inflammation acute

ANALGESIC & ANTI INFLAMMATORY AGENTSNur permatasari1

Heat Redness Swelling Pain Loss Of Func.The 5 Cardinal Signs of Nursing management: assessment, diagnosis, planning, intervention, evaluation 2pain classificationACUTE AND CHRONIC

SOMATIC AND VISCERAL

NEUROPATIC PAINNOCICEPTIVE PAIN DISREGULATION PAIN PSICHOSOMATICSensitization of Peripheral Nociceptors

4Chemical Mediators:Vasoactive amines - Histamine, SerotoninComplement system C1 C9 (Classic/alt)Kinin System Kallikrein BradykininClotting system FXII, FX, Fibrin, PlasminArachidonic acid metabolites:Prostaglandins - (cyclooxigenase)Leukotrienes (Lipoxigenase)Lipoxins anti-inflammatory.PAF, Cytokines (interleukins), Chemokines.H2o2, Nitric Oxide, Lysozymes,O2 free radicals 5PROSES INFLAMASI PADA SENDIDETEKSI INJURIMIGRASI LEKOSITAKTIVASI LEKOSITIL-1 TNF ALFASEL PMN CHONDROSIT SEL MAST SEL SINOVIUMELASTASE CAPTESIN G COLLAGENASE GELATINASE STROMELYSIN TRYPTASECHYMASE CAPTESIN D CAPTESIN L DAN B

DESTRUKSI TULANG RAWAN

UsesAnti-inflammatory agent.Analgesics.Antipyretics.AntithromboticsArthritisBack painSoft tissue injuries (sprains & strains)Dental painPost-operative painMenstrual painMigraineDelaying onset of premature labour.

XNSAIDNSAID (non steroid anti inflammation drugs)a. Anti-Inflammatory ActionsInflammation is characterised by redness, pain and swelling.These are thought to be caused by increased levels of prostaglandins.NSAIDs reduce the prostaglandin levels therefore reducing the symptoms of inflammation.They have varying degrees of anti-inflammatory properties.b. Antipyretic ActionsPyrogens increase the body temperature by activating macrophages & other cells to produce cytokines.These increase prostaglandin E2 synthesis in the hypothalmus (the bodys thermostat) which in turn increases the body temperature.NSAIDs inhibit prostaglandin E2 synthesis and lower the body temperature.All NSAIDs have antipyretic properties. Aspirin, ibuprofen and paracetamol are most commonly used for this purpose.c. Analgesic ActionsProstaglandins cause sensitisation of nerve cells to pain.They sensitise nociceptor fibres to bradykinins and 5HT.The pain relieving properties of NSAIDs are thought to be due to the inhibition of prostaglandins, particularly PGE2 & PGF2

d. Antithrombotic ActionsThe body maintains a balance between Thromboxane A2 (TXA2), produced by platelets & Prostaglandin I2 (PGI2), produced by the vascular endothelium.This allows adequate platelet aggregation within the body.NSAIDs reduce both TXA2 & PGI2 levels.Platelets cant synthesise cyclo-oxygenase enzymes & so become inactive.This causes the prostaglandin levels to increase & reduces platelet aggregation.Anti thrombotic effect of aspirin

Differential Actions of CyclooxygenasesNSAIDsCOX1ConstitutiveCOX2InducibleInflammatoryEndothelial integrityVascular patencyGastric mucosal integrityBronchodilationRenal functionPlatelet functionInflammationUnwanted side-effectsTherapeutic anti-inflammatory effectsPGE2PGF2aProteasesPGI2PGE2TXA2Housekeeping1/4/201215COX: cyclooxygenase, COX1 constitutive (endoplasmic reticulum), COX2 inducible (perinuclear envelope), COX3 brainNSAIDs: nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, acetaminophenPG: prostaglandins (PGI2 = prostacyclin, endothelial cells)TX: thromboxane (TXA2 = thromboxane, platelets)COX-1 and COX-2 serve identical functions in catalyzing the conversion of arachidonic acid to prostanoids. The specific prostanoid(s) generated in any given cell is determined by which distal enzymes in the prostanoid synthetic pathways are expressed. For example, stimulated human synovial cells synthesize small amounts of PGE2 and prostacyclin but not thromboxane or PGD or PGF2a. Following exposure to interleukin-1, synovial cells make considerably more PGE2 and prostacyclin, but they still do not synthesize PGD, TXB2 or PGF2a. The IL1-induced increase in PGE2 and prostacyclin is mediated through COX-2.Thus, while the species of prostanoid synthesized in a cell is dependent upon the specific distal synthetic enzyme(s) expressed, the amount synthesized is determined by the amount of COX 1 and 2 activities expressed. COX-1 is expressed in nearly all cells (except red cells) in their basal (unstimulated) state. COX-1 mediated production of thromboxane in platelets promotes normal clotting. And COX-1 mediated synthesis of prostaglandins in the kidney appears to be responsible for maintaining renal plasma flow in the face of vasoconstriction.Side effectsGastric irritation and ulceration.COX 1 produces prostaglandins that have a protective effect on the stomach lining. NSAIDs inhibit this enzyme & so it loses its function. Risk factors for NSAID ulcers ??Acute kidney failure.The kidneys are rarely damaged in normal people. Patients with heart failure, cirrhosis of the liver, renal disease or who are taking diuretics should not take NSAIDs as they cause kidney failure. Side effects (cont)Bleeding problems.Bronchospasm can occur (may make asthma worse).Liver function abnormalities.Headaches, Vertigo, Tinnitus, Dizziness (Salicylism)Metabolism.Salt & Water Retention.Hypersensitivity reaction

bronchospasm

Classes of NSAIDsTable showing the different classes of NSAIDs and some examples. Acetaminophen Does not have significant anti-inflammatory properties and as a result is not considered a true NSAID. Inhibits COX-3 Does not have the same degree of complications from the development of ulcerations. One of the first drugs of choicein the management of mild to moderate chronic pain. Conventional oral dose is 325 to 1000 mg.Analgesia without Anti-inflammationAcetaminophen-Pharmacokinetics A small percentage undergoes cytochrome P450 mediatedN-hydroxylation forming a highly reactive intermediate.

Associated with hepatoxicity when taken in large doses(10 to 15 g).

Neutralized with the sulphydryl reducing agent N-acetylcysteine*

COX-II Selective NSAIDS

CelecoxibApproved for osteo and rheumatoid arthritisLong term trial (CLASS) shows no difference in ulcerations between celecoxib and diclofenac or ibuprofenSlightly better than ibuprofen with respect to GI irritationRofecoxibApproved for osteo and rheumatoid arthritisLong term trial (VIGOR) shows significant improvement in ulcerations and GI irritation between rofecoxib and naproxenHowever, the incidence of thrombotic cardiovascular events is significantly higher (overall incidence still less than 2%)22CelecoxibApproved for osteo and rheumatoid arthritisLong term trial (CLASS) shows no difference in ulcerations between celecoxib and diclofenac or ibuprofenSlightly better than ibuprofen with respect to GI irritationSimilar efficacy

RofecoxibApproved for osteo and rheumatoid arthritisLong term trial (VIGOR) shows significant improvement in ulcerations and GI irritation between rofecoxib and naproxenHowever, the incidence of thrombotic cardiovascular events is significantly higher (overall incidence still less than 2%)Not yet clear if this is side effect of rofecoxib or protective effect of naproxenSimilar efficacyCOX-II Selective NSAIDS

etoricoxibValdecoxibFirst second generation coxibApproved for rheumatoid and osteoarthritis8 to 10 h half lifeEtoricoxibIn Phase 3 TrialsSecond Generation15 to 20 h half life23ValdecoxibFirst second generation coxibApproved for rheumatoid and osteoarthritis8 to 10 h half life

EtoricoxibIn Phase 3 TrialsSecond Generation15 to 20 h half life

COX-2 Inhibitors - Do they meet expectations?Renal and cardiac complications at least as great as conventional NSAIDS

No anti-thrombic activity

Gastrointestinal ulcerations reduced in short-term studies (approximately 1-2 years), long-term benefit - results still are not clear

Side effects 25

Pharmacokinetics 26

Binding to the glucocorticoid receptor complex prevents translocation af NFkappa B to the nucleus. ( NFkappa B is agent that can stimulate the expressions of proinflammatory protein) . So, glucocorticoids inhibit the expression of genes encoding for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor).

Glucorticoid principle and adverse effects

28Pharmacodynamic therapy with glucocorticoids. In unphysiologically high concentrations, cortisol or other glucocorticoids suppress all phases (exudation, proliferation, scar formation) of the inflammatory reaction, i.e.,the organisms defensive measures against foreign or noxious matter. This effect is mediated by multiple components,all of which involve alterations in gene transcription Mechanism of action: Binding to the glucocorticoid receptor complex prevents translocation af NFkappa B to the nucleus. ( NFkappa B is agent that can stimulate the expressions of proinflammatory protein) . So, glucocorticoids inhibit the expression of genes encoding for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor). Consequently, release of arachidonic acid is diminished, as is the formation of inflammatory mediators of the prostaglandin and leukotriene series. (see prostaglandin synthesis) Conversely, glucocorticoids augment the expression of some anti-inflammatory proteins, e.g., lipocortin, which in turn inhibits phospholipase A2. Desired effects. As anti-allergics, immunosuppressants, or anti-inflammatory drugs, glucocorticoids display excellent efficacy against undesired inflammatory reactions.Regimens for prevention of adrenocortical atrophy a) Circadian administration and The daily dose of glucocorticoid is given in the morning. Endogenous cortisol production will have already begun, the regulatory centers being relatively insensitive to inhibition. b) Alternate-day therapy: Twice the daily dose is given on alternate mornings.On the off day, endogenous cortisol production is allowed to occur.

29Gout

30Onset usually very rapid; extremely painful Mechanism of disease is acute precipitation of crystals of uric acidLeukocytes migrate in, engulf crystals, rupture and release inflammatory mediatorsStory: Rock Candy, Supersaturated Solutions, seeding, Immediate formation of crystals

Gout Treatment StrategiesTreatment of Acute Gout: indomethacin or other NSAID corticosteroids (rarely used today) colchicine second line therapyTreatment of Chronic Gout:1) Increase uric acid excretion uricosuric agents - probenecid2) Decrease uric acid production metabolic inhibition - allopurinol3) Decrease inflammatory response colchicine (low dose)31Different Problems; different strategiesAcute attack: Problem is pain and inflammationYou cannot remove crystalsTx for antiinflammation and to relieve painChronic attackProblem is buildup of uric acidEvaluate to determine if high production or low secretion then treat as properDO NOT use uricosurics or allopurinol in acute attacks, can ppt more uric acid

Uricosuric Agents

Probenecid

SulfinpyrazoneBenzbromaroneAgents decrease reabsorption of uric acid at the middle of the proximal tubule in the kidney

32Agents decrease reabsorption of uric acid at the middle of the proximal tubule in the kidneyEffectively lowers plasma concentration of uric acidUseful for patients who undersecrete uric acidCommon Adverse Effects. Probenecid is well tolerated. Approximately 2% of patients develop mild gastrointestinal irritation. It is ineffective in patients with renal insufficiency and should be avoided in those with creatinine clearance of