Bronchodilator and anti-inflammatory drugs in the treatment on asthma Flashcards
SABA
outline the mechanism and give a named example
they favour relaxation of ASM
act quickly (within 5 minutes - max effect at 30 minutes)
relaxation persists for 3-5 hours
they are 1st line relievers for mild, intermittent asthma
usually administered by inhalation
increases mucus clearance and decreases mediator release from mast cells and monocytes
tachycardia, cardiac dysrhythmia and hypokalaemia can occur
Examples: salbutamol, terbutaline
Xanthines
outline the mechanism and give a named example
uncertain mechanism - might inhibit isoforms of PDE that inactivate cAMP and cGMP (allowing these second messengers to go on and cause ASM relaxation)
Examples: Methylxanthines (e.g. theophylline, aminophylline)
LABA
outline the mechanism and give a named example
not recommended for acute relief
useful for nocturnal asthma
should not be used as monotherapy (LABA alone causes desentisation - decreases no. of B2 receptors in airway over time)
must be co-administered with a glucocorticoid
Examples: salmeterol (slow-acting), and formeterol (fast-acting)
disadvantages of oral therapy for asthma
slow systemic clearance
high systemic dose necessary to get appropriate concentration in the lung
high incidence of adverse effects
Beta 2 Agonists
outline the mechanism
physiological antagonists of all spasmogens (not by preventing things from binding) - they independently bind B2 receptors and favour relaxation
(by phosphorylation of MLCK and myosin phosphatase)
CysLT1 receptor antagonists
outline the mechanism
mast cells are activated and release LTA4 (metabolised to LTB4 and LTC4), which are transported to ECF. LTB4 causes inflammation: inflammatory cells to release CysLTs.
CysLTs bind to their receptors and cause bronchoconstriction (early phase) and inflammation (late phase).
However, CysLT1 antagonists block this from happening
CysLT1 receptor antagonists
give a named example
montelukast, zafirlukast
these are effective as add-on therapies
effective against antigen-induced and exercise-induced bronchospasm
administered by ORAL route
some headaches and GI upsets have been reported
methylxanthines
these have anti-inflammatory actions, and are also bronchodilators at high doses
they improve lung ventilation by increased diaphragmatic contractility
theophylline activates HDAC - decreasing transcription of genes for inflammatory proteins
administered by ORAL route
narrow therapeutic window (has adverse effects)
even at therapeutic concentrations can cause abdominal discomfort and nausea
problematic due to interactions involving CYO450s
role of glucocorticoids in the body
this is the main steroid hormone in the body. Regulates numerous responses:
-inflammatory responses to decrease
-immunological responses to increase
- also affects liver glycogen deposition, gluconeogenesis, glucose output from liver… and many others
Release of glucocorticoid is mediated by hormone from the anterior pituitary which tells the adrenal cortex to produce glucocorticoid
why are synthetic derivatives of cortisol used to treat asthma instead of cortisol?
endogenoud steroids have both glucocorticoid and mineralocorticoid actions. The latter are unwanted in treatment of inflammatory conditions.
So, synthetic derivatives of cortisol (e.g. beclometasone, budesonide, fluticasone) with little/ no mineralocorticoid activity are used for anti-inflammatory effects.
why is the inhalational route of glucocorticoid administration favoured in the treatment of mild/ moderate asthma?
to minimise adverse systemic effects
molecular mechanism of action of the glucocorticoids
they are lipophilic and so diffuse through membrane. In cytoplasm, they combine with GRa (glucocorticoid receptor), dissociating it from the heat shock protein. The activated receptor translocates to the nucleus, aided by “importins”. The activated receptor monomers assemble into homodimers and bind to GRE (glucocorticoid response elements) in the promotor region of specific genes, either transactivating or transrepressing their transcription.
examples of the cellular effects underlying the anti-inflammatory action of the glucocorticoids?
they decrease the formation of Th2 cytokines and cause Th2 cells to apoptose.
They prevent IgE production.
They prevent allergen-induced influx of eosinophils into the lung and cause eosinophils to apoptose.
They reduce the number of mast cells and decrease FcE expression on mast cells.
brief account of the clinical use of glucocorticoids in asthma
They prevent inflammation, and also resolve established inflammation.
They should not be given alone.
They should be used in management of the underlying condition. It takes more than 24 hours for them to have an effect: ineffective at relieving bronchospasm acutely.
Preferred method is inhalational, however sometimes oral is necessary.
coromones (cromoglicates)
second line drugs
used infrequently now
“mast cell stabilisers”: supress histamine release from mast cells
have no direct effect on bronchial smooth muscle
weak inflammatory effect
specific agent: sodium cromoglicate: delivered by inhalation, efficacy may take several weeks, requires frequent dosing, more effective in children
