21st March 2024

Patient Safety and Medicines Management

Elderly

Elderly patients are often subject to polypharmacy due to multiple co-morbidities. They are also more susceptible to side effects and adverse drug reactions in part because of their ageing physiology. Regular review and rationalisation of medication is therefore important for patient safety. The British National Formulary (BNF) guidelines recommend the use of STOPP (Screening Tool of Older Persons’ Prescriptions) and START (Screening Tool to Alert to Right Treatment) criteria. This was devised by experts to aid doctors prescribing for the elderly with the view to improve medication appropriateness and reduction of adverse effects. The pertinent points are summarised below.

Cardiovascular system

Several agents have been implicated in the STOPP/START criteria relating to the cardiovascular system. For the treatment of oedema with limited evidence of organ dysfunction, one should consider non-pharmacological treatments such as compression bandages and leg elevation. Loop diuretics should not be used for dependent oedema or as a first-line agent for hypertension.

ACE inhibitors (ACEi) are encouraged for systolic heart failure or coronary heart disease but should be stopped in those with hyperkalaemia. If co-prescribed with potassium sparring agents such as spironolactone, eplerenone and amiloride one must monitor potassium regularly. Beta-blockers and calcium channel blockers (CCBs) are encouraged for stable angina, although both dihydropyridines and non-dihydropyridine CCBs may exacerbate heart failure. Non-selective beta antagonists are best avoided in patients with bradycardia and obstructive airway disease. Thiazide diuretics act on the sodium/chloride co-transporter and have a propensity to cause electrolyte disturbances particularly hyponatraemia, hypokalaemia, hypercalcaemia and can exacerbate gout. Alpha blockers such as doxazosin and prazosin should be stopped in those with orthostatic hypotension or micturition syncope.

Amiodarone is a class III anti-arrhythmic which blocks potassium channels. It has a long half-life with significant adverse effects including hepatoxicity, lung fibrosis and thyroid dysfunction. It is effective in the treatment of supraventricular tachyarrhythmias however, in the elderly, other agents should be considered first-line if possible following review.

Digoxin works by inhibiting the sodium/potassium pump. It must be monitored with the levels taken usually 6 hours after the most recent dose. There is limited evidence for digoxin use in those with preserved ejection fraction and in accordance with the STOPP criteria should be stopped.  As well as this, cessation should occur if there is significant renal impairment (eGFR <30ml/min/1.73m^2) as it can lead to toxicity.

Statins are recommended for patients with known coronary heart disease, QRISK scores >10% and in patients with diabetes or chronic kidney disease of eGFR <60min/1.73m^2.

Hypertension

Antihypertensives should only be used if blood pressure is consistently greater than 140 / 90 mmHg. In those >80 years of age, a higher range of 150 / 90 mmHg is acceptable unless there is evidence of diabetes. Centrally acting antihypertensives (methyldopa, clonidine and moxonidine) are not as well tolerated by the elderly.

Gastrointestinal system

Metoclopramide is a dopamine receptor antagonist which can worsen Parkinson’s disease and must be avoided. Domperidone must be used cautiously in those with prolonged QTc and those co-prescribed CYP3A4 inhibitors (clarithromycin and ketoconazole). It is also contraindicated in those with underlying cardiac disease including congestive heart failure because it increases the risk of arrhythmias.

Proton pump inhibitors (PPI) are indicated for uncomplicated peptic ulcer disease and can be used in cases of severe oesophagitis or oesophageal strictures requiring dilation. PPIs are also used for those at risk of bleeding e.g. on antiplatelets, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, corticosteroids and non-steroidal anti-inflammatories (NSAIDs). In the elderly, simple antacids are not for long term use as these do not prevent symptoms but rather only provide temporary relief. Lifestyle advice is encouraged; mainly promoting avoidance of smoking, coffee, chocolate and fatty foods.

In the elderly population with constipation, all constipating agents should be avoided where possible. This includes anticholinergic drugs, oral iron, opioids, verapamil and aluminium antacids. Equally, in cases of diarrhoea, it is important to avoid exacerbating factors such as antimotility drugs, unnecessary PPI (C. difficile risk) and broad-spectrum antibiotics.

Respiratory system

For those with uncontrolled mild to moderate COPD who are on salbutamol, there should be an assessment of the following asthmatic features, previous secure diagnosis of asthma or atopy, a higher eosinophil count, substantial variation in FEV1 and/or substantial variation in peak expiratory flow (at least 20%). If features are present a long acting beta agonist (LABA) and inhaled corticosteroids (ICS) should be given. If no features are present, a LABA and LAMA can be given.

The stop criteria highlights considering cessation of anti-muscarinic bronchodilators (ipratropium and tiotropium) in those with a history of narrow angle glaucoma as it may exacerbate glaucoma and in those with bladder outflow obstruction as it may lead to urinary retention.

Inhaled corticosteroids are preferred to systemic corticosteroids for the maintenance of COPD due to the unnecessary exposure to long term systemic side effects. Theophylline with its narrow therapeutic index should not be used as monotherapy for asthma or COPD as there are safer and more effective alternatives.

Anticoagulants and antiplatelets

The use of anticoagulants and antiplatelets must be weighed with the bleeding risk. Any concurrent risk factors such as uncontrolled hypertension, bleeding diathesis and recent non-trivial spontaneous bleeding should be taken into account with potentially stopping agents (aspirin, clopidogrel, dipyridamole, warfarin and more).

Anticoagulation for deep vein thrombus and pulmonary embolism (without continuing provoking risk factors) does not need to be continued for more than 6 months and 12 months respectively as there is no proven added benefit. Direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban) are mainly renally excreted and thus if the eGFR levels are below 30 and 15, the drugs should be stopped respectively.

In those aged 65 and above with atrial fibrillation the CHA2DVASc and HAS-BLED scores are used to assess commencing anticoagulation and bleeding risk. The ORBIT tool is now recommended by NICE in place of the HAS-BLED tool to identify bleeding risk to help make decisions on anticoagulation. It is as follows:

Nervous system

Tricyclic antidepressants particularly dosulepin should be stopped in those with dementia (risk of worsening cognitive impairment), glaucoma (can worsen), cardiac conductive abnormalities (pro-arrhythmic effects) or prior history of constipation or urinary retention. One should be cautious in prescribing benzodiazepines and hypnotics if a fall has occurred in the past 3 months or if the patient has an acute or chronic respiratory failure (pO2 < 8.0 kPa or PCO2 > 6.5 kPa).

Antipsychotics have a wide range of adverse effects from extra-pyramidal side effects with gait disturbances to urinary incontinence and confusion. The necessity of these drugs should be weighed with the adverse effects, particularly when used long term. With the risk of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) from selective serotonin re-uptake inhibitors (SSRIs), stopping these agents would be appropriate in those with significant hyponatraemia (below 130 mmol/l). Citalopram and escitalopram are causes of QT-interval prolongation and thus must be monitored.

Anticholinergic agents have been linked to impaired cognition and physical decline in the elderly. These drugs can manifest with a wide spectrum of symptoms affecting the central nervous system (delirium, agitation and hallucinations) and peripheral nervous system (blurred vision, photophobia and reduced gastrointestinal peristalsis). The STOPP criteria highlights that these drugs should be stopped in those with a history of persistent bradycardia, heart block or recurrent unexplained syncope.

Anticholinergic burden scale

The anticholinergic burden scale lists the anticholinergic activity of a variety of drugs. A total score of three or more is considered clinically significant.

References

• O’Mahony D, STOPP (Screening Tool of Older Persons’ Prescriptions) and START (Screening Tool to Alert to Right Treatment) are explicit criteria that facilitate medication review in multi-morbid older people in most clinical settings. (2015)
• NHS Scotland, Polypharmacy Guidance (March 2015) <https://www.sehd.scot.nhs.uk/publications/dc20150415polypharmacy.pdf>

Hepatic and renal impairment

Hepatic impairment

Metabolism is the main method of elimination for many drugs. In severe liver disease, the cytochrome P-450 system is reduced but can be complex and unpredictable. Dose adjustments may need to be made particularly if the drug is metabolised in the liver.

Hypoalbuminaemia

Severe hepatic disease can lead to reduced levels of albumin which is the most abundant plasma protein. In this state, there is a decrease in plasma protein binding. The unbound drug is able to pass through the cell membrane and exert its effects on cells. Highly protein bound drugs such as doxycycline, phenytoin and prednisolone exert larger effects than usual.

Coagulopathy

Patients with severe liver function may have impaired synthesis of clotting factors. This leads to increased sensitivity to drugs such as phenindione and warfarin.

Encephalopathy

Patients with hepatic encephalopathy may have symptoms exacerbated by sedatives, opioids, constipating agents and electrolyte disturbances which can also be precipitated by diuretics.

Renal impairment

In those with renal impairment absorption, distribution, metabolism and elimination are all impaired. There is an overall increased risk of adverse drug reactions in part due to the accumulation of active metabolites and reduced secretion and resorption.

NSAIDs and COX II inhibitors should be avoided as they can lead to reduced glomerular filtration rate and acute interstitial nephritis. One should be cautious using opioids, tramadol, gabapentinoids and benzodiazepines as these may accumulate and lead to sedation and respiratory depression.

Nitrates and rate controlling antihypertensives should be used with care as may worsen renal hypoperfusion and the latter cause bradycardia. Digoxin and ACEi in settings of acute renal impairment can exacerbate hyperkalaemia. Thiazides, loop diuretics and potassium sparing diuretics can lead to electrolyte imbalances. Contrast media can have a direct tubular toxic effect, where appropriate patients should be hydrated before and after contrast.

Antihyperglycemics can accumulate leading to hypoglycaemia and metformin can lead to lactic acidosis. Low molecular weight heparin and direct oral anticoagulants may accumulate in patients with impaired renal function, leading to risk of bleeding. In patients taking warfarin, an acute rise in urea may raise INR.

References

• Bnf.nice.org.uk. 2022. Prescribing in the elderly, hepatic impairment, renal impairment, pregnancy | Medicines guidance | BNF content published by NICE. [online] Available at: <https://bnf.nice.org.uk/medicines-guidance>
• Bnf.nice.org.uk. 2022. Hypertension, epilepsy, diabetes, pregnancy and breastfeeding | Treatment summaries | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/treatment-summaries
• Bertram Katzung, Anthony Trevor, Basic and Clinical Pharmacology, 15th edn (San Francisco, CA: McGraw Hill / Medical, 2021).

Pregnancy and breastfeeding

Background

During all stages of preconception, pregnancy, labour and breastfeeding there is the potential for drugs to cause harm. During pregnancy the smallest effective dose of a drug should be prescribed, and only if the maternal benefit outweighs the foetal risk. It is recommended to take high dose folic acid before conception and during the first trimester.

Analgesia

Paracetamol is the first line option. Opioids can be used in the short term treatment of moderate to severe pain where paracetamol has not been effective. NSAIDs typically are avoided but can be used in the first or second trimester, they must be avoided in the 3ʳᵈ trimester due to the risk of closure of the fetal ductus. There is limited evidence of gabapentinoids in pregnancy.

Antihypertensives

The first line treatment is oral labetalol, alternatives are nifedipine and methyldopa. For women with hypertension (chronic or previous gestational), diabetes mellitus, autoimmune disease or CKD – aspirin is recommended from week 12 of pregnancy. Females already taking ACE inhibitors, thiazide/thiazide-like diuretics or angiotensin II receptor blockers (ARBs) should have these medications stopped and specialist opinion sought.

Antihyperglycaemics

In certain cases where the benefits of adequate blood glucose control outweigh the risks of harm, metformin can be continued for the pre-conception period and during pregnancy. Women with gestational diabetes who present with fasting plasma glucose of above 7 mmol/litre should be immediately started on insulin with or without metformin in combination with lifestyle advice.

Antiepileptics

NICE recommends lamotrigine and levetiracetam as the safer antiepileptics in pregnancy as monotherapy. Sodium valproate, phenytoin, topiramate, phenobarbital and carbamazepine are all associated with an increased risk of congenital abnormalities.

Antibiotics

The main antibiotic options throughout pregnancy involve penicillins and cephalosporins. Nitrofurantoin is safe throughout pregnancy except at term due to haemolytic anaemia in the neonate. Trimethoprim is only considered safe after the first trimester.

Breastfeeding

Many drugs given to lactating women are detectable in breast milk. The concentration is usually low however several drugs have significant effects on the nursing infant. BNF recommends continually checking the breastfeeding section for every drug as the data is constantly changing.

References

• Bnf.nice.org.uk. 2022. Prescribing in the elderly, hepatic impairment, renal impairment, pregnancy| Medicines guidance | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/medicines-guidance
• Bnf.nice.org.uk. 2022. Hypertension, epilepsy, diabetes, pregnancy and breast feeding | Treatment summaries | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/treatment-summaries
• Bisson, D., Newell, S. and Laxton, C., 2018. Antenatal and Postnatal Analgesia. BJOG: An International Journal of Obstetrics &amp; Gynaecology, 126(4).