Q1: Acetylcholine acting through muscarinic receptors reduces heart rate but increases gastrointestinal smooth muscle contraction. With reference to receptor signalling processes, discuss how acetylcholine can give rise to these opposing physiological effects in the heart and gastrointestinal tract. (100% marks)
Q2: Carvedilol (Coreg) is a beta-blocker used for treating hypertension. Carvedilol is metabolised by CYP2D6. Some humans express polymorphisms of CYP2D6 that are non-functional (about 5%) and others (about 1%), a form that is an ultra fast metaboliser.
What might be the effects of a normal anti-hypertensive dosing regime of carvedilol on a patient with non-functional CYP2D6 polymorphism and on a patient who is an ultra-fast metaboliser? (40% marks)
Beta-blockers should not be prescribed to asthmatics. Why? (30% marks)
Asthma combined with one of these CYP2D6 genotypes would be particularly dangerous. Which and why? (30% marks)
Q3: The following question involves some data interpretation based around the pA2 practical and workshop, but is based upon the lectures on the pharmacology of gastric acid secretion
Table 1: The antagonist activity of cimetidine in-vitro
tissue Agonist Estimated pA2 Approx Slope of Schild plot
Guinea pig atria histamine 6.1 1.0
isoprenaline 3.8 1.4
Guinea pig ileum histamine 3.3 1.5
carbachol 4.4 0.8
NOTE: The above table summarises the results from a series of organ bath experiments in which the contractile effects of histamine, isoprenaline and carbachol were measured on two separate in-vitro preparations: the guinea pig atria and the guinea pig ileum that express H2 receptors and H1 receptors respectively. Dose response curves for the agonists were produced on each of the tissue preparations and following this the effects of cimetidine on blocking these agonist responses were investigated. The results of these experiments were displayed as Schild plots and summarised in the above table.
Q3a: What evidence is shown in Table 1 demonstrating that cimetidine has high selectivity at blocking histaminergic 2 (H2) receptors over H1 receptors? (15% marks)
Q3b: What evidence is there from Table 1 that shows that cimetidine is a competitive reversible antagonist on H2 receptors in the guinea pig atria? (5% marks)
Q3c: Proton pump inhibitors have largely replaced H2 receptor antagonists as the most effective drugs of choice to suppress acid secretion in peptic ulcer disease therapy. Describe why proton pump inhibitors are more effective than H2 receptor antagonists at suppressing acid secretion as part of acid control therapies. NOTE: Your answer should include a description of the mode of action of the drugs you are describing. (70% marks)
Q3d: Are there any side effects of these drugs that are cause for concern for patients likely to be prescribed these medications? (10% marks)
