With cocaine pharmacokinetics

Cocaine was also the first aminoester local anesthetic, and its adverse effects differ from those of other local anesthetics. Owing to its rapid absorption by mucous membranes, cocaine applied topically can cause systemic toxic effects. There is a wide variation in the rate and amount of cocaine that is systemically absorbed. This variability can be affected by the type and concentration of vasoconstrictor used with cocaine and also accounts for the differences in cocaine pharmacokinetics in cocaine abusers (SEDA-20,128). 

G. Barnett, R. Hawks, and R. Resnick [/. Ethnopharmacol., 3, 353 (1981)] of the National Institute on Drug Abuse have studied cocaine pharmacokinetics in the human body. Cocaine was given to human subjects by intravenous administration. Gas chromatography-mass spectroscopy was used to determine the concentration of this drug in blood plasma samples. From the measurements reported below, determine whether the data are consistent with the response of a single CSTR to a pulse injection of tracer. Also determine the mean residence time of the material in the body. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

Sun L, Hall G, Lau CE. 2000. High-performance liquid chromatographic determination of cocaine and its metabolites in serum microsamples with fluorimetric detection and its application to pharmacokinetics in rats. J Chromatogr B Biomed Sci Appl 745(2) 315-323. 

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

A two-compartment open linear model has been described for the pharmacokinetic profile of cocaine after intravenous administration.14 The distribution phase after cocaine administration is rapid and the elimination half-life estimated as 31 to 82 min.14 Cone9 fitted data to a two-compartment model with bolus input and first-order elimination for the intravenous and smoked routes. For the intranasal route, data were fitted to a two-compartment model with first-order absorption and first-order elimination. The average elimination half-life (tx 2 3) was 244 min after intravenous administration, 272 min after smoked administration, and 299 min after intranasal administration. 

Smith, F. P. and Kidwell, D. A., Cocaine in children s hair when they live with drug-dependent adults. Pharmacology and Pharmacokinetics of Cocaine in Hair, presented at the Society of Forensic Toxicology Conference on Drug Testing in Hair, Tampa, FL, Oct. 29-30, 1994. To be published by National Institute on Drug Abuse. 

B. Pharmacokinetics Many shorter-acting local anesthetics are readily absorbed into the blood from the injection site after administration. The duration of local action is therefore limited unless blood flow to the area is reduced. This can be accomplished by administration of a vasoconstrictor (usually an a agonist sympathomimetic) with the local anesthetic agent. Cocaine is an important exception to this rale since it has intrinsic sympathomimetic action (because it in-... 

The combination of a pharmacodynamic model with a modem technique such as microdialysis is an attractive solution to assess pharmacokinetic/pharmacodyamic (PK/PD) relationships. Two separate stndies supported this idea. Esterom Solution is derived from the esterification of benzoylmethylecgonine (cocaine) and contains a mixture of components (McDonald and Lunte, 2003). This solution is intended to be a topical analgesic to relieve pain and increase the range of motion in patients with acute inflammation. A pharmacodynamic model can only provide information about the qualitative reduction in pain as a result of topical application of complete mixture. The dermal microdialysis analysis of tins mixture revealed that the only component that penetrated the skin was hydroxypropyl braizoylecgonine (McDonald and Lunte, 2003). Thus, the analgesic activity of the I Lstcrom Solution was caused by one component. 

C. Pharmacokinetics. Cocaine Is well absorbed from all routes, and toxicity has been described after mucosal application as a local anesthetic. Smoking and intravenous Injection produce maximum effects within 1-2 minutes, while oral or mucosal absorption may take up to 20-30 minutes. Once absorbed, cocaine is eliminated by metabolism and hydrolysis with a half-life of about 60 minutes. In the presence of ethanol, cocaine Is transesterified to cocaethyl-ene, which has similar pharmacologic effects and a longer half-life than cocaine. (See also Table 11-59.)... 

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