Defining and unpacking the core concepts of pharmacology education

DOI: 10.1002/prp2.894 ORIGINAL ARTICLE Defining and unpacking the core concepts of pharmacology education Marina Santiago1 | Elizabeth A. Davis2 | Tina Hinton3 | Thomas A. Angelo4 | Alison Shield5 | Anna-Marie Babey6 | Barbara Kemp-Harper2 | Gregg Maynard7 | Hesham S. Al-Sallami8 | Ian F. Musgrave9 | Lynette B. Fernandes10 | Suong N. T. Ngo11 | Arthur Christopoulos12 | Paul J. White12 1 Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia 2 Department of Pharmacology, Monash University, Clayton, Victoria, Australia 3 Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia 4 Eshelman School of Pharmacy, University of North Carolina- Chapel Hill, Chapel Hill, North Carolina, USA 5 Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce Canberra, Australian Capital Territory, Australia 6 Faculty of Medicine and Health, University of New England, Armidale, New South Wales, Australia 7 School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia 8 School of Pharmacy, University of Otago, Dunedin, New Zealand 9 School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia 10 School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia 11 Faculty of Sciences, The University of Adelaide, Roseworthy, South Australia, Australia 12 Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia Correspondence Paul White, 381 Royal Parade Parkville, Vic. 3052 Australia. Email: paul.white@monash.edu Abstract Pharmacology education currently lacks a research-based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC-PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory—a valid and reliable tool to assess learner attainment of concepts. In the current study, CC-PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug–response. First, a one-sentence definition was developed for each core concept. Next, sub-concepts were established for each core concept. These twenty core concepts, along with their respective Marina Santiago and Elizabeth A. Davis contributed equally to the study. The authors mourn the loss of our wonderful colleague, friend, and co-author, Associate Professor Elizabeth Davis, who passed away on October 26, 2021, and pay tribute to her enormous contribution to pharmacology education. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. Pharmacol Res Perspect. 2021;9:e00894. https://doi.org/10.1002/prp2.894 wileyonlinelibrary.com/journal/prp2 | 1 of 9 2 of 9 | SANTIAGO eT Al. definitions and sub-concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning. KEYWORDS concept inventory, core concept, health science education, pharmacology education, postgraduate education, science education, undergraduate education, unpacking 1 | I NTRO D U C TI O N have found it useful to develop supporting resources and materials. In biology, the Vision and Change initiative12 has been extensively In the early 1990s, physics educators were astonished to discover developed by expert educators, and includes definitions of core con- the low level of conceptual understanding of their graduates. cepts10 and instruments to assist educators to teach and assess stu- 1 Hestenes et al. demonstrated that even the best-prepared fourth- dent learning of core concepts.13 In some sub-disciplines of biology, year physics majors at elite US institutions were unable to apply such as physiology, more extensive resources have been developed key concepts. Since then, dedicated scholarly efforts to improve to unpack each core concept in detail, identifying sub-concepts and conceptual learning have transformed physics education interna- cases that exemplify each concept.11,14 The methods used to pro- tionally. Well-documented gains in students’ deep understanding of vide these resources usually involved multiple stages of discussions core physics concepts, as well as in educators’ ability to promote among many educators: for example, Vision and Change emerged and assess that learning, have been among the true success stories from “a series of conversations at regional and national meetings… of higher education reform. The strides made by physics educators, more than 500 biologists and biology educators discussed the need and more recently across a range of other disciplines, have yet to be to reform undergraduate biology education and provided a set of made in the discipline of pharmacology. unifying recommendations”.10 In physiology,Michael et al11 devel- A consensus list of core concepts could advance pharmacology oped a more rigorous and stage-wise method for unpacking core education in a number of ways. Disciplines such as psychology2,3; concepts, with an expert group developing a proposed unpacking, 4 5 6 information technology/cybersecurity ; dietetics ; biology, micro- which was then refined via input from survey respondents. biology,7,8 and mathematics9 have shown those core concepts can In pharmacology, as in other disciplines, identifying the core con- provide disciplines with evidence-based foundations for conceptual cepts was a necessary first stage,15 but there are additional tasks curricula. Concept inventories—valid and reliable tools to assess the that must be accomplished before these core concepts can be used attainment of core concepts—can be developed to assess and eval- to improve pharmacology teaching and learning. Educators will need uate these conceptual curricula. In biological sciences, for example, more than new names for core concepts in order to use them to core concepts provide focus on what is important and encourage inform curriculum design and teaching approaches. depth in the face of exponential growth in content.10,11 Pharmacology This study represents the second stage, namely to define and is one of several health science disciplines in which the explosion of unpack the core concepts of pharmacology education, describing biomedical knowledge troubles curriculum designers and educators. each element and identifying the key underpinning facets (sub- Moreover, health professional educators have specific needs to inte- concepts). We aimed to build on and adapt methods developed by grate knowledge from a range of primary disciplines, including chem- colleagues in physiology.11 Experienced Australasian pharmacol- 10 Core concepts would ogy educators worked iteratively to unpack the 20 core concepts, therefore assist educators and students to focus on deep learning istry, physiology, mathematics, and statistics. after which a round of feedback from an independent group of and the development of enduring conceptual frameworks. Australasian pharmacology experts helped us further clarify and refine the subconcepts. By unpacking this initial set of core concepts of pharmacology education, this Australasian study sought 1.1 | Using and unpacking core concepts to create a foundation upon which the international pharmacology community could build. The identification of core concepts within a discipline allows educa- The third stage will progress our work from Australia and New tors to focus on the foundational knowledge that is most important Zealand15 to produce a global list of core concepts in the disci- for graduates to know and understand. However, for educators to pline, and a concept inventory to test their attainment. This work, embed core concepts attainment into their curricula some disciplines now underway, will involve international pharmacology educators, | SANTIAGO eT Al. researchers, and students and will be conducted under the banner of the International Union of Basic and Clinical Pharmacology (IUPHAR) Education Section. 3 of 9 • Pharmacokinetics, which we termed “What the body does to the drug” (six concepts), • Pharmacodynamics, which we termed “What the drug does to the body” (nine concepts), and • System integration and modification of drug–response (four 2 | M E TH O DS 2.1 | Ethics approval concepts). Finally, during discussions within the groups, it became clear that we needed one additional and over-arching core concept, MUHREC project ID 22727 “Core concepts” was approved as low namely drugs, and this concept was unpacked by the entire CC-PEG. risk by the Monash University Human Research Ethics Committee. Therefore, the final number of core concepts unpacked was 20. 2.2 | Overall study design 2.4 | Unpacking of core concepts within working groups We previously identified core concepts of pharmacology education using a systematic process, starting with an exploratory survey, Members were asked to define each of the concepts assigned to then utilizing a “Core Concepts of Pharmacology Education Expert their working group, using a single sentence, and then to unpack Group” (CC-PEG) to extract and identify core concepts from survey concepts by applying the instructions below, which ensured that all responses.15 The same group conducted the current study, with the concepts were unpacked by at least one group member: aim of unpacking those core concepts. The CC-PEG comprised 12 participants (4 male, 8 female) who were selected, based on expres- “Unpacking” of a core concept into its constituent sions of interest, to form the expert group. This group was pharma- ideas (sub-concepts). Please unpack each concept cology educators who had, on average: 17 years of pharmacology by identifying 2- 4 sub-concepts that must be at- teaching experience; 4 pharmacology teaching awards, and 24 pub- tained in order to understand and apply the “parent” lications (a mix of education and biomedical research). Eleven CC- concept. PEG members represented four of the six states and one of the two territories in Australia, and the twelfth represented New Zealand. For example, in physiology the core concept of The independent expert review was carried out by five internation- homeostasis ally recognized experts in pharmacology; four male and one female. Homeostatic processes require a sensor inside the was unpacked into sub-concept body. We decided as a group to stay with one level of sub-concepts as standard, but if you are so inclined 2.3 | Expert group activities—Working Group formation you may identify sub-sub-concepts! Please make sure you describe each sub-concept in a sentence. The CC-PEG met in a virtual environment each fortnight for ap- Working groups met initially to reach consensus on both the proximately 3 months during 2021. The 20 core concepts were di- wording of the definition and the specific constituent ideas included vided into three clusters of related concepts for unpacking. Three as sub-concepts. working groups were created—one to focus on each cluster— each containing between three and six CC-PEG members, who self-nominated for the working group(s) that best reflected their expertise. 2.5 | Refinement of unpacking of core concepts across working groups Two working groups of the CC-PEG were named using common chapter headings within introductory sections of textbooks. A CC-PEG members were then asked to review and provide input on third working group was formed to unpack concepts that did not the definitions and sub-concept descriptions for all core concepts fit into either of the above groups, such as individual variation, or other than the ones they had developed within their own working had not met the 80% agreement threshold set in the first stage of group. The feedback provided included: (i) suggested changes to the this project15: pharmacological homeostasis and drugs and complex wording of definitions and sub-concepts; (ii) inclusion of new sub- systems. Given that the agreement for these two core concepts was concepts and deletion of others; and, (iii) transfer of sub-concepts to more than 70%, we wanted to determine whether unpacking these another, more appropriate, core concept. After consulting with the concepts would reveal latent concepts that could be more clearly members, working group leaders (MS, ED, and PW) were responsible labeled and articulated upon discussion. The final working group for making final decisions on changes to the unpacking of their core structure was therefore: concepts. 4 of 9 | SANTIAGO eT Al. 2.6 | Independent expert review 3 Once a complete draft of the definitions of each concept and related 3.1 | Unpacking of core concepts | R E S U LT S sub-concepts had been produced, we consulted experts in pharmacology from Australia and New Zealand, who had not previously The definitions and unpacking of each of the 20 identified core been involved in the process, to provide input. Five internationally concepts of pharmacology education are provided below. During recognized experts, each having delivered numerous invited inter- the unpacking process, questions arose as to whether some of the national pharmacology plenaries, provided detailed feedback on the concepts should be renamed. In some cases, the CC-PEG agreed to unpacking of the core concepts, with the final decision again made make minor modifications following those discussions. For example, by working group leaders. The CC-PEG met a further three times drug selectivity and specificity was renamed drug selectivity given that to incorporate the feedback received and finalize the core concept drug specificity for a single target is now recognized as a theoretical unpacking. concept not supported by empirical evidence, at least for small molecule drugs and likely even for antibody and nucleic acid therapeutics. For each concept described below, the opening sentence names 2.7 | Sources of information used and defines the concept. Sub-concepts that are required to fully understand the primary concept are then provided as bullet points. CC-PEG members were asked to record any textbooks, online materials, or other sources of information to which they referred when developing their definitions of concepts or identifying sub-concepts. 3.2 | Core concept 1: The central concept of pharmacology 1. A drug is a substance that, when introduced into the body, 2.7.1 | Textbooks and publications produces a biological effect. Rang, H.P., Flower, R., and Henderson, G. (2018). Rang & Dale's • Drugs can be classified based on the nature of the target to Pharmacology. 9th Ed. Elsevier. Amsterdam. Derendorff, H. and Schmidt, S. (Eds) (2019) Rowland and Tozer's Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 5th Ed. Wolters Kluwer. Neubig, R.R., Spedding, M., Kenakin, T., Christopoulos, A. and International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. (2003) International Union of Pharmacology Committee on Receptor Nomenclature which they bind, the clinical outcome they produce, or their physicochemical properties. • Some drugs are small molecules that produce effects via interactions with proteins, whilst other drugs, such as antibodies, antisense oligonucleotides, or small interfering RNA (siRNA), exert their effects as biological agents. • Drugs may exert their effects through multiple targets and/or target subtypes. and Drug Classification. XXXVIII. Update on terms and symbols • Some drugs do not bind to a macromolecular target; rather, in quantitative pharmacology. Pharmacological Reviews 55(4): they alter internal conditions to elicit a response (e.g., antacids 597– 606. change stomach pH; activated charcoal binds toxins and chem- Brunton, L.L., Chabner, B., and Knollmann, B.C. (Eds.) (2018) icals to prevent their absorption). Goodman & Gilman's The Pharmacological Basis of Therapeutics. 13th Ed. McGraw-Hill Education New York, NY, USA. Birkett, D.J. (2009) Pharmacokinetics Made Easy. 2nd Ed. McGraw-Hill Education. Sydney, Australia. 3.3 | Core concepts 2–7: What the body does to the drug Katzung, B.G., and Trevor, A.J. Basic and Clinical Pharmacology. 15th Ed. McGraw-Hill Education. Sydney, Australia. Kelly, E. (2013). Efficacy and ligand bias at the μ-opioid receptor. 2. Drug absorption refers to the movement of the drug from its site of administration to the systemic circulation. British Journal of Pharmacology, 169(7), 1430–1446. • The interaction between the physical and chemical characteristics (e.g., ionization, lipophilicity, molecular size, and functional 2.7.2 | Websites groups) of a drug and the various environments encountered during absorption determine how (and if) it enters the body. https://www.msdmanuals.com • The transfer of a drug across a membrane may involve a num- https://www.pharmacologyeducation.org ber of processes including active transport (uptake/efflux); https://www.icp.org.nz passive diffusion; carrier-mediated transport. | SANTIAGO eT Al. • The absorption rate is a measure of how quickly the drug enters the biological system. • The release of a drug from its dosage form, and into solution, determines whether a drug is available to be absorbed, as well as the rate and extent of absorption. 5 of 9 • Drug elimination is usually influenced by the concentration of the drug and its clearance, which is a measure of the efficiency of the removal mechanism. • Drug clearance is the volume of plasma that is cleared of the drug per unit time (e.g., liters/hour). • Overall drug clearance is the sum of hepatic clearance, renal 3. Drug distribution refers to reversible transfer of a drug between clearance, and clearance by other routes. locations in the body after absorption. • If the rate of elimination equals the rate of administration, a • The physical and chemical properties (e.g., ionization, lipo- • Elimination half-life is the time taken to reduce the drug con- steady-state concentration of the drug is achieved. philicity, molecular size, and functional groups) of a drug in- centration in the plasma by half. fluence its movement into and between different biological compartments. • The compartment characteristics (e.g., pH, blood flow, lip- 7. Bioavailability refers to the fraction of the administered dose that reaches the systemic circulation as an unmodified drug. id:water ratio, and uptake/efflux transporters) influence the differential distribution of drug throughout the body. • Drug binding to plasma proteins and tissue constituents can influence the movement of a drug within the body. • Bioavailability is quantified by comparing the area under the curve of the plasma concentrations achieved with a formulation compared with that seen after intravenous administration. • The apparent volume of distribution is a theoretical concept • The concentration of available drug in the plasma is influenced reflecting the extent to which the drug has moved from the by its release from the administered preparation, as well as its plasma into the tissues. absorption, excretion, and metabolism. • Only a fraction of the drug may enter the systemic circulation 4. Drug metabolism, or biotransformation, refers to the chemical modification of the drug within the body. if it undergoes pre-systemic biotransformation, which is referred to as first-pass metabolism. • Biotransformation may occur through functionalization (e.g., reduction, oxidation, or hydrolysis), or by conjugation with other biomolecules. 3.4 | Concepts 8–16: What the drug does to the body • The efficiency of drug-metabolizing enzymes is influenced by multiple factors, including genetic variation, disease state, and the co-administration of drugs that increase (induce) or 8. Drug target refers to the site to which the drug binds to produce an effect. decrease (inhibit) enzyme activity. • Biotransformation usually facilitates the removal of the drug from the body. • The product of biotransformation (metabolite) has its own absorption, distribution, metabolism, excretion, and potential drug activity. • A drug target is usually a macromolecule. • Molecular drug targets are usually proteins, or less commonly, nucleic acids. • Most drugs exert their effect through interaction with “classic” protein targets such as receptors, enzymes, ion channels, and transporters. 5. Drug excretion refers to the physical processes leading to the irreversible removal of drug and its metabolites from the body. • Interaction of a drug with a target is described in different ways depending on the target (e.g., agonist, antagonist, substrate, and inhibitor). • The removal of a drug from the body may occur via the kidneys into the urine, through the hepatobiliary system, or through other body systems (e.g., breast milk, lungs, skin, and saliva). 9. Mechanism of drug action refers to the way in which a drug interacts with its target to modify biological function. • Drug excretion by an organ is dependent on the physicochemical properties of the drug, as well as the anatomy and physiol- • Drugs usually alter the rate or magnitude of an intrinsic response. ogy of the organ (including the occurrence of transporters). • Drugs can either activate, inhibit, enhance, or attenuate intrinsic responses. 6. Drug elimination refers to the loss of drug through metabolic or ex- • Many drugs bind to the same site (orthosteric site) within a cretion processes, so that it is no longer able to be measured in its protein as an endogenous activator, mimicking or inhibiting original form. (Elimination differs from excretion in that it includes both the chemical modification and the physical removal of the drug, whereas excretion involves only the physical removal processes.) the action of the endogenous activator. • Some drugs exert their effects by binding to an allosteric site that is spatially distinct from the active, orthosteric, binding site. 6 of 9 | 10. Drug affinity refers to the ability of a drug to bind to its target. SANTIAGO eT Al. 14. Concentration–response relationship refers to the relationship between increasing drug concentration and magnitude of response. • Affinity is dependent on the chemical interactions between the drug and the target (bonding), as well as the steric match of the drug to its target (conformation and size). • Affinity is commonly quantified through the determination of the concentration of drug required to occupy 50% of the drug target at equilibrium (KD, equilibrium dissociation constant). • As the concentration or dose of a drug increases, the magnitude of the response increases from a threshold until a maximum response is obtained. • Concentration–response relationships are used to determine and compare agonist potency (EC50) and maximal effect (Emax). • Concentration–response relationships are used to determine 11. Drug efficacy refers to the ability of a drug to produce a given response from the target. whether a drug is an antagonist, a partial agonist, or a full agonist. • Concentration–response relationships are used to determine and compare antagonist potency, as well as the type of antagonism. • Efficacy represents the degree to which different drugs, acting at the same target, produce variable magnitudes of response when occupying the same proportion of target molecules. • Surmountable antagonists reduce agonist potency but not agonist maximum effect. • Insurmountable antagonists will reduce the maximum effect of an agonist, with or without effects on agonist potency. • Efficacy is graded (not all-or-nothing) and is dependent on the drug, the target, and tissue components. • Full agonists produce the maximal response of the system. 15. Drug safety refers to the balance of therapeutic benefits over harms. • Partial agonists do not produce the maximal system response even at saturating concentrations. • Antagonists have zero efficacy and produce no response when tested in isolation. • Inverse agonists reduce basal system responses by suppressing spontaneous receptor activity. • Clinical efficacy describes how well a drug treatment achieves its therapeutic aim and is distinct from drug efficacy. 12. Drug selectivity refers to the concentration-dependent preference of a drug for one target over others. • Most drugs show selectivity, based on the relative affinity of the drug for each target. • Selectivity depends on chemical structure, molecular size, and electrical charge. • Selectivity decreases with increasing drug concentration. • All drugs are potential poisons; it is the dose that is critical. • The higher the drug dose, the lower the selectivity, and the greater the chance of harm. • Adverse drug reactions are unwanted effects at therapeutic doses. • Drugs can interact with other drugs, food, complementary medicines, and disease to cause harm at therapeutic doses. 16. Drug tolerance refers to the reduced response to a drug following repeated or prolonged exposure. • Drug dose must be increased to maintain clinical efficacy when tolerance develops. • Drug tolerance involves multiple mechanisms, such as up- or down-regulation of target number as a result of repeated drug administration. 13. Drug potency refers to the amount of a drug, expressed as the concentration or dose, required for a given level of effect. 3.5 | Concepts 17–20: System integration and modification of drug response • Potency depends on both target (affinity and efficacy) and tissue (receptor number and drug availability) parameters. • The higher the potency, the lower the dose required for a given level of effect. • Highly potent drugs are often considered desirable because 17. Therapeutic window refers to a concentration range bounded at the lower end by the minimum concentration that produces the desired clinical effect and at the upper end, the concentration that produces unacceptable effects or where no further benefit is observed. lower doses can be used and therefore, less drug is available to cause off-target adverse effects. • Agonist potency is most commonly measured as the effective concentration required to produce 50% of the maximal response (EC50). • Antagonist potency can be measured as the concentration that reduces the response to an agonist. • Target plasma concentrations are described by exposure metrics (e.g., AUC and Css,avg) and correlate with the extent and duration of optimal clinical response. • Therapeutic window informs the target plasma concentration range when determining individualized dosages through therapeutic drug monitoring. | SANTIAGO eT Al. 18. Pharmacological homeostasis refers to the interplay between 4 | 7 of 9 DISCUSSION drug response and physiological homeostatic mechanisms. In the first stage of this project, the Core Concepts in Pharmacology • Drug action occurs in the context of homeostasis. Expert Group (CC-PEG), identified 20 core concepts that pharmacol- • Drug action can alter the activity of homeostatic sensors (e.g., ogy students should be expected to know, understand, remember, TRP channels), homeostatic control centers (e.g., altered set and apply correctly and effectively, years after graduation.15 In the points for temperature with NSAIDS), or homeostatic effec- second stage, to define and unpack those 20 core concepts of phar- tors (e.g., adrenoceptor up-regulation with beta-blockers). macology identified previously, CC-PEG developed an innovative, • Drug action is in turn modified by homeostatic processes (e.g., rigorous, iterative method informed by prior core concepts research tolerance due to receptor down-regulation, baroreflex blunt- in STEM disciplines. ing the effect of anti-hypertensive medications). 19. Drugs and complex systems refers to the interplay between 4.1 | Research-informed methodology drugs and patients, the latter being an integrated network of cells, tissues, and organs. The methods CC-PEG used to define and unpack the 20 core concepts of pharmacology education were informed primarily by rel- • Drug action results from the complex interactions between cells, organs, and body systems. evant prior research in biology10 and physiology.11,16 To develop definitions for each core concept and to identify the relevant sub- • Drug action in one cell type, organ, or system can affect other concepts—and to ensure maximum rigor and relevance—CC-PEG cell types, organs, or systems that interact with the first cell adapted and extended the expert-group approach used in physi- type, organ, or system. ology,16 adding additional steps. Firstly, CC-PEG extended and • Prediction of drug response in patients can be confounded by strengthened the iterative expert-group process used in physiology behavioral factors, such as poor adherence to treatment, and research by requiring each working group to come to within group biological factors, such as the interplay between cells, organs, agreement on definitions and sub-concepts, and then to refine and and body systems in disease contexts. finalize that work across groups—through virtual discussion until consensus was achieved. Second, to further cross-check their judg- 20. Individual variation refers to the fact that individuals respond ments and enhance rigor, CC-PEG employed an additional group of differently to a given drug, due to exogenous and endogenous experts in the field to conduct an independent review. Third, the (including genetic) factors that influence drug availability and/or comments and questions raised by the independent expert review- action. ers informed a final round of discussion and revision of the definitions and unpacking. By extending and enhancing the methods • Pharmacodynamic variability describes differences in the used in prior core concepts research, CC-PEG minimized individual amount and/or function of drug target molecules, and/or the biases, strengthened concept validity, and increased the likelihood associated signaling cascade components that influence the these definitions and sub-concepts will be accepted and used by the degree to which a drug can exert its effect. broader pharmacology education community. • Pharmacokinetic variability describes differences in the ability of a drug to access or move around the body, as well as altered metabolism of the drug and ability of the body to excrete the drug. • Disease-induced variability describes differences imposed by 4.2 | Core concepts, sub-concepts, and conceptual frameworks When unpacking physiology core concepts, Michael et al.,16 note that a disease state that change the ability of a drug to access the “Core concepts, or big ideas, are complex assemblages of interconnected target or act upon it. smaller ideas” and that unpacking of core concepts can be helpful • Sex- and/or age-induced variability describes differences that for students who are developing a conceptual framework within the relate to more general innate influences, rather than differ- discipline. For each of the 20 core concepts, we developed a first ences related solely to the individual. layer of sub-concepts. For many of the concepts, CC-PEG working • Environment-induced variability describes differences that groups identified “layers beneath” that could have been included, for occur due to such factors as dietary influences, toxin exposure, example, drug interactions, adverse drug reactions, and hypersensitiv- supplements, and complementary or alternative preparations. ity under drug safety would benefit from further unpacking. Future • As a drug needs to be taken by the patient as prescribed in studies could be conducted to unpack the full conceptual framework order to elicit the desired response, the level of drug adher- for some or all of these concepts. Michael et al.17 developed a hi- ence during treatment can have a significant influence on indi- erarchy of conceptual frameworks, in which each core concept is vidual variability. unpacked into critical components (equivalent to our definitions), 8 of 9 | SANTIAGO eT Al. constituent ideas (equivalent to our sub-concepts), and further to to grouping specificity and selectivity together. Recognizing that drug elaborations and amplifications. A critical step in the development of specificity encompasses both ligand specificity and binding site spec- conceptual frameworks is the articulation of relationships between ificity, we agreed that drug specificity, as a chemical concept, is bet- concepts and sub-concepts. We addressed this aspect in a novel ter understood through the lens of affinity for a target and should be manner via a simple concept map for the core concepts of pharma- included under that concept. Whilst concentration–response relation- cology produced as part of our previous study15; a future study to ship was initially identified as a core concept, during the subsequent diagrammatically link the sub-concepts to each other would provide unpacking we questioned whether or not it should stand-alone an invaluable tool for educators and students. or be integrated into other core concepts to provide a context for their measurement. Consensus was reached that the concentration– response relationship is fundamental to many key pharmacological 4.3 | What the body does to the drug (pharmacokinetic) concepts principles and, as such, is a core concept in its own right. Most importantly, across all discussions, we addressed the question of who the stakeholders might be. In our earlier study identifying Finding the appropriate wording was challenging for the working core concepts, we defined the scope as concepts that are “founda- group, as it was important to ensure that concepts were clear and tional for pharmacology students”.15 Consequently, we unpacked these relevant to the novice learner while covering all possibilities for accu- foundational core concepts with all students who study pharmacology racy. Appropriate wording seemed of particular relevance when con- in mind. We, therefore, decided not to further unpack more advanced, sidering the various contexts in which those concepts will be used, context-specific sub-concepts such as allostery, and to exclude as sub- which could include classrooms, laboratories, and clinical settings. concepts conformational change, constitutive activity, biased agonism, Given the interrelated nature of the core concepts we unpacked, spare receptors, and intrinsic efficacy. there was extensive discussion as to the core concept with which some sub-concepts best aligned. For example, first-pass metabolism decided that it was a better fit under drug elimination. Similarly, steady 4.5 | System integration and modification of drug–response concepts state plasma concentration, although initially considered a sub-concept Drugs and complex systems were by far the most difficult of the three of therapeutic window, became a sub-concept of drug elimination. concepts to unpack. Indeed, as drugs and complex systems and phar- was initially presented as a sub-concept of bioavailability, but it was The differentiation of excretion and elimination was, and contin- macological homeostasis narrowly failed to reach the pre-determined ues to be, a point of debate. Extensive discussion addressed whether endorsement in the initial study,15 we unpacked these concepts in an these terms should be included as individual concepts, or whether attempt to reveal latent or hidden ideas. Whilst the working group elimination should be a sub-concept of excretion and metabolism. A developed core and sub-concepts relating to complex, often mul- search of the literature revealed that the terms are often used inter- ticellular, and multiorgan level effects of drug action, which were changeably. However, when the concept of drug elimination is used, it endorsed by the CC-PEG wider group, we believe that this group of usually indicates both drug metabolism and excretion processes are ac- concepts requires further discussion. tive (chemical and physical processes), while excretion is restricted to Individual variation was seen as one of the most critical of all physical removal processes alone. As the elimination rate is an import- core concepts for students to attain, and the unpacking of this ant pharmacokinetic parameter in explaining drug behavior and can concept led to the largest number of sub-concepts. By contrast, be used to explain the removal of drug more thoroughly than by ex- pharmacological homeostasis (re-named from the original concept) cretion alone, we have included both as individual core concepts. We was fairly straightforward to unpack, based on the effect of the welcome the engagement of the international pharmacology commu- drug on the sensors, control centers, and effectors of homeostatic nity in this debate, in the expectation of achieving a consensus. processes, as well as the modulation of the effect of the drug by those processes. Pharmacological homeostasis is arguably a subconcept of the physiology core concept of homeostasis that had 4.4 | What the drug does to the body (pharmacodynamics) concepts previously been unpacked16 and assessed by a validated concept inventory.18 The pharmacodynamics working group contended with a number of key issues. Drug potency was originally subsumed under 5 | CO N C LU S I O N concentration–response relationship and was thought to be implicit in concepts of affinity and efficacy. After much discussion, we agreed Twenty previously identified core concepts of pharmacology edu- that drug potency constitutes a stand-alone concept. The concept cation were defined, grouped under four conceptual areas, and of drug specificity and drug selectivity also generated extensive de- for each, key sub-concepts were identified and explained. We be- bate. We readily acknowledged that drug selectivity depends greatly lieve that this work can provide educators with a resource to guide on drug concentration; however, there was confusion with regard the development of new curricula and the evaluation of existing | SANTIAGO eT Al. curricula. The development of a reliable and valid instrument to assess student understanding of those core concepts (concept inventory) will also be assisted by the unpacking of each core concept. Perhaps most importantly, educators can use the unpacked core concepts of pharmacology education within their teaching contexts to help students gain mastery of the foundations of the discipline. We anticipate that this framework will provide the basis for collaboration and curriculum refresh throughout the global pharmacology community, and we invite others to join in this important work. AC K N OW L E D G M E N T S The authors are extremely grateful to the following pharmacology experts for providing insightful and constructive feedback on the definitions and sub-concepts described in this study: Shane Bullock, Monash University; Kathleen Knights and John Miners, Flinders University; Evan Begg, Christchurch School of Medicine. C O N FL I C T O F I N T E R E S T The authors have no conflicts of interest with respect to this study. AU T H O R C O N T R I B U T I O N S All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; and been involved in drafting the manuscript or revising it critically for important intellectual content; and given final approval of the version to be published. Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DATA AVA I L A B I L I T Y S TAT E M E N T The data that support the findings of this study are available from the corresponding author upon reasonable request. 9 of 9 4. Parekh G, DeLatte D, Herman GL, et al. Identifying core concepts of cybersecurity: results of two Delphi processes. IEEE Trans Educ. 2017;61:11-20. 5. Tweedie J, Palermo C, Wright HH, Pelly FE. Using document analysis to identify core concepts for dietetics: the first step in promoting conceptual learning. Nursing Health Sci. 2020;22:675-684. 6. Hott AM, Huether CA, McInerney JD, et al. Genetics content in introductory biology courses for non-science majors: theory and practice. Bioscience. 2002;52:1024-1035. 7. 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