Harlan F. Hill

Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges

Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules permeability measurements are new. The measured permeability coefficient was then correlated with the drugs molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.

Placental Transfer and Neonatal Effects of Epidural Sufentanil and Fentanyl Administered with Bupivacaine during Labor

BackgroundThis randomized double-blind investigation was designed to study the placental transfer and neonatal effects of epidural sufentanil and fentanyl infused with bupivacaine for labor analgesia.

The Spinal Nerve Root Sleeve Is Not a Preferred Route for Redistribution of Drugs from the Epidural Space to the Spinal Cord

It has been frequently suggested that the spinal nerve root sleeve is a preferred route for redistribution of drugs from the epidural space to the spinal cord. To determine if this supposition is true, the authors measured the rate at which morphine, fentanyl, and lidocaine diffuse through dog and monkey meningeal specimens with and without a root sleeve. Two meningeal specimens of intact dura-arachnoid-pia mater were removed from each animal and placed in separate temperature-controlled diffusion cells. One specimen included a spinal nerve root sleeve; the other did not. The permeability of the tissues to each drug was then determined by placing the study drug in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and accumulated in the second reservoir. There was no difference in permeability between specimens with and without a nerve root sleeve for any drug in either species. Lidocaine was found to diffuse through the tissue significantly faster than fentanyl in both the dog and monkey even though fentanyl is nearly 48 times more lipid soluble than lidocaine. Morphine diffused through the tissue significantly slower than both lidocaine and fentanyl. The authors conclude that the spinal nerve root sleeve is not a preferred route of entry for drugs moving from the epidural space to the spinal cord. In addition, despite hypotheses to the contrary, lipid solubility does not appear to be the overriding determinant of meningeal permeability.

A computer-based system for controlling plasma opioid concentration according to patient need for analgesia

SummaryMicroprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.

Influence of Dexmedetomidine and Clonidine on Human Liver Microsomal Alfentanil Metabolism

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat

The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.

Placental Transfer and Neonatal Effects of Epidural Sufentanil and Fentanyl Administered with Bupivacaine During Labor

Background This randomized double-blind investigation was designed to study the placental transfer and neonatal effects of epidural sufentanil and fentanyl infused with bupivacaine for labor analgesia.