Case 3 – Turning Blue

Case centres on a COPD sufferer. He is a smoker, working on cutting down his cigarette consumption. Despite treatment he experiences progressive disablement due to COPD and repeated infections.

1. pathophysiology of COPD – emphysema (cause and consequence), polycythemia and inflammations
2. “nictotine fix” – composition of cigarette smoke, what it does, why is it addictive? smoking as a social/occupational risk
3. tests – how and why
4. treatments – pharmacology (mechanisms)
5. infections as complication of COPD

Airway tone and pressures

[K&C] Airway tone shows a circadian rhythm which is greatest at 0400 and lowest mid afternoon, hence asthma symptoms often worse early morning. Airways expand as lung volume is increased, and at full inspiration, TLC, they are 30-40% larger in calibre than at full expiration, RV. In COPD the small airways are narrowed and this can be partially compensated by breathing at a larger lung volume. The airways become smaller, and greater in number, towards the periphery. The total cross sectional area of airways increases and the resistance to airflow decreases, until the terminal airways where airflow occurs solely by diffusion. Air pressure increases towards the trachea as resistance increases.

Adrenoceptors on bronchial muscles respond to circulating catecholamines; there is no direct sympathetic innervation.

Between the alveolus and the mouth there is a point where airway pressure equals intrapleural pressure, and airways collapse temporarily, and tend to vibrate. The elastic recoil pressure of the lungs decreases with decreasing volume, so the collapse point moves towards the smaller airways. Where there is pathological loss of recoil pressure, e.g. COPD, the collapse point starts even further upstream and causes expiratory flow limitation. FEV1 is a useful clinical index of this phenomenon. To compensate, these patients often ‘purse their lips’ in order to increase airway pressure so that their peripheral airways do not collapse. On inspiration, the intraplueral pressure is always less than the intraluminal pressure within the intrathoracic airways, so there is no limitation to airflow with increasing effort. Inspiratory flow is limited only by the power of the inspiratory muscles.

In subjects with healthy lungs, maximal flow rates are rarely achieved even during vigorous exercise. In patients with severe COPD, limitation of expiratory flow occurs even during tidal breathing at rest. To increase ventilation these patients have to breathe at higher lung volumes and allow more time for expiration which both reduce the tendency for airway collapse. To compensate they increase flow rates during inspiration, where there is relatively less flow limitation.

http://www.pharmacology2000.com/Co-Existing_Disease/co_exist2a.htm

Treatments for COPD

Buproprion and NRT treatments for Smoking cessation

Bronchodilator and Glucocorticoid – see Asthma treatments

Oxygen Therapy

Extremely important in COPD exacerbations. Care must be taken to raise the arterial oxygen saturation, if possible to >90%, without increasing the arterial oxygen saturation. Low dose oxygen may be necessary (e.g. 24% by venturi mask, or 1-2L/min by nasal cannulae) if there is a tendency to retain carbon dioxide (type 2 respiratory failure (type 1 is hypoxaemic with PaO2 < 60mmHg (8 kPa) with a normal or low PaCO2; type 2 is hypercapnic with PaCO2 > 50mmHg (6.5 kPa) and frequently patient is also hypoxic. Respiratory failure can also be acute or chronic). Long-term domiciliary oxygen treatment, usually delivered via nasal cannulae, improves symptoms and survival in COPD with respiratory failure (with an arterial oxygen tension less than 7.3 kPa). It should not be used unless respiratory failure persists for 3-4 weeks despite optimal drug therapy and without a clinical exacerbation. It should not be used by smokers because of the fire risk. To improve survival, oxygen must be used for at least 15h per day.

Venturi masks can accurately provide concentrations 24-60% O2. Greater concentrations of oxygen (>60%) may damage the alveolar membrane when inhaled for more than 48 hours. Progression to the adult respiratory distress syndrome with high protein alveolar oedema and pulmonary radiographic infiltrates is associated with high mortality.

In healthy people, breathing is triggered by rising levels of carbon dioxide in the blood. However, in people with severe COPD, breathing may become controlled by an alternative system in which breathing is triggered by falling levels of oxygen in the blood. In this case, inhaling oxygen will tend to shut down breathing, with dangerous consequences. Careful testing, including blood tests, will therefore be necessary before starting oxygen therapy, but in many cases oxygen can be provided safely (in cases of hypoxia with chronic hypercarbia, tissue perfusion is important and may require mechanical ventilation). http://www.abpi.org.uk/publications/publication_details/targetCOPD/q4.asp

ABC of Oxygen, Acute oxygen therapy, NT Bateman, RM Leach, www.bmj.com/cgi/content/full/317/7161/798

Full face mask, and nose mask, from
www.saintmedical.com

Venturi valves and venturi mask kit from www.mayohealthcare.com.au

Coloured valves indicate oxygen concentrations, from blue (24% O2) to green (60% O2)

Antibiotics

(cefuroxime, erythormycin) – also link to semester 1 antibacterials

Agents affecting the cell wall: beta-lactam antibacterials

Cephalosporins (e.g. cefuroxime is a second generation cephalosporin)

Like penicillins, cephalosporins have a beta-lactam ring. To this ring is fused a dihydrothiazine ring, which makes them more resistant to hydrolysis by beta-lactamases. They inhibit bacterial cell wall synthesis in a manner similar to that of the penicillins.

Succeeding generations of cephalosporins tend to have increased activity against Gram-negative bacilli, usually at the expense of Gram-positive activity, and increased ability to cross the blood-bran barrier. Cefuroxime has activity against staphylococci and most streptococci, and some gram-negative bacteria such as haemophilus influenzae and Neisseria gohorrhoea; but not enterococci. They cross the blood-brain barrier well. It has high resistance to beta-lactamases. It is acid-labile and must be given by parenteral route, or as a prodrug for oral use – cefuroxime axetil, which has good absorption and is hydrolised at first pass through the liver to cefuroxime. It is excreted by kidney and has short half-life.

Unwanted Effects

• Nausea, vomiting, abdominal discomfort.
• Rashes, including erythema multiforme and toxic epidermal necrolysis
• can produce hypersensitivity reactions similar to those observed in penicillins. ~10% of those allergic to penicillins shop cross-allergy to cephalosporins. A history of serious reaction to penicillins precludes the administration of cephalosporins.
• Diarrhoea or antibiotic-associated colitis can be caused by disturbance of normal bowel flora. This is more common with oral cephalosporins.

Agents affecting bacterial protein synthesis

Macrolides, e.g. erythromycin

Macrolides interfere with bacterial protein synthesis by binding reversibly to the 50S subunit of the bacterial ribosome. This causes dissociation of the peptidyl transfer RNA (tRNA) from its translocation site. The action is primarily bacteriostatic (stops bacteria from reproducing, while not necessarily harming them otherwise).

Erythromycin has a similar spectrum of activity to broad-spectrum penicillins, and is often used for treatment in people who are penicillin-allergic. It is effective against Gram-positive bacteria and gut anaerobes, but has poor activity against Haemophilus influenzae. It is also used for infections by Legionella, Mycoplasma, Chlamydia, mycobacteria and Campylobacter species and for Bordetella pertussis. Although erythromycin is primarily bacteriostatic, it is bactericidal at high concentrations for some Gram-positive species, such as group A streptococci and pneumococci.

Bacteria become resistant to macrolides by activation of an efflux mechanism. To a lesser extent, there is also a gene mutation that encodes for a methyltranferase that modifies the target site on the ribosome.

Erythromycin is adequately absorbed from the gut. It is destroyed at acid pH and is, therefore, given as an enteric-coated tablet or as an ester prodrug (erythromycin ehtyl succinate), which is acid-stable. Erythromycin can also be administered intravenously. It is metabolised in the liver and has a short half-life.

Unwanted effects

• Epigastric discomfort, nausea, vomiting and diarrhoea are common with the oral preparation.
• Rashes
• Cholestatic jaundice with erythromycin, usually if treatment is continued for mote than 2 weeks.
• Prolongation of the Q-T interval on the ECG, with a predisposition to ventricular arrhythmias.
• Inhibition of p450 drug-metabolising enzymes and can elevate levels of drugs requiring these enzymes for metabolism, e.g. carbamazepine and ciclosporin.

Assessing COPD

(see also Pulse Oximetry)
Blood Pressure
COPD can cause high blood pressure in the lungs.  This can lead to “cor pulmonale,” a form of heart disease secondary to lung disease [www.americanheart.org]. Among all individuals, including those with COPD, there is a protective mechanism in the lung that causes constriction of blood vessels in areas of the lung that have a low concentration of oxygen. Instead, blood is diverted to other well-ventilated parts of the lung where exchange can take place. Unfortunately, although this mechanism improves the efficiency of oxygen and carbon dioxide exchange, the constriction of the blood vessels also causes the blood pressure in the lungs to rise, a condition called pulmonary hypertension. The increased pressure may lead to right-heart failure (vena cava –> right –> tricuspid –> lungs –> left –> bicuspid –> aorta). This often can be detected first in a patient by the presence of ankle swelling. Oxygen inhaled by patients with COPD can relax the blood vessels and decrease blood pressure in the lungs.
[http://www.medicinenet.com/chronic_obstructive_pulmonary_disease_copd/page7.htm]
Spirometry
Spirometry measures air flow and volume. Normally, the lung empties 70 percent to 75 percent of its total air volume within one second. It is now known that the forced expiratory volume in six seconds FEV6 is an excellent surrogate for FVC. Thus, doing a six-second expiratory manoeuvre is more pleasant for the patient and more convenient for the tester. Normal values for lung function in spirometry are based on patient age, gender and height. Because of arm and leg span differences, black non-smokers tend to have normal values of about 15 percent less than white non-smokers.
Lung function
Lung function measures elastic recoil, large and small airway resistance, interdependence between airways and alveoli, and muscular effort and coordination. In patients with ventilatory abnormalities, such as emphysema, airflow is limited by loss of elastic recoil, and in those with conditions like bronchospasm, mucosal oedema, mucus retention and inflammation, the airway narrows.
Since airflow disorders lower the FEV1 before the FVC, the ratio between the two is the starting point in interpretation. If the patient’s FEV1/FVC ratio is low, for instance less than 70 percent, then the patient has an obstructive defect. Patients with complete or nearly complete airway obstructions that resolve with inhaled bronchodilator use have asthma. Those with irreversible airflow obstructions have COPD. However, considerable overlaps between asthma and COPD are common. Marked hyperinflation, which leads to air trapping, lowers vital capacity.
Spirometric abnormalities are also predictors of heart attack, lung cancer and stroke. A low vital capacity in heart disease may be due to pulmonary congestion, pleural effusion, cardiomegaly or muscular weakness. With any degree of airflow obstruction, the risk of lung cancer is three to five times higher, depending on the patient’s age and smoking history.
http://www.nlhep.org/spirom1.html – National Lung Health Education Program and
http://www.nlhep.org/resources/SpirometryMadeSimple.htm – Spirometry Made Simple, TL. Petty

Polycythemia – defined as an increase in haemoglobin, PCV (packed cell volume) and red cell count. PCV is a more reliable indicator of polycythaemia than is Hb, which may be disproportionately low in iron deficiency. Polycythamia can be divided into absolute erythrocytosis where there is a true increase in red cell volume, or relative erythrocytosis where the red cell volume is normal but there is a decrease in the plasma volume. Absolute erythrocytosis is due to primary polycythemia (PV = Polycythemia vera) or secondary polycythemia. Secondary polycythemia can be due to an appropriate increase in erythropoeietin in response to anoxia eg through high altitude, heavy smoking, lung disease, cardiovascular disease (left-to-right shunt) or mutant high oxygen affinity haemoglobin, e.g. congenital polycythemia; or due to an inappropriate increase in erythropoietin, either congenital or due to renal or liver disease, tumours, or certain drugs. Heavy smoking can produce as much as 10% carboxyhaemoglobin and this can produce polycythemia because of a reduction in the oxygen-carryingcapacity of the blood. Complications of polycythemia include thrombosis, haemorrhage and cardiac failure. Treatment is by treating the precipitating factor. Venesection (giving blood) may be symptomatically helpful in the hypoxic patient, particularly if the PCV is above 0.55L/L.

Pulse Oximetry

Pulse oximetry is a simple non-invasive method of monitoring the percentage of haemoglobin (Hb) which is saturated with oxygen. The pulse oximeter consists of a probe attached to the patient’s finger or ear lobe which is linked to a computerised unit. The unit displays the percentage of Hb saturated with oxygen together with an audible signal for each pulse beat, a calculated heart rate and in some models, a graphical display of the blood flow past the probe. Audible alarms which can be programmed by the user are provided. An oximeter detects hypoxia before the patient becomes clinically cyanosed.

Nail varnish may cause falsely low readings. However the units are not affected by jaundice, dark skin or anaemia. Pulse oximetry cannot distinguish between different forms of haemoglobin. Carbo-xyhaemoglobin (haemoglobin combined with carbon monoxide) is registered as 90% oxygenated haemoglobin and 10% desaturated haemoglobin – therefore the oximeter will overestimate the saturation. The presence of methaemoglobin will prevent the oximeter working accurately and the readings will tend towards 85%, regardless of the true saturation.

Oxygen saturation does not reflect the patient’s ability to ventilate. Utilization of SpO2 in a patient with obstructive pulmonary disease may be very misleading. As the degree of lung disease increases, the patient’s drive to breathe may shift from an increased carbon dioxide stimulus to a hypoxic stimulus. Therefore, enhancing the patient’s Sp02 may limit his or her ability to ventilate. The baseline Sp02 for a patient with known severe restrictive disease needs to be considered. [http://www.aacn.org/WD/Practice/Docs/ch_14_PO.pdf]

Pulse oximeters may be used in a variety of situations but are of particular value for monitoring oxygenation and pulse rates throughout anaesthesia. They are also widely used during the recovery phase. The oxygen saturation should always be above 95%. In patients with long standing respiratory disease or those with cyanotic congenital heart disease readings may be lower and reflect the severity of the underlying disease.

In intensive care oximeters are used extensively during mechanical ventilation and frequently detect problems with oxygenation before they are noticed clinically. They are used as a guide for weaning from ventilation and also to help assess whether a patient’s oxygen therapy is adequate. In some hospitals oximeters are used on the wards and in casualty departments. When patients are sedated for procedures such as endoscopy, oximetry has been shown to increase safety by alerting the staff to unexpected hypoxia.

Oximeters give no information about the level of CO₂ and therefore have limitations in the assessment of patients developing respiratory failure due to CO₂ retention. On rare occasions oximeters may develop faults and like all monitoring the reading should always be interpreted in association with the patient’s clinical condition. Never ignore a reading which suggests the patient is becoming hypoxic. There is no doubt that pulse oximetry is the greatest advance in patient monitoring for many years and it is hoped that their use will eventually become routine during anaesthesia and surgery world wide. Since pulse oximeters cost at least £1200 their purchase will depend mainly on economic considerations.

http://www.nda.ox.ac.uk/wfsa/html/u05/u05_003.htm

How does an oximeter work? A source of light originates from the probe at two wavelengths (650nm and 805nm). The light is partly absorbed by haemoglobin, by amounts which differ depending on whether it is saturated or desaturated with oxygen. By calculating the absorption at the two wavelengths the processor can compute the proportion of haemoglobin which is oxygenated. The oximeter is dependant on a pulsatile flow and produces a graph of the quality of flow. Where flow is sluggish (eg hypovolaemia or vasoconstriction) the pulse oximeter may be unable to function. The computer within the oximeter is capable of distinguishing pulsatile flow from other more static signals (such as tissue or venous signals) to display only the arterial flow.

Smoking, health risk, and addiction

[K&C, and Marks et al Health Psychology]

General household surveys in UK show decline in prevalence of smoking in early 90s, but more recent increase in prevalence. At present, 28% of men and women >=16 years old smoke, most common (40%) 16-34 age group, and it is in this age group that the increase has occurred. Uptake of smoking occurs largely in adolescence, associated with parental and peer smoking. At age 15, more boys than girls smoke. A greater proportion of manual workers than professional workers smoke. Rates are higher than this, and increasing, in developing world. Brief psychological therapies for smoking cessation based on cognitive behavioural therapy are showing considerable promise.

Cigarette smoke contains polycyclic aromatic hydrocarbons and nitrosamines, which are potent carcinogens and mutagens in animals. It causes release of enzymes from neutrophil granulocytes and macrophages that are capable of destroying elastin and leading to lung damage. Pulmonary epithelial permeability increases even in symptomless cigarette smokers, and correlates with the concentration of carboxyhaemoglobin in the blood. This altered permeability possibly allows easier access to carcinogens.

http://cancersuraksha.blogspot.com/

<2% of smokers can limit themselves to occasional or intermittent smoking.

Effects of smoking on the lung:

• Large Airways: Increase in submucosal gland volume, increase in number of goblet cells; chronic inflammation, metaplasia and dysplasia of the surface epithelium.
• Small Airways: Increase in the number and distribution of goblet cells; airway inflammation and fibrosis. Epithelial metaplasia / dysplasia, carcinoma
• Parenchyma: proximal acinar scarring, increase in alveolar macrophage numbers, emphysema (centri-acinar, pan-acinar)

Sputum production and airflow limitation increase with daily cigarette consumption, and effort tolerance decreases, partly owing to high levels of carboxyhaemoglobin in bronchitis patients. Smoking and asbestos exposure are synergistic in producing bronchial carcinoma, increasing the risk in asbestos workers by up to 5-8 times that of non-smokers.

Quitting smoking

Cigarette smokers who change to other forms of tobacco can reduce the risk, even if they continue to inhale, and are better off changing to cigars or pipes.

Nicotine replacement therapy (NRT) and buproprion as aids to smoking cessation for those smoking >10/day. NRT is the preferred choice and there is no evidence that combined therapy offers any advantage. Therapy should be changed after 3 months if abstinence is not achieved

[Waller et al, Medical Pharmacology and Therapeutics]

Established cardiovascular disease is a caution for, but not a contraindication to, nicotine replacement therapy. Behavioural therapy enhances the success rate achieved by NRT. Use of NRT doubles the chance of achieving abstinence.

Buproprion is an atypical antidepressant. Most antidepressants are ineffective for smoking cessation, but the use of buproprion is associated with smoking cessation rates equal to or slightly greater than NRT. Treatment should be started 1 week prior to quit date. Additional benefit that smokers who use buproprion as an aid to quitting are less likely to gain weight.

Buproprion is a weak inhibitor of neuronal reuptake of noradrenaline and dopamine, and probably works by enhancing mesolimbic dopaminergic activity. It is given as a modified-release formulation and has a long half-life. Elimination is by hepatic metabolism, which also generates active metabolites. Unwanted effects include anxiety, headache, insomnia and dry mouth. There is an increased risk of epileptic seizures, and buproprion should be avoided if there is a past history of seizures. Recent evidence indicates that, in contrast to other antidepressants that have been studied, nortriptyline is as effective as buproprion for smoking cessation.

COPD

COPD refers to emphysema, chronic bronchitis, or a combination of the two. These cause severe difficulties in ventilation and in oxygenation of the blood, and are among the major causes of disability and death in the US.

Airway obstruction is not caused by increased smooth muscle contraction in these diseases as it is in asthma. In emphysema the cause of obstruction is destruction and collapse of the smaller airways. Emphysema is characterised by the destruction of the alveolar walls leading to an increase in compliance (compliance = the magnitude of change in lung volume produced by a given change in the transpulmonary pressure). Chronic bronchitis is characterised by excessive mucus production in the bronchi and chronic inflammatory changes in the small airways. Obstruction is caused by accumulation of the mucus in the airways and thickening of the inflamed airways. The same agents that cause emphysema, such as smoking, also cause chronic bronchitis, which is why the two diseases frequently coexist.

[Kumar and Clark]

The global initiative in obstructive lung disease (GOLD) predicts that COPD will become the third most common cause of death and fifth most common cause of disability world-wide by 2020.

The term COPD brings together a variety of syndromes associated with destruction of the lung and airflow obstruction. Chronic asthma, chronic bronchitis, emphysema, pink puffers and blue bloaters. “COPD is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.” (GOLD)

• Loss of elasticity and alveolar attachments of airways due to emphysema → reduces elastic recoil and airways collapse during expiration.
• Inflammation and scarring cause the small airways to narrow
• Mucus secretion blocks airways
• Combined these lead to hyperinflation of the lung and breathlessness

COPD is caused by long term exposure to toxic particles and gases. In developed countries, cigarette smoking accounts for 90% of cases. Airflow limitation increases with age, and increases more rapidly in smokers. The rate of increase in someone who has quit smoking is the same as that in someone who never smoked, although it may start from a lower level due to the damage of previous smoking. In developing countries, COPD is caused by cigarette smoking and smoke from cooking fuels. Only 10-20% of heavy smokers develop COPD, indicating individual susceptibility. Risk of death for person smoking 30/day is 20x that of a non-smoker. Autopsy studies have shown that substantial numbers of centri-acinar emphysematous spaces are found in the lungs of 50% of British smokers over the age of 60 years and are unrelated to the diagnosis of significant respiratory disease before death. Climate and air pollution have some affect. Urbanisation, social class and occupation may also have an effect on aetiology but difficult to separate from smoking.

In UK, COPD accounts for 7% of all days off work due to sickness. But the number of patients discharged from hospital with this diagnosis has been falling steadily and the death rate has fallen in the last 25 years from 200 to 70 per 100,000 in the UK.

Pathophysiology

The most consistent pathological finding is hypertrophy and increase in number of the mucus secreting goblet cells of the bronchial tree, evenly distributed throughout the lung but mainly seen in the larger bronchi. In more advanced cases the bronchi themselves are obviously inflamed and pus is seen in the lumen. Microscopically there is infiltration of the bronchi and bronchioles with acute and chronic inflammatory cells and lymphoid follicles in severe disease. In contrast to asthma, the lymphocytic infiltrate is predominantly CD8+. The epithelial layer may become ulcerated and, when the ulcers heal, squamous epithelium may replace the columnar cells. The inflammation is followed by scarring and a remodelling process that thickens the walls and leads to widespread narrowing in the small airways.

The small airways are particularly affected early in the disease, initially without the development of any significant breathlessness. This initial inflammation of the small airways is reversible and accounts for the improvement in airway function if smoking is stopped early. In later stages the inflammation continues even if smoking is stopped.

Further progression of the disease leads to progressive squamous cell metaplasia, and fibrosis of the bronchial walls. The physiological consequence of these changes is the development of airflow limitation. If the airway narrowing is combined with emphysema (causing loss of the elastic recoil of the lung with collapse of small airways during aspiration) the resulting airflow limitation is even more severe.

Emphysema is defined pathologically as dilation and destruction of the lung tissue distal to the terminal bronchiole:

• Centri-acinar emphysema – damage concentrated around the respiratory bronchioles; extremely common form of emphysema, and when of modest extent it is not normally disabling, but severe Centri-acinar emphysema is associated with substantial airflow limitation.
• Pan-acinar emphysema – less common, damage appears to involve the whole of the acinus, and in the extreme form the lung becomes a mass of bullae. Severe airflow limitation and Va/Q mismatch occur. This type of emphysema occurs in alpha1-antitrypsin deficiency.
• Irregular emphysema produces damage and scarring affecting the lung parenchyma patchily without particular regard for acinar structure.

Emphysema leads to expiratory airflow limitation and air trapping. The loss of lung elastic recoil results in an increase in TLC while the loss of alveoli results in decreased gas transfer.

Va/Q mismatch occurs partly because of damage and mucus plugging, and partly because of the rapid expiratory closure of the smaller airways owing to loss of elastic recoil. This leads to a decrease in PaO2 and an increase in the work of respiration.

PaCO2 excretion is not impaired to the same extent and many patients will show low normal PaCO2 values – the “pink puffers” who seek to maintain normal blood gases by increasing their respiratory effort. Other patients fail to maintain their respiratory effort and thus their carbon dioxide levels increase. In the short term, the rise in CO2 leads to stimulation of respiration but in the long term these patients often become insensitive to CO2 and come to depend on hypoxaemia to drive their ventilation. These patients appear less breathless, and because they run low O2 values they start to retain fluid and stimulate the production of erythrocytes (polycythemia). So they become bloated, plethoric and cyanosed. Attempts to abolish hypoxaemia by administering oxygen can make the situation much worse by decreasing respiratory drive in these patients who rely on hypoxia to drive their ventilation.

Loss of 50ml/yr FEV1 in COPD compared to 20mL/yr in healthy people.

Pathogenesis

Cigarette Smoking

Bronchoalveolar washes have shown that smokers have neutrophil granulocytes present within the lumen of the bronchial tree that are absent in non-smokers. Also, small airways of smokers are infiltrated by granulocytes capable of releasing elastases and proteases, which possibly help to produce emphysema. It is suggested that imbalance between protease and antiprotease activity may produce the damage. Alpha1-antitrypsin is a major serum antiprotease which can be inactivated by cigarette smoke.

The hypertrophy of mucous glands in the larger airways is thought to be a direct response to persistent irritation resulting from the inhalation of cigarette smoke. The smoke has adverse effect on surfactant, favouring overdistension of the lungs.

alpha1-Antitrypsin deficiency

alpha1-antitrypsin inhibitor is produced in liver, secreted into blood and diffuses into the lungs where it acts as antiprotesase that inhibits neutrophil elastase, a proteolytic enzyme capable of destroying alveolar wall connective tissue. There are >75 alleles of the alpha1-antitryptin inhibitor gene, of which 3 main phenotypes. ~1in5000 in UK are homozygous deficient, and those who develop chest disease are usually, but not always, smokers. Hereditary alpha1-antitryptin deficiency accounts for ~2% of emphysema cases.

Clinical Features

Characteristic symptoms are cough with production of sputum, wheeze and breathlessness following many years of smokers cough and frequent chest infections. Can be worsened by, e.g., cold, foggy weather, pollution. With advanced disease, breathlessness becomes severe even after mild exercise such as dressing.

Only sign in mild disease is wheeze throughout the chest. In severe disease patient is tachypnoeic with prolonged expiration, using accessory muscles to breathe, and may show intercostal indrawing on inspiration and pursing of lips on expiration

http://www.medicalook.com/Lung_diseases/Copd.html

[http://www.abpi.org.uk/publications/publication_details/targetCOPD/q2.asp]

More than 40 per cent of smokers aged 61-62 and 50 per cent of those aged 76-77 have COPD

Stopping smoking is the only measure that has been conclusively shown to slow further progression of the disease. After stopping smoking, the rate of decline of lung function slows, approaching that in non-smokers. Preventing a exacerbations of COPD is also important, as it has been found that frequent exacerbations are associated with a more rapid decline in lung function. Respiratory infections are a common cause of such exacerbations, so vaccination against influenza and pneumonia may help protect against accelerated decline in lung function. Combinations of inhaled steroids and bronchodilators used in more advanced COPD reduce the frequency and severity of exacerbations and also the risk of death.

In mild COPD (for example, where breathlessness occurs only on exercising), an inhaled short-acting bronchodilator may be sufficient to control the symptoms. If a single bronchodilator is not sufficient, a combination of two types of shortacting bronchodilators may be tried, or a longacting inhaled bronchodilator can be used instead. In more severe cases, guidelines recommend trying a combination of an inhaled long-acting bronchodilator and an inhaled corticosteroid for an initial period of four weeks. If this combination is still not sufficient to provide relief, theophylline, taken by mouth, may be added. However, this can cause unpleasant side-effects and must be closely monitored

Many other therapies can be used to improve the quality of life of people with COPD. Anxiety or depression can be treated by behavioural therapy and medication. Dietary advice can help prevent weight loss and muscle-wasting. Treatment with a mucolytic medicine may ease sputum production. Pulmonary rehabilitation increases exercise tolerance, promoting independence and emotional well-being. Disease flare-ups due to infections such as pneumonia and flu can be prevented by vaccination.

http://www.island-doctors.com/Health.html

<h2>Infections as complication of COPD</h2>

 

Patients with COPD often cope badly with respiratory infections, which can be precipitating cause of acute exacerbations. But its not clear if infections affect the progressive airflow limitation. Prompt use of antibiotics and flu jabs are appropriate.

 

 

 

 

 

 

 

 

 

 

Treatment Compliance and Adherence

[From Health Psychology, Marks et al, Communication: Messages and Meanings, p272]

3 approaches to study of doctor patient communication: ‘Deviant patient’, ‘authoritarian doctor’ or ‘interactive dyad’.

Health communication is a means through which health promotion is achieved. Health psychologists involvement with health promotion has been primarily concerned with health communication, so from health psychologist point of view they are largely the same thing. Public health communication e.g. media campaigns, and activities of health care professionals, e.g. doctor-patient communication.

Communication as route to information about the patient’s physical and/or mental state, and route to provide patient with ‘crucial information about necessary adjustments in lifestyle as well as treatment directives’. Also, has been suggested that effective communication can have a therapeutic effect in itself.

Doctor-patient communication is not always effective – according to Ley (1982) communication is the least satisfactory aspect of the doctor-patient encounter, ~1/3 of patients in UK say they are dissatisfied. Furthermore, patients’ understanding and memory of what they have been told by the doctor is limited. In addition, and possibly as a consequence, 1/3 to 1/2 of outpatients do not comply with doctors’ advice. And a substantial portion of patients problems remain undisclosed and undetected.

Ideas of patient-centred and doctor-centred communication

“Byrne and Long observed that doctors adopted a habitual style that they tended to use with most patients. Some doctors were more controlling than others. Suggested that patient-centred styles increase adherence to treatment, as well as satisfaction. -> training medical students in communication (from mid 80s). But limited success from this approach. Kreps advocated a consumer orientation to health care and heath promotion in order to address the imbalance of power between providers and consumers. Meeuwesen argues that until this imbalance is corrected, training in communication skills is unlikely to succeed.

Interactive dyad perspective, looking at the ‘communicative event’ to which both doctor & patient contribute.

There are a wide range of factors that influence doctor patient interaction – gender, culture, patient groups, age, stage of illness, disability. AIDs patients are often very informed, sometimes more than their doctors, as are disabled patients. Patient adherence to treatment, understanding, and satisfaction, as proxy outcome measures – true measure might be long term health status and quality of life.

Methods used to study doctor-patient communication:

• Interaction analysis systems – allow researcher to identity, categorise and quantify features of the doctor-patient encounter, e.g. analysing audio or video recordings – predominantly used to study doctor’s communication styles.
• Questionnaire studies – measure patients perceptions of doctor’s communication styles, and patient satisfaction.
• Qualitative textual analysis – e.g. discourse or conversation analysis – linguistic analysis of transcripts of doctor-patient interactions.
• Triangulation – combining methods of analysis – allow researcher to explore same topic from different perspectives.

Compliance – ‘the extent to which the patient’s behaviour … coincides with medical or health advice’ – notion of a dependent layperson and a dominant professional – fails to understand the complexity and legitimacy of patient behaviours that differ from clinical prescriptions. In a study of 54 rheumatology patients Donovan and Blake found that non-compliance was largely the result of reasoned decision-making – patients experimented with drug dosages and timing in order to manage side effects and effectiveness of drugs, and made decisions based on info from GPs, media, family and friends, as well as the consultant – ought to be concerned with provision of information that would allow patients to make informed decisions, rather than compliance per se – ‘concordance’.

Computer guided consultations

Through prompts and fixed sequencing of questions, the computer directs the flow of the interview, interviews can be longer and more detailed, but with less space for ‘small talk’ that may reveal psychosocial concerns on the part of the patient, and impacts on non-verbal communication, with doctors attention split between computer notes and patient, and more focus on computer than had been previously on prescribing pad and pen.

Role of communication in coping with illness

Ways in which communication mediates the illness experience itself, e.g. coping with illness and prognosis, informed consent, patient choice, decisions about testing

Treatment adherence and Patient empowerment [p291]

“Non-compliance is an unavoidable by-product of collisions between the clinical world and other competing worlds of work, play, friendship, and family life. (Trostle 1998, p1305)”

“The assumptions underlying the term compliance implies an authoritarian stance on the part of the physician or other health professional that are challenged by recent changes within health care systems”. In general, most people do not adhere to specific medical or health-care directives – at least not fully – estimates 50-75% or patients do not adhere to medical advice. 14-21% do not fill their prescriptions, 60% cannot identify their own medications, 30-50% of all patients ignore or compromise medication instructions, 12-20% of patients take other people’s medication. ~125,000 people with treatable ailments die each year in the USA die due to inappropriate medication usage. Asthma as particular problem with non-compliance.

Patient characteristics of non-adherent patient -less social support, more socially isolated, unstable families, certain cognitive deficits or emotional upsets may reduce adherence, type and severity of psychiatric disorder, environment, resources, expectations and attitude toward treatment, competing sociocultural and ethnic folk concepts of disease and treatment. no consistent relationship by age, sex, marital status, education, number of people in the household, social class and adherence. Strong association between patients health beliefs and adherence – Health Belief Model – perceived disease severity, susceptibility to the disease, benefits of the treatment recommended and barriers to following the treatment. But varying degrees of support for this model, different studies find different factors have greater or lesser influence on adherence. Social Learning Theory showed that patients with internal locus of control have better adherence.

Severity of disease and visibility of symptoms, and prognosis linked to adherence – non-linear relationship – patients with asymptomatic chronic diseases frequently do not comply with treatment – when symptoms frequent and unwanted, patients more likely to comply with treatment that offers the promise of removing them.

Treatment factors: lengthy or inconvenient waiting times, inconvenient clinic locations or organisation, complicated treatment, treatment methods that individual patients don’t like (e.g. calcium powders!), information overload causing patients to get confused, forget, or simply ignore much of the information. (Ley found that patients forget at least 1/3 of the information given by their physician) all decrease treatment adherence. Adherence declines with an increasing number of medications or doses and with the length of recommended treatment. It is estimated that adherence with long-term therapy declines to ~50% irrespective of illness or setting. Lack of feedback for the patient in terms of improvement in symptoms – e.g. when patients with hypertension are able to identify symptoms of their disease that are controlled by medication they are more likely to comply with it. Social side effects of a treatment in terms of stigma are shown to be just as important to adherence as physical side effects, and the extent to which the treatment disrupts the patient’s everyday life is also a factor.

Patient-physician relationships, classified as ‘patient-centred’ or ‘affiliative’ (interest, friendliness, empathy) or ‘authoritarian’ (physician controlled), affect adherence. Studies have shown that patients are more satisfied with those physicians who had high job satisfaction and who felt more secure in their work, e.g. when faced with conditions responsive to standard medical interventions. The more understanding the physician has of the patients system of illness-beliefs, and cultural norms and practices, the more compliant the patient is. Physicians view of the patient has an important effect, and there is a well-established social class effect that upper– and middle-class patients receive more information and attention from physicians and physicians frequently report more frustration with and less interest in lower- and working-class patients.

Meichenbaum and Turk (1987) identified 10 setting characteristics potentially associated with non-adherence: adherence is greater when the referral to a specialist is seen as part of the assessment rather than as a last resort, when care involves follow-up and is personalised, when appointments are individualised and waiting times are reduced, when treatment is available on site, when treatment is carefully supervised with home visits, special nursing care, etc, when there are good links between inpatient and outpatient services and when staff have a very positive attitude towards the treatment. In particular with long-term therapy there is evidence that regular follow-up by the physician increases adherence. Family members reminding and assisting the patient increases adherence, and it has been suggested that the patient’s partner’s views of the medication is the most important factor explaining adherence. Adherence is higher in cohesive families and lower in families in conflict.

In western society medicine has been based upon power and authority. Since it is founded on the assumption that it has the monopoly on truth, it follows that patient non-adherence is a result of ignorance and/or deviance. Trostle (1998) argues that the increasing research interest in medical compliance is a reflection of ‘a concern for market control combined with a concern for therapeutic power’. However this very concern with maintaining power may carry with it an equal and opposite reaction evidenced by a reluctance of patients to comply – reactance theory – patients feel they have a right to control their own behaviour and when they feel this right is threatened they resist. The more extensive and complex the treatment prescribed, the greater the threat to perceived freedom. This threat might be accepted if it was seen as worthwhile, but may  still sensitise the patient to additional threats to their freedom such that patients become resistant to additional demands. Non-compliance can thus be interpreted as a means of resisting medical dominance.

Late 20^th century saw public opposition to idea of powerful doctor and demands for greater control over health care (partly as a result of publicity about medical negligence and sexual harassment). Younger patients often more resisting and consumerist towards patient-doctor encounter, while older patients often more accepting of authority and may prefer a passive patient role. The more consumerist stance of certain patients is not always welcomed by physicians, who are sometimes reluctant give patients the information they request about their condition. Bertakis et al (1991) estimated that as many as 85% of patients who came to see their family doctor have some degree of psychosocial distress, but this is often ignored by the doctor – power of the doctor to define what is sickness, and lack of medical language and medical treatment for these social issues

Royal Pharmaceutical Society of Great Britain (1997) report described compliance as appropriate for welfare state and 1930s society rooted in benign paternalism, but suggests ‘concordance’ as an alternative model for doctor patient relationship based on mutual respect. “The price of compliance was dependency – it belongs to an older world. The price of concordance will be greater responsibility” both for the doctor and the patient.

To reduce non-adherence requires a reassessment of the contemporary medical-dominated health-care system, and an understanding of what it means to the patient to be ill.

Self-regulation – individuals with chronic illness actively monitor and adjust their medication on an ongoing basis. Non-adherence as a rational process and patient as rational problem solver. Testing the impact of varying dosages, controlling dependence and asserting to themselves and others that they are not dependent on prescribed medication, de-stigmatising and rejecting the illness label, a feeling that reducing the medication meant they were ‘getting better’, concern to control the harm a medicine might cause, modifying treatment regimes to fit symptoms, side effects and lifestyle. Many people have a range of fears abot medication.

Asthma – Horne and Weinman (1999) Those patients with strong medication necessity beliefs also perceived asthma as having a lengthy timeline and that its consequences were serious. Adams et al – deniers/distancers deny they have asthma, say they just have a bad chest, and so take relievers which help their bad chest, but not prophylaxic medicines which are a symbol of being asthmatic. Acceptors reluctantly accept they have asthma and take their medications, while still holding negative associations of people with asthma.

Medical error, iatrogenic illness, US Institute of Medicine report (2000) estimated that 44,000 – 98,000 Americans die each year as a result of medical error. That is more than die each year from motor-vehicle accidents, breast cancer or AIDS. UK Health Foundation report estimates 40,000 iatrogenic deaths each year in UK. 10-20% of these thought to be due to medication errors. In hospitals it is junior doctors who do most of the prescribing. They are the ones with the least knowledge, and who make most mistakes. One common problem raised by all of the recent reports has been medical silence: the reluctance of medical professionals, especially physicians, to report errors.

Empowerment – process whereby people gain mastery over their lives. Patients lay health beliefs and knowledge considered of equal or greater value than physicians health knowledge. Opportunityfor patients to tell their story. Medicine has the power not only to rewrite the patient’s story of illness but also to replot its course. If the story that is handed back is widely different to the patient’s own story, or irrelevant to their life, and the physician fails to recognise the distance between them, the interaction founders, leading to non-adherence.

Empowerment connects with the identification of the patient as responsible in some way for both their illness and their treatment, especially for illnesses associated with lifestyle practices such as smoking, diet and exercise. Transformation of patient from passive sufferer to active manager of their own suffering – from which it is a small step to locating with the patient the moral responsibility to become well. This provides the physician with the opportunity to evade responsibility for treatment of those problems for which they have limited insight, e.g. chronic illness and mental illness. E.g. doctors promoting the “fighting spirit” among cancer patients – can be disempowering when patient feels they cannot control the disease. Also Patient Controlled Anaesthesia – can be perceived as encouraging patients not to bother the staff.

Lord and McKillop Farlow note: “people mistakenly talk about “empowering families” or  “empowering professionals” as if empowerment is something one person does to another – empowerment as paternalism. Within a capitalist state this promotion of empowerment has a hidden agenda, allowing questions of oppression to be reframed as free individual choices among predetermined alternatives, allowing health care workers to blame the patient when strategy fails, and making health education a technology, a way to get people to think they are taking charge of their own health and exercising their rights instead of being dependent.

“The move towards empowerment is especially directed at those people who do not conform to mainstream values and practices rather than attempting to promote broader changes in social structures. The physician and other health care professionals can now continue to disparage the most deprived and marginalised not for their non-compliance but rather for their refusal to accept responsibility for self-management.”

Asthma

Reversible airways obstruction is the characteristic feature of asthma, which is often associated with an atopic disposition. Exposure to allergens, or possibly other environmental determinants, may then result in expression of the condition. Despite the presence of atopy and eosinophilia, neither is absolutely required for asthma without other concurrent risk factors. (Eosinophilia is an increase in peripheral blood eosinophilic leukocytes. Nonpathologic functions of eosinophils and the cationic enzymes of their granules include mediating parasite defense reactions, allergic response, tissue inflammation, and immune modulation. http://emedicine.medscape.com/article/199879-overview)

The most common symptoms of asthma are wheeze and breathlessness. In younger people, cough, especially at night, may the only symptom.

Asthma is characterised by intermittent episodes in which airway smooth muscle contracts strongly, markedly increasing airway resistance. The basic defect in asthma is chronic inflammation of the airways – causes include allergies, viral infections and sensitivity to environmental factors. Underlying inflammation makes the airway smooth muscle hyperresponsive and causes it to contract strongly in response to such things as exercise (especially in cold, dry air), cigarette smoke, environmental pollutants, viruses, allergens, normally released bronchoconstrictor chemicals. Incidence of asthma is increasing, possibly due in part to environmental pollution.

• WHO estimates that 235 million people currently suffer from asthma. Asthma is the most common chronic disease among children.
• Children of first generation immigrants have the same incidence of asthma as indigenous children in the overdeveloped world. The risk of developing asthma is about 7 in 100, but risk doubles for each first degree relative with atopy.
• Asthma is a public health problem not just for high-income countries; it occurs in all countries regardless of the level of development. Most asthma-related deaths occur in low- and lower-middle income countries.
• Asthma is under-diagnosed and under-treated. It creates substantial burden to individuals and families and often restricts individuals’ activities for a lifetime.
• Recurrent asthma symptoms frequently cause sleeplessness, daytime fatigue, reduced activity levels and school and work absenteeism. Asthma has a relatively low fatality rate compared to other chronic diseases.

COPD referes to emphysema, chronic bronchitis, or a combination of the two. These cause severe difficulties in ventilation and in oxygenation of the blood, and are major causes of disability and death.

[from Waller et al Medical Pharmacology and Therapeutics]

Asthma and COPD are considered to be distinct entities with clinical overlap. Both are inflammatory disorders of the bronchi. In asthma the underlying problem is a persistent and excessive Th2-dominated immune response and resulting inflammation; this is accompanied by reduced Th1 involvement in the structural and defensive status of tissues. The overall imbalance in T-helper cell types results in persistent inflammation, increased numbers of airways smooth muscle cells, proliferation of blood vessels, epithelial transformation into mucus-secreting cells and increased matrix deposition. Adequate suppression of the inflammation should be the basis of treatment, allowing resolution of the pathological changes. The predominant inflammatory cells are mast cells, eosinophils, and CD4 T-lymphocytes, with fewer macrophages. Important inflammatory mediators are leukotriene D4 (LTD4), histamine, a variety of cytokines including IL-4, IL-5, IL-9, IL-13, eotaxin and RANTES (regulated on activation normal T-cell expressed and secreted), and there is relatively little evidence of oxidative stress.

In asthma, all airways are involved in the inflammatory process, but the degree of fibrosis and mucus secretion are modest, with no parenchymal destruction. (The parenchyma are the functional parts of an organ in the body. This is in contrast to the stroma, which refers to the structural tissue of organs, namely, the connective tissues. E.g. in lungs, parencyma includes alveoli, alveolar ducts, respiratory bronchioles, terminal bronchioles. Early in development the mammalian embryo has three distinct layers: ectoderm (external layer), endoderm (internal layer) and in between those two layers the middle layer or mesoderm. The parenchyma of most organs is of ectodermal (brain, skin) or endodermal origin (lungs, gastrointestinal tract, liver, pancreas). The parenchyma of a few organs (spleen, kidneys, heart) is of mesodermal origin. The stroma of all organs is of mesodermal origin.)

Airway obstruction is not caused by increased smooth muscle contraction in these diseases as it is in asthma. In emphysema the cause of obstruction is destruction and collapse of the smaller airways. Emphysema is characterised by the destruction of the alveolar walls leading to an increase in compliance (compliance = the magnitude of change in lung volume produced by a given change in the transpulmonary pressure – a high degree of compliance indicates a loss of elastic recoil of the lungs). Chronic bronchitis is characterised by excessive mucus production in the bronchi and chronic inflammatory changes in the small airways. Obstruction is caused by accumulation of the mucus in the airways and thickening of the inflamed airways. The same agents that cause emphysema, such as smoking, also cause chronic bronchitis, which is why the two diseases frequently coexist.

<h2>Pathogenesis</H2>

 Chronic inflammation of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and eosinophils. This leads to the release of several powerful chemical mediators that can damage the epithelial lining of the airways, exposing nerve endings. Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree, which occurs in response to irritants. Some of the mediators act as chemotactic agents for other inflammatory cells, They also produce mucosal oedoma, which narrows the airways and stimulates smooth muscle contraction, leading to bronchoconstriction. Excessive production of mucus can cause further airways obstruction by plugging the bronchiolar lumen

Viral upper respiratory tract infections exacerbate the mucosal inflammatory process, while exposure to allergens, irritants or exercise can cause bronchoconstriction in sensitive airways. Attacks of asthma rapidly follow exposure to a provoking agent. Initial recovery may then be followed some 4-6h later by a late-phase bronchorestrictor response, which can leave the bronchi hyper-reactive to various irritants for several weeks.

Treatments for Asthma

<h2>British Guideline on the Management of Asthma</h2>

http://www.nda.ox.ac.uk/wfsa/html/u10/u1003_01.htm

Aim of oxygen therapy is to maintain SpO2>=92%.

SpO2 = the saturation level of oxygen in hemoglobin; can be determined by noninvasive method of pulse oximetry. ABGs should be taken for patients with SpO2 <92%

ABGs as marker of severity – Normal or raised PaCO2 >4.6kPa 35mmHg, Severe hypoxia PaO2 <8kPa, 60mmHg; Low pH (raised PaCO2 indicates near fatal asthma exacerbation)

<h2>Management of Asthma</h2>

Treatment of asthma has two aims: relief of symptoms and reduction of airways inflammation.

First aim of therapy is to reduce the chronic inflammation and airway hyperresponsiveness with anti-inflammatory drugs, particularly inhaled glucocorticoids and leukotrine inhibitors. The second aim is to overcome acute excessive airway smooth muscle contraction with bronchodilator drugs. These relax airway smooth muscle or block the actions of bronchoconstrictors. For example, one class of bronchodilator drugs mimics the normal action of epinephrine on beta-adrenergic (beta 2) receptors. Another class of bronchodilator drugs block muscarinic cholinergic receptors, which have been implicated in bronchoconstriction.

Severe asthma attack:

Inability to complete a sentence, pulse >=110bpm, PEFR <=50% of expected or previous best. Treat by ensuring adequate hydration, 40-60% oxygen by facemask, nebulised beta2-adrenoceptor such as salbutamol, preferably using oxygen. IV hydrocortisone and/or high-dose oral prednisolone

Life-threatening asthma attack:

Silent chest, bradycardia or hypotension, PEFR <=33% of expected or previous best, exhaustion, confusion or coma. Treat as above, plus nebulised ipratropium, IV aminophylline or beta2-adrenoceptor agonist such as salbutamol, IV magnesium sulphate, consider assisted ventilation if there is not rapid clinical improvement.

After recovery from a severe asthma attack, oral corticosteroids should be continued until there are no residual symptoms, especially at night, and the PEFR is at least 80% of the person’s previous best. High doses of these drugs can be stopped abruptly if used for 3 weeks or less, or tapered off if they have been used for a longer period.

Prophylaxis of recurrent attacks

First try to identify and avoid triggers. After initially gaining control of asthma symptoms, long-term treatment is guided by a stepwise treatment plan recommended by the British Thoracic Society / Scottish Intercollegiate Guidelines Network:

Step 1 – mild intermittent ashma – inhaled short acting beta2-adrenoreceptor agonist such as salbutamol, taken as required. For those who are intolerant to this treatment, inhaled ipratropium and oral theophylline are alternative options, but with a higher risk of unwanted effects with the latter.

Step 2 – regular preventer therapy – for adults, a corticosteroid such as beclomethasone is most often used. For children and some adults, an initial trial of cromoglicate or nedocromil can be undertaken, but these agents are generally less effective than inhaled corticosteroid. A leukotriene receptor antagonist could also be tried at this stage.

Step 3 – add-on therapy – in people taking moderately high doses of inhaled corticosteroid, a suitable add-on therapy would be a long-acting beta2-adrenoceptor agonist such as salmeterol. If there is no beneficial response to the beta2-receptor agonist, it should be stopped and the corticosteroid further increased. If control still remains poor, the increased corticosteroid dose together with a long-acting beta2-adrenoceptor agonist should be given. For persistent poor control, sequential add-on therapy with either a leukotriene receptor agonist, a modified-release theophylline formulation or a modified-release oral beta2-adrenoceptor agonist should be tried.

Step 4 – Addition of fourth drug. High-dose inhaled corticosteroid with a short-acting beta2-adrenoceptor agonist as required, and usually an inhaled long-acting beta2-adrenoceptor agonist plus a sequential trial of one or more of the following:

• leukotriene receptor antagonist
• oral modified-release thophylline formulation
• oral modified-release beta2-adrenoceptor agonist

Step 5 – continuous or frequent use of oral prednisolone. This is undertaken in addition to other measures outlined above

For people with resistant disease, especially those requiring oral corticosteroids, the use of immunosuppresive drugs such as ciclosporin or methotrexate has been advocated.

Inhalors

Drug delivery by aerosol spray allows the use of smaller doses and therefore reduces the risk of unwanted side effects. Particles >5micrometres will impact on upper airways and be swallowed. Particles <0.5um will not deposit in the lower respiratory tract and will be exhaled. Optimal size is 1-3um.

About 1/3 users find pressurised metered dose inhalers difficult. Even with optimal coordination, ~70-90% of aerosol is deposited in the oropharynx, then swallowed. Spacers – 750ml, 350ml for young children. Breath activated devices, delivering either aerosol or dry powder, require high airflow and are therefore less efficient than metered-dose inhalers, especially in those with severe airflow limitation. Nebulisers distribute drug from reservoir solution. Jet nebulisers pass air or oxygen through a narrow orifice to such drug solution from a reservoir into a feed tube with fine ligaments. The impact of the solution on these ligaments generates droplets. Ultrasonic jet nebulisers use a piezoelectric crystal vibrating at high frequency – vibrations transmitted through a buffer to the drug solution form a fountain of liquid in the nebulisation chamber. Ultrasonic nebulisers produce a more uniform particle size than do jet nebulisers. Up to 10x the amount of drug is required in a nebuliser to produce the same degree of bronchodilation achieved by a metered dose inhaler. Delivery is more efficient via a mouthpiece than via a mask.

<h2>Symptom-relieving dugs of airflow obstruction.</h2>

Beta2-adrenoceptor agonists, e.g. salbutamol, terbutaline, salmeterol, formoterol

The airways are rich in beta2-adrenoceptors, which are found on bronchial smooth muscle but also on several other cell types. Effects of receptor stimulation include:

• Bronchodilation via generation of intracellular cyclic adenosine monophosphate (cAMP)
• inhibition of mediator release from mast cells
• enhanced mucociliary clearance

Selectivity of an agonist for the beta2-adrenoceptors avoids systemic unwanted effects from stimulation of beta1-adrenoceptors. The selectivity of beta2-adrenoceptors is dose dependent. Inhalation of the drug aids selectivity since it delivers small but effective doses to the airways and minimises systemic exposure. The dose-response relationship for bronchodilation is log-linear, therefore, and tenfold increase in dose is required to double the effect. A metered-dose aerosol inhaler is the most frequently used delivery mechanism, but breath-activated devices and nebuliser solutions are available.

After inhalation, the onset of drug action is rapid, often within 5 minutes, Agents such as salbutamol have an intermediate duration of action (producing bronchodilation for up to about 6h), far longer than the natural adrenoceptor agonists. Their chemical structure prevents neuronal uptake and reduces their affinity for catechol-O-methyl transferase, which metabolises catecholamines.

The long-acting agent salmeterol bronchodilates for up to 12h by virtue of a long lipophilic side-chain on the molecule, which binds to an area adjacent to the active site of the receptor, producing prolonged receptor activation. Formoterol has a prolonged duration of action by entering the lipid bilayer of the cell membrane, from which it is gradually released to stimulate the receptor.

Salbutamol and terbutaline can also be given orally (as conventional or modified-release formulations), or by subcutaneous or intramuscular injections or by IV infusion. However, larger doses are required to deliver and adequate amount to the lungs by any of these routes. This reduces selectivity for beta2-adrenoceptors, and systemic unwanted effects can be troublesome.

Tolerance to pharmacological bronchodilation can occur with beta2-adrenoceptor agonists but not with inhaled antimuscarinic drugs. The Committee on Safety of Medicines has advised that salmeterol and formoterol should not be used for relief of acute asthma and should only be used along with a concurrently administered corticosteroid.

Unwanted effects:

• Fine skeletal muscle tremor from beta2-adrenoceptor stimulation
• Tachycardia and arrhythmias result from both beta1 and beta2-adrenoceptor stimulation when high doses of inhaled drug are used, or after oral or parenteral administration.
• Acute metabolic responses to high-dose beta2-adrenoceptor stimulation include hypokalaemia, hypomagnesaemia and hyperglycemia. They do not persist during long term use.
• Paradoxical bronchospasm has been reported with inhalation, usually when given for the first time or with a new canister.
• Headache

Concern has been expressed that regular use of high doses of inhaled beta2-adrenoceptor agonsits may be linked with asthma deaths by precipitation of serious arrhythmias. An alternative possibility is that high doses might allow people to tolerate initial exposure to larger doses of allergens or irritants, which then produce an enhanced late asthmatic response. However it is more likely that the use of high doses is really a reflection of the severity of the underlying asthma.

Anticuscarinic agents, e.g. ipratropium, tiotropium

The antimuscarinic drugs used for bronchodilation are non-selective and bind to all three types of muscarinic receptors in the lung. It remains uncertain whether they also have specific anti-inflammatory effects in addition to their actions on bronchial smooth muscle and mucus secretion. Main use is in COPD, where they are effective. Little use in mild to moderate asthma, but may have a place when added to beta2-adrenoceptor agonists in severe exacerbations of asthma.

Methylxanthines: theophyline, aminophyline

Methylxanthines are a group of naturally occuring substances found in tea, coffee, chocolate and related foodstuffs. Theophylline and its ester derivative aminophylline are the only compounts in clinical use, chemically similar to caffeine. Vasodilator, anti-inflammatory and immunomodulatory actions.

<h2>Anti-inflammatory drugs for airways obstruction</h2>

Corticosteroids e.g. beclamethasone, dipropionate, budesonide, hydrocortisone, fluticasone, propionate, mometasone, prednisolone

Glucocorticoids are the most effective class of drug in the treatment of chronic asthma but are relatively ineffective in COPD. The are recommended as preventer when inhaled beta2-androceptor agonists are used more than once daily. They act to suppress inflammation and the immune response. Powerful glucocorticoids, devoid of significant mineralcorticoid activity, are usually used. (see Steroids)

Intracellular events involved in the anti-inflammatory action

A major event in asthma is probably activation of glucocorticoid receptors that inhibit transcription of genes coding for the cytokines involved in inflammation. Glucocorticoid receptors recruit histone deacetylases to the transcription complex of activated inflammatory genes. The deacetylation of core histones at the transcription complex silence genes that have been activated by inflammatory stimuli. Used long term, corticosteroids reduce airway responsiveness to several bronchoconstrictor mediators and block both the early and late reactions to allergen. Following a delay of 6-12h, several anti-inflammatory actions occur which may be important in ashtma.

Short term anti-inflammatory effects include:

• Reduced inflammatory cell activation (including macrophages, T-lymphocytes, eosinophils and airway epithelial cells)
• Decreased IgE synthesis
• Reduced mucosal oedema and decreased local generation of inflammatory prostaglandins and leukotrienes by inhibition of phospholipase A2
• Beta-adrenoceptor upregulation, which restores responisveness to beta2-adrenoceptor agonists.

Longterm anti-inflammatory effects include:

• Reduced T-cell cytokine production and reduced dentritic cell signalling to T-cells
• Reduced eosinophil deposition in bronchial mucosa (by removing cytokine stimulation, reducing expression or epithelial adhesion molecules and enhancing apoptosis)
• Reduced mast cell deposition in bronchial mucosa (although the release of mediators from these cells is unaffected)
• Reversal of the excess epithelial cell shedding and goblet cell hyperplasia found in the bronchial epithelium in asthma.

Inhaled corticosteroids produce some improvement in asthmatic symptoms after 24h and a maximum response after 1-2weeks. Reduction in airway responsiveness to allergens and irritants occurs gradually over several months. Corticosteroids block the late-phase reaction to allergens in asthma. However, many of the chronic structural changes in the airways in asthma are unaffected by corticosteroids.

Pharmacokinetics: Corticosteroids can be used intravenously or orally in severe asthma. However, wherever possible they are given by inhalation of an aerosol or dry powder to minimise systemic unwanted effects. Desirable properties of the inhaled corticosteroid include low rates of absorption across mucosal surfaces (such as the lung, but also including the gut for swallowed drug) and rapid inactivation once absorbed. Beclomethasone dipropionate fulfils the former criterion but is only slowly inactivated once it reaches the systemic circulation. Mudesonide (which is inactivated by extensive first-pass metabolism in the liver if systemically absorbed) and fluticasone (which is very poorly absorbed from the gut) are not given orally and may be prefered if high doses of inhaled drug are needed, or for the treatment of children.

Unwanted effects: amount of swallowed drug can be minimised using a large-volume spacer. Hoarseness and oral candidiasis can occur with inhaled corticosteroids.