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Musculoskeletal System Role of antibiotics and antiinflammatory Dr. Harris Tata, M,Kes., SpOT CLINICS / HOSPITAL PASIENTS DIAGNOSTIC PROCESS ANAMNESTIC PHYSIC EXAMIN. SUPPORTING : - laboratory - radiology - electromedic - ect. THERAPEUTIC PROCESS KNOWLEDGE SKILL ATTITUDE INFORMATION: -RATIONAL (evidence based) -IRRATIONAL (assumption,intuitive, no data) DEFINE THE PROBLEM THERAPEUTIC OBJECT. SELECTING THERPEUT. STRATEGIES - non-pharmacological - pharmacological - surgical 2 Antibiotic VIRUS BAKTERI JAMUR PARASIT dll INFEKSI SISTEM BIOLOGI TUBUH MANUSIA SIMPTOM & SIGN PATOLOGIS TUMBUH dan BERBIAK 4 Infection Musculoskeletal Skin Infection Cellulitis Myositis Osteomyelitis Septic Arthritis Etc acute (subacute) chronic specific (eg TB) non specific(most common) Acute Osteomyelitis & Acute Arthritis Organism Gram +ve staphylococus aureus strep pyogen strep pneumonie Listeria monocytogenes (rare) Gram -ve haemophilus influnzae (50% < 4 y) e .coli pseudomonas auroginosa, proteus mirabilis Antibiotic Antibiotic Chemical molecules produced by a microorganism that kills or inhibits the growth of another microorganism Antibiotic Selection of the most appropriate systemic antibiotic therapy will therefore need to reflect the organism(s) isolated and sensitivity profile ( culture and sensivity test), Pharmacokinetic factors such as penetration into bone, presence of prosthetic material, vascular supply of the affected limb and the patient’s individual tolerance of the drugs Antibiotics Treatment of these infections can be difficult, usually involving a prolonged course of antibiotics, often with surgical intervention. The selection of antibiotics depends on sensitivity profile, patient tolerance and long-term goals, Inhibits cell wall synthesis Penicillins, Cephalosporins, Vancomicyn, Bacitracin, Astreonam Imipinem. The Cephalosporins Firs Generation cephalotin, cephapirin, cephaloridine, cephalexin, cephradine, cefactor, cefadroxyl Second generation cefoxiitin, cefamandole, cefuroxime, cefotiam, cefmetazole, cefonicid, ceforanide, cefotetan Third Generation cefotaxime, ceftrizoxine, ceftriaxone, ceftmenoxine, ceftazidine, cefoperazone, moxalactam Increase in cell membrane permeability Polymyxin Mystatin Amphotericin Ribosomal inhibition Bacteriostatic tetracycline, chloramfenicol, macrolides (erytromycine, clindamycin) Bacteriocidal gentamycin, streptomycin, tobramycin, amikacin, and neomycin. Interference with transcription and translation of bacterial DNA Quinolones Rifampin, Metronidazole Antimetabolite action Sulfonamid Dapsone Trimetoprin Para-aminosalycil acid Antibiotic classification base on their spectrum activity No antibiotic is effective against all microbes Principle antibiotics therapy 1. Susceptibility testing 2. Drug concentration in blood 3. Serum bactericidal titers 4. Route of administration 5. Monitoring of therapeutic response 6. Clinical failure of antibiotics therapy 1. Susceptibility testing The results of susceptibility testing establish the drug sensitivity of the organism These results usually predict the MIC of a antibiotics Choosing of the most effective and the least toxic drug, in time administration 2. Drug concentration in the blood • The measurement of drug concenctration may be appropriate when using antibiotics with low therapeutic index (aminoglycosides & vancomycin) 3. Route of administration Parenteral administration is prefered in most cases of serious microbacterial infections. Chloramphenicol, the fluoroquinolones and trimethoprim-sulfamethoxazole may be effective orally. 5. Monitoring of therapeutic response • Therapeutic response should be monitored clinically and microbiologically to detect the development of resistance or superinfection 6. Clinical failure of antimicrobial therapy Inadequate clinical or microbial response can result from : laboratory testing error, problems the drug (incorrect choice, poor tissue penetration, inadeqaute dose) the patient (poor host defense, undrained abcesses) the pathogen (resistance or superinfection) Antimicrobial drugs combination indication 1. Emergency situations 2. To delay resistance 3. Mixed infections 4. To achieve synergistic effects Clinical Applications The role of antibiotic in orthopedic surgery is multifold They can be used to prevent infection in elective surgery cases and to treat open fracture and established infection To prevent or treat infection s most effectively microbiology, pharmacology, toxicity, and cost antibiotics In general, the least toxic, least expensive, and most effective drug with narrowest spectrum and best penetration should be used PROFILAKSI dengan ANTIBAKTERIAL BEDAH -Bersih; infeksi rate < 2% -Bersih terkontaminasi: < 10% -Terkontaminasi: + 20% -Kotor: + 40% 23 Inflammatory Inflammation Triggered by tissue damage due to infection, heat, wound, etc. Four Major Symptoms of Inflammation: 1. Redness 2. Pain 3. Heat 4. Swelling May also observe: 5. Loss of function Nyeri inflamasi Pelepasan substansi kimia dan enzim (mediator) yang mempengaruhi aktivitas dan sensitifitas neuron Akibatnya Kenaikan aktivitas nociceptor Hiperalgesia Edema neurogenik Vascular Changes in Inflammation Mediators of blood flow and vascular permeability changes - vasoactive amines (histamine, serotonin, 5hydroxytryptamine) - vasoactive peptides (bradykinin, interleukin 1) - vasoactive lipids (prostaglandins, leukotrienes) Mediators of leukocyte chemotaxis - leukotriene B4 - Eosinophil chemotactic factor of anaphylaxis The anti-inflammatory Drugs Vasoactive lipids (prostaglandins, leukotrienes) NSAIDs SAID Pathway Overview Anti-inflammatory steroids Glucocorticoids NSAIDs aspirin Linoleic acid NSAIDs Benoxaprofen Zileuton Arachidonic acid Lipoxygenase Prostaglandin H2 synthase Prostaglandins (PG) Leukotrienes (LT) Thromboxane A2 synthase Thromboxanes (TXA) NSAIDs Dazoxiben Pathway Details IL-1 (inflammation) IL-1R Membrane phospholipids Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Phospholipase A2 (or PLC) Arachidonic acid NSAIDS (aspirin) O2 Cyclooxygenase PGH2 synthase PGG2 PG hydroperoxidase PGJ2 PGD2 PGD2 synthase PGI2 synthase PGI2 (PC) LTAGlutathione 4 Stransferase LTB4 LTC4 LTD4 2GSH GSSG LTE4 TXA2 synthase PGH2 TXA2 PGF PGF2 synthase PGE2 synthase PGE2 Differential Actions of Cyclooxygenases Unwanted sideeffects Constitutive COX1 NSAIDs Inducible Inflammatory COX2 PGI2 PGE2 TXA2 PGE2 PGF2a Proteases Therapeutic antiinflammatory effects Housekeeping Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function Inflammation Indomethacin , sulindac Meclofenamate, ibuprofen celecoxib, diclofenac, rofecoxib, lumiracoxib, and etoricoxib Prostacyclin (PGI2 epoprostenol) Alprostadil Misoprostol mifepristone Latanoprost Antileukotriene drugs zileuton, zafirlukast, and montelukast NSAIDs (non-steroidal antipyretic and antiinflammatory drugs) Most drugs have three major effects: - antipyretic (lowering a raised, not normal temperature) - due to a decrease in PGE2, which is generated in response to inflammatory proteins and is responsible for elevating the hypothalamic set-point for temperature control - analgesic (reduction of certain sorts of pain) - decrease PGs generation, relief of headache due to decreased PGs-mediated vasodilatation - anti-inflammatory (modification of the inflammatory reaction) decrease in PGE2 and PGI2 »»» less vasodilatation, less oedema Not all NSAIDs are equally potent in each of these actions. Classical prototypic compounds include: 1. Salicylates; aspirin, Diflunisal 2. Para-aminophenols; acetaminophen 3. Indoles; indomethacin, sulindac, Tolmetin 4. Aryl propionic acids; ibuprofen, fenoprofen, naproxen, ketoprofen 5. Fenamates; mefenamic acid, meclofenamate 6. Pyrazolon derivatives; phenylbutazone, oxyphenbutazo ne 7. Oxicams, Piroxicam , Meloxicam 8. Diclovenac, Ketorolac 9. Tolmetin, Nabumetone, Nimesulid 10. COX 2 selective: celecoxib and valdecoxib Anti-inflammatory steroid Pathway Details IL-1 (inflammation) IL-1R Membrane phospholipids Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Phospholipase A2 (or PLC) Arachidonic acid NSAIDS (aspirin) O2 Cyclooxygenase PGH2 synthase PGG2 PG hydroperoxidase PGJ2 PGD2 PGD2 synthase PGI2 synthase PGI2 (PC) LTAGlutathione 4 Stransferase LTB4 LTC4 LTD4 2GSH GSSG LTE4 TXA2 synthase PGH2 TXA2 PGF PGF2 synthase PGE2 synthase PGE2 Corticosteroids may regulate gene expression in several ways Figure 14-3 Anti-inflammatory effects of corticosteroids Clinical uses NSAID - Three major effects antipyretic, analgesic , antiinflammatory - Responses to these drugs and dose at which they are effective vary considerably from patient to patient - Treatment arthriitis rotator cuff tendinitis, plantar fascitis , tenosynovitis.etc - Indomethasin heterotropic ossification - Side effects gastrointestinal and platelet dysfunction Clinical uses COX-2 - New anti-inflamatory drugs , treating patient with out the untoward side effects of gastrointestinal and platelet dysfunction Corticosteroids - Corticosteroid injections can be administered in an intraarticular, intrabursal and intratendon sheath fashion - Side effect s rupture of tendon or ligament, osteoporosis or AVN Terima Kasih