Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol

Abstract

The pharmacokinetics of drugs in terminally ill patients can be complex and limited 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.

Midazolam: an essential palliative care drug

“…Decreasing Vd leads to increases in drug concen tration and effect for lipophilic drugs like mida zolam. 32 Low albumin levels, commonly seen in advanced illness, decrease the clearance of midazolam. 33 Elderly Midazolam clearance decreases in the elderly.…”

“…34 Liver blood flow decreases with age, and midazolam is a drug with a low hepatic extraction (0.3), so elimination prolongs in low hepatic blood flow states. 32,35 Pediatric In healthy neonates, the halflife (t 1/2 ) and the clearance (Cl) are 3.3fold longer and 3.7fold shorter, respectively, than in adults owing to low levels of CYP3A4 and CYP3A5. These enzymes do not surge until the fourth week of life.…”

Preventive drugs in the last year of life of older adults with cancer: Is there room for deprescribing?

“…This polypharmacy is particularly problematic among older individuals with advanced cancer because the potential to develop serious drug‐drug interactions is amplified by the use of anticancer agents and complementary medicines . Moreover, the probability of experiencing adverse drug reactions increases because the main pharmacokinetic parameters are affected not only by age but also by the physiological impact of cancer (eg, modified drug absorption due to gastrointestinal symptoms or to impairments in the gut wall function, a decrease in the volume of distribution caused by weight loss, or renal impairment due to the nephrotoxicity of chemotherapy) …”

“…7,8 Moreover, the probability of experiencing adverse drug reactions increases because the main pharmacokinetic parameters are affected not only by age but also by the physiological impact of cancer (eg, modified drug absorption due to gastrointestinal symptoms or to impairments in the gut wall function, a decrease in the volume of distribution caused by weight loss, or renal impairment due to the nephrotoxicity of chemotherapy). 9,10 Beyond pharmacology, polypharmacy within the context of advanced cancer also raises important questions from a clinical and ethical viewpoint. As cancer progresses and the prognosis worsens, the net benefit of each additional medicine gradually decreases while the risk of harm increases.…”

Safety and Effectiveness of Palliative Drug Treatment in the Last Days of Life—A Systematic Literature Review

“…5e13 The dying patient is affected by a state of physiological multiorgan failure, which in a number of ways may affect the effectiveness and adverse effects of drug therapy. 14 Patients may additionally be unable to selfreport symptoms or participate in treatment decisions due to reduced consciousness, and proxy assessments based on observations of physical and behavioral factors may diverge from patient experience. 15 Lastly, palliative drug therapy for dying patients should neither prolong suffering nor shorten life.…”