Anti-Inflammatory & Immunosuppressive Drugs 1

1. Anti-Inflammatory & Immunosuppressive Drugs 1 I-3 Fall 2012 Marieke Kruidering, Ph.D.

2. Pharmacology in I-3 Week 2 Anti-inflammatory and immunosuppressive drugs 1 & 2 TBL Week 4 Antibacterial drugs 1 Week 5 Antibacterial drugs 2 Antibacterial drugs 3 Drugs for mycobacterial infections Week 6 Antifungal drugs Week 7 Antiviral drugs 1 & 2 Week 8 Antiviral drugs 3 Week 9 Antiparasiticdrugs

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

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

5. Infection Inflammatory cascade: Triggers Immune response Tissue and/or vessel damage Inflammatory Mediators Acute Inflammatory Response Note this is a common & non-specific response - Redness - Heat - Swelling - Pain (allodynia) - Loss of function

6. Infection Anti-histamines NSAIDS Corticosteroids Drugs block production or effect of inflammatory mediators Tissue and/or vessel damage • Inflammatory Mediators • Vasoactive peptides: • Histamine,serotonin • The kinin system • Coagulation cascade • The complement system • Arachidonic Acid • metabolites

7. 3. Zileuton Montelukast, zafirlukast 2.NSAIDS (including aspirin) 1. Steroids Inflammatory Enzymes: PLA2 &COX Phospholipase A2 Arachidonic acid (AA) Lipoxygenase Cyclooxygenase (COX) Lipoxygenase products (leukotrienes) Prostaglandins & thromboxanes Inflammatory effects (inducible) Homeostatic Functions (stomach mucus) Inflammatory effects (esp. in asthma)

8. NSAIDS Stable prostaglandins PGD2,PGE2,PGF2 Thromboxane A2 Prostacyclin PGI2 Vasoconstriction Stimulate platelet aggregation Vasodilation Vasodilation Inhibition of platelet aggregation Eicosanoids: PGs & TXA Effects AA Cyclooxygenase (COX) Lipoxygenase • Leukotrienes) • Chemotaxis • Vasodilation PGH2,PGG2 unstable)

9. Notable NSAIDS naproxen (Naprosyn, Aleve) Aspirin ibuprofen (Motrin, Advil) etodolac (Lodine) cox 2 >cox1 indomethacin (Indocin) ketorolac (Toradol) - parenteral (IM) celecoxib (Celebrex)

10. N-acetyl--aminophenol Acetaminophen (Tylenol; AKA paracetamol) antipyretic, analgesic NOT anti-inflammatory NSAID Dose DependentTherapeutic Effects Anti-inflammatory Antipyretic, Analgesic Antithrombotic (aspirin only) 0 1 2 3 4 5 Daily dose of aspirin (g)

11. Syndrome of hepatic injury & encephalopathy in kids treated with aspirin after a viral illness Thrombosis (COX-2) Impaired labor (COX-1 & 2) Excessive shunting of arachidonic acid products to lipoxygenase pathway when COX is blocked Aspirin: salicylate poisoning (respiratory alkalosis followed by metabolic acidosis) Acetaminophen: liver failure 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: Dangerous in overdose (OTC: Can be fatal)

12. Acetaminophen Toxicity induces

13. 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)

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

15. Histamine Cimetidine, ranitidine

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

17. 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)

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

19. 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

20. 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

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

22. 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

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

24. Some Corticosteroids

25. 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; • Even though aspirin and acetaminophen are OTC overdoses can be fatal. • Corticosteroids have powerful anti-inflammatory and immunosuppressant actions but chronic use produces much toxicity

26. FYI: Eicosanoids As Drugs(Additional info that will NOT be tested in I-3)Tip: recognize the “prost” in the drug name so you know it is a prostaglandin analog

27. FYI.ASPIRIN: Antiplatelet effect Adverse effects: bleeding due to longer cox -1 inhibition in platelets than in endothelium (why?) Platelets have no nucleus thus cannot resynthesize COX-1 once it is inhibited by aspirin, while endothelial cells can regenerate COX-2. Net result: selective COX 1 inhibition & reduced platelet aggregation.