Therapeutic Drug Monitoring of Cardioactive Drug

Therapeutic drug monitoring of several cardioactive drugs, including digoxin, disopyramide, lidocaine, procainamide, mexiletine, tocainide, and quinidine are routinely performed in clinical laboratories because of the established correlation between serum drug concentrations and pharmacological response of these drugs. Moreover, drug toxicity can be mostly avoided by therapeutic drug monitoring. Digoxin is one of the most frequently ordered drugs among all cardioactive drugs in clinical laboratory. This drug has a narrow therapeutic window, and immunoassays employed in monitoring serum digoxin concentration are subjected to interference from both exogenous and endogenous compounds. This topic is discussed in detail in Chapter 6.

Disopyramide (4-diisopropylamino-2-phenyl-2-pyridyl) butyramide was synthesized in 1954, and its antiarrhythmic properties were discovered in 1964. The plasma protein binding of disopyramide is extremely variable in patients because of fluctuation of a1-acid glycoprotein concentrations in the serum. Moreover, binding of disopyramide to the serum proteins is stereoselective with R(-)-isomer approximately 66% protein bound and S(+)-isomer 79% protein bound (121). The therapeutic range of disopyramide is considered as 1.5-5.0^g/mL. Echizen et al. (122) recommended monitoring free fraction of disopyramide. Lidocaine is another cardioactive drug bound to a1-acid

Table 5

Therapeutic Drug Monitoring of Anticonvulsants

Table 5

Therapeutic Drug Monitoring of Anticonvulsants

Drug

Specimen Requirement

Therapeutic Rangeb Trough (pg/mL)

Cost"

Carbamazepine

Serum

4-12

$

Carbamazepine, 10,

Serum or plasma

0.4-4

$$

11-epoxide

Clonazepam

Serum or plasma

10-50

$$

Diazepam and

Serum

0.1-1.0

Nordiazepam

0.1-0.8

$$$

Felbamate

Serum

Range not well established (very toxic)

$$

Ethosuximide

Serum or plasma

40-75

$$

Gabapentin

Serum or plasma

2-12

$$$

Lamotrigine

Serum or plasma

1-4

$$$

Methsuximide

Serum or plasma

10-40

$$$

Phenytoin

Serum or plasma

10-20

$

Phenobarbital

Serum or plasma

15-40

$

Primidone

Serum or plasma

5-12

$

Valproic acid

Serum or plasma

50-100

$$

Zonisamide

Serum or plasma

10-40

$$$

$, < $75; $$, < $100; $$$, > $100; $$$$, > $150. a The costs are based on published charge for these tests in our hospital laboratory and reference laboratories.

b Therapeutic ranges are suggested ranges based on ranges used in our hospital laboratory as well as published ranges in textbooks and test catalogues of reference laboratories. Reference ranges may vary significantly depending on patient population, disease states, and others.

$, < $75; $$, < $100; $$$, > $100; $$$$, > $150. a The costs are based on published charge for these tests in our hospital laboratory and reference laboratories.

b Therapeutic ranges are suggested ranges based on ranges used in our hospital laboratory as well as published ranges in textbooks and test catalogues of reference laboratories. Reference ranges may vary significantly depending on patient population, disease states, and others.

glycoprotein. Free fraction of lidocaine may vary considerably in disease state, and it is discussed in Chapter 2. Mexiletine was synthetically developed, and this drug is mainly metabolized by the liver to parahydroxy mexiletine, hydroxymethyl mexiletine, and their corresponding alcohols, and metabolites are not considered active. The therapeutic range is considered to be 0.5-2.0 ^g/mL, although many patients experience toxicity at a serum level just exceeding the upper limit of the therapeutic range (123). KochWeser (124) established that the therapeutic range of procainamide is 4-10 ^g/mL. Procainamide is metabolized to an active metabolite; N-acetyl procainamide (NAPA). Lima et al. (125) reported that the combined concentrations of procainamide and NAPA over 25-30 ^g/mL increase the risk of toxicity. Decreased renal function may cause significant accumulation of procainamide and NAPA resulting in severe intoxication (126). Quinidine is a natural alkaloid found in cinchona bark. Since 1918, quinidine has been used as an antiarrhythmic drug. Wide variations in quinidine serum levels coupled with a narrow therapeutic range make therapeutic drug monitoring of quinidine essential. This drug is strongly bound to a1-acid glycoprotein, and the variations of pharmacologically free fractions have been reported in altered pathological conditions. Monitoring free quinidine concentration is discussed in Chapter 2.

Tocainide was developed as an oral analogue of lidocaine because lidocaine cannot be administered orally because of high first-pass metabolism. Tocainide and lidocaine have similar electrophysiological properties. Tocainide is cleared by hepatic metabolism and urinary excretion of unchanged drug. Unbound drug concentration is likely to correlate with total drug concentration, and there is no indication for monitoring free tocainide concentration because tocainide is only poorly bound to serum proteins (5-20%). Flecainide is a strong sodium channel blocker used in the treatment of various supraventricular tachyarrhythmias. Flecainide is mainly metabolized by cytochrome P450 (CYP2D6) and CYP2D6. The poor metabolizers of this drug showed a 42% reduction in flecainide clearance. This population represents 5-10% of Caucasians and less than 1% of Asians (127). The reported therapeutic range of trough flecainide concentration is 200-1000 ng/mL (0.2-1.0 ^g/mL), although severe adverse effect such as ventricular arrhythmia has occurred occasionally in patients whose serum flecainide concentration exceeded 1000 ng/mL (128). Reference ranges and cots of monitoring of cardioactive drugs are summarized in Table 6.

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