinical Pharmacology – 10th Ed. (2007)
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Uricosuric drugs
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 Antiinflammatory drugs NSAIDS: diclofenac, celecoxib, ibuprofen, piroxicam, etc. Glucocorticosteroids: prednisone, methylprednisolone, betamethasone, etc.  Disease modifying antirheumatic drugs (DMARDs): adalimumab, cyclosporine, etanercept, infliximab, leflunomide, methotrexate, sulfasalazine, gold (Auranofin®), etc. ANTIRHEUMATOID DRUGS