Expert Opinion on Drug Metabolism & Toxicology ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20 Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol L. G. Franken, B. C. M de Winter, H. J. van Esch, L. van Zuylen, F. P. M. Baar, D. Tibboel, R. A. A. Mathôt, T. van Gelder & B. C. P. Koch To cite this article: L. G. Franken, B. C. M de Winter, H. J. van Esch, L. van Zuylen, F. P. M. Baar, D. Tibboel, R. A. A. Mathôt, T. van Gelder & B. C. P. Koch (2016) Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol, Expert Opinion on Drug Metabolism & Toxicology, 12:6, 669-680, DOI: 10.1080/17425255.2016.1179281 To link to this article: https://doi.org/10.1080/17425255.2016.1179281 © 2016 The Author(s). Published by Informa Accepted author version posted online: 15 UK Limited, trading as Taylor & Francis Apr 2016. Group. Published online: 29 Apr 2016. Submit your article to this journal Article views: 918 View related articles View Crossmark data Citing articles: 6 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iemt20 EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2016 VOL. 12, NO. 6, 669–680 http://dx.doi.org/10.1080/17425255.2016.1179281 REVIEW Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol L. G. Frankena, B. C. M de Wintera, H. J. van Eschb, L. van Zuylenc, F. P. M. Baarb, D. Tibboeld,e, R. A. A. Mathôtf, T. van Geldera and B. C. P. Kocha aDepartment of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, the Netherlands; bPalliative Care Centre, Laurens Cadenza, Rotterdam, the Netherlands; cDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; dIntensive Care, Department of Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; ePain Expertise Centre, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; fHospital Pharmacy – Clinical Pharmacology, Academic Medical Centre, Amsterdam, the Netherlands ABSTRACT ARTICLE HISTORY Introduction: A variety of medications are used for symptom control in palliative care, such as Received 25 February 2016 morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these Accepted 13 April 2016 patients as a result of physiological changes that occur at the end stage of life. Published online Areas covered: This review gives an overview of how the pharmacokinetics in terminally ill patients 28 April 2016 may differ from the average population and discusses the effect of terminal illness on each of the four KEYWORDS pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considera- Haloperidol; midazolam; tions are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and morphine; palliative care; haloperidol). pharmacokinetics; terminal Expert opinion: The pharmacokinetics of drugs in terminally ill patients can be complex and limited illness evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended. 1. Introduction patient is bedridden, semi-comatose, and are no longer able to take oral medication. The aim of this review is to give an In palliative care, when curation is no longer possible, the goal overview of how the pharmacokinetics in terminally ill patient is to maintain or improve the quality of life. To achieve this, a differ from the average population, and how changes in the variety of medications, such as morphine, midazolam, and palliative, and especially the terminal phase, can affect drug haloperidol, are used for symptom control.[1] Changes in the exposure (Figure 1). We will discuss the effect of terminal pharmacokinetics of these drugs may cause increased or illness on each of the four pharmacokinetic processes: absorp- decreased drug blood concentrations, which can result in tion, distribution, metabolism, and elimination (ADME) and altered efficacy or increased risk of adverse drug reactions. give some considerations for three drugs commonly pre- To optimize the use of these drugs, an understanding of scribed in the terminal phase (i.e. morphine, midazolam, and pharmacokinetics in this specific patient population is there- haloperidol).[6] fore essential. Pharmacokinetic (Pk) parameters (e.g. drug clearance and volume of distribution) are subject to interpatient variability 2. Absorption and may be altered in the palliative population, as patients Terminally ill patients frequently suffer from gastro intestinal with cancer are known to differ from healthy volunteers with (GI) problems, such as constipation, nausea, vomiting, and regards to, for example, age, body weight, and plasma protein diarrhea. In the case of orally administered drugs, which are levels.[2] In addition, several physiological changes (e.g. used in the palliative care setting when patients are still able decreased fluid intake, a catabolic state, inflammation, and to take oral medication, these symptoms can influence both cachexia) occur at the end of life, which can also influence the rate of absorption and bioavailability of a drug. Changes in pharmacokinetics.[3–5] the absorption rate will affect time-to-peak concentrations So far there is limited knowledge on how these changes (T ), whereas changes in bioavailability will affect the initial affect the different drugs used in palliative care, in particular in max peak concentration (C ) and total exposure, expressed as the terminal phase, i.e. the last days before death in which a max area under the curve (AUC). If and to what extent a drug is CONTACT Linda G. Franken [email protected] Erasmus Medical Centre, Wytemaweg 80, room Na-219, 3015 CN, Rotterdam, the Netherlands © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 670 L. G. FRANKEN ET AL. physicochemical properties. Drugs that are weakly acidic are Article highlights best absorbed within the acid environment of the stomach. Though most drugs are weak bases (e.g. morphine, haloper- ● In terminally ill patients, pharmacokinetics may be altered as a result of co-morbidities and physiological changes that occur at the end idol, and midazolam) and are therefore absorbed in the alka- stage of life. line environment of the small intestine. ● The absorption of orally administered drug, can be altered signifi- cantly as a results of GI symptoms. In the palliative phase GI pro- blems should be closely monitored, and medication (both dose and 2.1.1. GI symptoms route of administration) should be reassessed if changes in GI motility occur. Absorption of oral drugs can be altered in terminally ill (can- ● The volume of distribution of drugs can vary in terminally ill patients cer) patients as this population often suffers from GI symp- due to changes in body composition and plasma proteins. This is particularly relevant for drugs for which rapid response is desired. toms, such as constipation, vomiting, diarrhea, or a delayed ● Drug metabolism can be diminished in case of liver disease, dehy- gastric emptying due to cachexia. Constipation (i.e. decreases dration, inflammation or cachexia. Care givers should be aware of GI motility) occurs in around 50% of the terminal cancer different reaction in patients with these symptoms and should look out for signs of altered efficacy and side effects in these patients, patients and can be a result of dehydration, hypercalcaemia, especially in the case of drugs with active metabolites. a bedridden state, and medication use (e.g. opiates).[7,8] ● Renal eliminated drugs (or metabolites) can accumulate in the final Decreased GI motility can result in a reduced absorption rate days of life if fluid intake is limited, which can cause side effects due to accumulation of drugs or metabolites as it takes longer for the drug to reach the site of absorption. ● As the interaction of drugs with the physiology of dying is complex [9–11] In the case of a sustained release formulation or drugs pharmacological treatment is probably best assessed in a multi-dis- with an enterohepatic circulation, decreased GI motility can ciplinary setting and the advice of a pharmacist, or clinical pharma- cologist, is highly recommended. increase the absorption as there is more contact time with the GI mucosa. This box summarizes key points contained in the article Constipation can also cause nausea and vomiting. Vomiting can