Pharmacokinetics of metoprolol in patients with acute myocardial infarction
a) What does the data suggest in terms of the relationship between the metabolism of metoprolol and heart rate?
The data shows that the concentration of Metoprolol in the blood plasma is affected by the initial heart rate at the admission of acute myocardial infarction patients and the metabolism of Metoprolol. All the patients were free of the following diseases; non- compensated diabetes 1, thyroid dysfunction, and liver or kidney diseases and free of taking drugs which could alter the cardiac rhythm. This suggests that there were no drug-drug interactions, but rather the clearance of the drug, higher therapeutic efficacy and minimal toxicity was achieved.
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Metoprolol is a β1-cardioselective adrenergic receptor blocker used to treat patients with angina, hypertension and myocardial infarction (Chen et al., 2005). The antagonistic effect of Metoprolol causes both a negative inotropic and chronotropic effect which results in a reduced heart rate and cardiac output. The antiarrhythmic effect of Metoprolol is dependent on the metoprolol concentration in the blood plasma after prolonged eight days, from Table 1 suggesting the small therapeutic window to attain maximum efficacy. Moreover, Metoprolol is a lipophilic drug that is administered orally irrespective of food intake (Lecaillon et al., 1985) as biotransformation of Metoprolol is higher even though its bioavailability is not as efficient at intravenous administration. The volume distribution of Metoprolol when taken orally passes it through the first-pass elimination is decreased as it is first stereoselectively metabolised by the liver before reaching the systemic circulation, and the kidneys excrete less than 5% of Metoprolol in the form of urine meaning it is greatly biotransformed (Berger et al., 2018) with a plasma half-life ranges of 3-7 hours in adults. Overall, the androgenic activation of the Metoprolol reduces the effects of catecholamine stimulation aiding the maintenance of steady cardiac performance.
The relationship between the metoprolol concentration in the blood plasma and the heart rate is supported by the quantification of the α-hydroxy metoprolol metabolite concentration as a result of metoprolol metabolism by the CYP 2D6 gene oxidising the Metoprolol to α-hydroxy Metoprolol (Ryu et al., 2016) as seen in Table 1. Group 1 with the highest heart rate at discharge resulted from the low metabolic ratio of an average of 1.04 with a heart rate of 71 beats/min, group 2 has the intermediate heart rate at discharge of 61 beats/min with an average of 13 as the metabolic ratio and group 3 with the lowest heart rate of 50 beats/min with an average of 22.6. The volume distribution of Metoprolol in blood plasma is significantly reduced when progressing from group 1 to group 3, which is consistent with the metabolic ratio increasing emphasising the clinical significance of Metoprolol in treating cardiovascular diseases. Metoprolol is a racemic mixture of S- enantiomer and R-enantiomers. The CYP2D6 metabolises the R-enantiomer of Metoprolol (Blake et al., 2013).
The overall trend seen in Table 1 between the metabolic ratios of Metoprolol and the heart rate depicts the active CYP polymorphism. Table 1 exhibits an inverse relationship between the metabolic rate and heart rate.
b) Discuss the possible reasons for the variation of metabolic rate in the patients.
The reasons for the variation of metabolic rate in the acute myocardial infarction (AMI) patients is a result of the CYP polymorphism, which affects the clearance of the Metoprolol taken. Previous findings with Metoprolol support the consistency of this data (Berger et al., 2018).
The CYP 450 has been reported to have four polymorphic forms; ultra-rapid metabolisers (UM), extensive metabolisers (EM), intermediate metabolisers (IM) and poor metabolisers (PM) (Zhou, 2009) each with a metabolic efficacy as evident in G1, G2 and G3 in Table 1. The contribution of CYP2D6 is substantial in Metoprolol, and hence a stronger gene-dose effect is seen with Metoprolol. In this case, the CYP2D6 isoform of the CYP 450 cytochrome exhibits an adverse side effects of increased heart rate which from a normal dosage of Metoprolol leading to acute myocardial infarction indicating the poor metaboliser characteristics in group 1 with a critically low average metabolic rate of 1.04, intermediate metaboliser of CYP2D6 gene in group 2 was evident with an average metabolic rate of 13 and ultra-rapid metaboliser of CYP2D6 gene results in the decrease in heart rate from 86 beats/minute to 50 beats/minute. External factors which affect the heart rate is also age-dependent, and since no evidence of the age of the 187 AMI patients was provided, along with the CYP2D6 polymorphism, the age has an impact in the heart rate. The age is a full factor that is dependent on the heart rate, blood plasma protein concentration and nutritional status.
The increase in metabolic ratio along with the decrease in heart rate shows that the drug clearance is not effective in group 1 with the highest heart rate indicating the increase in toxicity of un-metabolised Metoprolol which has not been eliminated by the Phase II metabolism where CYP 450 polymorphism is exhibited, of which poor metabolisers of CYP2D6 as seen in group 1 increase the chances of toxicity and risks of developing cancer (Bertilsson et al., 2002).
As the bioavailability is affected by the oral administration of Metoprolol which in turn affects the volume distribution throughout the body, which is further affected by external factors such as the body fat, muscle mass, age and the plasma protein concentration. Metoprolol being non-polar and fat-soluble hence it is delivered to the fat relatively slowly. This means that effective biotransformation is achieved by phase I metabolism, which involves metoprolol absorption by the liver before reaching the systemic circulation mediated approximately 30% by CYP2D6.
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Although the concentration of Metoprolol in the blood plasma is representable of the drug target concentration, this specific parameter is affected by plasma lipid level leading to a significant reduction in plasma non-esterified fatty acids which increases the risks of cardiovascular diseases (Beinart et al., 1979). This is evident in Table 1, which shows that the reduced metabolic ratio leading to an increase in heart rate could have been as a result of increased cholesterol levels as part of the Phase II metabolism.
Possible causations for a variation in metabolic rate can be the differences in ethnicity as seen in antihypertensive therapies (Johnson, 2008). The Caucasian race is known to have a slow drug metabolic rate to Metoprolol which emphasises the occurrence of genetic polymorphism; however the relationship between ethnicity and drug metabolism is yet to be studied further to validate the significance (Preissner et al., 2013).
c) What further studies should be carried out to insight better the reason for the differences in metabolic rate?
Genomic testing should be carried out to identify the reasons for the differences in metabolic rate. This aids in determining the genotype-phenotype relationship via CYP2D6 gene amplification the CYP2D6 poor metabolising isoform and the extensive metabolising isoform can be detected; however, the detection of ultra-rapid metabolizers remains unsuccessful due to the. However, the clinical usefulness of the genotyping in understanding the molecular genetics of CYP2D6 could help in the prediction of the catalytic activity (MR) within the EM phenotype. This further helps to enhance the knowledge of drug metabolism and the enzyme interaction aids to predict the drug-drug interactions and create a personalised drug treatment on the basis of the CYP profile of individual AMI patients with the use of clinical trials and the SuperCYP database (Preissner et al., 2013).
Genotyping patients prior to metoprolol treatment will allow the identification of PM and UM, which will potentially avoid side effects of Metoprolol of hypotension seen in group 3 with the smallest heart rate (Blake et al., 2013)
Phenotype analysis should be avoided as during prolonged drug intake as those drugs can inhibit the CYP2D6 activity and be useful for small therapeutic range drugs which could be cost-effective in the long-term (Gaedigk et al., 2017).
The pharmacokinetic parameters used to minimise the toxicity and maximise the drug efficacy by increasing the metabolic rate. The drug metabolism rate of an individual is influenced by genetic factors, comorbid conditions and drug interactions. The decrease in CYP450 cytochrome expression in the liver will alter the ADME pharmacokinetic parameters which can be done by computer-aided drug design tools (CADD) which can carry out drug structure bases approaches to predict the interactions of the drug and the CYP450 interactions to avoid adverse effects such as the changes in heart rate after the use of Metoprolol (Issa et al., 2017).
- Berger, B., Bachmann, F., Duthaler, U., Krahenbuhl, S. and Haschke, M. (2018) 'Cytochrome P450 Enzymes Involved in Metoprolol Metabolism and Use of Metoprolol as a CYP2D6 Phenotyping Probe Drug', Front Pharmacol, 9, pp. 774. doi: 10.3389/fphar.2018.00774.
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