Therapeutics of Obstructive Airway Diseases

Question 1

explain the patho-physiology of the inflammatory cascade in asthma and how this relates to pharmacological treatment

Answer 1

inherited or acquired factors - avoid precipitant

eosinophilic inflammation - inflammatory medication (corticosteroids, cromones, theophylline)

mediators, Th2 response - antileukotrienes or antihistamines, monoclonal antibodies (anti-IgE, anti IL-5)

hyper-reactivity of smooth muscle - bronchodilators

Question 2

describe the main classes of preventer and reliever drugs - preventers (anti-inflammatory)

Answer 2

corticosteroids;
used in asthma and COPD (can cause pneumonia in COPD due to immune suppression and impaired mucociliary clearance)
oral steroid (e.g. prednisolone) - acute exacerbations not maintenance (moderate persistent asthma onwards_
inhaled steroid (e.g. beclomethasone) - maintenance monotherapy in asthma (mild persistent onwards), used as ICS/LABA/LAMA combo in COPD (not monotherapy) (moderate persistent onwards)
reduces exacerbations in eosinophilic COPD
optimises lung delivery (extra fine solution HFA/Spacer)

cromones;
only in asthma
mast cell stabiliser
cromoglycate effective in atopic children (EIB)
inhaled route only (compliance with QID dosing)
not used much (poor efficacy)

leukotriene receptor antagonists;
only is asthma
montelukast - oral route, high therapeutic ration (once daily)
less potent anti-inflammatory than inhaled steroid
2nd line - complimentary non steroidal inflammatory additive to inhaled steroid
effective in EIB
effective in allergic rhinitis (anti-histamine)

anti-IgE;
e.g. omalizumab
inhibits binding to high affinity IgE receptor - inhibiting Th2 responses and associated IgE release from basophils/mast cells
injection every 2-4 weeks (patients with severe asthma only, expensive)
little effect on pulmonary function but reduces exacerbations

anti-IL5
e.g. mepolizumab
blocks the effects of TH2 cytokine IL-5 which is responsible for eosinophilic inflammation in asthma
injection every 2-4 weeks (patients with severe refractory eosinophilic asthma only, expensive)
little effect on pulmonary function or symptoms but reduces exacerbations and oral steroid sparing effect

anti-IL4alpha;
e.g. dupilumba
blocks effects of TH2 cytokines IL-4/13 which is responsible for eosinophilic inflammation, IgE, airway hyper reactivity and mucin production in asthma
injection every 2 weeks (patients with severe refractory asthma only, expensive)
suppresses IgE and FeNO
good effect on pulmonary function also reduces exacerbations and oral steroid sparing effect
also effective in atopic dermatitis and nasal polyposis

Question 3

describe the inhaler delivery systems and potential adverse effects

Answer 3

spacer device;
avoids coordination problems with pMDI
reduces oropharyngeal and laryngeal side effects side effects
reduces systemic absorption from swallowed fraction
acts as holding chamber for aerosol
reduces particle size and velocity
improves lung deposition

Question 4

explain the patho-physiology of COPD and how this relates to smoking cessation, oxygen and pharmacological therapies - refer to PP

Answer 4

aims of treating asthma;
abolish symptoms, minimise beta2-use, normalise FEV1, reduce PEF variability, reduce exacerbations, prevent long term airway remodelling, avoid triggers, suppress inflammatory cascade with inh steroid, stabilise smooth muscle, increase pulmoanry functions, improve QOL, prevent pulmonary heart desease;
smoking cessation - stopping smoking, the loss of FEV1 rate may return to normal
immunisation
pharmacotherapy
pulmonary rehab
oxygen

PDE4 inhibitors;
roflumilast - oral
COPD only 
minimal effect on FEV1 
reduces exacerbations - additive to LABA or LAMA
has adverse effects 
rarely used - may be an add on

mucolytics;
oral (e.g. carbocisteine, erdosteine
reduces sputum viscosity and aide sputum expectoration (reduces exacerbations) in COPD
rarely used - may be an add on

Question 5

describe the main classes of preventer and reliever drugs - relievers (bronchodilators)

Answer 5

beta2-agonists;
stimulate bronchial smooth muscle beta2-receptors; increasing cAMP
SABA - salbutamol
LABA - salmeterol/formoterol
combination inhalers - budsondie/formoterol :MART
used in both asthma and COPD
high therapeutic ratio when inhaled
beta 2 down regulation and tachyphylaxis with chronic LABA
systemic beta2 effects when given systemically or at high inhaled doses
high nebulised doses given in acute attack

muscarinic antagonists (anti-cholinergics);
blocks post junctional end plate M3 receptors
short acting - ipratropium
long acting - tiotorpium, glycopyrronium, umeclidinium, aclidinium
inhaled route - high therapeutic ratio
mostly used in COPD to reduce exacerbations on its own as in combination with LAMA/LABA
used in asthma as triply therapy at step 4 (tiotropium) as add on to ICS/LABA
high nebulised doses of ipraptropium used in acute COPD and in acute asthma

methyl-xanthines;
oral (theophyline) for mainenance therapy
SR formulation useful for nocturnal dips
used as add on to inhaled steroid as complimentary non steroidal inflammatory
IV (aminophyline) fr acute asthma attacks
non selective phosphodiesterase inhibitor (increased cAMP)
adenosine antagonist
low therapeutic ration - P450 drug interactions
used in asthma and CODP

Question 6

describe the muscarinic (cholinergic) receptors

Answer 6

M1 - enhance cholinergic reflex
M2 - inhibit ACh release
M3 - mediate bronchocontriction and mucus secretion

Question 7

describe treatment of asthma

Answer 7

oral prednisolone (or iv hydrocortisone)
nebulised high dose salbutamol/Neb ipratropium/iv aminophyline/magnesium 
60% oxygen
ITU assisted mechanical intubated ventilation if falling PaO2 and rising PaCO2 - do not use respiratory stimulant