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
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
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 www.sd-neurosurgeon.com/diseases/pit_tumors.html
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.