Airway Pharmacology

Question 1

What is the purpose of medicinal drugs?

Answer 1

• Diseases can cause a change or loss of function of cells within tissues and organs, leading to alternations of function of the diseased tissue itself.
• Drugs reverse this process

Question 2

Define Mechanism of action

Answer 2

The process by which a drug achieves its therapeutic effects

Question 3

What drug is used to treat asthma and what are its effects/ what does it treat?

Answer 3

Beta - 2 - agonist e.g salbutamol, an asthma bronchodilator.

It increases luminal area, decreases resistance and increases airflow

They treat hyposecretion, bronchospasm, cough and level of inflammation

Question 4

Give some examples of bronchodilators

Answer 4

• Beta-2 adrenergic receptor agonists
• Short-acting (SABA) e.g. salbutamol
• Long-acting (LABA) e.g. salmeterol
• Ultra long acting (ultra-LABA) e.g. indacaterol
• Long-acting muscarinic receptor antagonists (e.g. tiotropium)
• Phosphodiesterase inhibitors (e.g. theophylline)

Question 5

How does airway smooth muscle contract?

How can we increase contractile tone?

How does bronchodilator work?

Answer 5

• In order for contraction of smooth muscle, it requires Ca2+
• So increasing contractile tone is done by releasing more calcium from intracellular stores/ extracellular fluid or increasing the contractile machinery to the sensitivity of calcium ions
• Bronchodilator drugs act by binding to a specific receptor or enzyme expressed by the ASM cell and inducing an intracellular change which interrupts the contractile process (thereby causing relaxation).

Question 6

What causes bronchoconstriction?

Answer 6

1. Contractile mediators e.g cysLTs, Ach, PGs bind to a GPCR e.g M3
2. This activates the Gq pathway (in the ASMC cytosol) activating the intracellular signalling pathways
3. This causes the release of calcium from the SR, so we have an increase in calcium ion mobilisation and sensitivity causing muscle contraction

Question 7

How do beta - 2 - adrenergic receptor agonists treat asthma?

Answer 7

1. Beta - 2- agonist e.g salbutamol binds to a beta - 2 - adrenoreceptor activating the Gs pathway.
2. This causes adenylyl cyclase to convert ATP to cAMP activating protein kinase A
3. This decreases calcium ion mobilisation and sensitivity
4. This causes muscle relaxation

Question 8

Different classes of Beta - 2 agonists exist.

What are short-acting beta - 2- agonists?

Answer 8

Short-acting beta-2 agonists (SABAs) such as salbutamol are the first-line therapy in asthma and are administered when required as reliever therapy (e.g. when the patient experiences an asthma attack) by metered-dose inhaler.

Question 9

Different classes of Beta - 2 agonists exist.

What are long-acting beta - 2 - agonists?

Answer 9

Long-acting beta-2 agonists (LABAs) such as salmeterol or formoterol are used as an add-on, preventer treatment, in combination with inhaled corticosteroids (this is because there is evidence that the use of LABAs without corticosteroids increases the risk of sudden death) in metered-dose inhalers, with twice daily, continual dosing.

Question 10

What are Long-acting muscarinic receptor antagonists?

Answer 10

Long-acting muscarinic antagonists are a second class of bronchodilators e.g tiotropium

Question 11

What are long-acting muscarinic receptor antagonists used to treat and describe their mechanism of action

What conditions do they treat?

How do they treat them?

Why are they not as effective as bronchodilators?

What else can they treat?

Answer 11

• LAMAs are widely used to treat chronic bronchitis in COPD patients, and as an add-on, preventer therapy in asthma
• They block acetylcholine present on ASM cells. Acetylcholine is a mediator and neurotransmitter that binds to an M3 receptor expressed on the membrane of ASM cells that induces contraction.
• Therefore blocking this receptor induced relaxation
For this reason they are less effective as bronchodilators in asthma therapy, where acetylcholine typically has a more minor role in ASM contraction. Finally, LAMAs may also provide benefit in patients with obstructive airway diseases by reducing mucus secretion and inhibiting cough.

Question 12

Describe potential sites of where we can treat airway inflammation

Answer 12

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Question 13

Give an overview of anti-inflammatory drugs that are commonly used in asthma therapy

Answer 13

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Question 14

What are Corticosteroids?

Answer 14

Corticosteroids are used as preventer medication to reduce airway inflammation

Question 15

Give some examples of corticosteroids

Answer 15

• Inhaled corticosteroids
o Fluticasone
o Budesonide
o Beclometasone

• Oral/systemic steroids
o Prednisone
o Dexamethasone

Question 16

Describe the mechanisms of action of corticosteroids

Answer 16

• These drugs reduce allergic inflammation in asthma.
• In the first instance, drugs such as fluticasone and budesonide are administered by metered-dose inhaler in order to maximise the relative exposure of the drug to respiratory tissue vs. the systemic circulation. Corticosteroids achieve their anti-inflammatory effect by binding to glucocorticoid receptors present within the cytosol of immune and structural cell
• The drug then migrates into the nucleus where it binds to DNA, where it modulates transcription, translation and protein expression
• corticosteroids are able to decrease pro-inflammatory mediator and increase anti-inflammatory mediator expression, therefore shifting the balance and reducing the overall level of inflammation.
• The sites where they reduce inflammation:

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Question 17

What are leukotriene receptor agonists?

Where are they produced?

What do they do?

How are they involved for the treatment of inflammation?

How are they administered?

Answer 17

• Leukotrienes are a group of pro-inflammatory lipid mediators that are implicated in the asthmatic immune response.
• Leukotrienes are released by mast cells and eosinophils and induce further inflammation and airway pathology via receptor-mediated actions. Therefore drugs which antagonise (block) these receptors prevent these effects, reducing the level of inflammation.
• Leukotriene receptor antagonists such as montelukast are administered orally and used as an add-on preventer therapy with continual dosing.

Question 18

What are biologics?

How do they treat asthma?

Answer 18

• These refer to drugs consisting of complex biomolecules
• They are used in asthma therapy to block or inhibit specific pro-inflammatory protein involved in the inflammatory cascade
e.g Omalizumab (anti-IgE)

Question 19

How can drugs induce adverse effects, clinically in airway pharmacology?

Give an example such as salbutamol

Answer 19

• Interacting excessively with their primary target. E.g. opioids suppress cough at mild doses by inhibiting neural function within the brainstem, however higher doses this leads to respiratory depression and the risk of death)
• Interacting with targets expressed in other tissues (‘off-target effects’ - either the primary target is present in other tissues, or the drug binds to multiple targets). E.g. In addition to their effects on beta-2 receptors within the airway, beta-2 agonists activate both beta-1 and beta-2 receptors present within the heart, leading to cardiac side effects.

tremor - beta-2 receptors expressed on skeletal muscle)
• Tachycardia - beta-1 receptors expressed by cells of SA node in heart
• Palpitations - beta-1 receptors expressed by myocardium)

Question 20

How does using a metered dose inhaler reduce side effects?

Answer 20

Many drugs are delivered by inhalation via metered-dose inhaler to prevent adverse effects

The drug is directly applied to the target tissue and so the greatest dose is present at that site

However, all of the dose delivered by metered dose inhaler does not stay within the respiratory system. A large quantity of the drug is generally swallowed rather than inhaled due to poor inhaler technique

Question 21

Describe other routes of administration

Answer 21

• The drug is intended to have a systemic effect (e.g. oral steroids used to inhibit inflammation throughout the body).
• The drug has a narrow therapeutic window, and so a consistent dose must reach the systemic circulation (e.g. theophylline, a PDE inhibitor, is administered orally, to avoid the potential risk associated with multiple inhalations or varying amounts of drug being swallowed vs. inhaled).
• It is not possible (or cost-effective) to formulate the drug as an inhaler due to the physical/chemical properties of the drug (e.g. monoclonal antibodies such as the anti-IgE mAb, omalizumab, are delivered by injection).

Question 22

Give the adverse effects of corticosteroids

Answer 22

• Hypercortisolism – increased exposure to glucocorticoids
• Increased risk of infection (e.g. candidiasis) – suppression of immune system
• Depression – effects of glucocorticoids on the brain
• Osteoporosis – effects of glucocorticoids on bone metabolism