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Phenytoin Part 1

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Introduction to phenytoin dosing, products and major challenges with dosing

Welcome to farm phenytoin pharmacokinetics this is the first installment of probably several as we work our way through this the dosing of this drug that is very important and also kind of tricky so hang with me your the objectives are outlined here i’m not gonna spend much time on indications or products available but because we’re gonna jump right into that there the

Kinetics which are kind of tricky with this drug as i mentioned before we’ll do a few cases and then we’ll do some more cases in class as you know phenytoin is used for many different types of seizures and also for other neurologic problems and it’s such an effective drug that there are lots of drugs that are coming on the market to try to take its place because it is

You know like i said a stinker to dose so it would be nice if we don’t have to use it because of the problems that it does present as far as dosing in a safe and effective way he has a lot of side effects as well it’s available as a phenytoin acid so there’s no salt at street phenytoin there’s no you don’t have to worry about the salt associating and having to adjust

For that bioavailability of the drug is about 95 percent and it’s available as a 2 tab and a suspension this is usually used for kids the phenytoin sodium capsule obviously is a salt form and so you have to account for that it’s about 92% phenytoin the this is available in 100 milligram and 30 milligram capsules which does present problems with a nonlinear really

Cleared drug which we’ll talk about as we get into the dosing there’s a the capsules are used for once daily dosing because they are a extended-release formulation and there is one generic product that can be that can be substituted for the dyna linton which is kind of the standard brand name and that’s the milan brand of sodium extended-release sodium phenytoin

There is also an iv formulation and it’s really tough for it to stay in solution so you cannot dilute it until right before you use it it comes in an amp it with 50 milligrams per milliliter and it’s usually they come in hundred milligram amps and there’s larger ones too but usually you use the 100 milligram amps so there’s two milliliters in there you have to be

Sure that you do not give this drug faster than 50 milligrams per minute and 25 milligrams per minute if you’re in elderly patients or patients with cardiac disease because of the diluent that’s used in the formulation can cause profound hypotension and therefore cause blood pressure to drop and for there to be reflex tachycardia which can cause obviously stress on

The heart which is could cause big problems as you know you can only dilute this in normal saline this time of year we have you probably bring out little snow globes even though it’s like 60 out here which is weird but if you add phenytoin to d5w you will get a snow globe in your iv bag obviously you don’t want that to go into your patient so you only use normal

Saline to dilute phenytoin and you make sure that when you’re administering it there’s a filter needle in there in case there is any crystallization that forms even with the normal saline tillymann faast phenytoin is another iv form of phenytoin that is prescribed in phenytoin sodium equivalents it’s not you just figure out how much you’re gonna give of phenytoin

And then 75 milligrams per ml of fossa phenytoin equals 50 milligrams of phenytoin or if any toy and sodium equivalence so 2 ml of this vast phenytoin and tenth okay i’m not sure what i’m saying here so i’m gonna just skip this you just dose it as a if you give it the 2 ml vial i’m sorry the 2 ml vial is equal to 100 milligrams of phenytoin and the 10 ml vial is

Equal to 500 milligrams of phenytoin that is what i meant to say for this drug you can’t exceed more than 150 milligrams per minute so 3 mls per minute so you can give it a little faster which is important in status epilepticus all right i think i already mentioned that the milan brand of extended phenytoin sodium is a b-rated and can be substituted for phenytoin

Although this is maybe controversial with clinicians so with these products they come as a hundred and thirty milligram capsules their salt form is 0.92 bioavailability is 0.95 therapeutic range were shooting for for total concentrations is between 10 and 20 milligrams per liter and you will find out soon that it’s about 90% bound so if we’re gonna calculate free

Concentrations we want the free concentration to be between 1 and 2 milligram per liter so what are we gonna see if we get outside the therapeutic range on this drug well these are concentration dependent adverse drug reactions so there’s concentration dependent and there’s not kind of non concentration dependent obviously if their concentration dependent we can

Get rid of them by decreasing the concentration or minimize them by decreasing the concentration if they’re not concentration dependent we can’t do anything by changing the amount of drug we’re giving we’re just gonna have to change drugs if they’re unacceptable okay so as far as kinetics is concerned when we’re dosing a drug we want to be particularly concerned

About the concentration dependent adverse drug reactions so the biggest one we’re gonna see our cns effects like nystagmus ataxia decreased meditation so first thing you usually see is the nystagmus even in the therapeutic range you can see nystagmus at the high end once you get up in the thirty range you’ll see a taxi had difficulty walking diminished mental

Capacity when you get higher and then eventually drowsiness and you can slip into a coma that’s not good you can also see gingival hypertrophy you’ve probably already talked about this and making sure their dental care is really good but this is a concentration dependent adverse drug reaction so you can try to minimize it by keeping the concentration as low as possible

While maintaining seizure free beam sees our procedure free for the patient you also can get her chisholm and course facial features from too high or with high levels of this drug in immunological disturbances so you see a decrease in iga these are not concentration dependent so they’re more like allergic almost reactions so any hypersensitivities like rashes sle

Exfoliat of dermatitis which i have seen with this drug or a thema multiple armed a carbohydrate intolerance you can see hyperglycemia again that’s not concentration dependence you can’t really control it by decreasing the dose folic acid and vitamin d deficiencies anemias hepatitis and trudeau genesee okay bioavailability is usually somewhere between point eight

Five and point nine five a big thing with this drug is that food and tube feedings if the offending twin is being given orally in a patient that’s being tube fed or food in general can decrease significantly decrease the absorption of the drug not too sure about any transporter systems affecting the the gut metabolism but it’s probably not a substrate and it is

Ffp is approximately one so we know that it’s a low extraction drug and you knew this from looking at the bioavailability here volume of distribution is 0.7 liters per kilogram so it’s rate at total body water there if your if your patient is obese you would adjust the volume of distribution as stated here by adding a little portion of fat weight so in this case

You can see how we adjust the dosing weight here it’s not the same as for aminoglycosides or for creatinine clearance a little bit different it’s 90% bound to plasma proteins specifically albumin there are a lot of drug and disease interactions associated with this protein binding issue so the first thing we have is bioavailability problems with this drug second

Thing is we have is highly protein bound and there’s a lot of interactions specifically with other anti-epileptics which makes it even more complicated and as you probably know we often give many anti-epileptics together especially in difficult to manage patients so valproic acid has a higher affinity for albumin than does phenytoin so it may displace valproic

Acid may displace phenytoin from its fine sites other drugs with high affinity for albumin are salicylate sulfonylureas and phenylbutazone those drugs aren’t given as much but you still may see a displacement if they are obviously if you have hypoalbuminemia or renal impairment hepatic impairment you can see a an increase in the fraction unbound of phenytoin and

Since it’s highly bound to begin with you would be concerned about that so here’s here’s a way you can estimate the fraction unbound of phenytoin and also how it would change the volume of distribution so if you have a hypoalbuminemia patient your volume of distribution is can be estimated in in liters per kilogram if you take 2.8 the sludge factor and divide

It by the serum albumin and severe renal impairment it’s just a little bit different this equation these these things you may i’m not gonna have you memorize them i would give them to you but you need to know how to utilize them this one’s one i use all that’s used all the time in clinical practice and that is being able to figure out how the protein binding will

Change in head cool albumin a hypoalbuminemia patients and patients with renal impairment what this does is takes your concentration that you observed remember what’s the one thing we know well hopefully one thing that comes to mind when you know about binding what you know about protein binding is with high highly bound drugs you can use total concentration to

Estimate what’s happening with free unless there’s a binding change if there’s a binding chain then all bets are off and what this does is it takes your observed total concentration and using the serum albumin it adjusts that total concentration to actually reflect what it would be to show you what’s going on with free so it’s a fudge factor to actually change

The total to reflect really what’s happening with a free concentration so both hypoalbuminemia and renal impairment so you just take the concentration that if you order a total level of phenytoin you put it in to the numerator here and then you divide that by 0.2 times the serum albumin of the patient puts plus 0.1 you multiply these first and then add that’s okay

Follow your rules of or what’s it called again your power or i can’t think of what is it called but you know what i mean anyway that will adjust your total concentration to really reflect with what’s going on with the free concentration i use these all the time and we will use them in some cases as well the third tricky thing about phenytoin so so far we’ve got

Bioavailability issues binding issues and then the third big thing is that there’s nonlinear hepatic clearance so remember it’s a low extraction drug so clearance will be determined by enzyme activity and binding remember that enzyme activity is determined by v-max which is the capacity of the system over km plus c this is michaelis menten right again so v-max

Km plus the cam is the concentration at which you have reached half of your v-max and what you what i’ve told you in the past is that this concentration term usually falls out because the concentration is usually much less that we achieve in the therapeutic range is much less than the km so it falls out this is not the case with phenytoin so as your concentration

Increases what happens to your intrinsic clearance it decreases so that’s shown here as your concentration increases usually your in terms of clearance just stays the same it is not concentration dependent however with phenytoin as you increase the concentration the entrance of clearance starts to fall so this is crazy and it makes things really hard nonlinear

Enzyme activity in the therapeutic range so what does this mean for dosing we’ll talk about that in the next installment see you soon bye

Transcribed from video
Phenytoin Part 1 By Sandra Earle