DI between warfarin and macrolid drug family

[Aznfarmerboi]

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Hey guys, I am stumped on this. I ve tried looking it up in my text book and online but I am lost.

Does anyone know the exact mechanism of this drug interaction specifically erythromycin? All I know is that its a plasma bound protein??? and hence will compete with warfarin. Any help will be appreciated. My professor didnt really go into detail with this case study though nor told us much about it.

 

[PharmacyStud]

Warfarin is highly bound to albumin, abount 99%? This means that warfarin has a very low therapeutically active level. Erythromycin will bind to albumin, causing less warfarin to be bound to albumin. Even if it is 1% less warfarin bound to albumin, the therapeutically active warfarin will increase by 100 fold (since warfarin is such a highly protein bounded drug). This will of course lead to prolonged bleeding and etc. If I'm wrong, don't kill me.

 

[pinkyrx]

From the web:

MECHANISM OF INTERACTION: Erythromycin inhibits the metabolism and subsequent clearance of warfarin from the body. The activity of warfarin may also be prolonged due to alterations in the intestinal flora and its production of vitamin K for clotting factor production.

the interaction between warfarin and the macrolide antibiotics erythromycin and clarithromycin, through inhibition of the cytochrome P450 (CYP) 3A4 metabolic pathway, is well documented.

 

[sdn1977]

Actually...it is really complicated & I think depends if you are answering for a test or having to give actual advice...

Many factors, either alone or in combination, may influence a pts response to warfarin & erythromycin. Drugs may interact through pharmacodynamic or pharmacokinetic mechanisms. The pharmacodynamic mechanisms are synergism (impaired hemostasis or reduced clotting factory synthesis), compettive antagonism (Vit K) & altered physiologic Vit K metabolism (hereditary resistance). Pharmacokinetic mechanisms are mainly enzyme induction, enzyme inhibition & reduced plasma protein binding.

You already know about the protein binding. But..erythromycin is a substrate & inhibitor of the cytochrome p450 enzyme system (we think CYP3A, but may be others). There are at least 6 isoenzymes involved in the metabolism of warfarin (3A4 is one of them)...so inhibition of the metabolism warfarin is also involved.

Finally, there are more esoteric mechanisms which may be factors. Any antibiotic will affect the bowel flora & stable bowel flora is a factor in Vit. K synthesis which affects clotting factor synthesis. In addition, erythromycin causes frequent diarrhea, which is also a factor in altered effects of warfarin.

Hope this helps....there may be factors others remember, but this is what comes to mind immediately....

 

[Aznfarmerboi]

Actually...it is really complicated & I think depends if you are answering for a test or having to give actual advice...

Many factors, either alone or in combination, may influence a pts response to warfarin & erythromycin. Drugs may interact through pharmacodynamic or pharmacokinetic mechanisms. The pharmacodynamic mechanisms are synergism (impaired hemostasis or reduced clotting factory synthesis), compettive antagonism (Vit K) & altered physiologic Vit K metabolism (hereditary resistance). Pharmacokinetic mechanisms are mainly enzyme induction, enzyme inhibition & reduced plasma protein binding.

You already know about the protein binding. But..erythromycin is a substrate & inhibitor of the cytochrome p450 enzyme system (we think CYP3A, but may be others). There are at least 6 isoenzymes involved in the metabolism of warfarin (3A4 is one of them)...so inhibition of the metabolism warfarin is also involved.

Finally, there are more esoteric mechanisms which may be factors. Any antibiotic will affect the bowel flora & stable bowel flora is a factor in Vit. K synthesis which affects clotting factor synthesis. In addition, erythromycin causes frequent diarrhea, which is also a factor in altered effects of warfarin.

Hope this helps....there may be factors others remember, but this is what comes to mind immediately....

Thanks a lot! 🙂