Metabolism of drugs to toxic products
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- 1. METABOLISM OF DRUGS TO TOXIC PRODUCTS & THE CLINICAL RELEVANCE OF DRUG METABOLISM
2. 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.
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.
4. However, when these resources are exhausted, the toxic pathway become more & more stronger & spreads widely, resulting in apparent organ toxicity (carcinogenesis).
5. 6. The no of specific examples of such drugs that induced toxicity is expanding rapidly.
Trade Name: PARACETAMOL.
Acetaminophen induced hepatic toxicity.
It is analgesic antipyretic drug & quiet safe in therapeutic doses of 1.2g/d for an adult.
7. 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%.
8. WhenACETAMINOPHEN Become Toxic?
High therapeutic dose ofACETAMINOPHEN 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.
9. Thus, in the absence of hepatic GSH (IC nucleophiles), this reactive metabolite reacts with nucleophilicgrps of cellular proteins
w/h resulting in hepatotoxicity.
10. 11. How To Overcome This Situation?
Administration of N-acetylcysteine or Cysteamine within 8-16hours after overdosage of acetaminophen can protect victums from fulminanthepatotoxicity & death.
*Administration of GSH is not effective in this case b/c it does not cross cell membranes readily.
12. 13. 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.
14. 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
15. Genetic Factors
There are several drug-metabolizing systems introduced to differ among families or populations in genetically determined ways:
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
16. * 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.
17. 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 acetylationtriat is inherited as an autosomal recessive gene.
18. Non Genetic Factors
Diet & environmental factors:
Diet & environmental factors contribute to individual variations in drug metabolism.
Charcoal-broiled foods & cruciferous vegetables are used to induce CYP1A enzymes.
Whereas grapefruit juice is used to inhibit CYP3A metabolism of coadministered drug substrates.
Industrial workers exposed to some pesticides, metabolize certain drugs more rapidly than unexposed individuals.
19. 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.
20. 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.
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.
The most common strong inducers of drug metabolism are CARBAMAZEPINE, PHENOBARBITAL & PHENYTOIN.
22. 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 drugsthat are metabolized by those products that irreversibly inhibit the metabolizing enzyme..
Such as ETHINYL-ESTRADIOL, SECOBARBITAL etc.