Anti-inflammatory Drugs

1. Anti-inflammatory Drugs # Lab 4 #

2. 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

3. Signs of inflammation Redness: Due to vasodilatation by effects of releasing of histamine, bradykinin and prostaglandin. Hotness: Due to increased blood flow.

4. 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.

5. Inflammatory mediators: histamine 5-HT (serotonin) Bradykinin Prostaglandins (eg PGE2 ) Interleukines Substance P Nitrous oxide Main inflammatory mediator

6. 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.

7. 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) containing fibroblast and capillaries is formed. Phases of Inflammation

8. Classification of the Inflammation • Non – immunological : Induced by chemical irritants such as formalin • Immunological : Induced by infections such as bacterial infection

9. Anti-inflammatory Drugs Non-steroidal Steroidal - Cortisone - Hydrocortisone - Acetaminophen - Aspirin

10. Steroids (SAIDs) - Containing steroid moiety in their sturcure Glucocorticoids (GC) Cortisone

11. Glucocorticoids (GC) Synthetic Natural - Betamethasone • Dexamethasone - Predinsone - Cortisone - Hydrocortisone Fluorinated Glucocorticoids Liver enzymes Prednisolone

12. 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. -

13. GC inhibition phospholipase A2

14. 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

15. Side Effects : Moon face buffalo hump

16. Non-Steroidal Anti-inflammatory Drugs (NASID) • They don’t contain steroid moiety • They also have analgesic and antipyretic activity

17. 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

18. GC inhibition phospholipase A2

19. Cyclooxygenese ( COX ) Isoforms : COX 2 COX 1 - inducible • By inflammatory processes and mediators - Constitutive - Many tissues ( blood vessels stomach and kidney ) COX 3 has recently been described

20. Non-Steroidal Anti-inflammatory Drugs (NASID) selective COX2 inhibitors Non-selective COX inhibitors - Aspirin - Ibuprofen - Diclofenac - Meloxicam - Celecoxib - Rofecoxib

21. 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

22. 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 )

23. 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.

24. Inflammation = RP - LP C - T Response % = ــــــــــــــــــــــــــــــــــــــــX 100 C Response % >>>> Anti-inflammatory activity