Influence of Hypo and Hyperthermia on Disposition of Morphine

Bansinath, M.; Turndorf, Herman; Puig, Margarita M.

doi:10.1002/j.1552-4604.1988.tb03229.x

Cited by 34 publications

(21 citation statements)

References 23 publications

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“…There was a trend, however, for a smaller Vd ss at 18°C, which could increase t 1/2 . Consistent with this possibility, Bansinath et al (1988) examined the effects of hypo-and hyperthermia on morphine disposition and found increases in t 1/2 and decreases in Vd ss in hypothermic, but not hyperthermic, dogs compared with normothermic controls. Another potential reason for the increased t 1/2 at 18°C could be hypothermiainduced impairment of biliary secretion and microsomal function in the liver (Kalser et al, 1968).…”

Section: Discussionmentioning

confidence: 91%

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Banks¹,

Sprague²,

Kisor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18°C; n ‫؍‬ 5), room (24°C; n ‫؍‬ 7), and warm (31°C; n ‫؍‬ 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18°C, a hyperthermic response at 31°C, and did not significantly change core temperature at 24°C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t 1/2 ) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared with 24°C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18°C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24°C and 31°C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.

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Section: Discussionmentioning

confidence: 91%

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Banks¹,

Sprague²,

Kisor³

et al. 2007

Drug Metab Dispos

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“…Propofol blood concentrations were increased by approximately 20% both in healthy volunteers at 34°C and during hypothermic cardiopulmonary bypass, likely due to reduced intercompartmental clearances in the former (Russell et al, 1989;Leslie et al, 1995). In summary, reduced elimination during hypothermia has been shown for morphine, midazolam, and fentanyl in both animals and man (Koren et al, 1987;Bansinath et al, 1988;Fukuoka et al, 2004;Fritz et al, 2005). Study results are less uniform regarding apparent volume of distribution, where it was reported increased for midazolam and reduced for morphine and fentanyl (Koren et al, 1987;Bansinath et al, 1988;Fukuoka et al, 2004).…”

Section: Introductionmentioning

confidence: 87%

“…In summary, reduced elimination during hypothermia has been shown for morphine, midazolam, and fentanyl in both animals and man (Koren et al, 1987;Bansinath et al, 1988;Fukuoka et al, 2004;Fritz et al, 2005). Study results are less uniform regarding apparent volume of distribution, where it was reported increased for midazolam and reduced for morphine and fentanyl (Koren et al, 1987;Bansinath et al, 1988;Fukuoka et al, 2004). However, these studies were performed in vitro, in animals, children, and healthy volunteers, which are settings that limit their validity with regard to adult patients treated with TH after cardiac arrest.…”

Section: Introductionmentioning

confidence: 99%

“…Hypothermia can induce significant physiologic changes that affect drug disposition and action through changes in both metabolism and distribution (Kadar et al, 1982;Koren et al, 1987;Bansinath et al, 1988;Alcaraz et al, 1989;Beaufort et al, 1995;Leslie et al, 1995;Asokumar et al, 1998;Caldwell et al, 2000;Fukuoka et al, 2004;Tortorici et al, 2007;Arpino and Greer, 2008;Polderman, 2009). Reduced metabolism due to changes in enzyme activity during hypothermia may increase drug serum levels, and thus drug effects and duration of action (Polderman, 2004;Arpino and Greer, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…normothermic controls (Rink et al, 1956;Bansinath et al, 1988;Róka et al, 2008). CYP3A4 metabolizes both midazolam and fentanyl.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Hypothermia on the Disposition of Morphine, Midazolam, Fentanyl, and Propofol in Intensive Care Unit Patients

et al. 2012

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Therapeutic hypothermia (TH) may induce pharmacokinetic changes that may affect the level of sedation. We have compared the disposition of morphine, midazolam, fentanyl, and propofol in TH with normothermia in man. Fourteen patients treated with TH following cardiac arrest (33-34°C) were compared with eight matched critically ill patients (36-38°C). Continuous infusions of morphine and midazolam were stopped and replaced with infusions of fentanyl and propofol to describe elimination and start of infusion pharmacokinetics, respectively. Serial serum and urine samples were collected for 6-8 hours for validated quantification and subsequent pharmacokinetic analysis. During TH, morphine elimination half-life (t 1/2 ) was significantly higher, while total clearance (CL tot ) was significantly lower (median [semiinterquartile range (s-iqr)]): t 1/2 , 266 (43) versus 168 (11) minutes, P < 0.01; CL tot , 1201 (283) versus 1687 (200) ml/min, P < 0.01. No significant differences were seen for midazolam. CL tot of fentanyl and propofol was significantly lower in hypothermic patients [median (s-iqr)]: fentanyl, 726 (230) versus 1331 (678) ml/min, P < 0.05; propofol, 2046 (305) versus 2665 (223) ml/min, P < 0.05. Compared with the matched, normothermic intensive care unit patients, t 1/2 of morphine was significantly higher during TH. CL tot was lower during TH for morphine, fentanyl, and propofol but not for midazolam. Reducing the infusion rates of morphine, fentanyl, and propofol during TH is encouraged

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Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia

Frymoyer

Bonifacio

Drover³

et al. 2016

The Journal of Clinical Pharma

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Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82 – 5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n=106 for morphine; n=106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n=1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight.

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Influence of Hypo and Hyperthermia on Disposition of Morphine

Cited by 34 publications

References 23 publications

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Effects of Hypothermia on the Disposition of Morphine, Midazolam, Fentanyl, and Propofol in Intensive Care Unit Patients

Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia

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