Variability in Response to Medicines PDF

Variability in response to medicines Ethnic di4erences in drug response Drug response variability. Importance of CYP1A2 - CYP1A2 is an important drug metabolising enzyme (theophylline and olanzapine). - CYP1A2 also plays a role in detoxification and activation of carcinogens. CYP1A2 su...

Variability in response to medicines Ethnic di4erences in drug response Drug response variability. Importance of CYP1A2 - CYP1A2 is an important drug metabolising enzyme (theophylline and olanzapine). - CYP1A2 also plays a role in detoxification and activation of carcinogens. CYP1A2 substrates, inducers and inhibitors à you change intrinsic clearance. It is important for drugs which have a low hepatic extraction ratio. Ca4eine metabolism E4ect of diet CYP1A2 activity is lower in south Asians.  - Smoking à inducer - Oral contraceptive pill à inhibitor Ethnic di4erences in CYP1A2 Conclusions - South Asians have a significantly lower CYP1A2 activity than Europeans. - Oral contraceptive use inhibits CYP1A2 activity. - Smoking induces CYP1A2 activity. - Ethnic diIerence in CYP1A2 inducers Warfarin – variability in INR - Warfarin à very narrow safety margin. - Very variable, each line represents individuals. Determinants of warfarin response. - Multifactorial with interactions between PK and PD factors, include: o Age o Organ function o Genetic influences o Dietary influences o Concomitant medicines o Others Metabolism of warfarin Observations in the clinic Warfarin Drug Interactions - why are they clinically significant? - Narrow therapeutic range. - Low extraction ratio in the liver. o Importance of Clint. - Hepatic metabolism (CYP2C9) - (Not because it is) highly protein bound. à not significant. Warfarin drug interactions – multiple mechanisms. - AIect pharmacokinetics of warfarin - AIect pharmacokinetics of vitamin K - AIect blood clotting mechanism. - Drugs that can aIect the integrity of epithelial surfaces of the body. Warfarin drug and food interactions. - Starting or ceasing medicines for patients on warfarin requires careful attention to possible interactions. o Monitor INR and signs of bleeding. - Vitamin K rich foods can reduce the eIects. o Moderation. In summary - Variability in response can be due to pharmacokinetic and pharmacodynamic factors - Genes are important…. but the environmental factors can be very important as well - Understanding the cause of variability in response is essential for individualizing dose regimens. Quiz Studentamine is a new anticoagulant with the following PK/PD characteristics. 0.1 dose excreted unchanged urine à predominantly metabolised in liver. 10% is renally cleared. à rest hepatically cleared. Low extraction ratio à hepatic clearance mainly determined by fraction unbound. Fe 0.1 à change in renal function wouldn’t significantly aIect. Genetic mutation à not important since only 7% of CYP2D6 is metabolised. Genetic variation in CYP3A4 has very little eIect on overall metabolism. But vulnerable to food interaction à grapefruit, pomelo juice. (CYP3A4) Ethnic diIerences à probably not à CYP1A2 à only 5%. Age? à probably eIect it as it is anticoagulant. à have important eIect on clotting cascade.