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WEEK 19:
Pharmacogenetics:
| Question | Answer |
|---|---|
| why do patients fail to respond to treatment/ have adverse effect (2) | metabolism (renal function, drug-drug interactions, and resistance) and pharmacogenetics (ethnicity), |
| polymorphisms | ability to take many forms eg SNP (single nucleotide polymorphism) leading to mutation and amino acid substitution |
| example of SNP (single nucleotide polymorphism) | sickle cell anaemia |
| P450 cytochromes | make up a lot of enzymes involved in metabolism |
| examples of P450 genes | CYP2D6 and CYP3A4 |
| classes of metabolisers (4) | poor (not metabolised), intermediate, extensive, and ultra-rapid |
| what does the class of metabolisers (eg poor) depend on | variation of CYP2D6 |
| warfarin | oral anticoagulant metabolised by CYP2C9 polymorphism- acts a vitamin K antagonist where S-enantiomer reduces clearance so lower dose required |
| s warfarin mechanisms | inhibits VKOR (VKOR converts vitamin K into y-glutamyl carboxylase which activates blood clotting factors from innate to active - 2,7,9,10) |
| vitamin K epoxide reductase complex 1 (VKORC1) | gene encoding subunit 1 of VKOR |
| what happens when S warfarin is metabolised by CYP2C9 | inactivates metabolites which reduces warfarin being broken down which decreases warfarin activity (more left in blood) so dose needs to be decreased |
| warfarin therapeutic window | narrow |
| vitamin K rich foods do what | reduce effectiveness of warfarin eg brussel sprouts |
| aspirin resistance | 1/4 patients are resistance and it is not related to COX- can lead to increased risk of CVD as it is an anti-platelet |
| clopidogrel | anti-platelet and pro drug (inactive form) and first line treatment to overcome aspirin side effects |
| major determinant of clopidogrel efficacy | paraoxonase-1 (PON1) |
| what happens to clopidogrel when it is metabolised by PON1 Q192R | increases risk of thrombosis on stent |
| codeine -> morphine transformation | catalysed by CYP2D6, giving it analgesia (inability to feel) and CNS-depressant effects |
| haplotypes | combination of alleles/ set of SNPs found on same chromosome eg different haplotypes means different warfarin requirements |
| rosuvastatin prevalence and dose varies depending on | racial groups |
| metoprolol | enhanced actions in poor metabolisers |
| fluoxetine | enhanced actions in poor metabolisers |
| codeine | requires metabolic conversion so reduced response in poor metabolisers |
| tamoxifen | multiple metabolic pathways - in poor metabolisers imapired conversion to active antagonist and impaired survival in breast cancer |
| normal coagulation pathway | VKOR = activates vitamin K = coagulation |
| codeine properties | mild opiod properties |
| vitamin K importance | needed for activating clotting factors |
| which clotting factors does vitamin K activate | 2, 7, 9 , 10 |
| why would poor metabolisers show no response to analgesic effects of codeine | since codeine is an active metabolite so needs to be converted into morphine but poor metabolisers cannot do this |
| rosuvastatin BNF in caucasians | max dose 40mg |
| rousuvastatin BNF in asian origins | max dose 20mg |
Created by:
kablooey
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