Anti-Inflammatory & Immunosuppressive Drugs 1

1. Anti-Inflammatory & Immunosuppressive Drugs 1 I-3 Fall 2011 Susan Masters, Ph.D.

2. Pharmacology in I-3 Week 2 Anti-inflammatory and immunosuppressive drugs 1 & 2 Week 4 Antibacterial drugs 1 Antibacterial drugs 2 Antibacterial drugs 3 Week 5 Drugs for mycobacterial infections Week 6 Antifungal drugs Week 7 Antiviral drugs 1 Week 8 Antiviral drugs 2 Antiparasitic drugs

3. The Inflammatory Cascade Perceived threat Infection 2 Tissue injury Adaptive immune system Innate immune system Leukocyte & endothelial cell activation 1 Inflammatory mediators Inflammation (redness, edema, warmth, pain, tissue destruction)

4. Anti-inflammatory & Immunosuppressant Drugs 1 NSAIDS Acetaminophen Antihistamines Corticosteroids 2 Immunosuppressants Newer biologic agents Drugs for gout

5. Inhibitors of Eicosanoid Production Zileuton montelukast, zafirlukast NSAIDS (including aspirin) Phospholipase A2 Arachidonic acid 5-ASA (IBD) Lipoxygenase Cyclooxygenase (COX) Lipoxygenase products (leukotrienes) Prostaglandins & thromboxanes Inflammatory effects (esp. in asthma) Inflammatory effects Homeostatic functions IBD, inflammatory bowel disease; 5-ASA, 5-amino salicylic acid

6. Notable NSAIDS naproxen (Naprosyn, Aleve) aspirin ibuprofen (Motrin, Advil) indomethacin (Indocin) ketorolac (Toradol) - parenteral (IM) celecoxib (Celebrex)

7. N-acetyl--aminophenol Acetaminophen (Tylenol; AKA paracetamol) antipyretic, analgesic NOTanti-inflammatory NSAID Therapeutic Effects Anti-inflammatory Antipyretic, Analgesic Antithrombotic (aspirin only) 0 1 2 3 4 5 Daily dose of aspirin (g)

8. Syndrome of hepatic injury & encephalopathy in kids treated with aspirin after a viral illness Thrombosis (COX-2) Impaired labor (COX-1 & 2) Aspirin: salicylate poisoning Acetaminophen: liver failure Excessive shunting of arachidonic acid products to lipoxygenase pathway when COX is blocked NSAID & Acetaminophen Toxicity NSAIDS: Disruption of homeostatic function Aspirin: Reye syndrome GI upset & ulcers (esp. COX-1) Acute renal failure (COX-1 & 2) Bleeding (COX-1, esp. aspirin) NSAIDS: Rare hypersensitivity reaction Aspirin & acetaminophen: very dangerous in overdose

9. Acetaminophen Toxicity

10. The Inflammatory Cascade Perceived threat Infection Tissue injury Adaptive immune system Innate immune system Leukocyte & endothelial cell activation NSAIDS, acetaminophen Antihistamines Inflammatory mediators Inflammation (redness, edema, warmth, pain, tissue destruction)

11. IgE-Mediated Mast Cell Degranulation Resting Mast Cell Activated Mast Cell Histamine Proteases Heparin

12. Histamine Cimetidine, ranitidine

13. H1 Histamine Antagonists (Antihistamines) However, in the case of severe hypersensitivity reactions, including anaphylaxis, drugs of choice are: Epinephrine (need 1 vasoconstriction and 2 bronchodilation) and corticosteroids!

14. The Mighty Corticosteroids Perceived threat Infection Corticosteroids Tissue injury Adaptive immune system Innate immune system Corticosteroids Leukocyte & endothelial cell activation Corticosteroids Inflammatory mediators Corticosteroids Inflammation (redness, edema, warmth, pain, tissue destruction)

15. Glucocorticoids Regulate Transcription GR, glucocorticoid receptor; HSP, heat shock protein; IP, immunophilin;GRE, glucocorticoid receptor

16. Corticosteroids Inhibit Eicosanoid Production Corticosteroids Corticosteroids inhibit induction of COX-2 expression Lipocortin Phospholipase A2 Arachidonic acid Lipoxygenase Cyclooxygenase (COX) Lipoxygenase products (leukotrienes) Prostaglandins & thromboxanes

17. Glucocorticoids Are Powerful Immuno-suppressants Corticosteroids affect nearly every facet of immune function, although less inhibition of humoral arm than cell-mediated arm; they also induce apoptosis in rapidly-dividing leukocytes

18. Acute flare of a chronic inflammatory condition or organ rejection reaction Clinical Use of Glucocorticoids Self-limited reaction (eg, poison oak)

19. Toxicity of Chronic Systemic Glucocorticoids • Fat redistribution • Hypertension • Glucose intolerance • Impaired wound healing • Osteoporosis (prevent with bisphosphonates) • Cataracts • Gastric ulcers (prevent with omeprazole, misoprostol) • Risk of infection • CNS effects, including psychosis • Growth inhibition in children Cushing’s syndrome www.sd-neurosurgeon.com/diseases/pit_tumors.html

20. Adrenal Suppression with Chronic Systemic Glucocorticoids Hypothalamus CRH prednisone Anterior pituitary ACTH cortisol, aldosterone Adrenal cortex

21. Some Corticosteroids

22. Summary • Inhibitors of the production or action of inflammatory mediators (NSAIDS, antihistamines, presumably acetaminophen) provide symptomatic relief with reasonable safety in most people but do not ameliorate ongoing immune reaction; • Corticosteroids have powerful anti-inflammatory and immunosuppressant actions but chronic use produces much toxicity

23. Reminder - Studying Pharmacology • Drug names (focus on prototypes; use flash cards, tables) • Unusual chemical structures (eg, antibody, receptor, cytokine) • Mechanisms of action • Clinical uses • Pharmacokinetics (eg, notable route administration, elimination) • Adverse effects (predictable, unusual, teratogens) • Drug interactions (eg,CYP450 inducers, inhibitors, narrow therapeutic window AND a CYP substrate)

24. Eicosanoids As Drugs(Additional info that will NOT be tested in I-3)