Mekanisme Kerja Zat ToksikNendyah Roestijawati

31 Mei 2013

General Classification

Chemical allergiesIdiosyncratic reactionsImmediate vs delayed effectsReversible vs irreversibleLocal vs sistemic

Chemical Interactions

PotentiationAdditiveSynergisticAntagonistic

Chemical allergies

Type 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 basophiles

Activation 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 I

Effector phase : accumulation of preformed and newly synthesized chemical mediators that precipitate local and systemic effects

Degranulation 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

Mediators

Secondary 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 II

Differ 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 determinants

Complement-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 III

Localized response mediated by antigen-antibody immune complexes

Stimulated by microorganism and involve activation of complement trigger release of cytokines and recruitment of granulocytes increased vascular permeability and tissue necrosis

Post-infection complications such as arthritis and glomerulonephritis.

Arthus reaction

Local type III hypersensivitySlow, max 4-8hrsPigeon fanciers lung

Type IV

Intradermal or mucosal challenge CD4+ T-cells recognize MHC II (major histocompatibility class-II) antigens on antigen-presenting cells (Langerhans cell) differentiate to Th1 cells

Sensitization phase requires prolonged local contact at least two weeks

Repeat challenge induced Th1 cells release cytokines stimulating attraction phagocytic monocytes and granulocytes release lysosomal enzymes local tissue necrosis

Plant resins, jewelry

TYPE DESCRIPTIVE INITIATION MECHANISM EXAMPLES

  NAME TIME    

I IgE-mediated hypersensitivity 2-30 minsAg induces cross-linking of IgE bound to mast cells with release of vasoactive mediators

Systemic anaphylaxis, Local anaphylaxis, Hay fever, Asthma, Eczema

II Antibody-mediated cytotoxic hypersensitivity 5-8hrsAb directed against cell-surface antigens mediates cell destruction via ADCC or complement

Blood transfusion reactions, Haemolytic disease of the newborn, Autoimmune Haemolytic anaemia

III Immune-complex mediated hypersensitivity 2-8hrs

Ag-Ab complexes deposited at various sites induces mast cell degranulation via FcgammaRIII, PMN degranulation damages tissue

Arthus reaction (Localised); Systemic reactions disseminated rash, arthritis, glomerulonephritis

IV cell-mediated hypersensitivity 24-72hrsMemory TH1 cells release cytokines that recruit and activate macrophages

Contact dermatitis, Tubercular lesions

Idiosyncratic Reactions

Abnormal responses to drugs or chemicals resulting from uncommon genetic predisposition

Succinylcholine deficiency in plasma cholinesterase reduction in the rate of SC deactivation respiration fail to return to normal during postoperative period

Immediate vs Delayed Effects

Depending 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 systemic

Depend 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 phase

Drug-induced type II elicited through oral or parenteral administration

Potentiation

The toxic effect of one chemical is enhanced in the presence of toxicologically unrelated agent

A relatively nontoxic chemical alone has little or no effect (0), may enhance the toxicity of another co administered chemical (2) 0 + 2 > 2

Hepatotoxicity 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 effects

2 + 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 activity

1 + 2 > 3Combinations of ethanol and

antihistamine

Antagonistic

The opposing actions of two or more chemical agents, not necessarily administered simultaneously

Type :

1. Functional antagonism

2. Chemical antagonism

3. Dispositional antagonism

4. Receptor antagonism

Functional antagonism

The opposing physiological effects of chemical

CNS stimulants vs depressants

Chemical antagonism

Drugs or chemicals that bind to, inactivate, or neutralize target compounds

Chelators in metal poisoning

Dispositional antagonism

Interference of one agent with the ADME of another

Activated charcoal, Phenobarbital, diuretics

Receptor antagonism

The occupation of pharmalogical receptors by competitive or noncompetitive agents

Tamoxifen in the prevention of estrogen-induced breast cancer