Flashcards in Drug Metabolism Deck (28):
What is the difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics is how drugs work
Pharmacokinetics is the fate of drugs in the body
What happens during phase I of drug metabolism?
A reactive group is exposed on the parent molecule or a reactive group is added
What are the common types of chemical reaction in phase I?
Hydrolysis, oxidation, reduction
What does phase I require?
A complex enzyme system - cytochrome P450 (CYP)
What happens in phase II of drug metabolism?
The reactive intermediate is conjugated with a polar molecule to form a water-soluble complex
Name three common conjugates
What does phase II require?
UDPGA (a high energy cofactor)
Why do drugs need to be made water soluble?
Most are lipid soluble, so would be reabsorbed from the urine in the renal tubules.
What are pro drugs?
Drugs which are metabolised in the body to their active form
List some of the main sites of drug metabolism
Why is there variation in drug metabolism within the population?
People have different levels of enzymes and may even be lacking in some enzymes.
Name three well known enzyme inducors
Nicotine, ethanol, barbiturates
When would a drug go straight into phase II of drug metabolism?
When it already has a reactive group
What do enzyme inducers do?
Increase the metabolism of other drugs
What is the first pass effect?
Substances absorbed from the lumen of the ileum drain into the hepatic portal vein which goes straight to the liver - the site of metabolism of drugs.
Drug is extensively metabolised during its first pass so a higher dose is required.
What is alcohol converted to in the body and what enzymes are involved?
Alcohol oxidised to acetaldehyde - alcohol dehydrogenase
Acetaldehyde oxidised to acetate - acetaldehyde dehydrogenase
Acetate to acetyl CoA
Which product of alcohol metabolism is extremely toxic to cells and how is its concentration kept to a minimum?
Acetaldehyde dehydrogenase has a very low Km so removes it as soon as it is formed.
How does prolonged alcohol consumption affect the liver?
Acetaldehyde builds up - damage
Decreased NAD+/NADH ratio
Increased acetyl CoA - affects liver metabolism
What is NAD+ used for?
Beta oxidation of fatty acids
Conversion of lactate to pyruvate
Metabolism of glycerol
How can excessive alcohol consumption lead to lactic acidosis?
Lactate cannot be converted to pyruvate
Lactate accumulates in the blood
How can excessive alcohol consumption lead to gout?
Increased lactate on blood
Decreases kidneys' ability to excrete uric acid
Crystals of urate accumulate in tissues -> gout
How can excessive alcohol consumption cause hypoglycaemia?
Liver cannot use lactate or glycerol
Gluconeogenesis cannot be activated
What are the effects of high amounts of acetyl CoA in the liver?
Acetyl CoA is converted to fatty acids and ketone bodies - no NAD+ so cannot be oxidised
Fatty acids are converted to triacylglycerols which cannot be transported away from the liver due to a lack of lipoproteins. They accumulate in the liver - fatty liver
Ketone bodies could cause ketoacidosis.
What enzymes are used to test for liver function and why?
Transaminases and gamma glutyl transpeptidase
Damaged liver cells have leaky plasma membranes - enzymes lost into the blood
List some effects of a damaged liver
Hyperbilirubinaemia -> jaundice
Increased clotting time
Oedema due to low serum albumin
What drug is used to treat alcohol dependence and what does it do?
Inhibits acetaldehyde dehydrogenase causing symptoms of a hangover when alcohol is consumed
What happens when someone takes an overdose of paracetamol?
Normally metabolised by phase II pathway. This becomes saturated so phase I instead, producing the toxic metabolite NAPQI.
NAPQI is then metabolised in phase II, conjugation with glutathione. Depletes cells of glutathione, an important antioxidant.
Destruction of liver cells and leads to liver failure.