Drug metabolism.pdf

At the end of this e-learning session students will learn:
1. Definition of biotransformation/ Metabolism and different factor affecting metabolism
2. Discuss Phase I/ Non synthetic/functionalization reaction and Phase II/ Synthetic/ Conjugation reaction
3. Explain drug induction and drug inhibition
Reference:
Reference: • K D Tripathi. Essentials of Medical Pharmacology. Seventh Edition. Jaypee
Publication. Page no:23-29.

1. Drug Metabolism

2. BIOTRANSFORMATION (Metabolism)
●Chemicalalterationofthedruginthebodyis
calledasbiotransformation.
●Itisneededtorender
Nonpolar(lipid-soluble)compounds
polar(Watersoluble)
excretedinurine.

3. ●MostPolar(hydrophilicdrugs)e.g.
Streptomycin
littlebio-transformed
excretedunchanged.

4. ●The primary site for drug metabolism is liver
●Others sites are:-
●kidney
●intestine
●lungs
●Plasma

5. ●Biotransformation of drugs may convert
●Active drug inactive (Inactivation-I)
●e.g. ibuprofen, paracetamol

6. 2. Active drug Active metabolite
Eg.
●Morphine Morphine-G
glucuronide
(Active)(active)

7. 3.InactivedrugActivedrug
●eg.Prodrugsuchas:
●LevodopaDopamine
(Inactive)(Active)
●Advantagesofprodrugovertheactiveform:
●morestability
●betterbioavailability
●activatedselectivelyatthesiteofaction
●lesssideeffectsandtoxicity

8. Classification of bio-transformation reaction
I. Non-synthetic/Phase I/Functionalization reactions
active or inactive metabolite
•5 types
●Oxidation
●Reduction
●Hydrolysis
●Cyclization
●De-cyclization

9. II. Synthetic/Conjugation/ Phase II reaction
Mostly inactive metabolite
●VII Types:
(i) Glucuronide conjugation
(ii) Acetylation
(iii) Methylation
(iv) Sulphate conjugation
(v) Glycine conjugation
(vi) Glutathione conjugation
(vii) Ribonucleoside/nucleotide synthesis

10. Non-synthetic reactions
(i)Oxidation:Thisreactioninvolvesadditionof
oxygen/negativelychargedradicalorremoval
ofhydrogen/positivelychargedradical.
●Eg.Barbiturates,phenothiazines,imipramine,
ibuprofen,paracetamol

11. (ii)Reduction:Thisreactionistheconverseof
oxidation
●InvolvescytochromeP-450enzymesworkinginthe
oppositedirection.
●Eg.Chloralhydrate,chloramphenicol,halothane,
warfarin.

12. (iii)HydrolysisThisiscleavageofdrugmoleculeby
takingupamoleculeofwater.
Ester+H2OAcid+Alcohol
•Hydrolysisoccursinliver,intestines,plasmaand
othertissues.
●Eg:Procaine,lidocaine,procainamide,aspirin.
Esterase

13. (iv)Cyclization:Thisisformationofring
structurefromastraightchaincompounde.g.
Proguanil.

14. (v)De-cyclization:Thisisopeningupofringstructure
ofthecyclicdrugmoleculee.g.Barbiturates,phenytoin.

15. Phase II: Synthetic reactions
●TheseinvolveconjugationofthedrugoritsphaseI
metabolite
withanendogenoussubstratetoformapolarhighly
ionizedorganicacidwhichiseasilyexcretedinurineor
bile.

16. ●Thisisthemostimportantsyntheticreactioncarriedoutbya
groupofUDP-glucuronosyltransferases(UGTs).
●Compoundswithahydroxylorcarboxylicacidgroup-->easily
conjugatedwithglucuronicacidwhichisderivedfromglucose.
●Eg.chloramphenicol,aspirin,paracetamol,morphine,
metronidazole.
1. Glucuronide conjugation

17. •Hydroxylorcarboxylicacidgroup+glucuronicacid
UGTsConjugation
Increasemolecularweight
Excretedinbile
Reabsorbinintestine
EnterohepaticcirculationProlongaction

18. (ii) Acetylation
•Compoundshavingaminoorhydrazineresiduesare
conjugatedwiththehelpofacetylcoenzyme-Ae.g.
sulphonamides,isoniazid.
•Itshowsgeneticpolymorphism(slowandfast
acetylators).

19. (iii) Methylation
●Theaminesandphenolsgroupofdrugscanbe
methylated
●Methionineandcysteineactingasmethyldonorse.g.
histamine.

20. (iv) Sulphate conjugation
•Thephenoliccompoundsandsteroidsaresulfatedby
sulfotransferases(SULTs)
●e.g.chloramphenicol,sexsteroids

21. (v) Glycine conjugation
•Salicylatesandotherdrugshavingcarboxylic
acidgroupareconjugatedwithglycine,
●Itisnotamajorpathwayofmetabolism.

22. (vi) Glutathione conjugation
•Highlyreactivequinoneorepoxideintermediates
conjugatewithglutathione
Mercapturate.
●Itservestoinactivate-->highlyreactivequinoneor
epoxideintermediatesformedduringmetabolismof
certaindrugse.g.paracetamol

23. Drug Metabolizing Enzymes
●Microsomal enzymes
●Non-microsomal enzymes

24. Microsomal enzymes
●Location:smoothendoplasmicreticulum,primarilyin
liver,alsoinkidney,intestinalmucosaandlungs.
●Eg.ofME
●Monooxygenases,
●cytochromeP450,
●glucuronyltransferaseetc.

25. ●MEcatalyse
●oxidations
●reductions
●hydrolysis
●andglucuronideconjugation
●Microsomalenzymesareinducibleby
●drugs
●diet.

26. Non microsomal enzymes
●Location:Cytoplasm,mitochondriaofLiver&Plasma.
●EgofNME
●Flavoproteinoxidases
●Esterases
●Amidase
●Andconjugases.

27. ●Reactioncatalysedare:
●Someoxidationsandreductions,
●manyhydrolyticreactions
●andallconjugationsexcept:glucuronidation.
●Thenon-microsomalenzymesare
●notinducible
●butmanyshowgeneticpolymorphism.

28. ●Bothmicrosomalandnon-microsomalenzymesare
deficientinthenew-born
●moresusceptibletomanydrugse.g.chloramphenicol,
opioids.
●Lowdoseofdrugused-->usualdoseprodtoxicity

29. Q1: Enlist different sites of
metabolism of drugsin the body.
Q2: Functionalization reactions are
also called as --------.
Q3: Which types of Compounds
undergo acetylation reaction?

30. ACTIVITY II: Self study

31. INHIBITION OF DRUG METABOLISM
2types
1.Competitiveenzymeinhibition
2.Noncompetitiveenzymeinhibition
●Onedrugcancompetitivelyinhibitmetabolismof
anotherifitutilizesthesameenzymeorcofactors.
canprecipitatetoxicityoftheobjectdrug.

32. ●Metabolismofdrugswithhighhepaticextractions
dependentonliverbloodflow.
●eg.Propranololdecreaseshepaticbloodflow.
Reducesrateoflidocainemetabolism

33. MICROSOMAL ENZYME INDUCTION
Manydrugs,insecticidesandcarcinogensinteractwith
DNA
Increasethesynthesisofmicrosomalenzymeprotein
(cytochromeP-450andglucuronyltransferase).
Increasesrateofmetabolism.

34. ●Eg.Phenobarbitone-->inducersofCyp3AandCyp2D6
Increasetherateofmetabolismby2-4fold.

35. ●Polycyclichydrocarbonslike3-methylcholanthrene
andbenzopyrenefoundin
●cigarettesmoke
●charcoalboiledmeat
●andindustrialpollutants
InduceCYP1Aisoenzymes.

36. ●Otherimportantenzymeinducersare:
●Chloralhydrate
●phenylbutazone
●griseofulvin.

37. Consequences of microsomal enzyme induction
1.Decreaseintensityordurationofactionofdrugs
-->inactivatedbymetabolism.
Eg.Oralcontraceptives
2.Increaseintensityofactionofdrugs-->that
areactivatedbymetabolism.
Eg.Acuteparacetamoltoxicity

38. 3.Tolerance:Incaseofauto-induction.
Eg.Carbamazepine.
4.Precipitationofacuteintermittentporphyria-disease
inwhichanimportantpartofhaemoglobin,calledhaem,
isnotmadeproperly.
5.Interferewithadjustmentofdoseofanotherdrug.

39. 6.Interferewithchronictoxicitytestinginanimal.
7.Itaffectmetabolismofotherdrugseg.
1.Phenytoin
2.Warfarin
3.Oralcontraceptive
4.Chloramphenicoletc.

40. FIRST PASS (PRESYSTEMIC) METABOLISM
Definition:
●Metabolism of drug during its passage from site of
absorption into systemic circulation.
1. Orally administered drug
Come in contact withintestinal & liver enzyme
Undergoes first pass metabolism

41. 2. It is also occur in skin & lungs
lower magnitude

43. Attributes of drugs with high first pass metabolism:
(a)Higheroraldosethansublingualor
parenteraldose.
(b)Markedindividualvariationintheoraldose
duetodifferencesintheextentoffirstpass
metabolism.

44. (c)Oralbioavailabilityisapparentlyincreasedin
patientswithsevereliverdisease.
(d)Oralbioavailabilityofadrugisincreased
ifanotherdrugcompetingwithitforfirstpass
metabolism(e.g.Chlorpromazineandpropranolol).

45. Q1: How propranolol reduces the rate
of lidocaine metabolism?
Q2: Enlist few consequences of
microsomal enzyme induction.
Q3: What are the attributes of drugs
with high first pass metabolism?