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

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 7 Antiviral drugs 1 & 2 Week 8 Antiviral drugs 3 Week 6 Antifungal drugs Week 9 Antiparasitic drugs

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 ) Adverse effects ( predictable, unusual, teratogens ) Drug interactions ( eg, CYP450 inducers, inhibitors, narrow therapeutic window AND a CYP substrate )

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

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

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

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

Eicosanoids: PGs & TXA Effects AA Cyclooxygenase (COX) Lipoxygenase PGH 2,PGG 2 unstable) Stable prostaglandins PGD 2,PGE 2,PGF 2 1.Vasodilation Prostacyclin PGI 2 1.Vasodilation 2.Inhibition of platelet aggregation Thromboxane A 2 1.Vasoconstriction 2.Stimulate platelet aggregation NSAIDS Leukotrienes) Chemotaxis Vasodilation

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

NSAID Dose Dependent Therapeutic Effects N-acetyl-  -aminophenol Acetaminophen (Tylenol; AKA paracetamol) antipyretic, analgesic NOT anti-inflammatory Antithrombotic (aspirin only) Antipyretic, Analgesic Anti-inflammatory Daily dose of aspirin (g)

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

Acetaminophen Toxicity induces

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

IgE-Mediated Mast Cell Degranulation Histamine Proteases Heparin Resting Mast CellActivated Mast Cell

Histamine Cimetidine, ranitidine

H 1 Histamine Antagonists (Antihistamines) PrototypePropertiesClinical Uses Loratadine (Claritin) Fexofenadine (Allegra) Low affinity for muscarinic receptors, doesn’t cross BBB Allergic reactions Diphenhydramine (Benadryl) Muscarinic antagonist, crosses BBB Allergic reactions, dystonic rxtn to dopamine blockers, OTC sleep aid, antiemetic However, in the case of severe hypersensitivity reactions, including anaphylaxis, drugs of choice are: Epinephrine (need  1 vasoconstriction and  2 bronchodilation) and corticosteroids!

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

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

Corticosteroids Inhibit Eicosanoid Production Phospholipase A 2 Arachidonic acid Prostaglandins & thromboxanesLipoxygenase products (leukotrienes) Cyclooxygenase (COX)Lipoxygenase Corticosteroids inhibit induction of COX-2 expression Corticosteroids Lipocortin

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

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

Toxicity of Chronic Systemic Glucocorticoids Cushing ’ s syndrome 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

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

Some Corticosteroids Agent Forms Available Relative Anti- Inflammatory Activity Relative Salt- Retaining Activity Cortisol (hydro- cortisone) Oral, parenteral, topical 11 CortisoneOral0.8 PrednisoneOral40.3 Triamcinolone Oral, injectable, topical, inhaled 50 Dexamethasone Oral, injectable, topical 300 Fludrocortisone (mineralocorticoid) Oral0250

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

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 Drug NameAnalog OfClinical Use EpoprostenolPGI 2 Pulmonary hypertension DinoprostonePGE 2 Medical abortion, relax uterine cervix in preparation for induction of labor MisoprostolPGE 1 Peptic ulcer, medical abortion AlprostadilPGE 1 Maintain a patent (open) ductus arteriosus in neonates with certain cardiac malformations until emergency surgery; erectile dysfunction CarboprostPGF 2  Labor induction LatanoprostPGF 2  Glaucoma

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.