Science of Medicines Week 9 Flashcards
define elimination
the removal of a substance or termination of its biological action
In which two ways does elimination of substances in the body occur?
- metabolism
- excretion
define anabolism
the build-up of compounds
define catabolism
breakdown of compounds
Which organs are responsible for removal of substances?
- liver
- kidneys
- lungs
What are the aims of the phase I and phase II reactions in the liver?
to decrease lipid solubility and enhance renal elimination
How do molecules reach the liver?
through the hepatic artery and portal vein
What are the steps of enterohepatic circulation?
- compounds from the liver are secreted into the bile
- most are then reabsorbed in the small intestine
- circulated back to the liver
What do liver enzymes do to lipophilic molecules?
metabolise them to form polar products so they can be excreted in the urine
What are the two stages of liver metabolism?
Phase I and Phase II
What happens in phase I to molecules?
catabolic reactions and introduction of a functional group which adds as a ‘tag’ to provide a point of conjugation for phase II
What are the main mechanisms of catabolism in phase I?
oxidation, reduction, hydrolysis
Which enzymes carry out the phase I reaction?
liver microsomal enzymes from the cytochrome P450 family (CYP enzymes)
What type of molecule does liver metabolism deal with? Why?
mainly applicable to lipid soluble molecules as polar molecules can be excreted at least partly unchanged
How does cytochrome P450 enzymes differ?
they have different..
1. amino acid sequences
2. substrate specificity
3. susceptibility to inducers and inhibitors
define polymorphic form (enzymes)
an enzyme that exist in multiple different forms within the same species
What determines your cytochrome P450 enzymes?
different alleles in your genes -> different amino acid sequences
What does an individuals cytochrome P450 enzymes affect?
the rate of activity of the enzymes, therefore creates differences in side effects and drug response
What happens in phase II?
anabolism and involves the addition of a subtituent group to inactive the compound
What are examples of substituent groups added?
glucuronyl, sulphate, methyl, acetyl
What happens to the product after phase II?
several hydrophilic products are secreted into the bile and delivered to the small intestine where the conjugation and the drug is reabsorbed
What different processes do different enantiomers undergo?
- different pharmacological effects on receptors
- they are metabolised differently
What are the steps of pre-systemic first-pass metabolism?
- food and drugs are absorbed into small intestine and pass into the blood
- the blood is carried to the liver by the hepatic portal vein
- so hepatic microsomal enzymes can metabolise food or drugs before entering systemic circulation
For drugs administered by IV, is a higher or lower dose needed?
lower –> as there is no initial metabolism as drug goes straight into systemic circulation
For patients with less GI motility, is a higher or lower dose needed?
high dose as less absorption of drug into bloodstream
For patients with decreased liver function, is a higher or lower dose needed?
lower as there is less metabolism of the drug and metabolites may be toxic
define prodrug
a drug that is inactive when administered and is only activated when it is metabolised
define single nucleotide polymorphism
a DNA sequence variation with a different single nucleotide at a particular locus
What are the effects of SNPs on CYP450 enzymes?
the different nucleotide sequence may change the amino acid sequence
What do different polymorphic forms of enzymes lead to?
different rates of enzymatic activity and metabolism
fast metaboliser and active drug
higher dose needed
fast metaboliser and prodrug
lower dose needed as increased risk of toxic effect as fast activation
slow metabolisers and active drug
lower dose needed as metabolised slower -> may be toxic
slow metabolisers and prodrug
higher dose needed as prodrug will not be active for long
How are CYP450 profiles of patients roughly determined?
start patients on a low dose of the drug and take blood samples to find the amount of active drug in the blood and increase from there
Do CYP450 inducers make drugs work faster or slower?
faster as they increase the activity of the enzymes so drug is broken down and cleared quicker
What are 3 inducers of CYP450 enzymes?
brussel sprouts, smoking, St John’s Wort
What is an inhibitor of CYP450 enzymes?
grapefruit juice