Drug-drug interactions (DDI) are a frequently encountered phenomenon in palliative care (PC) setting; to best optimize management, clinicians should be aware of the pharmacokinetics and pharmacodynamics of the most commonly used drugs in this patient population. Based on a patient’s inherited alleles, age, sex, physiologic status, etc., pharmacotherapy will vary significantly from one patient to the next. Also, clinicians must be familiar with potential drug interactions. Several studies have elucidated the prevalence of DDI in palliative care from 31 to 75% across various health care settings. It is worth mentioning that palliative care medicine involves the concerted efforts of a multidisciplinary team to reduce disease burden for patients living with serious illnesses, whether provided concurrently with curative care or alone for comfort care.
Cytochrome P450 3A (CYP3A) is the most relevant drug-metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real-life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single-arm, prospective trial obtained a 4-hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.
Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure due to disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive, chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications are discussed.
As hospice and palliative care populations shift from the majority having a primary cancer diagnosis to most with a noncancer diagnosis, clinicians are challenged with caring for chronically ill patients with multiple comorbidities. In addition to traditional pain and symptom management, patients’ comfort goals are frequently addressed by managing the underlying disease and comorbid conditions. As a result, many patients have extensive medication profiles. This raises the potential for drug-drug interactions at cytochrome P450 pathways that can interfere with anticipated drug response. Likewise, polypharmacy can be problematic when using palliative care order sets and hospice comfort kits to manage emergent symptoms or as the patient approaches death. This is further complicated when medications are administered before a pharmacist’s review for drug interactions. This article provides an overview of cytochrome P450 and uses an unfolding case study approach to explore interactions that may occur within a patient’s medication profile or in combination with medications commonly used by palliative care and hospice.
BACKGROUND: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness.
AIM: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions.
DESIGN: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients' diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753.
SETTING/PARTICIPANTS: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status.
RESULTS: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction (p < 0.0001) in comparison with the cytochrome P450 3A activity of healthy subjects.
CONCLUSION: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.
PURPOSE: The undesired effects of midazolam can be life-threatening. This paper delineates the findings related to the pharmacokinetics, adverse effects and drug-drug interactions as well as associated therapeutic implications for safe midazolam use.
METHODS: A systematic review of literature was conducted.
RESULTS: The pharmacokinetics of midazolam depends on hepatic and renal functions, fat tissue mass, route and duration of administration, as well as potential drug-drug interactions. Palliative care patients constitute a high-risk group prone to side effects of drugs, due to polytherapy and multi-organ failure.
CONCLUSION: Midazolam is one of three most frequently administered drugs in palliative care. The indications for its use include anxiety, dyspnea, seizures, vomiting refractory to treatment, agitation, myoclonus, status epilepticus, restlessness, delirium, pruritus, hiccups, insomnia, analgosedation, palliative sedation and preventing or counteracting undesired effects of ketamine.
BACKGROUND: Drug interactions are a common cause for escalation of debilitating symptoms in palliative care patients. CYP3A is the most relevant CYP enzyme in humans involved in metabolism of about half of all available pharmaceuticals.
OBJECTIVE: To increase knowledge about the CYP3A enzyme and the impact of drug interactions on its activity to improve dosing in palliative care patients.
DESIGN: The prospective clinical trial uses a secure method of analyzing CYP3A activity in humans: Administration of a marker substance followed by the determination of its blood concentrations as well as the concentrations of its metabolite at certain points of time and corresponding metabolic clearance calculations.
SETTING: The ongoing trial is carried out at a palliative care unit under real-life clinical conditions.
MEASUREMENTS: A four-hour pharmacokinetic profile after oral administration of the marker substance (microdose of midazolam) will be obtained from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite will be quantified by mass spectrometry techniques. CYP3A activity will be calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients will be considered as well as recent blood test results and the patients' diagnoses.
CONCLUSIONS: This is the first prospective study dealing with drug metabolism in patients on a palliative care unit. The trial is based on reliable and established methods aiming to provide improved dosing regimens and thus optimize pharmacological therapies in this specialty.
Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics, and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients. To analyze the relationship of a combination of opioids, anxiolytics, and antipsychotics on survival and the change of night-time death percentage. A retrospective study of 765 consecutive patients admitted to hospice in Croatia over the period of four years (2013–2017). The main outcome was the total length of survival of hospice patients regarding different drug combination, along with night-time death percentage. Different combinations of opioids, anxiolytics, and antipsychotics were associated with longer survival in hospice compared with patients using no such drugs. When we included different parameters which affected overall survival into a multivariate analysis, only the patients who had the combination of both opioids, anxiolytics, and antipsychotics in their regular therapy were associated with longer survival in hospice (11 vs. five days, hazard ratio 0.54, P < 0.001). No combination of opioids, anxiolytics, and antipsychotics significantly changed the night-time death percentage. This research supports the safety of opioids, anxiolytics, and antipsychotics in the hospice setting when used both individually as well as in combination.
Aim : To determine the potential for drug interactions involving cytochrome P450 (CYP) in patients receiving palliative day care.
Methods : Drugs used by patients attending four specialist palliative day care centres were reviewed to identify combinations that could result in a pharmacokinetic interaction via any of the five main human forms of CYP.
Results : Of 160 patients, 145 (91%) were prescribed at least one drug that was a substrate, inhibitor or inducer of one of the five main CYP isoforms. Twenty-four drug combinations, involving 34 patients, could have given rise to a clinically important interaction.
Conclusions : Prescribers should be aware that in this group of patients, one in five are at risk of a clinically important CYP-mediated drug interaction.
L'auteur expose la complexité spécifique de la psychiatrie institutionnelle au regard de la chronicisation et de la fin de vie. Il insiste sur la problématique, devenue plus fréquente, qui est celle de l'institutionnalisation des patients atteints de schizophrénie. Il soulève une éventuelle incompatibilité de la sédation terminale avec l'imprégnation prolongée par les traitements antipsychotiques. Il affirme la nécessité d'être très prudent dans l'application de la loi et de renforcer l'information proche et continue du patient en fin de vie.
Cet article fournit les réponses au cas clinique n°77 proposé dans l'édition précédente (vol. 21 n°6) de la revue, portant sur un patient de 78 ans atteint d'un cancer de la prostate et recevant un traitement hormonal.
Les situations rencontrées dans les soins palliatifs exigent des considérations spéciales pour l'utilisation des anti-émétiques même si les nausées et les vomissements sont courants pour les patients concernés.
Les auteurs s'attachent à définir la place tenue par la morphine retard et les autres opioïdes à action lente en soins palliatifs. Ils expliquent aussi la manière dont ces produits agissent, doivent être administrés et sont éliminés par le corps humain.
Les auteurs décrivent une méthodologie qui permet d'analyser la compatibilité de deux médicaments. Ils l'appliquent à l'association successive de la morphine par voie parentérale avec huit autres substances souvent utilisées comme thérapeutiques palliatives. Les mélanges ont été testés pour leurs qualités physiques et chimiques de stabilité et de compatibilité, avec variations de dosage de chaque substance. Un schéma donne l'exemple de la morphine associée à la ranitidine. Deux autres représentent les stratégies d'analyse et de décision. Cette méthode se veut une aide à lafois à la recherche et à la pratique clinique.
Deux études publiées dans "Anesthésiology" présentent l'utilisation d'antagonistes morphiniques pour limiter les effets secondaires des opioïdes. La naloxone et le nalmefène ont été prescrits à des femmes après hystérectomie et bénéficiant d'une thérapeutique morphinique. Les symptômes indésirables comme les nausées, vomissements et prurit ont été diminués dans les deux groupes. De plus, il a été constaté la nécessité d'un dosage moindre de morphine avec la naloxone à bas dosage. Ces résultats posent des questions sur les actions et interactions des opioïdes agonistes et antagonistes.
L'article souligne les dangers d'interaction médicamenteuse dans les thérapeutiques de la douleur. Il l'illustre par la description du cas d'un patient cancéreux traité simultanément par fentanyl et itraconazole. Suite à la survenue de symptômes de toxicité opioïde, d'autres solutions thérapeutiques sont mises en place dont la méthadone, et finalement l'arrêt de l'itraconazole. Le commentaire porte sur les différents processus métaboliques enzymatiques d'inhibition ou d'induction compétitive ou non qui peuvent intervenir au niveau de la pharmacocinétique et de leurs possibles conséquences subcliniques ou cliniques.
Les thérapeutiques psychostimulantes, telles les amphétamines, ont une réputation passée qui a amené à une réduction de leur utilisation. Cette étude donne une présentation pharmacologique de ces produits. Elle montre leurs effets possibles pour traiter différents symptômes tels états dépressifs, douleur et fatigue, ces symptômes concernant différents types de patients : malades VIH, cancéreux, en soins palliatifs. Elle décrit les avantages et inconvénients de ces thérapeutiques dans l'amélioration de la qualité de vie des malades.