L25 - Liver Function - Metabolism Flashcards
How do molecules reach the liver? What type of molecules?
Through the hepatic artery and portal vein
- endogenous and ingested molecules and compounds
What happens to the molecules when they reach into the liver?
Some are secreted into bile, most reabsorbed in the SI
What molecules are metabolised by liver enzymes?
Lipophilic molecules (and drugs)
- to form polar products excreted in the urine
What are the two stages to the metabolism?
- phase I
- phase II
What are reactions and products like during phase I?
Catabolic - oxidation, reduction or hyrdolysis
Product - still or even more reactive
- mainly applicable to lipid soluble molecules (has to enter cells)
What happens during phase I reactions?
Introduces a functional group - provide point of conjugation
What are reactions carried out by in phase I?
Hepatic microsomal enzymes (found in ER inside hepatocytes)
What is the main microsomal enzyme from?
Cytpchrome P450 family (CYP enzymes)
What is the (CYP) Cytochrome P450 monooxygenase system? (2)
- family of haem enzymes
- different members of the family
What do cytochrome P450 enzymes differ in? (3)
- a/a seq
- substrate specificity
- susceptibility to inducers and inhibitor
What does variations in expression and polymorphic forms of CYP enzymes result in?
Species and inter-individual variation
-important implications in drug testing and drug response
What is the monooxygensae P450 cycle? (6)
- P450 w/ Fe3+ combines with drug
- e- from NADPH P450 reductase
- Fe reduced to Fe2+
- combines w/ O2, proton and 2nd e- = FeOOH-DH
- combines w/ proton = water and (FeO)3+DH
- (FeO)3+ extracts H+ to release DOH and regenerate P450
What are the Phase II reactions?
Anabolic
- involve conjugation (attachment of substituent group)
E.g/ glucuronyl, sulphate, methyl or acetyl group
What are most products like after phase II reactions?
Inactive
What is enterohepatic recirculation?
Hydrophilic conjugates are secreted into bile, delivered to SI, conjugation is removed and molecules/drug reabsorbed
What are racemic mixtures?
Molecules and drugs that exist in mixrtues of steroisomers
What can steroisomers have?
Different pharmacological effects, metabolised differently
What is an example of s drug that is a racemic mixture? (2)
Warfarin
- exists as R&S enantiomers
- metabolised by different CyP450 enzymes
What potential is there due to steroisomers?
Large range of srug interactions and effects of polymorphism
What is the presystemis firstpass metabolism?
Food/drugs entering the gut are absorbed into SI and pass into the blood
What happens to the blood in presystemic firstpass metabolism?
Carried to the liver by hepatic portal bein
What are food/drugs metabolised by before they enter the systemic circulation?
Hepatic mircosomal enzymes
What does the presystemic firstpass metabolism mean for a drug given orally compared to a drug given iv?
Orally - higher - as metabolised
Iv - lower - direct to blood
What does the presystemic firstpass metabolism mean for patients with decreased GI/liver function? (2)
- Lower motility - less absorption to blood
- Higher motility - more absorption = lower dosage
What are prodrugs?
Drugs which only become active once metabolised by microsomal enzymes
What can metabolism cause?
Change in pharmacological action
What are SNPs amd where are they commonly found?
Single nucleotide polymorphisms
- CYP450 enzymes
What can SNPs give rise to?
Different polymorphic forms which metabolise at different rates (fast, intermediate, slow)
What does a fast metaboliser have an effect on an active drug or a produrg?
Active drug - higher dose, inactivate more
Prodrug - toxic inc, exceeds therapeutic dose
What does a slow metaboliser have an effect on an active drug or a produrg?
Active drug - lower dose, may get toxic as API stays longer
Prodrug - decreases
What are dietary, lifestyle and medicinal inducers of CYP450? (3)
- brussel sprouts
- smoking
- st john’s wort
What are dietary inhibitors of CYP450?
Grapefruit juice
What can affect metabolism of other compouds/drugs?
Several drugs can increase the activity of the CYP enzymes
How are enzyme inducers useful?
Phenobarbital induces glucuroyl transferase
- can be administered to premature babies to increase cojugation and removal of bilirubin
How are enzyme inducers harmful? (2)
- coadministered drugs may be metabolised too quickly = reducing effect
- any toxic metabolites will be increased
What are paracetamol metabolites?
Highly hepatotoxic
- toxicity of overdose increased in patients with chronic alcohol consumption
What are examples of enzyme inducers?
Rifampicin (antibiotic) and warfarin (anticoagulant)
What does carbamazepine induce?
Its own metabolism
- required to start at a losw dose then increase
What can inhibition of enzyme activity do?
Prolong activity of a co-administered drug
What is an example of an enzyme inhibitor? (3)
- HIV medications are potent inhibitors of CYP450
- Metronizaole - S-warfarin
- Omeprazole - R-warfarin
