INFLAMATION, FEVER AND PAINAguslina KirtishantiFakultas Farmasi Ubaya

INFLAMASI/RADANGInflamasi/Radang adalah respon vaskular yang hasilnya merupakan pengiriman cairan, zat-zat yang terlarut, dan sel-sel dari sirkulasi darah ke jaringan-jaringan interstisial pada daerah cedera atau nekrosis.

Tujuan peradangan adalah : netralisasi dan pembuangan agen penyerang (mikroba dan toksin) dan sel/jaringan yang nekrosis serta mengadakan proses perbaikan atau pemulihan.

Dalam respon inflamasi/radang melibatkan sel intravaskular, sel dan matrik jaringan penghubung.Sel intravaskular yang bersirkulasi adalah : neutrofil, monosit, eosinofil, limfosit, basofil, dan platelet. Sel jaringan penghubung adalah : sel mast, fibroblast dan makrofag.Matrix jaringan penghubung/matrix ekstraselular : kolagen, elastin, glikoprotein (fibronektin, laminin, tenascin), proteoglikan.

Radang dibedakan menjadi 2 yaitu :Radang akutRadang kronis

RADANG AKUTRadang akut adalah respon awal dan segera terhadap agen penyebab injury. Proses pada radang akut mempunyai 3 komponen utama yaitu: Perubahan vaskular yang berakibat peningkatan aliran darahPerubahan struktur mikrovaskular yang menyebabkan protein plasma dan leukosit meninggalkan sirkulasi.Emigrasi leukosit menuju daerah radang.

3 Komponen Proses Radang Akut1. vasokontriksivasodilatasiAliran darah Kalor & ruborSirkulasi darah lambat2.Sirkulasi lambatPermeabilitas vaskulartumorViskositas drh stasis3.stasisMarginasi leukositEmigrasi leukositdolor

BBAGAN ALIRAN DARAH DALAM MIKROSIRKULASIKARENA ADANYA INJURYInjuryArteriolardilationIncreased BHPFluid loss toTissue spacesReduced flowRBCaggregationStasisIncreasedBlood viscosity

RESPON INFLAMASI

MEDIATOR KIMIA PADA RADANG AKUT

MediatorSourceAction

Vascular leakageChemotaxisOtherHistamineMast cell, platelets+-BradykininPlasma substrate+-PainC3aPlasma protein via lever+-Opsonic fragment (C3b)C5aMacrophages++Leukocyte adhesion,activationProstaglandinsMast cells, from membrane phospholipidsPotentiate other mediators-Vasodilation, pain, feverLeukotriene B4Leukocytes-+Leukocyte adhesion,activation

MEDIATOR KIMIA PADA RADANG AKUT

Leukotriene C4,D4,E4Leukocytes, mast cells+-Bronchocontriction, vasocontrictionOxygen metabolitesLeukocytes+-Endothelial damage, tissue damagePAFLeukocytes, mast cells++Bronchocontriction, leukocyte primingIL-1 and TNFMacrophage, other-+Acute phase reaction, endothelial activationChemokinesLeukocytes, other-+Leukocyte activationNitric oxideMacrophage, endothelium++Vasodilation, cytotoxicity

Most Likely Mediators in InflammationVasodilation prostaglandins nitric oxideIncreased vascular permeability vasoactive amines C3a and C5a bradykinin leukotrienes C4, D4, E4 PAF Substance PChemotaxis, leukocyte activation C5a leukotriene B4 Chemokines bacterial productsFever IL-1, IL-6, TNF prostaglandinsPain prostaglandins bradykininTissue damage neutrophil and macrophage lysosomal enzymes oxygen metabolites nitric oxide

Outcome of Acute InflammationinjuryAcute inflammationResolutionAbscess Formation

Healing Regeneration Scarring

Chronic inflammationmediatorsmediatorsPersistent infectionPersistent toxinAutoimmune diseases

RADANG KRONISRadang kronis adalah radang dengan durasi yang lama (minggu atau bulan), terjadi kerusakan jaringan dan perbaikan jaringan terjadi secara simultan. Radang kronis terjadi karena hal berikut :Infeksi yang menetap karena mikroorganisme seperti Mycobacterium tuberculosis, Treponema pallidum dan beberapa fungi.Pemaparan yang berlangsung lama terhadap agen toksik, baik eksogen maupun endogen, cth : silicosis dan atherosclerosis.Autoimmune diseases

KARAKTERISTIK RADANG KRONISInfiltrasi sel mononuklear : makrofag, limfosit, dan sel plasma.Kerusakan jaringan : diinduksi oleh sel radang.Perbaikan jaringan oleh jaringan penghubung/connective : angiogenesis dan fibrosis.

PATOGENESIS RADANG KRONISActivated T cellMonocyte/macrophageCytokine (IFN-)Nonimmune Activation(endotoxin, fibronektin,Chemical mediators)Activated macrophageTissue Injury : Toxic oxygen metabolites Proteases Neutrophil chemotactic factors Coagulation factors AA metabolites Nitric oxideFibrosis : Growth factors (PDGF, FGF, TGF) Fibrogenic cytokines Angiogenesis factors (FGF) Collagenases

FEVERTemperatur oral normal rata-rata adalah 36,7 C dan tidak boleh dari 0,5C.Temperatur rektal lebih tinggi 0,5C dari oral sedangkan temperatur aksilaris lebih rendah 0,5C.Perubahan temperatur dapat mempengaruhi fungsi selular karena kecepatan metabolisme sel bergantung pada temperatur. Dikatakan fever jika temperatur meningkat dari 1 - 4 C.

Mekanisme Hilangnya Panas dan Mekanisme Produksi PanasHilangnya panas dapat melalui 4 mekanisme :RadiasiEvaporasiKonduksiKonveksiProduksi panas dihasilkan oleh metabolisme sel dan selanjutnya harus dibuang untuk mencegah kelebihan panas dalam tubuh.Jika suhu tubuh turun maka panas diproduksi melalui reflex fisiologis (gemetar) dan respon behavioral (jumping in place).

MEKANISME TERMOREGULASI ThermoreceptorsHypothalamusSweatglandsDermalarteriolesSweat atSkin surfaceCerebralcortexDermalBlood flowShiveringBehavioralresponses

PATOGENESIS FEVERTrauma/Ischemic injuryInflammationInfectionEndogenouspyrogenSet point elevationFeverExogenouspyrogen

EXOGENOUS PYROGENSEndotoxin (LPS)VirusBakteriJamurSubstansi toksik seperti : bahan kimia dan obat-obatan.

Endogenous PyrogensIL-1 (Interleukin-1)TNF (Tumor Necrosis Factor)IFN (Interferon)MIP-1 (Macrophage Inflammatory Protein)IL-6

Endogenous pyrogen dihasilkan oleh sel fagositik (PMN, limfosit dan makrofag).

Rangkuman Mekanisme FeverInfections, toxins, immune complexes, neoplasiaIL-1/TNFIL-6HypothalamusProstaglandins E, NO, cytokines (IL-1)Vasomotor centerSympathetic nervesSkin vasocontrictionHeat dissipation Fever

PAINPain is an unpleasant sensory and emotional experience associated with actual or potential tissue damagePain is frequently the result of nociception, activity in the nervous system that results from the stimulation of nociceptors (pain-detecting neurons).

Classification of PainPain can be acute or chronic.Acute PainAcute pain usually is caused by soft tissue damage, infection and/or inflammation. Acute pain serves to alert after an injury or malfunction of the body.Chronic PainChronic pain may have no apparent cause or may be caused by a developing illness or imbalance. Duration of chronic pain is lasted 6 months or longer. The failure to treat acute pain properly may lead to chronic pain in some cases.

Sources of PainCutaneous painSomatic painVisceral painPhantom limb painNeuropathic pain

Physiology of NociceptionNociception is the system that carries signals of damage and pain from the tissues.Nociceptors can detect mechanical, thermal and chemical stimuli.There are two ways for nociceptive information to reach the central nervous system :Neospinothalamic pain pathwaysPaleospinothalamic pain pathways

Neospinothalamic pain pathwaysType of fibers : A delta fibers [small and myelinated fibers that conduct their action potentials relatively quickly (5 to 30 m/sec)].They are distributed only to the skin, mucous membranes, and selected serous membranes.They tend to fire immediately upon (intense) stimulation and cease firing when the stimulus is removed, producing the sensation of sharp pain.

B. Paleospinothalamic pain pathways

Pain fibers : C fibers (smaller than A delta in diameter, unmyelinated, and conducted impuls 0,5 2 m/sec).They are distributed to the same areas as the A delta fibers, but with much greater density. They are very widely distributed in deep tissue : in muscle and tendon, visceral peritoneum and the visceral organs themselves (myocardium, stomach, intestines). Action potentials in these fibers tend to be generated by substances that are associated with tissue damage or insult.C fibers carry information related to long-lasting, burning, often called dull pain, which is poorly localized and more diffusely distressing.

A delta nociceptors(sharp pain)C nociceptors(dull pain)Dorsal horninterneuronsNeospinothalamicpathwayPaleospinothalamicpathwayHigher perceptioncentersAcute Sharp painChronicDull painThe General Scheme for Underlying Perception of The Two Types of Pain

Pain Pathway