Michaelis- Menten Non-Linear metabolism & summary

So let’s finish up by taking a look at Michaelis Menten nonlinear metabolism. Capacity-limited saturable metabolism of phenytoin is a very significant consideration. Panettone is one of those drugs that does not always behave in linear fashion. There is a point at which increasing the dose does not cause a proportionate increase in serum concentration. Serum concentration may increase disproportionately to the point of severe toxicity this dosing increases the first-order nature of Michaelis Menten drug like phenytoin can become mixed order and then zero work to the point where the increasing the concentration does not cause an increase in the rate of metabolism.

We know that for a first-order drug as the daily dose increases the average steady-state concentration increases proportionately and this represents the fishtank model in which the higher the concentration, the greater the rate of elimination of drug as the net pulls more and more fish out of the tank with each pass of the net. However when we have a zero order elimination of drug with the Michaelis Menten drug in which the enzymes are saturated it’s more like a fisherman removing one fish at a time by catching it on a hook The diagram on the right illustrates this.

We see that early on with lower doses and lower serum concentrations phenytoin behaves as a first order drug and if the dose increases the serum concentration increases proportionately However as the dose increases to a certain level, we’ll begin to approach the state of metabolic saturation where the enzymes are becoming saturated and presenting more and more drug beyond that point at higher serum concentrations Creates a state in which the enzymes just can’t keep up because they’re saturated and beyond that point it can actually be a zero order process in which the sir level begins to rise very significantly disproportionately as the serum concentration or as the dose increases continually.

You can think of it as as individuals in a rowboat that’s taking on water and at first everybody grabs a bucket and begins bailing water and the more and more water comes into the boat faster and faster people bail that water out with the buckets but eventually there’s going to reach a point if the water is coming into the boat faster and faster and faster that they’ve saturated their ability to bail water out of the boat and the water that’s coming into the boat will just continually come in an increasing fashion and we were talking about a drug this can result in significant toxicity.

So the danger here is that when a drugs total steady-state concentration exceeds the Km with standard dosing. Then it becomes a serious concern that’s the case with a drug like phenytoin the v-max of phenytoin is usually somewhere in the ballpark of 500 milligrams per day and the typical dose for phenytoin for an adult is about 300 milligrams a day. So you’re already in the ballpark, most drugs the standard dosing produces certain concentrations that are far below the situation in which the metabolic enzymes would begin to be saturated but for phenytoin that can happen with standard dosing. So clinicians have to be very cautious of making sure that the serum level is not rising too rapidly.

For a drug with capacity Limited metabolism under what conditions should you be concerned about a disproportionate rise in total concentration at steady-state The daily dose are starting to approach the v-max and milligrams per kilogram per day. Yes, for a drug like phenytoin this is a very serious situation. And it’s it’s important to make sure that the daily dose that a patient is receiving it’s nowhere near the the v-max. That’s why I think it’s a good practice to never increase the dose of phenytoin by more than 100 milligrams per day at a time to make sure that the daily dose is not getting close to the v-max.

B is also a true statement the concentration is greater than the Km at that point when the concentration is equal to the Km, you’re at 1/2 v-max metabolic capacity and that’s the point at which things can start becoming dangerous. If the serum concentration is below the Km you’re still in fairly safe ground

And the drug elimination is becoming more of a zero order process that’s true that’s the situation in which the the serum level can begin to rise very rapidly as the dose increases So the answer to this question is E, A, B, and C are all correct. So to sum up, the key to solving the puzzle of renal and a panic dose adjustment is to focus on how the drug is eliminated.

If it’s a renal filtration process that excretes drugs we’re going to be looking at estimating crediting clearance or GFR and relating that to whether the drug is limited by the kidneys whether the FV is greater than 0.3 and whether the patient has a low GFR below 60 milliliters per minute. For hepatic metabolism that inactivates drugs were concerned about the fraction unbound intrinsic clearance and the liver blood flow based on whether the drug is low e or high e. If it’s low e we’re more concerned about intrinsic clearance and fraction unbound. If it’s high e we’re more concerned about liver blood flow.

In the fifth session of this online course, we will zero in on the dosing and monitoring considerations of amino glycosides and vancomycin.