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Transcript
Anti-inflammatory Drugs # Lab 4 # Inflammation: • it is a biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. • Inflammation may ends with either : Complete healing of tissues Permanent destruction of tissues Signs of inflammation • Redness: Due to vasodilatation by effects of releasing of histamine, bradykinin and prostaglandin. • Hotness: Due to increased blood flow. Signs of inflammation • Swelling: due to increased vascular permeability by the released mediators and increased the exudate in the inflammed area • Pain: due to irritation of nerve ending by inflammation and the pressure of the swelling on the nerve ending. • Inflammatory mediators: – histamine – 5-HT (serotonin) – Bradykinin – Prostaglandins (eg PGE2 ) – Interleukines – Substance P – Nitrous oxide Main inflammatory mediator Phases of Inflammation • Fluid phase (vascular phase): Increased vasodilatation leads to increased permeability of the vascular bed to plasma protein. - Increasing fluid will help in: 1- dilution of the irritant 2- increase conc. of antibodies from blood to inflamed area 3- supply nutrients to the immune cells. Phases of Inflammation • Cellular phase (exudative phase): Involves migration of tissue macrophages and polymorphonuclear leukocytes (PMNL) to the inflamed area. • Fibrous phase (proliferative phase): A new connective tissue (fibrous) Classification of the Inflammation • Non – immunological : Induced by chemical irritants such as formalin • Immunological : Induced by infections such as bacterial infection Anti-inflammatory Drugs Steroidal - Cortisone - Hydrocortisone Non-steroidal - Acetaminophen - Aspirin Steroids (SAIDs) - Containing steroid moiety in their sturcure Glucocorticoids (GC) Cortisone Glucocorticoids (GC) Synthetic Natural - Cortisone - Hydrocortisone Fluorinated Glucocorticoids - Betamethasone - Dexamethasone - Predinsone Liver enzymes Prednisolone Glucocorticoids (GC) Mechanism of Action : - They act by indirect inhibition of the enzyme phospholipase A2 which activate synthesis of arachidonic acid with subsequent formation of prostaglandins. - They induce synthesis of a protein “lipocortin-1” which has the inhibitory effect on phospholipase A2. GC inhibition phospholipase A2 Side Effects : • Immunosuppression • Hyperglycemia due to increased gluconeogensis, insulin resistance, and impaired glucose tolerance ("steroid diabetes"); • Steroid-induced osteoporosis: reduced bone density (osteoporosis, • Osteoporosis , higher fracture risk, slower fracture repair) • Redistribution of body fat: moon face, buffalo hump and truncal obesity. • Adrenal insufficiency • Muscle breakdown (proteolysis), weakness; reduced muscle mass and repair • Anovulation, irregularity of menstrual periods • Growth failure, pubertal delay • Increased plasma amino acids, increased urea formation; • Glaucoma due to increased cranial pressure Side Effects : Moon face buffalo hump Non-Steroidal Anti-inflammatory Drugs (NASID) • They don’t contain steroid moiety • They also have analgesic and antipyretic activity Mechanism of Action : • NSAIDs inhibit synthesis of PGs which are the main factors Playing a role in the inflammaltion. • Inhibit synthesis of PGs through inhibition of cyclooxygenase Enzymes which are responsible for production of PGs GC inhibition phospholipase A2 Cyclooxygenese ( COX ) Isoforms : COX 2 COX 1 - Constitutive - Many tissues ( blood vessels stomach and kidney ) COX 3 - inducible -By inflammatory processes and mediators has recently been described Non-Steroidal Anti-inflammatory Drugs (NASID) Non-selective COX inhibitors - Aspirin - Ibuprofen - Diclofenac - Meloxicam selective COX2 inhibitors - Celecoxib - Rofecoxib Side Effects : • Unwanted effects, owing largely to inhibtion of COX1 Particularly in the elderly and include : - Despepsia, nausea and vomiting , ulceration and gastric damage in chronic users, with risk of hemorrhage - Reversible renal insufficiency - Analgesic-associated nephropathy ( irreversible ) - Liver disorders, in high doses, e.g. acetaminophen Measurement the activity of anti-inflammatory drugs - Method : Paw Oedema Method - Principle : induction a chemical inflammation by injecting an irritant ( formalin ) into rat’s paw - Objective : measure the anti-inflammatory activity of diclofenac and hydrocortisone with different doses ) -Procedure : 1- select 5 rats 2- inject each rat 1 ml urethane for anesthesia. 3- select one as control and inject the rest of them intraperitoneal rat 1 >>> control rat 2 >>> 40 mg/kg diclofenac rat 3 >>> 80 mg/kg diclofenac rat 4 >>> 20 mg/kg hydrocortisone rat 5 >>> 40 mg/kg hydrocortisone 4- after 1 hr , inject 0.1 ml formalin in each rat ( 2 to 5 ) into their paws >>> to induce inflammation. 5- after 1 hr , take the reading using the plythysmometer of each rat paw ( right and left ). 6- calculate the inflammation and response % for each drug. Dose RP LP control 40 mg/kg vol. 80 mg/kg vol. 20 mg/kg hydro. 40 Inflammation mg/kg = RP - LP hydro. inflammat Response ion % C ___ T1 T2 T3 T4 C - T Response % = ــــــــــــــــــــــــــــــــــــــــX 100 C Response % >>>> Anti-inflammatory activity