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1997 Clinical pharmacology By Duy Thai

Why do we cough? • Coughing is the last stage of mucociliary clearance to get rid of mucous in our airways • It is a defensive mechanism to get rid of foreign material present in the airways • Coughing is a very frequent symptom in respiratory illnesses, especially: A. Those associated with increased mucous production (e.g. cystic fibrosis) • The physical presence of the mucous stimulates the cough reflex B. Post viral infections • Intractable cough and mucous hypersecretion are very serious medical conditions. Their pathophysiology is poorly understood and treatments are not very effective.

What is a cough? • Coughing involves 4 phases: 1. Inspiration 2. Compression of air against a closed glottis. • There is also active bronchial narrowing to produce sheer stress and turbulence • Laminar flow does not dislodge the mucous (or foreign particle) • A narrowed airway causes increased velocity and turbulence, dislodging the mucous. The closed glottis also creates a pressure drop (high pressure inside, low pressure outside) so that when the glottis opens, the air is forcefully expelled to the outside 3. Expression • The glottis is opened and the airways collapse to expel the cough (and whatever it may carry ) 4. Relaxation of the expiratory muscles and transient bronchodilation. Causes of increased mucous/decreased clearance 1. Primary ciliary dyskinesia • A genetic abnormality resulting in the cilia failing to beat or beat in an uncoordinated fashion 2. Acquired dyskinesia • Cilia are injured (e .g. due to smoking) and so cannot beat 3. Increase in pericellular fluid • The tips of the cilia (which are usually in contact with the gel phase) cannot touch the gel phase. and so cannot push it along towards the mouth 4. Increase in gel phase • The pure weight of the gel phase compresses the cilia 5. Alteration of mucous rheology (how the mucous flows ) • In asthma, the mucous is mixed with plasma, creating a thickened, gelatinous mucous • In bronchitis and in cystic fibrosis, the presence o co-infection results in an increase in white blood cells. As these cells die. their DNA mixes with the mucous to form a tangled plug which clogs up the system • DNase (Dornase α ) is a mucolytic drug which is used in cystic fibrosis to break up the DNA strands to help untangle the plug. 6. Epithelial differentiation • Increase in goblet cells (as seen in asthma) • Metaplasia of the glands • Guaifenesin is an expectorant which is useful in conditions where there is increased mucous production. It increases the clearance rate of mucous in an unknown way. Neurobiology of cough • Most cough receptors are located in the larynx and trachea • There is some evidence to suggest that there are also afferents leading to cough in the small bronchi, as bronchoconstriction in the small bronchi can trigger cough. • There may also be afferents in the alveoli, since fine inhaled dust which lodges in the alveoli (but escape the upper defences such as mucous and cilia) can cause cough. • There are 3 nerve fibre types which form the afferents leading to cough A. Myelinated irritant fibres B. Unmyelinated C fibres C. Slow adapting stretch receptors

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1997 Clinical pharmacology By Duy Thai Causes of cough 1. Mechanical A. Presence of mucous as a result of: • Acute/chronic bronchitis • Pneumonia • Bronchiectasis • Cystic fibrosis • Asthma B. Tumor C. Granulomas D. Blood (haemoptysis) E. Oedema F. Foreign body 2. Mediators/irritants A. Asthma B. Viruses C. Pollutants (NO, SO2) D. Interstitial lung disease (ILD) E. Angiotensin Converting Enzyme blockers (see later). 3. Extrathoracic A. Post nasal drip B. Oesophageal reflux C. Middle ear disease 4. Abnormal reflexes A. Viral infections (very important) B. Asthma (?) C. ILD (?) D. Idiopathic dry cough (very important) E. ACE blockers (very important) 5. Central mechanisms • Psychogenic cough • The afferent receptor sensitivity which initiates the cough reflex is a variable contributor to causing increased coughing, e.g. Type of cough Productive (presence of mucous) Non productive dry cough Epithelial damage (e.g. virus, ozone) which can lead to Asthma Asthma Receptor sensitivity Normal Increased Usually increased Also have epithelial damage but most often the cases do not have increased sensitivity Increased


ACE inhibitors

How do ACE inhibitors cause cough? • Angiotensin converting enzyme (ACE) converts Angiotensin I into Angiotensin II • It also breaks down bradykinin • Bradykinin is a very potent cough stimulus, why? • It activates B2 receptors which are present on the afferent nerves initiating cough • The B2 receptor is also coupled to make PGE2 • PGE2 synergises with the direct action of bradykinin by increasing the sensitivity of the afferents. • That is why COX inhibitors which inhibit the production of PGE2 and other prostaglandins (e.g. indomethicin, aspirin) may help alleviate cough.

Note that these must not be used in asthmatics because the can result in increased leukotrienes, which cause intense bronchospasm which could kill an asthmatic who already has a narrowed airway.

ACE inhibitors (e.g. captopri) stop ACE from breaking down bradykinin, hence it causes increased bradykinin levels, leading to excessive cough.

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1997 Clinical pharmacology By Duy Thai Pharmacology of cough 1. Opiates • Codeine • Dextrometorphan • Very potent drugs and very effective • 2 possible modes of action: A. Activate sensory fibres B. Probably centrally acting in the cough center in the medulla • Disadvantages: • Sedation, respiratory depression, addiction 2. Benzodiazapenes • CIonazepam • Reduces cough (psychogenic cough) 3. 5HT/NA modulating antidepressants • Almost completely ineffective • The antidepressant activity may reduce psychogenic cough 4. Demulcents (cough syrups) • Coat the irritant fibres in the larynx • The aromatic compounds used in the syrup may stimulate inhibitory receptors 5. Anaesthetic • Lidocaine • Prevents the cough and gag reflex by anaesthetising the nerves at the back of the throat. 6. Disodium cromoglycate (DSCG) • Prevent C fibres from triggering 7. β2 agonists • Open up the airway, reducing the blockage caused by the mucous or foreign body 8. Corticosteroids • Inhibit inflammation • Prevent nerves from remodelling (by preventing the release of various nerve growth factors from inflammatory cells) • Decrease the numbers of mediators • (The above 3 are useful in asthma) Colds • Common cause are viruses • Rhinovirus, coronavirus, influenza virus • Often associated with aches, pains, fever, sore eyes, stuffy heads, sore throat, blocked nose Pathogenesis • When the virus binds to the respiratory epithelium (via ICAMl), certain defences are activated (early responses and late specific immune responses) • Early responses • The infected cell produces: • IL6, IL1 1, IL8, TNFα , LIF (leukemia inhibitory factor) • Interferons • Shut down protein synthesis in the cell so that the virus cannot proliferate • Spill over to neighbouring cells to turn off protein synthesis in nearby cells • Cause upregulation of MHC1 molecules which present the viral peptides to T cells • Turn on prostaglandin synthesis (causing fever, pains) • Generally feeling crappy • Late response • CD8+ T cells come along and recognise foreign viral proteins on the MHC1 molecules on the infected cells • CD8+ cells release perforins (make holes in the cell membrane) which allows granzymes to enter. Granzymes switch on proteases inside the cell which kill the infected cell. • NK cells also come along, as does binding of antibody • The net result is loss of epithelium

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1997 Clinical pharmacology By Duy Thai • • When the epithelium is removed, secondary infection can occur Cytokines released by virally infected cells causes: 1. Increased numbers of mucous cells 2. LIF produced by the infected epithelium alters the number and types of nerves in the airways • LIF increases the number of sensory nerves • Increases the amount of peptides they contain The virus also destroys the M2 autoreceptors on cholinergic nerves • The M2 receptor is part of a negative feedback loop which turns off Ach release • If these receptors are reduced, there is upregulated vagal effects (e.g. bronchoconstriction) • Anticholinergics (ipratropium) may be useful in some people

Vasomotor tone in the nasal epithelium • The microvasculature of the nose is similar to erectile tissue in that it can become engorged with blood • When you get a stuffy nose, there is a net decrease in outflow, hence the vessels swell up and are filled with blood. • To clear up a stuffy nose, drugs which constrict the arteriole are useful • They limit the am blood entering the microvasculature and so congestion is relieved • These drugs are the α 1 agonists (cause constriction of the arterioles): • Topical decongestants (nasal sprays) • oxmetazoIine • Xylometazoline Long acting • Phenylephrine • Oral decongestants • Pseudoephidrine • Phenylpropanolamine • The microcirculation also has cholinergics, so it is possible to give ipratropium bromide as a nasal spray to help vasoconstriction • Histamine is the cause of nasal stuffiness in people with allergic rhinitis (the classical hayfever symptoms). In these people, antihistamines are or help • For severe cases, steroids are required Therapy of colds • Most colds clear up by themselves, so any drugs given are for palliative measures only • Chicken soup • NSAIDS & paracetamol (NOTASPIRIN!!!!!) • These are given to treat the aches and pains by blocking COX • COX is required in the synthesis of prostaglandins • PGE2 increases sensitivity of sensory nerve endings (hyperalgesia) • It also acts centrally in the hypothalamus to cause fever (hence COX inhibitors also prevent fever) • Aspirin should not be used when there is fever because it may cause Reyes syndrome (very important!!) • Decongestants α 1 agonists) • Antibiotics for secondary infections • Post viral therapy as appropriate • DSCG (works in 25%) • Ipratropium (works in 25%) • Steroids (works in 30%)

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