Renal failure, drug metabolism

Baliga, R., Ueda, N., Walker, P. D., Shah, S. V. (1999 Nov). Oxidant mechanisms in toxic acute renal failure. Drug Metabolism Reviews, 31 4), 971-997. 

Leblond FA, Giroux L, Villeneuve JP, Pichette V (2000) Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos 28 1317-1320... 

The renal clearance can be under estimated in the case of renal drug metabolism. The total drug clearance depends on bioavailability. Therefore, the most reliable estimate for the fraction eliminated by the renal route (fren) is given by the normal clearance (Clnorm) and drug clearance in case of acute and/ or chronic renal failure (Clfail), or from half-lives (Tl/2norm) and (Tl/2fail). 

Metabolism/Excretion - About 50% is excreted in the urine as the unchanged drug and 30% as metabolites (20% mono-N-dealkyIdisopyramide [MND]). The plasma concentration of MND is approximately one-tenth that of disopyramide. The mean plasma half-life is 6.7 hours (range, 4 to 10 hours). In impaired renal function, half-life values ranged from 8 to 18 hours. Therefore, decrease the dose in renal failure to avoid drug accumulation. 

Labetalol is almost completely absorbed from the gastrointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gastrointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circulation. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates. The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essentially unchanged in patients with impaired renal failure. 

The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

The ultimate disposition of minoxidU depends primarily on hepatic metabolism and only slightly on renal excretion of unchanged drug. Because of this, pharmacological activity is not cumulative in patients with renal failure. 

Diazoxide lowers blood pressure within 3 to 5 minutes after rapid intravenous injection, and its duration of action may be 4 to 12 hours. Interestingly, if diazoxide is either injected slowly or infused its hypotensive action is quite modest. This is believed to be due to a rapid and extensive binding of the drug to plasma proteins. Both the liver and kidney contribute to its metabolism and excretion. The plasma half-life is therefore prolonged in patients with chronic renal failure. 

Phenylbutazone (Butazolidin) is metabolized to oxy-phenbutazone (Phlogistol), and both compounds have all of the activities associated with the NSAIDs. Their use is accompanied by serious adverse reactions, such as anemia, nephritis, renal failure or necrosis, and liver damage. Because of their toxicity, they are prescribed only for the treatment of pain associated with gout or phlebitis or as a last resort for other painful inflammatory diseases resistant to newer and less toxic treatments. Interactions with a large number of other drugs... 

Species differences in the metabolism of drug may be due to the difference in the rate of metabolism or in their metabolites difference. Certain drugs have been found safe and non-toxic in animals, but when they were tested in human beings severe toxic effects were observed. For example, when sulfanilamide was tested in dog it was found safe and non-toxic, but when it was administered to human being, certain toxic effects like the hematuria, renal failure were observed. 

The major metabolic pathway for cisatracurium is Hofmann elimination, although renal and other organ clearance accounts for some elimination. The pharmacokinetics of cisatracurium are independent of dose in healthy adult patients up to doses of 0.2 mg-kg-1 and its elimination half-life is similar to that of atracurium (Table 6.4). In contrast to atracurium, the clearance of cisatracurium is slightly reduced and recoveiy slightly slower in patients with renal failure. Much less laudanosine is produced as a metabolite of cisatracurium as compared with atracurium even when the drug is given by continuous infusion over a prolonged period of time. 

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... 

Nitrofurantoin is well absorbed after ingestion. It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved. The drug is excreted into the urine by both glomerular filtration and tubular secretion. With average daily doses, concentrations of 200 mcg/mL are reached in urine. In renal failure, urine levels are insufficient for antibacterial action, but high blood levels may cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency. 

Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 mEq/L (or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger-than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis (Table 58-1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Pichette V, Leblond FA. Drug metabolism in chronic renal failure. Curr Drug Metab. 2003 4 91-103. 

As shown in the review of the homocysteine metabolism, vitamin B 2, vitamin B6, and folate are important cofactors in the metabolic pathways for homocysteine elimination, and consequently, deficiencies of these vitamins are characterized by elevated plasma concentrations of tHcy. Hyperhomocysteinemia is also frequently found in diseases such as renal failure, rheumatic and auto-immune diseases, hypothyroidism, and malignancies. Several drugs are also known to increase plasma tHcy concentrations (16-24). 

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