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Anti-inflammatory Drugs

Anti-inflammatory Drugs. Topic 10 : . Dr. Korawuth Punareewattana Dept. of Vet Phar & Tox Khon Kaen University. Anti-inflammatory Drugs. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Steroidal Anti-inflammatory Drugs Miscellaneous Drugs Pharmacological control of inflammation:

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Anti-inflammatory Drugs

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  1. Anti-inflammatory Drugs Topic 10 : Dr. Korawuth Punareewattana Dept. of Vet Phar & Tox Khon Kaen University

  2. Anti-inflammatory Drugs • Nonsteroidal Anti-inflammatory Drugs (NSAIDs) • Steroidal Anti-inflammatory Drugs • Miscellaneous Drugs Pharmacological control of inflammation: • Preventing the release of inflammatory mediators • Inhibiting their actions • Treating pathophysiologic responses to them

  3. NSAIDs General characteristics • Drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA) • Aspirin-like drugs or COX inhibitors Major action: • inhibit Cyclooxygenase (COX) Pharmacological effects • Suppress inflammation • Relieve pain • Reduce fever

  4. Prostaglandins (PGs) are derived from arachidonic acid Cell Membrane (phospholipids) phospholipase A2 Arachidonic acid cyclooxygenaseaspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG2, PGH2) prostacyclin prostaglandin thromboxane synthetase synthetase synthetase prostacyclin PGE2 PGF2 Thromboxane A2 PDX, PGI2 (vasodilator, (erythma (vasodilator (vasoconstriction antiaggregating) edema uterus contractor) platelet aggregation) pain, fever) Lipoxygenase (LOX) Leukotrienes

  5. NSAIDs: Classifications based on chemistry • Salicylic acid derivatives • Aspirin • Para-aminophenol derivatives • Acetaminophen • Indole and indene acetic acids • Indomethacin • Pyranocarboxylic acids • Etodolac • Ketorolac • Propionic acids • Ibuprofen • Naproxen • Ketoprofen • Carprofen • Vedaprofen • Fenamates • Meclofenamic acid • Tolfenamic acid • Pyrazolones or enolic acids • Phenylbutazone • Dipyrone • Oxicams • Piroxicam • Meloxicam • Nicotinic acid derivatives • Flunixin meglumine • Hydroxamic acid derivatives • Tepoxalin • Coxib-class NSAIDs • Deracoxib • Firocoxib

  6. NSAIDs:Cyclooxygenase • Cyclooxygenase has 2 forms: • COX-1 (good COX) : found in all tissues • Mediates “housekeeping chores” • Protect gastric mucosa • Support renal function • Promote platelet aggregation • COX-2 (bad COX) : found at sites of tissue injury • Mediates inflammation and sensitize receptors to painful stimuli • Also present in brain- mediates fever and contributes to perception of pain • Mediates a cytoprotective effect in damaged GI mucosa

  7. NSAIDs: effect of COX inhibition • COX-1 inhibition • Results largely in harmful effects • Gastric erosion and ulceration • Bleeding tendencies • Acute renal failure • Results in some beneficial effects • Protection against myocardial infarction • COX-2 inhibition • Results in beneficial effects • Suppression of inflammation • Alleviation of pain • Reduction of fever

  8. Classification of Cyclooxygenase Inhibitors • Drugs with anti-inflammatory properties NSAIDs—Nonsteroidal anti-inflammatory drugs: 2 types • First generation (inhibit both COX1 and COX2) Non-selective COX inhibitors - aspirin • Second generation (inhibit COX2 only) Preferential COX2 inhibitors (partial specificity for COX2) - celecoxib (human drug) - carprofen (canine drug) Selective COX2 inhibitors (full specificity for COX2) - rofecoxib (human drug) - deracoxib (canine drug) • Drugs without inflammatory properties • Acetaminophen

  9. NSAIDs: mechanism of action • NSAIDs • act to block the first step of prostaglandin synthesis • by binding to and inhibiting cyclooxygenase • Dose and drug dependent • The major therapeutic, toxic, and potency of NSAIDs • all relate to their ability to inhibit prostaglandin synthesis

  10. Differential effect of NSAIDs on the COX isoforms • Ratio of COX1 to COX2 (COX1:COX2 ratio) • describes the amount of drug necessary to inhibit the respective isoform of the cyclooxygenase enzyme (IC50) • Calculation: COX1:COX2 ratio = IC50COX1 / IC50COX2 • COX1 to COX2 ratio > 1 is desirable, or • COX2 to COX1 ratio < 1 • This means a drug can inhibit COX2 at lower conc, and is probably safer

  11. COX1: COX2 ratios of NSAIDs Examples • Aspirin 0.343 • Carprofen (racemix mixture) 129 • Carprofen (S isoform) 181 • Carprofen (R isoform) 4.19 • Etodolac 0.517 • Flunixin meglumine 0.635 • Ketoprofen 0.232 • Meclofenamic acid 15.4 • Meloxicam 2.9 • Phenylbutazone 2.64

  12. NSAIDs: Pharmacokinetics • As weak acids, well absorbed after PO • Small volume of distribution (10%) • Highly protein binding (90%) • Clearance: • hepatic metabolism both phase I and II • Conjugated metabolites -> urine

  13. NSAIDs: Pharmacological effects • Analgesia, antipyresis, and control of inflammation • Relative potency in lab animals and human • Meclofenamic acid > indomethacin > naproxen > aspirin • Relative potency in horses • Flunixin meglumine > meclofenamic acid > phenylbutazone > naproxen > aspirin • Aspirin -> permanent effect on platelet activity

  14. NSAIDs: Adverse reactions • Gastrointestinal system • GI ulceration • Hematopoietic system • Bleeding dyscrasias • All NSAIDs are able to impair platelet activity • Platelet aggregation defects caused by aspirin can last up to 1 week • Renal system • Analgesic nephropathy • In kidney, vasodilatory and tubuloactive prostaglandins are protective • Both COX1 and COX2 mediate renal effects of prostaglandins

  15. NSAIDs: GI ulceration • GI damage is the most common and serious side effect of NSAIDs • Dogs – very sensitive • Inhibition of COX1-stimulated PGE2-mediated bicarbonate and mucous secretion, epithelialization, and increased blood flow • Direct irritation of acidic drugs • Salicylates cause backdiffusion of acid -> injury to mucosal cells and submucosal capillaries

  16. NSAIDs: Specific Drugs in Vet Med Non-Selective COX inhibitors • Acetaminophen • Aspirin • Etodolac • Flunixin Meglumine • Ketorolac • Naproxen • Phenylbutazone • Piroxicam • Tolfenamic acid • Vedaprofen Preferential COX-2 inhibitors (Partial specificity for COX-2) • Carprofen (Rimadyl, Pfizer) • Meloxicam Selective COX-2 inhibitors (no significant effect on COX-1) • Deracoxib (Deramaxx, Novartis) • Firocoxib (Previcox, Merial) • Robenacoxib (Onsior, Novartis) • Mavacoxib (Trocoxil, Pfizer) Dual COX and LOX inhibitors • Tepoxalin • Ketoprofen

  17. NSAIDs: Non-selective COX inhibitors • Acetaminophen • Aspirin X

  18. NSAIDs: Non-selective COX inhibitors • Etodolac • Ketololac • Flunixin meglumine

  19. NSAIDs: Non-selective COX inhibitors • Naproxen • Phenylbutazone

  20. NSAIDs: Non-selective COX inhibitors • Piroxicam • Vedaprofen • Tolfenamic acid

  21. NSAIDs: Preferential COX2 inhibitors • Carprofen • Meloxicam

  22. NSAIDs: Selective COX2 inhibitors • Deracoxib (Deramaxx) • Firocoxib (Previcox) • Robenacoxib (Onsior) • Mavacoxib (Trocoxil)

  23. Steroidal Anti-inflammatory Drugs(Glucocorticoids, Corticosteroids) • Most frequently used and misused drugs in veterinary medicine • Needs an understanding of their actions on all body systems

  24. Control of endogenous glucocorticoid secretion Corticotropin-releasing factor (CRF) Adrenocorticotropic hormone (ACTH)

  25. Mechanism of action

  26. Mechanism of action • Glucocorticoid receptors • Intracellular, 3 subtypes at least • activated receptor-glucocorticoid complex • -> binds to glucocorticoid responsive element • -> modulate gene transcription • Target proteins could be induced or inhibited • result in pharmacologic effects of glucocorticoids • Differential gene regulation by glucocorticoids in different cells • The liver is the primary target • Half-life of the activated complex is about 10 hours

  27. Examples of proteins whose synthesis is targeted by glucocorticoid receptor regulation InducedInhibited • Lipocortin-1 Cytokines • Beta2-adrenoreceptor Natural killer receptor • Angiotensin-converting enzyme Inducible nitric oxide synthase • Neutral endopeptidase Cyclooxygenase Endotheslin Phospholipase Collagenase Stromelysin

  28. Physiologic effects: Metabolism • Protect glucose-dependent tissues (brain, heart) • Hyperglycemic effect • Increase gluconeogenesis, insulin antagonism • Increased breakdown of proteins • Skeletal muscles and collagen • Provides gluconeogenic precursors • Result in muscle wasting, delayed wound healing, and thinning of the skin • Promote lipolysis • Redistribution of body fat

  29. Physiologic effects: Hemolymphatic system • Increase the RBC content of the blood • Retarding erythrophagocytosis • Lymphopenia • Eosinopenia • Monocytopenia • Neutrophilia • Increased release from bone marrow • This blood cell profile: Stress leukogram

  30. Anti-inflammatory and Immunosuppressive effects • Inhibit early and late phases of the inflammation • Inhibit edema formation, fibrin deposition, leukocyte migration, phagocytic activity, collagen deposition, and capillary and fibroblast proliferation • Inhibit enzyme phospholipase A2 and COX-2 • Inhibit release of TNF-, IL-2, and platelet activating factor • Inhibit inducible nitric oxide synthase (iNOS) • Inhibit the synthesis of IL-1 and IL-2 • Immunosuppression is more pronounced on the CMI than humoral immunity

  31. Pharmacokinetics • Absorption • Several products are well absorbed orally • Topical use -> well absorbed • Long-term use - > systemic effect • Metabolism • Eliminated by oxidation or reduction, and followed by conjugation • Excreted principally via kidneys

  32. Glucocorticoid Preparations Duration of actionAnti-Inflam potency • Short acting (< 12 hr) • Hydrocortisone (identical to cortisol) 1 • Topical use • Intermediate acting (12 – 36 hr) • Prednisolone and Prednisone 4 • Methylprednisolone (has lipid antioxidant activity) 5 • Triamcinolone 5 • Alternate day administration • Long acting (48 hr) • Dexamethasone 30 • Betamethasone 30 • Highly potent glucocorticoids

  33. Hydrocortisone Preparations

  34. Prednisolone Preparations

  35. Triamcinolone Preparations

  36. Dexamethasone Preparations

  37. Therapeutic indications • Autoimmune diseases affecting skin • Pemphigus complex • Systemic lupus erythematosus • Discoid lupus erythematosus • Canine atopy (allergic inhalant dermatitis) • Otitis externa • Bronchial asthma in cats • CNS edema

  38. Therapeutic indications(continued) • Selected musculoskeletal disorders • Polymyositis, Eosinophilic myositis • Osteoarthritis • Low dose: chondroprotective • High dose: chondrodestructive (steroid arthropathy) • Inflammatory bowel disease • Eosinophilic granuloma complex in cats • Gingivitis and stomatitis in cats

  39. Therapeutic indications(continued) • Neoplasia • Lymphoma • Multiple myeloma • Mast cell tumors • Noninfectious conjunctival, corneal, and anterior uveal inflammatory diseases • Contraindicate in corneal ulcers • Immune-mediated hemolytic anemia and thrombocytopenia • Hypoadrenocorticism (Addison’s disease)

  40. Adverse effects • Iatrogenic adrenocortical insufficiency • Iatrogenic hyperadrenocorticism • Susceptibility to infection • Glucocorticoid-induced polyphagia • Muscle weakness and muscle atrophy (common in dogs) • Reversible hepatopathy • Polyuria and polydipsia • Pulmonary thromboembolism • Hypertension • Diabetes mellitus and hyperlipidemia

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