Metabolism of drugs to toxic products

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Metabolism of drugs to toxic products

  1. 1. METABOLISM OF DRUGS TO TOXIC PRODUCTS & THE CLINICAL RELEVANCE OF DRUG METABOLISM<br />Dr Aakifa Javed<br />
  2. 2. Metabolism of drugs & other foreign chemicals may not always be a harmless biochemical event, leading to detoxification & elimination of the compound.<br />INFACT, several compounds metabolically transformed to reactive intermediates that are toxic to various organs.<br />
  3. 3. Such TOXIC REACTIONS may NOT be apparent at low levels of exposure when alternative detoxification mechanisms are not yet compromised & the availability of ENDOGENOUS DETOXIFYING COSUBSTRATES (i.e, glutathione [GSH] , glucuronic acid, sulfate) is not limited.<br />
  4. 4. However, when these resources are exhausted, the toxic pathway become more & more stronger & spreads widely, resulting in apparent organ toxicity (carcinogenesis).<br />
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  6. 6. The no of specific examples of such drugs that induced toxicity is expanding rapidly.<br />For Instance:<br /> “ACETAMINOPHEN”<br /> Trade Name: “PARACETAMOL”.<br />Acetaminophen induced hepatic toxicity.<br />It is analgesic antipyretic drug & quiet safe in therapeutic doses of 1.2g/d for an adult.<br />
  7. 7. Normal Mechanism<br /> “ACETAMINOPHEN” normally undergoes GLUCURONIDATION & SULFATION to the corresponding conjugates w/h makeup 95% of the total excreted metabolites.<br />And the alternative P450-dependent GSH conjugation pathway makeup remaining 5%.<br />
  8. 8. When “ACETAMINOPHEN” Become Toxic?<br />High therapeutic dose of “ACETAMINOPHEN” leads to saturation of Glucuronidation & Sulfation pathways.<br />The P450- dependent pathway becomes more important.<br />Here hepatic GSH i.e available for conjugation, can prevent from hepatotoxicity BUT…<br /> Hepatic GSH can not regenerated as rapidly as it depleted.<br />So, with time, its depletion occur.<br />
  9. 9. Thus, in the absence of hepatic GSH (IC nucleophiles), this reactive metabolite reacts with nucleophilicgrps of cellular proteins<br />w/h resulting in hepatotoxicity.<br />
  10. 10.
  11. 11. How To Overcome This Situation?<br />Administration of N-acetylcysteine or Cysteamine within 8-16hours after overdosage of acetaminophen can protect victums from fulminanthepatotoxicity & death.<br />*Administration of GSH is not effective in this case b/c it does not cross cell membranes readily.<br />
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  13. 13. Clinical Relevance Of Drug Metabolism<br />The dose & frequency of administration required to achieve effective therapeutic blood & tissue levels w/h vary in different patients due to INDIVIDUAL DIFFERENCES IN:<br /> a. Drug Distribution.<br />b. Rates of drug metabolism.<br />c. Rates of drug elimination.<br />
  14. 14. These differences are determined by:<br /> 1. Genetic Factors:<br />i. Hydrolysis of esters<br /> ii. Acetylation of amines<br /> 2. Non Genetic Factors:<br />i. Diet & environmental factors<br /> ii. Age factors<br /> iii. Drug-drug interaction factors:<br /> a. Enzyme inducing drugs<br /> b. Enzyme inhibiting drugs<br />
  15. 15. Genetic Factors<br />There are several drug-metabolizing systems introduced to differ among families or populations in genetically determined ways:<br />Hydrolysis of esters:<br /> For Instance: SUCCINYLCHOLINE is an ester that is metabolized by plasma cholinesterase.<br /> In most individuals, this process occurs v. rapidly & a single dose of <br /> this neuromuscular blocking drug has a duration of action of about<br /> 5 MIN.<br />
  16. 16. * App 1 persn in 2500 has an abnormal form of this enzyme that metabolizes “succinylcholine” & similar esters much more slowly.<br />In such individuals, the neuromuscular paralysis produced by a single dose of succinylcholine may last many hours.<br />
  17. 17. ii. Acetylation of amines:<br />ISONIAZID & some other amines ( such as HYDRALAZINE & PROCAINAMIDE are metabolized by N-acetylation.<br />Slow acetylators (individuals deficient in accetylation capacity), may have prolong or toxic responces to normal doses of these drugs.<br />* Slow acetylationtriat is inherited as an autosomal recessive gene.<br />
  18. 18. Non Genetic Factors<br />Diet & environmental factors:<br />Diet & environmental factors contribute to individual variations in drug metabolism.<br />DIET:<br />Charcoal-broiled foods & cruciferous vegetables are used to induce CYP1A enzymes.<br />Whereas grapefruit juice is used to inhibit CYP3A metabolism of coadministered drug substrates.<br />ENVIRONMENTAL:<br />Industrial workers exposed to some pesticides, metabolize certain drugs more rapidly than unexposed individuals.<br />
  19. 19. ii. Age factors:<br />Inc. risk of pharmacologic or toxic action of drugs has been seen in v. young & v. old patients as compared to the adult ones. <br />This may be due to differences in absorption, distribution, elimination & drug metabolism.<br />Slower metabolism could be due to reduced activity of metabolic enzymes.<br />
  20. 20. iii. Drug-drug interaction factors:<br />Co-administration of certain agents may alter the disposition of many drugs.<br />Mech include the following:<br /> a. Enzyme inducing drugs:<br />Induction usually results from inc. synthesis of cytochrome P450-dependent drug-oxidizing enzymes, in the liver.<br />Many isozymes of the P450 family already exist, & inducers just selectively inc. subgroups of isozymes.<br />
  21. 21. But several days are usually required to reach max. induction & a similar amount of time is required to regress after withdrawl of the inducer.<br />The most common strong inducers of drug metabolism are CARBAMAZEPINE, PHENOBARBITAL & PHENYTOIN.<br />
  22. 22. b. Enzyme inhibiting drugs:<br />The most common inhibitors of drug metabolism involved in serious drug interactions are AMIODARONE, CIMETIDINE present in grapefruit juice.<br />SUICIDE INHIBITORS are drugs that are metabolized by those products that irreversibly inhibit the metabolizing enzyme..<br />Such as ETHINYL-ESTRADIOL, SECOBARBITAL etc.<br />
  23. 23. THANK<br /> YOU!<br />

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