Question 9

Describe the mechanism of action of drugs commonly used to treat acute severe asthma.

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College Answer

Answers to this question needed to address drugs that target the pathophysiology of
asthma: bronchospasm, inflammation (oedema and hypersecretion), and hyperreactivity to inhaled stimuli. Not all drugs used to treat less severe forms of the
disease are relevant in the critical care context.
A discussion of efficacy versus toxicity was included in better answers.
As a minimum, sympathomimetics, antimuscarinics, corticosteroids and
methylxanthines should have been included. The role of inhaled Adrenaline as a B2
-agonist mediating bronchodilatation and an alpha-agonist constricting the bronchial
mucosa was relevant to the discussion. Ketamine and volatile anaesthetics could
have been discussed as adjuncts to therapy in ventilated patients. More
controversial therapies such as Magnesium and Heliox are less commonly
prescribed, however marks were awarded for more comprehensive answers.
Syllabus B2a 2a
Reference: Goodman and Gilman's the Pharmacological Basis of Therapeutics 11th
Ed p717-736

Discussion

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

References

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.

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