Assessment of Severity
- Multiple methods to guide treatment
- Often not performed, rather clinical gestalt is used
- Australian therapeutic guidelines is a good start. GINA also have good guidelines. If hospitalised for an acute exacerbation, generally patients should be on a dose of corticosteroids
Non-pharmacological Management
- In susceptible pts, avoid NSAIDS and beta-blockers (for asthma only, for COPD they have mortality benefits)
- Avoid triggers if possible
- Strategies aimed at facilitating mucociliary clearance - only very indirect evidence. Avoid excessive physiotherapy though
Bronchodilators
Historical Insights
Beta-receptor
Pharmacological points
- Adrenaline was discovered in 1899 and 1901 and was found to have bronchodilating properties
- Used initially parentally and then aerosolised. Non-selective and had cardiotoxicity
- Isoprenaline had more beta- selectivity and had greater bronchodilating properties, but cardiotoxicity was still significant due to non-selective beta-1 agonism
- Salbutamol introduced 1969, longer lasting than isoprenaline (not broken down by COMT), is hydrophilic therefore works from te extracellular compartment accounting for rapidity of action, onset 2 - 3 min, peak 15 min. But binds weakly therefore diffuses quickly back to microcirculation according to equilibrium status between comparments - accounts for short duration of action (4-6h)
- Levabuterol is R enantiomer. some studies showed lesser hospitalisations and reduced dose needed, but controversial as there have been conflicting studies. More research is needed.
Beta-receptor
- Three isoforms, beta-1 (mainly heart), beta-2 (mainly lungs) and beta-3 (adipose tissue)
- 7 transmembrane domains, glycoprotein, 54% sequence homology between beta1 and beta2 accounting for some cross-reactivity in even the most selective agonists
- c-AMP mediated pathways reducing intracellular calcium in airway smooth muscle cells (pump out of cell, pump into sarcoplasmic reticulum). Uncoupling of c-AMP downstream processes may account for receptor desensitisation
- 9 common SNP polymorphisms are found in normal population. Some polymorphisms account for increased receptor downregulation following agonist exposure (gly16, gln27), glu27 is protective, and studies show glu27/glu27 pts with asthma are less reactive with higher PD20 for methacholine
- Gly16/gly16 had poorer responses to inhaled salbutamol
- Some contradictory studies to the above points also exist, therefore further research is needed.
Pharmacological points
- Formeterol is more lipophilic, highly Beta-2 specific and long acting. Because it is lipophilic it is taken up by the cell membrane, and from here it forms a depot through which it leaches out and interacts with the receptor. This accounts for its more prolonged effect, with duration of activity being ~12h. Because it is only moderately lipophilic, there is still molecules in the aqueous phase, allowing it to act quicker and therefore onset of action is 2 - 3 min
- Salmeterol has a very long side chain making it highly lipophilic. It diffuses very quickly and partitions strongly into the phospholipid bilayer and diffuses laterally across it very quickly. Because it is bound in the cell membrane, the duration of action is longer and the onset time is slower. Maximum onset action time 30 mins.
Short acting beta-2 agonists
- Have half life of 4 - 6h which guides their dosing interval
- Theoretical risk of increasing paradoxical airway inflammation and causing receptor down-regulation with overuse, but this has not been brought out in prospective studies.
- Initial doses often need to be higher because patients admitted to hospital have been using their SABA more frequently causing theoretical downstream receptor modification
- Initially continuous and regular use of SABA was widespread practice because of a short study that showed slightly higher peak flos at night and less need for "as needed rescue dose" of SABAs. But this was a study of only 1 week duration
- Epidemic of asthma mortality in New Zealand in 1976, hypothesised in part to be due to regular use of SABAs
- In mild asthma, RCT showed regular use compared to rescue use had no significant benefit, and no significant associated harm - period over 16 weeks.
- There are cAMP response elements in the human genome which can cause synthesis of pro-inflammatory cytokines, therefore lead to a theoretical risk of worsening asthma.
- Increased mortality with short acting beta agonists
- interestingly mortality rates were quite low until 1960s, only difference really was isoprenaline
- fenoterol in NZ in 1976 - when introduced more exacerbations and deaths, when taken away less exacerbations and deaths
- interestingly mortality rates were quite low until 1960s, only difference really was isoprenaline
- Tolerance
- Controversial
- There is a decrease in peak lung function in morning if there is regular use of Salbutamol - not borne out for salmeterol or formeterol
- Controversial
- Administration of beta-agonists can cause a slight drop in arterial pO2 by 5 mmHg, because of V/Q mismatching. Release of bronchoconstriction to areas of lung that have undergone hypoxic vasoconstriction