DRUG TREATMENT OF ASTHMA Asrar B. Malik, Ph.D

Transcription

1 DRUG TREATMENT OF ASTHMA Asrar B. Malik, Ph.D DRUGS USEFUL IN ASTHMA LEARNING OBJECTIVES 1. Know the working definitions of asthma and basic pathology of the disease. 2. Understand the role of various cell types and mediators in the pathogenesis of asthma. 3. Be familiar with autonomic innervation of the lung as it relates to asthma. 4. Know the rationale for the use of β-agonist therapy and its associated side effects. 5. Know the therapeutic actions of cromolyn and the rationale for its use. 6. Understand the rationale for the current trends in the use of corticosteroids for the treatment of asthma, and know the frequently used steroid analogs. 7. Understand the therapeutic actions and precautions in the use of theophylline and its analogs for the treatment of asthma. DRUG LIST SUBCLASS PROTOTYPE ANALOGS sympathomimetic epinephrine metaproterenol albuterol terbutaline salmeterol mast cell stabilizer cromolyn sodium nedocromil Na corticosteroid prednisone beclomethasone triamcinolone xanthine caffeine theophylline enprophylline aminophylline ASTHMA: Asthma is described as "the presence of prevalent narrowing of airways, which alters in severity either spontaneously or in response to treatment and which is characterized by increased Page 1 of 14

2 responsiveness of the trachea and bronchi to provocative stimuli". The basic abnormality of asthma is recognized to be increased excitability of smooth muscle or BHR (bronchial hyperresponsiveness, defined below). However, asthma cannot be defined in terms of BHR alone because: 1. BHR in response to bronchial constrictors is found in some subjects without symptoms of asthma 2. asthma can be induced by allergens in subjects who do not show BHR to bronchial constrictors Thus, the classical definition of asthma is not ideal; it avoids the assignment of a unique pathogenesis and pathology, and it fails to explain the different types of asthma. Accordingly, the definition of asthma is being refined as new information about its etiology becomes available. Working definitions: Asthma Atopy The presence of intermittent symptoms such as chest tightness, wheeze, and cough, together with demonstrable BHR. Production of IgE antibodies in response to aeroallergens (type I response). BHR (Bronchial Hyperresponsiveness) A 20% decrease in FEV 1 (Forced Expiratory Volume in I second) in response to a provoking factor that causes less than a 5% decrease in normal subjects (at the same dose); or a 20% increase in FEV 1 in response to an inhaled bronchodilating drug. (In asthmatics, the FEV 1 response to histamine or methacholine is 10- to 100-fold greater than normal subjects.) Early and Late Asthmatic Responses! Early: airway narrowing within 15 minutes after exposure to precipitating agent or episode; usually reverses in 30 to 60 minutes.! Late: occurs 4-8 hours later; may or may not follow early response (usually in occupational asthma). Page 2 of 14

3 Classifications of Asthma Extrinsic : Intrinsic: Occupational: asthma occurring in an atopic patient; can result in acute attacks; e.g. pollen asthma, exercise-induced asthma. no evidence of atopy; often begins in adults; can be chronic in nature. occurs with exposure to provoking agents at the workplace; symptoms usually lessen upon withdrawal from agent. Pathology of asthma: Bronchial wall in asthma (diagrammatic). Note the hypertrophied, contracted smooth muscle, edema, mucous gland hypertrophy, and secretion in lumen. General: 1. overinflated lungs that do not deflate upon pneumothorax 2. widespread mucous plugging of airways 3. no emphysematous changes Microscopic: 1. airway smooth muscle hypertrophy 2. bronchial mucosal edema 3. infiltration with eosinophils 4. desquamation of airway epithelium Page 3 of 14

4 Cells of Airway in Asthma 1. Bronchial smooth muscle: 1. abnormal in severe asthmatics 2. contractile response is supra-normal; relaxation is abnormal 2. Mediator-releasing cells: a. mast cells: 1. found on entire length of airway epithelium 2. cell numbers increased in asthmatics 3. in allergic asthma, release mediators at lower doses of secretagogues b. basophils: 1. involved in late phase of allergic reactions 2. in asthmatics, circulating basophils are hyperresponsive to histamine secretagogues 3. Mononuclear cells: Page 4 of 14

5 a. Macrophages: 1. scavengers in airways and alveoli; process antigens for presentation to lymphocytes 2. stimulate mediator release from mast cells b. Lymphocytes: 1. B-lymphocytes hypersecrete IgE (atopy) 2. T-helper cells make mast cell secretagogues (e.g. IL-3, eosinophil activating, and chemotactic factors) 4. Vascular endothelial cells: a. airway edema results from protein and fluid leakage from microvasculature b. endothelial cells contract in response to histamine, leukotrienes, and substance P 5. Eosinophils: a. infiltrate airways in asthma in response to mast cell-derived chemotactic factors b. release tissue-damaging proteins involved in the epithelial shedding; e.g. Major Basic Protein (MBP). 6. Airway epithelial cells: a. produce mediators; e.g. 5-HETE, LTB4, PGE 2 b. frequently shed in asthma as result of leukocyte adherence and transmigration c. epithelial shedding and increased epithelial permeability involved in development of bronchial hyperresponsiveness; tracheal segments devoid of epithelium show increased responsiveness to bronchoconstrictors (see figure 10-1 below) Figure Influence of airway epitheliuin (EP) on smooth muscle responses. Contractile response of bovine tracheal smooth muscle to histamine with (EP +) or without (EP -). Each point is the mean (+/-SEM) of ten observations. (Reprinted with permission from Barnes, P. J., Cuss, F. M. C., Palmer, J. B. D.: The effect of airway epithelium on smooth muscle contractility in bovine trachea (Br. J. Pharmacol. 86: , 1995) Page 5 of 14

6 7. Mucous-secreting cells (goblet cells, mucous glands): a. mucous plugging is common b. mucous secretion stimulated by cholinergic agonists and mast cell mediators 8. Role of mediators in asthma: a. histamine: 1. bronchoconstrictor 2. vasodilator 3. potently released in diseases in which BHR is not found; thus it is not likely that histamine solely causes BHR b. eosinophil chemotactic factor (ECF): 1. involved in development of BHR through damage to airway epithelium by eosinophil-derived MBP (see above) 2. released after allergic and exercise challenge c. "newly generated factors": 1. traditional term for prostaglandins and leukotrienes 2. important in asthma Summary of Basic Mechanisms Underlying Asthma 1. Intrinsic Asthma (lower pathway) a. T-lymphocytes are activated directly by allergens, then secrete lymphokines b. lymphokines activate eosinophils, which secrete mediators and damaging proteins c. mediators potentiate inflammation and damage epithelium, enhancing BHR d. important in chronic form of asthma Page 6 of 14

7 2. Extrinsic Asthma (upper pathway) a. allergens (or other stimuli) directly activate mast cells and/or eosinophils through surface-bound IgE b. released mediators elicits bronchoconstriction and can lead to chronic symptoms as well c. involved in severe acute attacks Autonomic Nervous System in Asthma Autonomic control of human airways 1. Beta-adrenergic system a. No direct sympathetic nerve supply to bronchial smooth muscle in humans b. $2-adrenoceptors are found along the bronchial tree on bronchial smooth muscle; agonists cause relaxation of BSM and bronchodilation c. Asthmatics rely on circulating catecholamines for $2-receptor stimulation (lower levels at night are associated with decreased lung function) d. $2-adrenoceptors are altered asthmatics in that long-term use of $-agonists does not desensitize the $-receptors as it does in normal or atopic subjects e. Asthmatics respond well to $-receptor agonists; if given by aerosol, bronchial responsiveness becomes normal for a short period 2. Alpha adrenergic system a. Role in asthma poorly understood b. In asthmatics stimulation may cause bronchoconstriction c. Agonists stimulate mediator release from mast cells 3. Cholinergic system Page 7 of 14

8 a. Innervates bronchial smooth muscle and mucous glands throughout airways b. Dominant constrictor mechanism in airways; also stimulates mucous secretion c. No evidence of altered cholinergic receptors in asthma In asthmatics, the afferent side of the cholinergic reflex is active due to changes in the exposure or sensitivity of the bronchial sensory nerve endings. This leads to reflex contraction of bronchial smooth muscle and mucous secretion. The idea supported by the ability of cholinergic blockers to protect some patients against allergen-or exercise-induced asthma. THERAPEUTIC TREATMENT OF ASTHMA There are two basic approaches in treatment of asthma: 1. interruption of function of inflammatory cells and mediator-releasing cells: 2. taking advantage of neural control of airway function. Systemically delivered drugs formed the basis for asthma therapy. Now the use of aerosols has increased: Aerosols: 1. provide high local dose (thus minimize side effects) 2. protect against provoking agents (systemically delivered drugs do not) β2 ADRENOCEPTOR AGONISTS Epinephrine has been used in the treatment of asthma since the beginning of the century; dessicated adrenal gland was given to asthmatics because it was believed to decrease airway swelling in the same way that it could blanch the skin. Since the bronchodilation is mediated through β2-receptors and the cardiac effects are mediated through βl-receptors, selective β2-agonists such as albuterol and terbutaline were introduced in the l960's. Salmeterol was introduced recently. Therapeutic actions of β2-agonists: 1. relax contracted bronchial smooth muscle 2. prevent bronchial smooth muscle contraction by various stimuli 3. increase mucous clearance 4. prevent mast cell mediator release 5. prevent edema induced by histamine, etc. by preventing increase in endothelial permeability Choice of drugs: 1. epinephrine Page 8 of 14

9 Delivery: a. not a good choice for asthma b. lacks $ 2 -receptor selectivity; $1-mediated cardiac effects c. short duration of action due to rapid uptake and metabolism d. its α-agonist activity is bronchoconstrictive 2. metaproterenol a. moderately selective β-agonist b. not a substrate for COMT; thus, longer duration of action c. given by inhalation 3. β2 -selective agonists (albuterol, terbutaline, salmeterol) a.. effective in bronchodilation, but no cardiac effects b. longer duration of action; not substrates for COMT c. available by inhalation and orally; similar duration of action (3-4 hrs) d. salmeterol is a nearly pure β2-selective, the others mostly β2 e. in general terbutaline: orally; albuterol: inhalation; salmeterol: inhalation but it is ONLY for prophylaxis because of slow onset and long t 1/2 1. by aerosol: a. good protection against provokers including allergens, exercise, histamine, and methacholine (mild to moderately severe asthma only) b. severe asthma: aerosol alone may not protect against all provokers, and inhaled cromolyn or corticosteroids may also be necessary (see below) c. often used in conjunction with other drugs; e.g. to promote better delivery of cromolyn or corticosteroids to the distal airways. 2. systemically: Side Effects: a. available orally and for injection b. weak therapeutic effects only; side effects greater c. use only if aerosol administration is excluded d. exception: sustained release forms useful for nocturnal asthma 1. due to extrapulmonary $2-receptors: dose-related and unusual with inhalation 2. muscle tremor due to skeletal muscle $-receptors 3. Tachycardia and palpitations due to reflex cardiac stimulation secondary to peripheral vasodilation, direct stimulation of atrial $1 receptors, and possible direct stimulation of myocardial $1 receptors 4. tolerance to side effects after prolonged use 5. metabolic effects: increased FFA, glucose, lactate after large systemic doses 6. hypokalemia (due to stimulation of K + entry into skeletal muscle) Page 9 of 14

10 7. V/Q mismatching due to pulmonary vasodilation 8. asthmatics do not develop tolerance to $2-agonists as normal subjects Traditionally, there has been a reluctance to use $2 agonists resulting from the mistaken impression that they have severe side effects. However, these are minimized at the relatively low doses delivered by metered dose inhalers. Clinical uses 1. the most widely used and effective bronchodilators 2. inhalers easy to use; effects are rapid and side effects are few 3. also protect against exercise-, cold air-and allergen indued asthma 4. bronchodilator of choice for acute asthma if used in nebulizer SODIUM CROMOGLYCATE (cromolyn sodium) Cromolyn sodium has been used in the U.S. for treatment of asthma since Therapeutic Actions: primarily prophylactic 1. when administered before challenge, it inhibits the response to: a. exercise b. allergens c. cold air 2. in long-term treatment: a. prevents early and late responses to allergens b. decreases bronchial responsiveness Mechanism of Action 1. mast cell stabilization a. inhibition of degranulation by a variety of stimuli, including cell-bound IgEallergen interactions b. inhibition of leukotriene production c. above actions due to blockage of calcium influx into mast cells 2. other cells a. suppresses release of chemoattractant peptides that recruit eosinophils, neutrophils, or monocytes b. reverses elevated receptor expression on leukocytes of asthmatic patients undergoing allergen challenge 3. no bronchodilator or antihistamine activity Page 10 of 14

11 Delivery Less than 1% of an oral dose of cromolyn is absorbed, so therapeutic effects are achieved through local administration via inhalation: Toxicity Uses 1. in 4% solution - by aerosol spray or nebulizer 2. powdered drug - as capsules to use in powered turbo-inhaler or as a metered dose inhaler 1. generally well-tolerated 2. infrequent adverse reactions: bronchospasm, cough, laryngeal edema, joint swelling or pain, headache rash, nausea 3. very rarely - anaphylaxis Prophylaxis of mild to moderate asthma, especially allergic asthma. Often administered in conjunction with an inhaled $2-agonist; e.g. albuterol, to ensure better access of cromolyn to the distal airways. Also used in allergic rhinitis. Nedocromil Sodium: has the same mechanism of action and uses as does cromolyn. There is no clinical difference. CORTICOSTEROIDS Systemic administration of corticosteroids has formed the basis for treatment of severe chronic or acute asthma since the 1950s. The side effects of systemically administered steroids are severe; however, recent development of aerosol forms has led to the re-evaluation of the therapeutic role of systemic administration in asthma. The most commonly used analogs by aerosol administration include: 1. beclomethasone dipropionate 2. availability: nasal spray inhaler 3. triamcinolone acetonide Mechanisms of action due to anti-inflammatory properties 1. reduces number and activity of inflammatory cells in airways 2. inhibits release of arachidonic acid metabolites 3. prevents increased vascular permeability 4. suppresses IgE binding 5. increases β-adrenergic responsiveness Page 11 of 14

12 Delivery 1. aerosol a. low- and high-dose forms b. few serious side effects c. favored for treatments lasting more than two weeks 2. oral or IV a. traditional route, especially when high doses required b. may not provide drug concentration sufficient to reach airway mucosa c. serious side effects have led to development of inhaled forms d. use for the shortest possible duration! e. for severe episodes: prednisone Goal: use lowest possible dose and use concurrently with β2-agonist therapy or oral theophylline (see below). Side Effects of inhaled preparations Clinical uses 1. dysphonia 2. oropharyngeal candidiasis 3. both can be reduced by mouth rinsing with water after administration and through use of appropriate spacers with the inhaler to avoid oral deposition. 1. for severe episodes 2. for prophylaxis (no acute beneficial effect) 3. little effect on early response, but will suppress late response to allergen challenge 4. indicated for patients who respond inadequately to cromolyn THEOPHYLLINE The bronchodilating effect of strong coffee was originally described by Hyde Salter during the last century. Methylxanthines have been used for treatment of asthma since Several derivatives are available, but none appear to be better than theophylline, though enprofylline (3-propylxanthine) may be more potent. Many xanthine salts are available; the most common, aminophylline, has increased solubility at neutral ph, rendering it useful for intravenous administration. Other salts have little advantage over aminophylline. Major therapeutic actions 1. relaxes bronchial smooth muscle 2. decreases mast cell mediator release Page 12 of 14

13 3. increases mucocilliary clearance 4. prevents microvascular leakiness Mechanisms of action 1. inhibition of phosphodiesterases a. increase intracellular camp 2. adenosine receptor antagonism a. adenosine causes bronchoconstriction in asthmatics b. bronchoconstriction prevented by theophylline at therapeutic concentrations c. however, enprofylline has no effect on adenosine-mediated bronchoconstriction 3. other a. increased epinephrine secretion form adrenal medulla; increase small and cannot account for the bronchodilation b. antagonizes some prostaglandins in smooth muscle Administration 1. Ineffective by inhalation; requires build-up of effective plasma concentration 2. Intravenous; for severe acute asthma only 3. Orally, (not recommended) tablets or elixir give wide fluctuations in plasma levels; however, sustained release preps can achieve a steady plasma concentration over 24 hr and are good for nocturnal asthma. A single dose of a slow-release preparation is often effective. Avoid mixtures of theophylline and β agonists or sedatives. Pharmacokinetics Dosage required to achieve an effective blood concentration varies considerably because of clearance factors: 1. theophylline is rapidly and completely absorbed 2. large differences in clearance rates due to hepatic metabolism by P450 system; factors affecting this include: increased clearance -induction of P450 by: rifampicin, phenobarbitone childhood high protein, low carbohydrate decreased clearance -reduced P450 by : cimetidine, erythromycin, allopurinol congestive heart failure pneumonia 3. dosage should be individualized; plasma levels should be measured after dosing with slow-release preps until steady-state is achieved. Page 13 of 14

14 Side effects Significant when plasma concentration reaches 20 mg/ml or higher low concentrations: headache, restlessness, increased acid secretion, diuresis high concentrations: convulsions, cardiac arrythmias in some patients CNS stimulation, possibly from adenosine receptor antagonism enprophylline has no adenosine receptor; antagonism at bronchodilating doses control side effects: initial dose should be light, rising slowly until the therapeutic plasma level is reached Clinical Uses theophylline: reverses bronchoconstriction in asthmatics, but is less potent than $-agonists drug of choice for nocturnal asthma since slow-release preps are more effective than slow-release $2-agonist preps theophylline and $2-agonists: have additive effects on bronchodilation, so if $2-agonist therapy alone does not offer relief, theophylline can be added to the regimen Page 14 of 14