VOL: 98, ISSUE: 15, PAGE NO: 43
MARTIN SHEPHERD, MSc, BPharm, MRPharmS, Head of Pharmacy and Therapy Services, Chesterfield and North Derbyshire Royal Hospital NHS Trust
Sponsored by PfizerOver the past 50 years the evolution of modern pharmacotherapy has, arguably, contributed more than any other health-care intervention to reducing the burden of ill health throughout the developed and developing worlds. However, the achievement has had major implications both for health-care organisations and patients: organisations have seen their drugs bills increase enormously (Fig 1), while there has been a proportionate rise in patients' expectations as to what the new medicines can do to improve their health (Audit Commission, 2001).
Over the past 50 years the evolution of modern pharmacotherapy has, arguably, contributed more than any other health-care intervention to reducing the burden of ill health throughout the developed and developing worlds. However, the achievement has had major implications both for health-care organisations and patients: organisations have seen their drugs bills increase enormously (Fig 1), while there has been a proportionate rise in patients' expectations as to what the new medicines can do to improve their health (Audit Commission, 2001).
The previous decade saw the development of extensive new treatments for conditions such as Parkinson's disease, glaucoma, rheumatoid arthritis and hypertension. However, in recent years, there has been growing concern as to the robustness of the evidence base on which drug treatment is constructed, and the pharmaceutical industry is increasingly being called to account for the promotional activities associated with new and costly treatments (Mason and Freemantle, 1998).
The National Institute for Clinical Excellence (NICE) now lays down the criteria for establishing the value of significant new treatments and for guiding health service providers on the priority that such developments should be afforded. However, just as every year innumerable new drugs are launched, the number of those that are withdrawn from the market for safety reasons has increased markedly, and the volume of medicines-related litigation similarly has grown alarmingly (Department of Health, 2000).
The prescription and administration of a medicine is perhaps the most frequent health-care intervention that takes place in the NHS. Yet such is the pace of development of modern medicines that there is an increasing number of pitfalls for the unwary.
The clinical and legislative principles that underpin the safe and effective use of medicines in hospitals, in nursing homes and in the community are complex and confusing and, in parts, fail to reflect the needs of modern clinical practice. The aim of this series of three articles is to offer guidance to nurses on how best to navigate the medicines minefield.
The effects of drugs on the body (pharmacodynamics) and the effects on the body of a drug over time (pharmacokinetics) are considered in the science of pharmacology. The availability of new medicines is often based on developments in the field of pharmacology following changes in our understanding of biochemical pathways. New drugs are frequently developed in direct response to developments in our understanding of the disease process and the place of enzymes, hormones, neurotransmitters, and immuno-active substances within it.
For example, new medicines have followed the discovery of the role of serotonin in depressive illness, dopamine in schizophrenia and tissue necrosis factor in inflammatory diseases of the bowel and joints (Box 1).
While an in-depth appreciation of clinical pharmacology is not essential to ensure safe drug use, it is important that practitioners possess a basic understanding of how a drug might be expected to exert its action once it has been administered. Moreover, such an understanding offers insight into how the effects of drugs might be experienced by the patient, and also the extent to which undesirable effects may be produced (Box 2).
Think Point: Think about a drug that you regularly administer in your clinical practice. Find out about its indications for use, mode of action and side-effects.
How drugs produce their effects
The vast majority of drugs produce their effects by reacting with specific protein molecules, called receptors, in the cell membrane. The drug-receptor interaction leads to a molecular change in the receptor, which then leads to a response. Such receptors are normally responsive to chemical stimuli produced by the body: for example neurotransmitters (acetylcholine, noradrenaline, or dopamine) or hormones (insulin, thyroxine or testosterone).
Drugs may mimic the body's natural stimuli and thereby act as agonists or they may inhibit them, acting as blockers to 'normal' physiological responses. For example, opioid agonists such as fentanyl and diamorphine mimic the body's own opioid neurotransmitters (for example, endorphins) by activating opioid receptors, thereby producing an analgesic effect. Conversely, the alpha-blockers prazosin and doxazosin block the action of alpha-adrenergic receptors in small blood vessels, thereby leading to vasodilation.
The extent to which a drug reacts selectively with different receptors defines how specific its actions are, and this in turn may determine how extensively its actions, both desirable and undesirable, are felt throughout the body. For example, there are two types of beta adrenoreceptors in the sympathetic nervous system: beta one and beta two. The beta one receptors are found in the tissues of the heart and, when stimulated, produce an increase in cardiac contractility and tachycardia. The beta two receptors are found in the smooth muscle of the bronchi and the blood vessels of the skeletal muscles.
When stimulated by adrenaline, these receptors cause smooth muscle relaxation. The beta-blocker propranolol is not selective for the adrenergic receptors in the heart, so it exerts its action on other physiological systems, those that are under adrenergic control. For example, the bronchioles may be constricted. Conversely, the selective beta-blocker atenolol has a much greater degree of selectivity and is therefore much less likely to cause bronchospasm.
The reaction of a drug with its receptor site is not a guarantee that an immediate therapeutic response will be generated. The speed of onset of a drug depends on what other pharmacological and physiological stages have to be translated before a therapeutic effect can be realised, and this varies greatly between drugs.
The administration of salbutamol into the lungs via metred-dose inhaler or nebuliser, for example, produces more or less immediate bronchodilation. Similarly, the use of sublingual glyceryl trinitrate produces rapid vasodilation, thereby reducing the symptoms of angina. Conversely, the symptomatic relief of depression may take up to three weeks when treated with an antidepressant such as fluoxetine or lofepramine.
Other mechanisms of drug action
Drugs that do not act directly on receptor sites may act principally through one of the following mechanisms:
- Enzyme inhibition: for example, angiotensin-converting enzyme (ACE) inhibitors such as ramipril and lisinopril are used in cardiovascular disease. These drugs work by blocking the conversion of angiotensin I to the powerful vasoconstrictor angiotensin II;
- Enzyme activation: for example, thrombolytic agents used after myocardial infarction. Fibrinolytic agents such as streptokinase and alteplase rapidly lyse thrombi by activating plasminogen to form the proteolytic enzyme plasmin. Plasmin then degrades the fibrin that forms the clot;
- Inhibition of cellular transport processes: for example, calcium channel blockers and proton pump inhibitors. Calcium channel blockers such as felodipine, amlodipine, nifedipine and diltiazem block the calcium channels in smooth muscle, thereby reducing or preventing muscle contraction and causing relaxation in the arteriolar smooth muscle. Proton pump inhibitors such as lansoprazole and rabeprazole inhibit the operation of the cellular pump that transports acid-forming hydrogen ions out of the gastric mucosa;
- Action by physico-chemical properties of the drug: for example, osmotic laxatives. Lactulose and magnesium sulphate increase the amount of water present in the bowel owing to an osmotic effect, thereby increasing the volume of the intestinal contents and stimulating peristalsis;
- Inhibition of biochemical processes: for example, infective agents that act by inhibiting biochemical processes that are unique to the target organism. The penicillins and cephalosporins, for example, inhibit the synthesis of the bacterial cell wall; aminoglycosides and tetracyclines inhibit bacterial protein synthesis; and quinolones such as ciprofloxacin inhibit the production of bacterial nucleic acid by inhibiting the enzyme responsible for producing the coils in DNA.
For a drug to achieve a therapeutic effect, it must not only reach its site of action but must also be present in sufficiently high concentration and for a sufficient length of time. If these criteria are not met, the effects of the drug will be sub-therapeutic.
The way a drug behaves in the body over time is described as its pharmacokinetic profile. This indicates the way it is absorbed, distributed around the body, metabolised and excreted once it has been administered.
These parameters, while not immediately of relevance to the nurse preparing to administer a medicine, will frequently influence many practical aspects of how the drug may be given. For example, how well the drug is absorbed via the gastrointestinal tract will determine whether it can be formulated as an oral medicine. For insulin-dependent diabetes patients, the fact that insulin cannot currently be formulated into an oral treatment means that, despite advances in the technology of insulin delivery such as disposable pen devices, treatment of the condition remains a cumbersome process for patients.
The planned launch of a formulation of inhaled insulin in the near future will, however, go some way to relieving this burden, particularly for patients who find injections difficult (Barnett, 2001).
The rate at which a drug is metabolised and excreted will determine how often it needs to be administered and, if it is being given intravenously, whether or not it can be given by a direct injection or as an infusion.
In older patients, age-related changes in a variety of physiological functions, most notably hepatic and renal functions, mean that the pharmacokinetic profile may be profoundly altered, and hence dose adjustments may be necessary to avoid toxicity. In general terms, older patients require smaller doses of all drugs compared with younger adults. Hence, it is rational to start with the lowest possible dose and then to titrate upwards according to response (Royal College of Physicians, 1997).
Narrow therapeutic index
For the small number of drugs with narrow margins between optimal and sub-optimal dosing, the so-called narrow therapeutic index (for example, phenytoin and gentamicin) means that detailed pharmacokinetic profiling forms an essential feature of their safe and effective use.
Although in less widespread use now for heart failure, digoxin remains a mainstay in the treatment of atrial fibrillation. While its clinical effect is principally measured by monitoring the heart rate, analysis of its pharmacokinetics via therapeutic drug monitoring frequently proves valuable in optimising its effect. This is particularly important in the presence of factors that may influence the pharmacokinetic profile. Digoxin levels are, for example, affected by hepatic and renal functions, and the presence of heart failure owing to reduced elimination of the drug. Hypothyroidism increases the plasma concentration of the drug and increases cardiac sensitivity to its effects. Hypokalaemia, hypercalcaemia, and hypomagnesaemia all have a similar effect.
Progress in drug development
While the majority of drugs in use today are administered by mouth, this route is probably the least reliable in terms of delivering the drug to the intended site of action in an appropriate concentration. A number of factors may act singly or in combination to reduce significantly the amount of drug absorbed via the gastrointestinal tract into the systemic circulation. These include:
- The effect of gastric motility: in patients in whom the rate of gastric emptying is increased, drug absorption will be reduced. The small intestine is the major site of absorption for drugs administered orally, hence gastric emptying is a significant determining factor of drug absorption;
- The existence of a malabsorption syndrome: in Crohn's or coeliac disease, for example, drug absorption may decrease or, in some instances, increase;
- The effect of gastric pH: some drugs are particularly sensitive to the acidic environment of the stomach and may be degraded before significant absorption occurs;
- Food: many drugs undergo a physico-chemical reaction in the presence of food, which reduces their absorption.
In many instances, the formulation of a drug offers a means by which shortcomings in the pharmacokinetic profile may be overcome. In the majority of such cases, formulation is used to increase the amount of drug likely to reach the intended site of action. For example, many of the drugs used in the treatment of asthma are suitable for administration by mouth, but if therapeutically active concentrations are to be reached in the lung, very large doses will need to be given. This will increase the risk of side-effects and could make treatment difficult for patients to tolerate.
By formulating drugs as aerosols, they can be administered directly into the lungs, thereby achieving high concentrations at the desired site of action, and reducing the risk of side-effects by avoiding the drugs' entry into the systemic circulation.
In recent years, pharmaceutical manufacturers have increasingly used the transdermal route as a means of delivering drugs into the systemic circulation. Many patients now receive their daily doses of analgesics, anti-anginals, hormone-replacement therapy and nicotine-replacement therapy through a stick-on patch that delivers a constant amount of drug over a 12- or 24-hour period.
Formulation may also be used to extend the duration of action of a drug by modifying the rate at which it is absorbed into the systemic circulation. Such modifications are usually used to reduce the number of doses that have to be given each day. For example, the development of modified-release formulations of morphine have made it possible to reduce the routine dose interval from every four hours or six times a day to once or twice a day. Such developments can have a significant influence on patients' attitude toward their drug therapy.
Practitioners should be cautious, however, in assuming that all such modifications to a drug's formulation will be beneficial. The development of modified-release formulations is a strategy frequently used by the pharmaceutical industry to lengthen the life of its products before they undergo patent expiry and the manufacturer loses its monopoly on the drug's manufacture. Many such developments lack sound evidence to support their use, and often attract criticism on the basis that they are frequently more expensive than equivalent non-modified-release formulations (Medicines Resource Centre, 1995).
Other examples of the use of formulation to alter pharmacokinetic profiling includes the use of enteric coating to avoid degradation by gastric acid, and the use of 'pro-drugs' which use the body's metabolic processes to convert agents into an active compound. For example, mesalazine, an aminosalicylate, is used extensively in the management of ulcerative colitis. It is, however, unstable in an acid environment.
Some preparations have been formulated with a pH-sensitive coating which protects the drug until it reaches a part of the bowel at the desired pH. A coat that dissolves at pH7 releases mesalazine in the terminal ileum and colon. A coat that dissolves at pH6 and above, releases it in the jejunum and ileum. Other formulations such as olsalazine and balsalazide rely on the bacterial breakdown of an inactive molecule to form mesalazine in the lower bowel.
More recently, the pharmaceutical industry has begun to make increasing use of specific optical isomers of a drug to attempt to reduce side-effects and increase efficacy. Examples include esomeprazole (isomer of the proton pump inhibitor omeprazole), desloratadine (isomer of the anti-histamine loratadine) and levobupivacaine (isomer of the local anaesthetic bupivacaine) (Dean, 2000).
Think Point: What determines the route by which a drug is given? Can this be changed according to clinical circumstance?
Medicines and risk management
While the development of modern pharmacotherapy has brought enormous changes to the way ill health is managed, the use of medicines to bring about health gain is not without risk. Indeed, the decision to use medicines to treat or prevent ill health is very much a matter of balancing risk and benefit. Such decisions need to take account of the efficacy of the drug, the likelihood of adverse reactions developing as a consequence of its use and their potential seriousness. A recent Audit Commission report (2001) suggests that such adverse events cost about £500m a year in additional days spent by patients in hospital (see Part 3: Managing medicines, which will published on April 23).
Adverse drug reactions
An adverse reaction to a drug is any response that is unintended and of no benefit to the patient. It may be related to the normal pharmacological action of the drug, so-called type A or augmented reactions. These reactions are related to the dose and can usually be predicted from the drug's pharmacological profile. Such reactions include the anticholinergic effects of antidepressants such as amitriptyline that cause a dry mouth and urinary retention, and the drowsiness caused by drugs such as diazepam.
Reactions that are unrelated to the drug's conventional pharmacology are described as type B or bizarre reactions. These are usually unrelated to the dose administered and are unpredictable. Such reactions include anaphylaxis to penicillins.
The morbidity associated with adverse reactions to drugs is undoubtedly significant. Adverse reactions are thought to occur in as many as 20% of hospital inpatients and are thought to be responsible for up to 4% of hospital admissions (Mannesse et al., 1997). There are some groups of patients in whom the risk of an adverse drug reaction is known to be higher, for example, in pregnant women or in breastfeeding mothers.
The problem of adverse drug reactions is particularly pertinent to older patients, in whom age-related physiological changes (for example, reductions in liver and renal functions) combine with the existence of multiple pathologies to increase significantly the risk of adverse reactions. Such risk is compounded in older patients by the use of many drugs known to be associated with a high incidence of adverse reactions, such as those acting on the cardiovascular and central nervous systems. Clearly, such considerations require diligence on the part of practitioners when reviewing the overall benefits of initiating drug treatment.
Think Point: If you thought that a patient had experienced an adverse drug reaction, what would you do?
For older patients, the risks of drug treatment are not solely related to the possibility of an adverse reaction. In the UK, those over 65 years old are the highest consumers of prescribed drugs (43%) (Royal College of Physicians, 1997). This age group is also particularly at risk of problems associated with drug interactions. A drug interaction is said to occur when the effects of one drug are altered by the effects of another. Such interaction often results in an adverse drug reaction.
The mechanisms by which interactions occur are complex but may be categorised into three basic types:
- Those relating to a physico-chemical reaction between two drugs: for example, mixing the antibiotic gentamicin with heparin in the same syringe or intravenous line leads to formation of a precipitate;
- Those relating to alterations of a drug's pharmacokinetic profile: for example, carbamazepine increases the metabolism of oestrogens contained in the oral contraceptive, so reducing its effectiveness;
- Interactions altering the effect of a drug at its site of action: for example, the administration of naloxone to a patient who has received morphine will result in the effects of the morphine being reversed, as naloxone displaces it from its receptor.
- Part 2 will look in more detail at the administration of medicines