Pharmacology of the lung - Essential respiratory medicine

Essential respiratory medicine. Shanthi Paramothayan

Chapter 3. Pharmacology of the lung

Learning objectives

■ To understand how medications used to treat pulmonary disease are given

■ To gain some understanding of the principles of drug deposition in the lungs

■ To learn about the different devices used to deliver drugs to the lungs

■ To learn about the medication used to treat obstructive airways disease

■ To understand the pharmacology of short-acting and long-acting bronchodilators

■ To understand the pharmacology of short-acting and long-acting anticholinergic drugs

■ To learn about the benefits and side effects of inhaled and oral corticosteroids

■ To learn how to prescribe longterm oxygen therapy

■ To understand the role of selective and non-selective phosphodiesterase inhibitors

■ To learn about the drugs given for acute asthma

■ To gain some understanding of anti-immunoglobulin E therapy

■ To appreciate the role of macrolides

■ To understand the indication for systemic and topical adrenaline

■ To gain some understanding of the drugs given for idiopathic pulmonary fibrosis

■ To gain knowledge of pharmacotherapy for smoking cessation

■ To gain some understanding of the types of drugs that damage the lungs

Abbreviations

ABG arterial blood gas

ABPA allergic bronchopulmonary aspergillosis

Ach acetylcholine

ARDS adult respiratory distress syndrome

BAL bronchoalveolar lavage

BTS British Thoracic Society

cAMP cyclic adenosine 3, 5, monophosphate

CAP community acquired pneumonia

CFC chlorofluorocarbon

COPD chronic obstructive pulmonary disease

CS corticosteroid

CT computed tomography

CXR chest X-ray

DPI dry powder inhaler

DPLD diffuse parenchymal lung disease

FGF fibroblast growth factor

FiO₂ inspired oxygen

FVC forced vital capacity

GCS glucocorticosteroid

HFA hydro-fluoroalkane

HPA hypothalamic pituitary axis

HSP-90 heat shock protein 90

ICS inhaled corticosteroid

IgE immunoglobin E

ILD interstitial lung disease

IPF idiopathic pulmonary fibrosis

kPA kilopascal

LABA long-acting β₂-agonist

LAMA long-acting muscarinic agonist

LTD4 leukotriene D4

LTOT long term oxygen therapy

MCE mucociliary escalator

MMAD mass median aerodynamic diameter

MRC Medical Research Council

mRNA messenger ribonucleic acid

NAC N-acetyl cysteine

NHS National Health Service

NIV non-invasive ventilation

NRT nicotine replacement therapy

NSIP non-specific interstitial pneumonia

OCS oral corticosteroid

OSAHS obstructive sleep apnoea/hypopnea syndrome

PDGFR platelet derived growth factor receptor

pMDI pressurised metered dose inhaler

RAST radioallergosorbent test

SAA short-acting anticholinergics

SABA short-acting β₂-agonist

SAD seasonal affective disorder

SBOT short-burst oxygen therapy

SWSD shift worker sleep disorder

UK United Kingdom

VEGF vascular endothelial growth factor

Drugs and the lung

Diseases of the lung are treated with a variety of drugs. In this chapter, the mechanisms of action, side-effect profile, and interactions of the commonly used drugs are discussed. The clinical indications for the use of these drugs are described in more detail in the relevant chapters that follow. Obstructive airways disease is discussed in Chapter 6, diffuse parenchymal lung disease in Chapter 7, respiratory infections in Chapter 8, respiratory failure in Chapter 13, and sleep disorders in Chapter 14.

Principles of drug deposition in lungs

Inhaled therapy has been used for centuries: sulphurs and volatile aromatic substances, such as methyl and eucalyptus, have been used to relieve respiratory symptoms for many years. An inhaler or a nebuliser will deposit the drug directly into the lungs where it is absorbed and works rapidly. Systemic side effects from inhaled therapy are less than with oral or intravenous treatment.

All inhaler systems are relatively inefficient, with only 8—15% of the drug reaching the lung, no matter how good the inhaler technique is. Particle distribution within the lungs can be measured by radio-labelling the drug and using a gamma camera to quantify deposition. The factors that determine particle deposition in the lungs include the size of the particle, the inspiratory flow rate, and the distance the particle needs to travel, which is determined by the method of inhalation. Factors that favour distal particle sedimentation include small size and low flow rate.

An aerosol is a suspension of fine particles of varying sizes with a favourable surface-to-volume ratio, which allows a small dose to disperse widely over the airways and the alveolar surfaces (Figure 3.1). There is an optimal particle size which favours deposition. The mass median aerodynamic diameter (MMAD) of the aerosol is the diameter about which 50% of the total particle mass resides and this affects where most of the particles that enter the lung are deposited. Large particles of >6 μm in diameter are more likely to be deposited centrally, smaller particles <5 pm in diameter reach the smaller airways and those of 2—3 pm in diameter reach the alveoli. Particles which are even smaller than this may not settle and are expired. Drug deposition is enhanced by turbulent flow which predominates in these central passages, and particularly at airway bifurcations.

Figure 3.1 Particle size and drug deposition.

A faster inspiratory flow rate results in the particles being deposited more centrally because of inertial impaction. Slow inhalation with breath-holding results in the particles reaching the peripheral and distal bronchioles. Particles deposited in the conducting airways, which stretch from the larynx to the terminal bronchioles, will become trapped in the mucociliary escalator (MCE). In healthy individuals, the MCE clears the particles within 6—24 hours after deposition, but the clearance will be delayed in conditions such as bronchiectasis, where there is ciliary damage. Small particles in the alveoli are cleared very slowly via alveolar macrophages and lymphatics. The solubility of the drug also affects how quickly the drug is absorbed and cleared from the lungs.

Inhaler devices

The three main types of inhaler devices are pressurised metered dose inhalers (pMDI), dry powder inhalers (DPI), and soft mist inhalers (SMI) (Figure 3.2). Despite the differences in drug delivery to the lung with these various devices, no significant difference in bronchodilator effect has been found.

A pressurised metered dose inhaler (pMDI) can be used alone or with a spacer. It comprises of a canister, which can store up to 200 doses of the drug, and a plastic actuator. The drug in the small canister is either dissolved or suspended as crystals in a liquid propellant mixture of hydro-fluoroalkane (HFA) which has replaced the chlorofluorocarbon (CFC) which is detrimental to the ozone layer. A low concentration of surfactant prevents aggregation of the small particles and acts as a lubricant.

The patient should be instructed to shake the canister thoroughly, remove the cap, place the mouthpiece of the actuator between the lips, breathe out steadily, release the dose while taking a slow, deep breath in, hold the breath for a count to 10 and wait a minute before repeating. The use of the different inhalers and nebuliser is demonstrated in the supplementary video (www.wiley.com/go/ ParamothayanEssential_Respiratory_Medicine)

The pMDI has several advantages: it is portable, relatively cheap, and small doses of the drug can be given. However, the elderly and young children can find it difficult to use as co-ordination is needed between actuation and inhalation. This can lead to poor compliance. Poor technique can result in deposition of the drug in the oropharynx rather than in the lungs. If inhaled corticosteroids (ICS) are being used, then oropharyngeal deposition can result in candidiasis and dysphonia. pMDI can be less effective in patients with significant airway obstruction as high inspiratory flow rates are required in this situation. It is generally recommended that the MDI is used with a spacer as this reduces oropharyngeal drug deposition and allows better penetration of the drug to the periphery of the lungs (Figure 3.3).

Figure 3.2 Several types of inhaler devices.

Figure 3.3 Individual using an MDI.

Dry powder inhalers (DPI) are breath- actuated devices that contain a desiccant which ensures that the powder is kept dry. Most adults and children prefer these as they require less coordination and are easier to use than a pMDI. The patient needs to be able to generate an inspiratory flow rate of at least 30lmin^-1 to ensure adequate drug deposition in the lungs and to reduce oropharyngeal deposition.

The turbohaler is the most commonly used DPI (Figure 3.4). It can hold 50—200 doses of the drug and a dose indicator gives a warning when only 20 doses remain. Patients are often concerned because they may not feel any sensation in their oropharynx when they inhale (Figure 3.5). Other DPI devices include the spinhaler, rotahaler, discs, and blisters. These devices are similar in their efficacy.

Figure 3.4 Turbohaler.

Figure 3.5 Patient using a turbohaler.

A spacer device improves drug delivery and is recommended for use with all aerosol inhalers, including the pMDI. A large spacer with a one-way valve is called a volumatic device (Figure 3.6). This increases the distance from the actuator to the mouth and allows the particles time to evaporate and slow down before inhalation. This results in a larger proportion of the particles being deposited in the lungs and minimises oropharyngeal drug deposition, thus decreasing the incidence of oropharyngeal candidiasis. Patients should inhale from the spacer device as soon as possible after a single actuation because the drug aerosol is very shortlived. Tidal breathing is as effective as single breaths. The use of a large volume spacer is essential in young children and is an alternative to a nebuliser. The able spacer and aerochamber (Figure 3.7) are smaller volumatic devices which are more portable.

Figure 3.6 Volumatic device (spacer).

Figure 3.7 Aerochamber.

The spacer should be cleaned once a month by washing in mild detergent and allowed to dry in air without rinsing. The mouthpiece should be wiped clean of detergent before use. More frequent cleaning should be avoided as this can affect the electrostatic charge and drug delivery. Spacers should be replaced every 6—12 months.

Tube spacers are tube-like attachments to the pMDI with a much smaller interval volume than the large volume spacers. They too enable the aerosol to slow down before reaching the mouth.

Several studies have shown that in acute asthma, multiple doses of a bronchodilator given through a spacer have a similar bronchodilatory effect as if the drug is given through a nebuliser. However, a nebuliser has the advantage in that it can be used when the patient is very breathless and unable to make the inspiratory effort.

Figure 3.8 Portable nebuliser.

A nebuliser (Figure 3.8) can deliver a higher dose of drug to the airways than an inhaler. A solution containing the drug, usually 1 mg ml^-1, is turned into an aerosol for inhalation.

Nebulised short-acting β₂-agonists (SABA) and anticholinergic medication are used to treat patients with exacerbation of asthma or COPD. Nebulised SABA can also be used to assess airway reversibility in patients with asthma and COPD. Nebulised methacholine and histamine can be used to assess bronchial hyper-reactivity, and nebulised hypertonic saline can be used to induce sputum. Nebulised colomycin is used to treat pseudomonas aeruginosa infection associated with bronchiectasis and cystic fibrosis, and nebulised pentamidine can be used to treat pneumocystis jirovecii infection. Nebulised opiate can be given to relieve intractable breathlessness in the palliative care setting. There is no evidence for the use of nebulised steroids in exacerbations of asthma or chronic obstructive pulmonary disease (COPD).

Jet nebulisers are more widely used than ultrasonic nebulisers. The jet nebuliser requires an optimum gas flow rate of 6—8 l min^-1, which can be either piped air or oxygen. In patients who present with type 1 respiratory failure and require nebulised drugs, 6 l of oxygen should be used to drive the nebuliser. In patients who are at risk of type 2 respiratory failure, air should be used to drive the nebuliser. Supplemental oxygen can be given at the same time via a nasal cannula to maintain the oxygen saturation between 88% and 92%. Management of respiratory failure is discussed in Chapter 13.

Many different designs of nebuliser chambers are available which produce aerosols with particles of different sizes, depending on the design of the baffles in the chamber and the gas flow rate. They usually hold 4—6 ml of solution and have a flow rate of 6-8 l min^-1. Droplets with a MMAD of 1—5 μm are deposited in the conducting airways and are therefore suitable for treatment of asthma, whereas a particle size of 1—2 μm is needed for the alveolar deposition of pentamidine. Approximately 10% of a nebulised drug reaches the lungs, with most of the aerosol mist being wasted.

The ultrasonic nebuliser delivers large particles of 3—10 μm from high frequency (1—2 mHz) sound waves induced by the vibration of a piezoelectric crystal which, when focused on the surface of a liquid, creates a fountain of droplets. It has less clinical use than the jet nebuliser.

Oxygen

Long term oxygen therapy (LTOT) is indicated for patients with chronic type 1 respiratory failure with a resting PaO₂ < = 7.3 kPa or those with a resting PaO₂ < = 8 kPa with evidence of peripheral oedema, polycythaemia (haematocrit >55%) or pulmonary hypertension. LTOT improves survival in patients with respiratory failure by reducing the risk of developing cor pulmonale. Controlled LTOT is indicated for patients with type 2 respiratory failure, but must be prescribed with care and closely monitored as there is a risk of CO₂ retention. The indications for oxygen therapy and principles of controlled oxygen are discussed in Chapter 13.

Figure 3.9 Oxygen cylinder. Source: ABC of COPD, 3rd edition, Figure 11.7

LTOT is given through a concentrator for those requiring oxygen for more than 15 h day^-1. The concentrator draws in air, filters out the nitrogen and concentrates the oxygen to reach 95% purity. The oxygen can be humidified to make it less drying to the nostrils (Figure 3.9). Other types of devices include oxygen reservoirs containing liquid oxygen or compressed oxygen. The percentage of inspired oxygen(FiO₂) required is determined by measuring the arterial blood gas (ABG) on air and then on oxygen. The concentrator can be pre-set to deliver the exact flow rate required. A back-up cylinder of oxygen is also supplied for use in an emergency, for example during a power cut, and can supply oxygen for several hours. If a flow rate of more than 51 min^-1 is needed, then more than one concentrator may be required.

Portable oxygen can be given for ambulant patients as bottled liquid oxygen which evaporates into the gas. Modern oxygen concentrators are light and portable and can be wheeled on a trolley. They have sufficient oxygen to last several hours and contain battery packs and electrical connections to charge them.

Oxygen can be prescribed for patients with intractable dyspnoea in the palliative care setting. There is little evidence that short-burst oxygen therapy (SBOT) is effective. Oxygen is flammable, so the patient and their family must be warned against the risks of smoking while on oxygen. Oxygen concentrators should be kept in a well-ventilated area, away from gas stoves and flames.

Inhaled drugs Inhaled drugs are primarily used to treat obstructive airways diseases, such as asthma, COPD, and bronchiectasis. The evidence and indications for the use of these drugs are discussed in Chapter 6.

β₂-adrenoceptor agonists: the smooth muscle of the airways from the trachea to the terminal bronchioles has β₂-adrenoceptors. Direct stimulation of these receptors results in activation of adenylate cyclase and an increase in cyclic adenosine 3, 5 monophosphate (cAMP). The cAMP activates protein kinase A, which then phosphorylates several target proteins within the cell, resulting in the lowering of intracellular calcium concentration by the active removal of calcium from the cell into intracellular stores. Protein kinase A also inhibits phosphoinositide hydrolysis and myosin light chain kinase, resulting in the opening of the large- conductance calcium-activated potassium channels that repolarise the smooth muscle cell and stimulate the sequestration of calcium into intracellular stores. The overall effect is relaxation of the airway smooth muscle and bronchodilatation.

Short-acting β₂-agonists (SABAs) bind to the β₂-adrenoceptors and are effective bronchodilators with minimal side effects. β₂-agonists also have some anti-inflammatory properties: they inhibit mediator release from mast cells, thus reducing the development of bronchial mucosal oedema after exposure to mediators such as histamine and leukotrienes. SABAs also inhibit the release of inflammatory peptides, such as substance P, from sensory nerves which contributes to bronchodilatation. They increase the mucus secretion from the submucosal glands and ion transport across the airway epithelium, thus enhancing mucociliary clearance. However, these short-acting β₂-agonists do not have a significant inhibitory effect on the chronic inflammation of asthmatic airways.

Salbutamol and terbutaline are the safest and most effective SABAs used for treating asthma with rapid improvement in breathlessness and wheezing (see Chapter 6). Salbutamol can be given at a dose of 100 μg/metered inhalation via a pMDI alone or with a volumatic device and through a nebuliser, 2.5 or 5 mg as required. In severe acute asthma, intravenous salbutamol could be considered, although careful cardiac monitoring would be required. Oral preparations of salbutamol may be used by patients who cannot manage the inhaled route, for example, children and the elderly.

Terbutaline, also a SABA, is usually given via a turbohaler or nebulised at a dose of 5—10 mg, up to four times a day. It can also be given subcutaneously at a dose of 250—500 μg four times a day, or intravenously at a dose of 3—5 μg ml^-1, which equates to 90—300 μg h^-1 for 8—10 hours. Bambuterol, a long-acting oral preparation and pro-drug of terbutaline, may be of value in nocturnal asthma, but is rarely used.

The onset of bronchodilatation occurs within minutes after inhalation of a SABA and the effect is sustained for 4—6 hours. Patients with asthma and COPD are advised to carry SABAs to be used when they become breathless. Their use can protect against various challenges such as exercise, cold air, and allergens. β₂-agonists are more effective in relieving breathlessness in asthma than in COPD as there is more reversibility in asthma. Patients with asthma who are only on SABA and are using it many times a day for symptom control should receive additional treatment, as monotherapy in asthma is associated with an increased risk of death.

The main side effects of SABA, which are dose- related, occur due to stimulation of the β-adrenocep- tors in the cardiac muscle and skeletal muscle, resulting in tachycardia (presenting with palpitations) and fine tremor, mainly of the hands. The selective β₂-agonists are associated with fewer side effects. Hypokalaemia can occur when β₂ agonists are given rapidly through a nebuliser, for example, in an acute exacerbation of asthma, because of the stimulation of potassium entry into skeletal muscle. The risk of hypokalaemia is increased when the patient is also being treated with theophylline, corticosteroids, and diuretics. β₂-agonists can also cause muscle cramps, headaches, paradoxical bronchospasm, urticarial angioedema, hypotension, and collapse. Tolerance can occur when the drug is given continuously due to down-regulation of the receptor. Theophylline, which can be used in acute asthma and COPD, can also cause tachycardia, so patients who are receiving both drugs should be carefully monitored.

Long-acting P₂-agonists (LABAs) have a slightly slower onset of action than SABAs but the bronchodilator effect is sustained for 12 hours; therefore, the drug should be taken twice a day. Salmeterol is a partial agonist which is given at a dose of 6 or 12 |ig and acts within 20 minutes. Formoterol has a more rapid onset of action and is licensed for short-term symptom relief and for the prevention of exercise-induced bronchospasm.

LABAs should not be used for the relief of an asthma attack. It is recommended that formoterol and salmeterol are given in combination with ICS in asthma and COPD as these drugs act synergistically to improve symptoms, reduce exacerbations, reduce hospitalisation, and improve compliance. Preparations are available with different doses of each component so that patients can step the dose up or down as required. LABAs can rarely cause QT-interval prolongation, taste disturbance, nausea, dizziness, rash, and pruritus.

Short-acting anticholinergic (SAA) drugs are specific antagonists of muscarinic receptors and inhibit cholinergic nerve-induced bronchoconstriction, resulting in bronchodilatation. Normal airways have a resting vagal bronchomotor tone caused by tonic cholinergic nerve impulses which release acetylcholine (Ach) near the airway smooth muscle. Cholinergic reflex bronchoconstriction may be initiated by irritants, such as cold air and stress. This effect may be exaggerated in patients with COPD because of the fixed narrowing of the bronchi. Anticholinergic drugs, therefore, have a greater bronchodilator effect in COPD than in normal airways.

SAAs protect against the acute effects of irritants, such as sulphur dioxide, inert dusts, and cold air by blocking cholinergic bronchoconstriction. Anticholinergics are ineffective against antigen- induced or exercise-induced bronchoconstriction because they have no effect on mast cells and have no anti-inflammatory properties; they do not block the release of inflammatory mediators, such as histamine and leukotrienes.

Anticholinergics are less effective bronchodilators than β₂-agonists in acute asthma and offer less effective protection against various bronchial challenges, although their duration of action is significantly longer. Anticholinergics are slower in onset than β₂-agonists, reaching a peak only 1 hour after inhalation, with effects persisting for more than 6 hours. They may be more effective in older patients with asthma who may have an element of fixed airway obstruction. In the treatment of acute and chronic asthma, anticholinergic drugs, when combined with β₂-agonists, may have an additive effect.

Ipratropium bromide (atrovent) is a quaternary compound of atropine and a non-selective anticholinergic that blocks the muscarinic M3 receptors in the smooth muscle of the airways. Ipratropium bromide can be given by pMDI at a dose of 20—40 μg three or four times a day in patients with COPD where it has some bronchodilator effect as well as reducing the amount of mucus production, thereby improving chronic cough. It can also be given in the nebulised form at a dose of 250—500 μg four times a day for acute asthma or acute exacerbation of COPD. It is topically active and not significantly absorbed from the respiratory tract, so systemic side effects are minimal. The side effects, which are secondary to the muscarinic, anticholinergic actions, include dry mouth, blurred vision, and urinary retention.

Oxitropium bromide has a similar action to ipratropium bromide but is available in higher doses by inhalation. Its effects may be more prolonged so can be useful in some patients with nocturnal asthma.

Long-acting muscarinic agonist (LAMA) drugs cause bronchodilation, reduce bronchos- pasm and mucus production, and have a prolonged duration of action caused by slow dissociation from muscarinic receptors. They are licensed for use in COPD as first-line agents and have the advantage that they only need to be taken once a day. They are also indicated for patients with chronic asthma.

Tiotropium is given at a dose of 18 μg daily with a duration of action of 18—24 hours. Aclidin- ium bromide is also approved for use in COPD and is available as a dry powder. In trials, LAMAs have been shown to improve quality of life, reduce exacerbations and hospital admissions but with no evidence of a reduction in mortality. LAMAs can cause a dry mouth, blurred vision, closed-angle glaucoma, urinary retention, cardiac arrhythmias, taste disturbance, dizziness, and epistaxis, but systemic side effects are rare because little systemic absorption occurs.

Combinations of LABA, inhaled corticosteroid (ICS), and LAMA, improve compliance, maximise bronchodilation, improve symptoms, improve exercise capacity, improve quality of life, and reduce exacerbations in patients with COPD.

Corticosteroids (CS) are the most effective and most commonly used drugs for the treatment of lung disease apart from antibiotics. They are potent anti-inflammatory drugs which have a variety of different systemic effects. Glucocorticosteroid (GCS) receptors are found in most cells in the body. This receptor is bound to two molecules of heat shock protein 90 (HSP-90) and 1 molecule of immunophilin. Binding of GCS to the receptor dissociates the receptor from the HSP-90 and results in conformational changes of the receptor complex. The GCS-receptor complex (Figure 3.10) binds to the promoter-enhancer regions of target genes and up-regulates or down-regulates the gene and thereby the gene product through various pathways.

Oral corticosteroids (OCS) have a high oral bioavailability and are rapidly absorbed across the epithelial lining of the gastrointestinal tract by diffusion. OCS are used in the treatment of exacerbation of asthma, COPD, and diffuse parenchymal lung diseases (DPLD), usually at a dose of 0.5—1 mg kg^-1 day^-1. OCS are also indicated for a variety of other conditions, such as sarcoidosis, allergic bronchopulmonary aspergillosis (ABPA), and vasculitis. Intravenous corticosteroids, such as methylprednisolone, are used to treat severe lung disease or when oral therapy is not possible, for example, when the patient cannot swallow or is vomiting.

Cortisone and prednisone are pro-drugs which require hydroxylation in the liver to the active compounds hydrocortisone and prednisolone. Prednisolone is more stable than cortisone, with twice the half-life and a much higher affinity for the glucocorticosteroid receptor. Dexamathasone is 25 x times more potent than hydrocortisone (Box 3.1).

All the systemically available GCS are metabolised by the cytochrome P450 system in the liver. The systemic half-life varies from 1.9 hours for hydrocortisone to 4.4 hours for dexamethasone. Their clearance rates can be altered by severe liver disease, including liver cirrhosis. OCS can have significant systemic side effects, which are listed in Box 3.2.

Figure 3.10 Glucocorticoid receptor complex and mechanism of action of corticosteroid.

Box 3.1 Comparison of systemic corticosteroids.

Drug	Equivalent glucocorticoid dose (mg)	Antiinflammatory potency	Mineralocorticoid potency	Biological half-life (hours)	HPA Axis suppression (mg)²
Hydrocortisone	20	1	1	8-12	20-30
Cortisone	25	0.8	0.8	8-12	25-35
Prednisolone	5	4	0.8	12-36	7.5
Methylprednisolone	4	5	0-0.5	12-36	7.5
Dexamethasone	0.75	30	0	36-54	1-1.5

Inhaled corticosteroids (ICS) are preferable to OCS for the treatment of obstructive airways diseases, such as asthma and COPD. The aim is to achieve the maximum anti-inflammatory effect in the lungs while minimising systemic absorption and unwanted side effects. A multicentre trial by the Medical Research Council (MRC) in 1956 first demonstrated improvement in acute asthma with ICS.

The commonly used ICS are beclomethasone, budesonide, and fluticasone which are lipophilic drugs and therefore effective when inhaled. They have a very high affinity for the GCS receptor, a hundred times greater than that of hydrocortisone. They also have a very efficient first-pass hepatic metabolism which results in an extremely low oral bioavailability. They are usually given combined with a LABA and given twice a day as this has been shown to improve symptom control, compliance, and better long term outcome.

The dose-response relationship for ICS is flat, so doubling the dose results in minimal benefit but with more side effects (Figure 3.11). It can take 6—8 weeks for ICS to achieve maximal clinical benefit and improvement in lung function. Airway hyper-responsiveness can continue to improve for up to 1—2 years.

Box 3.2 Side effects of oral corticosteroids.

Short term (days)

Medium term (weeks)

Long term (months)

Indigestion

Skin bruising

Insomnia

Psychosis

Skin bruising

Gastric ulcers

Insomnia

Psychosis

Posterior subcapsular cataracts

Osteoporosis

Growth retardation in children

Weight gain

Cushingoid appearance

Adrenal suppression

Hypertension

Diabetes

Avascular necrosis

Beclomethasone 17.21-dipropionate is biotransformed into its active metabolite beclomethasone mono-propionate in the liver but further metabolism of this is slower than that of budesonide and fluticasone. It is usually given at a dose of 200—2000 μg a day for asthma or COPD.

Budesonide has an oral bioavailability of 6—13%, with a high first-pass liver metabolism but minimal lung metabolism. After a single inhaled dose of 500 μg, the peak plasma levels are achieved within 30 minutes and the plasma halflife is two hours. Budesonide has a high binding affinity for the GCS receptor, ten times that of dexamethasone. Budesonide has a similar potency to beclomethasone.

Fluticasone is twice as potent as beclomethasone or budesonide and given at a dose of 25—250 μg twice a day (Figure 3.12). Fluticasone propionate has an oral bioavailability of <1%, which is the lowest available ICS. It has a rapid first-pass liver metabolism and poor absorption across the gut epithelium. Plasma half-life after intravenous administration varies from 3.7— 14.4 hours. This is because it is very lipophilic and is retained in the lipid stores. Fluticasone has the highest binding affinity to the GCS receptor, 18 times that of dexamethasone.

Figure 3.11 Dose response curve of inhaled corticosteroids.

Figure 3.12 Potency of inhaled corticosteroids.

Local side effects of ICS include oral candidiasis and dysphonia, both secondary to oropharyngeal deposition. Clinically obvious oral candidiasis occurs in 5—10% of adult asthmatics and in 1% of children. However, oropharyngeal cultures for Candida species have been demonstrated in up to 45% of children and 70% of adults using ICS. The risk of candidiasis increases when antibiotics and ICS are taken concomitantly, and greatly reduced by using a large volume spacer and by mouth rinsing after use. Dysphonia occurs in up to 30% of those who use ICS and can be reduced by using a spacer.

Systemic side effects of ICS occur because of the absorption of the drug into the systemic circulation and are dose-related. There is little evidence of clinically relevant systemic side effects at doses < 400 μg day^-1 of beclomethasone or budesonide in children and of <1000 μg day^-1 in adults.

Normal doses of ICS have no clinically relevant effect on the hypothalamic pituitary adrenal (HPA) axis. With very high doses of ICS/nebulised CS, some adrenal suppression may occur. In children, there may be a reduction in growth velocity. ICS can affect bone metabolism but there is little evidence that they cause osteoporosis at the conventionally used doses and no evidence that they cause an increased risk of fractures. ICS can result in biochemical changes in bones, but overall height is unaffected. Skin bruising occurs as a dose-dependent side effect of ICS in 47% of patients, usually at daily doses of >1000 μg day^-1. The incidence of skin bruising increases with age and duration of treatment.

Theophylline is indicated for the treatment of acute asthma, chronic asthma, and COPD. Caffeine, a methylxanthine with a small bronchodilator effect, was used to treat asthma in the early part of the twentieth century. Theophylline, also a methylxanthine, is a non-selective phosphodiesterase inhibitor which has minimal effect on bronchomotor tone in normal airways. It reverses bronchoconstriction in asthmatic patients by increasing intracellular cAMP concentration and by blocking the adenosine receptor, thereby reducing the bronchoconstriction that adenosine causes in asthmatic patients through activation of mast cells.

Theophylline has a smaller bronchodilator effect than β₂-agonists or ICS, but has an immunomodulatory role, reducing the number of T lymphocytes in the airways. Theophylline inhibits the late response to allergen challenge more effectively than the early response and inhibits the influx of eosinophils into the airways. Theophylline has an additive bronchodilator effect when used together with β₂- agonists, although this combination increases the risk of hypokalaemia and tachycardia.

Theophylline is used worldwide as a treatment for asthma. It is much cheaper than the current inhaled therapy and can be given orally. Although it is rapidly absorbed, it has a narrow therapeutic range because several factors affect plasma clearance. Many different formulations of slow release theophylline are available which differ in their pharmacokinetic profiles. It is usually given at a dose of 400 mg daily. While the aim is to achieve therapeutic drug levels of 10—20 mg l^-1, there is some evidence that plasma concentrations of 5—10 mg l^-1 may be effective, especially in combination with corticosteroids. Side effects occur with plasma levels over 20 mg l^-1 and include nausea in 10% of patients, and abdominal discomfort. Toxicity can result in tachyarrhythmias, and seizures, which are more common when the drug is given intravenously.

Theophylline is metabolised in the liver by the cytochrome P450 enzyme system and therefore interacts with many drugs that are also metabolised by this system. Drugs that are enzyme inducers, such as rifampicin and anticonvulsants, reduce the level of theophylline, as does excessive alcohol use. Drugs that are enzyme inhibitors, such as erythromycin or ciprofloxacin, increase the level of theophylline. Levels are also increased in heart failure, with viral infections, in those with liver cirrhosis, and in the elderly. Theophylline should be used with caution in patients with cardiac arrhythmias, severe hypertension, hyperthyroidism, epilepsy, and those at risk of hypokalaemia.

Aminophylline, the intravenous equivalent of theophylline, is a mixture of theophylline and eth- ylenediamine which is 20 times more soluble than theophylline alone. If the patient is not on oral theophylline, then a loading dose of 5 mg kg^-1should be given (up to a maximum of 500 mg) followed by a slow infusion of 0.5 mg kg^-1 h^-1 over at least 20 minutes for acute asthma and COPD. If intravenous aminophylline is given, a blood sample should be taken 4—6 hours after starting treatment. Plasma theophylline concentration should be measured five days after starting oral treatment and at least three days after any dose adjustment.

Roflumilast is a selective, long-acting phosphodiesterase-4 inhibitor, which is available as a tablet. It has been shown to reduce exacerbations in patients with severe COPD, especially when used in combination with LABA, for example, indacaterol or olodaterol. Side effects include diarrhoea, nausea, dizziness, and headaches.

Leukotriene antagonists are commonly used to treat allergic and exercise-induced asthma. Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are formed from arachidonic acid by the enzyme 5-lipo oxygenase. Leukotrienes stimulate the cys leukotriene 1 receptor, resulting in bronchoconstriction, activation and recruitment of eosinophils, microvascular leakage, and increased mucus production. Leukotriene D4 is the most potent of these. Elevated levels of leukotrienes are found in the bronchoalveolar lavage fluid and the urine of asthmatics.

Leukotriene 1 receptor antagonists block the effects of leukotrienes, causing bronchodilatation and reducing the eosinophilic response associated with inflammation. Leukotriene receptor antagonists are recommended for use in patients with mild to moderate asthma who are either unable to take ICS or who are not optimally controlled despite taking a combination of ICS and LABA. They are often used at Step 3 of the Asthma Management Plan. These drugs may benefit patients with asthma which is induced by exercise, allergens, cold air, and aspirin. Use of leukotriene inhibitors has been shown to reduce the need for short-acting bronchodilators. Leukotriene antagonists are given orally and generally well tolerated, with few side effects. There are differences in rates of absorption and metabolism between drugs in this class. Montelukast, 10 mg, can be given once a day whereas Zafirlukast, 20 mg, is given twice a day. Corticosteroids are not known to significantly inhibit the production of leukotrienes.

Magnesium sulfate is used to treat severe asthma. It is not entirely clear how it works, but it causes bronchodilation when given intravenously at a dose of 1.2—2 g over 20 minutes. A recent trial of intravenous or nebulised magnesium sulfate in adults with exacerbation of asthma found no benefit. However, a systematic review of randomised controlled trials found a reduction in hospital admissions in those with asthma exacerbations treated with magnesium sulfate and an improvement in lung function.

Sodium cromoglycate and nedocromil sodium belong to a group of drugs called the cromones and are licensed for use in asthma and rhinitis. Sodium cromoglycate is a derivative of khellin, an Egyptian herbal remedy that was found to protect against allergen challenge without a significant bronchodilator effect. Sodium cromoglycate stabilises the mast cell membrane, prevents degranulation, and inhibits the release of inflammatory mediators. Sodium cromoglycate is used in children as prophylaxis against the bronchoconstriction that can occur with exercise and cold weather. It has few significant side effects so is considered safe in children. Nedocromil sodium is structurally related and has very similar clinical effects.

Immunoglobulin E (IgE) levels are raised in patients with allergic asthma. IgE binds to receptors on mast cells and basophils, causing the release of inflammatory cytokines including histamine and cysteinyl-leukotrienes. IgE specific to allergens, such as house dust mite, can be measured by a radioallergosorbent (RAST) test. Anti-IgE therapy is used to treat allergic asthma.

Omalizumab (Xolair) is a recombinant IgG1 monoclonal antibody that binds to circulating IgE and prevents it from binding to the IgE receptor. The immune complexes formed by this process are then cleared by the liver. Omalizumab is indicated for patients with moderately severe or severe allergic asthma with IgE levels between 30 and 700 units ml^-1 and who are not optimally controlled despite the use of LABA/ICS combined inhaled therapy and leukotriene inhibitor. Randomised controlled trials have demonstrated a reduction in exacerbations in patients treated with this drug and a reduction in steroid use. Omali- zumab is given as a subcutaneous injection in hospital with close monitoring. Total IgE levels, which do not differentiate the free IgE from IgE complex to the drug, rise during treatment. The main concern about this treatment is anaphylaxis, which occurs in 1—2 in every 1000 patients, and can occur after any dose.

Mucolytic drugs are indicated in patients with COPD and bronchiectasis who are troubled by a regular productive cough which they find difficult to expectorate. The sputum of patients with COPD contains more glycoprotein which is more viscous and therefore difficult to expectorate. The retained secretions act as a culture medium and increase the frequency of infections. Thiol medications, such as N-acetyl cysteine (NAC) and erdosteine, contain free sulfhydryl groups which can split the glycoprotein bonds in mucus. They decrease the viscosity of the sputum within a few days of treatment and enhance mucociliary clearance. A Cochrane metaanalysis showed that NAC decreased the number of exacerbations in patients with COPD.

S-carboxymethylcysteine (carbocisteine) is also a mucoactive drug. Its structure and mechanism of action differs from that of NAC and erdosteine. Carbocisteine is well absorbed from the gastrointestinal tract, reaches peak serum concentrations within 2 hours, and has a plasma half-life of 1.5 hours. It penetrates lung tissues and makes bronchial secretions less viscous, thus aiding clearance. Carbocisteine has anti-inflammatory properties, scavenges free radicals in vitro, and may reduce the systemic inflammation associated with COPD. Alteration to the glycoprotein composition of the sputum may increase antibiotic penetration into bronchial secretions. There is some evidence that carbocisteine decreases cough sensitivity.

The clinical response to carbocisteine varies from one individual to another because of genetic polymorphism in the sulphoxidation capacity. NICE and British Thoracic Society (BTS) guidelines recommend the use of mucolytics in selected patients with COPD, particularly those troubled by chronic sputum production and frequent exacerbations. It is generally well tolerated. The main side effects are gastric ulcers and abdominal discomfort.

Adrenaline (epinephrine) is essential in the treatment of anaphylaxis, and 0.3—0.5 mg should be administered immediately as an intramuscular injection. This can be repeated at 10-minute intervals if required. Adrenaline works by preventing the release of mediators such as histamine and cysteinyl leukotrienes from mast cells, which cause bronchoconstriction and cardiovascular collapse. Side effects include anxiety, tachycardia, palpitations, pallor, and tremor. Rarely, adrenaline can result in angina, hypertension, myocardial infarction, and intracranial haemorrhage.

Topical adrenaline can be administered when there is bleeding after an endobronchial biopsy. The recommendations for the dose and amount which can be safely given vary in the different guidelines and there is no randomised trial evidence. The BTS Bronchoscopy guidelines recommend administering adrenaline, 1 : 10 000, through the bronchoscope onto the areas of bleeding while monitoring the heart rate and blood pressure. Many experts recommend giving this dose in 2 ml aliquots, not exceeding a dose of 0.6 mg.

Antibiotics are commonly used drugs for the treatment of bacterial infections. Inappropriate use of these has increased bacterial resistance to certain antibiotics. Antibiotics prescribed for respiratory tract infections, community acquired pneumonia, hospital acquired pneumonia, and Mycobacterium tuberculosis are discussed in Chapter 8.

Antituberculous drugs are given in combination and have many side effects. Compliance can be poor, especially as they must be taken for six months, so Directly Observed Therapy may be necessary. In addition, they interact with many other drugs through the cytochrome P450 enzyme system. Rifampicin in an enzyme inhibitor so can result in the elevation of plasma levels of several drugs, such as warfarin and anticonvulsants.

Macrolide antibiotics are used to treat many respiratory tract infections and community acquired pneumonia (CAP). Erythromycin is the original macrolide antibiotic but is poorly tolerated, with gastrointestinal side effects, prolonged QT interval, and elevated liver enzymes. Azithromycin and clarithromycin are derived from erythromycin after changes to the structure of the molecule. These newer drugs are more stable, have better oral bioavailability, are better tolerated, and have a broader spectrum of activity than erythromycin.

Macrolides bind to a subunit of bacterial ribosomes and inhibit protein synthesis. Clarithromycin and azithromycin are effective against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Mycobacterium avium complex. They are also used for their anti-inflammatory effects and in the prophylaxis of recurrent respiratory infections in patients with bronchiectasis, cystic fibrosis, and COPD.

As macrolides are metabolised by the cytochrome P450 system and are enzyme inducers, they interact with several drugs, including aminophylline, statins, warfarin, and anticonvulsants, and reduce the plasma level of these drugs. They should, therefore, be used with caution.

Modafanil is derived from adrafanil, a benzhydryl sulfinyl compound. Its exact mechanism of action is unknown, but it promotes alpha wave activity when awake and increases theta wave activity during sleep. It increases histamine levels in the hypothalamus and dopamine concentrations in the brain. Modafanil has been shown to increase wakefulness, alertness, concentration, and to improve mood.

It is licensed for use in narcolepsy, obstructive sleep apnoea/hypopnoea syndrome (OSAHS) and shift worker sleep disorder (SWSD). It can also be used for other hypersomnias, seasonal affective disorder (SAD), and fatigue secondary to chronic diseases. Case studies have suggested that it may benefit patients with type 2 respiratory failure who cannot tolerate non-invasive ventilation (NIV) or are unsuitable for NIV. Modafanil is given orally, either once or twice a day. It is a long-acting drug with a half-life of 15 hours. The main side effects include hypersensitivity reactions and psychiatric symptoms.

Doxapram is a respiratory stimulant which acts on the chemoreceptors in the carotid bodies and the respiratory centre in the medulla, increasing the respiratory rate. It can be used in patients with type 2 respiratory failure who cannot tolerate or are not suitable for NIV. It can also be used to treat respiratory depression secondary to opiate overdose in addition to naloxone. It is given intravenously but needs to be monitored carefully as it can cause arrhythmias and hypertension.

Pirfenidone is an anti-fibrotic drug which reduces fibroblast proliferation and the production of procollagens 1 and 11. It also has anti-inflammatory properties. It can be used in mild and moderately severe idiopathic pulmonary fibrosis (IPF) with forced vital capacity (FVC) of 50—80% predicted. It has been shown to reduce the decline in vital capacity and disease progression and may reduce mortality (see Chapter 7). Pirfenidone has many side effects, which include nausea and photosensitivity.

Nintedanib is an orally active tyrosine kinase inhibitor which targets vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet derived growth factor receptor (PDGFR). It inhibits angiogenesis but the exact mechanism of action in pulmonary fibrosis is not clear. It has been shown in trials to reduce the decline in FVC and time to exacerbation in patients with IPF. It can also be used with docetaxel as second-line treatment for non-small cell lung cancer.

Drugs prescribed for smoking cessation

Smoking is responsible for at least 5% of hospital admissions and is a preventable cause of ill health. Approximately 17% of adults in the UK smoke, but two-thirds of them have expressed a desire to quit. There is strong evidence that smoking cessation reduces morbidity and mortality, is cost-effective and should be emphasised to every patient at every encounter. All healthcare professionals, including pharmacists, should be encouraged to ‘Ask, Advise, Assist and Arrange’ to help smokers to quit.

Smoking cessation interventions are evidence- based and cost-effective. Repeated interventions and multiple attempts are often needed to permanently quit. A combination of behavioural support and pharmacological therapy increases the number of smokers who stop smoking. Counselling can be done one-to-one, in groups or via telephone, for example, the ‘Quitline’. Some patients stop smoking after receiving psychotherapy, hypnotherapy, and acupuncture but these are not available on the NHS. There is evidence that banning cigarette smoking in public places has reduced the prevalence of smoking.

While brief advice from a doctor results in 2% of smokers stopping, the addition of medication increases this significantly. Drugs that are prescribed include nicotine replacement therapy (NRT), bupropion, and varenicline. NRT, given as patches, gums, lozenges, and sprays has been shown to double the chance of quitting in clinical trials. NRT reduces the symptoms of nicotine withdrawal, which includes irritability, restlessness, craving, anxiety, depression, and insomnia. NRT provides nicotine in a slower and safer way than cigarette smoke, without the tar and carbon monoxide. A transdermal nicotine patch should be applied daily, initially 21 mg day^-1 for four weeks, reducing to 14 mg day^-1for two weeks and then 7 mg day^-1 for two weeks. The onset of action is rather slow and therefore nicotine chewing gums, lozenges, inhalators, and nasal sprays can provide more rapid peak blood levels as the drug is absorbed directly through the buccal or nasal mucosa. Very few individuals become addicted to NRT. Weight gain is a common concern among smokers who want to quit, and this should be addressed in the counselling cessations.

Buproprion (Zyban) is an anti-depressant which works by increasing levels of dopamine and noradrenaline in the central nervous system. It has been found to double the rate of smoking cessation compared to placebo but is less effective than varenicline. A dose of 150 mg daily for three days, followed by 150 mg twice a day for 7—12 weeks, is given. There is evidence that a longer period of treatment may reduce relapse. It may be a good choice in those who are particularly concerned about weight gain and in those in whom varenicline is contra-indicated. The most worrying side effect of Buproprion is seizures which occurs in 0.1%, so it should be avoided in those with epilepsy or those with other risk factors for seizures. Buproprion can also cause insomnia, agitation, dry mouth, and headaches.

Varenicline (Champix) is a partial agonist which binds to the alpha-4 P-2 subunit of the nicotinic acetylcholinergic receptors in the brain. It blocks nicotine from binding to the receptor and, as a partial agonist, it reduces the symptoms of nicotine withdrawal. Varenicline is the most effective and cost-effective treatment for smoking cessation, with a rate of smoking cessation three times higher than with placebo. Several trials have found varenicline to be superior to buproprion or NRT. Varenicline is contra-indicated in individuals with a psychiatric history as it may predispose to suicidal ideation. It should also be used with caution in individuals with cardiovascular problems, particularly coronary artery disease and peripheral vascular disease.

E-cigarettes are available that deliver nicotine without the carcinogens in cigarette smoking. Vaping is now popular, and some studies have shown that this helps individuals from smoking cigarettes. The long term effects of vaping are not known, but many doctors feel that it is a safer option than smoking. Therefore, it could be considered when the patient is unable to stop smoking after trying all the other available measures.

Drugs that damage the lungs

A variety of drugs can damage the lung parenchyma, resulting in alveolitis, non-specific interstitial pneumonia (NSIP), pulmonary fibrosis, and adult respiratory distress syndrome (ARDS). As discussed in Chapter 7, a detailed history should be taken of all the medication the patient has taken in the recent past. If there is any indication that a drug may be implicated, then it should be stopped. The patient may need oxygen if hypoxic, and systemic glucocorticoids, for example, oral prednisolone 40—60 mg daily or intravenous methylprednisolone.

A chest X-ray (CXR) and a computed tomography (CT) thorax can show several different patterns, including alveolar opacities, interstitial or mixed opacities and focal nodular areas of consolidation. A bronchoalveolar lavage (BAL) may be required to rule out infection, malignancy, and pulmonary haemorrhage. A lung biopsy is rarely helpful once there is established fibrosis.

Box 3.3 Drugs causing diffuse parenchymal lung disease.

• Amiodarone	• Carmustine
• Methotrexate	• Chlorambucil
• Nitrofurantoin	• Naproxen
• Sulphonamides	• Flecanide
• Chemotherapy agents	• Statin

Box 3.3 lists some of the common agents. A more comprehensive list will be found at www. pneumotox.com

Chemotherapy drugs frequently result in pulmonary toxicity (Figure 3.13, Figure 3.14). Patients will present with cough and breathlessness, the differential diagnosis for which includes infection, pulmonary emboli, heart failure, and lung metastases. If the patient has had radiotherapy, then radiation damage will also be a possible cause (Figure 3.15). Parenchymal lung damage from drugs and radiation is discussed in Chapter 7.

Figure 3.13 CT thorax showing nitrofurantoin toxicity.

Figure 3.14 CT showing bleomycin toxicity.

Figure 3.15 CXR showing radiation-induced fibrosis.

■ Drug deposition in the lung is affected by the size of the particle, its solubility, the inspiratory flow rate, and the distance travelled.

■ The inhaled route has many benefits over the systemic route.

■ There are several devices for inhaling medication, but only 10% of the drug reaches the lungs.

■ pMDI devices should be used with a volumatic device to improve drug deposition and reduce oropharyngeal deposition.

■ Dry powder inhalers are easier to use but require an inspiratory flow rate of 30 l min^-1.

■ Obstructive airways diseases are treated with a combination of SABA, LABA, SAA, and LAMA to optimise bronchodilation.

■ ICS reduce chronic inflammation and bronchodilate the airways in asthma and COPD.

■ ICS have fewer systemic side effects compared to OCS.

■ Phosphodiesterase inhibitors have a role in the treatment of obstructive airways diseases.

■ LTOT is indicated in patients with type 1 or type 2 respiratory failure with a PaO₂ < 73 kPa or 8 kPa and signs of cor pulmonale and polycythaemia.

■ Magnesium sulfate is indicated in patients with acute asthma.

■ Leukotriene antagonists are indicated in patients with allergic, exercise-induced, or aspirin-induced asthma.

■ Anti IgE therapy (Omalizumab) can be given to patients with allergic asthma and raised IgE who are not optimally managed on other medication.

■ Macrolides are antibiotics which have a wide spectrum of antibiotic and anti-inflammatory properties.

■ Mucolytic drugs should be considered in patients with COPD and bronchiectasis who have chronic sputum production and frequent exacerbations.

■ Intramuscular adrenaline at a dose of 0.3-0.5 mg should be given to patients presenting with anaphylaxis.

■ Topical adrenaline (1 : 10000) can be given through the bronchoscope when bleeding occurs after an endobronchial biopsy.

■ Doxapram is a respiratory stimulant that could be used in patients with type 2 respiratory failure who are unable to tolerate NIV.

■ Modafanil increases histamine levels in the brain, promotes wakefulness, and is indicated for narcolepsy, OSAHS, shift worker sleep disorder, and seasonal affective disorder.

■ Perfenidone and nintedanib are new drugs for the treatment of idiopathic pulmonary fibrosis.

■ NRT, Buproprion, and varenicline are safe, effective, and cost-effective drugs prescribed for smoking cessation.

■ A variety of drugs are toxic to the lungs and damage the lungs in several different ways.

MULTIPLE CHOICE QUESTIONS

3.1 Which of these factors does NOT influence the deposition of the drug in the airways?

A Inspiratory flow rate B Size of the drug particle C Turbulence of air flow D Age of the patient E Solubility of the drug

Answer: D

Drug deposition in the airways depends on the size of the particle, the inspiratory flow rate, the turbulence of the air flow, and the solubility of the drug. The age of the patient will only be relevant if they are unable to generate a sufficient inspiratory flow rate.

3.2 Which of the following statements about theophylline is true?

A Theophylline blocks the muscarinic cholinergic receptors in bronchial mucosa

B Theophylline blocks the movement of eosinophils into the lungs

C Theophylline causes significant bron- chodilation in normal airways

D Theophyllin e is the most potent bronchodilator available

E Theophylline should be given intravenously as it is poorly absorbed from the gut

Answer: B

Theophylline, a methylxanthine, is a phosphodiesterase inhibitor. It does not affect the cholinergic receptor but does decrease the movement of eosinophils into the lungs. It is a weak bronchodilator compared to corticosteroids or β₂-agonists. It is well absorbed from the gastrointestinal tract and can be given orally.

3.3 Which of the following statements is true?

A Theophylline has no clinical benefit if the plasma level is less than 10 mg l^-1

B Macrolides will decrease the plasma concentration of theophylline

C The commonest side effects of theophylline are cardiac

D Intravenous aminophylline can be given safely if the patient is on oral theophylline

E Plasma theophylline concentration should be measured five days after starting oral treatment

Answer: E

There is some evidence that plasma theophylline level of < 10 mg l^-1 may have some benefit when given with corticosteroids and or β₂ agonists. Macrolides are enzyme inhibitors so they reduce the clearance of theophylline by the cytochrome P450 enzyme system, thus increasing the plasma theophylline concentration. The commonest side effects of theophylline are gastrointestinal. The plasma theophylline level should be measured in patients taking this drug before intravenous aminophylline is given. The plasma concentration should be measured five days after starting the medication.

3.4 Which of the following statements about leukotrienes and leukotriene receptor antagonists is true?

A Leukotriene E4 is the most potent leukotriene

B Increased levels of leukotriene are found in the urine of patients with asthma

C Leukotriene receptor antagonists increase eosinophilic infiltration of airways

D Leukotriene receptor antagonists have no benefit in patients with exercise-induced asthma

E Leukotriene receptor antagonists have no benefit if the patient is already on oral corticosteroids

Answer: B

Leukotriene D4 is the most potent of the leukot- rienes, all of which are derived from arachidonic acid. Increased levels of leukotrienes are found in the urine and bronchoalveolar lavage of patients with asthma. Leukotriene receptor antagonists block the influx ofeosinophils into the airways and so have an anti-inflammatory effect. They are therefore useful in the management of asthma induced by exercise, cold air, allergen, or aspirin. Corticosteroids have no effect on this pathway, so leukotriene receptor antagonists are indicated, even if the patient is already on steroids.

3.5 Which of the following statements about Omalizumab is true?

A Omalizumab is a monoclonal antibody that binds to circulating IgE

B Omalizumab is indicated only for patients with life-threatening asthma

C Omalizumab is available as an oral preparation

D Anaphylaxis occurs in 1% of patients treated with Omalizumab

E Anaphylaxis usually occurs after several treatments with Omalizumab

Answer: A

Omalizumab, a monoclonal antibody that binds to circulating IgE, can be used for patients with moderately severe asthma who are not optimally controlled on LABA and ICS. It is given as a subcutaneous injection. Anaphylaxis occurs in 0.1% of patients and can occur even after the first dose.

3.6 Which of the following statements about inhaled corticosteroids (ICS) is true?

A ICS cause adrenal suppression at a dose of 600 μg daily

B ICS increase the risk of osteoporosis and fractures at a dose of 800 μg daily

C ICS are hydrophilic drugs with a low affinity for the glucocorticoid receptor

D ICS have a flat dose-response curve so doubling the dose has minimal benefit but with increased side effects

E The effectiveness of ICS is reduced if given with LABA

Answer: D

ICS are not known to have significant systemic side effects at doses less than 1000 μg daily in adults. ICS are lipophilic drugs with a high affinity for the glucocorticosteroid receptor, ICS have a flat dose-response curve, therefore, it is better to add another drug, such as a LABA rather than double the dose. ICS and LABA are often given in combination and have a synergistic effect.

3.7 Which of the following statements about oral corticosteroids is true?

A Cortisone is an active compound and binds to the glucocorticoid receptor

B Prednisone is hydroxylated in the liver to prednisolone, the active compound

C Hydrocortisone is more potent than dexamethasone

D Corticosteroids are poorly absorbed from the gastrointestinal tract

E Glucocorticosteroid receptors are not found in lung tissue

Answer: B

Cortisone and prednisone are pro-drugs which are hydroxylated in the liver to the active drugs hydrocortisone and prednisolone. Dexamethasone is 25 times more potent than hydrocortisone. Corticosteroids are absorbed rapidly from the gastrointestinal tract, therefore are mostly given orally. Glucocorticosteroid receptors are found in most tissues in the body.

3.8 Which of the following statements about anticholinergic drugs is true?

A Anticholinergic drugs are effective against exercise-induced asthma

B Anticholinergic drugs have a greater bronchodilator effect than β₂-agonists

C Anticholinergic drugs block the release of histamine from mast cells

D Anticholinergic drugs are more effective in the airways of COPD patients than normal airways

E Short-acting anticholinergic drugs have a shorter duration of action than B₂-agonists

Answer: D

Anticholinergic drugs are not anti-inflammatory so do not affect histamine or leukotriene release. They are not effective against allergen-induced or exercise-induced bronchoconstriction. They are less effective bronchodilators than β₂-agonists but have a longer duration of activity, lasting 4—6 hours. They are more effective in COPD as the cholinergic bronchoconstrictor reflex is exaggerated in these patients due to chronic, fixed obstruction.

3.9 Which one of the following questions about macrolides is true?

A Azithromycin is never used to treat community acquired pneumonia

B Erythromycin can cause ototoxicity if given for more than two weeks

C Macrolides have anti-inflammatory properties

D Macrolide resistance occurs in less than 5% of the population

E Macrolides work by destroying the bacterial cell wall

Answer: C

Macrolides have anti-inflammatory properties although the exact mechanism is unknown. They inhibit protein synthesis in bacterial ribosomes but resistance is increasing and approaching 25%. Macrolides can be used to treat CAP, and ototoxicity is not a common side effect of macrolide treatment.

3.10 Which of the following statements about smoking cessation is true?

A Nicotine replacement therapy (NRT) is ineffective in patients who smoke more than 20 cigarettes a day

B NRT should not be given together with varenicline

C Buproprion blocks the nicotinic anticholinergic receptors in the brain

D Varenicline is the most effective treatment for smoking cessation

E The majority of smokers do not wish to stop smoking

Answer: D

More than two-thirds of smokers wish to stop. NRT increases the quit rate compared to placebo and can be given in combination with Buproprion or Varenicline. Varenicline is a partial agonist of the nicotinic anticholinergic receptors. Buproprion is an anti-depressant which increases the levels of noradrenaline and dopamine in the brain.