Abstract
Patients on a range of drug therapies are often not monitored appropriately, even though this can improve patient safety. Knowledge of the effects of drugs on non-target body systems is essential to guide monitoring and interpretation of monitoring tests
Considerable guidance is available on the safety monitoring required for many commonly used drugs. In some cases, where a clinical effect correlates with drug concentrations, this involves monitoring concentrations of the drug in blood (therapeutic drug monitoring). In other cases, such monitoring is of limited value, although knowing drug concentrations can help in diagnosing toxicity. Secondary effects of the drug on other body systems may also be monitored by using other tests or measurements.
Audits of compliance with drug safety monitoring recommendations in a range of prescribing situations have shown that monitoring of compliance remains an important area for improvement as a contributor to patient safety.1 2 3 4 5
This article considers two scenarios involving the cardiovascular drugs digoxin and amiodarone and the monitoring required to detect their therapeutic and adverse effects. It also reviews the evidence based and consensus guidance that is available.
Summary points
Drug safety monitoring in routine practice is often suboptimal
Consensus guidance for safely monitoring a wide range of drugs is available
Safe prescribing of drugs also requires a basic understanding of physiological, pathological, and pharmacological influences on the action of a drug and of its pharmacokinetics
Blood concentrations of drugs often do not correlate closely with activity or toxicity, which can be influenced by several other factors
“Therapeutic ranges” are produced as guides to a drug's activity, potential toxicity, or both: prescribers should know how to use these ranges
Case 1
A 71 year old man with longstanding congestive heart failure and atrial fibrillation was reviewed routinely by his general practitioner. The patient was being managed with perindopril 8 mg daily, combined with digoxin 187.5 µg daily for rate control of his atrial fibrillation. One month previously he had started taking frusemide 40 mg daily because of worsening ankle oedema associated with his heart failure. He was receiving long term anticoagulation with warfarin, stabilised at a dose of 5 mg daily.
At review he had slight ankle oedema but no other clinical signs of heart failure. His pulse was 86 beats/minute in atrial fibrillation and his blood pressure was 136/84 mm Hg. Renal function and digoxin measurement were reported as sodium 135 mmol/l, potassium 3.8 mmol/l, urea 7.2 mmol/l, and creatinine 105 µmol/l (estimated glomerular filtration rate 63 ml/min/1.73 m2). His serum digoxin concentration was 1.8 nmol/l (therapeutic range 1.0-2.6 nmol/l).
Three weeks later the patient presented with recurrent nausea over the previous four days, with vomiting on two occasions. His renal function results were similar to two weeks before, with a normal serum potassium of 4.1 mmol/l, although a digoxin measurement was reported as 2.7 nmol/l. The doctor telephoned the laboratory to discuss the large apparent rise in the digoxin concentration and for advice on further management.
This discussion revealed that the first blood sample had been taken when the patient had been seen initially in an evening surgery and the second when he had been reviewed in a morning surgery. The doctor understood that the patient took his medicines in the morning. A repeat digoxin sample taken eight hours after dosing and measurement of serum magnesium were organised. The repeat digoxin result was 2.0 mmol/l and the patient's magnesium was reported as being 0.4 mmol/l (normal range 0.75-0.95 mmol/l).
The patient was admitted to hospital for supervised intravenous magnesium sulphate supplementation. His dose of digoxin was omitted for two days and then reduced to 125 µg daily and he was started on oral magnesium glycerophosphate replacement.
Case 2
A 64 year old woman had been started six weeks previously by her local cardiologist on a loading regimen of amiodarone for symptomatic paroxysmal atrial fibrillation which had continued to recur despite initial treatment with sotalol. She had been treated with anticoagulants at the time of diagnosis six months before, and her international normalised ratio (INR) had been maintained close to a target of 2.5 on a daily dose of 6 mg of warfarin, which had been reduced to 4 mg because of a rise in her INR after her loading doses of oral amiodarone. She presented to her general practitioner with a history of a further short (30 minutes) episode of palpitations and light headedness typical of her previous attacks. This had developed after an episode of diarrhoea and vomiting attributed to a “bug” that other family members had had. Her doctor noted that she was in atrial fibrillation with an irregular pulse of 96 beats per minute and organised a blood sample for measurement of serum amiodarone.
Following local guidance her doctor also checked a routine thyroid function test and liver profile. The thyroid function results were reported as thyroid stimulating hormone 0.4 mIU/l (reference range 0.4-5 mIU/l) and free thyroxine (FT4) 30 nmol/l (reference range 11-23 nmol/l). When the doctor telephoned her local laboratory to discuss whether the patient required antithyroid treatment or review of her amiodarone treatment, she was advised that the laboratory would add free tri-iodothyronine (FT3) to the thyroid profile, and that amiodarone measurement was unlikely to be helpful in this situation unless non-compliance was suspected. The FT3 was returned as 4.2 pmol/l (reference range 2.8-7.1 pmol/l)
After discussion with the cardiologist, the patient was reassured that more time might be needed for her amiodarone to reach adequate concentrations in tissue. The patient had one further short episode of palpitations over the next six weeks, after which she had no further symptoms. Her warfarin dose was subsequently reduced further to 3 mg daily because of a further rise in her INR.
Discussion
These two cases illustrate several pitfalls in therapeutic drug monitoring and safety monitoring when digoxin and amiodarone are used.
Case 1
In the first case, a serum sample was taken for digoxin only a few hours after the dose and produced a result compatible with toxicity, in a normokalaemic patient who was subsequently found to be hypomagnesaemic. Timing of the sample is important for digoxin measurement. Current recommendations are for the sample to be taken 8-12 hours after the previous dose. In addition, a digoxin result within the “therapeutic range” does not exclude digoxin toxicity, as individual susceptibility varies considerably.
Various cations affect the excitability of different nerve and muscle cells in the body, including the myocardium. Changes in the serum concentrations of potassium, magnesium, or calcium may lead to arrhythmias. The cardiac consequences of severe hypokalaemia or hypomagnesaemia are both important, particularly as hypomagnesaemia can worsen pre-existing hypokalaemia, and the likelihood of problems is increased by coronary artery disease and in patients taking digoxin.6 Low serum potassium concentrations can reduce the renal excretion of digoxin and increase myocardial uptake of digoxin; this is relatively well known, and hypokalaemia-induced digoxin toxicity is fairly well recognised in clinical practice.7 Although in this case the patient's serum potassium concentration remained within the population reference range despite his loop diuretic, possibly as a result of the angiotension converting enzyme inhibitor, he had developed diuretic-induced hypomagnesaemia. Hypomagnesaemia predisposes to digoxin toxicity and also leads to hypocalcaemia and hypokalaemia. Hypomagnesaemia seems to cause hypokalaemia via the Na/K ATPase pump, which depends on magnesium and is responsible for retention of potassium. Hypomagnesaemia causes defective release of parathyroid hormone, resulting in hypocalcaemia.
Hypomagnesaemia, although quite common in hospitalised patients, is under-recognised in clinical practice. The patient may develop muscular tremors, tetany, or altered mental state, but these symptoms may be misinterpreted. Magnesium depletion can result from decreased absorption or, more commonly, increased loss from the intestines (for example, diarrhoea) or renal losses. Diuretic-induced hypomagnesaemia is common, particularly in elderly patients taking digitalis,8 and increases susceptibility to the toxic effects of digoxin, which may occur in patients who are within the “therapeutic range.”9 As magnesium salts are poorly absorbed orally, this patient was admitted for intravenous replacement before being given oral magnesium.
The evidence based guidance for safety monitoring in patients taking digoxin is summarised in box 1. Although routine digoxin measurement is not recommended in clinically and biochemically stable patients,10 existing guidelines emphasise changes in clinical state, the concomitant use of drugs that may impact on toxicity,11 and recognition of situations predisposing to toxicity12—notably renal insufficiency.13 Even if no recognised concomitant medications or medical conditions could have altered the pharmacokinetic profile or indirectly altered its cardiac effects by pharmacodynamic interactions, the presence of toxic symptoms such as nausea, vomiting, visual disturbance (yellow-green discoloration), or severe dysrhythmias may prompt an urgent measurement.
Box 1: What safety monitoring is required in a patient receiving digoxin in primary care?
Measure plasma digoxin to diagnose toxicity or to monitor for potential toxicity developing from a change in dose, the patient's clinical state, or other drug therapy
Serum potassium and renal function indices should be measured at intervals depending on the patient's clinical state and other drugs taken
Samples for digoxin measurement should be taken at least 8-12 hours after the last dose, and 8-10 days after any change in dose
Plasma monitoring is not necessary in clinically and biochemically stable patients
Case 2
In the second case, amiodarone produced thyroid test results resembling biochemical thyrotoxicosis, which is a recognised complication of treatment with amiodarone, although it is rarer than amiodarone-induced hypothyroidism in countries with high environmental iodine content such as the United Kingdom.14 Amiodarone interferes with the peripheral conversion of FT4 to FT3 and may produce a rise in FT4 to levels above the reference range, with a fall in FT3.15 In parallel, an acute illness in this case can produce various effects on thyroid hormone results, including a fall in thyroid stimulating hormone (TSH), described under the term non-thyroidal illness.16 Few if any laboratories routinely measure FT4, FT3, and TSH in standard thyroid profiles; many use a TSH measurement to screen for primary thyroid disease before performing further tests. In the case of patients receiving amiodarone, measurement of FT3 is required for interpreting results when FT4 or TSH values are outside reference limits, and it is important that information about drugs taken is available to the laboratory so that the correct thyroid tests can be selected and erroneous interpretation avoided. The fall in this patient's warfarin requirements was consistent with the decrease in renal clearance of warfarin during treatment with amiodarone17; clearance may take weeks to months because of the large volume of distribution (up to 5000 litres in an adult) and the consequently long half life of the drug (up to 60 days during chronic treatment). Similarly, although oral loading with 400-600 mg daily is used in the initial weeks of treatment, achieving full anti-arrhythmic activity may take many weeks.
Use of amiodarone can result in many other adverse effects, especially at doses of greater than 200 mg daily. Many organ systems other than the thyroid are affected, including the lungs (pneumonitis, fibrosis), liver (raised liver enzymes), nervous system (neuropathy), and skin (discoloration). Although several clinical monitoring strategies are suggested (box 2), after initial treatment the need for ongoing treatment should be considered, and where possible the dose should be decreased or rationalised if other effective treatments are available.
Box 2: What safety monitoring is required in a patient receiving amiodarone in primary care?
Minimum safety monitoring at baseline and every six months on patients treated with amiodarone if levels are within the population reference range:
Thyroid profile (TSH, FT4, and FT3 where applicable)
Liver enzymes (aspartate aminotransferase, AST) and renal function (“urea and electrolytes”) Clinical evaluation
Annual chest x ray, electrocardiogram, and clinical assessment
Prothrombin ratio monitoring weekly during the first seven weeks of warfarin treatment, after which warfarin should be adjusted depending on response
Evidence note
The therapeutic interactions and toxicities of digoxin and amiodarone have been identified from observational studies. Studies of monitoring practice are limited by their setting, as practices vary between and within countries, between primary and secondary care, and over time as practice evolves. Nevertheless the high reported figures for mistimed samples or samples that are inappropriate for monitoring digoxin, or for incomplete monitoring for amiodarone, from the more recent of these studies provide strong circumstantial evidence that incorrect monitoring remains an important patient safety issue. A review of interventions indicates that a combination of education and active interventions can change requesting practices,18 although the guidance found on monitoring relies primarily on expert and consensus opinions that are based on observational studies of the incidence of toxicity and at-risk groups for toxicity.
Useful websites
Lab tests on Line (www.labtestsonline.org.uk)—a comprehensive guide to laboratory tests and their use for patients
Cochrane Library (www.nelh.nhs.uk/cochrane.asp)—information and systematic reviews on evidence based medicine. The Cochrane Collaboration is beginning reviews on laboratory diagnostic testing
Journal of Clinical Pathologists (www.jclinpath.com)—electronic access (by subscription) to the Journal of Clinical Pathology, with full content of the questions and answers examined in this article
Clinical evidence (www.clinicalevidence.com)—summaries of current evidence based management guidelines
PRODIGY (www.prodigy.nhs.uk)—clinical decision making guidelines principally for general practitioners
E Medicine (www.emedicine.com)— comprehensive resource for medical practitioners with links to public information classified by disease type
We thank Mrs Susan Richardson for typing this manuscript, A Taylor who coauthored the original review answers, and the clinical practice section of the Association of Clinical Biochemists (in particular I D Watson, C van Heyningen, and D Freedman) for commenting on this document. We also thank D Housley (Association of Clinical Biochemists), R Gama, (Association of Clinical Pathologists), and N Campbell (Royal College of General Practitioners), who kindly reviewed the original work and added valuable comments in addition to those of the steering group, and I Watson, who coauthored the original guidance.
Competing interests: None declared.
This is the ninth article in this series
References
- 1.Stelfox HT, Ahmed SB, Fiskio J, Bates DW. Pharmacoepidemiology and drug utilisation. Monitoring amiodarone's toxicities: recommendations, evidence and clinical practice. Clin Pharmacol Ther 2004;75:110-22. [DOI] [PubMed] [Google Scholar]
- 2.Canas F, Tanasijevic M, Ma'luf N, Bates DW. Evaluating the appropriateness of digoxin level monitoring. Arch Intern Med 1999;159:363-8. [DOI] [PubMed] [Google Scholar]
- 3.Schoenenberger R, Tanasijevic M, Jha A, Bates D. Appropriateness of antiepileptic drug level monitoring. JAMA 1995;274:1622-6. [PubMed] [Google Scholar]
- 4.Eagles J, McCann I Macleod T, Paterson N. Lithium monitoring before and after the distribution of clinical practice guidelines. Acta Psychiatr Scand 2000;101:349-53. [DOI] [PubMed] [Google Scholar]
- 5.Reid LD, Horn JR, McKenna DA. Therapeutic drug monitoring reduces toxic drug reactions: a meta-analysis. Ther Drug Monitoring 1990;12:72-8. [DOI] [PubMed] [Google Scholar]
- 6.American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 10.1: Life-threatening electrolyte abnormalities. Circulation 2005;112(suppl 24):IV121-5. [Google Scholar]
- 7.Litonjua MR, Penton S, Robinson C, Daubert GP. Digoxin: the monarch of cardiac toxicities. J Pharm Pract 2005;18:157-68. [Google Scholar]
- 8.Martin BJ, McAlpine JK, Devine BL. Hypomagnesaemia in elderly digitalised patients. Scott Med J 1988;33:273-4. [DOI] [PubMed] [Google Scholar]
- 9.Young IS, Goh EM, McKillop UH, Stanford CF, Nicholls DP, Trimble ER. Magnesium status and digoxin toxicity. Br J Pharmacol 1991;32:717-21. [PMC free article] [PubMed] [Google Scholar]
- 10.Smellie WSA, Forth J, Sundar S, Kalu E, McNulty CAM, Sherriff E, et al. Best practice in primary care pathology. Review 4. J Clin Pathol 2006;59:893-902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Drug Interactions: cardiac glycosides. British National Formulary March 2006;52(Appendix 1):685-6. [Google Scholar]
- 12.Aronson JK Hardman M, Reynolds DJ. ABC of monitoring drug therapy: digoxin. BMJ 1992;305:1215-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cantu TG, Ellerbeck EF, Yun SW, Castine SD, Kornhouser DM. Drug prescribing for patients with changing renal function. Am J Hosp Pharm 1992;49:2944-8. [PubMed] [Google Scholar]
- 14.Hanna FWF, Lazarus JH, Scanlon MF, Controversial aspects of thyroid disease. BMJ 1999;319:894-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hallworth M, Capps N. Individual drugs: amiodarone. In: Therapeutic drug monitoring and clinical chemistry. London: ACB Venture Publications 1993:35-7.
- 16.Butler J, Pope R. Thyroid dysfunction.. In: Marshall WJ, Banger SK, eds. Clinical biochemistry—metabolic and clinical aspects. Edinburgh: Churchill Livingstone, 1995:331-54.
- 17.Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002;121:19-23. [DOI] [PubMed] [Google Scholar]
- 18.Solomon DH, Hideki H, Daltroy L, Liang MH. Techniques to improve physicians' use of diagnostic tests. JAMA 1998;280:2020-7. [DOI] [PubMed] [Google Scholar]