Airway pharmacology

Question 1

Define mechanism of action

Answer 1

process by which drug achieves its therapeutic

effects

Question 2

What does increasing contractile tone involve?

Answer 2

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)

Question 3

How do bronchodilator drugs act?

Answer 3

binds to specific receptor or E expressed by ASM cell inducing intracellular change interrupting contractile process –> relax

Question 4

How do β2 adrenergic receptor agonists act?

Answer 4

• Agonism on β2 adrenergic receptors on ASM
• stimulates Gs
• ↑adenylate cyclase
• ↑cAMP
• ↑PKA inhibiting MLCK
• ↓Ca2+ mobilisation
• relax

Question 5

eg of Short-acting β2 agonist (SABAs) + when’s it used?

Answer 5

salbutamol

first-line therapy in asthma, administered as reliever therapy by metered-dose inhaler

Question 6

eg of Long-acting β2 agonist (LABAs) + when’s it used?

Answer 6

salmeterol, formoterol

add-on, preventer, used w inhaled corticosteroids in metered-dose inhalers, 2x daily, continual dosing

Question 7

Why use LABA w corticosteroids?

Answer 7

decreases risk of sudden death

Question 8

eg of long-acting muscarinic receptor antagonists (LAMAs) + when’s it used?

Answer 8

tiotropium

treat chronic bronchitis + add-on, preventer therapy in asthma. Daily dose continual basis via metered-dose inhalers

Question 9

How do long-acting muscarinic receptor antagonists work?

Answer 9

• blocks Ach receptors on ASM
• Ach can’t bind to M3 on ASM + glands
• less bronchoconstriction

Question 10

Why are long-acting muscarinic receptor antagonists less effective for asthma therapy?

Answer 10

Ach plays minor role in ASM contraction

Question 11

How do long-acting muscarinic receptor antagonists benefit patients w obstructive airway diseases?

Answer 11

reducing mucus secretion + inhibiting cough

Question 12

Why will the anti-inflammatory efficacy of a certain pharmacological treatment vary depending on its individual mechanism of action?

Answer 12

inflammation has diff initiating factors (allergens vs. tobacco), immune cells, tissue environments (protease-anti protease balance, level of oxidative stress), cytokines,inflammatory mediators

Question 13

eg of corticosteroids + when is it used?

Answer 13

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

Question 14

How do corticosteroids work?

Answer 14

• 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

Question 15

What are leukotrienes?

Answer 15

group of pro-inflammatory lipid mediators that are implicated in asthmatic immune response, released by mast cells and eosinophils

Question 16

eg of leukotriene receptor antagonists + when is it used?

Answer 16

montelukast

orally, add-on preventer therapy w continual dosing for asthma

Question 17

eg of biologics + when is it used?

Answer 17

omalizumab

asthma

Question 18

How do biologics work?

Answer 18

Drugs = mAb block/inhibit a specific pro- protein (IgE or IL-4, IL-5, IL-13) involved in inflammatory pathway

Question 19

eg of mast cell stabilisers + when is it used?

Answer 19

sodium cromoglicate

allergies, asthma

Question 20

How do mast cell stabilisers work?

Answer 20

Prevents degranulation of mast cells (not in asthma?) and/or sensory nerve activation

Question 21

eg of PDE4 inhibitors + when is it used?

Answer 21

roflumilast

COPD

Question 22

How do PDE4 inhibitors work?

Answer 22

• Inhibits cAMP metabolism

- Intracellular signalling effects leads to changes in protein expression + neutrophil responses

Question 23

What are the ways drugs can cause adverse effects + eg?

Answer 23

-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

Question 24

How to prevent adverse effects of drugs + why?

Answer 24

delivered by inhalation via metered-dose inhaler so applied directly to target tissue w highest dose

Question 25

Why doesn't all dose via metered dose inhaler stay within respiratory system?

Answer 25

drug swallowed due to poor inhaler technique

Question 26

How can poor inhaler technique be improved?

Answer 26

use spacer devices + proper 'training'

Question 27

Why are some drugs given orally + eg?

Answer 27

-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

Question 28

What are the adverse effects of Salbutamol?

Answer 28

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

Question 29

Why’s clenbuterol used for doping in sports?

Answer 29

Activation of β2 skeletal muscle—> hypertrophy + muscle growth

Question 30

When do corticosteroids lead to adverse effects?

Answer 30

Used long-term, at high doses, in patients at risk of independently developing the complications (osteoporosis in post-menopause)

Question 31

What are the adverse effects of corticosteroids?

Answer 31

Growth retardation, skin ulcers, depression, candidiasis, hypercortisolism, osteoporosis

Question 32

What are the features of cost-benefit analysis when prescribing?

Answer 32

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

Question 33

What are the rules by NICE to produce recommended therapeutic strategies?

Answer 33

* 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)

Question 34

What are the steps for asthma therapy?

Answer 34

- SABA - ICS - LABA, ↑ ICS, LTRA, PDEi - max ICS, 4th drug - oral CS, specialist care, anti-IgE

Question 35

eg of Phosphodiesterase inhibitor?

Answer 35

theophylline

Question 36

eg of Inhaled corticosteroids?

Answer 36

Fluticasone, Budesonide, Beclometasone

Question 37

eg of Oral/systemic steroids?

Answer 37

Prednisone, Dexamethasone

Question 38

What are the steps for COPD therapy?

Answer 38

- Smoking cessation, education,lifestyle/environment interventions - SABA for exacerbations - LAMA/LABA - Inhaled corticosteroids if frequent exacerbations - Long term oxygen therapy - Surgical interventions (LVRS, transplantation)