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PHARMACOLOGY OF INFLAMMATION

PHARMACOLOGY OF INFLAMMATION. David J. Mokler, Ph.D. October 29, 2009. OBJECTIVES. After studying this material the student should ; Describe the role of prostaglandins in the inflammatory response.

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PHARMACOLOGY OF INFLAMMATION

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  1. PHARMACOLOGY OF INFLAMMATION David J. Mokler, Ph.D. October 29, 2009

  2. OBJECTIVES • After studying this material the student should; • Describe the role of prostaglandins in the inflammatory response. • Describe the mechanism of action of non‑steroidal drugs used in the treatment of inflammation. • Describe the pharmacology and toxicology of the non‑steroidalanti‑inflammatory agents. • Discuss the toxicity of acetaminophen

  3. OBJECTIVES • After studying this material the student should; • Discuss the proper and rational use of corticosteroids in the treatment of inflammation. • Discuss the toxic effects of the corticosteroids used in chronic therapy.

  4. NSAIDs – COX INHIBITORS • Aspirin • Indomethacin (INDOCIN) • Proprionic Acid Derivatives • Ibuprofen (MOTRIN, RUFEN, ADVIL, NUPRIN) • Naproxen (NAPROSYN) • Piroxicam (FELDENE) • Nabumetone (RELAFEN) • Ketorolac (TORADOL) • Acetominophen (TYLENOL, TEMPRA, others)

  5. NSAIDs – COX INHIBITORS • COX2 Inhibitors • Celecoxib (CELEBREX)

  6. PROSTAGLANDINS • History • 1930 ‑ Kurzrok and Lieb • 1930s ‑ Goldblatt, Euler "prostaglandin"‑ lipid‑ soluble acid • 1962 ‑ isolation of PGE1 and PGF1 • 1964 ‑ synthesis from arachadonic acid • Arachadonic acid metabolites via cyclo-oxygenase • Released by mechanical, thermal, chemical, bacterial and other trauma

  7. PROSTAGLANDINS

  8. PROSTAGLANDINS • Effects • produce ­ blood flow in injured region, ­ vascular permeability, enhance lymphocytic infiltration • may modulate release of histamine from mast cells ‑ PGD2 stimulates, PGE2 and PGI2 inhibits • oxygen radicals produced as byproduct of synthesis ® inflammation • potentiate pain‑producing effects of kinins • produce fever in hypothalamus • PGE1 and PGE2 stimulate osteoclasts ® bone resorbtion

  9. Fever

  10. PROSTAGLANDINS • Effects • PGE1 and PGD2 inhibit platelet aggregation • TXA2 induces aggregation • PGA2, PGE1 and PGE2 induce erythroporesis • PGFs contract, PGEs relax bronchial smooth muscle, non‑pregnantand pregnant uterus

  11. Two Forms ofCyclo-oxygenase (COX) • COX-1 • Produces prostanoids that mediate homeostaticfunctions • Constitutively expressed • Especially important in: • – Gastric mucosa; small- • and large-bowel mucosa • – Kidney • – Platelets • – Vascular endothelium • COX-2 • Produces prostanoids that mediate inflammation, pain, and fever • Induced mainly at sites of inflammation by cytokines • Constitutive expression in: • – Brain • – Kidney (mainly animal data)– Female reproductive tract DuBois RN, et al. FASEB J. 1998;12:1063–1073.

  12. Mechanism of Action of Anti-inflammatory Agents Arachidonic acid COX-2–targeted agents X COX-1 COX-2 X X Traditional NSAIDs Prostaglandins Thromboxane Prostaglandins Mediate inflammation,pain, and fever Supportsplateletfunction Protect gastroduodenalmucosa

  13. LEUKOTRIENES • arachidonic acid metabolites from lipoxygenase • may be inhibited by some NSAIDs, inhibited by steroids

  14. LEUKOTRIENES

  15. LEUKOTRIENES • Effects • LTB4 potent chemotaxic substance • act on endothelium of postcapillary venules to cause exudation of plasma • 5‑HPETE and 5‑HETE induce release of histamine from basophils • LTC4 and LTD4 potent bronchoconstrictors • LTD4 is the slow reacting substance of anaphylaxis (SRSA) ® bronchoconstriction, histamine release, ­ vasopermeability

  16. OTHER MEDIATORS OF INFLAMMATION • Histamine • 5‑hydroxytryptamine (Serotonin) • Bradykinins • Vasopermeability • histamine release • prostaglandin synthesis • Pain

  17. NSAIDsSALICYLATES • Aspirin – acetylsalicylic acid (ASA)

  18. NSAIDsASPIRIN (ASA) • Mechanism of action • inhibits prostaglandin synthesis by acetylation of cyclooxygenase • Pharmacological actions • Analgesia • Anti-inflammatory • Antipyretic action

  19. NSAIDsSALICYLATES • Pharmacokinetics • rapid absorption- low pH increases absorption- high pH increases solubility, enhances absorption • peak blood levels: 2 hours • up to 90% protein bound in plasma • metabolism in liver‑glycine or glucuronide conjugates; 10% is free salicylate • excretion in urine • free salicylate excretion (not metabolites) may be enhanced by making the urine more alkaline

  20. NSAIDsSALICYLATES • Toxicity • large doses will increase depth of respiration • nausea and vomiting • salicylism ‑ chronic treatment of high doses- confusion-delerium- tinnitus – dizziness • increased bleeding time • gastric ulceration (especially with alcohol) • hemorrhage • may alter uric acid excretion (dose dependent)

  21. Toxicity • Overdose • acid‑base changes ‑ usually acidosis, metabolic & respiratory • High doses suppress respiration → respiratory acidosis • Uncouple oxidative phosphorylation in cells → metabolic acidosis

  22. PROPRIONIC ACID DERIVATIVES • Ibuprofen (MOTRIN, ADVIL, NUPRIN) • rapidly absorbed after oral administration, peak concentration 1 to 2 hours • extensively (99%) protein bound, 90% excreted as metabolites in urine • Naproxen (NAPROSYN) • longer half life, therefore 2 x day dosing • inhibits PMN migration • Piroxicam (FELDENE) • Nabumetone (RELAFEN)

  23. PROPRIONIC ACID DERIVATIVES • anti‑inflammatory, anti‑pyretic, analgesic • inhibit cyclooxygenase, inhibit leukocyte migration possibly by inhibition of lipoxygenase • Better anti-inflammatory than aspirin?

  24. PROPRIONIC ACID DERIVATIVES • Toxicity – this relates to all NSAIDs • Increased bleeding time • Gastric bleeds • Long term may cause liver toxicity • Hypertension and renal failure especially in the elderly • Edema • CNS – dizziness, confusion, drowsiness, anxiety

  25. Ketorolac (TORADOL) • High potency, analgesia equivalent to morphine • Used for moderate to severe pain • Not for mild pain • Short term peri-operative use • Similar side effects to other NSAIDs

  26. Indomethecin (INDOCIN) • Potent inhibitor of cyclooxygenase, inhibits PMN migration • Analgesic, anti‑inflammatory and anti‑pyretic ‑ similar to aspirin • Rapidly and completely absorbed following oral administration, 90% protein bound, low concentrations in CSF but plasma levels in synovial fluid • Toxicity ‑ 35 to 50% of patients receiving therapeutic doses report side effects: GI ‑ anorexia, nausea, abdominal pain, ulceration of upper GI tract: CNS ‑ severe frontal headache most common (25‑50%), dizziness, vertigo, light‑headedness, mental confusion: hematopoietic reactions, hypersensitivity (cross-sensitivity with aspirin)

  27. Mean Plasma half-lives of different NSAIDS DrugHalf-life (hr) Short Aspirin0.25 Diclofenac 1.1 Etolodac 3.0 Ibuprofen 2.1 Indomethacin 4.6 Ketoprofen 1.8 Long Diflunisal 15 Naproxen 14 Phenylbutazone 68 Piroxicam 57 Sulindac 14

  28. Acetaminophen (TYLENOL) •  Actions • Analgesic, antipyretic properties comparable to salicylates • Weak inhibitor of prostaglandin biosynthesis in periphery, more activity in CNS • Identification in 2002 of COX-3 in brain that has a higher affinity for acetaminophen – now thought to be a splice variant of COX-1 • Weak anti-inflammatory action • No effect on respiration • No effect on platelets • No effect on uric acid excretion

  29. Acetaminophen (TYLENOL) • Pharmokinetics • rapid absorption • peak blood levels: 1‑2 hours • acetaminophen to glucuronide conjugation • excreted in urine

  30. Acetaminophen (TYLENOL) • Toxicity • Allergic reactions (rare) • Toxicity at therapeutic doses • 2 extra strengths = 1000 mg • FDA panel recommends no more than 650 mg per dose • Recommends total daily dose less than 4000 mg • Evidence of long term hepatic toxicity with long term use • Use of acetaminophen in many combination products

  31. Acetaminophen (TYLENOL) • Toxicity in overdose • No acute signs but medical emergency • Hepatic necrosis, renal tubular necrosis emerges over days • Hypoglycemic coma • Treatment • acetylcysteine

  32. COX2 inhibitor • Celecoxib (CELBREX) • Selectively inhibit COX2 – inducible cyclo-oxygenase • May be no better than non-selective inhibitors

  33. Gastrointestinal Toxicity With Celecoxibvs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis The CLASS Study: A Randomized Controlled Trial JAMA 284(10): 1247, 2000 http://jama.ama-assn.org/issues/v284n10/rfull/joc01227.html

  34. Figure 2. Annualized Incidence of Upper Gastrointestinal Tract Ulcer Complications Alone and With Symptomatic Gastroduodenal Ulcers

  35. Figure 3. Patients With Decreases inHematocrit and/or Hemoglobin at 6 Months

  36. Figure 4. Patients With Increases in Serum Creatinine and/or Serum Urea Nitrogen and With Elevations in ALT and AST at 6 Months

  37. What happened to the COX-2 inhibitors??

  38. Rofecoxib (VIOXX) withdrawn • In APPROVe trial • Designed to evaluate the efficacy of rofecoxib, 25 mg, in preventing recurrence of colorectal polyps in 2,600 patients with a history of colorectal adenomas • The increased cardiovascular risk began after 18 months of treatment with rofecoxib and persisted. At three years, cumulative incidence of cardiovascular events was 7.5 per 1,000 patients receiving placebo compared with 15 per 1,000 patients receiving rofecoxib

  39. Mechanisms of cardiovascular toxicity • COX-1 helps promote thrombosis and COX-2 helps inhibit it, blocking COX-2 but not COX-1 could theoretically increase the risk of myocardial infarction and other thrombotic events.

  40. Mechanisms of cardiovascular toxicity (con’t) • Depression of prostaglandin I2 formation by coxibs might be expected to elevate blood pressure, accelerate atherogenesis, and increase the thrombotic response to rupture of an atherosclerotic plaque. In patients at higher cardiovascular risk, coxibs would be more likely to predispose to a clinical event early in the course of treatment

  41. CONSIDERATIONS OF THERAPY WITH NSAIDs • Most NSAIDs are similar in efficacy • Patient variability in efficacy and toxicity • Classification by duration of action • Side effects serve as the basis for therapeutic choice • Inhibition of cyclooxygenase varies as to distribution in body fluids • Aspirin and para‑aminophenol toxicity • Blood dyscrasias

  42. TREATMENT OF ARTHRITIS WITH NSAIDs • Reduced inflammation slows progress of disease • High dose therapy • Aged population • monitor renal function • monitor blood for dyscrasias • Use best tolerated agent and lowest cost

  43. ANTI-INFLAMMATORY STEROIDS David J. Mokler, Ph.D. October 29, 2009

  44. CORTISOL • Chemistry & Metabolism • major glucocorticoid in humans • synthesized from cholesterol in cells of the zonafasiculata and zonareticularis of the adrenal cortex • released under the influence of ACTH • 20 mg secreted per day in adult in the absence of stress • 95% bound in blood to corticosteroid binding globulin • T½ 90‑110 min; increased with large amounts or hypothyroidism • reduced and conjugated in liver, excreted in urine as 11‑oxy 17‑ketosteroids

  45. Physiologic and Pharmacological Effects • Widespread effects ‑ homeostasis • Dose‑related and "permissive" effects • Effects on metabolism • Protects glucose-dependent tissue (brain and heart) • In periphery decreases glucose utilization • Increases blood glucose • Stimulates gluconeogenesis • glycogen stores • Anti‑insulin effects

  46. Physiologic and Pharmacological Effects • Cardiovascular • decrease capillary permeability, incr in Na+ retention • Blood elements • ↑ hemoglobin and red blood cells, ↑ PMN leukocytes • ↓ lymphocytes, eosinophils, monocytes, basophils • ↓ lymphoid tissue and immune response

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