Mekanisme Kerja Zat Toksik

Nendyah Roestijawati
31 Mei 2013
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, cell-
mediated 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-A eosinophil chaemotaxis
NCF-A neutrophil 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 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 hypersensivity
Slow, max 4-8hrs
Pigeon 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 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
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