Peter J. Meffin

Role of concentration-dependent plasma protein binding in disopyramide disposition

Plasma disopyramide concentration-time data and plasma protein binding measurements were obtained in 12 patients requiring disopyramide for suppression of their cardiac arrhythmias. The fraction of disopyramide unbound to plasma proteins varies from approximately 0.19 to 0.46 over the therapeutic range of total plasma concentrations (2–8 mg/liter). Data from single and multiple intravenous doses were analyzed using two models based on the hypothesis either that clearance is independent of the total disopyramide plasma concentration (total clearance model) or that clearance is independent of the concentration of disopyramide unbound to plasma proteins (free clearance model). This analysis indicates that only the free clearance model satisfactorily describes the data as a linear system. Using the free clearance model and data obtained from single doses, multiple intravenous infusions were designed for each patient which would rapidly attain and maintain predetermined plasma disopyramide concentrations. The calculated and observed disopyramide concentrations were in close agreement. In the 12 patients studied, at any given total disopyramide plasma concentration, there was an approximately twofold range in the fraction of disopyramide unbound to plasma proteins. Mean plasma protein binding data are therefore of little value in a given patient for predicting free disopyramide concentrations from measurements of total disopyramide concentration. Difficulties in the clinical management of patients receiving disopyramide, resulting from the nonlinear disposition of the usually measured total disopyramide concentrations, are discussed.

Enhanced Bioavailability and Decreased Clearance of Analgesics in Patients with Cirrhosis

The effect of moderate cirrhosis on the bioavailability and systemic clearance of three model analgesic compounds (pethidine, pentazocine, and salicylamide) with substantial first-pass metabolism was examined in 8 cirrhotic subjects and 4 agematched healthy controls. There was a 46% decrease in the clearance of pentazocine and a 278% increase in bioavailability. The corresponding figures for pethidine were 36% and 81%. The area under the plasma curve after oral salicylamide was increased by 551% in cirrhotic subjects compared with controls. This study demonstrated that drugs with the highest hepatic clearance will have the largest relative increases in bioavailability in cirrhotic patients due to portosystemic shunting. The decrease in clearance and increase in bioavailability will have multiplicative, rather than simply additive, effects on total area under the curve and, if related, pharmacologic response.

Influence of congestive heart failure on blood levels of lidocaine and its active monodeethylated metabolite

The blood concentrations of lidocaine and its active monodeethylated metabolite, monoethylglycinexylidide (MEGX), were measured in 31 patients who were receiving infusions of lidocaine intravenously. In 3 patients who were studied intensively, the elimination half‐life of MEGX was 120 min, which was similar to the elimination half‐life of lidocaine (139 min). An additional 3 patients demonstrated a higher ratio of the concentration in blood of MEGX to lidocaine, and the MEGX may have contributed, in 1 patient, to the central nervous system toxicity that occurred during the infusion. Elevated concentrations of MEGX in blood were associated with congestive heart failure (r = 0.5, p = 0.004). Our data suggest that the elimination of MEGX may be decreased in patients with depressed cardiac output and sympathomimetic compensation.

Clinical pharmacokinetics of antiarrhythmic drugs.

HE therapeutic and toxic effects of antiarrhythmic drugs depend on drug concentration at the sites of action. Since a specific receptor for most antiarrhythmic drugs has not been defined, it is not possible to determine concentrations at these sites. However, drug concentrations in body fluids, such as plasma or whole blood, often correlate with pharmacologic response. Disposition of the drug in the body is accomplished by multiple processes: drug absorption, distribution into tissue, transfer through body membranes, removal through the urine and other excreta, and chemical transformation in the liver and other organs. These processes are largely responsible for determining concentration of the drug in blood or plasma and at the drug’s site of action. Intersubject variation in drug disposition accounts for much of the variability in response observed when a standard dose of drug is given to a series of patients. Thus, drug concentration correlates better with pharmacologic and clinical response than does drug dose. The strategy of clinical pharmacokinetics is to adjust drug dose to produce blood or plasma concentrations with a high probability of producing the desired response while avoiding toxicity. Pharmacokinetics is the study of drug disposition, and clinical pharmacokinetics is its application to the treatment of patients. Mathematical models are useful in predicting drug concentrations in various parts of the body in relation to dose, route of administration, and time. Although the mathematical details of these models may become complex, an understanding of the general principles of drug disposition permits the clinician more effective use of each available antiarrhythmic drug for patients with heart disease. Application of these 1 principles also enables clinicians to anticipate

Antiarrhythmic drugs: clinical pharmacology and therapeutic uses.

SummaryThe effective therapy of cardiac arrhythmias requires accurate cardiac diagnosis, identification and treatment of specific initiating factors, and appropriate drug therapy. If antiarrhythmic drug therapy is required, therapeutic goals should be determined in advance and treatment that is based on sound physiological and pharmacokinetic rationale should be initiated. Careful follow-up should be undertaken, including monitored documentation of drug effects, observation for side-effects, and drug plasma concentration-response correlations. Antiarrhythmic drugs differ in specific patterns of absorption, volumes of distribution, plasma protein binding and elimination (metabolism and excretion). Disease states may alter these properties. Only by applying a thorough understanding of each drug’s individual pharmacological characteristics can maximum benefit be obtained.Lignocaine is effective against ventricular arrhythmias of many aetiologies, and in the acute situation is usually the agent of first choice. Recently, prophylactic lignocaine has been advocated for younger patients with acute myocardial infarction. Quinidine has a long history of usefulness in both ventricular and supraventricular arrhythmias. It is effective in maintaining sinus rhythm after cardioversion from atrial fibrillation or flutter, and is perhaps the most widely used oral agent in the management of chronic ventricular arrhythmias. Procainamide is a versatile drug with uses comparable with those of quinidine. In addition, it may be administered parenterally in an acute or subacute setting. The anticonvulsant drug phenytoin remains an agent of somewhat limited utility. However, it is recognised as a primary agent for the treatment of digitalis-induced arrhythmias.β-Adrenoceptor blocking drugs are useful for treating arrhythmias due to excessive catecholamine release, for digitalis excess, for therapy of acute and chronic supraventricular arrhythmias, for ventricular arrhythmias unresponsive to first-line agents, and potentially as prophylaxis against sudden death in ambulatory patients with coronary artery disease. These agents have also been useful in preventing tachyarrhythmias associated with Wolff-Parkinson-White syndrome, and in prophylaxis of delayed repolarisation arrhythmias. Propranolol is better tolerated but less effective than quinidine or procainamide in treating chronic ventricular arrhythmias.Bretylium may be useful in the treatment of ventricular fibrillation that is refractory to conventional therapy. Tocainide and mexiletine are relatively new, orally effective agents with structural similarities to lignocaine. Disopyramide, another new antiarrhythmic agent, has actions and versatility which resemble those of quinidine, but it may be better tolerated. Verapamil, whose mechanism of action involves blockade of slow ionic currents, appears to be a highly effective drug for therapy of acute supraventricular tachycardia. Aprindine, amiodarone, and acebutolol are examples of other new antiarrhythmic agents whose properties are discussed.Benefits of antiarrhythmic therapy must always be weighed against the risk of side-effects. For lignocaine, these are primarily neurological and are related to plasma concentration. An initial loading dose or doses followed by constant infusion represents the correct mode of administration. Diseases which alter hepatic blood flow affect lignocaine metabolism, and thus patients with heart failure should receive both smaller initial boluses and smaller infusion rates than normals. The major problems with quinidine therapy are the high incidence of side-effects, such as diarrhoea, leading to intolerance, and the risk, if small, of sudden death from idiosyncratic quinidine-induced ventricular fibrillation. Intravenous administration of procainamide must be carefully monitored to avoid hypotension. In patients with heart failure, smaller boluses should be given and maintenance doses may need to be reduced. The necessity for frequent (3- to 4-hourly) doses and the high incidence of drug-induced lupus after long-term usage have decreased the utility of procainamide for chronic arrhythmia control.With intravenous administration, phenytoin may cause hypotension if administered rapidly. Toxicity with oral therapy may be manifested by nystagmus, ataxia and lethargy. Propranolol is contraindicated where cardiac function depends upon sympathetic stimulation; congestive heart failure has been precipitated in this setting. Sudden withdrawal of propranolol in non-hospitalised patients with severe anginal symptoms may be associated with serious rebound phenomena. When used intravenously, much smaller dosages than for oral use are used, and slow incremental administration with blood pressure and electrocardiographic monitoring is indicated.Side-effects with mexiletine and aprindine have been problematic and include cardiovascular and neurological toxicity. The most frequent side-effects of oral disopyramide are anticholinergic, including dry mouth, constipation and urinary hesitancy. The myocardial depressant potential of verapamil contraindicates its use in patients with marked underlying cardiac dysfunction.

Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide

To study the influence of acute hepatic disease on the disposition of tolbutamide, we measured tolbutamide plasma protein binding and pharmacokinetic parameters after intravenous administration of the drug to 5 subjects during and after apparent recovery from acute viral hepatitis. Although during the acute phase of illness protein binding of the drug decreased in all, volume of distribution of tolbutamide (0.15 ± 0.03 L/kg) did not change. Clearance based on total concentration of tolbutamide in plasma increased in all subjects during the acute phase of study (26 ± 5.4 ml/hr/kg) in comparison to the recovery phase (18 ± 2.8 ml/hr/kg, p < 0.02). Protein binding decreased after unconjugated bilirubin was added to plasma from the recovery phase, but not to the extent observed during the acute phase of illness at comparable levels of bilirubin. Clearance based on unbound drug concentration, calculated by dividing the observed plasma clearance by the fraction of unbound drug in plasma, did not differ significantly between the 2 study phases (300 ± 47 and 260 ± 39 ml/hr/kg). These observations suggest that the increase in clearance based on total drug concentration in plasma during hepatitis can be attributed solely to decreased plasma binding. This decrease in binding may be attributed in part, but not entirely, to increased concentration of bilirubin during illness. The concentration of unbound drug in plasma at steady‐state is determined by the rate of drug administration and the clearance based on unbound drug. If this clearance does not change during hepatic disease, no dosage alterations for tolbutamide and other comparable drugs are necessary to maintain a constant concentration of unbound drug.

High-pressure liquid chromatographic analysis of drugs in biological fluids: III. Analysis of disopyramide and its mono-n-dealkylated metabolite in Plasma and urine☆

A high-pressure liquid chromatographic analysis for disopyramide (I) and its mono-N-dealkylated metabolite (II) in plasma and urine is described. The analysis, in which I and II together with an internal standard are chromatographed as ion pairs with heptanesulphonic acid, employs a simple and rapid method of sample preparation. The method is more sensitive, reproducible, and rapid than previously reported gas chromatographic methods.

Influence of acute viral hepatitis on phenytoin kinetics and protein binding

Patients with liver disease are thought to have abnormal responses to drugs metabolized by the liver. although supportive evidence is sparse. The influence of acute viral hepatitis on the pharmacokinetics and protein binding of phenytoin (DPH) was examined in 5 patients. A longitudinal study design was used so that each patient acted as his own control. DPH clearance was unaffected by acute viral hepatitis over the concentration range studied. but the percentage of un bound DPH increased by an average of nearly one‐third during acute viral hepatitis. A small decline in serum albumin concentration and elevated serum bilirubin levels may be responsible for the alterations in protein binding. These results indicate that acute inflammatory liver disease has complex and perhaps paradoxical effects on drug disposition. Clinical and laboratory observations including plasma drug concentrations. still provide the best means for adjusting dosage regimens in patients with fluctuating hepatic function.

Influence of viral hepatitis on the disposition of two compounds with high hepatic clearance: lidocaine and indocyanine green.

The disposition of lidocaine and indocyanine green was studied in 6 individuals during and after recovery from an episode of acute viral hepatitis. Both compounds are highly cleared from the blood by the liver so that clearance of both should be sensitive to changes in hepatic blood flow. During the acute phase of illness, clearance of indocyanine green decreased without apparent change in volume of distribution, whereas clearance of lidocaine, decreased in 4, did not change in I, and increased in 1 during the acute phase of hepatitis. Volume changes for lidocaine were also variable. We observed no significant correlation between any parameters of lidocaine disposition and any of several tests of liver function or any parameters of indocyanine green disposition. The absence of correlation between pharmacokinetic parameters of the disposition of lidocaine and indocyanine green indicates that the influence of hepatic disease on the hepatic processes that lead to the elimination of each compound is not predictable. No useful clinical correlates are now available by means of which to predict lidocaine disposition in patients with altered hepatic function.

Prazosin determination by high-pressure liquid chromatography using fluorescence detection.

A high-pressure liquid chromatographic procedure using fluorescence detection for the analysis of prazosin in whole blood and plasma is described. It employs a simple and rapid method of sample preparation. Prazosin and an internal standard are chromatographed as ion-pairs with pentane sulfonic acid. The method is sensitive and reproducible with accurate detection as low as 0.2 ng/ml in whole blood and 0.5 ng/ml in plasma with a coefficient of variation of 5.6% and 5.4% respectively. If propranolol or quinidine is present, modifications of chromatographic conditions are used which separate prazosin from these two drugs. Prazosin is stable when frozen for a long period or refrigerated for short periods.