Lecture 5: Inflammation 2

Lecture 5: Inflammation 2 Glucocorticoid Side Effects · none/minimal side effects in acute or local treatment · risk of systemic side effects in long term and systemic routes (PO, IV, IM) · use of biologic glucocorticoids decreases/stops adrenal corticoid synthesis ↳ must "wean” patient off slowly so body can make its own again · Cushing's syndrome: overtreatment with systemic glucocorticoids that leads to exaggerated side effects of affected systems ↳ massive weight gain in midsection + stretch marks ↳ fat pads (Buffalo hump) ↳ proteolysis of muscle leads to skinny arms + legs Chronic Inflammation · acute inflammation: <10 days · chronic inflammation: 10+ days ↳ 1st an acute inflammation ↳ followed by proliferation of lymphocytes, macrophages, fibroblasts, endothelial cells, collagen, etc. · Tissue destruction by repetitive inflammatory cascade · scar tissue formation ↳ less vascular ↓functionality ↳ less flexible ↳ less strong · continuous cycle leads to susceptibility to neoplasm (cancer) Diagnoses Marked by Inflammation: · Allergic rhinitis · Dermatitis · Psoriasis · Arthritis · IBD · Asthma · COPD Allergic Rhinitis · most common, nasal symptomology · triggered by inhaled allergens → hypersensitivity · signs & symptoms: rhinitis* (nasal discharge, swelling), conjunctivitis (eyes), sneezing, snoring, itching, headache from nasal-sinus congestion · Bloodwork: high eosinophils · treatment: treat first with antihistamines (pre/post exposure), then with intranasal corticosteroids (super potent) for nasal mucosal inflammation ↳ drugs: fluticasone (Flonase, Aramys), mometasone (Nasonex), budenoside (Rhinocort) Atopic Dermatitis (eczema) · allergy-triggered; autoimmune profile ↳ high IgE in plasma · chronic inflammation of the skin ↳ deficient skin barrier, itching, scar formation "lichenification", risk of super-infection · treatment: moisturize ↳ topical glucocorticoids (cream) ↳ antihistamines for itchiness ↳ antibiotics/antivirals for infection Psoriasis · chronic inflammatory skin disease · risk factors: family history, triggers (skin trauma, stress, climate, medications) · skin changes: ↳ hyperkeratosis → thickening of Keratin layer ↳ thinned stratum granulosum ↳ dilated dermal papillae (blood vessels?) · signs & symptoms: dry, scaly skin patches, non-priuretic (non-itchy) mostly · treatment: glucocorticoids (local, systemic as needed) and moisturizing creams Rheumatoid Arthritis (RA) · systemic, autoimmune disorder characterized by disfigurement and inflammation of multiple joints · risk factors: family history, gender · inflammation of connective tissue triggered by an antigen ↳ proliferation of WBC, pro-inflammatory mediators, and granulation tissue ↳ Pannus: dysfunction of the synovial cavity (joint is larger) ↳ destruction of surrounding tissues (bone, cartilage) · progressive and autoimmune destruction of healthy endogenous tissues · Signs & symptoms: synovial joint inflammation (hands, knees, C-Spine), general fatigue, anorexia · bloodwork: high reactive C-protein (pro-inflammatory mediator) · treatment: NSAID's, glucocorticoids (PO route) ↳ can also be treated with biologic drugs → parenteral route (SC) Suffix -mab Biologic Drug Treatment ① Response modifying agents ↳ inhibits pro-inflammatory cytokines (interleukins, integrins) · drugs: Infliximab, Adalimumab, Ustekinumab ② DMARDs → disease modifying anti-rheumatic drugs ↳ enhances anti-inflammatory mediators(adenosine) · drugs: methotrexate Pannus Osteoarthritis (OA) · degenerative disorder of articular cartilage ↳ "Wear and tear" from overuse · risk factors: mechanical stress, obesity, age, gender · cartilage changes: ↳ decreased proteoglycans ↳ weakening collagen network ↳ pro-inflammatory mediator release → further inflammation ↳ cartilage tissue destruction → bone-bone in articulating surface! · treatment: NSAIDs, glucocorticoids ↳ local cortisone joint injection helpful Inflammatory Bowel Disease (IBD) · environmental factors cause immune system to malfunction, leading to inflammation · risk factors: family history · systemic manifestations can occur in skull, joints, and blood · trigger: endogenous host flora is recognized as noxious antigen · Crohn's disease: Entire GI is inflamed, characteristic patchy lesions and sores in mouth · Ulcerative colitis: continuous inflammation inside the colon · diagnosis: endoscopy or colonoscopy ↳ may see fistula or adhesion to body wall by improper healing/fusion · treatment: Sulfasalazine ↳ also biologics and glucocorticoids Drug: Sulfasalazine (Azulfidine, Salazopyrin) · DMARD vs NSAID · Sulfasalazine (PO) → metabolized in colon "prodrug" → active metabolites: ↳ 5-ASA = local NSAID effect ↳ sulfapyridine = systemic ADME + anti-inflammatory = side effects - - Drug: 5-ASA (Asacol, Teva, Mesalamine) · aspirin-like NSAID (Salicylate) · clinical efficacy: IBD, especially UC · PO, rectal admin. Asthma · chronic inflammatory airway disorder (not autoimmune) · risk factor: family history · trigger: noxious stimuli · Inflammation + pro-inflammatory mediators activating further inflammation ↳ mast cell degranulation ↳ WBC signalling: T-cells + interleukins! also eosinophils, basophils, neutrophils, and macrophages - TH2-helper cells Signal B-cells to synthesize IgE → cross-links receptors a mast cell degranulation ↳ chronic inflammatory mucosa changes → hypersensitivity + high goblett cell activity (lots of mucous) · outcome: bronchial inflammation, bronchoconstriction, mucous production · Signs and symptoms of attack: ↳ wheezing, shortness of breath, decreased/no air entry into lungs, chest tightness ↳ tachycardia ↳ anxiety, panic ↳ fatigue · limited inspiration + longer expiration phase (hard to exhale trapped air) ↳ hyper-inflated lungs with limited gas exchange ↳ hypoxemia, hypercarbia, and high pulmonary pressures lead to high RVEDP and thus low CO Asthma Management and Treatment · management focuses on stabilizing bronchial inflammation & minimizing number of attacks ↳ "Maintenance drugs" or "controllers" ↳ daily treatment protocol and compliance, control triggers · treatment with "rescue drugs" or "relievers” - - - - Inhaled anti-inflammatory Drugs · local effect in bronchioles · low systemic effect → low side effects ① Glucocortecoids · first line "maintenance" treatment → prophylaxis against attacks · PO administration (inhalers or nebulizers) · drugs: Pulmicort (Budenoside), Qvar (Becomethasone), Florent (Fluticasone) ② Mast Cell Stabilizers · inhibit histamine release from mast cells · drug: Cromolyn ↳ inhaler 3-4 times a day ↳ slow onset ↳ synergy with glucocorticoids ③ Leukotriene Modifiers · block leukotriene receptors + prophylaxis · drug: Montelukast (Singulair) ↳ PO, systemic ↳ slow onset ↳ prophylaxis, synergy treatment ④ Biologics: monoclonal antibodies Not inhaled, SC · drug: Xolair (omalizumab) · SC · long-term treatment plan · high affinity for IgE ↳ binds free IgE → decreases antigen binding → no degranulation ↳ decreases expression of mast cell-bound IgE → no degranulation Asthma Rescue Treatments · treatment of bronchoconstriction (inhaler) · 2 drug classes: ① Beta 2 Adrenergic Antagonists ② Anticholinergics · potent, fast acting · less potent · stimulate SNS B2 receptors directly · antagonize PNS (bronchodilate) · drugs: · Slower onset ↳ Salbutamol (Ventolin) · synergy with beta 2 adrenergic agonists - fast onset, high affinity · drug: Atrovent (Ipatropium) ↳ Formoterol (Oxeze, Turbohaler) Severe Asthma Attack ER Treatment 1. O2 2. Beta2 adrenergic agonists, nebulizer is best ↳ Ventolin Epinephrine (Adrenaline) 3. Sympathomimetics, IV · IV infusion ↳ epinephrine (adrenaline) · Potent 4. Magnesium sulfate, IV · short half-life 5. Anticholinergics, nebulizer · goal: bronchodilation ↳ Atrovent ↳ also decrease mast cell degranulation 6. Glucocortecoids, IV ↳ vasoconstriction → perfusion ↳ Dexamethasone · Side effect: SNS stimulation 7. Antihistamines?, IV ↳ Benadryl Magnesium Sulfate (MgS04), IV · drug classes: electrolyte; enzymatic activator; calcium channel blocker · inhibition of Ca channels in smooth muscle → reduced excitability → bronchodilation · stabilization of mast cells & T-cells → decreased pro/inflammatory mediators · enhanced release of NO → pulmonary vasodilation → improved gas exchange ↳ side effect of hypotension Allergy Treatment Overview · titrate to effect for severe bronchodilation · local allergy or contact dermatitis: ↳ antihistamine, topical Anaphylaxis ↳ eg. Benadryl (diphenhydramine) cream · systemic inflammation and severe vasodilation · known allergen, systemic exposure present: · massive amounts of histamine release leads to systemic effects ↳ antihistamine, non-drowsy preferred · signs & symptoms: evidence of allergy, bronchconstriction, ↳ Reactin (cetirizine), I tablet qd hypotension · eye symptoms post-exposure: ↳ note: in asthma it would be only lungs, no evidence of ↳ Antihistamine, topical to eye allergy, and hypertension rather than hypotension ↳ Patanol (olopatadine) eye drops · treatment: · if allergen exposure anticipated in high doses: ↳ epinephrine, IM or IV adrenergic agonist class ↳ prophylaxis with leukotriene modifiers ↳ dexamethasone, IV ↳ singulair, I tablet x2 days pre-exposure ↳ antihistamines, IV ↳ + IV fluids (treats hypotension) - - - > - - Anaphylaxis vs. Asthma Attack · main issue in anaphylaxis: systemic vasodilation and bronchoconstriction ↳ treatment focuses on perfusion & airway/breathing · main issue in asthma: airway/breathing ↳ treatment focuses on airway/breathing