Procainamide renal elimination

Terminate IV therapy if persistent conduction disturbances or hypotension develop. As soon as the patient s basic cardiac rhythm appears to be stabilized, oral antiarrhythmic maintenance therapy is preferable (if indicated and possible). A period of approximately 3 to 4 hours (one half-life for renal elimination, ordinarily) should elapse after the last IV dose before administering the first dose of oral procainamide. 

Procainamide is eliminated by hepatic metabolism to NAPA and by renal elimination. Its half-life is only 3-4 hours, which necessitates frequent dosing or use of a slow-release formulation (the usual practice). NAPA is eliminated by the kidneys. Thus, procainamide dosage must be reduced in patients with renal failure. The reduced volume of distribution and renal clearance associated with heart failure also require reduction in dosage. The half-life of NAPA is considerably longer than that of procainamide, and it therefore accumulates more slowly. Thus, it is important to measure plasma levels of both procainamide and NAPA, especially in patients with circulatory or renal impairment. 

Procainamide INa (primary) and IKr (secondary) blockade Slows conduction velocity and pacemaker rate prolongs action potential duration and dissociates from INa channel with intermediate kinetics direct depressant effects on sinoatrial (SA) and atrioventricular (AV) nodes Most atrial and ventricular arrhythmias drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction Oral, IV, IM eliminated by hepatic metabolism to /V-acetylprocainamide (NAPA see text) and renal elimination NAPA implicated in torsade de pointes in patients with renal failure Toxicity Hypotension long-term therapy produces reversible lupus-related symptoms... 

Procainamide and active metabolite /V-acetylprocainamide (NAPA) are renally eliminated. 

Approximately 50% of procainamide is excreted unchanged in the urine by glom-ernlar filtration with proximal tnbnlar secretion. NAPA is renally eliminated. ... 

To maintain therapeutic levels, a more dilute IV infusion at a concentration of 2 mg/mL is convenient (1 g in 500 mL 5% dextrose injection), and may be administered at 1 to 3 mL/min. If daily total fluid intake must be limited, a 4 mg/mL concentration (1 g in 250 mL of 5% dextrose injection) administered at 0.5 to 1.5 mL/min will deliver an equivalent 2 to 6 mg/min. Assess the amount needed in a given patient to maintain the therapeutic level principally from the clinical response. Adjust based on close observation. A maintenance infusion rate of 50 mcg/kg/min to a person with a normal renal procainamide elimination half-life of 3 hours should produce a plasma level of about 6.5 mcg/mL. 

To control ventricular arrhythmias, a total procainamide dosage of 2-5 g/d is usually required. In an occasional patient who accumulates high levels of NAPA, less frequent dosing may be possible. This is also possible in renal disease, where procainamide elimination is slowed. 

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. 

FIGURE 16.11 Simplified scheme of procainamide metabolism. In individuals with normal kidney function, renal excretion of unchanged drug accounts for more than half the elimination of a procainamide dose, wdiereas acetylation by NAX2 accounts for only 24% and 17% of elimination in rapid and slowr acetylators, respectively. A small amount is of procainamide is metabolized to a hydroxylamine, wdiich is in equilibrium with a postulated chemically unstable and reactive nitroso compound that is capable of haptenic binding to histone proteins. 

The use of serum procainamide concentration measurements in monitoring therapy has been reviewed (58,68). Serum concentrations of 4-10 gg/ml are associated with therapeutic benefit in over 90% of patients with ventricular tachydysrhythmias, and toxicity becomes highly likely over 12 gg/ml. However, the main metabolite of procainamide, acecainide, has antidysrhythmic activity of its own thus, because metabolism varies widely between individuals, and because acecainide is eliminated by the kidneys, serum concentration measurement of procainamide alone has limited usefulness, particularly in renal insufficiency. There is currently little information on the interpretation of combined measurement of the two compounds. 

Interactions of cimetidine and other H -receptor antagonists with the renal secretion of several drugs have been repeatedly described, and comprehensively listed [146]. Thus, cimetidine inhibits renal secretion of procainamide in humans and prolongs its elimination half-life [147,148]. Similar inhibitory effects have been shown on creatinine, ranitidine and many other cationic compounds [149]. 

Penicillins and cephalosporins have short half-lives (0.5-1.5 h) in domestic animals because these antibiotics are secreted by the proximal renal tubules and, due to their high degree of ionization, are not reabsorbed from the distal nephron. The half-lives of lipid-soluble weak organic acids (e.g. sulphadi-methoxine, sulphadiazine, phenobarbitone) and organic bases (e.g. trimethoprim, procainamide, amphetamine) of which a significant fraction (> 20%) of the dose is eliminated by renal excretion may be influenced by the urinary pH reaction. Under acidic urinary conditions, which are normally present in carnivorous species, weak acids are reabsorbed from the distal renal tubules, whereas the excretion of weak bases is enhanced. 

D. Enhancement of Elimination Enhancement of elimination is possible for a number of toxins, including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity due to fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidiflcation may be useful in toxicity due to weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to avoid acidosis and renal failure in rhabdomyolysis. Hemodialysis or hemoperfusion enhances the elimination of many toxic compounds, including acetaminophen, ethylene glycol, formaldehyde, lithium, methanol, procainamide, quinidine, salicylates, and theophylline. Cathartics such as sorbitol (70%) may decrease absorption and hasten removal of toxins from the gastrointestinal tract. 

In a patient with renal impairment, the elimination half life of procainamide is reported to be 14 h (The range is 9 3 h) ... 

In patients with renal impairment, the elimination half life of procainamide is reported to be 14 h (range, 9-43 h). When a 250 mg procainamide tablet is administered to a renally impaired subject, the absorption rate constant and the elimination rate constant are reported to be 2.8 h and 0.0495 h , respectively. However, the intercept of the plasma concentration-time profile is observed to be 1.556 pgmL . ... 

In a patient with cardiac failure and shock and the renal impairment, the apparent volume of distribution and the elimination half life (ti/2) of procainamide are reported to be 1.5Lkg and 14h, respectively. 

A 61-year-old man who had sustained ventrieular tachycardia, which did not respond adequately to oral procainamide, was found to be a fast acetylator of procainamide, which resulted in particularly high serum levels of the procainamide metabolite (7V-acetylprocainamide) when compared with the procainamide levels. When he was also given para-aminobenzoic acid (PABA) 1.5 g every 6 hours for 30 hours, to suppress the production of this metabolite, the serum level of procainamide increased, that of Al-acetylproeainamide decreased, and control of his arrhythmia improved. However, a later study in 10 healthy subjects, who were also fast acety lators, found that PABA did not significantly affect the pharmacokinetics of procainamide. In addition, although PABA inhibited the production of A-acetylprocainamide, it also inhibited renal excretion, so that the AUC and elimination half-life were increased. This suggests that PABA may in fact not be useful for increasing the efficacy and safety of procainamide. ... 

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