💊Pharmacology💊 - Asthma Flashcards
Case history:
Katie Lucero (3 years)
Great difficulty in breathing.
Whistle like wheeze when exhaling and is occasionally coughing.
Slight temperature (38.2oC).
Further history and physical examination reveal nothing.
Has had mild breathlessness before
Usually when she has an infection of some type
What is the patients problem?
First presentation of asthma
No allergic trigger - likely precipitated by the viral infection
What are the therapeutic objectives for a patient with a first presentation of asthma?
Short term - Relief
Relieve symptoms of breathlessness and expiratory wheeze
Long term - Prevention
Dampen/prevent the late phase of the asthma attack (inflammation stage)
Reduce risk of further attacks
What else must be done in a child under 5 presenting with asthma?
Careful and frequent monitoring
Develop a written asthma plan to help minimize symptoms/adjust treatment as necessary
What is usually the first treatment option for someone with a first presentation of asthma?
Salbutamol
What type of drug is salbutamol?
B2-(adrenergic) receptor agonist
How do B2-receptor agonists work?
Adenylate cyclase activation - enzyme responsible for converting ATP into cAMP
Increase in cAMP levels - cAMP binds to and activates protein kinase A (PKA)
Activation of PKA - reduces intracellular calcium levels - enhances activity of calcium pumps and decreases calcium influx
Inhibition of Myosin Light Chain Phosphorylation - Both direct inhibition of myosin light chains and indirect from reduced calcium
No Myosin-Actin Interaction → Muscle Relaxation
Why is inhalation preferred to the oral route for asthma mediations?
Inhalation allows drug to take a local effect
Oral route results in systemic dispersion
Why are nebulizers the best method for delivering asthma drugs in emergency situations?
Many drug solutions - can deliver combinations
Minimal patient cooperation needed
Can deliver to all patient ages
Concentration and dose can be modified
Only requires a normal breathing pattern to use (e.g. unlike an inhaler, where you need to coordinate an inhalation with the delivery of the drug)
How much of an inhaled dose of a drug (e.g. salbutamol) is actually able to influence lung action?
Approximately 20%
Why does such a low proportion of an inhaled dose reach the lungs and take effect?
Very large proportion is swallowed
Some drug is simply exhaled out again
Some drug that is absorbed in the lungs actually enters the systemic circulation, rather than remaining in the area where to effect is desired
Some cleared by the mucociliary system
Why is a spacer very clinically useful, especially in children?
Outline the vicious cycle of eosinophilic asthma
Common viral infections (e.g. rhinovirus) are known to release mediators that specifically activate eosinophils
Eosinophils can induce epithelial damage (e.g. due to release of major basic protein)
This increases susceptibility to viral infections
Cycle repeats
What is the mechanism of action of fluticasone in eosinophilic inflammation?
Glucocorticoid receptor activation
Anti-inflammatory gene expression - induces transcription of anti-inflammatory proteins - inhibit phospholipase A2 and reduce production of pro-inflammatory mediators - leukotrienes and prostaglandins
Suppression of Pro-inflammatory Genes - Represses transcription of pro-inflammatory cytokines (e.g., IL-5, IL-13)
Reduction in Eosinophil Recruitment and Survival - Decreases chemotactic signals - promotes eosinophil apoptosis
Despite a major swallowed component, fluticasone propionate has a bioavailability of less than 1%. Why?
Extensive First-Pass Metabolism - extensive metabolism by liver P450 enzymes before reaching circulation
Poor gastrointestinal absorption
High lipophilicity - lipophilic nature increases local tissue retention in the lungs but limits systemic absorption when swallowed
What is the mechanism of action of montelukast?
Leukotriene receptor antagonists - prevents leukotrienes from triggering bronchoconstriction, inflammation, mucus production and airway hyper-responsiveness
Key effects:
-Reduces bronchoconstriction
-Decreases airway inflammation and mucus production
-Inhibits eosinophil recruitment and activation
-Improves lung function and relieves asthma/allergy symptoms
