What a drug does to the body
What the body does to a drug
How do the metabolites of a drug usually compare to the original form?
They are usually less pharmacologically active, with a few exceptions
Give three exceptions to the rule that metabolites of drugs are less pharmacologically active than the original
- Primidone to phenobarbitone
- Pethidine for norpethidine
- Codeine to morphine
Describe the characteristics of a pro-drug
Stable and relatively unreactive
What happens to pro-drugs in phase 1 metabolism?
A reactive group is exposed on the parent molecule, or added to the molecule
What is the result of the exposure of a reactive group in phase I metabolism?
It generates a reactive intermediate that can be conjuated in phase II with a water-soluble molecule to form a water soluble complex
What are the most common chemical reactions that occur in phase I metabolism?
What to the chemical reactions in phase I metabolism require?
A complex enzyme system called the cytochrome P450 (CYP) system, and a high energy cofactor, NADPH
What happens to the reactive intermediate from phase I in phase II metabolism?
It is conjugated with a polar molecule to form a water soluble complex in a process called conjugation
What is the most common conjugate used in phase II metabolism?
Why is glucaronic acid the most common conjugate used in phase II metabolism?
Becasue it's an available by-product of cell metabolism
Other than glucoronic acid, what else can drugs be conjugated with in phase II metabolism?
- Sulphate ions
What does phase II metabolism require?
Specific enzymes and a high-energy cofactor- uridine diphosphate glucuronic acid
What happens to substances absorbed from the lumen of the ileum?
The enter the venous blood
Where does the venous blood from the ileum drain?
Into the hepatic portal vein, which is then transported directly to the liver
What is the problem with venous blood from the ileum being transported directly to the liver?
The liver is the main site of drug metabolism, as it contains all the necessary enzyme systems, and so any drug absorbed from the ileum may be extensively metabolised during the first pass through the liver - the first pass effect
What % of an oral dose of paracetamol is metabolised by the first pass effect?
What do the enzymes in the cytochrome P450 system contain?
How many different haem-containg enzymes are the in the cytochrome P450 system?
About 50, and polymorphisms in the human population
What is the most important isoform in the cytochrome P450 system?
What % of drug metabolism is CYP3 A4 responsible for?
What is the CYP co-factor?
What accounts for variation in drug metabolism in the population?
- Genetic factors
- Environmental factors
In terms of genetics, why can drug effects vary from person to person?
We all differ slightly in the level of expression of metabolic enzymes
Give three examples of a genetic difference that might have a big effect on drug metabolism?
- Some individuals may lack the gene that codes for a crucial enzyme such as CYP3 A4
- Some people are described as slow acetylators, as they lack the main enzyme responsible for the acetylation reaction in phase II
- Some people have relatively low levels of pseudocholinesterase enzymes in the plasma, which affects their ability to metabolise drugs containg an ester bone
Give an example of a drug containing an ester bond, and what it does?
Suxamethonium, which is a muscle relaxant used during anasthesia
How can the environment effect drug metabolism?
If two drugs are given together, the metaboilsm of one drug may affect the metabolism of another
How can the metabolism of one drug affect the metabolism of another?
Enzyme induction or inhibition can occur
Give three examples of enzyme inducers