Variability in Response to Drugs

Abstract

There is great inter-individual variability in the way people respond to a drug (Box A). Some of this variability is predictable in the presence of clinical factors known to impact upon the pharmacokinetics and/or pharmacodynamics of a drug. For example, an age-related decrease in overall metabolic capacity of the liver, because of reductions in liver mass, liver enzyme activity and hepatic blood flow, results in the elderly being at a significantly higher risk of toxicity from drugs metabolized in the liver. Similarly, an age-related decline in renal function can reduce the excretion of active drugs and metabolites, e.g., morphine-6-glucuronide and morphine-3-glucuronide, increasing the risk of toxicity from morphine.Genetic variations also contribute towards differences in drug response. Clinically, these are less predictable, although some may be detected with specific testing. They are particularly important for drugs metabolized by cytochrome P450 (CYP450) with the rate of metabolism either reduced or increased. Examples of how these manifest include: reduced or no response because of ➢ the failure to convert a pro-drug to its active form ➢ increased metabolism of an active drug to an inactive metabolite increased toxicity because of ➢ more rapid conversion to the active form or to a metabolite which is more active than the parent drug ➢ failure to metabolize an active drug to inactive metabolite(s). Other genetic variations, such as genes coding for receptors or drug transporters also can influence overall response, e.g., the m-opioid receptor or P-glycoprotein transporter and the response to opioids. Induction or inhibition of CYP450 activity also can result from a drugedrug or drugefood interaction causing similar manifestations to those resulting from genetic variation. Each of these factors is considered in more detail below.

Survival implications of opioid use before and after liver transplantation

“…Opioid analgesics serve an important role in management of both acute and chronic pain, but heightened awareness of an “epidemic” of complications related to the misuse, abuse, and inherent potential toxicity of prescription opioids is a timely topic . Concerns about opioid‐related toxicity are even greater with regard to patients with end‐stage organ failure due to altered drug protein binding, metabolism, and excretion, leading to accumulation of parent agents and potentially toxic metabolites . We recently linked the national transplant registry with pharmacy fill records and found that prescription opioid fills before kidney transplant were associated with increased risk of complications after the transplant procedure …”

How to use opioid analgesics effectively and safely. Individual choice of the opioid in patients with cancer pain from the perspective of 2022

“…Pokazuje ono, że leczenie niskimi dawkami silnych opioidów nie musi być dla pacjenta bardziej korzystne (stąd rekomendacja nie stosuj rutynowo) -efekt leczenia jest zależny od wielu czynników, m.in. nasilenia i dynamiki bólu oraz uwarunkowań genetycznych [19]. W badaniu Ventafriddy i wsp.…”

“…Poszczególne opioidy różnią się pod względem właściwości farmakokinetycznych zależnych od procesów wchłaniania, dystrybucji, metabolizmu i eliminacji z organizmu [19,54]. Poniżej omówiono zróżnicowanie leków opioidowych pod względem metabolizmu i eliminacji z organizmu, ponieważ te cechy bezpośrednio wpływają na ich efekt i przydatność w terapii.…”

“…Literatura nie wskazuje na istotne znaczenie tego metabolitu w praktyce, w związku z czym buprenorfinę omówiono w tej grupie opioidów. Wszystkie leki metabolizowane do aktywnych pochodnych i eliminowane z moczem w postaci aktywnych cząstek wymagają ostrożnego stosowania u pacjentów z zaburzoną czynnością nerek [19,34,35,37,[55][56][57]. Szczególną uwagę należy zwrócić na rolę metabolitów morfiny: M3G i morfino-6-glukuronianu (M6G) [56,63].…”

Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain

“… 1 This individual pain vulnerability can be manifested as large variability in developing chronic pain under a similar pathological condition, in variable pain magnitude and sensitivity under acute and chronic pain conditions, and in differential responses to analgesic drugs. 2 , 3 In many pain-causing injuries or diseases, not all patients actually develop chronic pain. 1 , 2 , 4 , 5 Besides the intrinsic features such as gender and age, there are many known risk factors that can predispose individuals to the development of chronic pain, including genetic and epigenetic changes, biological adaptations, neuropsychological disorders, and prior stressful life events including pain experience.…”