Pharmacokinetic and Pharmacodynamic Considerations in Drug Therapy of Cardiac Emergencies

Pentel, Paul R.; Benowitz, Neal L.

doi:10.2165/00003088-198409040-00001

Cited by 36 publications

(8 citation statements)

References 139 publications

(32 reference statements)

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“…GFR reduction by inflammatory stimuli has been reported previously (19)(20)(21). In clinical trials, GFR reduction was reported during inflammation especially when blood flow and/or blood pressure were substantially reduced, for example, in hypodynamic septic shock associated with a lowered cardiac output, which leads to a significant reduction in the clearance of a variety of drugs (34). In previous studies, i.p.…”

Section: Discussionmentioning

confidence: 70%

Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil

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Smith

2013

Antimicrob Agents Chemother

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bThe purpose of this study was to determine if the disposition of cefadroxil, an ␣-amino-containing ␤-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma cefadroxil concentration-time profiles.

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Section: Discussionmentioning

confidence: 70%

Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil

Huh

Keep

Smith

2013

Antimicrob Agents Chemother

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“…Particularly if such a technique were minimally invasive, such as positron emission tomography (PET), this might be used to examine perturbations in myocardial drug handling which probably occur during cardiac emergencies (Pentel & Benowitz 1984). Thus, an individual approach to therapy with cardioactive drugs might become possible.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Uptake of Drugs and Clinical Effects

Horowitz

Powell

1986

Clinical Pharmacokinetics

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The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Data on blood flow to the vital organs are, however, scarce. an increase in hepatic flow occurs with isoproterenol or glucagon, and a decrease with p-adrenoceptor antagonists (Pentel & Benowitz 1984). A decrease in hepatic blood flow, as measured by the clearance of indocyanine green, has been reported (Koska et al 1981).…”

Section: Technical and Physiological Aspects 0/ Cardiopulmonary Bypassmentioning

confidence: 98%

Cardiopulmonary Bypass and the Pharmacokinetics of Drugs

Buylaert¹,

Herregods²,

Mortier³

et al. 1989

Clinical Pharmacokinetics

119

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Cardiopulmonary bypass is accompanied by profound changes in the organism that may alter the pharmacokinetics of drugs. Drug distribution can be altered, for example, by changes in blood flow and by haemodilution, with a decrease in protein binding; a decrease in the elimination of some drugs can be caused by impairment of renal or hepatic clearance, due, for example, to lowered perfusion and hypothermia. The subject was reviewed in the Journal in 1982, and the emphasis of the present review is on new data related to specific drugs. The following substances are dealt with: benzodiazepines, cephalosporins, digitalis glycosides, general anaesthetics, glyceryl trinitrate (nitroglycerin), lignocaine (lidocaine), muscle relaxants, nitroprusside, opiates, papaverine and propranolol. For many of these substances an abrupt decrease has been observed in serum concentration upon initiation of bypass, which is explained by haemodilution and an increase in distribution due to decreased protein binding. For nitrates and some opiates, adsorption to the bypass apparatus was shown to be important. The gradual increase in serum concentrations seen during cardiopulmonary bypass with some drugs after the initial fall is usually explained by redistribution of the drug and/or decrease in its elimination. The same phenomena are thought to explain why in the post-bypass period a concentration increase occurs, or at least a slower decrease than expected. However, drug elimination has been directly measured in only a few studies. The short duration of the bypass procedure and the continuous changes during the process hamper a rigorous pharmacokinetic evaluation. Studies allowing more precise understanding of the mechanisms underlying the observed concentration changes are needed, but are difficult to design. Similarly, more data are awaited on the pharmacodynamic and clinical consequences of the concentration changes.

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Pharmacokinetic and Pharmacodynamic Considerations in Drug Therapy of Cardiac Emergencies

Cited by 36 publications

References 139 publications

Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil

Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil

Myocardial Uptake of Drugs and Clinical Effects

Cardiopulmonary Bypass and the Pharmacokinetics of Drugs

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