Isoproterenol pharmacokinetics

The sympatholyfics of this type interfere with the /3i- and /S2-adrenoceptor subtypes. Via this mechanism the stimulating influence of the sympathetic nervous system on the heart and the metabolism and its inhibiting influence on smooth muscle is blocked. /3-Adrenoceptor blocking agents, or /3-blockers, mostly have a typical isoproterenol-like structure with an isopropylamine or a tertiary butylamine group and a substituted phenoxy moiety bound to the isopropanol backbone. The substituents determine the physicochemical properties of the particular drug and thereby its pharmacokinetic proflle. 

Pharmacokinetics Phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. The pharmacologic effects of phenylephrine are terminated at least partially bythe uptake of the drug into the tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified. 

Pharmacokinetics Isoproterenol can be absorbed systemically by the sublingual mucosa but is more reliably absorbed when given parenterally or as an inhaled aerosol. It is a marginal substrate for COMT and is stable to MAO action. 

These results show that acipimox acts to inhibit cAMP-stimulated hpolysis through suppression of intracellular cAMP levels, with a subsequent decrease in PKA activity. The anti-lipolytic activity of acipimox is associated with a quantitative shift of HSL from the LD to the cytosol in rat adipocytes, suggesting that, by decreasing intracellular cAMP levels, acipimox can reduce the association of HSL with TAG substrate of the LD. Pharmacokinetic studies show that the plasma concentration of acipimox in man after a single 250 mg oral dose reaches 33 gM, and remains above 7 gM for 6-8 h [448]. In comparison, acipimox is a potent anti-lipolytic agent at a concentration of 10 gM and above, in human adipose tissue stimulated maximally and sub-maximally by isoproterenol [449]. Thus, plasma acipimox levels correlate well with its in vitro effect on hpolysis and cAMP synthesis in rat adipocytes. 

Catechol bioisosteres are often utilized to overcome pharmacokinetic and toxicological issues linked to this moiety. SuccessfiJ examples of bioisosteric replacement of catechols can be found in catecholamines. Benzimidazole analogues of the adrenergic agonists norepinephrine and isoproterenol (Figure 2.10) were... 

Microdialysis with off-line analysis has also been successfully employed for the investigation of the pharmacokinetics of an enantiomeric drug, isoproterenol [68,69]. CE has been shown to be an extremely powerful method for the separation of enantiomeric compounds. It is possible to place the chiral selector in the run buffer, precluding the need for very expensive modified LC columns. Due to the small volume requiranenfs of CE, very little additive is required. 

CEEC with methyl-O-P-cyclodextrin as the modifier was used to monitor the pharmacokinetics of (-) and (+) isoproterenol by I.V. microdialysis sampling. Using a combination of peak stacking and electrochemical detection, limits of detection of 0.6 ng/mL were achieved. Isoproterenol has a very short half-life. A flow rate of 1 pL/min was used for the microdialysis sampling. It was possible to analyze the 1 pL samples and monitor the pharmacokinetics of the isoproterenol enantiomers with a temporal resolution of one minute (Figure 14). 

Figure 14 Pharmacokinetic profile for protein-free isoproterenol (A) (+) isoproterenol and (B) (-) isoproterenol. (Reprinted with permission from Ref. 69.)...

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