Drug Metabolism Flashcards
Drug metabolism/Biotransformation is the __________ modification of drugs in the body which transforms relatively _________ agents into produce more ______, hydrophilic products which can easily be excreted.
Chemical
Lipophilic
Polar
What is the main pathway to remove drugs from the body
Drug metabolism
Examples of drugs that are activated by metabolism is
Enalapril to enalaprilat
Codeine to morphine
What are the 3 outcomes of drug metabolism
Active metabolite
Active drug
Inactivation
Drugs are mainly __________ and are easily transported across the cell membrane into the cells where they undergo biotransformation.
Lipophilic
Common sites of metabolism are
LIVER
lungs
Kidney
Git
Skin
Drug metabolism occurs in almost all organs of the body T/F
True
Drug metabolism involves 2 types of enzymes these are
Microsomal
Non microsomal
Drug metabolism is categorized MAINLY into 2 main reactions
Phase 1
Phase 2
Must phase 1 occurs before phase 2
No
Phase 3 rxns have been described what is it mainly involved in
the removal of drugs that have undergone phase 1 and or 2 reactions by transporters (P-glycoprotein)
Phase 1 rxns are also known as ________ &__________
Functionalization rxns
Synthetic rxns
Phase 1 rxns convert parent compound into a more polar (=hydrophilic) metabolite by
adding or unmasking functional groups
These functional groups include
-OH
-SH
-NH2
-COOH
5 types of phase 1 rxns
Oxidation
Reduction
Hydrolytic rxn
Cyclization
Decyclization
Phase 2 rxn is __________ with __________ substrate to FURTHER __________aqueous __________
Conjugation
Endogenous
Increase
Solubility
The endogenous substrates of phase 2 include
GAGAS
glucoronide
sulfate
acetate
amino acid
glycine
What is the true detoxification step in metabolism
Phase 2
Microsomal enzymes are located on what cellular organelle? And in what organs
Smooth endoplasmic reticulum
In Liver,
Kidney
Lungs
Intestinal mucosa
Examples of microsomal enzymes are
Monooxygynases
Cytochrome P450
UGT (Uridine 5’-diphospho-glucuronosyltransferas)
Epoxide hydroxylases
Microsomal enzymes are only involved in Phase 2 rxns
T/F
False
Phase 1&2
Non Microsomal enzymes are found in
Cytoplasm
Mitochondria
Plasma
Examples of non Microsomal enzymes are
Esterases
Amidases
Microsomal cytochrome P450 monooxygenase family of enzymes, which ________ drugs
Oxidize
Characteristics of cytochrome p450
Act on structurally unrelated drugs
Metabolize the widest range of drugs
membrane-bound, heme-containing protein.
The human CYP family consists of ____ genes, with ____ families and ___ subfamilies.
57
18
44
CYP3A4
3:
A:
4:
Family
Subfamily
Gene
Modufication of CYP ACTION can occur in 3 ways
• Induction of drug metabolizing enzymes
• Inhibition of drug metabolizing enzymes
• Biological Factors
Biological factors include
Species/Strain differences - fast acetylators vs slow acetylators
Disease state
Sex differences(M F )
Circadian rhythm
Age
Diet
Pregnancy
Inter specie and intra specie differences – rats/mice versus humans
•Genetic differences –
(fast metabolizing – depolarizing muscle blockers, fast acetylators vs slow acetylators )
Testosterone an enzyme inducer t/f
T
Inhibition of CYP enzymes causes 3
- Decreased degradation of co-medicated drugs
Increased drug plasma concentrations
Risk of severe adverse events.
Examples of inhibitors
cimetidine,
Isoniazid,
MAO Inhibitor (Phenelzine)
Grapefruit juice
Induction of CYP enzymes causes
Increased degradation of co-medicated drugs
Decreased drug plasma concentrations
Loss of pharmacological effect
Risk of therapeutic failure.
Examples of cyp inducers are
barbiturates,
carbamazepine,
rifampicin,
cyclophosphamide
St John wort
Glucocorticoids
Gray baby syndrome is
And the deficient enzyme is
an adverse reaction to chloramphenicol
The UDP-glucuronyl transferase enzyme system in infants,
(especially premature infants, is not fully developed and incapable of metabolizing the excessive drug load needed to excrete chloramphenicol)
Testosterone induces the drug metabolizing system T/F
T
First pass effect aka
Presystemic metabolism
First pass is the metabolism of drug during its passage from _______________ into _____________ _________ and it occurs with _______, ______ & _______administration
Absorption site
Systemic circulation
Oral drugs, skin, lungs
In the GIT drugs are metabolized by __________________ & ______
the intestinal and gut wall enzymes
liver
Drugs given __________ bypasses the first pass metabolism
Intravenously
First pass effect is a determinant of
Bioavailability
4 drugs with extensive first pass effect
LMNP
Lidocaine
Nitroglycerin
Propranolol
Morphine
To combat first pass drugs are given
___________ or ________
as high oral dose
via other routes of administration
Other factors may also affect first pass effect are 3
•- increased bioavailability in liver disease
•- effects of other drugs
•- individual variation in oral drug absorption
Phase 1 drug and enzyme enzyme is
Alcohol
Cytochrome p450 oxidase
Dehydrogenase
Reduction drug& enzymes
Eg Levodopa
Cytochrome p450 reductase
Decarboxylase
Hydrolysis drug and example
Lidocaine : local anesthetic agents
Esterase
Amidase
What do we add in phase 1
Functional group
What do we add in phase 2
Endogenous substance
Glucoronidation
Acetylation
Sulphation
Glycine conjugation
Methylation
Gluthathione conjugation
Glucoronide
Acetate
Sulphate
Glycine
Methyl group
Gluthatione
