Airway pharmacology Flashcards
Define mechanism of action
process by which drug achieves its therapeutic
effects
What does increasing contractile tone involve?
Ca2+ mobilisation (Ca2+ entering cytosol from intracellular stores or ECF)
Increasing contractile machinery’s calcium sensitivity (the level of Ca2+ required to produce certain level of contraction)
How do bronchodilator drugs act?
binds to specific receptor or E expressed by ASM cell inducing intracellular change interrupting contractile process –> relax
How do β2 adrenergic receptor agonists act?
- Agonism on β2 adrenergic receptors on ASM
- stimulates Gs
- ↑adenylate cyclase
- ↑cAMP
- ↑PKA inhibiting MLCK
- ↓Ca2+ mobilisation
- relax
eg of Short-acting β2 agonist (SABAs) + when’s it used?
salbutamol
first-line therapy in asthma, administered as reliever therapy by metered-dose inhaler
eg of Long-acting β2 agonist (LABAs) + when’s it used?
salmeterol, formoterol
add-on, preventer, used w inhaled corticosteroids in metered-dose inhalers, 2x daily, continual dosing
Why use LABA w corticosteroids?
decreases risk of sudden death
eg of long-acting muscarinic receptor antagonists (LAMAs) + when’s it used?
tiotropium
treat chronic bronchitis + add-on, preventer therapy in asthma. Daily dose continual basis via metered-dose inhalers
How do long-acting muscarinic receptor antagonists work?
- blocks Ach receptors on ASM
- Ach can’t bind to M3 on ASM + glands
- less bronchoconstriction
Why are long-acting muscarinic receptor antagonists less effective for asthma therapy?
Ach plays minor role in ASM contraction
How do long-acting muscarinic receptor antagonists benefit patients w obstructive airway diseases?
reducing mucus secretion + inhibiting cough
Why will the anti-inflammatory efficacy of a certain pharmacological treatment vary depending on its individual mechanism of action?
inflammation has diff initiating factors (allergens vs. tobacco), immune cells, tissue environments (protease-anti protease balance, level of oxidative stress), cytokines,inflammatory mediators
eg of corticosteroids + when is it used?
fluticasone, beclometasone, budesonide
most effective at reducing allergic inflammation in asthma via metered-dose inhaler to maximise relative exposure of drug to respiratory tissue vs systemic circulation
How do corticosteroids work?
- binds to glucocorticoid receptors in cytosol of immune + structural cells
- drug-receptor migrates to nucleus
- binds to DNA, modulating transcription, translation, protein expression
- decrease pro-inflammatory mediator + increase anti-inflammatory mediator expression
What are leukotrienes?
group of pro-inflammatory lipid mediators that are implicated in asthmatic immune response, released by mast cells and eosinophils
eg of leukotriene receptor antagonists + when is it used?
montelukast
orally, add-on preventer therapy w continual dosing for asthma
eg of biologics + when is it used?
omalizumab
asthma
How do biologics work?
Drugs = mAb block/inhibit a specific pro- protein (IgE or IL-4, IL-5, IL-13) involved in inflammatory pathway
eg of mast cell stabilisers + when is it used?
sodium cromoglicate
allergies, asthma
How do mast cell stabilisers work?
Prevents degranulation of mast cells (not in asthma?) and/or sensory nerve activation
eg of PDE4 inhibitors + when is it used?
roflumilast
COPD
How do PDE4 inhibitors work?
- Inhibits cAMP metabolism
- Intracellular signalling effects leads to changes in protein expression + neutrophil responses
What are the ways drugs can cause adverse effects + eg?
-Interacting excessively w primary target:
opioids suppress cough by inhibiting neural function within brainstem but leads to respiratory depression
-Interacting w targets expressed in other tissues:
eg β2 agonists activate both β1+2 receptors in heart leading to cardiac side effects
How to prevent adverse effects of drugs + why?
delivered by inhalation via metered-dose inhaler so applied directly to target tissue w highest dose
Why doesn’t all dose via metered dose inhaler stay within respiratory system?
drug swallowed due to poor inhaler technique
How can poor inhaler technique be improved?
use spacer devices + proper ‘training’
Why are some drugs given orally + eg?
-systemic effect:
oral steroids to inhibit body inflammation
-drug has narrow therapeutic window so consistent dose must reach the systemic circulation:
theophylline avoids risk associated w multiple inhalations or varying amounts of drug being swallowed vs inhaled
-expensive to formulate inhaler due to physical/chemical properties of drug:
monoclonal antibodies - anti-IgE, mAb, omalizumab
What are the adverse effects of Salbutamol?
SAN + myocardium has β1, some β2, β2 agonist interacts w β1 so tachycardia+ palpitations
β2 in skeletal muscle so tremor (not major issue as tolerance develops), hypertrophy+muscle growth
Sudden death if not used w corticosteroids
Why’s clenbuterol used for doping in sports?
Activation of β2 skeletal muscle—> hypertrophy + muscle growth
When do corticosteroids lead to adverse effects?
Used long-term, at high doses, in patients at risk of independently developing the complications (osteoporosis in post-menopause)
What are the adverse effects of corticosteroids?
Growth retardation, skin ulcers, depression, candidiasis, hypercortisolism, osteoporosis
What are the features of cost-benefit analysis when prescribing?
BENEFITS - drug efficacy
increase: quality of life, life expectancy
decrease: symptoms, severity
COST - adverse effects
increase: risk of developing other disease
decrease: quality of life
-economic costs
What are the rules by NICE to produce recommended therapeutic strategies?
- All patients w sig bronchospasm given SABA
- Drugs w greater general efficacy (SABA before LAMA)
- Drugs w ↓ adverse effects(SABA→ SABA + ICS → +PDEi)
- Drugs w broad mechanisms of action(ICS before omalizumab)
- Cheaper drugs before more expensive drugs (ICS before omalizumab)
- Less drugs before more(SABA → SABA + ICS, SABA + ICS + X)
- Combine drugs if decreases risk of adverse effects (LABA w ICS)
What are the steps for asthma therapy?
- SABA
- ICS
- LABA, ↑ ICS, LTRA, PDEi
- max ICS, 4th drug
- oral CS, specialist care, anti-IgE
eg of Phosphodiesterase inhibitor?
theophylline
eg of Inhaled corticosteroids?
Fluticasone, Budesonide, Beclometasone
eg of Oral/systemic steroids?
Prednisone, Dexamethasone
What are the steps for COPD therapy?
- Smoking cessation, education,lifestyle/environment interventions
- SABA for exacerbations
- LAMA/LABA
- Inhaled corticosteroids if frequent exacerbations
- Long term oxygen therapy
- Surgical interventions (LVRS, transplantation)
