Session 6 (1) - Drug metabolism Flashcards
Define pharmacology
study of how chemical agents affect the function of living systems
Pharmacodynamics
what a drug does to the body (remember, D’s)
Pharmacokinetics
Casual + Scientific definition
what the body does to the drug
The study of the time course of drugs and their metabolites in the body
What four things does pharmacokinetics involve?
ADME Absorption Distribution Metabolism Elimination
Metabolites of drugs are usually less pharmacologically active. Give one drug which is more pharmacologically active after metabolism
Codeine –> Morphine
What is the function of Phase 1 metabolism, and what three processes does it use to do this?
Adds or exposes reactive group. Oxidation, reduction, hydrolysis.
Why do you add or expose a reactive group on drug in phase 1 metabolism?
generates a reactive intermediate that can be conjugated (in Phase II) with a water-soluble molecule to form a water-soluble complex.
What enzyme system is used in phase 1 metabolism, and what cofact is used?
cytochrome P450 (CYP) system and a high-energy cofactor, (NADPH).
What is the purpose of phase 2 metabolism?
conjugated of reactive intermediate with a water-soluble molecule to form a water-soluble complex.
What are the conjugates commonly used in drug metabolism? What is cofactor used?
Glucoronic acid, sulphate ions and glutathione
UDPGA cofactor
What is first pass effect, and how is it caused?
Substances absorbed from the lumen of the ileum enter the venous blood, which drains into the hepatic portal vein and is transported directly to the liver. Liver is main site of drug metabolism, so extensively metabolised during first pass through liver.
What two things can cause variation in drug metabolism within the population?
Genetic factors
Environmental influences
How can genetic factors effect drug metabolism? (3)
Heterogeneity, each individual genetically distinct.
May lack gene for crucial enzyme (CYP3 A4, accounts for 55% metabolism)
Some described as slow acetylators, as lack gene required for acetylation in phase II. Profound affect on rate of metabolism.
Some have low levels of pseudocholinesterase, which affects ability to metabolise drugs containing an ester bond, such as suxamethionine, a muscle relaxant.
How can environmental influences effect drug metabolism?
Two drugs given together, then metabolism of each drug may interfere with the other. Enzyme inhibition or induction may occur.
Pesticide, ethanol, nicotine and barbituates common culprits.
What is the usual metabolism of a therapeutic dose of paracetamol?
Conjugates with glucronide or sulphate in phase II
What happens if a toxic dose of paractemol is taken?
Undergoes phase I metabolism, toxic metabolite NAPQI produced. Toxic to hepatocytes, undergoes conjugation with glutathione, which is an important anti-oxidant - LIVER FAILURE
Give pathway for alcohol metabolism in body
What cofactors are needed?
ALCOHOL–> alcohol dehdrogenase –> ACETALDEHYDE –> aldehyde dehydrogenase –> ACETATE –> atp –> ACETYL COA
NAD+ reduced to NADH
What feature of aldehyde dehydrogenase makes it good for job?
Low Km (substratee conc when reactive at half maximum velocity), keeps toxic acetaldehyde to a minimum
What happens with prolonged alchol consumption?
Acetaldehyde accumulates causing liver damage, decreased NAD+/NADH ratio
increased acetyl - CoA which effects liver metabolism
What are the usual uses of NAD+?
- Fatty acid oxidation
- Conversion of Lactate –> Pyruvate
- Metabolism of Glycerol
What are the effects of low NAD+/NADH ratio?
4
- Lactic acidosis, due to accumulation of lactate in blood.
- Reduces kidneys ability to excrete uric acid. Crystal of urate accumulate in tissues, causing gout
- Gluconeogenesis cannot be activated (low NAD+/Low lactate use/Low glycerol use) so fasting hypoglycaemia is a problem
- Acetyl CoA cannot be oxidised
Why is high acetyl coA an issue in alchohol toxicity?
- Cannot be oxidised due to low NAD+, so increased synthesis of fatty acids and ketones
- Fatty acids not transported due to lack of lipoproteins
- Fatty liver develops
- Ketoacidosis
Why is there a decrease in liver function in alcoho toxicity?
Due to accumulation of acetaldehyde in hepatocytes
How can a damaged liver be diagnosed?
ALT, AST transaminases present
Gamma glutamyl transpeptidase
Name four things reduced liver function can result in
- Jaundice, as bilirubin cannot be conjugated
- Hyperammonaemia, decreased urea production
- Decreased lipoproteins + clotting factors + albumin, decreased protein synthesis
- Decreased serum albumin, oedema
Give an indirect effect of alcohol
Likely to be vitamin and mineral defiencies and may also be inadequate protein and carbohydrate uptake
How does alcohol effect GI tract? What does this result in?
oss of appetite/diarrhoea/impaired absorption of nutrients,
Vitamin deficiency symptoms are often seen in alcoholics.
How can alcohol dependency be treated?
Disulfiram
It is an inhibitor of the aldehyde dehydrogenase enzyme:
If the patient drinks alcohol, Acetaldehyde accumulates in blood, giving ‘hangover’ symptoms.
How is paracetamol metabolised?
Phase two conjugation with glucuronide or sulphate
What happens when someone has a toxic dose of paracetamol?
Phase 2 pathways become saturated so phase 1 metabolism takes place. Produces NAPQI (toxic to hepatocytes) which undergoes phase 2 conjugation with glutathione
What is glutathione?
An antioxidant which allows you to measure cellular toxicity
What does a toxic overdose of paracetamol cause?
Destruction of liver cells and liver failure which leads to death within several days
