Mekanisme Kerja Zat ToksikNendyah Roestijawati31 Mei 2013

General ClassificationChemical allergiesIdiosyncratic reactionsImmediate vs delayed effectsReversible vs irreversibleLocal vs sistemic

Chemical InteractionsPotentiationAdditiveSynergisticAntagonistic

Chemical allergiesType I antibody-mediated reactionsType II antibody-mediated cytotoxic reactionsType III immune complex reactionsType IV delayed-type hypersensitivity, cell-mediated immunity

Type ISensitization phase : triggered by contact with unrecognized antigen binding of the antigen to immunoglobulin E present on the surface of mast cells and basophilesActivation phase : follows after an additional dermal or mucosal challenge with the same antigen degranulation of mast cell and basophils with subsequent release of histamine and other soluble mediators

Type IEffector phase : accumulation of preformed and newly synthesized chemical mediators that precipitate local and systemic effectsDegranulation of neutrophils and eosinophils completes the late-phase cellular response

Mediators Primary mediators Histamine Vascular permeability, sm contractionSerotonin vascular permeability, sm contractionECF-A eosinophil chaemotaxisNCF-A neutrophil chaemotaxis, proteases mucus secretion, connective tissue degradation

MediatorsSecondary mediatorsLeukotrienes vascular permeability, sm contractionProstaglandins vasodilation, sm contraction, platelet activationBradykinin vascular permeability, sm contractionCytokines numerous effects inc. activation of vascular endothelium, eosinophil recruitment and activation

Type IIDiffer from type I in the nature of antigen, the cytotoxic character of the antigen-antibody reaction, and the type of antibody form (IgM or IgG)Antibodies are formed against target antigens that are altered cell membrane determinantsComplement-mediated reactions (CM), antibody-dependent cell mediated cytotoxicity (ADCC), antibody mediated cellular dysfunction (AMCD), transfusions reactions, Rh incompatibility reactions, autoimmune reactions, and drug induced reactions

Type IIILocalized response mediated by antigen-antibody immune complexesStimulated by microorganism and involve activation of complement trigger release of cytokines and recruitment of granulocytes increased vascular permeability and tissue necrosisPost-infection complications such as arthritis and glomerulonephritis.

Arthus reactionLocal type III hypersensivitySlow, max 4-8hrsPigeon fanciers lung

Type IVIntradermal or mucosal challenge CD4+ T-cells recognize MHC II (major histocompatibility class-II) antigens on antigen-presenting cells (Langerhans cell) differentiate to Th1 cellsSensitization phase requires prolonged local contact at least two weeksRepeat challenge induced Th1 cells release cytokines stimulating attraction phagocytic monocytes and granulocytes release lysosomal enzymes local tissue necrosisPlant resins, jewelry

TYPEDESCRIPTIVEINITIATIONMECHANISMEXAMPLESNAMETIMEIIgE-mediated hypersensitivity2-30 minsAg induces cross-linking of IgE bound to mast cells with release of vasoactive mediatorsSystemic anaphylaxis, Local anaphylaxis, Hay fever, Asthma, EczemaIIAntibody-mediated cytotoxic hypersensitivity5-8hrsAb directed against cell-surface antigens mediates cell destruction via ADCC or complementBlood transfusion reactions, Haemolytic disease of the newborn, Autoimmune Haemolytic anaemiaIIIImmune-complex mediated hypersensitivity2-8hrsAg-Ab complexes deposited at various sites induces mast cell degranulation via FcgammaRIII, PMN degranulation damages tissueArthus reaction (Localised); Systemic reactions disseminated rash, arthritis, glomerulonephritisIVcell-mediated hypersensitivity24-72hrsMemory TH1 cells release cytokines that recruit and activate macrophagesContact dermatitis, Tubercular lesions

Idiosyncratic ReactionsAbnormal responses to drugs or chemicals resulting from uncommon genetic predispositionSuccinylcholine deficiency in plasma cholinesterase reduction in the rate of SC deactivation respiration fail to return to normal during postoperative period

Immediate vs Delayed EffectsDepending on the mechanism of toxicitySedatives-hypnotics immediateCarcinogens delayed

Reversible vs Irreversible The effects of most drugs or chemicals are reversible until a critical point is reachedReversibility of chemicals effect may be enacted through 1. Administration of antagonist2. Enhancement of metabolism or elimination3. Delaying absorption4. Intervening with another toxicological procedure that decrease toxic blood concentration 5. Terminating of the exposure

Local vs systemicDepend on site of exposureSkin or lungs are frequent targets of chemical exposureOral exposure systemic effectHypersensivity types I and IV precipitated by local activation of immune response following a sensitization phaseDrug-induced type II elicited through oral or parenteral administration

Potentiation The toxic effect of one chemical is enhanced in the presence of toxicologically unrelated agentA relatively nontoxic chemical alone has little or no effect (0), may enhance the toxicity of another co administered chemical (2) 0 + 2 > 2Hepatotoxicity of carbon tetrachloride is greatly increased in the presence of isopropanol

Additive Two or more chemicals whose combined effects are equal to the sum of the individual effects2 + 2 = 4Combination of sedative-hypnotics and ethanol (drowsiness, respiratory depression)

Synergistic By definition, synergistic effect is indistinguishable from potentiation, except in some references, both chemicals must have cytotoxic activity1 + 2 > 3Combinations of ethanol and antihistamine

Antagonistic The opposing actions of two or more chemical agents, not necessarily administered simultaneouslyType :1. Functional antagonism2. Chemical antagonism3. Dispositional antagonism4. Receptor antagonism

Functional antagonismThe opposing physiological effects of chemicalCNS stimulants vs depressants

Chemical antagonismDrugs or chemicals that bind to, inactivate, or neutralize target compoundsChelators in metal poisoning

Dispositional antagonismInterference of one agent with the ADME of another Activated charcoal, Phenobarbital, diuretics

Receptor antagonismThe occupation of pharmalogical receptors by competitive or noncompetitive agentsTamoxifen in the prevention of estrogen-induced breast cancer