Pharmacology of AsthmaAZL & YSP

Dept. Pharmacology & Therapeutic, School of MedicineUniversitas Sumatera UtaraMei 2008, KBK, Respirasi, FK USU, Medan

Pathophysiology of AsthmaAirway inflammationCytokines Bronchial hyper-responsivenessHipersensitifity type 1AlergenAntibodi (IgE)Mast cellMediators (Histamin, Lekotrien, etc)Slow phaseAirflow limitation

Pathologic FindingsBronchoconstrictionHyperinflation of the lungsHyperplasia of the smooth muscle surrounding the bronchial and bronchiolar wallsThickening of the basement membraneMucosal edemaDesJardin, T, Burton, G: Clinical Manifestations and Assessment of Respiratory Disease. St. Louis, Mosby, 1995

Chemicals Involved in InflammationIgE HistamineTryptase Leukotrienes (LTC4)Platelet activating factor (PAF)Prostaglandins (PGD2)

Interleukins (IL-4, IL-5)Granulocyte-macrophage colony stimulating factor (GM-CSF)Tumor Necrosis Factor (TNF)Major Basic Proteases (MBP) Eosinophil Cationic Protein (ECP)

Patho-physio-pharmacology of AsthmaBarnes PJ

Asthma componentsHealthy airwayAsthmatic airwaySmooth muscleEpitheliumAveolar septumSmooth musclecontractionEpithelial shedding / damageInflammation and oedemaMucus and plasma exudationBarnes PJ

General Goals of Asthma TherapyRelief airways tightening / bronchoconstriction immediately.Education of asthma management.

Prevent chronic symptoms and asthma exacerbations during the day and nightMaintain normal activity levelsHave normal or near-normal lung functionHave no or minimal side effects while receiving optimal medications

Intervention in AsthmaInducersTriggersInflammationeosinophilsECPAirwaysHyper-responsivenessExercise induced asthma SymptomsCough, chest tightnessWheeze, dyspneaAirways obstructionAvoidanceof allergens, infectionsInhaled corticosteroids2 agonist bronchodilators

General Pharmacologic Approach to the Treatment of AsthmaRelievers Short-acting bronchodilators2-adrenergic agentsAnti-cholinergic (Parasympatholytic) agents

Controllers CorticosteroidsLong-Acting bronchodilators2-adrenergic agentsMethylxanthines Cromolyn sodiumLeukotriene inhibitorsAnti-IgE monoclonal antibodies

Relievers

Historical PerspectiveDatura stramonium (1802)Epinephrine (1903)Ephedrine (1926)Isoproterenol (1940)Isoetharine (1951)Metaproterenol (1961)Beta2-adrenergic agents via MDI (1973)Ipratropium bromide (1987)Salmeterol (1994)Levalbuterol (1999)

Patho-Physio-Pharmacology of Bronchodilators

Adrenergic Bronchodilators Short-Acting AgentsCatecholaminesEpinephrineIsoproterenolIsoetharineResorcinol agentsMetaproterenolSaligenin agentsSalbutamolPirbuterolBitolterol

b-AgonistsMechanism of Action -relax smooth muscle within the airways, causing bronchodilation. Short ActingSalbutamol (Various Brands)Levalbuterol (Xopenex)Biltolterol (Tornalate)Pirbuterol (Maxair)Isoproternol (Medihaler-Iso)Metaproternol (Alupent)Terbutaline (Brethaire)Long ActingSalmeterol (Serevent)Formoterol (Foradil)

Classification of agonists2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in 2 selectivity. The selectivity of 2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure. agonists are generally divided into short (4-6 h) and long (>12 h) acting agents.

Beta AgonistsShort actingGeneric nameDuration of action2-selectivitySalbutamol4-6 h+++Levalbuterol8 h+++Metaproterenol4-6 h++Isoproterenol3-4 h++Epinephrine2-3 h-Long actingSalmeterol12+ h+++Formoterol12+ h+++

Beta-2 Adrenergic Agonists Short acting agentsMode of administrationInhaled/ParenteralModes of actionRelax airway smooth muscleEnhance mucociliary clearanceDecrease vascular permeabilityMay modulate mediator release from mast cells and basophils

Role in therapyMedication of choice for treatment of acute exacerbations of asthma and useful in the pretreatment of exercise-induced bronchospasm (EIB)Used to control episodic bronchoconstrictionIncreased used or even daily use of these agents is a warning of deterioration of asthma and indicates the need to institute or to intensify regular anti-inflammatory therapy.Beta-2 Adrenergic Agonists Short acting agents

Side EffectsTremorPapitations and tachycardiaHeadacheInsomniaRise in blood pressureNervousnessDizzinessNausea

Beta-2 Adrenergic Agonists Short acting agents

SalbutamolMainstay of Therapy for Many YearsCharacteristicsDosing every 4-6 hoursDosage FormsMDI (HFA), Unit Dose Vials for Nebulizers, Oral Solutions, Oral TabletsAdvantages- quick action, rescue therapySide Effects/ProblemsThe most common side effects are heart palpitations, irregular, rapid heartbeat, anxiety, and increased blood pressure.

Anticholinergic BronchodilatorsTertiary Ammonium CompoundsAtropine sulfateScopalamineQuaternary Ammonium CompoundsIpratropiumTiotropium

Anticholinergic BronchodilatorsMode of administrationInhaledMechanisms of actionBlock the effects of acetylcholine released from cholinergic nerves in the airways (i.e., reduce intrinsic vagal cholinergic tone to the airways).Block reflex bronchoconstriction caused by inhaled irritantsThey do not diminish the early and late allergic reactions and have no effect on airway inflammation.Less potent bronchodilators than inhaled beta-2 agonists, and in general, have a slower onset of action (30-60 min to maximum action).

Anticholinergic BronchodilatorsRole in therapyAdditive effect when nebulized together with a rapid-acting beta-2 agonist for exacerbations of asthmaIt is recognized that Ipratropium can be used an alternative bronchodilator for patients who experience adverse effects such as tachycardia, arrhythmias, and tremors from beta-2 agonists.Side effectsDryness of the mouth and bitter taste

Controllers

ControllersCorticosteroidsLong-Acting bronchodilators2-adrenergic agentsMethylxanthines Cromolyn sodium/NedrocromilLeukotriene inhibitorsAnti-IgE monoclonal antibodies

CorticosteroidsInhaled Glucocorticoids BeclomethasoneFlunisolideFluticasoneTriamcinoloneBudesonide, and MometasoneSystemic GlucocorticoidsPrednisoneMethylprednisolonePrednisoloneDexamethasone

Inhaled GlucocorticoidsMechanisms of actionReduces pathologic signs of airway inflammation mediated in part by inhibition of production of inflammatory cytokinesAirway hyperresponsiveness continues to improve with prolonged treatmentRole in therapyMost effective anti-inflammatory medication for the treatment of asthma

Inhaled GlucocorticoidsSide effectsLocal adverse effects include oropharyngeal candidiasis, dysphonia, and occasional coughing from upper airway irritation.Because there is some systemic absorption, the risks of systemic adverse effects will depend on the dose and potency of the Glucocorticoids as well as its bioavailability, absorption in the gut, metabolism by the liver, and the half-life of its systemically absorbed fraction.Contraindication:hypersensitivity, nasal infection and haemorrhage, candidiasis orofaring, and patient with recurrent epistaxis.

Inhaled GlucocorticoidsBeclomethasone dipropionateDosage: 200-1000gBudesonideDosage: 200-800gFlunisolide500-2000gFluticasone100-500gTriamcinolone acetonide400-2000g

Systemic GlucocorticoidsMode of administrationOralParenteralMechanisms of actionSame as for inhaled Glucocorticoids however systemic Glucocorticoids may reach different target cells than inhaled drugsRole in therapyLong-term oral Glucocorticoids therapy (daily or alternate-day) may be required to control severe persistent asthma.

Systemic Glucocorticoids side effectsOsteoporosisArterial hypertensionDiabetesHypothalamic-pituitary axis suppressionCataractsGlaucomaObesitySkin thinning leading to cutaneous striaeEasy bruisingMuscle weaknessFatal herpes virus infections have been reported among patients who are exposed to these viruses when they are taking systemic Glucocorticoids

Adrenergic Bronchodilators Long-Acting AgentsSustained-released salbutamolSalmeterolFormoterol

Modes of administrationInhaledOralMechanisms of actionSame as short-acting beta-2 agonistsEffects persists for at least 12 hours

Adrenergic Bronchodilators Long-Acting Agents

Role in therapyLong-acting inhaled beta-2 agonists should be considered when standard introductory doses of inhaled Glucocorticoids fail to achieve control of asthma before raising the dose of inhaled Glucocorticoids.Because long-term treatment with these agents does not appear to influence the persistent inflammatory changes in asthma, this therapy should be combined with inhaled GlucocorticoidsFluticosone propionate salmeterol and bedesonide-formoterol inhalers (Advair)Adrenergic Bronchodilators Long-Acting Agents

Side effectsInhaled beta-2 agonists cause fewer systemic adverse effect (e.g., cardiovascular stimulation, skeletal muscle tremors, and hypokalemia) than oral therapy particularly if the oral regimen includes theophylline. Adrenergic Bronchodilators Long-Acting Agents

SalmeterolDosing - every 12 hoursDosage Forms MDI, Discus (powder), combination with steroidAdvantages long acting, less tolerance to effects than salbutamol- decreases need to increase corticosteroid dose Side Effects/ProblemsSlow onset of effectHeadache, tremor, palpitations, and nervousness are the most frequent side effects.

FormoterolDosing every 12 hoursDosage Forms aerosolized powderSimilar to Spinhaler (drug in gelatin capsule)Advantageshas both a rapid-onset bronchodilator is long-acting but not as a rescue medicineSide Effects/ProblemsThe most common side effects are headache, palpitations, and tremor. Less common side effects include agitation, restlessness, sleep disturbance, muscle cramps, and increased heart rate

Naturally Occurring Agents Caffeine (Coffee and kola beans; tea leaves)Theophylline (Tea leaves)Theobromine (Cocoa seeds or beans)Synthetic DerivativesDyphyllineProxyphyllineEnprophyllineXanthine Agents

Methylxanthines Mode of administrationOral or ParenteralMechanisms of actionThe bronchodilator effect may be related to phosphodiesterase inhibition (>10mg/L); anti-inflammatory effect is due to an unknown mechanism and may occur at lower concentrations (5-10mg/L). This latter mechanism may involve the inhibition of cell surface receptors for adenosine, which modulate adenylyl cyclase activity (contraction of isolated smooth muscle and to provoke histamine release from mast cells.Most studies show little or no effect on airway hyperresponsivenessRole in therapySustained release theophylline is effective in controlling asthma symptoms and improving lung function (i.e., nocturnal symptoms; may be used as an add-on therapy to low or high doses of glucocorticoids)

Methylxanthines Side effects (serum concentrations > 15g/mL)*Gastrointestinal symptoms nausea, vomitingCNS SeizuresCardiovascular tachycardia, arrhythmiasPulmonary stimulation of the respiratory center

*Monitoring theophylline levels is advised when high-dose therapy (>10mg/kg body weight is used or when a patient develops an adverse effect on the usual dosage

Mast Cell Stabilizing AgentsMechanism of Action:inhibit the activation of mast cells within the airway, thereby preventing release of mediators that provoke asthma symptoms. alter the function of delayed chloride channels in the cell membraneconsidered by some as a type of NSAID. Used for preventing asthma attackAdvantages:As the prophylaxis of asthma attack caused by allergen, exercise, aspirin, and working.Used for long term medicationDisadvantages:Using dosage four times a dayExpensiveLess effectivity than inhaled corticosteroidside effects: throat iritation, cough, dry mouth, and bad taste of tongue.

Cromolyn & NedocromilDosing QIDDosage Forms MDI or Nebulized solution (Cromolyn)Advantages - alternative to steroids/b-agonistsSide Effects/ProblemsDaily dosing required (works prophylactically)Cromolyn (throat irritation or dryness, wheezing, nausea, coughing, and a bad taste in the mouth).Nedocromil (bad taste, nausea, abdominal pain, and vomiting).

Leukotriene modifiers Zafirlukast, Montelukast, and ZileutonA relatively new class of anti-asthma drugs that include cysteinyl leukotriene 1 (CysL T1) receptor antagonists (montelukast, zafirlukast) and 5-lipoxeygenase inhibitor (zileuton)

Leukotriene modifiersMode of administrationOralUsing dosage four times a day (Zileuton)Mechanism of actionReceptor antagonists block the CysLT1 receptors on airway smooth muscle and thus inhibit the effects of cysteinyl leukotrienes that are release from mast cells and eosinophils 5-lipoxygenase inhibitors block synthesis of leukotrienes.

Leukotriene modifiersRole in therapyThese agents have a small and variable bronchodilator effect, reduce symptoms, improve lung function, and reduce asthma exacerbations.Effect of these drugs is less than that of low-doses of inhaled glucocorticoids. There is evidence that the use of these drugs as an add-on may reduce the dose of inhaled glucocorticoid required by patients with moderate to severe asthma.Note that leukotriene modifiers are less effective than long-acting inhaled beta-2 agonists as an add-on therapy.

Leukotriene modifiersSide effectsThese drugs are usually well tolerated, and few if any class-related effects have been recognized.Zileuton has been associated with liver toxicity and monitoring liver test is recommendedThere are several reports of Churg-Strauss syndrome associated with the leukotriene modifier therapy (typically associated with a reduction of systemic glucocorticoids)Contraindication:patients with coronary heart disease, and cardiac arrhythmias.

IgE Antibody OmalizumabUsed as intravenous or intramuscular anti-asthma.diminishing the production of IgE through effects on interleukin 4 or on IgE itself have been evaluatedSoluble recombinant IL-4 receptor that can be delivered by aerosolRecombinant human monoclonal antibody that forms complexes with free IgE (rhuMAb or omalizumab blocks the interaction of IgE with mast cells and basophils.Attenuates the early-phase and late phase airway obstruction response to allergen and suppressed the accumulation of eosinophils in the airwaysAdvantages:- Decreasing the degrees of asthma- Reducing the used of corticosteroid- Repaired nasal symptoms for patients with allergic rhinitis.Disadvantage: very expensive

Routes of AdministrationInhaledMetered dose inhalers (MDI)SpacersDry powder inhalers (DPI)Nebulized (wet) aerosolsOralParenteralSubcutaneousIntramuscularIntravenous

Pharmacokinetics of anti-asthmaInhalerSub-cutaneVenaportaeBloodflowUrineMembranemucousOralExcretion

Is there an advantage to using a nebulizer, as opposed to an MDI, for delivery of medications for the treatment of asthma?

Studies comparing Nebulizers to MDIs with SpacersChou KJ, et al. Metered-Dose Inhalers with Spacers vs Nebulizers for Pediatric Asthma. Arch Ped Adol Med 149:201-5,1995. Nebulized beta-agonist therapy had been the standard of care for patients with acute asthma exacerbations. Several studies in adults, however, have found metered dose inhaler (MDI) administration to be as effective. Use of the MDI instead of nebulizer administration would be economically beneficial and easier for both patients and clinicians.

(MDI+ spacer) vs Nebulizer

Are antihistamines useful in the prophylaxis and/or treatment of asthma?

Clin Exp Allergy. 29 Suppl 3:98-104,1999.Effectiveness of H1 antagonists in adults with seasonal asthma

Conclusions of Analysessevere persistent asthma no significant clinical effect moderate persistent asthma clinical benefits of H1 antagonists are apparent but require higher-than-usual doses and are not worth the risk to patientmild seasonal asthma and allergic rhinitis coexistantsignificant improvement in asthma symptoms at usual dosing Clin Exp Allergy. 29 Suppl 3:98-104,1999.

Key PointsShort-acting beta2-agonists: Therapy of choice for relief of acute symptoms and prevention of EIB.Anticholinergics: May provide some additive benefit to inhaled beta2-agonists in severe exacerbations. May be an alternative for patients who do not tolerate inhaled beta2-agonists.Systemic corticosteroids: Used for moderate-to-severe exacerbations to speed and prevent recurrence of exacerbations.

Key PointsCorticosteroids: Most potent and effective anti-inflammatory medication currently availableCromolyn sodium and nedrocromil: Mild-to-moderate anti-inflammatory medication.Leukotriene inhibitors: May be considered an alternative therapy to low dose inhaled corticosteroids or cromolyn sodium or nedrocromil for patients >12 years of age with mild persistent asthma.

Key PointsLong-acting beta2-agonists: These drugs are typically used concurrently with anti-inflammatory medications for long-term control of symptoms, especially nocturnal symptoms.Methylxanthines: Sustained release theophylline is a mild-to-moderate bronchodilator used principally as an adjuvant to inhaled corticosteroids for prevention of nocturnal asthma symptoms.

Treatment Protocols

EtiologyGenetic factors AtopyEnvironmental factorsVirusesAllergensOccupational exposure

Factors that Influence Asthma Development and ExpressionHost FactorsGeneticAtopyAirway hyperresponsiveness GenderObesityEnvironmental Factors Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections Diet

Factors that Exacerbate AsthmaAllergensRespiratory infectionsExercise and hyperventilationWeather changesSulfur dioxideFood, additives, drugs

Major Cells Implicated in Inflammatory ResponseMast cellsan important cell type in the asthmatic lung. These cells produce numerous mediators that contribute to the development of asthma, including: histamine, cysteinyl leukotrienes, tryptase, tumor necrosis factor-alpha, prostaglandin D2, and cytokines including IL4, IL-5 and IL-13 LymphocytesEosinophilsNeutrophils

Inflammatory processesBarnes PJ

Classification of Asthma Severity:Clinical Features Before Treatment

SeverityDays with SymptomsNights with SymptomsPEF or FEV1.0Severe PersistentContinualFrequent 60%Moderate PersistentDaily 5/month> 60% < 80%Mild Persistent3-6/ week3-4/month 80%Mild Intermittent 2/week 2/month 80%

IgE Antibodies

Busse, WW, Lemanske, RF: NEJM 344:350-362, 2001

*Slide 10Asthma is a complex disease involving many different cellsCurrent thinking on the pathophysiology of asthma regards it as a specific type of inflammatorycondition, involving, in particular, mast cells, eosinophils and T lymphocytes, which releasea wide range of inflammatory mediatorsThese mediators act on cells in the airway, leading to contraction of smooth muscle, oedemadue to plasma leakage and mucus plugging, all of which contribute to the narrowing ofthe airwaysActivation of the sensory nerves in the airway wall is thought to be an important factorin triggering episodes of coughing *Slide 11In addition to constriction (narrowing) of the airways, asthma is also associated with specificinflammatory changes. These inflammatory processes include exudation of mucus and plasma,oedema and shedding of the damaged epitheliumNarrowing of the airways in asthma is produced by a combination of smooth musclecontraction, thickening of the airway wall, oedema and mucus in the airway lumen***Slide 12In the early stages of asthma, inflammatory processes, such as infiltration of the airway wallwith white blood cells, disruption of the epithelium and mucus plugging of the airway lumen,are thought to be potentially reversible with effective anti-inflammatory treatmentChronic uncontrolled or poorly controlled asthma is associated with a variety of structuralchanges in the airway wall, which in turn leads to a progressive reduction in the reversibilityof the airway obstruction in response to a bronchodilatorStructural changes, such as thickening of the basement membrane, hyperplasia of the mucusglands and hypertrophy of the airway smooth muscle ultimately progress to the developmentof irreversible fibrosis (remodelling)