PK: Drug Metabolism Flashcards
Main routes of loss of drug from the body
Processes by which there is loss of drugs from the body
Kidneys
Hepatobiliary system
Lungs
// Metabolism and excretion
What are xenobiotics
What are these compounds susceptible to
Foreign chemicals - most drugs are xenobiotics
Susceptible to transformation by mechanisms evolved to modify these compounds
Drug metabolism/biotransformation
Collective term for these enzymatic alterations
What happens to lipophilic drugs in the body
Not excreted
What happens to hydrophilic metabolites in the body
They are excretable
What does water solubility result in @ the kidneys
Increased renal excretion
Decreased tubular absorption
Name the 4 important ways metabolism alters a drug
- Convert an active drug into an inactive drug
- Convert an inactive prodrug to an active drug
- Convert an active drug to an active or toxic metabolite
- Convert an unexcretable drug to an excretable metabolite
Overview of the main routes of drug administration and elimination
Name the principal organ of drug metabolism
Hence what effect is it responsible for
Liver
First Pass Effect
(Skin, lungs, GIT and kidneys also contribute to drug metabolism)
What enters and exits the liver
What important organelle is found in the liver
What enzymes are found in the liver
Phase I metabolism
Main function is to prepare drugs for phase II metabolism
Functional groups e.g. -OH, -NH2, -COOH introduced into drug molecule
Phase II metabolism
Groups in a drug molecule (which may or may not result from phase I) are CONJUGATED with HYDROPHILIC groups
This increases water solubility and ease of excretion
What do phase I reactions include
FUNCTIONALISATION RXNS
- Oxidation - metabolism of approx 75% of all drugs - catalysed by the mixed function oxidase (MFO) system - cytochrome P450 // NADPH // molecular O2
Most common Oxidation/reduction system of phase I drug metabolism
P450 enzyme system of the liver is the most common
CYP1 family
Primarily metabolise carcinogens, some drugs as well
CYP2 family
Metabolise many important drugs
CYP3 family
Most abundant family in human liver (60% of drugs)
Describe the substrate specificity of oxidases
How are these enzymes named
Most oxidases exhibit broad substrate specificity many of the P450 enzymes have overlapping specificities
P450 followed by number of P450 enzyme family, captial letter of the subfamily and an additional number to identify the specific enzyme e.g. P450 3A4
Define hydroxylation
What sort of metabolism is it
Give an example of a drug metabolised in this way
Addition of an -OH grp
A type of phase I oxidation rxn
LIDOCAINE (a local anaesthetic) - hydroxylation is the first step in its metabolism
Give an example of dehydrogenation (phase I rxn)
Where is the majority of ethanol metabolised
Where is a minority metabolised
What is the next step in ethanol’s metabolism
- Most ethanol is metabolised by the liver
- The kidneys and bone marrow oxidise ethanol to a small extent
- The next step is to further oxidise the acetaldehyde to acetate (CH3COO-)
What happens in the metabolism of acetaldehyde (met. of alcohol)
Oxidation of the acetaldehyde occurs enxymatically in the mitochondria
Relies on the enzyme Aldehyde Dehydrogenase (ALDH)
Acetate is then released to the blood for subsequent oxidation to CO2 by other tissues
What is disulfiram used for
Where does it accumulate
What is its bioavailability
Used in the management of alcoholism, it helps to maintain abstinence
Highly lipid soluble - accumulates in adipose tissue
80% bioavailability after an oral dose
Pathophysiology of disulfiram
Alcohol mainly metabolised in the liver to acetaldehyde by ADH which is then oxidised to acetate by aldehyde dehydrogenase (ALDH)
MOA of disulfiram
Irreversibly inhibits the oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on ALDH
Disulfiram causes a 5-10x increase in the conc of acetaldehyde which produces unpleasant side effects
Overview of phase I rxns
Phase 2 rxns include…
Conjugations with glucuronide, sulphate
Hydrolysis often included here
What happens in phase II metabolism
What is needed for these rxns to take place
Name the main rxns
- A hydrophilic group is conjugated with a grp already in the molecule (may or may not result from phase I metabolism) giving a water-soluble product which is excreted in bile or urine
- These conjugation rxns are catalysed by transferase enzymes and various coenzymes are also needed
- MAIN RXNS:
- Glutathione conj.
- Glucuronic acid conj.
- Sulfate conj.
- Glycine conj.
What sort of rxns are phase II rxns
What are the substrates for these rxns
What is formed
What typically happens to drugs
- biosynthetic
- Substrates include both metabolites of phase I rxns and compounds that already contain chemical grps appropriate for conjugation e.g. hydroxyl, amine or carboxyl moieties
- Formation of covalent link between functional grp and endogenously derived conjugating molecule
- Typically drugs are made more polar and pharmalogically inactive EXCEPT morphine glucuronide
In phase II rxns, drugs are made more polar and pharmacologically inactive, TYPICALLY. What is the exception
Morphine glucuronide
Define glucuronidation
Give examples of drugs metabolised in this way
- UDP-glucuronyl transferase catalyses the transfer of glucuronic acid from UDPGA to a substrate resulting in a glucuronidated substrate and leaving uridine 5’-diphosphate
- Acetaminophen (paracetamol)
- Morphine
- Oxazepam
Define prodrugs
Inactive compounds that are metabolised into their active, therapeutic forms
Metabolite of tamoxifen
How does it differ from its parent
4-hydroxytamoxifen
30-100 x more active than its parent
Metabolite of codeine (3-methoxymorphine)
What enzyme carries out this rxn
What happens if this enzyme is not present
What is codeine often combined with
- Morphine
- CYP2D6 - demethylation - 20% analgesic potency of morphine
- About 10% of population is resistant to the analgesic effect of codeine because they lact the demethylating enzyme that converts it to morphine
- Often combined with paracetamol or NSAIDs in proprietary analgesic preparations
- synergistic effect but potential for safety concerns
Metabolite of enalapril
Enalprilat
Metabolite of prednisone
Prednisolone
With what drugs does site specific action occur
Sulfasalazine and 5-ASA
Synonym for paracetamol
Acetaminophen
Main metabolic pathway for paracetamol
how much of its metabolism does this pathway account for
45-50%
Minor metabolic pathway for paracetamol
How much does it account for
4-5%
Name the product of the paracetamol metabolic pathway that is toxic
NAPQI is toxic to the liver but at low doses (1-2 g) this is not a problem as it conjugates with glutathione (GSH) and is excreted
How is paracetamol fatal at high doses
Dose of 10-15g
The glutathione pathway becomes saturated and NAPQI attacks the liver and this can be fatal
Name the P450 forms induced by ethanol
CYP1A2
CYP2E1
CYP3A4
Alcohol abusers have 4x levels of these enzymes in their livers over non-drinkers
What happens when CYP2E1 and CYP3A4 are induced by alcohol
A greater amount of paracetamol is converted to NAPQI
What substance helps in conjugation of NAPQI with glutathione
NAC
Treatment of paracetamol overdose
Paracetamol nomogram
Give acetylcysteine
MCQ
MCQ
