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INTRODUCTION

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A solid understanding of the pharmacology of neuraxially administered drugs is vital to the practice of anesthesiology as it informs the clinician in choosing the proper agents to safely achieve analgesia and anesthesia in a wide variety of settings.

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OPIOIDS

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Pharmacokinetics of Epidurally Administered Opioids

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Epidurally administered opioids must make their way out of the epidural space if they are to reach their site of action in the spinal cord’s dorsal horn. Experimental data indicate that there are two main processes that interfere with an opioid’s ability to reach the cerebrospinal fluid (CSF) from the epidural space: (1) clearance of the drug into plasma and (2) partitioning of the drug into other tissues. The extent to which these processes affect a drug’s distribution is dependent on the drug’s lipid solubility. Highly lipid-soluble drugs (ie, fentanyl, sufentanil) reach lower peak concentrations in the CSF compared to hydrophilic drugs (ie, morphine) after deposit into the epidural space. The reason for this is twofold: first, lipophilic drugs more readily partition into the epidural fat, where they remain until they are slowly re-released back into the epidural space; second, since lipophilic drugs more easily traverse vascular walls, they are more rapidly cleared from the epidural space into the plasma. The majority of this vascular clearance seems to occur in the rich capillary network of the dura mater. The ability of epinephrine to reduce the clearance rate of drugs from the epidural space has been attributed to its capacity to reduce dural blood flow.

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Administering an opioid into the epidural space does not guarantee a spinal site of action. When very lipophilic opioids (ie, fentanyl) are administered by continuous epidural infusion, they may not produce analgesia by a spinal mechanism. Instead, owing to their tendency to rapidly clear into the plasma, lipophilic opioids can redistribute through the bloodstream to the brainstem, producing unwanted side effects (ie, sedation, respiratory depression).

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Pharmacokinetics of Intrathecally Administered Opioids

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As in the epidural space, the pharmacokinetics of opioids in the intrathecal space is determined by their lipid solubility. Lipophilic (hydrophobic) opioids tend to move out of the aqueous CSF compartment, primarily diffusing across the meninges and into the epidural fat. Because of this tendency to move quickly out of the CSF, lipophilic opioids have limited bioavailability at spinal cord sites rostral to the site of administration. This explains why lipophilic opioids (ie, fentanyl) are not associated with the delayed respiratory depression seen with hydrophilic opioids (ie, morphine) when given intrathecally. Unlike fentanyl, morphine is able to remain primarily in the CSF, where it gradually spreads toward the brainstem, eventually producing respiratory depression.

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Just as administration of an opioid into the epidural space does not guarantee a spinal site of action, placing an opioid into the intrathecal space does not assure a selective spinal mechanism. Although all opioids likely ...

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