Bronchodilators and anti inflammatories

Use of bronchodilators and anti-inflammatories in conditions.

1. Bronchodilators and Anti-inflammatories HDT 2:2 – Semester 2

2. Respiratory Physiology Breathing is usually controlled by the respiratory centre in the medulla oblongata with input from pontine and higher cortical centres, as well as vagal afferents from the lungs. Efferent pathways influencing the airways include parasympathetic nerves and non-adrenergic non-cholinergic (NANC) inhibitory nerves. The bronchial tone is influenced by the state of the mucosa and the activity of glands. Efferent pathways involved in respiratory regulation are mainly autonomic. Parasympathetic innervation is mainly in the bronchi and bronchioles, where innervation of smooth muscle and glands is seen. The ganglia are located in the bronchi walls, where three types of muscarinic receptor are found. M 1 receptors are found on postganglionic fibres where they allow nicotinic transmission, whilst M 2 are autoregulatory inhibitory receptors that allow negative feedback. M 3 are the main receptors found in smooth muscle and mediate bronchoconstriction and mucus secretion. Sympathetic innervation is found in blood vessels and glands of the lungs but not the smooth muscle. Despite this, β -adrenoceptors are found in the epithelium, glands, alveoli and smooth muscle of the lungs. Agonism of these receptors, which are almost exclusively β 2 receptors, results in increased mucociliary clearance, inhibition of inflammatory mediators from mast cells and bronchodilation. Afferent pathways include irritant receptors in the airways (associated with myelinated vagal fibres) which respond to stimuli like sulphur dioxide, cigarette smoke, cold air, ammonia, endogenous inflammatory mediators and capsaicin.

3. Pathogenesis of Asthma Asthma is characterised by the hypersensitivity of irritant receptors in the airways to stimuli that would otherwise not elicit and effect in healthy people. Patients present clinically with wheeze, shortness of breath, cough and chest pain. The narrowing of the airways is reversible in asthma and so can be treated with bronchodilators and anti-inflammatories. However, the bronchoconstriction in COPD is irreversible and less responsive to bronchodilator therapy. COPD is also called “chronic bronchitis” and has a strong link with smoking. Sufferers of asthma have difficulty in breathing out due to the obstructive nature of the condition. Although (as mentioned) this is reversible, it can progress with age to become irreversible like COPD. In any case, asthma attacks are characterised by two phases; an immediate and a late phase. Asthmatics have activated T cells in their bronchial mucosa that release Th2 cytokines. These cytokines act as chemoattractants that draw eosinophils to the mucosa, as well as other inflammatory granulocytes. IL-5 and gmCSF prepare eosinophils for cysteinyl leukotriene and inflammatory granular protein production, which damage the mucosa and lead to hyper-responsiveness. Some asthmatics may also develop allergen-specific IgE that binds to allergen in the airways, leading to cross-linking of IgE molecules at mast cell surface, which leads to degranulation and release of leukotriene B 4 and histamine, which are potent bronchoconstrictors. Omalizumab is an anti-IgE antibody that opposes this mechanism of exacerbation.

4. Pathogenesis of Asthma The immediate phase of the asthma attack begins abruptly as allergen interacts with surface-bound IgE on mast cells, leading to degranulation and release of several spasmogens that cause rapid bronchospasm. The spasmogens include; leukotriene B 4 , TNF- α, IL-13, IL-4, IL-5, histamine and prostaglandin (PG) D 2 . Chemokines are also released which recruit eosinophils and mononuclear cells (lymphocytes and dendritic cells) to the area in preparation for the delayed/late response. The late phase can be nocturnal and is the progressive and destructive, caused by recruitment of more inflammatory cells as part of the inflammatory response. Activated eosinophils in particular cause epithelial degradation, whilst growth factors released from other inflammatory cells lead to hypertrophy and hyperplasia of the smooth muscle cells of bronchial and bronchiolar tissue. Loss of epithelial cells makes irritant receptors and C fibres more accessible to irritants (allergens) which further facilitates bronchial hyper-reactivity. The formation of mucus plugs also occurs, which is the results of eosinophil infiltration, epithelial degradation and excess mucus secretion, which further narrows airways and leads to obstruction. The immediate response (bronchospasm) is treated with bronchodilators ( β 2 agonists). The late/delayed response (inflammation and hyper-reactivity) is treated with glucocorticoids (corticosteroids).

5. β 2 -adrenoceptor Agonists Drugs in this class include; β 2 - agonists, xanthines, leukotriene antagonists and muscarinic receptor antagonists. β 2 - agonists dilate via direct action on beta adrenoceptors on bronchial smooth muscle. They also reduce inflammatory mediator release from mast cells, inhibit TNF- α release and increase mucociliary clearance. Their anti-inflammatory effect is minimal over time due to sensitisation of the mast cells, on which the β 2 receptors are expressed. Short-acting agonists include salbutamol and terbutaline, which are inhaled. They have an effect within 30 minutes and a duration of action of 3 – 5 hours. Long-acting agonists include salmeterol and formoterol, which are also inhaled and have a duration of 8 – 12 hours. They are not used PRN but instead adjunct to glucocorticoids where asthma is inadequately controlled. Side effects are due to systemic absorption, and include tremor, headache, tachycardia and dysrhythmias. Terbutaline implants are also available to release a sustained level of terbutaline in patients with brittle asthma.

6. Xanthines Xanthines include; theophylline/aminophylline, theobromine and caffeine. These drugs work via as yet unclear mechanisms, but have been linked to PDE inhibition, which leads to increased levels of intracellular cGMP and cAMP, which facilitate smooth muscle relaxation. Some xanthines also have an anti-adenosine effect at A 1 and A 2 receptors. The side effects of xanthines are common and can be fatal, due to the narrow therapeutic window of 30 - 100μmol/L (side effects above 110μmol / L). They include; respiratory stimulation (increased rate), tachycardia (chronotropic and inotropic effects), mild/moderate diuresis, CNS stimulation (affects sleep and alertness). Methylxanthines are given orally in sustained-release formulations, whilst aminophylline can also be given by slow intravenous infusion. Theophylline is absorbed well following oral administration, has a half life of about 8 hours and is metabolised by P450 enzymes. Xanthines are a second-line treatment in patients who have not responded adequately to β 2 - agonists. Their metabolism makes then susceptible to drug-drug and disease-drug interactions with CYP450 inducers and inhibitors, as well as disease states such as smoking, cardiac failure and liver disease. Xanthines are prescribed by brand name due to different patient responses.

7. Muscarinic Antagonists Muscarinic antagonists used to treat asthma include ipratropium, tiotropium and oxitropium. Tiotropium is longer acting than the rest and can be given in maintenance treatment of COPD, whilst ipratropium is rarely used regularly, and is instead used to treat cough caused by irritant stimuli. Ipratropium is of limited use, as it antagonises muscarinic receptors indiscriminately, which means it also blocks M 2 autoregulatory receptors and may therefore increase Ach release in postganglionic fibres. It’s not particularly effective against irritation posed by allergens but does inhibit prolonged mucus secretion and so can help in avoiding dense mucus plugs. It could also increase mucociliary clearance. Ipratropium has no effect on the late/delayed phase of asthma attacks. It is highly polar also and (as it is given by aerosol inhalation) has little effect on muscarinic receptors outside of the bronchi. Maximum effect is within 30 minutes, and duration is 3 – 5 hours. The side effects are few and uncommon, and muscarinic antagonists (inhaled) are safe to use with beta-agonists. There is also a danger in giving patients with glaucoma a nebulised muscarinic antagonist as it can accumulate around the face and lead to increased intraocular pressure. Muscarinic antagonists are only ever given by inhalation.

8. Cysteinyl Leukotriene Antagonists These drugs include montelukast and zafirlukast, which both act exclusively at CysLT 1 receptors located on respiratory mucosa and inflammatory cells. The lukasts have some bronchodilating effect that is additive with beta-agonism. They inhibit exercise-induced asthma and also decrease both early and late responses to allergen. They reduce sputum eosinophilia for unknown reasons and so when used with muscarinic antagonists can reduce mucus plug formation. The side effects are headache and mild GI disturbances mainly. Respiratory tract infections can also occur, due to bronchodilation leading to ingress of foreign bodies and dampening of the inflammatory responses. Leukotriene antagonists are usually used in stage 3 treatment with inhaled corticosteroids where beta agonists have been inadequate.

9. PDE 4 Inhibitors The only drug in this class used clinically is roflumilast. PDE 4 is the main PDE in inflammatory cells and cells found in the lung, and so its inhibition leads to increased cAMP in bronchial and bronchiolar smooth muscle which leads to bronchodilation. Side effects include insomnia, headache and GI disturbances. There are also some psychiatric side effects like suicidal ideation.

10. Glucocorticoids Drugs in this class include fluticasone, mometasone, beclometasone, budesonide and ciclesonide. Glucocorticoids exert their anti-asthmatic effect through inhibition of Th2 cytokine formation, which recruit and activate eosinophils, as well as increasing expression of and sensitivity to IgE. They also have some inhibitory action on the production of vasodilators PGE 2 and PGI 2 . These drugs also up-regulate β 2 expression in the respiratory mucosa (allowing greater bronchodilating responses), decrease microvascular permeability and reduce cytokine release from eosinophils. They also inhibit the production of IL-3, which leads to decreased mast cell numbers in the respiratory mucosa, which suppresses the immediate phase response to allergens (less mast-cell bound IgE). Their action is achieved via intracellular (nuclear) receptors. Resistance to glucocorticoids is seen, for unknown reasons. The number of glucocorticoid receptors could change and be the cause of resistance, whilst histone deacetylase (HDAC) concentrations could also affect it.

11. Glucocorticoids The side effects aren’t common with inhaled corticosteroids, but this route can lead to oral thrush (limited by spacer use), voice hoarseness and sore throat. Excessive doses can cause adrenal suppression, which necessitates carrying a steroid treatment card. This is more common in children. This side effect occurs due to decreased levels of ACTH via a negative feedback loop. Decreased need for the adrenal cortex to produce glucocorticoids results in shrinkage of the tissue (atrophy). If this is not considered and therapy is stopped abruptly, then the body is not equipped to produce sufficient hormones including adrenaline, when it is required to. This will result in hypotensive crises and death and so requires steady stepping-down of doses. Long-term steroid use results in side effects becoming more of an issue, with adrenal suppression, osteoporosis, immune suppression and fat redistribution becoming more likely. Regular bronchodilator use can necessitate inhaled corticosteroid (i.e. beclometasone). Severe cases may need high-potency alternatives (i.e. budesonide). Rescue courses of oral prednisolone may be needed at any stage when severity increases.

12. Cromoglicate and Nedocromil These drugs are rarely used despite their safety, because of a short duration of action and weak anti-inflammatory effects. The mechanisms by which these drugs work are poorly understood, with evidence suggesting that mast cell stabilisation (resistance to degranulation) may play a role in anti-inflammatory effects. Studies have also shown depression of exaggerated neuronal reflexes and dampening of C-fibre responses located near vagal afferents that can lead to hyper-reactivity. Despite relatively poor anti- infammatory effects when compared to corticosteroids, these drugs show improvement in both the immediate and late/delayed phases of asthma attacks.

13. Anti-IgE Therapies Omalizumab is the only drug used in the treatment of asthma in this class. It is recommended by NICE only for use in cases of persistent, severe allergic asthma. This is due to its high cost. As an anti-IgE antibody, it prevents the crosslinking of cell surface mast cell IgE molecules which would lead to mast cell degranulation and release of inflammatory cytokines. This makes omalizumab very effective in the treatment of allergen-induced (IgE-mediated) asthma. The drug is given via subcutaneous injection every 2 – 4 weeks at a dose that is titrated up according to serum IgE levels. Issues associated with anti-IgE therapy include increased susceptibility to helminthic infections, and hypersensitivity reactions.