Mekanisme Kerja Zat Toksik

General Classification
Chemical allergies Idiosyncratic reactions Immediate vs delayed effects Reversible vs irreversible Local vs sistemic

Chemical Interactions
Potentiation Additive Synergistic Antagonistic

Chemical allergies
Type I antibody-mediated reactions Type II antibody-mediated cytotoxic reactions Type III immune complex reactions Type IV delayed-type hypersensitivity, cellmediated immunity

Type I
Sensitization 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 contraction Serotonin vascular permeability, sm contraction ECF-Aeosinophil chaemotaxis NCF-Aneutrophil chaemotaxis, proteases mucus secretion, connective tissue degradation

Mediators
Secondary mediators Leukotrienes vascular permeability, sm contraction Prostaglandins vasodilation, sm contraction, platelet activation Bradykinin vascular permeability, sm contraction Cytokines 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 antigenantibody 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 hypersensivity Slow, max 4-8hrs Pigeon fanciers lung

Type IV
Intradermal or mucosal challenge CD4+ Tcells 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

IgE-mediated hypersensitivity

2-30 mins

Ag 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

5-8hrs

Ab 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

24-72hrs

Memory 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 toxicity Sedatives-hypnotics immediate Carcinogens delayed

Reversible vs Irreversible
The effects of most drugs or chemicals are reversible until a critical point is reached Reversibility of chemicals effect may be enacted through 1. Administration of antagonist 2. Enhancement of metabolism or elimination 3. Delaying absorption 4. Intervening with another toxicological procedure that decrease toxic blood concentration 5. terminating of the exposure

Local vs systemic
Depend on site of exposure Skin or lungs are frequent targets of chemical exposure Oral exposure systemic effect Hypersensivity 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 = 4 Combination 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 > 3 Combinations 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 Re-uptake of noradrenalin and serotonin into the respective neurones

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 estrogeninduced breast cancer