Respiratory Pharmacology

Question 1

What is asthma?

Answer 1

• Reversible airflow obstruction (expiratory wheeze)
• Airway inflammation
• Bronchial hyper responsiveness (BHR, airways are irritable)
• Narrowing of lumen
• Airway produces mucous- builds up inside airway passage

Question 2

Describe extrinsic asthma

Answer 2

• Identifiable external trigger
• Allergy to common environmental agent (developed allergy)
• Typically develops in childhood (atopic march)
• Young children get eczema which resolves with age- may then develop asthma symptoms

Question 3

Describe intrinsic asthma

Answer 3

• No obvious external trigger
• Often develops in adults after a viral infection
• Smoking might play a role
• Tends to be more severe and difficult to control

Question 4

What triggers asthma?

Answer 4

• Allergy- household-pets, dust
• Inflammation- worsened by respiratory infection
• Work place- exposed to chemicals- inflammatory response
• Exercise
• Constriction- exercise, temp changes, strong odours, emotion, cold air
• Other: tobacco, medications, food additives, air pollution, reflux diseases

Question 5

Describe FEV1 in asthma

Answer 5

• Normal in between attacks
• Allergen exposure- less rapid FEV1, below 50% in minutes
• Wheezing

Question 6

Describe the early phase response in asthma

Answer 6

• Early phase response driven by mast cells-degranulated
• -> Histamine, leukotriene C4 and prostaglandin D2
• Lung function recovers (60-90 mins)

Question 7

Describe the late phase response in asthma

Answer 7

• Driven by eosinophils- recruited airways following early phase
• Leukotriene C4 (lipid mediator)
• Eosinophil granule proteins- basic proteins that damage
• Cytokines (inflammatory and newly synthesised 4-8 ours)

Question 8

Describe the pharmacological approach of relievers in asthma

Answer 8

• Block or reverse bronchial smooth muscle contraction
• No effect on underlying inflammation- symptomatic relief
• Given by inhaler for ‘rescue’ in acute attacks
• Long-acting drugs for chronic bronchodilation

Question 9

Describe the pharmacological approach of preventers in asthma

Answer 9

• Taken every day for prophylaxis

- Reduces airway inflammation or BHR

Question 10

Describe the autonomic control of airways

Answer 10

• Parasympathetic input- McT3 receptors
• Bronchoconstriction + mucus hyper secretion
• Anti-musc block ACh and reduce symptoms
• Adr interact B1 receptors on heart
• B2 agonists activate B2 receptors which leads to Bronchodilation and decreased mucus secretion (sympathetic)
• Adr is only used in extreme cases- not day-to-day

Question 11

Describe β-2 adrenoceptor agonists as relievers

Answer 11

• Stimulate β-2 receptors
• ATP–> cAMP (leads to bronchodilation and maybe inhibit mast cell activation)
• E.g. Rimiterol (short- 2hrs), salbutamol (medium- 5 hrs) and Salmeterol (long- 24 hrs)

Question 12

Describe short-acting β-2 agonists

Answer 12

• E.g. salbutamol
• Dosage- inhaler as needed, nebuliser and IV- status asthmaticus
• Often + steroid for moderate asthma
• Side effects: skeletal muscle tremor, hypokalaemia, receptor dawn regulation

Question 13

Describe long-acting β-2 agonists

Answer 13

• Salmeterol- binds to an eco-site via flexible tail and repeatedly stimulates receptor
• Formoterol- dissolves in plasma membrane and diffuses out to stimulate receptor

Question 14

What are the effects of long and short acting β-2 agonists?

Answer 14

• Salbutamol must be taken every 4-6 hrs to maintain bronchodilation
• Salmeterol 1/2x a day and is useful in nocturnal asthma
• Overuse- receptor down-regulation
• If patient is using β-2 agonist inhaler regularly- add steroid to treat underlying inflammation

Question 15

Describe methylxanthines as relievers

Answer 15

• Target phosphodiesterases
• Same effect
• E.g. theophylline- slow release oral preparation
• E.g. aminophylline- more soluble- IV use
• Increases cAMP by stopping its breakdown into AMP
• • inhibition of PDE

Question 16

Describe the use of theophylline as a methylxanthine reliever

Answer 16

• Not front-line drug in UK
• Oral administration only
• Variable gut absorption and hepatic metabolism
• Plasma conc increased by heart failure, liver disease and some drugs
• Plasma conc decreased by smoking, alcohol and other drugs
• Side effects: nausea, insomnia, dysrhythmia) can be severe due to narrow TI

Question 17

Describe how anti-muscarinics can be used as relievers

Answer 17

• Parasympathetic
• Mc 1 and 3 receptors
• Blocks Ach interaction and reduces bronchoconstriction and hyper secretion
• Inhaled
• Low efficacy- added for moderate-severe asthma
• Side effects- poorly absorbed in lung so classic anti-musc side effects rare
• E.g. ipratrpoium, oxitropium and tiotrpium (all atropine-like)

Question 18

What are preventers?

Answer 18

• Target inflammation

- Main group- corticosteroids

Question 19

What is the mechanism of action of corticosteroids?

Answer 19

• Diffuse across membrane and bind to intracellular glucocorticoid receptors
• GRE inhibition
• • inhibit inflammatory genes cytokine, COX2, adhesion molecules and IGs
• GRE induction
• • anti-inflam genes- IL10, annexin 1, β-2-adrenoceptor, ribonucleases

Question 20

What are the actions of corticosteroids in inflammatory cells?

Answer 20

• T lymphocytes
• -> reduction in numbers of eosinophils by apoptosis, cytokines and number of mast cells
• Reduction in cytokines- macrophages
• Reduction in numbers od dendritic cells

Question 21

What are the actions of corticosteroids in structural cells?

Answer 21

• Epithelial cells
• Endothelial cells- reduced leakage
• Airway smooth muscle- increased β-2 receptors and decreased cytokines
• Mucus glands- decreased mucus secretions

Question 22

Describe the administration of corticosteroids

Answer 22

• Beclomethasone/ Budesonide- daily inhalers
• Fluticasone- daily inhaler, most potent, first-pass hepatic metabolism reduces systemic side effects
• Oral prednisolone- severe asthma
• IV hydrocortisone- status asthmaticus
• Compliance with steroid inhalers is often poor because results not often shown physically

Question 23

What are effects of chronic oral steroids?

Answer 23

• Abnormalities in fat, protein and carboydrate metabolism
• Rare with inhaled steroids used properly
• Long-term use leads to Cushingoid features

Question 24

Describe the use of steroids in children

Answer 24

• Recommended inhaled steroids for chldren
• Risk reduced with lowest possible dose, limiting systemic side effects with effective inhaler technique and using drugs such as fluticasone (inactive by 1st pass metabolism)
• No evidence for growth restriction with inhaled steroids