Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-04-01 Epub Date: 2024-03-14 DOI:10.1007/s40262-024-01355-6
Teijo I Saari, John Strang, Ola Dale
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引用次数: 0

Abstract

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Abstract Image

纳洛酮的临床药代动力学和药效学。
纳洛酮是世界卫生组织(WHO)列出的基本药物,是治疗阿片类药物呼吸抑制的首选药物,也是目睹阿片类药物过量的普通人的首选药物。纳洛酮通过竞争性置换μ-阿片受体(MOR)上的阿片激动剂发挥作用。其效果取决于阿片激动剂的药理特性,如与 MOR 受体的分离率和受害者的体质。治疗的目的是在恢复呼吸(而非意识)和避免戒断之间取得平衡,在初始剂量为 0.4-2 毫克后,通过滴定来实现。由于清除率高,纳洛酮会迅速排出体外[半衰期 (t1/2) 60-120 分钟]。代谢物无活性。主要给药途径有静脉注射、肌肉注射和鼻内注射,后者主要用于带回家的纳洛酮。鼻腔生物利用度约为 50%。鼻腔吸收[达到最大浓度的平均时间(Tmax)为 15-30 分钟]可能比肌肉注射慢,因为在用药过量的受害者中,呼吸逆转的时间比肌肉注射纳洛酮晚。志愿者的药代动力学在个体内、个体间和研究间的变异性很大。目标人群的变异性尚不清楚。1 毫克静脉注射的作用持续时间为 2 小时,肌肉注射和鼻内注射的作用持续时间可能更长。海洛因过量后,0.4-0.8 毫克的初始肠外剂量通常足以恢复呼吸。芬太尼过量可能需要更大剂量的纳洛酮。针对阿片类药物过量的对照临床试验是可行的,但在合成阿片类药物的组群中却不存在。模型研究为药物治疗提供了宝贵的见解,但不能取代临床试验。非专业人员在进行临时干预时,应始终能够获得至少两种剂量的试剂盒。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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