potential applications of free drug level monitoring in cardiovascular therapy
TRANSCRIPT
Summary
Clinical Pharmacokinetics 9 (Suppl. I): 79-83 (1984) 0312.5963/84/0001-0079/$02.50/0 © ADIS Press Limited. All rights reserved.
Potential Applications of Free Drug Level Monitoring in Cardiovascular Therapyt
Raymond L. Woosley, Lyle A. Siddoway, Katherine Thompson, Irene Cerskus and Dan M. Roden Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville
Cardiovascular drugs. as a class, have low therapeutic indices, but also have great therapeutic potential. Plasma concentration information is therefore often of value when using these drugs. U'!!ortunately, the total plasma concentration may not reflect the concentration of pharmacologically active free drug, since a number of factors including disease stales, heparin anticoagulation, non-linear binding characteristics, and in vitro artefacts can affect the protein binding of these agents. This may also explain their poor dose-response relationships and great interindividual variability in plasma concentration data. Careful studies relating bound and free drug concentration to pharmacological response may provide the clinician with a better guide to therapy, and enhance the usefulness of these drugs.
Cardiovascular drugs, as a class, have a high potential for therapeutic benefit, but are also capable of causing major toxicity. For example, they are useful in the treatment of heart failure and prevention of sudden cardiac death, and yet can precipitate each of these events at clinically useful doses. Since cardiovascular drugs, as a class, have low therapeutic indices, efforts to reduce toxicity and improve response might be directed toward monitoring plasma concentrations to maintain these within the 'therapeutic range'. This, of course, presupposes a correlation between pharmacologi-
cal effect and plasma concentration of the drug. Although such a relationship exists, there is usually a great deal of overlap between the therapeutic and toxic dosages of these drugs, such that with some drugs, 30 to 40% of patients can develop side effects at plasma concentrations which are within the usual therapeutic range. Obviously, there is much room for improving the correlation between plasma drug concentration and response.
The pharmacological effect, both therapeutic and toxic, depends on the amount of drug able to interact with the target tissue receptors. Once a drug molecule binds to plasma protein it is unable to leave the vascular compartment and bind at the effector sites. Thus, only unbound (free) drug is considered to be pharmacologically active. Yet
t Supported by US Public Health Service grants Nos 5M01 RR-95 and GM31304. Dr Dan M. Roden is a recipient of the Clinician Scientist Award of the American Heart Association.
Applications in Cardiovascular Therapy
plasma concentration data usually reflect the total (bound + free) drug in plasma. Protein binding of drugs can be influenced by a number of factors, which will in turn alter the amount of available free drug. We will examine how free rather than total drug monitoring of cardiovascular drugs holds the potential for providing a better correlation with drug effects and thus improving therapy with these agents.
1. Factors Influencing Interpretation of Cardiovascular Drug Plasma Level Data 1.1 Presence of Disease-Induced Elevations in Binding Proteins
The 2 most important plasma proteins to which drugs bind are albumin and aI-acid glycoprotein (AAG), although some drugs also bind extensively to lipoproteins and a-globulins (Piafsky, 1980). In fact, while albumin is the major binding protein for most acidic drugs, other plasma proteins may be more important in the binding of cardiovascular drugs, many of which are basic compounds. Changes in the plasma concentration of these proteins will obviously alter the availability of free, pharmacologically active, compound.
AAG binds a number of antiarrhythmic drugs, including quinidine (Fremstad et aI., 1976), propranolol (Sager et aI., 1979), lidocaine (lignocaine) [Piafsky and Knoppert, 1978], and disopyramide (Haughey and Lima, 1982). Physiological stress results in an increased plasma concentration of this protein. Elevated levels have been described in many conditions, including myocardial infarction, renal failure, and postoperatively - situations where cardiovascular drugs are likely to be important. For instance, many coronary care units administer lidocaine to all patients with suspected myocardial infarction. Over the next few days, the level of AAG can change markedly depending on whether an infarct was actually sustained (about 30% of cases will not have sustained an infarction). Since AAG is an avid binder of lidocaine, ifall else is constant, patients with myocardial infarction will likely have much lower free fractions oflidocaine, higher total
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concentrations, but the same free concentrations compared with those without infarct. Not surprisingly, Wyman et a1. (1983) found a very poor relationship between the pharmacological effect of lidocaine and total blood concentrations.
Similarly, David et a1. (1982) reported that AAG is the major plasma binding protein for disopyramide. Following acute myocardial infarction, the AAG concentration was elevated when measured on days 5 and 12 compared with levels on day 1 and 3 to 20 weeks after infarct. At days 5 to 12, the ratio of bound to free disopyramide was approximately 3 times that on day 1, but returned to initial levels by 3 to 20 weeks. Thus, changes in AAG concentration paralleled changes in the amount of bound disopyramide. These data underscore the potential advantage of monitoring free drug levels in patients, especially at times of acute stress.
Grossman et a1. (1982) investigated the binding oflidocaine in patients with renal disease and found that the percentage of free lidocaine was reduced in uraemic and transplant patients, but nephrotics did not differ from control subjects. The reduction in free drug concentration was associated with increased AAG in both uraemic and transplant patients, but there was no change in AAG in the nephrotic patients. The binding ratio of lidocaine correlated well with AAG concentration in all patient groups and controls.
Propranolol and quinidine binding is also dependent on AAG concentration, the percentage of free drug being inversely proportional to AAG concentration.
1.2 Displacement of Drug from Protein Binding Sites
Aside from quantitative changes in the concentration of binding protein, displacement of drug from protein binding sites can also affect free drug levels. The displacement may be an in vitro artefact, simply as a result of the blood collection device. Decreased total plasma concentration, probably as a result of decreased protein binding and redistribution of unbound drug into red blood cells, has
Applications in Cardiovascular Therapy
been reported for a number of cardiovascular drugs, including propranolol (Cotham and Shand, 1975), quinidine (Kessler et aI., 1979), lidocaine (Stargel et aI., 1979), and disopyramide (Haughey and Lima, 1982), when samples were collected into rubberstoppered 'Vacutainer' tubes. It has been shown that a plasticiser present in the rubber stoppers cbmpetitively inhibits binding of basic drugs to AAG (Borga et aI., 1977). Although the plasticiser has since been removed from the rubber stoppers, earlier studies may well have used these tubes and the data should be suspect.
Displacement of drug from protein binding sites has also been reported after the administration of heparin. Heparin, in vivo, but not in vitro, activates lipoprotein lipases which generate free fatty acids from triglycerides. The free fatty acids in turn displace certain drugs, including lidocaine, propranolol, quinidine, phenytoin, verapamil, digoxin and digitoxin, from protein binding sites (Brown et aI., 1981; Storstein and Janssen, 1976). Storstein and Janssen (1976) found that in uraemic patients the free fraction of digitoxin rose from 2.6% to 6.9%, and free digoxin rose from 78.3% to 87.1 % during haemodialysis. Experiments in control subjects injected with heparin produced similar changes in free concentrations of the cardiac glycosides, paralleled by increases in fatty acids, suggesting that the heparin-induced release of free fatty acids displaced digoxin and digitoxin from albumin binding sites. These decreases in protein binding led to a reduction in total drug concentration. Thus, although uraemic patients on haemodialysis can be maintained on similar doses of digoxin and digitoxin as non-dialysed patients, their plasma concentrations of total drug will be lower; these should not be interpreted as warranting an increase in dosage.
A further complication is that the activated lipase continues to generate free fatty acids in vitro after blood sampling. Using lipase inhibitors, added to blood samples obtained after in vivo heparin administration, Brown et al. (1981) found a diminished heparin-induced elevation of free fatty acids and free fraction of lidocaine, although the values were still greater than control. Although the inhibitors reduced propranolol binding in control
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samples, they did not diminish the heparin-induced elevation in the free fraction of this drug. Thus, great care must be taken in interpreting plasma level data when heparin has been used to anticoagulate the patient for haemodialysis, cardiac catheterisation or for therapeutic purposes.
1.3 Non-Linear Binding Characteristics
The antiarrhythmic drug disopyramide is particularly complex in its disposition kinetics, and illustrates the problems which can arise if total drug concentrations are taken at face value when a drug demonstrates concentration-dependent plasma binding. Disopyramide presents a special problem in that unlike most drugs with concentration-dependent binding where the free concentration remains a constant fraction of the total plasma concentration, at least for concentrations within the therapeutic range, disopyramide shows a nonlinear distribution. The therapeutic range usually quoted for disopyramide is 2 to 4 p.g/ml. Meffin et aJ. (1979) calculated that doubling the total concentration from 2 p.g/ml to 4 p.g/ml would necessitate a 4-fold increase in dose rate. This doubling of the total plasma concentration would be accompanied by a 4-fold increase in free disopyramide concentration.
1.4 Interindividual Variability in Protein Binding
1.4.1 Disopyramide Meffin et al. (1979) reported great interindiv
idual variability in the degree of plasma protein binding of disopyramide. When this drug first became available, we attempted to correlate total disopyramide plasma levels with antiarrhythmic efficacy and adverse effects in 27 patients on long term therapy (Reele et aI., 1979). The drug effectively suppressed arrhythmias in 16 of the patients over a very broad range of total plasma concentrations (1.5 to 7.0 p.g/ml). 11 patients experienced serious side effects, commonly urinary retention or congestive heart failure, at total plasma concentrations usually within the therapeutic range; in only
APplications in Cardiovascular Therapy
1 case was the plasma concentration outside the usually quoted therapeutic range. In the light of present knowledge, this broad range of effective plasma concentrations and lack of definition of therapeutic and toxic concentrations is not surprising. Free disopyramide concentrations may have provided a clearer concentration-response relationship.
1.4.2 Quinidine The free fraction of quinidine has also been re
ported to be extremely variable. Kates (1980) found a range of 50 to 95% for quiziidine binding in 27 patients. This could explain why some patients demonstrate a marked drug effect at very low plasma concentrations, while others require higher concentrations for a therapeutic response. It may also explain the development of torsades de pointes at very low doses and low plasma concentrations of quinidine. This potentially lethal complication of quinidine therapy occurs in 1 to 3% of patients and is characterised by marked QT prolongation and the emergence of new, malignant arrhythmias. This has been considered an idiosyncratic reaction, but may be due to very high free drug or free active metabolite concentrations in plasma.
In general, the data base used to guide quinidine therapy is rather poor. Studies performed some 30 years ago (Sokolow and Ball, 1956) measured the plasma concentration associated with conversion of atrial fibrillation. A wide range of concentrations was found, but most patients' arrhythmias converted at a plasma concentration of 3 to 8 J.Lg/ mi. These data have been extrapolated to ventricular arrhythmias, and are still the basis for much of the therapeutic drug level monitoring for quinidine. The assay used in these studies measured both quinidine and its metabolites. More recently, with the use of an HPLC assay specific for quinidine, a therapeutic range of 0.72 to 5.92 J.Lg/ml in patients with ventricular extrasystoles has been suggested (Carliner et ai., 1980). However, the metabolites of quinidine may have pharmacological activity (Holford et ai., 1981). Since quinidine is a notoriously poorly tolerated drug, there is a need for careful studies delineating the relationship be-
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tween plasma concentrations of quinidine and its known metabolites and both therapeutic and toxic activity. Monitoring of free quinidine concentrations and perhaps free concentrations of metabolites may provide a better guide to therapy. Indeed, Woo and Greenblatt (I979) studied the relationship of acute ECG changes due to intravenous quinidine in 12 healthy volunteers and found a better correlation with free than with total drug concentrations. Heart rate, QRS duration and QTc were all significantly related to free quinidine concentrations, while QTc alone correlated with total drug concentration.
2. Application of Free Level Monitoring in Optimising Cardiovascular Therapy
The clinical significance of changes in plasma protein binding depends on a number off actors for a particular drug, including its clearance profile, the extent of protein binding, and its distribution kinetics. For drugs whose clearance is restrictive, that is, dependent on free fraction, a decrease in protein binding would result in increased systemic clearance and a decrease in total drug concentration, although the concentration of free drug would be unchanged due to increased ciearance. Drugs such as propranolol and lidocaine which are avidly extracted by the liver or kidneys would show an increase in free concentration as a result of decreased binding, although the total drug concentration would remain unchanged. Since free drug in the plasma equilibrates with that at effector receptor sites, the increase in free concentration might result in exaggerated pharmacological activity. In any case, predictions regarding clinical effect can only be general, at best, given the large interindividual variations in protein binding and the effects of liver and renal disease on drug clearance.
Much criticism of therapeutic drug monitoring stems from a weak correlation between total plasma concentration and pharmacological effect and the notion that physicians might treat according to the plasma level, losing sight of the total clinical picture. There is probably some validity to these criticisms. In many cases, physicians can, and do, go
Applications in Cardiovascular Therapy
by Clinical evidence alone. However, when concomitant disease states, stress, and other factors complicate therapy, plasma level information can serve a useful purpose in guiding therapy. It must, however, reflect the concentration of drug available for pharmacological activity, taking into account active metabolites and possible interfering factors.
Cardiovascular drugs are considered to have low therapeutic indices; it may be that we simply are not using them as effectively as we might. Optimum use of such drugs can only come with better data bases established by controlled clinical trials associating total and free concentration of drug with pharmacological effect. Such studies are difficult to perform, but may well be worth the effort.
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Author's address: Dr Raymond L. Woosley, Division of Clinical Pharmacology. Vanderbilt University School of Medicine. Nashville, Tenn. 37232 (USA).