Compare and contrast the pharmacology of salbutamol and ipratropium bromide.

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College Answer

Overall candidates had a superficial knowledge of these level 1 drugs. To pass candidates needed to identify points of difference and overlap in various areas such as structure, pharmaceutics, pharmacokinetics, pharmacodynamics, mechanism of action, adverse effects and contraindications.

Discussion

These things usually work better as a table:

Name Salbutamol Ipratropium bromide
Class Bronchodilator Bronchodilator
Chemistry Synthetic sympathomimetic amine, structurally analogous to catecholamines Quaternary ammonium derivative of atropine
Routes of administration IV, nebulised Nebulised
Absorption Poor oral bioavailability; but it is still somehow available as a syrup. When given as a nebuliser, approximately 10% of an inhaled salbutamol dose is deposited in the lungs. Less than 1% of the inhaled drug dose is absorbed through the bronchial mucosa; minimal oral bioavailability, but because the majority of the administered dose is swallowed 2% of the systemic levels are due to oral absorption
Solubility Alkaline drug with two ionisable groups, phenolic hydroxyl group (pKa = 9.3) and
the secondary amine group (pKa 10.3). Freely soluble in acidic solutions.
pKa is 15.3; highly alkaline drug. Insoluble in lipids, but highly soluble in water. Does not penetrate the blood-brain barrier, unlike atropine.
Distribution VOD is 1.3L/kg; minimally protein bound VOD is 2.4-4.6 L/kg; about 20% protein-bound
Target receptor Beta-2 receptor; less selective for beta-1 Non-selective muscarinic receptor antagonist; bronchodilator effect is mainly mediated by the M3 receptors
Mechanism of action Beta-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. This results in increased protein kinase A activity, which results in the inhibition of phosphoinositol hydrolysis, which in turn results in decreased intracellular Ca2+ levels. With less intracellular calcium, the bronchial smooth muscle tone decreases. By blocking the M3 muscarinic receptor, ipratropium prevents the increase in cyclic GMP which is caused by the binding of acetylcholine with that receptor on bronchial smooth muscle. Increase in cyclic GMP normally causes bronchoconstriction; thus, blocking in produces bronchodilation. By a related effect, muscarinic blockade also results in a decrease in bronchial mucous gland secretion.
Metabolism Metabolised in the liver (extensive first-pass metabolism); The main metabolite is the biologically inactive salbutamol-o-sulphate. It can also be de-aminated by oxidative
deamination or conjugated with glucuronide.
60% is metabolised in the liver into inactive metabolites, and 40% is excreted unchanged in the urine.
Elimination The elimination half-life of salbutamol is 118 minutes (range 69 to 162 minutes); unchanged drug and metabolite are 72% excreted in the urine within the first 24 hours. Half-life is similar to atropine (approximately 1.5-3 hours)
Time course of action Airway resistance decreases within 5 to 15 minutes after inhalation of salbutamol; the maximum effect is seen at 60 to 90 minutes, and some level of activity persists for 3 to 6 hours. Onset is seen within 3-5 minutes of administration, peak response is seen at about 1.5-2 hours, some effect is still seen up to 6 hours after administration.
Clinical effects Bronchodilation, tachycardia, hypokalemia, hyperlactatemia, insomnia, muscle cramps Bronchodilation, tachycardia, dry mouth, increased viscosity of airway secretions
Single best reference for further information Sandoz product monograph Boehringer monograph

References

References

Cazzola, Mario, et al. "Pharmacology and therapeutics of bronchodilators." Pharmacological reviews 64.3 (2012): 450-504.