Question 11(p.2)

Describe the mechanisms of action of drug groups commonly used to treat acute severe asthma.

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College Answer

Common drugs listed were
• Beta 2 agonists salbutamol and adrenaline
• Steroids
• Magnesium
• Phosphodiesterase inhibitors
In order to obtain marks for that class of drug the mechanism of action had to be described
e.g. for theophylline; acts as a bronchodilator by inhibiting the breakdown of cyclic AMP and
cyclic GMP.
There were several excellent answers to this question.


Drugs used in the Treatment of Asthma
Mechanism of action Examples
β-agonists (Waldeck, 2002)
  • Bind to G-protein coupled receptors
  • Increase the cAMP concentration in bronchial smooth muscle cells
  • cAMP activates Protein Kinase A
  • Active PKA inactivate myosin light-chain kinase and activates myosin light-chain phosphatase, leading to smooth muscle relaxation
  • High potency and efficiacy, but also high toxicity
  • Salbutamol
  • Adrenaline
  • R-enantiomer is usually the more effective one
Antimuscarinic agents (Soler & Ramsdell, 2014)
  • Muscarinic acetylcholine receptors are G-protein coupled receptors
  • Activation of muscarinic (M3) receptors results in a rise in cyclic GMP, increasing the availability of intracellular calcium
  • This leads to clinical effects (for M3 receptors in the lung, bronchoconstriction and increased bronchial secretion)
  • Antimuscarinic drugs act as competitive antagonists of the acetylcholine receptor, and prevent these clinical effects
  • High potency and efficacy, low toxicity
  • Ipratropium bromide
  • Tiotropium
  • Atropine
Corticosteroids (PJ Barnes, 1996)
  • Corticosteroids bind to cytoplasmic glucocorticoid receptors
  • These receptors, when activated, become dimers and are transported to the nucleus, where they regulate gene transcription
  • This downregulates the syhtesis of proinflammatory cytokines and enzymes involved in the synthesis of inflammatory mediators such as cyclooxygenase and phospholipase
  • High potency and efficacy, high long term toxicity
  • Hydrocortisone
  • Prednisolone
  • Methylprednisolone
  • Budesonide
  • Ciclesonide
Methylxanthines (Tilley, 2011)
  • Methylxanithines are nonselective adenosine receptor antagonists, but their main mechanism of action in asthma is by their nonselective inhibition of phosphodiesterase
  • By inhibiting phosphodiesterase, these drugs increase the intracellular concentration of cyclic AMP in airway smooth muscle cells
  • cAMP activates Protein Kinase A
  • Active PKA inactivate myosin light-chain kinase and activates myosin light-chain phosphatase, leading to smooth muscle relaxation
  • Low potency and efficiacy, high toxicity
  • Theophylline
  • Aminophylline
Magnesium sulphate (Noppen, 1990; Irazuzta et al, 2017)
  • Antagonists of calcium at the NMDA receptor-gated calcium channels, which produces smooth muscle relaxation
  • Also inhibits acetylcholine and histamine release
  • Low potency, low efficacy, low toxicity
  • Magnesium sulphate
Ketamine (Goyal & Agrawal, 2013; Sato et al, 1998)
  • NMDA receptor antagonist; blockade of these receptors reduces availability of intracellular calcium
  • Howeverm, ketamine seems to produce bronchodilation by a mechanism which is independent of the NMDA receptor
  • Instead it appears to interfere with a calcium-dependent step in histamine-induced bronchoconstriction
  • Low potency and efficiacy, potentially high toxicity
  • Ketamine
Volatile anaesthetics (Mondoñedo et al, 2015; Yamakage, 2002)
  • Decrease intracellular calcium concentration by an unknown mechanism, probably by inhibition of IP3- induced calcium release
  • Thought to be also due to decreased calcium sensitivity and inhibition of Protein Kinase C activity
  • High potency, low toxicity
  • Isoflurane
  • Sevoflurane
  • Enflurane
Helium-oxygen mixtures
  • Decrease the density of inspired gases
  • This decreases the Reynolds number, i.e. decreases the likelihood of turbulent flow through narrow airways
  • As laminar flow  is usually associated with lower resistance than turbulent flow at any given flow rate, the use of helium decreases the respiratory resistance in bronchospasm
  • This improves gas exchange and the distal delivery of nebulised medications
  • Low potency, nil toxicity
  • Helium


Zdanowicz, Martin M. "Pharmacotherapy of asthma." American journal of pharmaceutical education 71.5 (2007).

Waldeck, Bertil. "β-Adrenoceptor agonists and asthma—100 years of development." European journal of pharmacology 445.1-2 (2002): 1-12.

Soler, Xavier, and Joe Ramsdell. "Anticholinergics/antimuscarinic drugs in asthma." Current allergy and asthma reports 14.12 (2014): 484.

Barnes, Peter J. "Molecular mechanisms of steroid action in asthma." Journal of allergy and clinical immunology 97.1 (1996): 159-168.

Tilley, Stephen L. "Methylxanthines in asthma." Methylxanthines. Springer, Berlin, Heidelberg, 2011. 439-456.

Noppen, Marc, et al. "Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma." Chest 97.2 (1990): 373-376.

Irazuzta, Jose Enrique, and Nicolas Chiriboga. "Magnesium sulfate infusion for acute asthma in the emergency department." Jornal de pediatria 93 (2017): 19-25.

Goyal, Shweta, and Amit Agrawal. "Ketamine in status asthmaticus: a review." Indian journal of critical care medicine: peer-reviewed, official publication of Indian Society of Critical Care Medicine 17.3 (2013): 154.

Sato, Tetsumi, et al. "The role of the N-methyl-D-aspartic acid receptor in the relaxant effect of ketamine on tracheal smooth muscle." Anesthesia & Analgesia 87.6 (1998): 1383-1388.

Khan, Khurram Saleem, Ivan Hayes, and Donal J. Buggy. "Pharmacology of anaesthetic agents II: inhalation anaesthetic agents." Continuing Education in Anaesthesia, Critical Care & Pain 14.3 (2014): 106-111.

Mondoñedo, Jarred R., et al. "Volatile anesthetics and the treatment of severe bronchospasm: a concept of targeted delivery." Drug Discovery Today: Disease Models 15 (2015): 43-50.

Yamakage, M. "Editorial II: Effects of anaesthetic agents on airway smooth muscles." (2002): 624-627.