Pharmacology, polypharmacy and the older adult: a review

Prescribing a medicine is the most common clinical intervention in the NHS (National Institute for Health and Care Excellence (NICE), 2015). The trend in prescribing continues to grow year on year and the number of prescription items dispensed increased from 2006 to 2016 by 47% (NHS Digital, 2016). Prescribing in older people is very common, and it is estimated that, in England, more than 1 in 10 people aged over 65 years take at least eight different prescribed medications each week. This increases to nearly one-in-four among those aged over 85 years (Age UK, 2019).

Ageing

Ageing brings about a number of changes in the body, and the ageing process begins to affect the way the body handles medicines around the time a person reaches their forties.

A combination of pharmacokinetic, pharmacodynamic and homeostatic changes slowly develops and becomes clinically significant as the person gets older. There is considerable variation in the onset rate and extent of significance. Biological age is a more important indicator than chronological age when trying to identify an older person who is at risk of an adverse reaction to prescribed medications.

Frailty

Frailty is a multifactorial syndrome associated with functional impairment and increased susceptibility to morbidity and mortality. The clinical definition of frailty is ‘a state of vulnerability to poor resolution of homeostasis after a stressor event and is a consequence of cumulative decline in multiple physiological systems over a lifespan’ (Clegg et al, 2013:752). Adults with frailty lack the reserve to deal with an adverse event and are at a significantly increased risk of adverse drug reactions. For older people living with frailty, a small event, such as commencing a new drug, may result in a major change in health and function.

Multimorbidity and older people

Multimorbidity refers to the presence of two or more long-term conditions. It includes mental and physical health conditions, such as depression and diabetes. It also includes learning disabilities and symptomatic presentations, such as chronic pain and frailty. Sensory impairments including sight and hearing loss are recognised. Alcohol and substance misuse are also included as part of multimorbidity. Evidence-based prescribing practice has traditionally considered best practice for single diseases. However, for older people living with a number of health conditions, this leads to increasing complexity of treatment approaches, often requiring more challenging drug regimens, which increases the risk of the older person experiencing adverse drug reactions. The increasing recognition of these risks has led to the development of NICE guidance (2016), which focuses on the clinical management of multimorbidity and polypharmacy.

Pharmacokinetic changes

Pharmacokinetics relates to what the body does to the drug, including absorption, distribution, metabolism and excretion. With ageing, there are changes in all these areas, and some changes are clinically significant and should be routinely considered when reviewing patients and their medicines.

Drug absorption

In normal ageing, the absorption rate is slowed down, and there are a number of gastrointestinal changes. Most changes in absorption are thought to be not clinically significant. However, some changes that affect absorption have been noted. Older people may have an increased gastric pH, sometimes related to medicines such as proton pump inhibitors, and a decrease in gastric emptying that may affect absorption. The changes to active transport results in reduced absorption of vitamin B12, iron and calcium. The changes in the gastric mucosa lead to reduced dopa decarboxylase, which increases the absorption of leva dopa (Mangoni and Jackson, 2004).

First-pass metabolism and bioavailability

Following oral administration, drugs enter the hepatic portal vein to the liver. Several age-related changes are known to influence liver function, including a reduction in the total liver size and a reduction of blood flow to the liver. Ageing is associated with a reduction in the first-pass metabolism, thought to be due to a reduction in liver mass and blood flow. (Mangoni and Jackson, 2004). Many drugs are metabolised by the liver and, for these drugs, a reduction in liver function affects removal. Ageing affects the efficiency of some of the liver's metabolic and synthetic functions, and overall metabolism tends to be only slightly impaired in the absence of liver disease. For example, the cytochrome P 450 pathway is downregulated, meaning that drugs metabolised by this path may need dose adjustments; however, the conjugation pathway is not affected. This results in increased bioavailability of drugs undergoing extensive first-pass metabolism and the reduced activation of pro-drugs that are activated in the liver. Adding new medicines increases the likelihood of introducing an inducer or inhibitor of cytochrome P 450, thereby increasing the chance of a drug-drug interaction. This is especially important to consider when stopping, starting or adjusting an enzyme-affecting drug-especially in older patients already taking several medications. Routine liver function tests are a poor guide to measuring the capacity of the liver to metabolise drugs, as these tests indicate liver damage, not metabolic effectiveness. The clinical significance of age-related changes in the liver are difficult to predict and can vary greatly between individuals. It is important to note that some older people may have acquired liver disease as a result of an adverse drug reaction, cancer, viral infection or alcohol abuse. These people may require significant dose reductions when commencing hepatotoxic drugs. The ability of the liver to withstand stress decreases with age, and the healing time after damage is slower. Hepatotoxic drugs may cause more severe injury in older people; for example, paracetamol in people with alcoholism or underling liver disease can cause toxicity in doses as low as 4–8 g per day. Other drugs that require caution include amiodarone, statins, phenothiazines, ciprofloxacin, erythromycin, fluconazole, isoniazid, valproate and methyldopa.

Drug distribution

After absorption, the drug travels to its site of action via the bloodstream. The drug passes through cell linings of the organs into interstitial fluid. Its uptake depends on blood flow and tissue mass. Normal physiological ageing causes changes in the body, and this can have a significant effect on the distribution of the drug. With age, body fat generally increases and total body water decreases. Increased fat increases the volume of distribution for highly lipophilic drugs and may increase their elimination half-lives. The relative reduction in total body water will lead to a reduced volume of distribution and increased serum concentration of water-soluble drugs (e.g. gentamicin and digoxin). The relative increase in body fat leads to an increased volume of distribution and longer half-life of lipid-soluble drugs (e.g. diazepam). Drug distribution is largely dependent on body composition, and there may be a need to reduce the dosage or dosing interval (Alder et al, 2016).

Drug excretion

Excretion is the most significant age-related pharmacokinetic change and is both predictable and measurable. After 30 years of age, the renal blood flow declines progressively at a rate of 10% per decade. Two-thirds of people aged between 70 and 80 years will have about half the renal function of a young adult. The total size of the kidneys decreases with age, as does the number of functioning nephrons (Joint Formulary Committee, 2021). Ageing is accompanied by a reduction in both glomerular and tubular function.

Renal function may also be affected by the presence of comorbidities. Decreased renal function results in a reduction in drug clearance, and older patients may, therefore, require lower or less frequent doses (Navaratnarajah and Jackson, 2016). Creatinine is a waste product from muscles due to wear and tear. Older people have less muscle mass and lower levels of physical activity, which leads to less creatinine production. As a result, creatinine levels often remain within normal limits, despite a decrease in glomerular filtration rate (GFR). Maintenance of normal serum creatinine levels can mislead clinicians, who assume that normal levels of creatinine clearance (CrCl) reflect normal kidney function (Luscin and Linnebur, 2018). The GFR is the key indicator of renal function and estimated glomerular filtration rate (eGFR) is mathematically derived using serum creatinine level, sex, age and race. eGFR is usually calculated during blood tests, although it is only an estimate.

An understanding of drug pharmacokinetics is necessary in order to make appropriate dosing decisions in patients with renal disease. The Joint Formulary Committee (2021) suggested that the Cockcroft and Gault formula is the preferred method for estimating renal function or calculating drug doses in patients with renal impairment who are older or at extremes of muscle mass; it provides an estimate of CrCl, which is not equivalent to eGFR.

Pharmacodynamics

Pharmacodynamics is defined as what the drug does to the body or the response of the body to the drug. In older people, the effects of similar concentrations of a drug at the site of action may be greater or smaller than those in younger people, and this is often due to pathological changes in organs.

Older adults are particularly sensitive to anticholinergic drug effects. Many drugs that are commonly prescribed to older people have anticholinergic effects. Older adults, most notably those with cognitive impairment, are particularly prone to central nervous system adverse effects, and the older person may become more confused and drowsier. Anticholinergic drugs also commonly cause a number of unwanted side effects. Even at low doses, these drugs can increase the risk of heatstroke by inhibiting diaphoresis. In general, older adults should avoid drugs with anticholinergic effects when possible. A list of commonly used anticholinergic medicines and side effects is provided in Table 1.

Helpful resources

The British National Formulary (BNF) (https://bnf.nice.org.uk/) is free to access for all clinicians online. It cautions that, if it is necessary to prescribe drugs whose effect is altered by hepatic or renal disease, appropriate drug dose adjustments should be made, and patients should be monitored adequately. The general principles for prescribing are outlined under Prescribing in Hepatic Impairment and Prescribing in Renal Impairment. Information about drugs that should be avoided or used with caution in hepatic disease or renal impairment can be found in drug monographs under Hepatic impairment and Renal impairment. Further information on dosage regimes for specific drugs can be found in the summary of product characteristics (SPC), which can be found in the electronic medicines compendium (https://www.medicines.org.uk/emc#gref).

Adverse drug reactions and high-risk drugs

An important study by Pirmohamed et al (2004) estimated a prevalence of 6.5% of hospital admissions judged as being due to an adverse drug reaction (ADR). The study determined the avoidability of admissions related to an ADR. Only 28% of the ADRs were assessed as unavoidable, while 9% were classified as definitely avoidable. Box 1 presents a list of the most high-risk drugs associated with ADRs associated with hospital admissions.

Polypharmacy

The term ‘polypharmacy’ simply translates to ‘many medicines’. There are a range of definitions relating to this term (Masnoon et al, 2017). A numerical score to define polypharmacy and identifying patients who are at risk of polypharmacy may be less then helpful: up until fairly recently, patients taking four or more medications were considered to be at risk of polypharmacy (NICE, 2016). More recently, polypharmacy has been subdivided into two domains; appropriate and inappropriate polypharmacy. Appropriate polypharmacy is prescribing for a person for complex conditions or for multiple conditions in circumstances where medicines use has been optimised and where the medicines are prescribed according to best evidence. Inappropriate or problematic polypharmacy is viewed as the prescribing of multiple medicines inappropriately, or where the intended benefit of the medicine is unrealised (NICE, 2016).

Box 1.List of the most high-risk drugs associated with hospitalisation for adverse drug reactions

• Non-steroidal anti-inflammatory drugs (NSAIDs) (29.6%)
• Diuretics (27.3%) Warfarin (10.5%)
• Angiotensin-converting enzyme (ACE) inhibitors (7.7%)
• Antidepressants (7.1%)
• Beta-blockers (6.8%)
• Opiates (6.0%) Digoxin (2.9%)
• Prednisolone (2.5%)
• Clopidogrel (2.4%)

Pirmohamed et al, 2004

NICE guidelines (2016) suggests that anyone taking 15 or more medicines should be treated as at risk of polypharmacy and medication-related harm. NICE also advised that any adult taking 10–14 regular medicines should be assessed for risks associated with polypharmacy. Patients taking fewer than 10 regular medicines should also be assessed for risk factors, including age, multiple comorbidities and frailty, and they should be identified as being at risk of polypharmacy. A number of variables may lead to ADRs. Patients with three or more long-term conditions will take between 6 and 13 regular medicines, and the number of medicines prescribed generally increases with every new diagnosis. In a recent study (Dumbreck et al, 2015) reviewing the NICE guideline recommendations for prescribing in 12 individual long-term conditions, the authors found 133 drug-drug interactions for type 2 diabetes mellitus guidelines and the other single-disease prescribing guidelines. There were 32 potentially serious drug-disease interactions between drugs recommended for type 2 diabetes mellitus and the medicines regimen recommended for the other 11 long-term conditions.

Generally, patients at the highest risk of inappropriate polypharmacy are those living with severe frailty, taking the most medicines and taking high-risk medicines.

There are a number of tools to support patients and clinicians to optimise medicines use and address problematic polypharmacy. An important first step is to appropriately identify older people with multimorbidity and taking multiple medicines in practice.

Appropriate polypharmacy requires consideration of the patient and the medication regime at every point of contact with the older person. All prescribing or deprescribing decisions should ideally be structured around a shared decision-making model that requires collaboration between the patient and clinician to support the patient to reach a decision about treatment (NHS England, 2019).

Regular medicines reviews are a key requirement for ensuring that medicines remain appropriate and acceptable for the patient. The community nurse has a pivotal role to play in making certain that medicines reviews are scheduled and in identifying when, who and how the medicines review will be conducted. It is important that community nurses also enquire about and establish how dispensing and administration of medicines will take place. This role often requires in-depth enquiry and planning by the community nursing team and is a key step in supporting adherence to medicine regimens. The community nurse is also the lynchpin for ongoing monitoring and identifying medicines-related harm in older patients who are housebound and often frail. Communication and patient engagement are central to ensuring that medications are taken as prescribed. The community nurse is ideally situated to discuss any concerns with the older person and carers and to explore wishes and preferences regarding medicines usage; this can be used to identify adherence issues and to enquire about unwanted side effects of regular medicines.

There are a number of tools to support medicines optimisation in clinical practice, and it is important that the community nurse is familiar with what tools are routinely used locally and who can offer support in the review of medicines for patients who are considered at risk. The STOPP START Toolkit supports medications review and helps identification of potentially inappropriate prescriptions in older people. START stands for Screening Tool to Alert doctors to Right (i.e. appropriate) indicated Treatments (Gallagher et al, 2008). The tool identifies unnecessary polypharmacy and highlights potential unwanted interactions. It is also useful in reviewing the under-utilisation of appropriate medicines that should be started. Other tools include STOPPFrail, which is a screening tool of older persons' prescriptions in frail adults with limited life expectancy (Lavan et al, 2017) and is presented as a list of potentially inappropriate prescribing indicators designed to support practitioners with stopping medicines in older patients who have end-stage irreversible pathology, a poor one-year prognosis, severe functional impairment or severe cognitive impairment or both. Symptom control is the priority rather than prevention of disease progression. The Royal Pharmaceutical Society hosts a medicines optimisation hub with a range of good practice guidelines and resources to support practice.

Conclusion

Regular medicines play a vital role in healthcare for older people. The pharmacology of ageing results in many physiological changes that can result in drugs having an enhanced or unpredictable effect in older people. Many authors caution of the importance of adopting a ‘start low and go slow’ approach and recommend that initiating new medicines must be carefully balanced by the risks and benefits for the patient. This cautious approach is particularly important for patients living with multimorbidities or frailty or polypharmacy. A number of drugs are well known to lead to adverse drug reactions, and some drugs are particularly problematic and considered high risk for older people.

The community nurse can help to identify and flag patients at risk of inappropriate or problematic polypharmacy using locally or nationally agreed criteria and ensure that the multidisciplinary team is aware of any medicines-related concerns that the patient, their supporters or the nurse may have about medicines use in practice. The community nurse is urged to develop a pathway for their older patients at risk of inappropriate or problematic polypharmacy in order that the patient receive regular reviews by a clinical pharmacist who has the necessary skills and expertise to review medications and make recommendations accordingly.

Key Points

• Medicines are the most widely used therapeutic intervention used in healthcare
• There are important biological and pharmacological differences in how an older person responds to medicines
• Clinical guidelines and prescribing guidelines for individual long-term conditions may not be appropriate for an older person living with multimorbidity and frailty
• Medicines optimisation is an important area of clinical practice for district nurses
• National Institute for Health and Care Excellence guidelines on multimorbidity discuss how to reduce polypharmacy and there are a number of useful tools available in supporting medicines optimisation with older people
• Community nurses are encouraged to work closely with the multidisciplinary team and the older person in order to discuss appropriate polypharmacy and inappropriate polypharmacy as part of routine care

CPD REFLECTIVE QUESTIONS

• How do you identify and care for patients living with multimorbidity?
• What criteria can you use in your nursing assessment to identify older people who may be at risk of problematic or inappropriate polypharmacy?
• Do you know where to signpost older patients taking multiple medicines to support them with medicines optimisation and review?
• How do you keep updated and do you know where to access relevant and up to date local and national guidance to support medicines optimisation?