Procainamide acetylation

Olsen H, Mjeirland J. Ethanol-induced increase in procainamide acetylation in man. BrJClin Pharmacol (1982) 13, 203-8. 

Procainamide may be adininistered by iv, intramuscular (im), or po routes. After po dosing, 75—90% of the dmg is absorbed from the GI tract. About 25% of the amount absorbed undergoes first-pass metaboHsm in the fiver. The primary metabolite is A/-acetylprocainamide (NAPA) which has almost the same antiarrhythmic activity as procainamide. This is significant because the plasma concentration of NAPA relative to that of procainamide is 0.5—2.5. In terms of dmg metabolism there are two groups of patients those that rapidly acetylate and those that slowly acetylate procainamide. About 15—20% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 60—90 min. Therapeutic plasma concentrations are 4—10 lg/mL. Plasma half-lives of procainamide and NAPA, which are excreted mainly by the kidneys, are 2.5—4.5 and 6 h, respectively. About 50—60% is excreted as unchanged procainamide (1,2). 

About 30% of the patients on chronic procainamide dosing develop a systemic lupusfike syndrome consisting of arthralgia, myalgia, skin rash, and fever. Patients who are slow acetylator phenotypes may be prone to this condition. Some may exhibit pleuropneumonic involvement and hepatomegaly... 

The N-acetyl procainamide (NAPA) metabolite blocks rapid potassium channels. cHas p-blocking properties. 

The answer is b. (Hardman, pp 868 869.) Persons with low hepatic iY-acetyltransferase activity are known as slow acetylators. A major pathway of metabolism of procainamide, which is used to treat arrhythmias, is iV-acetylation. Slow acetylators receiving this drug are more susceptible than normal persons to side effects, because slow acetylators will have higher-than-normal blood levels of these drugs N-acetylprocainamide, the metabolite of procainamide, is also active. 

Woosley, R.L. et al., Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome, New Engl. J. Med., 298, 1157, 1978. 

Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally. A metabolite (/V-acetylprocainamide, NAPA) has class 3 activity. Excessive accumulation of NAPA has been implicated in torsade de pointes during procainamide therapy, especially in patients with renal failure. Some individuals rapidly acetylate procainamide and develop high levels of NAPA. The lupus syndrome appears to be less common in these patients. 

Although the two forms of the enzyme have preferred substrates, there is overlap between them such that no substrate seems to be exclusively acetylated by one or the other. Some preferred NAT1 substrates are p-aminobenzoic acid and p-aminosalicylic acid and sulfanilamide, whereas preferred substrates for NAT2 include isoniazid, hydralazine, procainamide, and dapsone. 

Acetylation. Most mammalian species are able to acetylate aromatic amino compounds, the major exception being the dog. Thus, for a number of amino compounds such as procainamide (chap. 4, Fig. 43), sulfadimethoxine, sulfamethomidine, sulfasomizole, and the N4 amino group of sulfanilamide (chap. 4, Fig. 68), the dog does not excrete the acetylated product. However, the dog does have a high level of deacetylase in the liver and also seems to have an acetyltransferase inhibitor in the liver and kidney. Consequently, acetylation may not be absent in the dog, but rather the products may be hydrolyzed or the reaction effectively inhibited. 

Figure 5.23 Frequency distribution for the acetylation of (A) procainamide (B) and p-aminobenzoic acid in human subjects. Data represents excretion of acetylated product in the urine 6 hours after dosing. Source From Ref. 28.

It should be noted that in the hamster the situation is the reverse, with p-aminobenzoic acid and p-aminosalicylic acid being polymorphically acetylated and sulfamethazine and procainamide monomorphically acetylated. 

Dangman KH, Hoffman BF. In vivo and in vitro antiarrhythmic and arrhythmo-genic effects of iV-acetyl procainamide. J Pharmacol Exp Ther 1981 217 851-862. 

Pharmacokinetics Procainamide [pro kane A mide] is absorbed following oral administration. [Note The intravenous route is rarely used because hypotension occurs if the drug is too rapidly infused.] Procainamide has a relatively short half-life of 2-3 hours. A portion of the drug is acetylated in the liver to N-acetylprocainamide (NAPA), which has little effect on the maximum polarization of Purkinje fibers but prolongs the duration of the action potential. Thus, NAPA has properties of a Class III drug. NAPA is eliminated via the kidney, and dosages of procainamide may need to be adjusted in patients with renal failure. 

Mongey AB, Sim E, Risch A, Hess E (1999) Acetylation status is associated with serological change but not clinically significant disease in patients receiving procainamide. J Rheumatology 26 1721-1726... 

Okumura K, Kita T, Chikazawa S et al. (1997) Genotyp-ing of N-acetylation polymorphism and correlation with procainamide metabolism. Clin Pharm Ther 61 509-517... 

Disposition in the Body. Readily absorbed after oral administration and widely distributed throughout the body bioavailability 75 to 95%. The major metabolite, V-acetylprocainamide (ace-cainide), has similar pharmacological activity to procainamide the acetylation of procainamide is subject to genetic polymorphism. Up to about 80% of a dose is excreted in the urine of normal subjects in 24 hours, about 50 to 60% as unchanged drug and up to about 30% as V-acetylprocainamide (less in slow acetylators). Other metabolites include monodesethylprocainamide and monodesethyl-V-acetylprocainamide. 

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