8- Drug Elimination Flashcards
What is the purpose of biotransformations in terms of Metabolism
Alters the pharmacological activity by increasing hydrophilic character to render metabolites water soluble which aids
What are polar, hydrophilic groups
OH NH2 COOH
What are examples of Non-Polar, Hydrophobic groups
CH2, CH3 C6H5
What are the two ways the hydrophilicity of a molecule
By introducing or unmasking polar functional groups into the molecule.
By removing non-polar functional groups into the molecule.
What will happen to terbutaline if it goes through oxidative deamination.
Removal of an amine group via a CYP450 enzyme.
What will happen to codeine if it goes through oxidative O-dealkylation.
An alkyl group will be removed from an oxygen molecule via a CYP450 enzyme.
What would happen to propranolol if it goes through N-dealkylation
The removal of an alkyl group from a nitrogen group via a CYP450 enzyme.
What are Phase 1 reactions of drug metabolism
Covert parent compound into a more hydrophillic metabolite by adding or unmasking functional groups.
Oxidation
Reduction
Hydrolytic Cleavage
Isomerization
What are phase 2 reactions of metabolism
Conjugation with endogenous substrate to further increase aqueous solubility.
Via glucuronidation, salvation, amidation
What is the major organ for drug metabolism
The liver
What processes do extrahepatic microsomal enzymes put drugs through and where are they found
Found in the digestive system, put through oxidation, conjugation and hydrolysis.
What are examples of processes that hepatic microsomal enzymes would put drug through.
Oxidation, Conjugation
What are examples of processes that hepatic non-microsomal enzymes would put drug through
Sulfation, GSH, Alcohol/aldehyde dehydrogenase, hydrolysis, ox/reduct
What are the two types of oxidation reactions
N-dealkylation O-dealkylation
What is cytochrome p450
A hemoprotein containing an iron atom which can alternate between ferrous and ferric states.
Electron acceptor
Where is Cytochrome p450 found.
Found mainly in the liver but sometimes the lungs.
What cytochrome isoform is used in ibuprofen metabolism.
CYP450 2D6
How does CYP450 metabolise drugs
The drug substrate enters the binding site of CYP450.
The haem co-factor transfers oxygen onto drug molecule.
Therefore making it more polar.
What are the steps of aromatic hydroxylation by CYP450
Substrate needs a C-H for the P450 to cleave
H transferred onto P450- Fe-O to form a hydroxide
OH transferred from p450 back to substrate where original CH was cleaved
What is the process of aromatic hydroxylation via CYP450 enzymes.
Substrate needs a C-H for P450 to cleave.
H transferred onto P450- Fe-O to form hydroxide
OH transferred from P450 back to substrate where original CH was cleaved
What is the process of O-dealkylation of ethers via a CYP450 enzyme
Substrate needs a CH for P450 to cleave
H transferred onto P450 Fe-O to form a hydroxide
OH transferred from P450 back to substrate where original CH was cleaved
What is the name for the functional group that forms after O-dealkylation of ethers and N-dealkylation of amines
Hemi-acetal
What happens to the Semi-Acetal group during O-dealkylation of ethers
C between two heteroatoms is unstable and breaks down
The alkyl group is removed as an aldehyde
What is the process of N-dealkylation of amines via a CYP450 enzyme
Substrate needs a C-H for P450 to cleave
H transferred onto P450-Fe-O to form hydroxide
OH transferred from P450 back to substrate where original C-H was cleaved
The C bond becomes unstable and breaks releasing the acetyl group as an aldehyde.
What does “nor” infront of a metabolite indicate and what are examples
That an alkyl group has been removed from a Nitrogen.
Morphine to Nor-morphine
Propranolol to Nor-propranolol
What does “Des” in front of a metabolite indicate and examples
An alkyl group has been removed from an oxygen or a nitrogen, is always followed by the alkyl group that has been removed.
Metoprolol to Desmethyl metoprolol (removal of a methyl group) or Didesmethyl metoprolol ( removal of both alkyl groups)
Are oxidation rwactions catalysed by CYP450 enzymes.
NO
What is flavin.
The monoxygenase system is present in the liver mainly but also in gut and lung.
Oxidizes nitrogen, sulfur and phosphorus heteroatoms directly.
What is methanol broken down into and what can the metabolite cause
Methanol to formaldehyde to Formic acid which can lead to the destructiuon of the optic nerve.
What enzyme is cocaine hydrolysed by
Esterases
What enzyme is lidocaine hydrolysed by
Amindases
What enzyme is required for glucuronidation
UDP-glucuronosyltransferase (UGT)
What is glucuronidation
The conjugation of a glucuronic acid group to the metabolite.
What is sulfation
The attatchment of a sulfate group onto the metabolite
What co-factor is required for sulfation
PAPS
3’-Phosphoadenosine-5’-phosphosulfate
What enzymes catalyse transfer of sulfate to substrate
Sulfotransferases (SULTs)
What is the by-product of a sulfation reaction
Adenosine
What is the enzyme that assists in glutathione conjugation
Glutathione-S-transferase (GST)
What is Glutathione important for
A protective factor for removal of potentially toxic electrophiles.
What is the toxic metabolite of Paracetamol
NAPQI
What is the function of glutathione in paracetamol metabolism
As soon as NAPQI is made glutathione reacts with the toxic electrophiles to deactivate them.
What does NAPQI toxicity lead to.
Hepatic cell death leading to liver failure
How does drug molecules larger than 400 MW leave the body
Via Bile after phase 2 reactions
What isoform does grapefruit interact with and what drugs
Contains a CYP4503A4 inhibitor so interacts with for example felodipine/Amlodipine
What is the results of CYP2D6 poor metabolisers
Too slow drug metabolism
Too high drug levels at normal dosage
High risk of adverse drug reactions
No response from certain drugs eg codeine
What is the results of CYP2D6 ultrarapid metabolisers
Too rapid drug metabolism
No response at normal dosage
