Assessing the impact of clinically relevant medicinal chemistry teaching: Learning gains from case study approachAbstract
Considering the unique role of medicinal chemistry in the pharmacists’ formation, in this work we assessed the impact of medicinal chemistry teaching on the interpretation of a clinical situation using statistical and learning gain analysis. Lectures were conducted with or without medicinal chemistry information about the drugs involved, and pre and post-tests were applied. Pharmacy students (n = 35) were divided into two experimental groups (control and test) and presented with a case report selected from literature involving statin-related myopathy when a pre-test was applied. A lecture containing pharmacological information on statins was delivered to the students from the control group. In contrast, the test group received the same information, but medicinal chemistry elements of statins were inserted, and afterward post-test was applied. The scores from the pre-test and post-test were statistically evaluated and used to calculate Cohen’s d, Hake’s, and Dellwo’s G learning gains to compare the performance of the students from both groups. The results showed that students from the test group obtained significantly higher performance in the post-test and higher learning gain values. In summary, medicinal chemistry elements provided important knowledge to unveil the reported clinical situation and to provide skills for adequate drug selection to avoid statin-related myopathy.
Keywords:
Case studies; Learning gain; Clinical pharmacy; Medicinal chemistry; Pharmacy practice
INTRODUCTION
Traditionally, pharmacy courses have medicinal chemistry as an obligatory discipline in the curriculum since the discipline is considered an essential part of the pharmacist’s formation. In recent years, changes in the professional role attributed to pharmacists made clear the necessity of the formation with a focus on clinical pharmacy, raising important questions to medicinal chemistry teachers/professors, such as “How can medicinal chemistry provide skills and abilities to a clinical pharmacist in this new professional context?” and “how chemistry could make a difference in the real practice of clinical pharmacy?” For traditional medicinal chemists, the discipline’s content mainly focuses on industrial pharmacy, and teaching is therefore focused on drug discovery and development techniques, rational design of new drugs, and related abilities. This knowledge has its obvious value in understanding the discovery of new medicines and their effective and safe application in clinical practice. However, in this new context, medicinal chemistry information should provide a background beyond drug discovery techniques, including extensive discussion of how approved drugs’ structure-activity relationship (SAR) can bring information about pharmacotherapy decisions and drug selection in a real situation (Fernandes, 2018). Although several examples of this approach have already been published (Fernandes, 2018; Kahn, Deimiling, Philip, 2011; Alsharif, Faulkner, 2020; Beleh, Engels, Garcia, 2015), few systematic studies reporting the effectiveness of such strategy and statistical measurement of this effect are available with this regard. Measuring the results from teaching activities and increments in the student’s knowledge after a lecture or an activity is not a trivial task. Conventional teaching techniques use tests to measure retained knowledge, but the obtained score and the developed skills and abilities for professional practice are not directly correlated. Due to this, educational researches usually present metrics to measure the learning after a teaching intervention. Several different measurements are discussed in the literature. However, learning gain measurements such as Cohen’s d effect (Cohen, 1988), Hake’s (Hake, 1998) and Dellwo’s (Dellwo, 2010) gains are frequently reported in educational studies for this purpose. Each approach has advantages and limitations but generally reflects the performance after pre and post-structured tests. In the present work, the results of a systematic study of the potential contributions that medicinal chemistry can provide to understanding a real clinical situation reported in the literature are presented (Gama et al., 2005). To achieve this, test questions were built from a clinical case study before presenting instructional material containing (or not) medicinal chemistry elements of pharmacological properties from statins.
MATERIAL AND METHODS
A group of 35 volunteer students enrolled in the Federal University of São Paulo pharmacy course were selected and included in the study. The inclusion criteria were as follows: a) previously approved in the discipline of basic pharmacology (this is important to understand basic concepts involved in the clinical case report); b) had no previous enrollment in medicinal chemistry discipline (to avoid potential background knowledge that could interfere in the results from the control group). The students could only participate as volunteers, so their performance in the study did not affect their academic grades or influence graduation requirements. The procedures were evaluated and approved by the Research Ethics Committee of the Federal University of São Paulo (project number 1174/2018) and registered at the Brazilian National Research Ethics Committee - CONEP (CAAE 00493218.9.0000.5505).
A clinical case report (Gama et al., 2005) was selected from the literature and adapted to simplify the time consumed during the activity while keeping the main points about the presented situation. The final case report was presented as described below.
“A 71-year-old woman was admitted to the emergency with intense fatigue, malaise, and reporting brownish urine. During examination, intense muscle pain was reported, especially on the legs and hips, which worsened in the last few days, leading to impaired deambulation. The patient was overweight (body mass index 29.7 kg/ m2) and was under daily treatment with aspirin (100 mg), atenolol (50 mg), amlodipine (10 mg), and simvastatin (80 mg). In the past, the statin was kept at 20 mg daily for 2 years and six months before admission was increased to 40 mg due to poor efficacy [low-density lipoprotein (LDL) levels ranging from 190 to 220 mg/dL]. A month ago, the statin dose was increased to 80 mg (LDL levels 150 to 170 mg/dL). The blood analysis revealed uremia 406 mg/dL, creatinine 8.98 mg/dL, creatine kinase (CK) 13,000 U/L, aspartate transferase (AST) 372 U/L, and alanine transferase (ALT) 38 U/L. Urine analysis returned intense positive for myoglobin.”
This case report was presented to these students with five related questions (Table I). The construction of these questions was carried out by us considering our experience as pharmacists and medicinal chemists using the following criteria: questions 1 and 2 - very simple, no important background required; question 3 - pharmacology background needed; questions 4 and 5 - pharmacology background required, but chemical information is also provided within the question. To each correct answer, 2 (two) points were attributed, up to a maximum score of 10 (ten). This test was defined as a pre-test (T0).
Seven days after the pre-test, the participants were randomly separated into control (n = 19) and test (n = 16) groups. Instructional lectures for 10-15 minutes about dyslipidemia treatment and the pharmacology of statins were then presented to the students. Participants from the control group were presented with a lecture containing only pharmacological information. In contrast, the students from the test group were presented with a similar lecture with additional chemical structures and physicochemical properties of statins, with visual emphasis given on the key molecular aspects of statins’ pharmacology (visual indication of the structure and its relationship with the pharmacological effect). Afterward, the students from both groups were submitted to a second round with the same case report and questions (post-test) to obtain a second score (T1). Considering the crescent complexity of the questions from 1 to 5, the T1 scores were further corrected by weighting factors equal to 1 (questions 1 and 2), 2 (question 3), and 3 (questions 4 and 5) to generate a novel weighted score was defined as T1w.
The average scores and standard errors of the mean (SEM) for each group were calculated for T0, T1, and T1w, and the values are presented in Table II. The differences were statistically evaluated using the unpaired non-parametric Mann-Whitney test. The scores on T0 and T1 were used to calculate Cohen’s d effect (Cohen, 1988), Hake’s (Hake, 1998), and Dellwo’s (Dellwo, 2010) gains according to the formula reported elsewhere. The obtained values are depicted in Table II.
Results obtained in the study. The scores T0, T1 and T1w are the mean score of the group with respective standard error of mean (SEM). Normalized gains Cohen´s d, Hake´s G and Dellwo´s G were calculated as described in the original publications
RESULTS AND DISCUSSION
Medicinal chemistry has become a key discipline in pharmacy education and pharmacist formation. The previous publication reports examples of clinical case studies considering a medicinal chemistry perspective that could help the student and/or the pharmacist unveil specific observed drug-related effects (Fernandes, 2018). These examples illustrate situations that could be predicted or solved using medicinal chemistry concepts and should be prioritized during the medicinal chemistry course in the pharmacy graduation, especially considering the clinical abilities pharmacists must-have nowadays. Although several examples of the contributions of SAR knowledge to pharmacotherapy decisions and clinical outcomes related to drug effects are available (Alsharif, Faulkner, 2020; El Sayed, Chelette, 2014), systematic studies reporting this contribution are beyond our knowledge.
In this perspective, we performed a longitudinal study with 35 students by applying a questionnaire containing 5 multiple-choice questions based on a clinical case report. After this pre-test, a lecture was presented to the students divided into two groups (test and control groups) involving or not, respectively, chemical aspects of statins and their relationship with myalgia and rhabdomyolysis. After the lecture, the students had the opportunity to answer the same questionnaire again, and the scores’ differences were evaluated through statistics and a learning gains approach. During both pre- and post-tests (T0 and T1), students could answer the questions using pharmacological and/or chemical information since both were described in the test.
The results in Table II showed that although both groups of students improved their performance after the lectures, the students who received chemical information about the drugs involved had higher scores than those who received only pharmacological information. A thorough discussion of the key points considered in the clinical cases is presented below. We recommend performing this discussion with the students after presenting the clinical case report as an instructional strategy to illustrate the importance of knowing the chemical aspects of medicinal drugs in a practical situation.
Statins (e.g., simvastatin) are frequently related to myositis and increase rhabdomyolysis risk (a serious condition caused by massive muscular injury) (Tournadre, 2020). These drugs lower cholesterol production rates by inhibiting the hydroxymethyl glutaryl coenzyme A reductase (HMGCoAR), which is involved in the liver’s initial steps of cholesterol biosynthesis (Schachter, 2005). On the other hand, since this enzyme is also part of the ubiquitination and prenylation biosynthetic pathways, statins can lead to multiple cellular injuries, especially on muscle cells (Tournadre, 2020). These myopathy-related effects are the main severe side effects caused by statins, which occur by inhibition of extra-hepatic HMGCoAR. Muscle damage can be assessed by measuring CK serum levels (Holbrook et al., 2011) since CK is an organ- specific enzyme. In consequence, high CK values (as observed in the clinical case) indicate that muscle cell injury is occurring, releasing a high amount of CK from muscular tissue to serum. Progression of such injury leads to massive muscle damage, increasing plasma myoglobin levels (another muscle-specific protein), which is eliminated by the kidney, causing renal failure and brown-colored urine. Thus, liver-directed statins could avoid such toxicity by producing selective effects on hepatic cholesterol production (Pfefferkorn et al., 2007). Due to their pharmacokinetic properties (Figure 1), statins are first distributed to the liver following absorption. However, high doses can increase concentration in extra- hepatic tissues, especially muscles (García et al., 2003). The more lipophilic statins are more prone to produce toxic effects in the muscles since their distribution volume is increased compared to less lipophilic compounds. A study published by White (2002) shows the correlation between logD 7.4 (the distribution coefficient n-octanol/ water in pH 7.4) of statins and their potential to cause myopathies. More hydrophilic statins (with lower logD 7.4 values) can reduce this risk.
Considering this, it is expected that more lipophilic statins (such as simvastatin, lovastatin, and atorvastatin) have a higher risk of producing myositis and rhabdomyolysis than more hydrophilic statins (such as pravastatin and rosuvastatin) (Tournadre, 2020; Schachter, 2005; Holbrook et al., 2011). With this regard, it is expected that the students develop the ability to analyze the lipophilicity of statins by judging the carbon/heteroatom ratio and the meaning of logP/logD values during their medicinal chemistry course. The non-lactonized carboxylic acid, in addition to the hydroxyl and sulfonamide groups in pravastatin and rosuvastatin, respectively, decreases their lipophilicity leading to negative logD 7.4 values that indicate hydrophilicity at physiological pH (Figure 2) (Fernandes, 2018; White, 2002; Awad et al., 2017). These more hydrophilic compounds have a lower volume of distribution, avoiding extra-hepatic effects (including muscles), and are therefore considered safer.
It is well known that cholesterol biosynthesis follows the circadian rhythm, leading to higher cholesterol production during the night. First-generation statins (class 1) have short half-lives and should be administered at night to maximize their efficacy in reducing cholesterol levels (Awad et al., 2017). On the other hand, synthetic second-generation statins (class 2) can produce effects that last for several hours and, therefore, can be administered in different periods, keeping the efficacy and avoiding repeated administration, which also increases the toxicity risks for these drugs.
Regarding metabolic stability, class 1 statins (molecules that contain the decaline ring and butyrate ester moiety) present lower plasma half-life due to the ester group rapidly hydrolyzed by plasma carboxyesterases. The metabolites formed following hydrolysis are considered inactive since the presence of the ester motif increases the affinity to the enzyme by performing important interactions with HMGCoAR. In the synthetic class 2 statins, this group was substituted by a 4-fluorophenyl motif, which performs similar interactions with the enzyme but is metabolically more stable, producing long-lasting effects (Istvan, Deisenhofer, 2001). Hence, it is expected that the students will be able to identify which statins could produce shorter effects by determining if the lability site (the butyric ester) is present in these molecules.
The questions presented in Table I were constructed to illustrate the main points to be identified by the students regarding lipophilicity and metabolic stability of statins. As discussed in these previous paragraphs, these points are crucial to understanding the clinical outcome presented in the reported case.
From the obtained results (Table II), it can be noted that both student groups showed significantly increased scores from T0 to T1 (p < 0.01). This means that students from both groups improved their results from T0 to T1 tests, denoting the positive effect of the lecture on their ability to understand the clinical situation. The average score on T0 was not different between the control and test groups, but an important difference was noted in the T1 scores. Students who received the lecture containing medicinal chemistry information (test group) showed higher scores than the students from the control group (p < 0.01), suggesting that the representation of chemical structures added information during the evaluation of myotoxicity risk for each statin. However, these higher scores could also be attributed to correct answers on the first questions from the test. To evaluate if the scores were higher on the last questions, the scores were weighted by growing factor values generating the T1w scores. The obtained T1w scores were also higher for the test group, confirming that students from the test group obtained higher scores on the last questions than those from the control group.
To analyze the results using normalized educational assessments, the scores from T0 and T1 were used to calculate learning normalized Cohen’s d, Hake’s G, and Dellwo’s G gains. As shown in Table II, the obtained gain values to the control group were lower than the obtained to the test group, corroborating with the raw mean scores obtained with T0 to T1. Cohen (1988) defined that a d-value > 0.8 denotes a high learning effect, and d-values < 0.2 are considered a low effect (Cohen, 1988). Hake (1998) described comparable values, stating that G < 0.3 values mean low learning gain, while values G > 0.7 mean high learning gains (Hake, 1998). The control group had low d-values and moderate Hake’s and Dellwo’s G gains, while the test group obtained moderate d-values and high G gains.
Cohen’s d is obtained by the difference from the mean values between T0 and T1, followed by normalization by the group’s standard deviation (Cohen, 1988). On the other hand, Hake’s gain normalizes these means by the mean score obtained in the T0, thus not simply considering the raw difference between the scores (Hake, 1998). Dellwo’s gain aids in Hake’s method the “loss factor”, a penalty factor for wrong questions correctly answered in the pre-test (Dellwo, 2010). Consequently, Dellwo’s gain considers not only acquisition but also retention of the information after the teaching activity. The analysis of these gain values suggests that both groups had improved performance after the lectures. However, higher gains were obtained when chemical structures of the drugs were presented and discussed during the lecture. Although slight differences among the gain values from different methods are observed, the general interpretation is very similar: the presentation of chemical structures led to higher gains.
During both lectures, the students received the information from Figure 1. However, students from the test group also had the visual information contained in the structures of statins, as described in Figure 2. This visual information about the pharmacology of statins provided by medicinal chemistry content is valuable for the learning process because it gives different learning opportunities by visualization and not only by auditory and/or textual information (Barclay, Jeffres, Bhakta, 2011). Visualization of chemical structures allows auditory learners to acquire knowledge by their preferred learning style (Leite, Svinicki, Shi, 2010). Interestingly, studies using visual, aural, read/write, and kinesthetic (VARK) questionnaires reported that pharmacy students are usually visual learners (Saleem et al., 2015). Undoubtedly, medicinal chemistry provides such visual information about the drugs, contributing to the learning consolidation for visual learners.
In summary, the systematic study presented strong evidence that clinically relevant medicinal chemistry adds important knowledge for pharmacists on their professional skills, making a real difference from other health professionals. The chemical basis given by this discipline provides critical assessment for drug selection and clinical outcome, as represented by this case report. Considering the medicinal chemistry role as a mandatory discipline to the pharmacist’s graduation, its contributions should rely beyond the traditional focus on drug design and discovery process and constitute an important basis for pharmacist formation as a healthcare professional.
ACKNOWLEDGEMENTS
The authors are thankful to Coordination for the Improvement of Higher Level Personnel - CAPES (financial code 001) and to São Paulo Research Foundation - FAPESP (grant nº 2019/24028-8) for the financial support to this work. JPSF is also thankful to the National Council for Scientific and Technologic Development - CNPq for the scientific fellowship awarded (grant nº 307829/2021-9).
REFERENCES
-
Alsharif NZ, Faulkner MA. Implementation of the pharmacists’ patient care process in a medicinal chemistry course. Am J Pharm Educ. 2020;84(2):7556. DOI: 10.5688/ajpe7556
» https://doi.org/10.5688/ajpe7556 -
Awad K, Serban MC, Penson P, Mikhailidis DP, Toth PP, Jones SR, et al. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol. 2017;11(4):972-85. DOI: 10.1016/j.jacl.2017.06.001
» https://doi.org/10.1016/j.jacl.2017.06.001 -
Barclay SM, Jeffres MN, Bhakta R. Educational card games to teach pharmacotherapeutics in an advanced pharmacy practice experience. Am J Pharm Educ . 2011;75(2):33. DOI: 10.5688/ajpe75233
» https://doi.org/10.5688/ajpe75233 -
Beleh M, Engels M, Garcia G. Integrating a new medicinal chemistry and pharmacology course sequence into the PharmD curriculum. Am J Pharm Educ . 2015;79(1):13. DOI: 10.5688/ajpe79113
» https://doi.org/10.5688/ajpe79113 - Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates Publishers; 1988.
- Dellwo DR. Course assessment using multi-stage pre/ post testing and the components of normalized change. J Scholarship Teach Learn. 2010;10(1):55-67.
-
El Sayed KA, Chelette CT. Laboratory exercises to teach clinically relevant chemistry of antibiotics. Am J Pharm Educ . 2014;78(2):37. DOI: 10.5688/ajpe78237
» https://doi.org/10.5688/ajpe78237 -
Fernandes JPS. The importance of the medicinal chemistry knowledge in the clinical pharmacist’s education. Am J Pharm Educ . 2018;82(2):6083. DOI: 10.5688/ajpe6083
» https://doi.org/10.5688/ajpe6083 -
Gama MPR, Pellegrinello S, Alonso SSQ, Coelho JF, Martins CFL, Biagini GLK. High doses statins administration causing rhabdomyolysis: case report. Arq Bras Endocrinol Metabol. 2005;49(4):604-9. DOI: 10.1590/s0004-27302005000400021
» https://doi.org/10.1590/s0004-27302005000400021 - García MJ, Reinoso RF, Sánchez-Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003;25(6):457-81.
-
Hake RR. Interactive-engagement versus traditional methods: a six-thousand-student survey of mechanics test data for introductory physics courses. Am J Phys. 1998;66(1):64-74. DOI: 10.1119/1.18809
» https://doi.org/10.1119/1.18809 -
Holbrook A, Wright M, Sung M, Ribic C, Baker S. Statin- associated rhabdomyolysis: Is there a dose-response relationship? Can J Cardiol. 2011;27(2):146-51. DOI: 10.1016/j.cjca.2010.12.024
» https://doi.org/10.1016/j.cjca.2010.12.024 -
Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160-4. DOI: 10.1126/science.1059344
» https://doi.org/10.1126/science.1059344 -
Kahn MOF, Deimiling MJ, Philip A. Medicinal chemistry and the pharmacy curriculum. Am J Pharm Educ . 2011;75(8):161. DOI: 10.5688/ajpe758161
» https://doi.org/10.5688/ajpe758161 -
Leite WL, Svinicki M, Shi Y. Attempted validation of the scores of the VARK: learning styles inventory with multitrait-multimethod confirmatory factor analysis models. Educ Psychol Measurement. 2010;70(2):323-39. DOI: 10.1177/0013164409344507
» https://doi.org/10.1177/0013164409344507 -
Pfefferkorn JA, Choi C, Song Y, Trivedi BK, Larsen SD, Askew V, et al. Design and synthesis of novel, conformationally restricted HMG-CoA reductase inhibitors. Bioorg Med Chem Lett. 2007;17(16):4531-7. DOI: 10.1016/j.bmcl.2007.05.097
» https://doi.org/10.1016/j.bmcl.2007.05.097 - Saleem F, Hassali MA, Ibrahim ZS, Alrasheedy A, Aljadhey H. Learning styles of pharmacy undergraduates: Experience from a Malaysian University. Pharm Educ. 2015;15:173-7.
-
Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-25. DOI: 10.1111/j.1472- 8206.2004.00299.x
» https://doi.org/10.1111/j.1472- 8206.2004.00299.x -
Tournadre A. Statins, myalgia, and rhabdomyolysis. Joint Bone Spine. 2020;87(1):37-42. DOI: 10.1016/j. jbspin.2019.01.018
» https://doi.org/10.1016/j. jbspin.2019.01.018 -
White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol. 2002;42(9):963-70. DOI: 10.1177/009127000204200902
» https://doi.org/10.1177/009127000204200902
