Mediator AntagonistsMediator Antagonists

Chapter 12Chapter 12

Mechanisms of Mechanisms of inflammation in asthmainflammation in asthma

Types of asthmaTypes of asthma

1.1. Extrinsic dependent on allergiesExtrinsic dependent on allergies

2.2. Intrinsic shows no sensitization to Intrinsic shows no sensitization to allergensallergens

With both forms airway inflammation is With both forms airway inflammation is evident causing bronchoconstriction, evident causing bronchoconstriction, airway swelling, mucus secretion and airway swelling, mucus secretion and obstructionobstruction

Allergic responseAllergic response

Primarily involves mast cells and Primarily involves mast cells and immunoglobin Eimmunoglobin E

Lymphocytes (T cells) activated by an Lymphocytes (T cells) activated by an antigen result in the production of IgEantigen result in the production of IgE

IgE binds to mast cellsIgE binds to mast cells Releases mediators of inflammation Releases mediators of inflammation

such as prostaglandins, leukotrienes, such as prostaglandins, leukotrienes, histamine, platelet aggregating factor, histamine, platelet aggregating factor, and cytokinesand cytokines

Allergic response Allergic response

Mediators from mast cell cause Mediators from mast cell cause vascular leakage, vascular leakage, bronchoconstriction, mucus bronchoconstriction, mucus secretion, and mucosal swellingsecretion, and mucosal swelling

Once initiated the inflammatory Once initiated the inflammatory response causes the release of response causes the release of eosinophils, neutrophils, and eosinophils, neutrophils, and lymphocytes which increase the lymphocytes which increase the severity of the inflammationseverity of the inflammation

Disodium Disodium cromoglycate/Cromolyn cromoglycate/Cromolyn

sodiumsodium Comes from the seeds of a plant Ammi Comes from the seeds of a plant Ammi

visagnavisagna Extract of khellin taken from here-Extract of khellin taken from here-

originally used to treat colicoriginally used to treat colic Prophylactic agent to prevent asthmatic Prophylactic agent to prevent asthmatic

reactionsreactions Not related to any other drug category Not related to any other drug category

such as beta agonists, xanthines, or such as beta agonists, xanthines, or glucocorticoidsglucocorticoids

Indications for useIndications for use

Prophylactic management of asthmaProphylactic management of asthma Prevention of exercise induced Prevention of exercise induced

asthmaasthma For allergic rhinitisFor allergic rhinitis Extrinsic asthmaExtrinsic asthma

Mode of actionMode of action

Prevents mast cell degranulationPrevents mast cell degranulation Blocks release of chemical mediatorsBlocks release of chemical mediators Must be used as a pretreatmentMust be used as a pretreatment May work by preventing calcium from May work by preventing calcium from

allowing the contraction of the filaments allowing the contraction of the filaments on the mast cell which release the on the mast cell which release the mediatorsmediators

Does not work as an antagonist on the Does not work as an antagonist on the mediators themselvesmediators themselves

Does not affect alpha or beta receptorsDoes not affect alpha or beta receptors

Mode of action cont.Mode of action cont.

Does not prevent antibody formation, Does not prevent antibody formation, the attachment of IgE, and the the attachment of IgE, and the combination of antibody-antigen combination of antibody-antigen reactions-only prevents the release reactions-only prevents the release of the mediatorsof the mediators

Dosage and administrationDosage and administration

Spinhaler (dry powder inhaler)-can Spinhaler (dry powder inhaler)-can be irritating and cause coughing or be irritating and cause coughing or bronchoconstriction. May need beta bronchoconstriction. May need beta 2 agonist prior to or after tx.2 agonist prior to or after tx.

Ampule for nebulization (20 mg/2ml). Ampule for nebulization (20 mg/2ml). Brand names Aarane or Intal Brand names Aarane or Intal

MDIMDI Nasal solution(Nasalcrom)Nasal solution(Nasalcrom)

Side EffectsSide Effects

Safe drugSafe drug Dry powder causes throat irritation, Dry powder causes throat irritation,

hoarseness, dry mouthhoarseness, dry mouth Nebulizers associated with cough, Nebulizers associated with cough,

wheezing, sneezingwheezing, sneezing

Clinical ApplicationsClinical Applications

Drug is only prophylactic and should Drug is only prophylactic and should not be used during acute not be used during acute bronchospasm. No bronchodilating bronchospasm. No bronchodilating action.action.

No affect on the adrenal system and No affect on the adrenal system and can’t be used as replacement for can’t be used as replacement for corticosteroidscorticosteroids

May take 2 to 4 weeks for May take 2 to 4 weeks for improvement in patient’s symptomsimprovement in patient’s symptoms

Nedocromil sodium (Tilade)Nedocromil sodium (Tilade)

Cromolyn sodium type drugCromolyn sodium type drug Prophylactic therapy for asthma Prophylactic therapy for asthma

managementmanagement Inhibits mast cell mediator releaseInhibits mast cell mediator release Can inhibit eosinophil activityCan inhibit eosinophil activity

LeukotrienesLeukotrienes

Production from leukocytes.Production from leukocytes. Release of leukotrienes during Release of leukotrienes during

inflammatory reaction causes inflammatory reaction causes narrowed airways, excessive mucus narrowed airways, excessive mucus production, airway inflammationproduction, airway inflammation

Role of leukotrienes in Role of leukotrienes in asthmaasthma

Leukotrienes originally called SRSALeukotrienes originally called SRSA Released by inflammatory cellsReleased by inflammatory cells Directly contract airway smooth muscleDirectly contract airway smooth muscle 1000 x more potent than histamine in 1000 x more potent than histamine in

causing bronchial contraction and the causing bronchial contraction and the contraction lasts longercontraction lasts longer

Also stimulate hypersecretion of mucusAlso stimulate hypersecretion of mucus

LeukotrienesLeukotrienes

Also stimulate vascular permeability Also stimulate vascular permeability which causes airway swellingwhich causes airway swelling

Antileukotriene therapyAntileukotriene therapy

Inhibit the production and block the Inhibit the production and block the action of leukotrienesaction of leukotrienes

Two main classes: leukotriene Two main classes: leukotriene synthesis inhibitors and leukotriene synthesis inhibitors and leukotriene receptor antagonistsreceptor antagonists

Pharmacologic agentsPharmacologic agents

Montelukast (singulair)Montelukast (singulair) Leukotriene receptor antagonistLeukotriene receptor antagonist Blocks leukotrienes at receptor siteBlocks leukotrienes at receptor site Improves airway obstruction, may Improves airway obstruction, may

keep episodes from worsening in keep episodes from worsening in chronic asthmachronic asthma

Pharmacologic agentsPharmacologic agents

Zafirlukast (Accolate)Zafirlukast (Accolate) Receptor antagonist used in the tx of Receptor antagonist used in the tx of

chronic asthmachronic asthma Inhibits bronchoconstriction.Inhibits bronchoconstriction.

Pharmacologic agents Pharmacologic agents

Zileuton (Zyflo)Inhibits formation of Zileuton (Zyflo)Inhibits formation of leukotrienesleukotrienes

Inhibits bronchoconstriction caused Inhibits bronchoconstriction caused by various allergensby various allergens

Side effectsSide effects

Accolate(Zafirlukast)-headache, Accolate(Zafirlukast)-headache, nausea, diarrhea, abdominal pain, nausea, diarrhea, abdominal pain, infectioninfection

Zileuton(Zyflo)-headache, abdominal Zileuton(Zyflo)-headache, abdominal pain, loss of strength, stomach upsetpain, loss of strength, stomach upset

Montelukast(Singulair)- does not Montelukast(Singulair)- does not have these side effectshave these side effects