Bronchodilators

Inflammatory mediators released by activated mast cells

NC Hwang 2008

symptoms of overdose tachycardia, dose-related beta-mediated hypokalaemia and hyperglycaemia, chest pain; dizziness; dry mouth, fatigue, general feeling of discomfort or illness, feeling faint, headache, high or low blood pressure, impaired consciousness, irregular or fast heartbeat, lightheadedness, nausea, nervousness, seizures, sleeplessness, sweating, tremor tachyphylaxis / tolerance loss of bronchoprotective action /down regulation loss in ability to inhibit the response to subsequent challenge with exercise, methacholine, antigen challenge

Asthma therapy bronchodilators (short term relievers) increase airway calibre by relaxing airway smooth muscle resulting in reversal of airway constriction includes sympathomimetic agents (2adrenoceptor agonists, methylxanthine drugs); and antimuscarinic agents anti-inflammatory drugs (long-term controllers) corticosteroids inhibitor of mast cell degranulation leukotriene pathway inhibitors Mechanism of smooth muscle relaxation

hypoxaemia only if the ventilation/perfusion ratio in the lungs worsens supplementary oxygen may be necessary drug interactions -adrenergic blocking agents may block its bronchodilatation effect may decrease the plasma concentration of digoxin taken with non-potassium-sparing diuretics, may worsen salt imbalance in the blood taken with with -agonists and methylxanthines may result in dysrhythmias while taking or within 2 weeks of taking MAO inhibitors or tricyclic antidepressants, levalbuterol may cause a change in blood pressure or pulse rate delivery via inhalational route aerosol deposition depends on particle size the pattern of breathing (tidal volume and rate of airflow) geometry of the airways particle size in optimum size range of 2-5 m, 80-90% of the total dose of aerosol is deposited in the mouth or pharynx under 1-2 m, remain suspended and may be exhaled, deposition can be increased holding the breath after inspiration freon propellants fluorocarbons may sensitise the heart to circulating catecholamines such an effect occurs only at very high myocardial concentrations Adrenaline effective, rapid onset injected subcutaneously 0.3-0.4ml of 1:1000 solution, i.e. 300-400 g (emergency treatment of severe asthma) inhaled as a microaerosol from a pressurised canister effects 2: maximal bronchodilatation in 15 minutes, lasts 60-90 minutes 1: tachycardia, arrhythmias, worsening of angina pectoris

SYMPATHOMIMETIC AGENTS stimulate adenylyl cyclase and catalyse the formation of cAMP in the airway tissues resulting in relaxation of airway smooth muscle inhibit release of bronchoconstrictive substances from mast cells inhibit microvascular leakage increase mucociliary transport by ciliary activity or by affecting the composition of mucous secretion with 1 activity: adrenaline, ephedrine, isoprenaline 2-selective agents : salbutamol, terbutaline, metaproterenol, bitolterol, levalbuterol (R-albuterol) precautions avoid in pregnancy potential to interfere with contractions during labour

Bronchodilators
Ephedrine indirect-acting sympathomimetic agent displacement of noradrenaline from the nerve-ending binding sites to the extracellular fluid, where it then acts at receptor sites of the effector cells substrate for uptake across neuronal membrane into axoplasm, making carrier available on the inner surface of the membrane for the outward transport of noradrenaline (facilitated exchange diffusion) competing for vesicular uptake process compared with adrenaline longer duration oral activity pronounced central effects lower potency Isoprenaline effective, rapid acting bronchodilator inhaled as a microaerosol from a pressurised canister, 80-120 g effects 2: maximal bronchodilatation in 5 minutes, lasts 60-90 minutes 1: tachycardia, arrhythmias, worsening of angina pectoris 2-selective drugs differ structurally from adrenaline in having a large substitution on the amino group the position of the hydroxyl groups on the aromatic ring effective after inhaled or oral administration have a long duration of action and significant 2 activity inhalational route offers greatest local effect on airway smooth muscle with minimal systemic effects

NC Hwang 2008

Terbutaline 15% bioavailability after oral administration 20% bound to plasma protein Vd 1.8 L/kg effective concentration 2.3 ng/ml plasma clearance 3.5 ml/min/kg, increased in pregnancy t is 15 hours 55% excreted unchange in the urine subcutaneous administration (0.25mg) for emergency treatment of severe asthma longer duration of action, cumulative effects may be seen after repeated injections Salmeterol potent 2 agonist developed for increased duration of action (12 hours or more) through increased lipophilicity rather than resistance to metabolism high lipid solubility permits drug to dissolve in smooth muscle cell membrane in high concentration functions as slow release depot, provides drug METHYLXANTHINE DRUGS important ones theophylline (tea), theobromine (cocoa), caffeine (coffee) methylated xanthines xanthine is a dioxypurine, structurally related to uric acid theophylline is the most effective bronchodilator and the theophylline preparation most commonly used for therapy is aminophylline metabolised via demethylation, demethylated xanthines are excreted in the urine

administration metered-dose inhalers 2.5-5mg of salbutamol [(S)-albuterol], or 15mg of metaproterenol diluted in 1-2.5ml of saline/water for delivery from nebuliser to adjacent beta receptors over a long period

mechanism of action inhibition of phosphodiesterase inhibition of cell surface receptors for adenosine receptors modulate adenylyl cyclase activity adenosine has been shown to cause contraction of isolated airway smooth muscle, enhance histamine release from cells in the lungs anti-inflammatory action inhibition of late response to antigenic challenge inhibition of lymphocyte function, especially CD4+ and CD8+ lymphocytes modest reduction in airway mucosal inflammation

Bronchodilators
effects on the central nervous system with low dose, causes mild cortical arousal with increased alertness and deferral of fatigue in sensitive individuals, 100 mg may cause nervousness and insomnia with very high dose, medullary stimulation and convulsions occur tremors and nervousness are primary side effects in patients taking large doses of aminophylline for asthma effects on the cardiovascular system direct positive chronotropic and inotropic effects, sinus tachycardia, increased cardiac output with low doses, peripheral vascular resistance and blood pressure rises, probably through release of catecholamine with large doses, relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction effect on the gastrointestinal tract stimulate secretion of gastric acid and digestive enzymes effects on the kidneys methylxanthine, especially theophylline are weak diuretics increase glomerular filtration and reduced tubular sodium reabsorption effect on airway smooth muscle bronchodilatation, tolerance does not develop inhibit antigen induced release of histamine from lung tissue effect on skeletal muscle potent effects in improving contractility and in reversing fatigue of the diaphragm in patients with obstructive lungs disease, accounts for theophyllines ability to improve the ventilatory response to hypoxaemia and to diminish dyspnoea in patients with irreversible airflow obstruction pharmacokinetics administration base is only slightly water-soluble, administered as salt commonly used salts are aminophylline (86% theophylline), oxtriphylline (64% theophylline) well absorbed from gastrointestinal tract, especially anhydrous formulation, 96% bioavailability absorption via rectal route unreliable distribution distributed to all body compartments, cross the placenta and pass into breast milk protein binding of theophylline about 60%, decreased in elderly and cirrhosis Vd 0.5L/kg metabolism metabolized in the liver by methylation (to caffeine); 8-hydroxylation ; and demethylation followed by oxidation by xanthine oxidase

NC Hwang 2008 reduced in cirrhosis, decreased hepatic blood flow increased following induction of hepatic enzymes by cigarette smoking mean plasma clearance: adult, 0.69 ml/kg/min; children, 1-1.5 ml/kg/min; decreased in prematures, neonates, young infants, cirrhosis, congestive heart failure, hepatitis, hypothyroidism, obesity t of 9 hours in healthy adult 15% of administered theophylline excreted unchanged

adverse effects plasma concentrations <20 mg/L: nervousness, insomnia plasma concentrations >20 mg/L: anorexia, nausea, vomiting, abdominal discomfort, headache, anxiety plasma concentrations >40 mg/L: seizures, arrhythmias ANTIMUSCARINIC AGENTS mechanism of action competitively inhibition in the airways, acetylcholine is released from efferent endings of the vagus nerve, vagal activity causes bronchoconstriction and increase in mucous secretion Atropine sulphate routes of administration intravenously by inhalation, 1mg side effects of nebulised atropine local drying effect in the mouth systemic absorption results in urinary retention, tachycardia, loss of vision accommodation, agitation Ipratropium quaternary ammonium derivative of atropine poorly absorbed via the lungs and does not readily enter the central nervous system maximum response develops over 30-90 minutes, significant effects may persist for more than 4 hours small amount that is absorbed is eliminated from plasma with t of 3 hours CORTICOSTEROIDS mechanism of action potentiates the effects of beta-agonists inhibition of eosinophilic airway mucosal inflammation in asthmatic airways inhibition of production of cytokines, the production of cytokines is believed to be central in the initiation of inflammatory cascade provoked by antigen inhalation and viral infection routes of administration oral and parenteral formulation for urgent treatment, for patients who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy

Bronchodilators
inhalational aerosol most effective way to decrease systemic adverse effects of corticosteroid therapy (adrenal suppression) lipid soluble corticosteroids such as beclomethasone, triamcinolone, flunisolide, and budesonide chronic use effectively reduce bronchial reactivity and improves pulmonary function in patients with mild asthma dose and time dependent, improvement seen after weeks to months adverse effects (with increasing dosages) oral candidiasis hoarseness of voice, dysphonia thinning of skin purpura bone resorption carbohydrate and lipid metabolism hypothalamic-pituitary-adrenal axis suppression LEUKOTRIENE PATHWAY INHIBITORS Leukotrienes protect against aspirin (NSAID) induced asthma, due to inhibition of prostaglandin synthase, shifting arachidonic acid metabolism to the leukotriene pathway exercise induced bronchospasm atopic asthmatic subjects production leukotrienes result from action of 5-lipoxygenase on arachidonic acid and are synthesised by a variety of inflammatory cells (eosinophils, mast cells, macrophages, basophils) in the airways

NC Hwang 2008

types 5-lipoxygenase inhibitor: zileuton, a hydroxyurea, that chelates the active site iron of 5-LP; ZD2138 FLAP (5-lipooxygenase activating protein) antagonist: MK886, MK0591 LTD4 receptor antagonist: tomelukast, zafirlukast, montelukast (Singulair), pobilukast, verlukast, pranlukast adverse effects Zafirlukast: elevation of liver enzymes in patients taking high doses (>80 mg twice daily), dose should be limited to 40mg twics daily INHIBITOR OF MAST CELL DEGRANULATION of value when taken prophylactically stable but insoluble salts, poorly absorbed from gastrointestinal tract, low bioavailability administered as microfine powder or aerosolised solution inhibit both antigen- and exercise-induced asthma reduce overall level of bronchial reactivity no effect on airway smooth muscle tone, ineffective in reversing asthmatic bronchospasm mechanism of action inhibition of early response to antigen inhibition of pulmonary mast cell degranulation in response to a variety of stimuli, including the interaction of allergen with cell-bound IgE inhibition of late response action on eosinophils alteration in the function of delayed chloride channels in the cell membrane reducing the accumulation of intracellular Ca++ induced by antigen in sensitized mast cells, inhibiting cellular activation action on airway nerves inhibition of cough Cromolyn acute pretreatment blocks bronchoconstriction caused by antigen inhalation exercises aspirin causes of occupational asthma chronic use causes a decrease in bronchial hyper-reactivity perhaps by protecting the airway against the inflammatory effects of the chemical mediators of anaphylaxis reduce symptoms of allergic rhinitis administered by inhalation of aerosol spray or nebulizer or powdered drug only 1% of the drug is absorbed systemically, which is then excreted unchanged in the urine and bile in about equal proportions peak concentrations in plasma occur within 15 minutes of inhalation t of 45-100 minutes after inhalation, about 20 minutes following intravenous injections

LTB4 is a potent neutrophil chemoattractant LTC4 and LTD4 cause bronchoconstriction, increased bronchial reactivity, mucosal oedema, mucus hypersecretion

Bronchodilators
adverse effects localized to the sites of deposition throat irritation bronchospasm, wheezing cough laryngeal oedema mouth dryness chest tightness systemic reversible dermatitis myositis gastroenteritis pulmonary infiltration with eosinophilia anaphylaxis

NC Hwang 2008

ANTI-IGE MONOCLONAL ANTIBODIES rhuMAb-E25 a recombinant humanized monoclonal antibody developed by immunizing mice with human IgE targeted against the portion of IgE that binds to its receptors (FC-R1 and -R2) on the mast cells and other inflammatory cells does not activate IgE already bound to mast cells and does not provoke mast cell degranulation prolonged administration lowers plasma IgE and significantly reduced the magnitude of both early and late bronchospastic responses to antigen challenge