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