Obstructive airway disease pharmacology Flashcards
What does parasympathetic stimulation of the cholinergic nerve fibres to the bronchial smooth muscle receptors and gland cell receptors cause?
- bronchial smooth muscle contraction mediated by M3 muscarinic ACh receptors on ASM cells
- increased mucus secretion mediated by M3 muscarinic ACh receptors on gland (goblet) cells
What does parasympathetic stimulation of the noncholinergic nerve fibres to the airway smooth muscle cause?
bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP)
What does sympathetic stimulation of the airways cause?
- bronchial smooth muscle changes
- gland cell changes
- epithelial cell effects
- vascular smooth muscle effects
- bronchial smooth muscle relaxation via 2-adrenoceptors (β2-ADR) on ASM cells activated by adrenaline released from the adrenal gland
- decreased mucus secretion mediated by B2-adrenoceptors on gland (goblet) cells
- increased mucociliary clearance mediated by B2-adrenoceptors on epithelial cells (mucociliary elevator)
- vascular smooth muscle contraction, mediated by α1-adrenoceptors on vascular smooth muscle cells
In chronic asthma what are the 5 changes that occur to the bronchioles due to long standing inflammation?
1: increased mass of smooth muscle (hyperplasia and hypertrophy)
2: accumulation of interstitial fluid (oedema)
3: increased secretion of mucus
4: epithelial damage (exposing sensory nerve endings)
5: Sub-epithelial fibrosis
What are the two components of bronchial hyper-responsiveness in asthma?
1: hypersensitivity - Epithelial damage, exposing sensory nerve endings (C-fibres, irritant receptors), contributes to increased sensitivity of the airways to bronchoconstrictor influences
2: Hyper-reactivity
What type of hypersensitivity reactions occur in the immediate and delayed phases of an asthma attack?
Immediate phase = type 1 hypersensitivity reaction
Delayed phase = type 4 hypersensitivity reaction
What kind of hypersensitivity reaction do type 1 t-helper cells mediate?
Delayed-type hypersensitivity response involved igG and macrophages (cell mediated)
What kind of hypersensitivity reaction do type 2 t-helper cells mediate?
antibody-mediated immune response involving IgE
What is the difference between the response produced to an allergen by an atopic vs a non-atopic individual?
Atopic individual: allergen undergoes phagocytosis by an antigen presenting cell and there is a STRONG type 2 T-helper cell response
Non-atopic individual: allergen undergoes phagocytosis by an antigen presenting cell and there is a LOW-LEVEL type 1 T-helper cell response
(For reasons that are not yet understood, some people have a predisposition to respond to antigens by making antibodies of the IgE class. The trait tends to run in families suggesting a genetic component. These people are said to suffer from atopy.)
What is the difference between the early and late phases of asthma?
Early phase: allergen activate mast cells to release spasmogens/cysLT’s/histamine = bronchospasm and early inflammation
Late phase: mast cells also release chemotaxins/chemokines that attract type 2 Thcells, monocytes and inflammatory cells (esp. eosinophils) = epithelial damage, airway inflammation, airway hyperresponsiveness = bronchospasm, wheezing, mucus oversecretion and cough
What are the 3 ‘reliever’ drugs for asthma, what do they act to do?
What are the three ‘preventor’ drugs for asthma, what do they act to do?
Which category do methylxanthines come under?
Relievers: act as bronchodilators
- short acting B2 adrenoceptor agonists (SABAs)
- Long acting B2 adrenoceptor agonists (LABAs)
- cysLT1 receptor antagonists
Controllers/preventors: act as anti-inflammatory agents that reduce airway inflammation
- Glucocorticoids
- Cromoglicate
- Humanised monoclonal IgE antibodies
Methylxanthines come under both categories
In adults: describe the stepwise treatment protocol for asthma
-when do you consider stepping up?
1: SABA + low dose inhaled corticosteroid
2: consider adding a LABA (as a combination inhaler)
3: if no response to LABA - stop LABA and increase ICS dose
if response to LABA but not adequate, continue LABA and consider increasing ICS
OR
if response to LABA but not adequate continue LABA and ICS and consider adding LTRA, SR theophylline or LAMA
4: consider trials of
increasing ICS to high dose
adding a fourth drug - LAMA, beta agonist tablet, LTRA, SR theophylline REFER SPECIALIST
5: use daily steroid tablet, maintain high dose ICS, SPECIALIST
Consider stepping up if SABA is used more than three times weekly
What is the difference in: -Pharmakokinetics -Dose -systemic conc. of drug -incidence of adverse effects -compliance -ease of admin -effectiveness in aerosols vs oral tablets
Pharmaco:
Aerosol - slow absorp. from lung surface v rapid systemic clearance
Oral - good oral absorp. and slow systemic clearance
Dose:
Aerosol - low dose delivered rapidly to target
Oral - high systemic dose necessary to achieve an appropriate conc. in the lung
Systemic conc. of drug:
Aerosol - low
Oral - high
Incidents of adverse effects:
Aerosol - low
Oral - high
Compliance:
Aerosol - good with bronchodilators, bad with anti-inflamm. drugs
Oral - good
Ease of admin:
Aerosol is more difficult
Effectiveness:
Aerosol is good in mild to mod disease but oral is good even in severe disease
What are the main actions of SABA’s? example. How long do they take to work, when is there maximal effect and how long do they persist for? Adverse effects?
Salbutamol
- relax smooth muscle, increase mucus clearance and decrease mediator release from mast cells and monocytes
- act within 5 mins, maximal effect within 30mins, relaxation persists for 3-5hrs
- few adverse effects, most commonly fine tremor. tachycardia, cardiac dysrhthmia and hypokalaemia can occur
What is an example of LABA? what is this useful for?
- salmeterol/formoterol
- long acting b2-agonist
- good for nocturnal asthma (act for approx. 8hrs)
What is an example of a cysteinyl leukotriene receptor antagonist? how do they work? how are they administered?
- montelukast/zafirlukast
- they block the cysteinyl leukotriene receptors which when activated causes bronchoconstriction and inflammation = relax bronchial smooth muscle
- administered orally
Give an example of methylxanthines? how do they work? how are they administered? Adverse effects? what is therapeutic window?
- theophylline
- relax smooth muscle
- increase diaphragmatic contractility
- potentiate anti-inflammatory effect of glucocorticoids
- oral
- adverse effects: nausea/vomiting/abdo discomfort/headache
- therapeutic window is narrow and at supratherapeutic conc. = dysrhythmia, seizures, hypotension
What are examples of glucocorticoids used in asthma treatment?
Beclometasone, budesonide, fluticasone
How do glucocorticoids work in general?
they are lipophylic and enter cells by diffusion across the plasma membrane, here they work to switch on or switch off transcription of specific genes
-generally they increase transcription of genes encoding anti-inflammatory proteins and they decrease transcription of genes encoding inflammatory proteins
What are the 4 ways glucocorticoids work to decrease inflammation in bronchial asthma?
- decrease formation of type 2 helper cell cytokines
- they prevent production of IgE abodies
- they prevent allergen induced influx of eosinophils
- they reduce the number of mast cells
What are the most common side effects of inhaled steroids?
-dysphonia
-oropharyngeal candidiasis
(due to deposition of steroid in the oropharynx)
What are cromones? example? how are they administered?
- second line drugs used prophylactically for allergic asthma in children/young adults
- sodium cromoglycate
- AKA mast cell stabilisers
- inhaled route
What can COPD be clinically divided into?
Chronic bronchitis:
- inflammation of bronchi and bronchioles
- cough
- clear mucoid sputum
- infections with purulent sputum
- increasing breathlessness
Emphysema:
- distension and damage to alveoli
- destruction of acinial pouching in alveolal sacs
What is the pathophysiology of COPD?
smoking/air pollution leads to stimulation of resident alveolar macrophages which causes them to produce cytokines = activation of neutrophils, CD8 T cells, increased macrophage numbers = release of matrix metalloproteinases e.g. elastase and free radicals
What is the main type of drug used for COPD? what are their 2 actions in COPD? Adverse effects?
M3 muscarinic antagonists: they block the effect of Ach on M3 receptors, preventing airway smooth muscle contraction
1: relax bronchospasm caused by irritant stimuli (as irritant stimuli initiate a vagal reflex that liberates ACh)
2:Decrease mucus secretion
Few adverse effects
What is an example of a short acting muscarinic antagonist, what is an example of a long acting muscarinic antagonist?
SAMA: ipratropium/oxitropium
LAMA: tiotropium/aclidinium-
Which is superior: tioptropium or ipratropium
-tiotropium as it has selectivity for M3 muscarinic receptors
What are the 6 advantages of using a spacer device when administering aerosol drugs?
- avoids co-ordination problems
- reduced oropharyngeal and laryngeal side effects
- reduces systemic absorption from swallowed fraction
- acts as a holding chambed for aerosol
- reduces particle size and velocity
- improves lung deposition
What is an Anti-IgE drug? how does it work? how is it administered? is it used for asthma or COPD?
- IgE monoclonal antibody: omalizumab
- inhibits binding to IgE receptor = inhibit mediator release from basophils/mast cells
- injection every 2-4 weeks
- used in step 5 of the asthma treatment pathway
What is an Anti-IL5 drug? How does it work? How is it administered? is it used for asthma or COPD?
- mepolizumab
- blocks effects of type 2 T helper cell cytokin IL-5 which is responsible for the eosinophilic inflamm. in asthma
- injection every 4 weeks-
- used in step 5 of the asthma treatment pathway
What is a PDE4 inhibitor? is this used in asthma or COPD? adverse effects?
-Roflumilast –oral tablet od
-Indicated for COPD only
-Minimal effect on FEV1 –anti-inflammatory action
-Reduces exacerbations –additive to LABA or LAMA
Adverse effects : Nausea/Diarrhoea/Headache/Weight loss
Rarely used - as add on to LABA/LAMA in frequent exacerbators instead of ICS
What is an example of a mucolytic drug? what does this act to do? when is it used?
Oral carbocisteine , erdosteine
To reduce sputum viscosity and aide sputum expectoration [and reduce exacerbations ] in COPD
Rarely used –only as add on to other treatments
What is the treatment regime for acute asthma?
O- high flow oxygen
S - Salbutamol 5mg nebulised
P - prednisolone oral 40mg (daily for at least 5 days or until recovery) OR hydrocortisone 100mg IV
I - ipatropium nebulised (0.5mg 4-6hrly)
M - Iv magnesium sulphate if severe and not responding to salbutamol (1.2-2mg IV infusion over 20mins SENIOR)
AN - anaesthetist
(A - Consider aminophylline for children with severe or life-threatening asthma unresponsive to
maximal doses of bronchodilators and steroids.)
What does COPD management depend on?
GOLD stage:
: At risk
Normal Spirometry Chronic Symptoms (cough, sputum production) GOLD 0 was introduced in the GOLD 2001 publication, but was no longer used in GOLD 2010
1: Mild COPD
FEV1/FVC < 70%
FEV1 > or equal to 80% predicted
With or without chronic symptoms (cough, sputum production)
2: Moderate COPD
FEV1/FVC < 70%
FEV1 between 50 and 80% predicted
With or without chronic symptoms (cough, sputum production)
3: Severe COPD
FEV1/FVC < 70%
FEV1 between 30 and 50% predicted
With or without chronic symptoms (cough, sputum production)
4: Very Severe COPD
FEV1/FVC < 70%
FEV1 < or equal to 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
Exacerbation history
Symptom severity - mMRC or CAT
= this puts the patient into group A to D
What are the treatments of COPD in patients in the groups A to D?
A = SAMA/SABA PRN B = LAMA C = LABA/LAMA or ICS/LABA D = ICS/LABA/LAMA
Immunise patients - influenza pneumococcal
Smoking cessation
Oxygen therapy
What examples of LAMA-LABA combinations are there?
- tiotropium/olodaterol
- Aclidinium/formoterol
What is an example of LABA-ICS combination?
beclometasone/formoterol
What is an example of a LABA-LAMA-ICS combination?
beclometasone/formoterol/glycopyrronium
What is the treatment for acute COPD exacerbation?
Nebulised high dose salbutamol + ipratropium
Oral prednisolone
Antibiotic (amoxycillin/doxycycline) if infection
24-28% O2 titrated against PaO2/PaCO2
Physio to aide sputum expectoration
Non invasive ventilation to allow higher FiO2
ITU Intubated assisted ventilation only if reversible component (eg pneumonia)
