Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide

Jm, Strong; De, Mayfield; Aj, Atkinson; Bc, Burris; Raymon, Frank; Lt, Webster

doi:10.1002/cpt1975172184

Cited by 67 publications

(16 citation statements)

References 5 publications

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“…Elevated plasma concentrations and significant toxic effects have been observed in the most critically ill patients, notably those with congestive heart failure (Halkin et al 1975;Prescott et al 1976;Thomson et al 1973). If a patient population contains a significant percentage of cirrhotics and/or subjects with severe refractory heart failure, monitoring of free lignocaine concentrations as well as potentially toxic metabolites (monoethylglycinexylidide, glycinexylidide) could be useful (Drayer et al 1983;Halkin et al 1975;Strong et al 1975). However, it should be recalled that turnaround time must be of the order of 1 hour to have a major therapeutic impact.…”

Section: Lignocaine (Lidocaine)mentioning

confidence: 99%

Free Drug Concentration Monitoring in Clinical Practice

Svensson

Woodruff

Baxter

et al. 1986

Clinical Pharmacokinetics

169

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Recent advances in techniques to determine free drug concentrations have lead to a substantial increase in the monitoring of this parameter in clinical practice. The majority of drug binding to macromolecules in serum can be accounted for by association with albumin and alpha 1-acid glycoprotein. Albumin is the primary binding protein for acidic drugs, while binding to alpha 1-acid glycoprotein is more commonly observed with basic lipophilic agents. Alterations in the concentrations of either of these macromolecules can result in significant changes in free fraction. Diseases such as cirrhosis, nephrotic syndrome and malnourishment can result in hypoalbuminaemia. Burn injury, cancer, chronic pain syndrome, myocardial infarction, inflammatory diseases and trauma are all associated with elevations in the concentration of alpha 1-acid glycoprotein. Treatment with a number of drugs has also been shown to increase alpha 1-acid glycoprotein serum concentrations. A wide variety of biological fluids have been examined for their ability to provide an estimation of free drug concentration at receptor sites. The most useful fluid for estimating free drug concentrations appears to be plasma or serum, with subsequent treatment of the sample to separate free and bound drug by an appropriate technique. The two most widely used methods are equilibrium dialysis and ultrafiltration. Of these two, ultrafiltration has the greatest utility clinically because it is rapid and relatively simple. The major difficulty associated with this method involves the binding of drug to the ultrafilters, but significant progress has been made in solving this problem. Several authors have endorsed the routine use of free drug concentration monitoring. Data examining the clinical usefulness of free drug concentration monitoring for phenytoin, carbamazepine, valproic acid, disopyramide and lignocaine (lidocaine) are reviewed. While available evidence suggests that free concentrations may correlate with clinical effects better than total drug concentrations, there are insufficient data to justify the recommendation of the routine use of free drug concentration monitoring for any of these agents at present.

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Section: Lignocaine (Lidocaine)mentioning

confidence: 99%

Free Drug Concentration Monitoring in Clinical Practice

Svensson

Woodruff

Baxter

et al. 1986

Clinical Pharmacokinetics

169

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“…Two active and potentially toxic metabolites, monoethylglycinexylidide (MEGX) (Halkin et al, 1975) and glycinexylidide (GX) (Strong et al, 1975), are formed. These metabolites are eliminated by both metabolic and renal routes.…”

Section: Lignocaine (Lidocaine)mentioning

confidence: 99%

Pharmacokinetics in Patients with Cardiac Failure

Benowitz

Meister

1976

Clinical Pharmacokinetics

131

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Cardiac failure is often associated with disturbances in cardiac output, autonomic nervous system activity, central and systemic venous pressures, and sodium and water metabolism. These disturbances influence the extent and pattern of tissue perfusion, may lead to tissue hypoxia and visceral congestion, and may alter gastrointestinal motility. By these mechanisms, cardiac failure potentially affects absorption and disposition characteristics of drugs, which may necessitate adjustment in dosage regimen for optimum therapy. Lignocaine is the drug which has been studied most extensively in cardiac failure. Volumes of distribution and clearance are decreased. As a drug whose metabolism is largely limited by liver blood flow, decreased blood flow to the liver accounts for some of the change in clearance, but impaired hepatic metabolism appears also to play a role in some patients. Accumulation of active metabolites of lignocaine and procainamide in patients with cardiac failure can influence therapeutic and toxic effects. Theophylline metabolism, which is largely independent of blood flow, appears to be reduced significantly in patients with severe cardiac failure and necessitates reduction of dosage. In the presence of severe cardiac failure, digoxin clearance may be less than anticipated on the basis of estimates of renal function. Quinidine plasma levels may be higher after single doses due to reduced volume of distribution. Quinidine metabolites are believed not to be pharmacologically active but may create confusion with nonspecific assays. Specific assays are recommended in cardiac failure, especially complicated by renal insufficiency. Data are lacking relating pharmacokinetic alterations to haemodynamic measurements in patients with cardiac failure. Whereas the direction of change in pharmacokinetic parameters may be predicted, variability in the magnitude of change is so great that determination of drug concentration in blood remains as essential adjunct to therapy.

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“…It is generally accepted that the therapeutic effect of antidepressant agents may be a consequence of an increased availability of norepinephrine at postsynaptic sites. the feedback inhibition of brain norepinephrine neurons by tricyclic antidepressants was due to an a-receptor mediation (4). This finding would explain the increase of the availability of norepinephrine at postsynaptic receptor sites after an antidepressant treatment.…”

Section: Resultsmentioning

confidence: 86%