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

Pharmacology in I-3Week 2Anti-inflammatoryand immunosuppressivedrugs 1 & 2Week 4Antibacterial drugs 1Antibacterial drugs 2Antibacterial drugs 3

Week 5Drugs for mycobacterialinfectionsWeek 7Antiviral drugs 1

Week 8Antiviral drugs 2Antiparasitic drugsWeek 6Antifungal drugs

The Inflammatory CascadeInflammation (redness, edema,warmth, pain, tissue destruction)Inflammatory mediatorsLeukocyte & endothelial cell activationTissue injuryAdaptive immunesystemInnate immunesystemPerceived threatInfection12

Anti-inflammatory & Immunosuppressant Drugs1NSAIDSAcetaminophenAntihistaminesCorticosteroids2ImmunosuppressantsNewer biologic agentsDrugs for gout

Inhibitors of Eicosanoid ProductionPhospholipase A2Arachidonic acidProstaglandins & thromboxanesLipoxygenase products(leukotrienes)Cyclooxygenase (COX)LipoxygenaseInflammatory effects(esp. in asthma)Inflammatory effectsHomeostaticfunctionsNSAIDS (includingaspirin)5-ASA (IBD)IBD, inflammatory bowel disease; 5-ASA, 5-amino salicylic acidZileutonmontelukast, zafirlukast

Notable NSAIDSibuprofen (Motrin, Advil)naproxen (Naprosyn, Aleve)ketorolac (Toradol)- parenteral (IM)indomethacin (Indocin)celecoxib (Celebrex)aspirin

NSAID Therapeutic Effects

NSAID & Acetaminophen ToxicityGI upset & ulcers (esp. COX-1)Acute renal failure (COX-1 & 2)Bleeding (COX-1, esp. aspirin)NSAIDS: Disruption ofhomeostatic functionNSAIDS: Rarehypersensitivity reactionAspirin: Reye syndromeAspirin & acetaminophen: very dangerous in overdose

Acetaminophen Toxicity

The Inflammatory CascadeInflammation (redness, edema,warmth, pain, tissue destruction)Inflammatory mediatorsLeukocyte & endothelial cell activationTissue injuryAdaptive immunesystemInnate immunesystemPerceived threatInfectionNSAIDS, acetaminophenAntihistamines

IgE-Mediated Mast Cell DegranulationHistamineProteasesHeparinResting Mast CellActivated Mast Cell

HistamineCimetidine, ranitidine

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!

PrototypePropertiesClinical UsesLoratadine (Claritin)Fexofenadine (Allegra)Low affinity for muscarinic receptors, doesnt cross BBBAllergic reactionsDiphenhydramine (Benadryl)Muscarinic antagonist, crosses BBBAllergic reactions, dystonic rxtn to dopamine blockers, OTC sleep aid, antiemetic

The Mighty CorticosteroidsInflammation (redness, edema,warmth, pain, tissue destruction)Inflammatory mediatorsLeukocyte & endothelial cell activationTissue injuryAdaptive immunesystemInnate immunesystemPerceived threatInfectionCorticosteroidsCorticosteroidsCorticosteroidsCorticosteroids

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

Corticosteroids Inhibit Eicosanoid ProductionPhospholipase A2Arachidonic acidProstaglandins & thromboxanesLipoxygenase products(leukotrienes)Cyclooxygenase (COX)LipoxygenaseCorticosteroidsinhibit inductionof COX-2 expressionCorticosteroidsLipocortin

Glucocorticoids Are Powerful Immuno-suppressantsCorticosteroids 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 GlucocorticoidsSelf-limited reaction (eg, poison oak)

Toxicity of Chronic Systemic GlucocorticoidsCushingssyndrome 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 childrenwww.sd-neurosurgeon.com/diseases/pit_tumors.html

Adrenal Suppression with Chronic Systemic GlucocorticoidsHypothalamusAnteriorpituitaryAdrenal cortexCRHACTHcortisol,aldosteroneprednisone

Some Corticosteroids

AgentForms AvailableRelative Anti-Inflammatory ActivityRelative Salt-Retaining ActivityCortisol (hydro-cortisone)Oral, parenteral, topical11CortisoneOral0.80.8PrednisoneOral40.3TriamcinoloneOral, injectable, topical, inhaled50DexamethasoneOral, injectable, topical300Fludrocortisone (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;

Corticosteroids have powerful anti-inflammatory and immunosuppressant actions but chronic use produces much toxicity

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)

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

Drug NameAnalog OfClinical UseEpoprostenolPGI2Pulmonary hypertensionDinoprostonePGE2Medical abortion, relax uterine cervix in preparation for induction of laborMisoprostolPGE1Peptic ulcer, medical abortionAlprostadilPGE1Maintain a patent (open) ductus arteriosus in neonates with certain cardiac malformations until emergency surgery; erectile dysfunctionCarboprostPGF2Labor inductionLatanoprostPGF2Glaucoma

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