Pharm 5 - Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
eliminate or reduce the pharmacological activity of a drug
makes the drug more polar and soluble so it can be excreted easily
What is hepatic first pass metabolism?
Metabolic conversion of the drug into something different before it enters the circulation
the effect of the drug first time it goes into the liver
What effect does extensive first pass metabolism have on bioavailability?
extensive first pass metabolism = low bioavailability
How can you avoid hepatic first pass metabolism?
Give a drug IV
What are the three types of reactions that fall under Phase 1 reactions?
Oxidation
Reduction
Hydrolysis
What is the purpose of Phase 1 metabolism?
To create or unmask functional groups which can be used in Phase II reactions
How do Phase 1 reactions affect polarity of the drug?
little effect on polarity
Which enzyme system is important to drug metabolism?
Cytochrome p450
Family of 57 enzymes found in liver
What are the substrates of the cytochrome p450 mediated oxidation reaction?
drug, NADPH, oxygen and protons
What are the products of the cytochrome p450 mediated oxidation reaction?
hydroxylated drug, NADP+, water
Describe the oxidation cycle of cytochrome p450.
- Drug binds to the iron in cp450
- electron from NADPH is picked up by Fe3+ iron, making it Fe2+ iron
- Fe2+ gives the electron to oxygen making it unstable
This happens again
- so oxygen is now O2- and very unstable.
- hydroxylated drug + water released
What is N-demethylation? And what does its reaction produce?
oxidation of a methyl group in a nitrogen environment
produces a formaldehyde - HCHO
What does N-demethylation do to a drug?
removes the pharmacology of a drug
What is O-demethylation?
Oxidative attack of P450 on methyl group attached to oxygen
Converts oxygen to hydroxyl group and releases formaldehyde
What is N-oxidation? Describe the type of bond formed?
oxidation of the nitrogen group itself
Nitrogen has 2 free electrons to form a dative bond with water
generates an amino acid
What enzyme catalyses the N-oxidation reaction?
Flavin containing monooxygenase
Describe a condition involving this enzyme.
Flavin containing monooxygenase deficiency - Fish odour syndrome
People without this enzyme cannot convert trimethylamine, so it stays and it is foul smelling
Describe alcohol oxidation.
Alcohol is first converted to acetaldehyde by alcohol dehydrogenase.
Then converted to acetic acid
Where in the cell are flavin containing monooxygenase and CP450 found?
Endoplasmic reticulum
Where is alcohol dehydrogenase found?
Cytoplasm
Where do reduction reactions tend to take place and why?
GI tract as low oxygen environment
State 2 types of hydrolysis enzymes?
Esterases and Amidases
Name 6 types of Phase II reactions.
Glucuronidation Acetylation Sulphation Methylation Amino acid conjugation Glutathione Conjugation
How do you get the name of the enzyme for each Phase II reaction?
add transferase to the end
What effect do phase II reactions have on the drugs?
make drugs more polar and water soluble so they can be excreted more easily
What is the most common phase II reaction?
Glucuronidation - addition of a sugar to a molecule
What is the importance of glutathione conjugation?
conjugated with electrophiles so they are excreted
electrophiles are damaging to DNA, often generated during metabolism
State a conjugating agent used for glucuronidation
UDPGA
State an important property of the conjugates formed from glucuronidation and its impact on its excretion.
large molecular weight products so cannot be be filtrated via glomerulus
excreted in bile
What is the conjugating agent in acetylation and what is the product?
acetyl choline
product = acetylated derivative of the drug
What is the conjugating agent for methylation?
S-adenosyl
What effect does methylation have on polarity?
Decreases polarity
What is the conjugating agent used in salphation?
PAPS -
What are the properties of the derivative formed in sulphation?
sulphuric acid derivative of the drug
very polar and very soluble
What type of molecule is glutathione?
Tripeptide consisting of glycine, glutamine, cysteine
What effect does drug metabolism have on biological half life, duration of expose, and accumulation of drugs in the body?
Decreases ALL
