Asthma and COPD Lecture Notes PDF

Asthma and chronic obstructive pulmonary disease (COPD) Eng Wee Chua In this lecture, we’re going to talk about the treatments of asthma and COPD....

Asthma and chronic obstructive pulmonary disease (COPD) Eng Wee Chua In this lecture, we’re going to talk about the treatments of asthma and COPD. 1  Learning outcomes At the end of this lecture, you should be able to:  Select a suitable device, based on its characteristics, for delivering a topical drug.  Describe the mechanisms of action, pharmacokinetic attributes, and adverse effects of the drugs used to treat asthma and COPD.  Relate their mechanisms to the pathophysiology of asthma and COPD. 2  Introduction: Pulmonary pharmacology  Asthma and COPD: among the most common chronic diseases.  Both cause chronic inflammation of the airways.  BUT the underlying inflammatory mechanisms are different, so they respond differently to therapy. First, let’s put things into context and talk a bit about the pathophysiology of asthma and COPD. They are among the most common chronic diseases. Both cause chronic inflammation of the airways – kind of their key feature. BUT the underlying inflammatory mechanisms are different, so they respond differently to therapy. So, for instance, some drugs are more effective against asthma than COPD, and vice versa. 3  Asthma You can see here that a variety of inflammatory cells are culpable of the airway hypersensitivity seen in asthma. I’m not going to cover the mechanism in detail; but I just want to point out here that asthma is more like an allergic reaction. Two key types of cells commonly associated with allergy are mast cells and eosinophils. As you will see later, all this is quite different from what’s going on in COPD. 4  COPD Unlike asthma, COPD is more of a disease caused by irritants that eventually cause destruction of the airways. You can see here that the cell types involved are quite different from asthma, where neutrophils seem to play a key role, releasing proteases that wreak havoc on the airways. So, overall, we can conclude that the inflammation in asthma is eosinophilic, while that in COPD is neutrophilic. Again, because of this and other differences, the management of COPD is quite different from that of asthma. 5  Inhalation is the preferred route because of several advantages. Once inside the lungs, a drug: may act directly on the target cells. may get distributed into more peripheral airways. may get metabolised. may largely get retained in the airways. In the treatments of asthma and COPD, inhalation is the preferred mode of drug delivery because of relatively low risks of adverse effects. However, the inhalation route is not as efficient as you might think it is. Of the total drug delivered by a metered-dose inhaler, only 10-20% ends up in the lower airways – I would say this proportion is quite low. The rest gets absorbed through the gut and is subjected to first-pass metabolism before it enters the systemic circulation. So, it’s important to teach a patient how to use an inhaler properly to optimise the delivery of the drug. Inside the lungs, the fate of the inhaled drug is poorly understood. The drug may act directly on the target cells to exert its therapeutic effects; it may get distributed into more peripheral airways; it may get converted into more active metabolites; if it has a large molecular weight, it may get retained in the airways. 6  Delivery devices Spacer Dry powder Some (dis)advantages of chambers inhalers (DPI) these devices: MDI: May be difficult to use. Spacer: Pressurised Reduces the amount of metered- Nebulisers drug inhaled deposited in dose the oropharynx. inhalers Easier to use. (MDI) DPI: Easier to use than an MDI. The powder can be an irritant. Oral route Parenteral route May not be suitable for children MDI Further reading: Shirmanesh YK, Jones MD. Physical ability of people with rheumatoid arthritis and age-sex matched controls to use four commonly prescribed inhaler devices. Respir Med. 2018;135:12-14. A breath-actuated inhaler would be easier to use than a pMDI, as no coordination between breathing and actuation is needed. The usage instructions are simple. The patient only has to: 1) Breathe out; 2) Open the mouthpiece and put it in their mouth; and 3) Start breathing in deeply, which activates the device. Therefore, in patients with impaired dexterity and who may find it difficult to use an inhaler (e.g., those with rheumatoid arthritis), a breath-actuated inhaler would be a better choice than an MDI. Easi-Breathe (a breath-actuated inhaler) and Turbohaler (a dry-powder inhaler) were proven in a study to be easier to use than an MDI. 8  Drugs used in asthma and COPD Other drug Bronchodilators Corticosteroids classes β2-agonists, e.g. Extensive first-pass: salbutamol, budesonide, Mediator antagonists salmeterol, fluticasone, (antileukotrienes) formoterol mometasone Low first-pass: Theophylline Immunosuppressive beclomethasone (methylxanthine) therapy (anti-IgE) dipropionate Muscarinic New drugs still in antagonists, e.g. ipratropium, development, e.g. K+ tiotropium channel openers This gives you an overview of the drugs used to treat asthma and COPD. We’re going to focus on bronchodilators and corticosteroids. They target the two major aspects of asthma and COPD i.e., the symptoms (bronchodilators) and the underlying inflammation (steroids). We have three groups of bronchodilators – β2-agonists, theophylline, and muscarinic antagonists; and two groups of corticosteroids – those that undergo extensive first-pass metabolism and those that don’t. First-pass metabolism reduces the bioavailability of a corticosteroid and so its adverse effects. 9  Mechanisms leading to or preventing bronchodilation Now, before we get to the different groups of bronchodilators, it may pay to take a look at the mechanisms that cause or prevent bronchodilation. So, bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by β-agonists, which increase the rate of its synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its breakdown. Here, I just want to add that different subtypes of PDEs exist, and they serve a variety of physiological functions. Acetylcholine and adenosine can constrict the airways. Therefore, bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists. 10  β2-selective agonists  Strategies to ↓ β1-mediated adverse effects:  Development of drugs with β2 selectivity.  Structural modifications to ↓ metabolism by COMT & ↑ bioavailability.  Administration via inhalation (aerosol, dry powder).  Treatment of choice in asthma.  Primary mechanism: Now, let’s look at the first group of bronchodilators – β2-agonists. In the past, several strategies were used to minimise β1-mediated adverse effects and develop the β2- agonists we have today. These include development of drugs with β2 selectivity; structural modifications to reduce metabolism by COMT and enhance bioavailability; and administration via inhalation in the form of aerosol or dry powder to decrease the risk of systemic adverse effects. β2-agonists are the treatment of choice in asthma. Of course, the primary mechanism is by causing bronchodilation through the action of cAMP to relieve breathing difficulty in patients with asthma. 11  Molecular actions of β2-agonists to induce relaxation of airway smooth muscle cells. Activation of β2 receptors (β2AR) results in activation of adenylyl cyclase (AC) via a stimulatory G protein (Gs), leading to an increase in intracellular cyclic AMP and activation of PKA. PKA phosphorylates a variety of target substrates, resulting in: 1. Opening of Ca2+-activated K+ channels (KCa), thereby facilitating hyperpolarisation OR repolarisation of the smooth muscle cell and causing relaxation; 2. Acute inhibition of the PLC-IP3 pathway and its mobilisation of cellular Ca2+; 3. Increased Na+/Ca2+ exchange; 4. Increased Na+,Ca2+-ATPase activity; and 5. Decreased myosin light chain kinase (MLCK) activity required for smooth muscle contraction. EWC: Both mechanisms 3 & 4 remove Ca2+ from the cell. 12  β2-agonists: additional mechanisms in asthma Precursors Phospholipase A2 Leukotrienes Histamine Source: Harrison’s Principles of Internal Medicine β2-agonists have some additional mechanisms that also contribute to their therapeutic effect against asthma. They may suppress the release of leukotrienes and histamine from mast cells in lung tissue, enhance mucociliary function – clearing excess mucus from the airways, decrease microvascular permeability – reducing plasma leak and oedema, and possibly inhibit phospholipase A2 responsible for the synthesis of leukotrienes. In asthma, a variety of inflammatory mediators, such as histamine and leukotrienes, cause bronchoconstriction. The effects of these mediators are not blocked by muscarinic antagonists. 13  Short-acting β2-agonists  Have a rapid onset and are thus important in the treatment of acute severe asthma.  Little differences between agents:  DOA: ~3-4 hours.  Variation in β2 selectivity not clinically significant. Other agents: Levalbuterol Orciprenaline Terbutaline Salbutamol (albuterol) Overall, β2-agonists can be classified based on their duration of action. The differences in their duration and onset of action cause them to have different therapeutic uses. Short-acting agents typically have a rapid onset and are thus important in the treatment of acute severe asthma. In terms of the duration of action, there is little difference between agents. Their therapeutic effects last between 3-4 hours. They may vary in their β2-selectivity but the difference is not clinically significant. The examples of short-acting β2-agonists I have here are terbutaline, salbutamol, levalbuterol, and orciprenaline. 14  Long-acting β2-agonists  Long DOA >12 hours.  Improve asthma control when given twice daily.  C.f. short-acting β2-agonists (4-6 times daily).  May be used alone in COPD BUT should be combined with an inhaled corticosteroid in asthma.  Salmeterol:  Has a slow onset.  High lipophilicity may cause more extrapulmonary side effects. Fluticasone & salmeterol Long-acting β2-agonists have duration of action of >12 hours, roughly 3-4 times as long as that of short-acting agents. So, because of the long duration of action, they are better at controlling asthma; and they need to be given less frequently i.e., twice daily compared with 4-6 times daily with short-acting β2-agonists. Long-acting β2-agonists can be used in the treatments of asthma and COPD. They may be used alone in COPD BUT should be combined with an inhaled corticosteroid in asthma. An example of a long-acting β2-agonist I have here is salmeterol. It has a slow onset so it shouldn’t be used to relieve acute asthma attacks. It is known to be quite lipophilic; so, it might be easier for it to be absorbed into the systemic circulation and cause extrapulmonary side effects. 15  Long-acting β2-agonists Formoterol: DOA similar to salmeterol BUT faster onset. Source: Anderson GP. Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective β2-adrenoceptor agonist bronchodilator. Life Sci. 1993;52(26):2145-60. Now let's look at the mechanisms that explain why some β2-agonists are longer- and faster-acting than the others. What we have here is a β2-receptor embedded in a cell membrane waiting to be activated by a β2-agonist. Above it is the aqueous biophase that a β2-agonist has to overcome to reach the receptor. Salbutamol: hydrophilic; able to get across the aqueous biophase and reach the receptor but is ‘washed’ away quickly, hence rapid onset and short duration of action. Formoterol: intermediate hydrophilicity; a fraction of the drug reacts with the receptor to produce an effect; the other fraction inserts into the lipid bilayer of the cell membrane and is slowly released to activate the receptor; hence rapid onset and long duration of action. Salmeterol: lipophilic; most of the drug inserts into the lipid bilayer and little is available to react with the receptor; hence slow onset and long duration of action. 16  β2-agonists: Adverse effects  Excessive stimulation of β receptors.  Much less likely with inhalation therapy. ↑ plasma concentrations of glucose, lactate, & free fatty acids. Caution: diabetic patients. ↓ concentration of K+. Caution: patients with cardiac disease. Stimulation of Reflex cardiac β2 receptors in stimulation skeletal muscle Stimulation of myocardial β1 and β2 receptors The adverse effects of β2-agonists are caused by excessive stimulation of β receptors. The adverse effects are much less likely with inhalation therapy. Tremor is caused by stimulation of β2-receptors in the skeletal muscle. Tachycardia is caused by reflex cardiac stimulation triggered by β2-mediated peripheral vasodilation; and direct activation of cardiac β1- and β2-receptors. As β2-receptors have important roles in glucose metabolism, activating the receptors can significantly increase plasma concentrations of glucose, lactate, and free fatty acids. This is why you have to use β2-agonists with caution in diabetic patients. Finally, β2-agonists can cause hypokalaemia by promoting the entry of K+ ions into the skeletal muscle. K+ ions are involved in heart contraction; so, hypokalaemia increases the risk of an abnormal heart rhythm. This adverse effect could be particularly dangerous in patients with cardiac disease. 17  Further reading Tachyphylaxis  Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation. Respir Med. 2005;99(5):566-71. Long-term safety of β2-agonists  Chowdhury BA, Dal Pan G. The FDA and safe use of long- acting beta-agonists in the treatment of asthma. N Engl J Med. 2010;362(13):1169-71. 18  Theophylline  Structurally related to caffeine.  Inexpensive so still widely used in developing countries.  Use declining in others because:  of its side effects.  it is less effective than inhaled β2-agonists or corticosteroids.  Mechanisms:  Bronchodilation:  Inhibits PDE, ↑ cAMP.  Antagonises the action of adenosine.  Anti-inflammation:  Prevents the translocation of NF-κB into the nucleus.  ↓ the expression of inflammatory genes. Now, let’s talk about theophylline – another bronchodilator. It’s structurally related to caffeine; so, the two overlap in their mechanisms. Theophylline is inexpensive so it’s still widely used in developing countries. The popularity of theophylline is declining in other countries because of its many side effects – no thanks to its complex mechanisms – and its lower effectiveness compared with inhaled β2-agonists or corticosteroids. You can break down the complex mechanisms of theophylline into two categories – how it promotes bronchodilation and reduces inflammation. It inhibits PDE, increasing the level of cAMP and promoting bronchodilation. It also antagonises the action of adenosine, which constricts the airways. It prevents the translocation of NF- κB, a pro-inflammatory transcription factor, into the nucleus, reducing the expression of inflammatory genes. 19  Theophylline IL-8 Attracts neutrophils Here you can see theophylline has a variety of effects on the inflammatory and structural cells. I just want to point out two of its effects that are particularly relevant to the pathogenesis of asthma and COPD. Theophylline causes death of eosinophils; and this would be beneficial to patients with asthma. It also decreases the level of IL- 8 in patients with COPD, thereby reducing neutrophil chemotactic response. Again, remember that neutrophils play a key role in the pathogenesis of COPD. 20  Theophylline: Pharmacokinetics  Therapeutic range: 5-15 mg/L.  Metabolised by CYP1A2; apart from interindividual differences, the activity of this enzyme can be influenced by several factors:  Increased clearance: Enzyme Children Cigarette inducers, e.g. (1-16 yo) smokers phenytoin  Decreased clearance: Enzyme Liver Pneumonia Heart inhibitors, e.g. disease failure erythromycin The pharmacokinetics of theophylline is quite tricky; and there are pitfalls you must be aware of. First, theophylline works within a narrow therapeutic range of 5-15 mg/L. Adverse effects are likely outside the therapeutic range. It’s metabolised by CYP1A2, whose activity can be influenced by a number of factors. So, the clearance of theophylline is increased in children, cigarette smokers, and in patients taking enzyme inducers such as phenytoin. FYI – Cigarette smoke contains polycyclic aromatic hydrocarbons which can induce CYP1A2. The clearance of theophylline is decreased in patients with liver disease, pneumonia, heart failure, and those taking enzyme inhibitors such as erythromycin. So, overall, you would expect that adjustment to the dose of theophylline would often be necessary to make sure drug concentrations stay within the therapeutic range. 21  Theophylline: Adverse effects Side effect Proposed mechanisms Nausea & PDE4 inhibition & Neuron firing in the vomiting increased cAMP levels vomiting centre Headaches Dilation of cerebral blood vessels Gastric discomfort Gastric acid secretion Diuresis A1 receptor Reduced reabsorption antagonism of fluid & sodium ions Behavioral ? ? disturbance (?) Cardiac PDE3 inhibition & A1 Increased cardiac arrhythmias receptor antagonism contractility & rate Epileptic seizures A1 receptor Central over-excitation antagonism Nausea and vomiting: inhibition of PDE4, increased levels of cAMP which triggers neuron firing in the vomiting centre of the brain. Headache: cAMP promotes dilation of cerebral blood vessels; distention of the blood vessels may activate nerve terminals in the vessel walls. Gastric discomfort: cAMP can promote gastric acid secretion. Diuresis: Adenosine receptor antagonism blocks proximal tubular reabsorption of fluid and sodium ions. Cardiac arrhythmia: cAMP can increase cardiac contractility and rate. Epileptic seizure: In the brain stimulation of the adenosine receptors produces an inhibitory effect. So, antagonism of the receptors may result in central over-excitation and consequently seizure. 22  Muscarinic antagonists  No major effect in healthy individuals.  Beneficial effect in COPD results from blockade of M3-mediated bronchoconstriction (the Gq- PLC-IP3-Ca2+ pathway).  BECAUSE chronic inflammation in COPD may trigger release of acetylcholine from airway cells, causing hyperresponsiveness. Now, let’s look at the third class of bronchodilators – muscarinic antagonists. They have no major effect in healthy individuals but substantial effect in patients with COPD. You can understand it this way. In patients with COPD the airway is already narrow, so ‘anything’ – such as acetylcholine – that narrows the airway further would have a major effect. The beneficial effect muscarinic antagonists in COPD results from the blockade of M 3- mediated bronchoconstriction. This action is especially relevant because in COPD, there is an increased level of acetylcholine. Chronic inflammation in COPD may trigger the release of acetylcholine from airway cells. This makes muscarinic antagonists more effective than β2-agonists against COPD. 23  Note: The Gq-PLC-IP3-Ca2+ pathway The M1, M3 and M5 receptors are stimulatory and couple primarily to the mobilization of intracellular Ca 2+. An increase in cytoplasmic Ca2+ results from the coupling of these receptors with the heterotrimeric G protein Gq, which leads to stimulation of the effector enzyme phospholipase C (PLC) and the release of inositol-(1,4,5)-trisphosphate [IP3]. The M2 and M4 receptors are inhibitory and negatively modulate adenylyl cyclase (AC) to reduce cytoplasmic concentrations of cAMP. 24  Muscarinic antagonists  Ipratropium:  DOA, 6-8 hours.  Slow onset, 30-60 min.  Tiotropium:  Long-acting.  Dissociates slowly from M3 and M1, but more rapidly from M2.  Bronchodilator of choice for COPD.  Oxitropium: similar to ipratropium in regard to receptor blockade but may be longer-acting. Here I have several examples of muscarinic antagonists. Ipratropium is relatively short-acting with its DOA of 6-8 hours; it also has a slow onset of 30-60 min. Tiotropium is long-acting (i.e., it needs to be given less frequently) and superior to ipratropium in terms of receptor selectivity. It is more selective towards M3 receptors – the main therapeutic target in the treatments of asthma and COPD. This is because it dissociates slowly from M3 and M1 receptors, but more rapidly from M2 receptors. This is why tiotropium is the bronchodilator of choice for COPD. Oxitropium is similar to ipratropium in regard to receptor blockade but may be longer-acting. 25  Muscarinic antagonists: Adverse effects  Generally well tolerated – systemic side effects are uncommon.  BUT the following side effects may be bothersome:  Unpleasant bitter taste of inhaled ipratropium.  Paradoxical bronchoconstriction in patients treated with ipratropium but NOT tiotropium.  Glaucoma in elderly patients given nebulised ipratropium.  Dry mouth in patients given tiotropium (10-15%). Muscarinic antagonists are generally well tolerated; and systemic side effects are uncommon. BUT some side effects may be bothersome. Inhaled ipratropium can produce an unpleasant bitter taste. Inhaled ipratropium but not tiotropium can cause paradoxical – something unexpected – bronchoconstriction. This is because ipratropium is not as M3-selective as tiotropium; blockade of M2 receptors increases the release of acetylcholine from nerve endings, leading to bronchoconstriction. Nebulised ipratropium can cause glaucoma in elderly patients. This is possibly because some of the drug may ‘escape’ from the nebuliser and act directly on the eye – remember that muscarinic antagonism inhibits drainage of aqueous humour. Finally, dry mouth may occur in 10-15% patients given tiotropium i.e., this is quite a common side effect of tiotropium. 26  Corticosteroids  Discovered in the 1950s.  Inhaled corticosteroids:  First-line therapy in asthma.  Effective “controller”.  Much less effective in COPD and reserved only for patients with severe disease. But why is this so Corticosteroids are important immunosuppressants discovered in the 1950s. Inhaled corticosteroids are the first-line therapy in asthma. They are effective “controller” therapy – bringing the symptoms under control. However, they are much less effective in COPD and reserved only for patients with severe disease. This may be because they are not very effective against neutrophilic inflammation – a key feature of COPD; and in COPD, there's plenty of structural damage, which is difficult to reverse. Compared with COPD, asthma is more of an 'inflammatory' than a structural disease. 27  Mechanism of anti- inflammatory action of corticosteroids in asthma To understand the mechanisms of action of corticosteroids, you must first understand how the expression of inflammatory genes is controlled in a cell. Inflammatory genes are activated by inflammatory stimuli, resulting in the activation of the transcription factor NF-κB. Transcription factors are an important group of proteins that regulate gene expression. A key feature is that they are sequence-specific i.e., they bind to specific regions within DNA. p50 and p65 here are members of the NF-κB family of transcription factors. So, they translocate to the nucleus and bind to specific recognition sites and also to coactivators, such as CBP, which have histone acetyltransferase (HAT) activity. Transcription factors do not act alone in the regulation of gene expression, and they need the help of other proteins such as coactivators. So, CBP adds acetyl groups to histones and change their organisation. DNA is wrapped tightly around histones to form chromatin. The organisation of chromatin can determine whether gene transcription is activated or repressed. Loose association between DNA and histones allows the gene transcription machinery to bind to DNA and promotes gene expression. Adding acetyl groups to histones ‘opens up' chromatin to increase gene transcription. Corticosteroids bind to cytosolic glucocorticoid receptors; and the receptor-ligand complexes translocate to the nucleus and inhibit HAT activity. Ultimately, this 28 suppresses the expression of inflammatory genes. 28  Effect of corticosteroids on inflammatory and structural cells in the airways. As you can see here, corticosteroids have a variety of effects on inflammatory and structural cells. Let’s focus on the inflammatory cells – where they mainly inhibit the activity of the cells. So, you can link this to the potent immunosuppressant effects of corticosteroids. 29  Synergism between corticosteroids and β2-agonists Corticosteroids β2-agonists Enhance β2 Increase translocation responsiveness of liganded GR AND receptors AND Prevent tolerance to Enhance binding of GR β2-agonists. to DNA. Corticosteroids and β2-agonists are often used in combination; and there’s beneficial interaction between them. Corticosteroids increase β adrenergic responsiveness and reverse β receptor desensitisation in airways. Tolerance to β2-agonists could develop over time after long-term use. At the molecular level, corticosteroids increase the expression of β2-receptors in the lungs. So, β2-agonists kind of ‘repay’ corticosteroids by enhancing the action of glucocorticoid receptors (GR), resulting in increased nuclear translocation of liganded glucocorticoid receptors and enhancing their binding to DNA. So, overall, β2-agonists and corticosteroids enhance each other's effects in asthma therapy. 30  Corticosteroids: Adverse effects Local side effects Systemic side effects Dysphonia Adrenal suppression and Oropharyngeal insufficiency candidiasis Growth suppression Cough Bruising Osteoporosis Cataracts Glaucoma Metabolic abnormalities (glucose, insulin, triglycerides) Psychiatric disturbances (euphoria, depression) Pneumonia Corticosteroids are known to be quite ‘nasty’ in terms of their adverse effect profiles. They cause many adverse effects, as listed in the table here. So, I’m not going to go over the adverse effects in detail. 31 Note: The HPA axis Overview of the hypothalamic-pituitary- adrenal (HPA) axis and the immune inflammatory network. Also shown are inputs from higher neuronal centers that regulate CRH secretion. + indicates a positive regulator, − indicates a negative regulator, + and − indicates a mixed effect, as for NE (norepinephrine). In addition, arginine vasopressin stimulates release of ACTH from corticotropes. 32  Corticosteroids: Pharmacokinetics and choice The extent of first-pass metabolism may influence the development of systemic adverse effects: > Fluticasone Budesonide Mometasone Beclomethasone propionate furoate dipropionate Advantage: reduced adverse effects; preferred in patients requiring high doses and in children. Many inhaled corticosteroids are now available including beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate. They are all equally effective as anti-asthma drugs, but there are differences in their pharmacokinetics. Budesonide, fluticasone, and mometasone have a lower oral bioavailability than beclomethasone dipropionate because they are subject to greater first-pass hepatic metabolism; this reduces adverse effects. So, they are preferred in patients who need high doses of inhaled corticosteroids and in children. 33  Corticosteroids: Pharmacokinetics, adverse effects, and choice Ciclesonide Active metabolite (prodrug) Esterase Comparison of potencies: Triamcinolone, flunisolide < beclomethasone dipropionate = budesonide < fluticasone propionate Flunisolide Triamcinolone So, considering the ‘nasty’ side effects that could be caused by corticosteroids, ciclesonide is an option that could be relatively lung-selective with lower risks of systemic adverse effects. It is a prodrug that is converted to the active metabolite by esterases in the lung, giving it a low oral bioavailability. It may pay to also know the potencies of different corticosteroids, as this is related to their potential adverse effects. Sitting in the middle are beclomethasone dipropionate and budesonide, which are equally potent. Triamcinolone is the least potent, while fluticasone propionate is the most potent, of the corticosteroids listed here. 34  FYI: Not covered in this lecture  Leukotriene receptor antagonists:  Montelukast.  Zafirlukast.  Cromoglycates and nedocromil:  Mast cell stabilisers’.  Omalizumab:  Anti-IgE monoclonal antibody. 35