Procainamide elimination

Procainamide 12-1 7 mg/kg, no faster than 20 mg/minute 1-4 mg/minute Cimetidine, ranitidine, and trimethoprim inhibit procainamide elimination... 

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. 

Concurrent use of the fluoroquinolones with theophylline causes an increase in serum theophylline levels. When used concurrently with cimetidine, the cimetidine may interfere with the elimination of the fluoroquinolones. Use of the fluoroquinolones with an oral anticoagulant may cause an increase in the effects of the oral coagulant. Administration of the fluoroquinolones with antacids, iron salts, or zinc will decrease absorption of the fluoroquinolones. There is a risk of seizures if fluoroquinolones are given with the NSAIDs. There is a risk of severe cardiac arrhythmias when the fluoroquinolones gatifloxacin and moxifloxacin are administered with drains that increase the QT interval (eg, quini-dine, procainamide, amiodarone, and sotalol). 

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. 

Drugs that may be affected by trospium include those eliminated by active tubular secretion (eg, digoxin, procainamide, pancuronium, morphine, vancomycin, metformin, and tenofovir). 

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... 

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. 

PROCAINAMIDE ANTIBIOTICS - TRIMETHOPRIM Procainamide levels are t by trimethoprim Trimethoprim is a potent inhibitor of organic cation transport in the kidney, and elimination of procainamide is impaired Watch for signs of procainamide toxicity 1 the dose of procainamide, particularly in the elderly... 

CIMETIDINE, RANITIDINE ANTIARRHYTHMICS-AMIODARONE, FLECAINIDE, MEXILETINE, PROCAINAMIDE, PROPAFENONE Likely t plasma concentrations of these antiarrhythmics and risk of adverse effects Cimetidine inhibits CYP2D6-mediated metabolism of flecainide, mexiletine, procainamide and propafenone. Ranitidine is a much weaker CYP2D6 inhibitor. Cimetidine is a potent inhibitor of organic cation transport in the kidney, and the elimination of procainamide is impaired Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid suppression therapy... 

A 58-year-old man is hospitalized in cardiac intensive care following an acute myocardial infarction. He has had recurrent episodes of ventricular tachycardia that have not responded to lidocaine, and an intravenous infusion of procainamide will now be administered. The patient weighs 80 kg and expected values for his procainamide distribution volume and elimination half-life are 2.0 L/kg and 3 hours, respectively. 

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. 

Individuals also vary widely in their elimination kinetics of isoniazid, procainamide, and other substrates of N-acetyltransferase (NAT2). Peripheral neuropathy associated with the use of isoniazid, an antituberculosis drug, first surfaced more than 40 years ago. It is now known that the slow acetylator phenotype represents approximately 40-50% of Caucasians, and results in decreased clearance of drug with increased potential for associated toxicities. 

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]. 

Metabolism/elimination Procainamide is hepatically acetylated to AFacetylpro- Berth propafenone and moricizine are mainly hepatically... 

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. 

Answer E. Cimetidine is an inhibitor of the hepatic cytochrome P450 isoform that metabolizes phenytoin, consequently decreases its clearance, and thus increases its elimination half-life. The hepatic metabolism of many other drugs can be inhibited by cimeti-dine, possibly necessitating dose reductions to avoid toxicity, including beta blockers, iso-niazid, procainamide, metronidazole, tricyclic antidepressants, and warfarin. 

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