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Transcript
The pharmacology of type I
hypersensitivity
Immune system Module
Types of hypersensitivity :
• Type I reaction:
• Mechanism: IgE-mediated noncytotoxic
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mediator release from basophilic leukocytes and
tissue mast cells.
The drug causes formation of tissue-sensitising IgE
antibodies that are fixed to mast cells or
leucocytes.
On subsequent administration of drug complex
activates and release the active substances e.g.
histamine, leuckotrienes, prostaglandins, PAF
Examples : Anaphylactic shock, Urticaria, Extrinsic
asthma and allergic rhinitis.Aspirin and other
NSAID drugs may cause an asthmatic attack.
Type II reactions
• Antibody -dependent cytotoxic type.
• Mechanism: Complement-mediated injury involving
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antibodies (IgM and IgG) and any cell with
isoantigen.
The drug or metabolite combines with a protein in
the body, so the body treat it as a foreign protein
and forms (IgM and IgG) that combine with
antigen and activate complement which damage
cells.
Examples :
RH hemolytic disease of the newborn
Thrombocytopenia: may occur after exposure to
heparin.
Aplastic anemia: chloramphenicol, sulphonamide.
Type III reactions:
• Mechanism: Immune complex initiated by
soluble antigen-antibody complexes (mainly
IgG). i.e. (A-AB complex formation).
• Leucocytes attracted to the site of reaction
engulf the complex and release active
substances including lysosomal enzymes
inflammatory process.
• Examples :
• Serum sickness occurs 1-3 weeks after
administration, Lupus nephritis, Drug fever,
Some glomerulonephritis
Type IV reactions:
• "Delayed" or cellular hypersensitivity
(lymphocyte-mediated type).
• Mechanism:Antigen-specific receptors develop
on T-lymphocytes ; on subsequent
administration → Local or tissue allergic
reaction e.g. contact dermatitis.
• Treated by glucocorticoids
+`adrenaline+`antihistaminic.
• Examples: Contact dermatitis.
• Tuberculin hypersensitivity
• allograft rejection.
Drug treatment of hypersensitivity
reactions
• 1-Antihistaminics.
• 2- Corticosteroids.
• 3-Adrenoceptor agonists e.g.epinephrine.
I-H1 antihistaminics
• These drugs do not affect synthesis or release
of histamine;rather,they block H1 receptors of
the target tissue.
• They are classified into two generations:
• First generation:
• effective but less specific;have additional
effetcs on cholinergic,adrenergic or serotonin
receptors(cause variety of adverse effects).
• Penetrate CNS and cause sedation.
Examples:chlorpheniramine,diphenhyd
ramine,diamenhydrinate &
promethazine.
• Second generation:
• specific for H1 receptors, can not pass
CNS thus, cause less sedation than first
generation.
• Loratadine,desloratadine and
fexofenadine show the least
sedation(non sedating).
Mechanism of anti-allergic activity of H1
antihistaminics:
• By blocking H1 receptors,these drugs are useful
in treating allergies caused by antigens acting
on IgE antibody- sensitized mast cells where
histamine is the principal mediator e.g.allergic
rhinitis and urticaria.
• They are ineffective in treating bronchial
asthma because histamine is one of several
mediators for asthma.
Other therapeutic uses:
• 1-motion sickness &nausea:
diphnhydramine,diaminhydrinate&
meclizine arethe most effective against
motion sickness.The antiemetic action is
independent to their antihistaminic or
other actions.
• 2- Insomnia: as they have strong sedative
properties e.g.diphenhydramine The use
of first generation is contraindictated in
where wakefulness is critical.
Adverse effects: first generation members
have low specificity and affect other receptors
• 1- Sedation :Other CNS effects are incorordination,
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blurred vision and tremors.They are not indicated for
persns who must remain alerts e.g.drivers.
2- Dry mouth,urinary retention & sinus tachycardia:
due to anticholinergic activity of these drugs.
3-Hypotension,dizzness & reflex tachycardia:due to αadrenergic receptors.
4-Increased appetite (action on serotonin receptors).
5-Drug interactions: CNS depressants increase their
CNS adverse effects.MAOIs potentiate their
anticholinergic effects.
II-Corticosteroids
• Glucocorticoids show greater anti-inflammatory
effects than antihistaminics.
• They are beneficial in treatment of the
symptoms of bronchial asthma,allargic
rhinitis,and drug, serum, and transfusion
allergic reactions.Yet, they are not curative .
• Mechanism of action as anti-allergic drugs: they
interfere in mast cell degranulation(i.e.mast cell
stabilizers), thus, decrease histamine release
and capillary permeability.
• They can be applied topically or systemically.
Adverse effects :
• The most common adverse effects of long term
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therapy is osteoporosis (supplement with Ca++ and
vitamin D) .
Cushing syndrome with high dose of corticosteroids.
Diabetes,hypertension,salt and water retention &
hypokalemia.
Cataract,glaucoma,depression,euphoria,and even
psychosis.
Increase acid and enzyme secretion(contraindicated in
peptic ulcer).
Abrupt withdrawal of these drugs causes acute
adrenal insufficiency syndrome which may be fatal.
III-Adrenergic agonists:
• Anaphylactic shock and related immediate (type I)
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IgE-mediated reactions affect both the respiratory and
the cardiovascular systems. This usually respond
rapidly to the parenteral administration of
epinephrine. Epinephrine is the physiological
antagonist of histamine on smooth muscles,and it acts
on different receptors.
It is the drug of choice in treating systemic
anaphylaxis and other conditions that involve massive
release of histamine because epinephrine activates α,
β1, and β 2 receptors, all of which may be important in
reversing the pathophysiologic processes underlying
anaphylaxis.
Glucocorticoids and antihistamines may be useful as
secondary therapy in anaphylaxis; however,
epinephrine is the initial treatment.
They act as mast cell stabilizers in bronchial
asthma.
- α-adrenergic agonists(e.g.phenylephrine) are
used topically or systemically for treatment of
allergic rhinitis.
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• Combination of these drugs with antihistaminics
are frequently used for this condition.
• They should not be used more than few days
because of rebound congestion that occures on
discontinuation of these drugs