Elimination of drugs and toxins

This chapter reviews the basic principles of poisoning, initial management, and specialized treatment of poisoning, including methods of increasing the elimination of drugs and toxins. 

Measures to enhance elimination of drugs and toxins have been overemphasized in the past. Although a desirable goal, rapid elimination of most drugs and toxins is frequently not practical and may be unsafe. A logical understanding of phamiacokinet-ics as they apply to toxicology (toxicokinetics) is necessary for the appropriate use of enhanced removal procedures. 

The GIT supplements the kidney in the elimination of wastes and toxins. The P-glycoprotein of enterocytes, which is implicated in multi-drug resistance, plays a critical role. This export carrier exhibits varying responses to the different polyphenols present in green tea (Wang et al, 2002), and is inhibited by one or more components of grapefruit juice (Wagner et al, 2001). It is... 

Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication. 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

The primary function of the kidneys is to rid the body of waste materials that are either ingested or produced by metabolism, and to control the volume and composition of the body fluids. The toxins absorbed by the different routes are biotransformed and enter the blood. They are then eliminated through the urine, feces, and air. Since the kidneys receive approximately a quarter of the cardiac output, it is an important organ for the exposure of toxicants and their metabolites. Recent incidents of pet food toxicity and diethylene glycol toxicity indicate that contamination of animal and human food and drugs, respectively, can lead to severe mortahty and morbidity as a result of renal toxicity. 

For instance, urea, the product of protein digestion from which the term urine is derived, must be removed. Other waste products of metabolism must be removed. Any toxins produced by bacteria must be removed. Any drug residue or other unusable material must be removed. Any excess hormone must be removed. Glucose, on the other hand, should not be eliminated and proteins should not be secreted. Vitamins need to be saved, as does calcium and a certain amount of sodium and other minerals. However, water must be regulated. Too much water in the blood would be bad because if blood were too dilute, then not enough nutrients would be transported to the cell. If blood had too little water, then the physical process of pumping the blood around would be... 

Prior to 2002, most studies published on physiologically-based pharmacokinetic models focused on the distribution and elimination of environmental toxins such as dioxin, styrene, and organic solvents [68-70]. PBPK models for drug molecules generally relied on tissue/plasma partition coefficients (Kps) measured in rat [71-73]. 

The major function of xenobiotic metabolism is the elimination of physiologically useless compounds, some of which may be harmful wimess the many toxins produced by plants. This evolutionary function justifies the designation of detoxification originally given to reactions of xenobiotic metabolism. However, numerous xenobiotics and even a marked number of drugs are known to yields toxic... 

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