Mechanism of drugs used in the treatment of respiratory disease

Question 1

Aim of bronchodilators

Answer 1

Rescue patient from bronchospasm

Question 2

Aims of anti-inflammatories

Answer 2

Reduce frequency of attacks
Reduce severity of attacks
Limit structural remodelling

Question 3

Examples of bronchodilators

Answer 3

B-adrenoceptor agonists
Xanthines e.g. caffeine
Muscarinic receptor antagonists
Leukotriene receptor antagonists
Histamine receptor antagonists
Methods all involve inhibition of contraction

Question 4

Anti-inflammatory classes

Answer 4

Glucocorticoids
Cromoglicate and nedocromil
Anti-IgE
Mechanisms all involve inhibition of inflammation

Question 5

B-adrenoceptor agonists mechanism

Answer 5

cAMP dependent, causes smooth muscle relaxation

Question 6

Short acting B2-adrenoceptor agonists

Answer 6

E.g. salbutamol, terbutaline

Hydrophilic in nature, short duration of action (4-6 hours)

Question 7

Long acting B2-adrenoceptor agonists

Answer 7

E.g. salmeterol, formoterol
Lipophilic in nature
Leech out of membrane prolonging duration of action (>12 hours)
Must not be given in the absence of a corticosteroid

Question 8

(Old) mechanism for xanthines

Answer 8

Phosphodiesterase metabolises cAMP
Methylxanthines inhibit PDE, maintaining high cAMP levels
Achieves bronchial smooth muscle relaxation

Question 9

Examples of xanthines

Answer 9

Theophyline

Aminophyline

Question 10

Muscarinic receptor antagonists mechanism

Answer 10

Aim is to block post-synaptic M3 receptors
Effects are limited by lack of selectivity leading to antagonism of M2 autoreceptors (prevents ACh release)
Blocking M2 knocks out benefit of blocking M3 as more ACh released

Question 11

Muscarinic receptor antagonist examples (best for COPD)

Answer 11

Ipratropium: onset of action 30 mins, lasts 3-5 hours, not selective for M receptor subtypes, may decrease mucus secretion and increase mucociliary clearance
Tiotropium: longer acting, once daily dosing

Question 12

Adverse effects of muscarinic receptor antagonists

Answer 12

Minimal when inhaled, anti-muscarinic side effects e.g. dry mouth, sedation

Question 13

Leukotriene receptor antagonists

Answer 13

Cysteinal leukotrienes (very potent) act on CysLT1 receptor in respiratory mucosa, montelukast and zafirlukast antagonise the receptor, prevents bronchiolar contraction mediated by LTs, inhibits early and late phase responses to irritants

Question 14

Anti-inflammatory drugs

Answer 14

Used to reduce severity and frequency of asthma attacks
Limit progression of disease by inhibiting remodelling
Reduce night-time asthma attacks by preventing late-phase

Question 15

Glucocorticoids

Answer 15

No immediate effect

Step 1 inhalation therapy when bronchodilator is used more than once daily

Question 16

Glucocorticoids immunosuppression

Answer 16

Il-10 decreases cytokine formation which decreases the recruitment and activation of inflammatory T cells

Question 17

Glucocorticoids anti-inflammatory action

Answer 17

Induces lipocortin-1 synthesis which decreases inflammatory mediators
Suppresses COX-2 induction thus decreases inflammatory prostanoid production
Can reduce severity of early phase response and prevent late phase response

Question 18

Glucocorticoids mechanism

Answer 18

Two glucocorticoid receptors bind a glucocorticoid molecule, forming a functional unit, which enters the nucleus of the cell, which decreases pro-inflammatory gene products and increases anti-inflammatory gene products

Question 19

Steroid cards

Answer 19

initial dose: card not needed
Intermediate dose: card considered
High dose: card needed

Question 20

Cromoglyacte and nedocromil

Answer 20

Not in common use, poor/variable efficacy shown in antigen-, exercise- and irritant- induced asthma, weak anti-inflammatory effects, mechanism unclear

Question 21

If anti-inflammatories don’t work?

Answer 21

Steroid-sparing agents/ cytotoxic immunosuppressants e.g. azathioprine, methotrexate, cyclophosphamide, ciclosporin
Continuous subcutaneous terbutaline infusion
Omalizumab (attacks human IgE)

Question 22

Omalizumab mechanism

Answer 22

Binds to free IgE, reducing cell-bound IgE
Reduces high affinity receptors, reduces mediator release, reduces allergic inflammation
Prevents asthma exacerbations and reduces symptoms