Role of antibiotics and antiinflammatory Musculoskeletal System Role of antibiotics and antiinflammatory Dr. Harris Tata, M,Kes., SpOT

DIAGNOSTIC PROCESS THERAPEUTIC PROCESS CLINICS / HOSPITAL PASIENTS DIAGNOSTIC PROCESS THERAPEUTIC PROCESS KNOWLEDGE SKILL ATTITUDE ANAMNESTIC PHYSIC EXAMIN. SUPPORTING : - laboratory - radiology - electromedic - ect. DEFINE THE PROBLEM THERAPEUTIC OBJECT. SELECTING THERPEUT. STRATEGIES - non-pharmacological - pharmacological - surgical INFORMATION: -RATIONAL (evidence based) -IRRATIONAL (assumption,intuitive, no data)

Antibiotic

INFEKSI VIRUS BAKTERI JAMUR PARASIT dll SISTEM BIOLOGI SIMPTOM & SIGN TUBUH MANUSIA SIMPTOM & SIGN PATOLOGIS TUMBUH dan BERBIAK

Infection Musculoskeletal Skin Infection Cellulitis Myositis Osteomyelitis acute (subacute) chronic specific (eg TB) non specific(most common) Septic Arthritis Etc

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 Susceptibility testing Drug concentration in blood Serum bactericidal titers Route of administration Monitoring of therapeutic response 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 Emergency situations To delay resistance Mixed infections 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 Bersih; infeksi rate < 2% Bersih terkontaminasi: < 10% Terkontaminasi: + 20% Kotor: + 40% BEDAH

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, 5-hydroxytryptamine) 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

Anti-inflammatory steroids 6/12/2018 Pathway Overview Linoleic acid NSAIDs Benoxaprofen Zileuton Anti-inflammatory steroids Glucocorticoids Arachidonic acid NSAIDs aspirin Prostaglandins (PG) Leukotrienes (LT) Prostaglandin H2 synthase Lipoxygenase Thromboxanes (TXA) Thromboxane A2 synthase NSAIDs Dazoxiben PG: prostaglandins - PGG2, PGH2 (constriction), PGD2 (constriction or vasodilation), PGE1 (vasodilation), PGE2 (vasoconstriction/dilation), PGF2a (constriction), PGI2 (prostacyclin, dilation, inhibition of platelet adhesion) LT: leukotrienes - LTB4, LTC4, LTD4, LTE4 (multiple roles, microvascular vasoconstriction) TBX: thromboxanes - TXA2 (constriction, platelet adhesion), TXB2 (constriction) NSAIDs: nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, acetaminophen (not really an NSAID); anti-inflammatory steroids work by boosting levels of lipocortin (an annexin, Ca2+-dependent inhibitor protein/enzyme that inhibits phospholipase A2); lipocortin-1 = annexin-1 Most of the enzymes are located in the smooth endoplasmic reticulum Brain/nerves - PGD2, PGE2, and PGF2 Kidneys - PGE2 and PGI2 Lungs - PGD2 Synovial cells - PGE2 and PGI2 when stimulated by interleukin-1 Vascular beds - PGE2 and PGI2 & PGH2 and TXA2

Pathway Details IL-1 (inflammation) Membrane phospholipids 6/12/2018 Pathway Details IL-1 (inflammation) IL-1R Membrane phospholipids Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Arachidonic acid Phospholipase A2 (or PLC) LTA4 NSAIDS (aspirin) PGG2 LTC4 Glutathione S-transferase LTB4 PGH2 synthase Cyclooxygenase O2 LTD4 LTE4 PGH2 2GSH GSSG PG hydroperoxidase PGJ2 PGD2 synthase TXA2 TXA2 synthase PGD2 PGI2 (PC) PGF2a PGE2 PGI2 synthase PGE2 synthase PGF2 synthase IL: interleukin-1 IL-1R: interleukin-1 receptor NSAIDS: nonsteroidal anti-inflammatory drugs, aspirin (irreversible inhibitor of COX-1), ibuprofen (lesser ratio of COX-1/COX-2), acetaminophen (Tylenol, does not affect COX-1 or COX-2 but may indicate presence of a COX-3 or PCOX-1a or PCOX-1b isoforms that are not involved in PG synthesis but address fever and pain); anti-inflammatory steroids boost levels of Ca2+-dependent inhibitor protein lipocortin PG: prostaglandin GSH: glutathione (reduced form) GSSG: glutathione disulfide (oxidized form) PC: PGI2 or prostacyclin PGE2 synthase is also denoted PG endoperoxidase E isomerase, microsomal form is key enzyme Recall that most of the enzymes are located in the smooth endoplasmic reticulum

Differential Actions of Cyclooxygenases 6/12/2018 Differential Actions of Cyclooxygenases Housekeeping Unwanted side-effects Endothelial integrity Vascular patency Gastric mucosal integrity PGI2 COX1 Constitutive TXA2 PGE2 Bronchodilation Renal function Platelet function NSAIDs PGE2 PGF2a COX2 Inducible Inflammatory Inflammation Proteases Therapeutic anti-inflammatory effects COX: cyclooxygenase, COX1 constitutive (endoplasmic reticulum), COX2 inducible (perinuclear envelope), COX3 brain NSAIDs: nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, acetaminophen PG: 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.

Alprostadil Misoprostol mifepristone Latanoprost Prostacyclin (PGI2 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, oxyphenbutazone 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) Membrane phospholipids 6/12/2018 Pathway Details IL-1 (inflammation) IL-1R Membrane phospholipids Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Arachidonic acid Phospholipase A2 (or PLC) LTA4 NSAIDS (aspirin) PGG2 LTC4 Glutathione S-transferase LTB4 PGH2 synthase Cyclooxygenase O2 LTD4 LTE4 PGH2 2GSH GSSG PG hydroperoxidase PGJ2 PGD2 synthase TXA2 TXA2 synthase PGD2 PGI2 (PC) PGF2a PGE2 PGI2 synthase PGE2 synthase PGF2 synthase IL: interleukin-1 IL-1R: interleukin-1 receptor NSAIDS: nonsteroidal anti-inflammatory drugs, aspirin (irreversible inhibitor of COX-1), ibuprofen (lesser ratio of COX-1/COX-2), acetaminophen (Tylenol, does not affect COX-1 or COX-2 but may indicate presence of a COX-3 or PCOX-1a or PCOX-1b isoforms that are not involved in PG synthesis but address fever and pain); anti-inflammatory steroids boost levels of Ca2+-dependent inhibitor protein lipocortin PG: prostaglandin GSH: glutathione (reduced form) GSSG: glutathione disulfide (oxidized form) PC: PGI2 or prostacyclin PGE2 synthase is also denoted PG endoperoxidase E isomerase, microsomal form is key enzyme Recall that most of the enzymes are located in the smooth endoplasmic reticulum

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

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