Drug and Alcohol Metabolism Flashcards
Define pharmacodynamics
What a drug does to the body
Define pharmacokinetics
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?
- Oxidation
- Reduction
- Hydrolysis
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?
Glucoronic acid
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
- Glutathione
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?
90%
What do the enzymes in the cytochrome P450 system contain?
Haem
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?
CYP3 A4
What % of drug metabolism is CYP3 A4 responsible for?
About 55%
What is the CYP co-factor?
NADPH
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
- Ethanol
- Nicotine
- Barbituates
What is paracetamol?
A widely available anti-pyretic drug
What happens to paracetamol at therapeutic levels?
It conjugates with glucuronide or sulphate in phase II
What happens to paracetamol at toxic doses?
The gluronide and sulphate pathways become quickly saturated, and paracetamol undergoes phase I metabolism to produce the toxic metabolite NAPQI
What are the toxic effects of NAPQI?
- It is toxic to hepatocytes, causing liver failure over a period of several days
- It undergoes conjugation with glutathione, which is an important anti-oxidant
Where is the major site of alcohol metabolism?
The liver
Give the stages in the metabolism of alcohol
- Alcohol to acetaldehyde, by the action of the enzyme alcohol dehydrogenase
- Acetaldehyde to acetate, by the action of the enzyme aldehyde dehydrogenase
- ATP forms AMP and 2Pi, and converts acetate to acetyl-CoA
What molecule does the complete oxidation of alcohol require?
NAD+, forming reduced NADH
What allows toxic acetaldehyde levels to be kept to a minimum?
Aldehyde dehydrogenase has a low Km
What can happen with prolonged alcohol consumption?
- Acetaldehyde can accumulate, causing liver damage
- The decreased NAD+/NADH ratio, and increased acetyl-CoA affect liver metabolism
What is CYP2E1?
An inducible enzyme that also metabolises alcohol via oxidation
What is NAD+ used for?
- Fatty acid oxidation
- Conversion of lactate to pyruvate
- Metabolism of glycerol
What are the potential consequences of the decreased NAD+/NADH ratio that results from prolonged alcohol consumption?
- Accumulation of lactate in the blood might cause lactic acidosis
- Will reduce the kidneys ability to excrete uric acid, and so crystals of urate may accumulate in the tissues, causing gout
- Gluconeogenesis cannot be activated, and so fasting hypoglycaemia may be a problem
Why can’t gluconeogenesis be activated when there is a low NAD+/NADH ratio?
Because decreased NAD+ results in decreased lactate use, and so decreased glycerol use
What causes the high acetyl-CoA in prolonged alcohol consumption?
Acetyl-CoA cannot be oxidised due to the decreased NAD+/NADH ratio
What is increased as a result of the high acetyl-CoA in chronic alcohol consumption?
There is increased synthesis of fatty acids and ketone bodies
What happens to the fatty acids produced due to prolonged alcohol consumption?
They are converted to triacylglycerols, but cannot be transported because there is a lack of lipoproteins, therefore fatty liver develops
What can be used as an indicator of liver damage?
The levels of enzymes such as transaminases and gamma glutamyl transpeptiase
Why is the presence of transaminases and gamma glutamyl transpeptidase in the blood an indicator of liver damage?
Because damaged liver cells have leaky plasma membranes and so these enzymes can be lsost to the blood
What can reduced liver function result in?
- Decreased uptake of conjugated bilirubin, leading to hyperbilirubinaemia and jaundice
- Decreased urea production, leading to hyperammonaemia and increased glutamine
- Decreased protein synthesis, leading to decreased albumin, clotting factors, and lipoproteins
- Decreased serum albumin may produce oedema
- Decreased clotting factors increases blood-clotting time
- Decreased lipoproteins can cause lipid build up in the liver
What are the nutritional indirect effects of alcohol?
- Likely to be vitamin and mineral deficiencys
- May be inadequate protein and carbohydrate uptake
What are the direct effects of alcohol on the GI tract?
There is often loss of appetite, diarrhoea, and impaired absorption of nutrients (vitamin K, folic acid, pyridoxine and thiamine)
What can thiamine deficiency lead to?
Wernicke-Korsakoff syndrome, with mental confusion and unsteady gait
What drug is used to treat alcohol deficiency?
Disulfiram
How does disulfiram work?
It is an inhibitor of the aldehyde dehydrogenase enzyme, whereby if the patient drinks alcohol, acetaldehyde accumulates in the blood, giving hangover symptoms
