HUF 2-14 Drugs which modify ventilatory and airway function

Question 1

What is asthma?

Answer 1

• chronic airway inflammation
• recurrent, reversible constriction and obstruction of airway
• bronchial hypersensitivity (irritants, chemicals, cold air, exercise)
• intermittent attacks of shortness of breath, coughing and wheezing

Question 2

Pathophysiology of asthma

Answer 2

antigens
=> histamine from mast cells
=> cytokine
=> PG (e.g. PGD2), PAF, CysLT(C4, D4, E4)
=> cytokines lead to further generation of CysLT (cytosine releasing Th2 cells, monocytes, eosinophils)
=> epithelial damage

• bronchial sm. ms. constriction
• airway inflammation and hypersensitivity
• ↑ mucus secretion from airway epithelia

Question 3

Late phase of asthma attack

Answer 3

• nocturnal
• progressing inflammatory reaction
• CysLT, cytokines and other products of inflammatory cells
  => damage and loss of epithelium
  => pain perceptive mechanisms more accessible to irritant stimuli
  => bronchial hyperactivity
• growth factors from inflammatory cells
  => sm. ms. cells hypertrophy and hyperplasia
  => proinflammatory mediators and growth factors from sm. ms. cells

Question 4

Aspirin-sensitive asthma

Answer 4

• aspirin, paracetamol, NSAID (coxib)
  => precipitate asthma (∵ COX pathway blocked, AA shunted to LT production)
• <10% of asthmatic subjects
• abnormal LT production and sensitivity
• ↑ CysLT
• ↑ expression of CysLTR on inflammatory cells

Question 5

Drug treatments for asthma

Answer 5

Bronchodilators for status asthmaticus

1. Fast acting, short duration β2 agonists
2. Muscarinic receptor antagonists

Prophylaxis (preventive measures)

3. Slow acting, long duration β2 agonists
4. PDE inhibitors
5. CysLT receptor CysLT1 antagonists
6. 5-lipoxygenase inhibitor
7. Glucocorticoid
8. Mast-cell stabilisers
9. Humanised monoclonal anti-IgE Ab

Question 6

Fast acting, short duration β2 agonists

Answer 6

• relieve acute asthma attack (status asthmaticus)
• Salbutamol
• Terbutaline
• ↓ intracellular [Ca2+] and MLC phosphorylation (myosin light chain)
• muscle relaxation

Question 7

Muscarinic receptor antagonists

Answer 7

• Ipratropium
• block M3R
• inhibit cholinergic bronchoconstriction reflex

Question 8

Slow acting, long duration β2 agonists

Answer 8

• Salmeterol

Question 9

PDE inhibitors

Answer 9

• ↑ intracellular [cAMP]
  => ↓ bronchial sm. ms. tone
• Theophylline: PDE isotype non-selective
• narrow therapeutic index
• cardiac arrhythmia
• Roflumilast: PDE4 selective inhibitor
• less cardiac undesirable effects

Question 10

5-lipoxygenase inhibitor

Answer 10

• Zileuton

- ↓ production of CysLT

Question 11

CysLT receptor CysLT1 antagonists

Answer 11

• Montelukast
• Zafirlukast
• block spasmogenic activity of CysLT

Question 12

Glucocorticoid

Answer 12

• Beclomethasone (fluorinated steroid - inhaled)
• preventative treatment (prophylaxis)
• acute asthma attack

Common long-term side effect:
- candidiasis (overgrowth of candida fungus in pharynx)

Question 13

Mast-cell stabilisers

Answer 13

• Cromoglycate
• Nedocromil
• inhibit mediator release from mast cells
  => less sensitive to irritant stimuli
• ↓ activation of eosinophils, neutrophils and macrophages

Question 14

Humanised monoclonal anti-IgE Ab

Answer 14

• Omalizumab
• bind to human active IgE in circulation
  => less IgE will bind to mast cells
  => mast cells less sensitive to irritants

Question 15

Treatment for rhinorrhea

Answer 15

H1-antihistamines

• 1st gen: sedative, anti-muscarinic, anti-adrenergic, anti-serotoninergic
  e. g. Diphenhydramine, Chlorpheniramine
• 2nd gen: more selective to peripheral H1; NOT cross BBB
  => less sedative
  e.g. Loratadine, Fexofenadine, Cetirizine
• relieve allergic rhinitis
  e.g. stuffy nose (sinus pressure) / post-nasal drip

Question 16

Treatment for nasal decongestion

Answer 16

Decongestants
1. Phenylephrine
- α1 agonist
- vasoconstriction
=> shrinkage of nasal and sinus mucosa

2. Pseudoephedrine
   - α1 agonist (blood vessels)
   => vasoconstriction, ↓ mucus production
   - β2 agonist (airway)
   => relaxation of bronchial sm. ms.
   - stimulate CNS
   => wakefulness
   => non-drowsy

Question 17

Cough reflex

Answer 17

Mucus / Phlegm (mechanical or chemical irritation)
=> cough receptors along airway (rapidly adapting irritant receptors)
=> aff. fibres from receptors in airways
=> vagus and sup. laryngeal n.
=> cough centre in medulla
=> respiratory pattern generator
=> eff. fibres in somatic n. to respiratory ms.
=> expiratory ms. contraction

• Cough medicine NOT recommended for children under 6 (∵ side effects)

Question 18

Treatment for productive cough (phlegmy)

Answer 18

1. Expectorants / Mucokinetics
   - ↑ volume and hydration of secretions in respiratory tract
   => easier to expel phlegm from airways
   e.g. Guaifenesin, Ipecacuanha, Ammonium chloride
2. Mucolytics
   - break down mucus
   - disulfide bonds link mucoprotein strands in phlegm
   - liquefies mucus to aid elimination of solidified mucus
   e. g. Acetylcysteine

Net result: coughing can clear mucus from airways more easily

Question 19

Treatment for non-productive cough (dry cough)

Answer 19

Cough suppressants (antitussives)
- suppress cough reflex by direct effect on cough centre in CNS

1. Centrally acting antitussive
   - Codeine (opioid): opioid μ receptor agonist in cough centre
   - Dextromethorphan: NMDA receptor antagonist in cough centre
   - 1st gen. antihistamines: sedative and antimuscarinic actions (also ↓ post-nasal drip)
2. Peripherally acting antitussive
   - Linctus or lozenges for soothing pharynx
   - Benzonatate: anaesthetise stretch receptors in respiratory passages, lungs and pleura
   (Side effects: dizziness, numbness of tongue, mouth and throat)