ANTI INFLAMMATORY DRUGS AND - PowerPoint Presentation

1. ANTI INFLAMMATORY DRUGSANDANALGESICS

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 tissuesPermanent destruction of tissues

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

4. Signs of inflammationSwelling: due to increased vascular permeability by the released mediators and increased the exudate in the inflammed areaPain: due to irritation of nerve ending by inflammation and the pressure of the swelling on the nerve ending.

5. Inflammatory mediators:histamine5-HT (serotonin)Bradykinin Prostaglandins (eg PGE2 ) InterleukinesSubstance PNitrous oxide Main inflammatorymediator

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

7. Anti-inflammatory DrugsSteroidalNon-steroidal- Cortisone- Hydrocortisone- Acetaminophen- Aspirin

8. Non-Steroidal Anti-inflammatory Drugs(NSAID) They don’t contain steroids They also have analgesic and antipyretic activity

9. 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

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11. Non-Steroidal Anti-inflammatory Drugs(NSAID)Non-selective COX inhibitorsselective COX2 inhibitors- Aspirin- Ibuprofen- Diclofenac- Meloxicam- Celecoxib- Rofecoxib

12. Side Effects : Unwanted effects, owing largely to inhibition of COX1 Particularly in the elderly and include :- Dyspepsia, nausea and vomiting , ulceration and gastric damage in chronic users, with risk of hemorrhage- Analgesic-associated nephropathy ( irreversible )- Liver disorders, in high doses, e.g. acetaminophen

13. ParacetamolMechanism of actionInhibits prostaglandin synthesis in the brain but minimally at peripheryMinimal anti-inflammatory activity - Thus not usually considered as a NSAIDNo effect on platelet function

14. Pharmacokinetics of paracetamolWell absorbed from stomachInactivated in the liver -Conjugation with glucuronide - 60% Sulphate - 30% Oxidation -5-10%Oxidation forms N acetyl-p-Benzoquinoneimine (NABQI) -a highly reactive metabolite NABQI conjugates with glutathione and is rapidly inactivated

15. Clinical usesAnalgesic - efficacy similar to aspirinAntipyretic

16. Pharmacokinetics in Paracetamol overdoseIn overdose, capacity of conjugation is exceeded and more undergo oxidation - more NABQI formed - not enough glutathione to inactivateOxidises thiol (SH groups) of vital enzymes in liver and kidneys - liver & renal failure

17. N-acetyl cysteine and methionine are used in treatment of overdose - combines with NABQI as it formed and prevents damage to cellsShould be given during the acute stage within 24 hours to be effective if Serum paracetamol is elevated when plotted in Rumack-Matthews Normogram

18. Therapeutic doses of paracetamol Usual adult dose - 1g 6 hourlyPaediatric dose - 10-15mg/kg/doseMaximum dose - 90mg/kg/dayPreparations available – tablets/syrups/suppOveruse of paracetamol exceeding the above doses during febrile illnesses in Sri Lanka have led to liver failure and deathDuring febrile illness, starvation, and dehydration liver more susceptible to injury

19. What are NSAIDs and how do they work?Drug with analgesic( without impairing consciousness ), antipyretic, and anti-inflamammatory effectsweak acids, PH 3-5, well absorbed from stomach and intestinal mucosaprotein-bound in plasma ( albumin),metabolised in the liver

20. ProstaglandinsProstaglandins : produced by the cells, promote inflammation, pain, and fever; blood clotting function of platelets; protect the lining of the stomach from damaging effects of acid.two COX enzymes, COX-1 and COX-2. produce prostaglandins that promote inflammation, pain, and fever

21. What are NSAIDs and how do they work ?NSAIDs block the COX enzymes , reduce prostaglandins, inflammation, pain, and fever are reduced. COX-1 produced prostaglandins that support platelets and protect the stomach.Reduced prostaglandins that protect the stomach and support blood clotting, so NSAIDs can cause ulcers in the stomach and promote bleeding.

22. For what conditions are NSAIDs used?RAOAInfalmmatory arthritis, Acute goutMetastatic bone painDysmenohhoeaHeadache, migrainPostoperative painPyrexia ( fever)IleusRenal colic

23. For what conditions are NSAIDs used?Aspirin (also an NSAID) : inhibit the clotting of blood( platelet aggregation ) ,prevent strokes and cardiovascular attacks

24. Differences between NSAIDsvary in potency, duration , eliminated from body, how strongly they inhibit COX-1 (tendency to cause ulcers and promote bleeding )The more an NSAID blocks COX-1, the greater to cause ulcers and promote bleeding.

25. Differences between NSAIDsCelecoxib (Celebrex), blocks COX-2 but little on COX-1, classified as a selective COX-2 inhibitor ,cause less bleeding and fewer ulcers.Aspirin is a unique NSAID, the only NSAID inhibits clotting of blood for a prolonged period (4 to 7 days), ideal for preventing blood clots that cause heart attacks and strokes

26. Differences between NSAIDsMost NSAIDs inhibit the clotting of blood for only a few hours Ketorolac (Keto) is a very potent NSAID and is used for moderately severe acute pain that usually requires narcotics Ketorolac (Keto) causes ulcers more frequently than other NSAID. Therefore, it is not used for more than five days. Individuals who do not respond to one NSAID may respond to another.

27. Side effects of NSAIDsGastrointestinalDirect irritation : acidic molecules Indirect irritation: inhibit COX-1, reduce protective prostaglandinsS/S: nausea, vomiting, dyspepsia, gastric ulcer/bleeding, diarrheaDuration of therapy, dose should be strictly regulated

28. Side effects of NSAIDsRenalDecrease prostaglandins→ constriction of afferent arteriole → decreased renal perfusion →alter renal functionS/S: salt and fluid retension, hypertensionCaution: NSAID with ACE inhibitor, diureticRare: ARF, ATN, nephrotic syn.

29. Side effects of NSAIDsOthersAllergy: shortness of breath Asthma : a higher risk for serious allergic reactionwith a serious allergy to one NSAID are likely to have similar reaction to a different NSAID photosensitivity

30. Combinational RiskIf COX-2 inhibitor taken, should not use a traditional NSAID concomitantlyWith daily aspirin therapy, should use other NSAID carefully, they may block the cardioprotective effect of aspirin

31. During pregnancyNot recommended during pregnancy, particular 3rd trimesterCause early closure of fetal ductus arteriosus, and fetal renal toxicity, premature birthAcetaminophen is more safe during pregnancyIn France, NSAID and aspirin is contra-indicated after 6 months of pregnancy

32. COX-2 inhibitors Celecoxib (Celebrex ® )Rofecoxib (Vioxx ® )Valdecoxib (Bextra ® )

33. COX 2 inhibitors (Coxibs)Cyclo-oxygenase metabolises arachidonic acid into prostaglandins Phospholipids (in cell wall)Arachidonic acidPhospholipase A2 (inhibited by steroids)Prostaglandins(thromboxane, prostacyclin, other PGs)LeukotriensCyclooxygenase(Inhibited by NSAIDS)lipoxygenase

34. Cyclo-oxygenaseCOX exists in 2 forms - COX 1 and COX 2COX-1 is predominantly constitutive (constantly formed by cells regardless of growth conditions) although activity is increased 2-4 fold by inflammationCOX 1 is present in most tissues especially stomach, platelets and kidneysCOX 1 in stomach produces prostaglandins which protect the mucosa

35. Cox-2Cox- 2 is inducible by 10-20 fold by inflammatory stimuli in many cells including macrophages, synoviocytes, chondrocytes, fibroblasta and endothelial cells.Cox-2 is present in low concentrations in GI mucosaIf COX -2 can be inhibited without inhibition of COX-1 theoretically side effects like GI irritation will be lessThe NSAIDS differ in their relative inhibition of COX -1 and COX -2

36. COX -2 inhibitorsRecognition of differential action of drugs on the 2 isoforms led to development of selective COX2 inhibitorsThese have selectivity for inhibiting COX -2 at least 5 times that of COX-1Includes rofecoxib, celecoxib, meloxicam, nabumetoneThey have less adverse events in GI tractNon COX -2 inhibitors - all other NSAIDS They inhibit COX 1 as much or more than COX -2

37. COX -2 inhibitors (Coxibs)As effective as NSAIDSGI side effects were thought absent/minimal but they are seen, but less than with NSAIDS Still significantly associated with dyspeptic symptoms and may be due to inhibition of constitutively expressed protective COX -2 in stomachPeptic ulcers occur but less than with NSAIDS - but contra indicated if P/H of ulcer

38. Other side effects of CoxibsAlmost similar to other NSAIDSWater retention and peripheral edema HypertensionRise in creatinineARF in patients taking diuretics and/or ACEIAllergic reactions -rashes, angioedemaConcern about increased MI in patients with IHD taking rofecoxib

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

40. Glucocorticoids (GC)NaturalSynthetic - Cortisone- Hydrocortisone- Betamethasone Dexamethasone-FluorinatedGlucocorticoidsPrednisolone

41. Glucocorticoids (GC)Mechanism of Action :They act by indirect inhibition of the enzyme phospholipase A2which activate synthesis of arachidonic acid with subsequentformation of prostaglandins. They induce synthesis of a protein “lipocortin-1” which hasthe inhibitory effect on phospholipase A2.--

42. phospholipase A2GC inhibition

43. 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

44. Side Effects :Moon facebuffalo hump

45. Questions?

46. THANK YOU