There is a large and ever-growing list of these medications, too many to include here. TDM data for some members of this group are summarized in Table 37-25. Several have been selected for more detailed discussion here.
Procainamide. Procainamide is used to control certain ventricular arrhythmias and can be given orally or intravenously. Only about 10% is bound to serum protein. Maintenance is usually achieved by oral medication. About 85% of the oral dose is absorbed, mostly in the small intestine. About 50% of the drug is excreted unchanged by the kidneys. About 50% is metabolized, predominantly by the liver. The major metabolite of procainamide is N-acetylprocainamide (NAPA), which constitutes about 25%-30% of the original dose (7%-40%). NAPA is produced in the liver by a process known as N-acetylation. It has antiarrhythmic properties about equal to that of its parent compound. About 10% is bound to serum protein and about 85% is excreted unchanged by the kidneys. It has a serum half-life about twice that of procainamide. Therefore, NAPA levels continue to rise for a time after procainamide levels have stabilized. There is approximately a 1:1 ratio of procainamide to NAPA after both have equilibrated. Poor liver function may decrease NAPA formation and produce a high ratio (> 1.0) of procainamide to NAPA (i.e., less NAPA relative to the amount of procainamide). Even though procainamide degradation may be decreased, it is only 25%-30% metabolized in the liver, so that it is not affected as much as NAPA. On the other hand, poor renal function decreases NAPA excretion and decreases the procainamide/NAPA ratio to less than 1.0 (i.e., more NAPA relative to procainamide). Even though procainamide excretion may also be decreased, the amount of NAPA excreted through the kidneys is much higher than the amount of procainamide, so that poor renal function affects NAPA proportionally more than procainamide. Another factor is the acetylating process of the liver, which is an inherited characteristic. Isoniazid and hydralazine are also metabolized by this system. About one half of the population are slow acetylators and about one half are fast acetylators. Fast acetylation produces more NAPA (tending to produce a procainamide/NAPA ratio < 1.0), and slow acetylation produces less NAPA (procainamide/NAPA ratio > 1.0). Assessment of acetylation status is dependent on adequate renal function, since poor renal function can affect the procainamide/NAPA ratio. About 50% of patients on long-term procainamide therapy develop antinuclear antibodies, and up to 30% may develop a syndrome very similar to systemic lupus erythematosus. Slow acetylators are more likely to develop these conditions than fast acetylators.

Since both procainamide and NAPA have antiarrhythmic action and since several factors influence their levels and their relationship to each other, most authorities recommend that both be assayed and that therapeutic decisions be based on the sum of both rather than on either one alone. Therapeutic range for the combination of procainamide and NAPA is 10-30 µg/ml (42.50-127.47 µmol/L). Specimens for TDM are usually obtained just before the next scheduled dose to evaluate adequacy of dosage. Peak levels or specimens drawn during symptoms are needed to investigate toxic symptoms.

There are two types of procainamide oral preparations, standard (relatively short acting) and sustained release (SR). For the standard type, peak absorption levels are usually reached in about 1.5 hours (range, 1-2 hours) after an oral dose. However, some persons absorb procainamide relatively slowly, and the peak may be delayed up to 4 hours after the dose, close to the time one would expect a trough level. In one study, this occurred about one third of the time. Therefore, some investigators recommend both peak and trough for initial evaluation. Patients with acute myocardial infarction or cardiac failure are more likely to have delayed absorption. Serum half-life is about 3 hours (2-4 hours). Time to steady state is about 18 hours (11-20 hours). Therefore, the half-life is considered a short one, and there is a greater fluctuation in serum values compared with an agent with a long half-life. The peak level after oral SR procainamide occurs about 2 hours after the dose (range, 1-3 hours) but may not occur until later in patients with slow absorption. Time to steady state is about 24-30 hours.

Lidocaine. Lidocaine (Xylocaine) hydrochloride is a local anesthetic that has antiarrhythmic properties. Used as an antiarrhythmic, it is generally given intravenously to patients who are seriously ill. Lidocaine is lipid soluble and distributes rapidly to many tissues. When it is given as a single bolus, plasma levels fall rapidly, with perhaps as much as a 50% decrease in about 20 minutes. On the other hand, drug given by IV infusion reaches a plateau rather slowly because so much of the drug is distributed to peripheral tissues. Therefore, administration is usually done with one or more bolus loading dose injections followed by IV infusion. The half-life of lidocaine is 1-2 hours, and time to steady state is 5-10 hours (5-12 hours). About 70% is protein bound; of the total that is protein bound, about 30% is bound to albumin and 70% to alpha-1 acid glycoprotein. Lidocaine is about 90% metabolized in the liver, with 5%-10% excreted unchanged by the kidneys. The major hepatic metabolites of lidocaine also have some antiarrhythmic effect. The primary metabolites are themselves further metabolized in the liver, with less than 10% of the primary metabolites being excreted unchanged in urine.

Conditions that produce an increase in plasma lidocaine levels are severe chronic liver disease (decreased drug inactivation), chronic renal disease (decreased excretion), and congestive heart failure (reduced volume of distribution). In acute myocardial infarction, there is increase in the binding protein alpha-1 acid glycoprotein and a subsequent increase in plasma total lidocaine values; however, bound drug is pharmacologically inactive, and the nonbound active fraction often does not increase. Propranolol has been reported to decrease lidocaine clearance, producing higher plasma values.

Complications related to lidocaine therapy have been reported in 6%-20% of cases. Therapeutic drug monitoring requires a method that is fast and that can be performed without much delay. HPLC and EMIT are the two most frequently used methods. Colorimetric methods are also available. It has been recommended that lidocaine specimens be drawn 12 hours after beginning therapy and then daily. In seriously ill patients, in those whose arrhythmias persist in spite of lidocaine, and when lidocaine toxicity is suspected, assay every 12 hours could be helpful. The therapeutic range is 1.5-5 µg/ml.

Tocainide. Tocainide (Tonocard) is an analog of lidocaine that also is used to treat ventricular arrythmias. Tocainide has some advantages over lidocaine since tocainide can be given orally and has a longer half-life (about 15 hours; range, 12-18 hours) due to much less first-pass hepatic metabolism. The half-life may be increased with severe liver disease or chronic renal failure. About 10% is bound to serum protein. The metabolites of tocainide are excreted in the urine and do not have antiarrythmic activity. Peak serum levels are reached 1.5-2.0 hours after an oral dose. Steady state is reached in 3 days. Therapeutic range is 4-10 µg/ml. Assay is usually done by HPLC.

Quinidine. Quinidine has been used for treating both atrial and ventricular arrhythmias. There are two forms of quinidine: the sulfate and the gluconate. Both are available for oral administration in both regular and long-acting (SR) preparations. The gluconate form can be given intravenously. Oral regular quinidine sulfate has a time to peak value of about 2 hours (range, 1-3 hours), a serum half-life of about 6 hours (range, 5-8 hours), and a time to steady state of about 24 hours. Regular oral quinidine gluconate has a time to peak value of about 4 hours. SR quinidine sulfate (Quinidex) has a time to peak value of about 2 hours, a serum half-life of about 20 hours, and a time to steady state of about 4 days. SR quinidine gluconate (Quiniglute, Duraquin) has a time to peak value of about 4 hours and a half-life of about 10 hours. However, when the SR preparations are used, there is relatively little fall in serum levels after the initial dose before subsequent doses. About 80% of quinidine (literature range, 60%-90%) is bound to serum proteins. Quinidine is metabolized by the liver, with about 10%-20% excreted unchanged in urine by glomerular filtration. Urine excretion is influenced by urine pH.

Factors that may decrease quinidine levels include hypoalbuminemia, drugs that compete for albumin binding, and drugs that activate hepatic enzyme activity, such as phenytoin and phenobarbital. Factors that tend to increase quinidine levels include congestive heart failure, poor renal function (prerenal or intrinsic renal disease), and possibly severe liver disease. Renal excretion is increased by acidification of the urine and decreased by urine alkalinization.

Several methods are available for quinidine assay. The most commonly used are fluorometric procedures, with or without preliminary extraction steps. These measurements include quinidine and several of its metabolites. Certain other fluorescing compounds may interfere. Extraction eliminates some but not all of the metabolites. More specific methods include HPLC and EMIT. Values for the direct (nonextracted) fluorescent methods are about 50% higher than those using HPLC or EMIT (i.e., the therapeutic range with the nonextracted fluorometric method is about 3-8 µg/ml [9.25-24.66 µmol/L], whereas the range using the double-extracted fluorometric method or HPLC is 2.3-5 µg/ml [7.09-15.41 µmol/L]). The specimen for TDM should be drawn just before the next dose is to be given (residual or trough level).

Reasons for TDM of quinidine include the following:

1. Various quinidine commercial products differ considerably in absorption.
2. Toxic levels of quinidine can produce certain arrhythmias that could be due to patient disease (either from noncontrol or noncompliance).
3. There is a possibility of drug interaction, because patients taking quinidine are likely to be taking several drugs or to receive additional drugs in the future.
4. Patient disease may modify quinidine metabolism or excretion (old age frequently is associated with reduced renal function, which modifies renal excretion of quinidine).

Flecainide. Flecainide (Tambocor) is another drug used for ventricular arrythmias, including premature ventricular contractions and ventricular tachycardia or fibrillation. About 95% is absorbed. Food or antacids do not affect absorption. After absorption, roughly 40% is bound to serum proteins. About 30% (range, 10%-50%) is excreted unchanged in the urine. The major metabolites have no antiarrythmic activity. Peak plasma levels after oral dosage are reached in about 3 hours (range, 1-6 hours). Serum half-life averages 20 hours (range, 7-27 hours) and may be longer in patients with severe renal disease or congestive failure. Steady state is reached in 3-5 days. Propranolol increases flecainide serum levels approximately 20%. Hypokalemia or hyperkalemia may affect the therapeutic action of flecainide. Flecainide paradoxically aggravates ventricular arrythmias in about 7% of patients, especially in the presence of congestive heart failure.

Digoxin. Digoxin could be included in the section on toxicology, since most serum assay requests are for the purpose of investigating possible digoxin toxicity. However, an increasing number of studies have demonstrated unsuspected overdosage or underdosage (30% toxicity and 11% underdigitalization in one study), and requests for baseline levels are becoming more frequent. The volume of requests and the relative ease of performance (by immunoassay) make this assay readily available, even in smaller laboratories. The widespread use of digoxin, the narrow borderline between therapeutic range and toxicity, and the nonspecific nature of mild or moderate toxic signs and symptoms that mimic a variety of common disorders (diarrhea, nausea, arrhythmias, and ECG changes) contribute to the need for serum assay.

Digoxin therapeutic drug monitoring data

About 20%-30% of digoxin is bound to serum albumin. About 80% (range, 60%-90%) is excreted unchanged by the kidneys. About 20% is metabolized in the liver, with most of this being excreted as digoxin metabolites. About 10% of the adult population metabolizes a greater percentage of digoxin (which may be as high as 55%). After an oral dose is given, serum levels rise to a peak at 30-90 minutes and then slowly decline until a plateau is reached about 6-8 hours after administration. Digoxin assay specimens must be drawn at least 6 hours (preferably at least 8 hours) after the last dose in either oral or IV administration, to avoid blood levels that are significantly higher than would be the case when tissue levels have equilibrated. The 6- to 8-hour time span mentioned is minimum elapsed time; specimens may be drawn later. In many cases more information is obtained from a sample drawn shortly before the next scheduled dose. Serum half-life is approximately 36-38 hours. Normal therapeutic range is 0.5-2.0 µg/100 ml (0.6-2.56 nmol/L).

Various metabolic disorders and medications may alter body concentration or serum levels of digoxin or may affect myocardial response to usual dosage. The kidney is the major route of excretion, and a decrease in renal function sufficient to raise serum creatinine levels will elevate serum digoxin levels as well. In renal failure, digoxin half-life may be extended to as long as 5 days. Hypothyroidism also increases digoxin serum values. On the other hand, certain conditions affect patient response to digitalis without affecting blood levels. Myocardial sensitivity to digoxin, regardless of dose, is increased by acute myocardial damage, hypokalemia, hypercalcemia, hypermagnesemia or hypomagnesemia, alkalosis, tissue anoxia, and glucagon. Drugs that produce hypokalemia (including various diuretics, amphotericin B, corticosteroids, or glucose infusion) thus predispose to toxicity. Other medications, such as phenylbutasone, phenytoin, and barbiturates (which activate hepatic degradation mechanisms), or kaolin (Kaopectate), antacids, cholestyramine, and certain oral antibiotics such as neomycin (which interfere with absorption) tend to be antagonistic to the effect of digitalis. Quinidine elevates digoxin levels in about 90% of patients by 50%-100% (range, 30%-330%). The effect on digoxin levels begins within 24 hours, with peak effect in 4-5 days. Certain other medications can increase serum digoxin levels to some extent.

Interfering substances. Digoxin can be measured by a variety of immunoassay methods. Digoxin-like cross-reacting substances have been reported in many patients (not all) in the third trimester of pregnancy, infants up to 6 months of age (the effect peaking at 1 week of age), patients with renal failure, and patients with severe liver disease. Different kits are affected to different extents. Some investigators report that the cross-reacting substances bind to serum proteins. In most cases the cross-reaction increases serum digoxin less than 1.0 µg/100 ml, but sometimes the effect may be greater.

Antidigoxin antibody therapy. Another analytical problem occurs when digitalis toxicity is treated with fragments of antidigoxin antibodies (Fab, “antigen-binding fragments”). These fragments are prepared by first producing antidigoxin IgG class antibody in animals, then enzymatically splitting off the antigen-binding variable regions (Fab portion) of the IgG molecule. This eliminates the “constant” region of the IgG molecule, which is the most antigenic portion of the molecule. The antidigoxin antibody Fab fragments bind to plasma and extracellular fluid digoxin. This creates a disturbance in equilibrium between free (unbound) digoxin within cells and within the extracellular compartments, so that some intracellular digoxin moves out of body cells to restore the equilibrium. The digoxin-Fab bound complexes are excreted in the urine by glomerular filtration. Their elimination half-life with normal renal function is about 15-20 hours (range, 14-25 hours).

Laboratory digoxin assay is involved for two reasons. First, a pretherapy baseline is required to help establish the diagnosis of digoxin toxicity and to help estimate the dose of Fab fragments needed. Second, after injection of the Fab dose, another assay is helpful to determine if adequate therapy was given, either because pretreatment digoxin tissue levels were higher than estimated or too much of the Fab fragment dose was lost in urine before sufficient digoxin had diffused out of the body cells. It is necessary to wait at least 6-8 hours after therapy for a postdose assay, to allow for equilibration time between cells and extracellular fluid. An assay system specific for free digoxin is necessary (usually done by a technique such as microfiltration, which separates unbound from Fab-bound digoxin), because the Fab-digoxin bound complexes are included with unbound (free) digoxin in total digoxin assays. Soon after therapy begins there is greatly increased Fab-digoxin bound complex formation in plasma (and, therefore, elevated total digoxin levels, sometimes as high as 20 times pretreatment levels), whereas free digoxin levels are low. Later, 12-20 hours after the initial therapeutic dose, plasma free digoxin reequilibrates, and may reach toxic levels again if sufficient intracellular digoxin has not been captured. It may take several days to excrete all the Fab-digoxin bound complexes, and the serum total digoxin level may remain elevated more than 1 week if there is poor renal function.

Digoxin assay clinical correlation. In various studies, there is a certain amount of overlap in the area that statistically separates normally digitalized patients from those with toxicity. This overlap exists because it is difficult to recognize mild degrees of toxicity, because patient sensitivity to digitalis varies, and because the assay technique itself, no matter how well done, like all laboratory tests displays a certain amount of variation when repeated determinations are performed on the same specimen. Regardless of these problems, if the clinical picture does not agree with the level of toxicity predicted by digoxin assay values, and laboratory quality control is adequate, the physician should not dismiss or ignore the assay results but should investigate the possibility of interference by improper specimen collection time interval, drug interaction, or metabolic alterations. However, the assay should be repeated first, to verify that a problem exists.

Digitoxin. Digitoxin is more than 95% bound to serum albumin. Serum half-life is about 8 days (2.5-16.5 days). Digitoxin is about 90% metabolized in the liver. About 5%-10% is excreted unchanged through the kidneys. Drugs that activate hepatic enzyme systems, such as phenytoin and barbiturates, increase metabolism of digitoxin and decrease serum levels. Hypoalbuminemia and drugs that compete for binding sites on albumin also tend to decrease digitoxin serum levels. The long half-life of the drug means that toxicity is difficult to overcome, so digoxin has mostly replaced digitoxin in the United States. The therapeutic range of digitoxin is 15-25 ng/ml.