💊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
How can NSAIDs induce asthma (AERD)?
NSAIDs (e.g., aspirin) inhibit cyclooxygenase (COX-1), reducing prostaglandin production - excess leukotrienes
Results in severe bronchoconstriction, airway inflammation, and mucus production
Why is Montelukast particularly useful for NSAID (Non-steroidal anti-inflammatory drug)-induced asthma?
Blocks leukotriene effects (via CysLT1 receptor inhibition)
Reduces bronchoconstriction and airway inflammation caused by leukotriene overproduction
What is the primary mechanism of action of salbutamol?
B2 receptor agonist
Activation reduces Ca2+ entry - prevents smooth muscle contraction
What is the primary mechanism of action of fluticasone?
Very powerful
Multiple actions on many different cell types
Directly decreases inflammatory cells and cytokines produced
What is the primary mechanism of action of mometasone?
Very powerful
Multiple actions on many different cell types
Directly decreases inflammatory cells and cytokines produced
What is the primary mechanism of action of budesonide?
Very powerful
Multiple actions on many different cell types
Directly decreases inflammatory cells and cytokines produced
What is the primary mechanism of action of montelukast?
Antagonism of CysLT1 leukotriene receptor on eosinophils, mast cells and airway SMCs
What is the drug target of salbutamol?
Beta 2 (β2) adrenergic receptor
What is the drug target of fluticasone?
Glucocorticoid receptor
What is the drug target of mometasone?
Glucocorticoid receptor
What is the drug target of budesonide?
Glucocorticoid receptor
What is the drug target of montelukast?
CysLT1 leukotriene receptor
What are the main side effects of salbutamol?
Palpitations/agitation
Tachycardia/arrythmias
Hypokalaemia (at higher doses)
What are the main side effects of fluticasone?
Local side effects:
-Sore throat
-Hoarse voice
-Opportunistic oral infections
Systemic side effects:
-Growth retardation in children
-Hyperglycaemia
-Decreased bone mineral density
-Immunosuppression
-Effects on mood
(Many others)
What are the main side effects of mometasone?
Local side effects:
-Sore throat
-Hoarse voice
-Opportunistic oral infections
Systemic side effects:
-Growth retardation in children
-Hyperglycaemia
-Decreased bone mineral density
-Immunosuppression
-Effects on mood
(Many others)
What are the main side effects of budesonide?
Local side effects:
-Sore throat
-Hoarse voice
-Opportunistic oral infections
Systemic side effects:
-Growth retardation in children
-Hyperglycaemia
-Decreased bone mineral density
-Immunosuppression
-Effects on mood
(Many others)
What are the main side effects of montelukast?
Mild side effects:
-Diarrhoea
-Fever
-Headaches
-Nausea/vomiting
Serious side effects:
-Mood changes
-Anaphylaxis
