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

2. 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)

3. Antibiotic

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

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

6. 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

7. Antibiotic
Antibiotic  Chemical molecules produced by a microorganism that kills or inhibits the growth of another microorganism

8. 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

9. 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,

10. Inhibits cell wall synthesis
Penicillins,
Cephalosporins,
Vancomicyn,
Bacitracin,
Astreonam
Imipinem.

11. 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

12. Increase in cell membrane permeability
Polymyxin
Mystatin
Amphotericin

13. Ribosomal inhibition
Bacteriostatic  tetracycline, chloramfenicol, macrolides (erytromycine, clindamycin)
Bacteriocidal  gentamycin, streptomycin, tobramycin, amikacin, and neomycin.

14. Interference with transcription and translation of bacterial DNA
Quinolones
Rifampin,
Metronidazole

15. Antimetabolite action
Sulfonamid
Dapsone
Trimetoprin
Para-aminosalycil
acid

16. Antibiotic classification base on their spectrum activity
No antibiotic is effective against all microbes

17. Principle antibiotics therapy
Susceptibility testing
Drug concentration in blood
Serum bactericidal titers
Route of administration
Monitoring of therapeutic response
Clinical failure of antibiotics therapy

18. 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)

19. 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

20. 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)

21. Antimicrobial drugs combination indication
Emergency situations
To delay resistance
Mixed infections
To achieve synergistic effects

22. 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

23. PROFILAKSI dengan ANTIBAKTERIAL
Bersih; infeksi rate < 2%
Bersih terkontaminasi: < 10%
Terkontaminasi: + 20%
Kotor: + 40%
BEDAH

24. Inflammatory

25. 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

26. Nyeri inflamasi
Pelepasan substansi kimia dan enzim (mediator) yang mempengaruhi aktivitas dan sensitifitas neuron
Akibatnya
Kenaikan aktivitas nociceptor
Hiperalgesia
Edema neurogenik

27. 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

28. The anti-inflammatory Drugs

29. Vasoactive lipids (prostaglandins, leukotrienes)
NSAIDs
SAID

31. 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

32. 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

33. 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.

34. Alprostadil Misoprostol mifepristone Latanoprost Prostacyclin (PGI2
Indomethacin , sulindac
Meclofenamate, ibuprofen
celecoxib, diclofenac,
rofecoxib, lumiracoxib, and
etoricoxib
Prostacyclin (PGI2
epoprostenol)
Alprostadil
Misoprostol
mifepristone
Latanoprost

35. Antileukotriene drugs
zileuton,
zafirlukast, and
montelukast

36. 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.

37. 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

38. Anti-inflammatory steroid

39. 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

40. Corticosteroids may regulate gene expression in several ways

41. Figure 14-3
Anti-inflammatory effects of corticosteroids

42. 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

43. 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

44. Terima Kasih