Tocainide dosing

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Transferring to mexiletine When transferring from other Class I oral antiarrhythmics to mexiletine, based on theoretical considerations, initiate with a 200 mg dose, and titrate to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last disopyramide dose or 8 to 12 hours after the last tocainide dose. 

Light-headedness, dizziness, or nausea occurs in approximately 15% of patients, paresthesias and numbness in 9%, and tremor in 8%. These adverse effects are generally mild in intensity, transient, and dose related. Overall, however, approximately 20% of patients prescribed tocainide discontinue therapy because of such effects. Serious immune-based side effects, such as pulmonary fibrosis, have been reported, and blood dyscrasias, such as agranulocytosis and thrombocytopenia, may occur in up to 0.2% of patients. 

Disposition in the Body. Almost completely absorbed after oral administration. About 20 to 50% of a dose is excreted in the urine as unchanged drug in 24 hours, and about 20 to 30% as a glucuronide conjugate, which is thought to be tocainide carbamoyl 0-) -D-glucuronide (TOCG) an additional metabolite, lactoxylidide has also been detected in urine. 

Adverse cardiovascular effects have been reported in 6-55% of cases. After a single dose of tocainide the most common effect is hypotension with bradycardia (12). Angina pectoris has also been reported (13). 

Absorption Lidocaine is ineffective orally 60% to 70% of an oral dose is metabolized by the liver before reaching the systemic circulation. It is only administered IVfor arrhythmias. Both mexiletine and tocainide are well absorbed orally. 

Congestive heart failure and uremia reduce renal clearance and the volume of distribution and increase the clearance half-life. Tocainide is not highly protein bound, so it does not exhibit die protein-binding phenomenon described for lidocaine after myocardial infarction. Clinically, the dose should be reduced proportionally to glomerular filtration to maintain therapeutic levels. 

Moricizine (600 to 900 mg/day given every 8 hours in three equally divided doses) is indicated in the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that are life threatening. Because of the proarrhythmic effects of moricizine, its use should be reserved for patients in whom the benefits of treatment outweigh the risks. Moricizine is a class 1C antiarrhythmic agent with potent local anesthetic activity and myocardial-membrane-stabilizing effects. It shares some of the characteristics of the class lA (disopyramide, procainamide, or quinidine), of class IB (lidocaine, mexiletene, phenytoin, or tocainide), or class 1C agents (encainide, flecainide, or propafenone) in that it reduces the fast inward current carried by sodium ions. Moricizine shortens phase 2 and 3... 

Hoffmann, K.J. Renberg, L. Gyllenhaal, O. Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers. Biopharm. Drug Dispos. 1990, 11, 351-363. 

Preliminary findings of a study found that when 5 healthy subjects took 30 mL of an unnamed antacid four times a day for 48 hours before and 58 hours after a single 600-mg dose of tocainide, the urinary pH rose from 5.9 to 6.9, the total clearance of tocainide fell by 28%, the peak serum levels fell by 19% from 4.2 to 3.4 micrograms/mL, the AUC rose by 33% and the half-life was prolonged from 13.2 to 15.4 hours. ... 

In a preliminary report of a study, 4 days of treatment with cimetidine [dose not stated] in 11 healthy subjects had a small effect on the pharmacokinetics of tocainide 500 mg given intravenously over 15 minutes, whieh was not considered elinieally important. In another study, cimetidine 300 mg four times daily for 2 days reduced the AUC of a single 400-mg oral dose of toeainide in 7 healthy subjects by about one-third. The peak... 

The AUC of a single 600-mg oral dose of tocainide was reduced by almost 30% and the half-life was also reduced by about 30%, from 13.2 to 9.4 hours, in 8 healthy subjects given rifampicin 300 mg twice daily for 5 days. ... 

This response is consistent with the well-recognised enzyme inducing effects of rifampicin. Information is limited to this single dose study, but the interaction would seem to be established and may be of clinical importance. Monitor any patients given rifampicin for evidence of reduced tocainide serum levels and reduced effects. Increase the dosage as necessary. Reduce the tocainide dosage if the rifampicin is withdrawn. More study is needed. 

Single doses of lidocaine 200 mg, flecainide 100 mg and tocainide 500 mg had no effect on caffeine clearance in 7 healthy subjects given a single 366-mg dose of caffeine. ... 

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