- Email: [email protected]
Understanding medicines: extending pharmacology education for dependent and independent prescribing (Part II)
Article
Understanding medicines: extending pharmacology education for dependent and independent prescribing (Part II) Helen L. Leathard
Helen L Leathard BSc, PhD, Reader in Pharmacology and Human Physiology, Department of Nursing Studies and Centre for Health Research & Practice Development, St Martin’s College, Lancaster LA 1 3JD, UK. Tel.: 01525 384 615; Fax: 01524 384 581; E-mail: h.leathard@ucsm. ac.uk Manuscript accepted: 19 December 2000
272
This paper relates to the extent and depth of understanding of medicines that is required for supply and administration of medicines under group protocol (dependent prescribing) (Crown 1998, 1999) for patients who are taking concurrent medications or independent prescribing from extended formularies or the entire British National Formulary. This includes a concise account of the level of understanding needed of: classifications, actions and effects (pharmacodynamics), duration of action and pharmacokinetics, interactions, and drug discovery, development and evaluation. A final section relates to aspects which students have found most challenging and provides examples of helpful explanations of concepts that have been found difficult. The limited familiarity of most nurses with chemistry is the greatest cause for anxiety, and yet it is unrealistic to argue the case for this subject as a prerequisite to a career in nursing. Instead, taking a pragmatic view of the need to meet students where they are, and making creative use of domestic analogies and images, has served to make pharmacology accessible. Examples of these aids to understanding are outlined. © 2001 Harcourt Publishers Ltd
Introduction The first of these two papers provided a conceptual analysis of nurses’ needs for knowledge and understanding of pharmacology for a variety of clinical situations, and pointed to the foreseeable need for increasing the content of pharmacology in preregistration and postregistration nurse education programmes. This second article illustrates what might be reasonable extents and depths of pharmacological
Nurse Education Today (2001) 21, 272–277
doi:10.1054/nedt.2001.0554, available online at http://www.idealibrary.com on
knowledge and understanding to underpin safe prescribing of systemically acting medicines. This includes a concise account of the level of understanding needed of: ● ● ● ● ●
Classifications Actions and effects (pharmacodynamics) Duration of action and pharmacokinetics Interactions Drug discovery, development and evaluation.
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
This is followed by a report identifying some of the inherent challenges for nurse education together with some suggestions, from personal experience, for coping with the difficulties experienced. For this purpose I will focus on pharmacology as the study of medicines, as distinct from clinical pharmacology being the application of pharmacology in particular clinical settings where it needs to be integrated with diagnosis and care plans including other therapies.
Classifications of medicines Medicines are known by a mixture of therapeutic, pharmacological and chemical classifications. None is perfect and various combinations are in common usage. In my experience, the chemical classifications are the most difficult for those without extensive understanding of organic chemistry, and chemical names tend to be used as labels without full understanding of their meaning. This is not necessarily a problem in relation to clinical practice, but it does provide a rationale for using other classifications whenever possible. The British National Formulary (Mehta 1998) uses primarily a therapeutic classification, but many drugs appear in multiple sections. Pharmacological classifications are really helpful because they serve as concise reminders of mechanisms of action and this can serve as a key to recall of actions and effects. Combinations of classifications are in common usage, such as: opioid analgesics, non-steroidal antiinflammatory drugs, benzodiazepine anxiolytics, tricyclic antidepressants, antihypertensive ACE (angiotensin converting enzyme) inhibitors, cardiac glycosides, oral hypoglycaemic agents, and it is helpful to be aware of the significance of these.
Actions and effects of medicines (pharmacodynamics) The effects of medicines can be beneficial or adverse. They are the product of the mechanisms of action of the various pharmacologically active agents (drugs) within the medicine. Effects that are inevitable accompaniments of the desired therapeutic effects are commonly referred to as side-effects. They may be beneficial, adverse or neutral but are mainly regarded as unwanted.
© 2001 Harcourt Publishers Ltd
Detailed study of the mechanisms of action of drugs at cellular and molecular levels is the province of the specialist pharmacologist, but some understanding of mechanisms of action is essential for all prescribers. Recognition and reporting of adverse drug reactions is also something that nurses can play an important part in, and this was very clearly discussed by Morrison-Griffiths et al. (1998). This too is facilitated by understanding how drugs interact with physiological systems. Various drugs derived from natural sources, such as morphine and aspirin, were, however, used successfully in therapeutics for many years before their mechanisms of action were discovered. So, while medicines can be administered safely following routine procedures, reflective practice in relation to medicines requires secure understanding of relevant pharmacology. Most drugs work by activating or blocking receptors or by inhibiting enzymes that either synthesise or inactivate biological mediators. Therefore, the understanding of pharmacodynamics depends upon understanding of drug-receptor and drugenzyme interactions, and recognition that many receptors are, or are closely linked to, enzymes. It is important for prescribers to understand the concepts of drug-receptor and drug-enzyme interactions because these largely determine the quantitative relationships between dose and concentration of drug and its pharmacological effect, and are responsible for selectivity of drug action.
Definitions of some important terms ●
●
●
●
Receptors are defined as those parts of a cell with which a drug or biological mediator interacts in order to produce its effect. They have evolved to mediate the actions of hormones and neurotransmitters but serve also as targets for drug action Enzymes, or enzyme systems, are biological catalysts that promote biochemical reactions in the body without being altered by them Agonist is a technical word used to describe a drug that interacts with a receptor to activate (or stimulate) it and thus produce a direct effect An antagonist is a drug that interacts with a receptor or adjacent site to interfere with the
Nurse Education Today (2001) 21, 272–277 273
Understanding medicines (Part II)
●
activation of the receptor by a biological mediator or other drug. It produces its effect indirectly by reducing (inhibiting) or preventing an ongoing process Enzyme inhibitors also work indirectly because they increase or decrease the concentration of biological mediator available for action.
Most drugs that are used as medicines interact reversibly with receptors or enzymes, so that the degree of their action parallels the concentration of the drug in the circulation. For those drugs that have irreversible interactions with receptors or enzymes, their duration of action depends upon the rate of synthesis of new receptor or enzyme proteins; this varies from tissue to tissue. Similarly, the effects of those drugs that act genomically (affecting genes in the cell nucleus) to stimulate the formation of new tissues or enzymes outlast the duration of the drug in the circulation.
Duration of action of medicines and pharmacokinetics The duration of action of a drug determines the range of possible frequencies of its administration. This and the possibilities for different formulations giving different durations of action depend largely on the pharmacokinetics of the drug components of medicines. While there is little need for detailed knowledge of the processes of drug distribution, metabolism and excretion for each medicine, a general understanding of the principles of these aids good understanding of safe frequencies of administration. It also provides a rationale for the need for caution in particular patient groups (paediatric, elderly, those with renal or hepatic impairment). These factors are considered briefly in turn.
Routes of administration Prescribers need extensive knowledge and understanding of the factors governing and restricting the availability of routes for administration of drugs. Major factors are the physico-chemical properties of drugs in relation to the physico-chemical properties of cell membranes and other barriers to drug
274
Nurse Education Today (2001) 21, 272–277
movements. Understanding of drug passage across membranes requires assimilation of the following concepts: ● ● ● ● ●
Diffusion Osmosis Lipid solubility Aqueous solubility Functional groups on covalently-bonded compounds, and the impact on functional interactions between these parameters of variations in pH. A thorough understanding of blood flow through various tissues and the possible influences upon this of ageing and diseases is also crucial for prescribing effective therapy. Other considerations include ability to assess the desirable and undesirable or risky features of various routes of administration available for patients who cannot take medicines orally.
Bioavailability This is a term used to refer to the quantity of drug that is available for action in the body, and is commonly calculated as a percentage of the dose given. Bioavailability may be restricted by presystemic metabolism (by enzymes in the gut or liver after oral administration, before the drug reaches the circulation) or systemic metabolism (by enzymes in the blood and other tissues). Plasma protein binding reduces bioavailability because they are not free to diffuse out of the blood stream to target tissues while they are attached to plasma proteins. Their duration of action is, however, increased by this means because the drugs are equally unavailable for hepatic metabolism or renal excretion. Rapid excretion can reduce bioavailability of slowly absorbed drugs as well as shortening their duration of action. For some drugs there is considerable interpatient variation in these factors that affect bioavailability, either genetically determined or influenced by disease, and these can be sufficiently great to necessitate careful titration of doses by the prescriber to achieve optimal therapeutic effect. The underlying reasons must be understood.
Drug metabolism and excretion The concentration of drug in the circulation represents not only the concentration available to
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
act but also the concentration available for metabolism and excretion. Because of the potential impact of organ-specific disease, the prescriber needs to be aware of the major sites of elimination of each drug. The kidneys and urinary excretion are quantitatively the most important for most drugs. Excretion via the liver into bile and then faeces (or enterohepatic circulation) or exhalation are other possibilities for systemic drugs, and there are diverse other means of eliminating locally administered medicines. The prescriber also needs to know which drugs require hepatic metabolism to render them sufficiently water soluble to be excreted in urine. There also needs to be some awareness of the two main processes of hepatic metabolism, commonly referred to as phases one and two, because these are implicated differentially in genetically determined variations in drug susceptibility and in causation of adverse drug–drug interactions. Understanding of principles and prime examples of enzyme induction, enzyme inhibition, hepatic activation of prodrugs (medicines that are administered as inactive chemicals but modified by the liver to produce pharmacologically active agents) and production of active metabolites is also needed for safe prescribing.
Interactions Numerous possible drug–drug interactions are listed in an appendix to the BNF and many of these are not usually of clinical significance. Nurse prescribers will need good ability to recognize any that are relatively common within their area of practice. They will also need to be able to access reference sources for occasions when patients on multiple drug therapy develop unexpected signs or symptoms that might have their basis in an adverse drug interaction.
Drug discovery, development and evaluation ‘They do test new drugs don’t they?’ In a chapter under this quizzical title Freeman (1991, p.13) asserted that many people who prescribe or administer medicines have little understanding of the preclinical and clinical stages of the production of a new medicine. In fact, the introduction of a new medicine is underpinned
© 2001 Harcourt Publishers Ltd
by more rigorous regulation than is applied to any other therapy. It is important that health-care professionals should recognise that such rigorous appraisal is not applied to food additives, diverse complementary therapies, surgical techniques or, indeed, other orthodox therapies. It is important that nurses should understand the principles of drug discovery, development and clinical evaluation so that they can have justified confidence in their effectiveness and safety and can appreciate why animal studies are an essential part of this process. This contentious issue was debated quite recently (Blake & Collins 1999). Blake, who has Friedrich’s ataxia, an incurable genetic disease that affects the central nervous system, argued cogently for the need for medical research that includes carefully regulated and monitored experiments on animals. Collins, provided a contrasting, emotive argument that not all adverse effects of drugs are detected by animal experiments and, therefore, their use is unjustified. Such debates will undoubtedly continue. Currently, pharmacological studies on animals almost invariably precede trials in humans. It is these clinical trials of medicines that prescribers need a sound understanding of if they are to be able to evaluate claims of effectiveness and safety based on publications in journals or appearing in promotional literature. Specific information on the principles of clinical trials is provided in many textbooks of clinical pharmacology, such as that of Laurence et al. (1997), and authors such as Sackett et al. (1997) have produced more general guidance on interpretation of research findings to underpin evidence-based practice.
Challenges in education for nurses, and some suggestions Personal experience attests that the greatest difficulty most nurses or student nurses have in understanding pharmacology lies in its basis in chemistry. Unlike students of medicine, nursing students are not required to have passed A-level or even GCSE chemistry, and there are cogently argued reasons why this subject is not prioritized. Traditional nursing courses seem to have focused on what might best be described as functional anatomy. They provide descriptive accounts of what the various body systems do without exploring how they function at a level of detail
Nurse Education Today (2001) 21, 272–277 275
Understanding medicines (Part II)
that requires an understanding of chemistry and biochemistry. If pharmacology-based practice is going to be reflective rather than ritualistic the actions of medicines will need to be understood in relation to physiology and pathophysiology, and this necessarily involves some engagement with certain basic elements of chemistry and biochemistry. Through the extensive experience mentioned in the first of these two papers I have found that the amount of chemistry needed is quite limited. Furthermore, the process of this engagement can be eased through the use of domestic analogies to illustrate pharmacological principles; selected examples of these are outlined below. The mechanism of action of many drugs involves interaction with receptors or active sites of enzymes; either by mimicking the action of a physiological mediator (agonist) or by blocking it (antagonist). A qualitative analogy is provided by reference to locks and keys. Two similar but not identical keys can be inserted into the same lock, but only one will activate the mechanism (agonist), while the other (antagonist) fails to activate the mechanism and prevents access of the correct key to the activating mechanism. A simple quantitative model that can be used in class consists of a cardboard box with indentations in the base to represent receptor sites (20 seems to work well), and marbles to represent physiological mediators or drug molecules. Agonist dose-response curves can be produced by gradually introducing standardsized marbles and gently shaking the box, then counting how many receptor sites are occupied. Large marbles can then be used to represent antagonist drug molecules and agonist doseresponse curves redetermined in the presence of various doses of antagonist to demonstrate rightward shifts of the agonist dose-response curve. Within an hour of ‘playing’ with marbles in small groups and repeatedly relating observations to the real situation with a circulating tutor, most students overcome apprehensions over interpretation of the curves displayed in textbooks, and feel at ease with the basis of the sigmoid curve relationship between response and the logarithm of the dose in simple systems. The selectivity or specificity of drugs for particular receptors is related to the properties of ‘functional groups’ on covalently bonded
276
Nurse Education Today (2001) 21, 272–277
molecular cores. Two analogies have been found useful to illustrate this concept. One is a tree with a relatively stable and unchanging trunk, representing the main part of the drug molecule, with twigs and leaves as the ‘functional groups’ that interact with environmental influences such as sunlight, birds and insects. A second analogy is a building as the molecular core with its inhabitants as ‘functional groups’ coming and going in dynamic equilibrium, intermittently meeting and interacting with others. The lottery machine with many balls in motion and occasional ones locating in the selection compartment is a useful image of molecules in motion close to receptor or enzyme sites and occasionally interacting with them. At the submolecular level, the apparent solidity of space occupied by rapidly orbiting electrons can be modelled by a rotating door. The fixed centre of the door represents the atomic nucleus, and the rotating arms represent the electrons. When the door is rotating rapidly it is impossible to enter any of the space within the radius of the arms; the space seems to be filled entirely. The space-filling ability of electrons surrounding atomic nuclei is very similar but their rotation is in three dimensions, filling a sphere. A dinner table set for eight, but with six, seven, nine or ten guests arriving can be used to illustrate some of the features of ionisation processes for those many atoms that have an outer shell that is completely occupied by eight electrons. By way of introduction to pharmacokinetics, the diffusion of colour from a tea bag and the osmotic passage of water into the bag to swell it, and influence of sugar upon these processes provide familiar starting points. Similarly, oil and vinegar salad dressings and the need for emulsifying agents to stabilise their mixing, or the use of detergents to clean greasy dishes lend familiarity to the basic principles of oil–water partitioning effects. These need to be understood when considering the passage of drugs across membranes and the implications of the lipid solubility of drugs for their absorption from the gut, diffusion from sites of injection (other than intravenous), penetration into the central nervous system and elimination in the urine. The use of these and similar analogies has formed an essential part of meeting my students where they are in order to lead them on (educate in the prime meaning of the word) to greater
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
understanding. Once initial barriers are deconstructed by cutting through the scientific jargon and discussing basic principles in accessible language the potential of most nurses to develop good understanding of pharmacology seems to become virtually unlimited. I hope that this paper will stimulate discussion of and research into effective ways and means of making pharmacology a readily accessible subject for future generations of nurses, without the need for an A-level qualification in chemistry, so that they can be involved as fully as possible in that part of caring for patients that involves medicines. Acknowledgements
I am pleased to thank Dr Shane Bullock, Dr Michael Cook and Dr Michael Walsh for their invaluable comments on typescripts of this paper. References Blake A, Collins B 1999 Animal testing: for and against. Nursing Times 95 (8): 32–33
© 2001 Harcourt Publishers Ltd
Crown J 1998 Review of Prescribing, Supply and Administration of Medicines: A report on the supply and administration of medicines under group protocols. Department of Health, London Crown J 1999 Review of Prescribing, Supply & Administration of Medicines. Final Report. Department of Health, London Freeman J 1991 They test new drugs don’t they. In: Glaxo Group Research (eds) Drug Safety – A Shared Responsibility. Churchill Livingstone, Edinburgh, p 13–26 Laurence D R, Bennett P N, Brown MJ 1997 Clinical Pharmacology. Churchill Livingstone, Edinburgh Mehta D K 1998 (Executive Editor) British National Formulary (BNF) Volume 36 British Medical Association and the Royal Pharmaceutial Society of Great Britain Morrison-Griffiths S, Pirmohamed M, Walley T 1998 Reporting of adverse drug reactions: practice in the UK. Nursing Times 94(10): 52–54 Sackett D L, Richardson W S, Rosenberg W, Haynes R B 1997 Evidence-based Medicine. Churchill Livingstone, Edinburgh
Nurse Education Today (2001) 21, 272–277 277
Understanding medicines: extending pharmacology education for dependent and independent prescribing (Part II) Helen L. Leathard
Helen L Leathard BSc, PhD, Reader in Pharmacology and Human Physiology, Department of Nursing Studies and Centre for Health Research & Practice Development, St Martin’s College, Lancaster LA 1 3JD, UK. Tel.: 01525 384 615; Fax: 01524 384 581; E-mail: h.leathard@ucsm. ac.uk Manuscript accepted: 19 December 2000
272
This paper relates to the extent and depth of understanding of medicines that is required for supply and administration of medicines under group protocol (dependent prescribing) (Crown 1998, 1999) for patients who are taking concurrent medications or independent prescribing from extended formularies or the entire British National Formulary. This includes a concise account of the level of understanding needed of: classifications, actions and effects (pharmacodynamics), duration of action and pharmacokinetics, interactions, and drug discovery, development and evaluation. A final section relates to aspects which students have found most challenging and provides examples of helpful explanations of concepts that have been found difficult. The limited familiarity of most nurses with chemistry is the greatest cause for anxiety, and yet it is unrealistic to argue the case for this subject as a prerequisite to a career in nursing. Instead, taking a pragmatic view of the need to meet students where they are, and making creative use of domestic analogies and images, has served to make pharmacology accessible. Examples of these aids to understanding are outlined. © 2001 Harcourt Publishers Ltd
Introduction The first of these two papers provided a conceptual analysis of nurses’ needs for knowledge and understanding of pharmacology for a variety of clinical situations, and pointed to the foreseeable need for increasing the content of pharmacology in preregistration and postregistration nurse education programmes. This second article illustrates what might be reasonable extents and depths of pharmacological
Nurse Education Today (2001) 21, 272–277
doi:10.1054/nedt.2001.0554, available online at http://www.idealibrary.com on
knowledge and understanding to underpin safe prescribing of systemically acting medicines. This includes a concise account of the level of understanding needed of: ● ● ● ● ●
Classifications Actions and effects (pharmacodynamics) Duration of action and pharmacokinetics Interactions Drug discovery, development and evaluation.
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
This is followed by a report identifying some of the inherent challenges for nurse education together with some suggestions, from personal experience, for coping with the difficulties experienced. For this purpose I will focus on pharmacology as the study of medicines, as distinct from clinical pharmacology being the application of pharmacology in particular clinical settings where it needs to be integrated with diagnosis and care plans including other therapies.
Classifications of medicines Medicines are known by a mixture of therapeutic, pharmacological and chemical classifications. None is perfect and various combinations are in common usage. In my experience, the chemical classifications are the most difficult for those without extensive understanding of organic chemistry, and chemical names tend to be used as labels without full understanding of their meaning. This is not necessarily a problem in relation to clinical practice, but it does provide a rationale for using other classifications whenever possible. The British National Formulary (Mehta 1998) uses primarily a therapeutic classification, but many drugs appear in multiple sections. Pharmacological classifications are really helpful because they serve as concise reminders of mechanisms of action and this can serve as a key to recall of actions and effects. Combinations of classifications are in common usage, such as: opioid analgesics, non-steroidal antiinflammatory drugs, benzodiazepine anxiolytics, tricyclic antidepressants, antihypertensive ACE (angiotensin converting enzyme) inhibitors, cardiac glycosides, oral hypoglycaemic agents, and it is helpful to be aware of the significance of these.
Actions and effects of medicines (pharmacodynamics) The effects of medicines can be beneficial or adverse. They are the product of the mechanisms of action of the various pharmacologically active agents (drugs) within the medicine. Effects that are inevitable accompaniments of the desired therapeutic effects are commonly referred to as side-effects. They may be beneficial, adverse or neutral but are mainly regarded as unwanted.
© 2001 Harcourt Publishers Ltd
Detailed study of the mechanisms of action of drugs at cellular and molecular levels is the province of the specialist pharmacologist, but some understanding of mechanisms of action is essential for all prescribers. Recognition and reporting of adverse drug reactions is also something that nurses can play an important part in, and this was very clearly discussed by Morrison-Griffiths et al. (1998). This too is facilitated by understanding how drugs interact with physiological systems. Various drugs derived from natural sources, such as morphine and aspirin, were, however, used successfully in therapeutics for many years before their mechanisms of action were discovered. So, while medicines can be administered safely following routine procedures, reflective practice in relation to medicines requires secure understanding of relevant pharmacology. Most drugs work by activating or blocking receptors or by inhibiting enzymes that either synthesise or inactivate biological mediators. Therefore, the understanding of pharmacodynamics depends upon understanding of drug-receptor and drugenzyme interactions, and recognition that many receptors are, or are closely linked to, enzymes. It is important for prescribers to understand the concepts of drug-receptor and drug-enzyme interactions because these largely determine the quantitative relationships between dose and concentration of drug and its pharmacological effect, and are responsible for selectivity of drug action.
Definitions of some important terms ●
●
●
●
Receptors are defined as those parts of a cell with which a drug or biological mediator interacts in order to produce its effect. They have evolved to mediate the actions of hormones and neurotransmitters but serve also as targets for drug action Enzymes, or enzyme systems, are biological catalysts that promote biochemical reactions in the body without being altered by them Agonist is a technical word used to describe a drug that interacts with a receptor to activate (or stimulate) it and thus produce a direct effect An antagonist is a drug that interacts with a receptor or adjacent site to interfere with the
Nurse Education Today (2001) 21, 272–277 273
Understanding medicines (Part II)
●
activation of the receptor by a biological mediator or other drug. It produces its effect indirectly by reducing (inhibiting) or preventing an ongoing process Enzyme inhibitors also work indirectly because they increase or decrease the concentration of biological mediator available for action.
Most drugs that are used as medicines interact reversibly with receptors or enzymes, so that the degree of their action parallels the concentration of the drug in the circulation. For those drugs that have irreversible interactions with receptors or enzymes, their duration of action depends upon the rate of synthesis of new receptor or enzyme proteins; this varies from tissue to tissue. Similarly, the effects of those drugs that act genomically (affecting genes in the cell nucleus) to stimulate the formation of new tissues or enzymes outlast the duration of the drug in the circulation.
Duration of action of medicines and pharmacokinetics The duration of action of a drug determines the range of possible frequencies of its administration. This and the possibilities for different formulations giving different durations of action depend largely on the pharmacokinetics of the drug components of medicines. While there is little need for detailed knowledge of the processes of drug distribution, metabolism and excretion for each medicine, a general understanding of the principles of these aids good understanding of safe frequencies of administration. It also provides a rationale for the need for caution in particular patient groups (paediatric, elderly, those with renal or hepatic impairment). These factors are considered briefly in turn.
Routes of administration Prescribers need extensive knowledge and understanding of the factors governing and restricting the availability of routes for administration of drugs. Major factors are the physico-chemical properties of drugs in relation to the physico-chemical properties of cell membranes and other barriers to drug
274
Nurse Education Today (2001) 21, 272–277
movements. Understanding of drug passage across membranes requires assimilation of the following concepts: ● ● ● ● ●
Diffusion Osmosis Lipid solubility Aqueous solubility Functional groups on covalently-bonded compounds, and the impact on functional interactions between these parameters of variations in pH. A thorough understanding of blood flow through various tissues and the possible influences upon this of ageing and diseases is also crucial for prescribing effective therapy. Other considerations include ability to assess the desirable and undesirable or risky features of various routes of administration available for patients who cannot take medicines orally.
Bioavailability This is a term used to refer to the quantity of drug that is available for action in the body, and is commonly calculated as a percentage of the dose given. Bioavailability may be restricted by presystemic metabolism (by enzymes in the gut or liver after oral administration, before the drug reaches the circulation) or systemic metabolism (by enzymes in the blood and other tissues). Plasma protein binding reduces bioavailability because they are not free to diffuse out of the blood stream to target tissues while they are attached to plasma proteins. Their duration of action is, however, increased by this means because the drugs are equally unavailable for hepatic metabolism or renal excretion. Rapid excretion can reduce bioavailability of slowly absorbed drugs as well as shortening their duration of action. For some drugs there is considerable interpatient variation in these factors that affect bioavailability, either genetically determined or influenced by disease, and these can be sufficiently great to necessitate careful titration of doses by the prescriber to achieve optimal therapeutic effect. The underlying reasons must be understood.
Drug metabolism and excretion The concentration of drug in the circulation represents not only the concentration available to
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
act but also the concentration available for metabolism and excretion. Because of the potential impact of organ-specific disease, the prescriber needs to be aware of the major sites of elimination of each drug. The kidneys and urinary excretion are quantitatively the most important for most drugs. Excretion via the liver into bile and then faeces (or enterohepatic circulation) or exhalation are other possibilities for systemic drugs, and there are diverse other means of eliminating locally administered medicines. The prescriber also needs to know which drugs require hepatic metabolism to render them sufficiently water soluble to be excreted in urine. There also needs to be some awareness of the two main processes of hepatic metabolism, commonly referred to as phases one and two, because these are implicated differentially in genetically determined variations in drug susceptibility and in causation of adverse drug–drug interactions. Understanding of principles and prime examples of enzyme induction, enzyme inhibition, hepatic activation of prodrugs (medicines that are administered as inactive chemicals but modified by the liver to produce pharmacologically active agents) and production of active metabolites is also needed for safe prescribing.
Interactions Numerous possible drug–drug interactions are listed in an appendix to the BNF and many of these are not usually of clinical significance. Nurse prescribers will need good ability to recognize any that are relatively common within their area of practice. They will also need to be able to access reference sources for occasions when patients on multiple drug therapy develop unexpected signs or symptoms that might have their basis in an adverse drug interaction.
Drug discovery, development and evaluation ‘They do test new drugs don’t they?’ In a chapter under this quizzical title Freeman (1991, p.13) asserted that many people who prescribe or administer medicines have little understanding of the preclinical and clinical stages of the production of a new medicine. In fact, the introduction of a new medicine is underpinned
© 2001 Harcourt Publishers Ltd
by more rigorous regulation than is applied to any other therapy. It is important that health-care professionals should recognise that such rigorous appraisal is not applied to food additives, diverse complementary therapies, surgical techniques or, indeed, other orthodox therapies. It is important that nurses should understand the principles of drug discovery, development and clinical evaluation so that they can have justified confidence in their effectiveness and safety and can appreciate why animal studies are an essential part of this process. This contentious issue was debated quite recently (Blake & Collins 1999). Blake, who has Friedrich’s ataxia, an incurable genetic disease that affects the central nervous system, argued cogently for the need for medical research that includes carefully regulated and monitored experiments on animals. Collins, provided a contrasting, emotive argument that not all adverse effects of drugs are detected by animal experiments and, therefore, their use is unjustified. Such debates will undoubtedly continue. Currently, pharmacological studies on animals almost invariably precede trials in humans. It is these clinical trials of medicines that prescribers need a sound understanding of if they are to be able to evaluate claims of effectiveness and safety based on publications in journals or appearing in promotional literature. Specific information on the principles of clinical trials is provided in many textbooks of clinical pharmacology, such as that of Laurence et al. (1997), and authors such as Sackett et al. (1997) have produced more general guidance on interpretation of research findings to underpin evidence-based practice.
Challenges in education for nurses, and some suggestions Personal experience attests that the greatest difficulty most nurses or student nurses have in understanding pharmacology lies in its basis in chemistry. Unlike students of medicine, nursing students are not required to have passed A-level or even GCSE chemistry, and there are cogently argued reasons why this subject is not prioritized. Traditional nursing courses seem to have focused on what might best be described as functional anatomy. They provide descriptive accounts of what the various body systems do without exploring how they function at a level of detail
Nurse Education Today (2001) 21, 272–277 275
Understanding medicines (Part II)
that requires an understanding of chemistry and biochemistry. If pharmacology-based practice is going to be reflective rather than ritualistic the actions of medicines will need to be understood in relation to physiology and pathophysiology, and this necessarily involves some engagement with certain basic elements of chemistry and biochemistry. Through the extensive experience mentioned in the first of these two papers I have found that the amount of chemistry needed is quite limited. Furthermore, the process of this engagement can be eased through the use of domestic analogies to illustrate pharmacological principles; selected examples of these are outlined below. The mechanism of action of many drugs involves interaction with receptors or active sites of enzymes; either by mimicking the action of a physiological mediator (agonist) or by blocking it (antagonist). A qualitative analogy is provided by reference to locks and keys. Two similar but not identical keys can be inserted into the same lock, but only one will activate the mechanism (agonist), while the other (antagonist) fails to activate the mechanism and prevents access of the correct key to the activating mechanism. A simple quantitative model that can be used in class consists of a cardboard box with indentations in the base to represent receptor sites (20 seems to work well), and marbles to represent physiological mediators or drug molecules. Agonist dose-response curves can be produced by gradually introducing standardsized marbles and gently shaking the box, then counting how many receptor sites are occupied. Large marbles can then be used to represent antagonist drug molecules and agonist doseresponse curves redetermined in the presence of various doses of antagonist to demonstrate rightward shifts of the agonist dose-response curve. Within an hour of ‘playing’ with marbles in small groups and repeatedly relating observations to the real situation with a circulating tutor, most students overcome apprehensions over interpretation of the curves displayed in textbooks, and feel at ease with the basis of the sigmoid curve relationship between response and the logarithm of the dose in simple systems. The selectivity or specificity of drugs for particular receptors is related to the properties of ‘functional groups’ on covalently bonded
276
Nurse Education Today (2001) 21, 272–277
molecular cores. Two analogies have been found useful to illustrate this concept. One is a tree with a relatively stable and unchanging trunk, representing the main part of the drug molecule, with twigs and leaves as the ‘functional groups’ that interact with environmental influences such as sunlight, birds and insects. A second analogy is a building as the molecular core with its inhabitants as ‘functional groups’ coming and going in dynamic equilibrium, intermittently meeting and interacting with others. The lottery machine with many balls in motion and occasional ones locating in the selection compartment is a useful image of molecules in motion close to receptor or enzyme sites and occasionally interacting with them. At the submolecular level, the apparent solidity of space occupied by rapidly orbiting electrons can be modelled by a rotating door. The fixed centre of the door represents the atomic nucleus, and the rotating arms represent the electrons. When the door is rotating rapidly it is impossible to enter any of the space within the radius of the arms; the space seems to be filled entirely. The space-filling ability of electrons surrounding atomic nuclei is very similar but their rotation is in three dimensions, filling a sphere. A dinner table set for eight, but with six, seven, nine or ten guests arriving can be used to illustrate some of the features of ionisation processes for those many atoms that have an outer shell that is completely occupied by eight electrons. By way of introduction to pharmacokinetics, the diffusion of colour from a tea bag and the osmotic passage of water into the bag to swell it, and influence of sugar upon these processes provide familiar starting points. Similarly, oil and vinegar salad dressings and the need for emulsifying agents to stabilise their mixing, or the use of detergents to clean greasy dishes lend familiarity to the basic principles of oil–water partitioning effects. These need to be understood when considering the passage of drugs across membranes and the implications of the lipid solubility of drugs for their absorption from the gut, diffusion from sites of injection (other than intravenous), penetration into the central nervous system and elimination in the urine. The use of these and similar analogies has formed an essential part of meeting my students where they are in order to lead them on (educate in the prime meaning of the word) to greater
© 2001 Harcourt Publishers Ltd
Understanding medicines (Part II)
understanding. Once initial barriers are deconstructed by cutting through the scientific jargon and discussing basic principles in accessible language the potential of most nurses to develop good understanding of pharmacology seems to become virtually unlimited. I hope that this paper will stimulate discussion of and research into effective ways and means of making pharmacology a readily accessible subject for future generations of nurses, without the need for an A-level qualification in chemistry, so that they can be involved as fully as possible in that part of caring for patients that involves medicines. Acknowledgements
I am pleased to thank Dr Shane Bullock, Dr Michael Cook and Dr Michael Walsh for their invaluable comments on typescripts of this paper. References Blake A, Collins B 1999 Animal testing: for and against. Nursing Times 95 (8): 32–33
© 2001 Harcourt Publishers Ltd
Crown J 1998 Review of Prescribing, Supply and Administration of Medicines: A report on the supply and administration of medicines under group protocols. Department of Health, London Crown J 1999 Review of Prescribing, Supply & Administration of Medicines. Final Report. Department of Health, London Freeman J 1991 They test new drugs don’t they. In: Glaxo Group Research (eds) Drug Safety – A Shared Responsibility. Churchill Livingstone, Edinburgh, p 13–26 Laurence D R, Bennett P N, Brown MJ 1997 Clinical Pharmacology. Churchill Livingstone, Edinburgh Mehta D K 1998 (Executive Editor) British National Formulary (BNF) Volume 36 British Medical Association and the Royal Pharmaceutial Society of Great Britain Morrison-Griffiths S, Pirmohamed M, Walley T 1998 Reporting of adverse drug reactions: practice in the UK. Nursing Times 94(10): 52–54 Sackett D L, Richardson W S, Rosenberg W, Haynes R B 1997 Evidence-based Medicine. Churchill Livingstone, Edinburgh
Nurse Education Today (2001) 21, 272–277 277