May 24, 2006

Liver and Medications

Here's how to think about the effect of the liver on drugs:

When you eat a drug, some of it gets bound to protein (albumin) and some circulates freely.  Your body uses free, non-protein bound drug.

Most drugs are mostly protein bound-- notable exceptions are lithium, Ritalin, Lexapro (40%) and Effexor (40%).  Low albumin-- as could occur in cirrhosis, severe malnutrition, etc-- increase the availability of the free form of the drugs. So low albumin + valium = more valium for you.



Next is volume of distribution (Vd)-- drugs with high Vd will diffuse into fluid spaces.  So patients with a lot of edema will end up with lower useful drug (because it diffused into third spaces.)  Be aware that diuresis may consequently increase the dose as it returns to circulation.

First pass metabolism is also important. First pass metabolism means that a substantial portion of the drug is metabolized quickly-- or, conversely, won't be metabolized if your liver is damaged.  The appropriate doses of medications are based on functioning livers.   For example, tricyclics are metabolized by 50% on first pass; which means, in the absence of a liver, you are actually giving twice as much drug as what you think you are prescribing.  Zyprexa has 40% first pass.  Dilantin, by contrast, has low first pass metabolism, so the dose is about the same.

There are two phases of liver metabolism.
Phase 1 occurs in smooth endoplasmic reticulum: reduction, oxidation, and hydrolysis.  All the cytochrome P450 happens in Phase 1.
Phase 2 occurs in periportal region of portal triad:  glucoronidation, acetylation, sulfation.

The trick of this is to understand that liver damage (cirrhosis, etc) affects Phase 1, not Phase 2.

This is why Ativan (lorazepam), Serax (oxazepam) and Restoril (temazepam)-- all metabolized primarily by Phase 2-- are favored in drinkers or cirrhotics.  Also, renally metabolized or cleared drugs will not be as much affected (for example, Neurontin.)

I hope this was helpful.  Please drink responsibly.