Elimination by the Kidneys

FIGURE 6.4 Elimination of foreign chemicals by the kidney. Chemicals that have been taken up into the bloodstream are filtered at the glomerulus and enter the renal tubule with the glomerular filtrate. Once in the renal tubule, some chemicals tend to stay in the tubule and be excreted in urine, while others tend to diffuse out of the renal tubule and be reabsorbed into the bloodstream. The electrical polarity of the foreign chemical plays an important role in determining whether the chemical is excreted or reabsorbed. (Reprinted with permission from David Shier, Jackie Butler and Ricki Lewis, Hole s Human Anatomy and Physiology, 7th ed. [Dubuque Wm. C. Brown, 1996], 811.) 

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Time to peak plasma concentration depends on the rate of IV dosing but is usually achieved in 45—90 seconds. Therapeutic plasma concentrations are 1.5—5.0 )J.g/mL, and concentrations above 5 )J.g/mL maybe toxic. The elimination half-life after a bolus iv dose is 8 min the elimination half-life after a 24 h iv infusion is about 100 min. The dmg is eliminated by the kidneys. Ten percent is unchanged and the remainder is in the form of inactive metabolites... 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Creatinine is a metabolic breakdown product of muscle and usually has a constant value in an individual. Its value ranges from 0.6 mg/100 mL of serum to 1.2 mg/100 mL of serum. Creatinine is almost exclusively eliminated by the kidneys. Therefore, if the level of creatinine increases in the serum, it is likely that the capability of kidneys to eliminate the drugs is reduced. As a general rule, if the serum creatinine level (Ccr) is doubled, the kidney function is one-half. If the Ccr is quadrupled, the renal (kidney) function is one-fourth or 25%. 

Liver Chemical Processing. For protection from dangerous accumulation of various toxins, the body has evolved methods to eliminate foreign substances. Potentially harmful chemicals can originate from myriad sources including foods, liquids, air, and, of course, medications. The liver s role is to inactivate these chemicals and to convert (metabolize) them to water-soluble forms (i.e., forms that dissolve in water rather than fat), which can more easily be filtered and eliminated by the kidneys. 

Excretion - Thyroid hormones are primarily eliminated by the kidneys. 

Excretion - About 95% of the lithium dose is eliminated by the kidney. 

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Entecavir undergoes both glomerular filtration and net tubular secretion. 

Drugs affected by renal function impairment Because entecavir primarily is eliminated by the kidneys, coadministration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. 

Renal function impairment Emtricitabine and tenofovir disoproxil fumarate are principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with Ccr 30 to 49 mL/min do not administer the combination to patients with Ccr less than 30 mL/min or patients requiring hemodialysis. 

Renal function Impairment Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of emtricitabine is recommended for patients with impaired renal function (see Administration and Dosage). 

Magnesium sulfate, applied intravenously is often used as tocolytic. The mechanism of action is not completely clear but might involve a competition with calcium on the cellular level. Precautions in the sense of magnesium plasma level monitoring must be taken in patients with renal insufficiency since this divalent kation is eliminated by the kidneys. Relatively high plasma concentrations are necessary to achieve a sufficient tocolysis. The relatively frequent side effects are respiratory depression, depressed reflexes, headaches, palpitation and skin flushing in the mother and muscle relaxation and, rarely, CNS depression in the fetus. 

Agents include acarbose, miglitol and voglibose. Only bacterial breakdown products of acarbose are absorbed which are then rapidly eliminated by the kidneys. Adverse events mainly consist of gastrointestinal complaints which in rare cases can be confused with ileus. Some hepatotoxicity has been reported. 

Lenalidomide, a derivative of thalidomide, was introduced in 2004. Patients with multiple myeloma stage II/III, who have undergone at least one previous treatment can be treated with bortezomib or with lenalidomide in combination with dexamethasone. There is good oral absorptin with peak plasma levels at 0.5-4 hours. Lenalidomide is maily eliminated by the kidneys with a half-life of circa 3-9 hours. Teratogenicity cannot be excluded. Side effects include thrombosis, pulmonary embolus, and hepato-toxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. 

Angiotensin II, the primary end product of the renin-angiotensin system, acts on the juxtaglomerular cells to inhibit the release of renin this process is therefore a negative feedback mechanism. The half-life of renin in the circulation is 10 to 30 minutes, with inactivation occurring primarily in the liver. Small amounts of renin are eliminated by the kidneys. Pure human renin... 

Pharmacokinetics Completely absorbed. Distributed in extracellular space. Metabolized and eliminated by the kidney. Half-life 2-3 hr. 

Pharmacokinetics Absorbed through the cornea where the isopropyl esterprodrug is hydrolyzed to acid form to become biologically active. Highly lipophilic. The acid of latanoprost can be measured in the aqueous humor during the first 4 hours and in the plasma only during the first hour after local administration. In cornea, latanoprost is hydrolyzed to the biologically active acid. Metabolized in liver if it reaches systemic circulation. Metabolized to 1,2-dinor metabolite and 1,2,3,4-tetranor metabolite. Primarily eliminated by the kidneys. Half-life 17 min. 

Pharmacokinetics Distributed primarily in extracellular fluid. Primarily eliminated by the kidneys. Half-life 1.3 hr (increased in impaired renal function). 

Pfiarmacokinetics Rapidly and completely absorbed. Metabolized in the liver. Primarily eliminated by the kidneys. Unknown if removed by hemodialysis. HflJf-Hfe Approximately 2 days. 

Vecuronium has an elimination half-life of about one hour (Table 6.4) and is metabolised to 3-, 17-, and 3,17-hydroxy metabolites, the main route of elimination being via the liver. The metabolites have potent neuromuscular blocking action and are eliminated by the kidneys. As a result, the effects of vecuronium are prolonged in hepatic and renal disease. The metabolites may be responsible for cases of prolonged paralysis seen after long-term administration of vecuronium to patients in intensive care units. The effects of vecuronium are also prolonged in the elderly and in hypothermia due to the kinetic factors. 

Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into red blood cells with liberation of cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney. 

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. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated in the urine as inactive metabolites. 

The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2-3 hours) and is nearly as complete as with intravenous administration. The duration of effect for furosemide is usually 2-3 hours and that of torsemide is 4-6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. 

Oxytocin is administered intravenously for initiation and augmentation of labor. It also can be administered intramuscularly for control of postpartum bleeding. Oxytocin is not bound to plasma proteins and is eliminated by the kidneys and liver, with a circulating half-life of 5 minutes. 

When povidone-iodine is used as a rinsing solution in body cavities, absorption of the whole macromolecular complex is possible. The complex has a molecular weight of about 60 000 and cannot be eliminated by the kidneys or metabolically. It is filtered by the reticuloendothelial system (4,8,9). 

Since iodine is eliminated by the kidneys, renal insufficiency increases the risk of toxicity, and the risk may be further increased by metabolic acidosis (44,45). 

The kidneys are the sites of elimination of water-soluble chemicals that are removed from the blood by the process of reverse filtration. Two characteristics are primarily responsible for determining whether a chemical will be eliminated by the kidneys size and water solubility. 

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