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)
