Question 4(p.2)

Define the mechanisms of action and adverse effects of metoprolol and glyceryl trinitrate when used to manage myocardial ischaemia.

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College Answer

For a good answer candidates were expected to make some mention of the link 
between myocardial O2 demand / heart rate / contractilty. This was often overlooked, 
and candidates who did tended to not respond to what the question was asking, that 
is “when used to manage myocardial ischaemia”.
Good answers had a structured response. For a good answers candidateswere 
expected to mention metoprolol effects of reducing left ventricular wall stress , 
decreased C AMP / mechanism, decreased hear rate, contractility, resultant 
decreased O2 demand as well as adverse effects include Bradycardia / heart block / 
hypotension / bronchconctriction, etc. In relation to Glyceryl trinitrate, to mention 
dilation via nitric oxide, predominately venodilatation, decreased venous return, 
LVEDP, Wall stress, decreased demand O2 demand and increased supply via coronary vasodilation and adverse effects include hypotension / tachycardia tolerance / headache.
Candidates are reminded that if they are to use non standard abbreviations, then 
those abbreviations must be defined somewhere within their answer.
Syllabus: C1c, 2d, C2b, 2e, C2a, 2d
References: Goodman and Gilman's the Pharmacological Basis of Therapeutics, 
Chp 32


When one is asked to define something, it usually refers to the act of precisely describing a meaning, or marking out the boundaries or limits of an expression. It is therefore not surprising that the exam candidates "tended to not respond to what the question was asking". "Explain" or "outline" would have been better choices than "define".  The college seem to have wanted a structured response, but... what kind of structure could you possibly use?  After thinking about it for a little while, one could probably try tabulate their answer. It would be fruitless to try to somehow combine the drugs or contrast them because their effects are so different, and so instead their effects have been remixed into a sort of haemodynamic structure, using the rate/rhythm/preload/afterload/contractility variables which define a lot of cardiovascular drug properties.

Drug properties Desirable effect Adverse effect
Metoprolol decreases heart rate This decreases myocardial oxygen consumption and increases diastolic filling time, improving coronary perfusion The decreased heart rate leads to decreased cardiac output, which in turn may decrease coronary perfusion
GTN causes a compensatory increase in heart rate This ameliorates the negative inotropic effects of decreased preload Myocardial oxygen consumption is increased because of this compensatory effect

GTN decreases preload

This decreases the stroke volume and therefore reduces myocardial oxygen demand. 
Additionally, pulmonary venous congestion is decreased, which decreases the work of breathing, decreasing the demand on cardiac output
The decrease in preload can also lead to decreased cardiac output and hypotension
GTN has some minimal afterload-reducing effect GTN decreases peripheral vascular resistance, decreasing LV afterload and therefore decreasing the myocardial oxygen demand This effect is only seen at high doses, where the benefit may be outweighed by the hypotension and reflex tachycardia
GTN is a selective coronary arteriodilator Even in small doses, GTN can selectively decrease coronary vascular resistance, improving blood flow through narrowed arteries  
Metoprolol decreases contractility This decreases cardiac oxygen demand and improves supply/demand matching during periods of ischaemia. Decreased contractility can lead to decreased cardiac output and hypotension
Metoprolol is  long-acting This allows the effect to be sustained with intermittent dosing,  Adverse effects are difficult to reverse and therapy is harder to titrate
GTN is short-acting This allows rapid control of acute angina, and careful titration of therapy There is little susteined effect. Also, tolerance develops.
Other effects of metoprolol

Metoprolol preserves sinus rhythm. This improves cardiac output by preserving the diastolic "atrial kick".

Metoprolol also suppresses ventricular arrhythmogenicity.

Peripheral β2-mediated vasoconstriction may counterproductively increase afterload

Other effects of GTN   Vasodilation in other vascular beds can give rise to adverse effects (eg. headache).


Münzel, Thomas, and Andreas Daiber. "Pharmacology of nitrovasodilators." Nitrite and Nitrate in Human Health and Disease. Humana Press, Cham, 2017. 195-216.

Torfgård, Kristina E., and Johan Ahlner. "Mechanisms of action of nitrates.Cardiovascular drugs and therapy 8.5 (1994): 701-717.

Schulz, V. "Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate." Clinical pharmacokinetics 9.3 (1984): 239-251.

Gharaibeh, Munir N., and Garrett J. Gross. "Comparative relaxant effects of nitroglycerin in isolated rings from various canine vascular beds." General pharmacology 15.3 (1984): 217-221.