The pharmacology of type I hypersensitivity Immune system Module

Types of hypersensitivity : Type I reaction: Type I reaction: Mechanism: IgE-mediated noncytotoxic mediator release from basophilic leukocytes and tissue mast cells. Mechanism: IgE-mediated noncytotoxic 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. 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 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. 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. Antibody -dependent cytotoxic type. Mechanism: Complement-mediated injury involving antibodies (IgM and IgG) and any cell with isoantigen. Mechanism: Complement-mediated injury involving 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. 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 : Examples : RH hemolytic disease of the newborn Thrombocytopenia: may occur after exposure to heparin. RH hemolytic disease of the newborn Thrombocytopenia: may occur after exposure to heparin. Aplastic anemia: chloramphenicol, sulphonamide. Aplastic anemia: chloramphenicol, sulphonamide.

Type III reactions: Mechanism: Immune complex initiated by soluble antigen-antibody complexes (mainly IgG). i.e. (A-AB complex formation). 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. Leucocytes attracted to the site of reaction engulf the complex and release active substances including lysosomal enzymes  inflammatory process. Examples : Examples : Serum sickness occurs 1-3 weeks after administration, Lupus nephritis, Drug fever, Some glomerulonephritis Serum sickness occurs 1-3 weeks after administration, Lupus nephritis, Drug fever, Some glomerulonephritis

Type IV reactions: "Delayed" or cellular hypersensitivity (lymphocyte-mediated type). "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. 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. Treated by glucocorticoids +`adrenaline+`antihistaminic. Examples: Contact dermatitis. Examples: Contact dermatitis. Tuberculin hypersensitivity Tuberculin hypersensitivity allograft rejection. allograft rejection.

Drug treatment of hypersensitivity reactions 1-Antihistaminics. 1-Antihistaminics. 2- Corticosteroids. 2- Corticosteroids. 3-Adrenoceptor agonists e.g.epinephrine. 3-Adrenoceptor agonists e.g.epinephrine.

I-H 1 antihistaminics These drugs do not affect synthesis or release of histamine;rather,they block H 1 receptors of the target tissue. These drugs do not affect synthesis or release of histamine;rather,they block H 1 receptors of the target tissue. They are classified into two generations: They are classified into two generations: First generation: First generation: effective but less specific;have additional effetcs on cholinergic,adrenergic or serotonin receptors(cause variety of adverse effects). effective but less specific;have additional effetcs on cholinergic,adrenergic or serotonin receptors(cause variety of adverse effects). Penetrate CNS and cause sedation. Penetrate CNS and cause sedation.

Examples:chlorpheniramine,diphenhyd ramine,diamenhydrinate & promethazine. Second generation: Second generation: specific for H 1 receptors, can not pass CNS thus, cause less sedation than first generation. specific for H 1 receptors, can not pass CNS thus, cause less sedation than first generation. Loratadine,desloratadine and fexofenadine show the least sedation(non sedating). Loratadine,desloratadine and fexofenadine show the least sedation(non sedating).

Mechanism of anti-allergic activity of H 1 antihistaminics: By blocking H 1 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. By blocking H 1 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. 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. 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. 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, blurred vision and tremors.They are not indicated for persns who must remain alerts e.g.drivers. 1- Sedation :Other CNS effects are incorordination, 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. 2- Dry mouth,urinary retention & sinus tachycardia: due to anticholinergic activity of these drugs. 3-Hypotension,dizzness & reflex tachycardia:due to α- adrenergic receptors. 3-Hypotension,dizzness & reflex tachycardia:due to α- adrenergic receptors. 4-Increased appetite (action on serotonin receptors). 4-Increased appetite (action on serotonin receptors). 5-Drug interactions: CNS depressants increase their CNS adverse effects.MAOIs potentiate their anticholinergic effects. 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. 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. 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. 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. They can be applied topically or systemically.

Adverse effects : The most common adverse effects of long term therapy is osteoporosis (supplement with Ca ++ and vitamin D). The most common adverse effects of long term therapy is osteoporosis (supplement with Ca ++ and vitamin D). Cushing syndrome with high dose of corticosteroids. Cushing syndrome with high dose of corticosteroids. Diabetes,hypertension,salt and water retention & hypokalemia. Diabetes,hypertension,salt and water retention & hypokalemia. Cataract,glaucoma,depression,euphoria,and even psychosis. Cataract,glaucoma,depression,euphoria,and even psychosis. Increase acid and enzyme secretion(contraindicated in peptic ulcer). Increase acid and enzyme secretion(contraindicated in peptic ulcer). Abrupt withdrawal of these drugs causes acute adrenal insufficiency syndrome which may be fatal. Abrupt withdrawal of these drugs causes acute adrenal insufficiency syndrome which may be fatal.

III-Adrenergic agonists: Anaphylactic shock and related immediate (type I) 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. Anaphylactic shock and related immediate (type I) 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, β 1, and β 2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. It is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine because epinephrine activates α, β 1, 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. 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. Combination of these drugs with antihistaminics are frequently used for this condition. 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 They should not be used more than few days because of rebound congestion that occures on discontinuation of these drugs