Anesthetics pharmacokinetics

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. 

Several general anesthetics (isoflurane, ketamine, thiopental, etomidate) have one or more chiral carbons and thus exist as pairs ot stereoisomers. In many cases one stereoisomer is more potent than the other at providing anesthesia despite little difference in pharmacokinetics (Christensen Lee, 1973 Benthuysen et ak, 1989 Harris et ak, 1992 Dickinson et ak, 1994). The stereoisomers have equal hydrophobic properties and partition equally into the membrane. 

PHARMACOKINETIC CHARACTERISTICS INFLUENCING THE CLINICAL APPLICATION OF INTRAVENOUS AND INHALATIONAL ANESTHETICS ... 

Mechanism of Action An amide-type local anesthetic that shortens the action potential duration and decreases the effective refractory period and automaticity in the His-Purkinje system of the myocardium by blocking sodium transport across myocardial cell membranes. Therapeutic Effect Suppresses ventricular arrhythmias. Pharmacokinetics Very rapidly and completely absorbed following PO administration, Protein binding 10%, Metabolized in liver. Excreted in urine. Half-life 15 hr. 

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. 

Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992 76 334—41. 

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26-2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect. 

Table 26-2 Pharmacokinetic Properties of Several Amide Local Anesthetics. ...

Wood M. Pharmacokinetic drug interactions in anesthetic pratffiteB.Pharmacokinet, 1991 21 285-307. 

Pharmacokinetic properties of the intravenous anesthetics are summarized in Table 25-2. 

Tabrizi-Fard, M.A. and H.L. Fung. 1998. Effects of nitro-L-arginine on blood pressure and cardiac index in anesthetized rats a pharmacokinetic-pharmacodynamic analysis. Pharm. Res. 15 1063-1068. 

Veteran s Health Administration Office of Quality and Performance. Local Anesthetics Pharmacologic, Pharmacokinetic, and Clinical Characteristics. Management of Postoperative Pain. Available online at http //www.oqp.med.va.gov/cpg/PAJN/pain cpg/content/Pharmac/tableLA2.htm. 

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

Fong KL, Crysler CS, Mico BA, Boyle KE, Kopia GA, Kopaciewicz L, Lynn RE. Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion. Drug Metab Dis 1988 16 201-6. 

Feldman HS, Dvoskin S, Halldin MH et al. (1997) Comparative anesthetic efficacy and pharmacokinetics of epidurally administered ropivacaine and bupivacaine in the sheep. Regional Anesthesia 22 451 160... 

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). 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

---