Bronchodilator and Anti-Inflammatory Drugs in Asthma Flashcards
give an outline of the pharmacological management of asthma
relievers (act as bronchodilators)
controllers/preventers (act as inflammatory agents that reduce airway inflammation);
glucocorticoids
cromoglicate
humanised monoclonal IgE antibodies
methylxanthines act as both delivers and controllers
explain the mechanisms of action and indications of short and long acting beta2-ADR agonists
reliever (bronchodilator)
beta2-ADR agonistic act as physiological anatagonaits of all spasmogens
molecular mechanism of airway smooth muscle relaxation (reduction in intracellular Ca2+ concentration and activation of large conductance of K+ channels)
reduce harmful stimulation one cardiac beta2-ADR
use of non-selective beta-ADR (propranolol) can be contraindicated - risk of bronchospasm
SABA;
salbutamol (albuterol, terbutaline)
first line of treatment for mild asthma
increases mucous clearance and decreases mediator release from mast cells and monocytes
LABA (salmeterol, formoterol)
treatment for nocturnal asthma
must always be co-administered with glucocorticoid
explain the mechanisms of action and indication of Cysteinyl leukotriene (CysLT1) receptor antagonists
relievers (bronchodilators)
CysLT1 receptor antagonists act competitively at CysLT1 receptor.
CysLTs (LTC4, LTD4, LTE4) derived from mast cells and infiltrating inflammatory cells cause smooth muscle contraction, mucus secretion and oedema
CysLT1 receptor anatagnostis (montelukast, zafirlukast)
effective add on therapy against early and late bronchospasm in mild asthma (not recommended for relief of acute asthma)
combines with other medications in chronic asthma
effective against antigen-induced and exercise-induced bronchospasm
relax bronchial smooth muscle in response to CysLTs
explain the mechanisms of action and indications of xanthines
reliever (bronchodilator)
methylxanthines (theophylline, aminophylline)
uncertain molecular mechanism of action - inhibition of isofroms of phosphodiesterase (PDE) that inactivate cAMP
combines bronchodilators (high doses) and anti-inflammatory actions
inhibits mediator release from mast cells
increases mucus clearance
increases diaphragmatic contractility and reduces fatigue (improving lung ventilation)
theophylline activates histone deacetylase (HDAC), potentiates the anti-inflammatory action of glucocorticoids
second line drugs used in combination with beta2-ADR agonists and glucocorticoids
very narrow therapeutic window
exerts adverse effects at supra-therapeutic concentrations that result from actions involving CNS, CVS , GI and kidney including dysrhythmia, seizures and hypotension
can cause nausea, vomiting, abdominal discomfort and headache
has numerous drug interactions (problematic)
describe the role of glucocorticoids
anti-inflammatory agent - a major class of steroid hormone synthesised and released on demand
the main hormone of glucocorticoid is cortisol (hydrocortisone) and it regulates many processes;
decrease in inflammatory responses
decrease in immunological responses
increase in liver glycogen deposition
increase in gluconeogenesis
increase in glucose output from liver
decrease in glucose utilisation
increase in protein catabolism
increase in bone catabolism
increase in gastric acid and pepsin secretion
explain why synthetic derivatives of cortisol, rather than cortisol itself, are used in treatment of asthma
endogenous steroids posses glucocorticoid and mineralocorticoid (regulation of salt by kidney, unwanted for inflammatory conditions)
synthetic derivates of cortisol are used as they have no mineralocorticoid activity
explain why the inhalation route of glucocorticoid administration is favoured in treatment of mild, or moderate, asthma
glucocorticoids have no direct bronchodilator action and are ineffective in relieving bronchospasm when given acutely
they are the mainstay of treatment in the prophylaxis of asthma and preferably delivered by the inhalation route to minimise adverse systemic effects
outline the molecular mechanism of action of the glucocorticoids
glucocorticoids signal via nuclear receptors (class 1), specifically GRalpha
- glucocorticoids are lipophilic molecules - enter cells by diffusion across plasma membrane
- within cytoplasm, they combine with GRalpha, producing dissociation of inhibitory heat shock proteins (e.g. HSP90). The activated receptor translocates to the nucleus aided by importins
- within the nucleus, activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of specific genes
- the transcription of specific genes is either transactivated or transgressed to alter mRNA levels and the rate of synthesis of mediator proteins
gives examples of the cellular effects that underline the anti-inflammatory action of glucocorticoid
inflammatory cells; DECREASES eosinophil number (via apoptosis) T-lymphocyte cytokines mast cell number macrophage cytokines dendritic cell number
structural cells;
decreases cytokines and mediators of epithelial cells
decrease leak of endothelial cells
increase beta2-receptors and decrease in cytokines in airway smooth muscle
decrease in mucus secretion of mucus glands
increase of anti-inflammatory proteins
decrease of inflator proteins
provide a brief account of the clinical use of glucocorticoids in asthma
prevent inflammation
resolve established inflammation
they do not alleviate early stage bronchospasm caused by allergens or exercise
long term treatment is effective (in combination with LABAs)
provide a brief account of the clinical use of glucocorticoids in mild/moderate asthma
given by inhalation
efficacy develops over several days
adverse effects - dysphonia (hoarse, weak voice)
oropharyngeal candidiasis (thrush)
provide a brief account of the clinical use of glucocorticoids in chronic, severe or rapidly deteriorating asthma
oral prednisone used in combination with inhaled steroid to reduce the oral dose required and minimise unwanted systemic effects
bronchodilator drugs are co-administered
patients should be strongly encouraged total sufficient inhaled glucocorticoid to control symptoms and avoid disease progression which may be irreversible
comment upon cromoglicate in the treatment of asthma
cromones;
infrequently used
mast cell stabilisers (suppress histamine release from mast cells), not the basis in their action in asthma
no direct effect upon bronchial smooth muscle, has a weak anti-inflammatory response
decrease in sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release
specific agent - sodium cromoglicate inhaled reduces both phases of asthma attach efficacy takes several weeks to develop to block late-phase reaction - requires frequent dosing more effective in children
comment upon omalizumab in the treatment of asthma
monoclonal antibodies directed against IgE;
binds IgE via Fc to prevent attachment to FCe receptors - suppresses mast cell response to allergens
reduces expression of FCe receptors in various inflammatory cells
expensice
administered via IV
monoclonal antibodies directed abasing IL-5
