all right so the last thing that's important for pharmacokinetics is being able to design and optimize a dosage regimen this is really kind of like the crux of pharmacokinetics so whenever you're talking about giving a particular dosage regimen it's really important because it talks about three particular things what's the dose of the drug that i'm going to give what's the dosing interval so how frequently am i going to be able to give this drug is it going to be once a day is it going to be twice a day is it going to be three times a day and then what's the best route of administration to give this drug if i'm giving a po versus if i'm giving it iv and when we construct a particular type of dosage regimen we can think about the easiest one one of the easy ones of being able to accomplish perfect therapeutic concentrations without having to really think and get complicated with respect to the dose the dosing interval which route it's actually really easy whenever you have a continuous infusion because continuous infusions the route of administration is iv the the dose that we give it obviously depends upon what type of effect we're trying to achieve and in the dosing interval it's obviously going to be particularly the constant and so when we talk about continuous infusions what do we kind of see with our graph here it's really really cool so what happens is when you look at the graph of a continuous infusion is as you try to increase the concentration of the drug so it's basically if i'm putting somebody on a cardipine infusion for blood pressure i'm trying to target a particular blood pressure i want their systolic blood pressure less than 140. so titrate the actual drug the dosage per unit time based upon that that goal getting their blood pressure less than 140 millimeters mercury systolic and so what you have to do is is you'll start seeing that maybe the patient requires more drug and you increase the drug concentration over time and over time and it starts to get to a peak peak peak and once you reach that peak plasma concentration what you'll notice is is that if you stop giving the drug right you just eventually said okay turn the infusion off what would you notice about the concentration it would eventually start falling off and it would become eliminated well the drug administration and dosing is starting to go up up up up up guess what else is occurring at the same time as i'm giving this drug so as this drug is being pushed into the circulation increasing the concentration of the drug inside of the actual bloodstream guess what else is happening with the drug the drug is going to the liver it's actually being metabolized it's also going to the kidneys and it's being excreted so the elimination of the drug is going to start doing what the elimination is going to start increasing and then what you'll start seeing is the concentration of the drug decreasing but whenever you have a patient on a continuous infusion what you'll notice is you'll get to a perfect point where the dosing of the drug starts to become equivalent to the elimination of the drug so you get them to a particular concentration of the drug where their dosing rate so the rate at which you're delivering administering the drug becomes perfectly equal to their elimination rate so there's not basically it's like an equilibrium so the amount of drug that's coming in is equal to the amount of drug that's being eliminated from the body and because of that what will i notice i'll notice this kind of plateau this steady state if you will that the concentration of the drugs remains about the same because my dosing rate the rate that i'm giving the drug maybe it's at 15 milligrams you know per minute or whatever and the elimination rate is equal to that and so i'm eliminating the same amount of drug that's actually coming into the systemic circulation and that's a beautiful concept because once we get to this point where the concentration of the drug is kind of staying the same where the dosing rate is equivalent to the elimination rate that's a very particular time you know what this is called you know what this concentration is where we hit this particular state this is called your steady state concentration so it's called your steady state concentration so the steady state concentration is the concentration at which the dosing rate is equivalent to the elimination rate now here's what you may be asked on the exam what is the time that it takes to be able to get you to steady state concentration how much time does it take to be able to reach steady state concentration of the drug well this comes back to half-life and if you guys remember we said that whenever we're trying to eliminate so if we would e for eliminate when we eliminate it took four to five half-lifes to be able to eliminate how much of the drug 95 of the drug the same thing is to be able to reach steady state concentration it takes about four to five half-lives to be able to get it to the concentration inside of the actual bloodstream where it's equal to the amount that's being eliminated so the time required to reach your steady state concentration is heavily dependent upon the half-life and the amount of half-lives it takes to be able to reach steady-state concentration is about four to five half-lifes that's what i want you guys to remember so it takes four to five half-lives to eliminate 95 of the drug but it also takes four to five half-lives to reach a steady-state concentration of the drug which is where the dosing rate is equal to the elimination rate boom roasted now the concentration that we basically approach our reach when we hit steady state so whenever the dosing rate is equivalent to the elimination rate has nothing to do with the half-life the actual drug concentration i could let's say i was at 10 milligrams per minute and i finally reached steady state at 10 milligrams per minute let's say i wanted to increase the concentration of the drug because now i want to drop their blood pressure to less than 120. so now i've got to increase the concentration of the drug as i increase the concentration of the drug to like 15 milligrams per minute eventually what will happen is i'll eventually reach this point where the 15 milligrams per minute that i'm dosing them at will equal the elimination rate so this will be their new steady state concentration their new steady state concentration will be right here but the time that it takes for them to be able to reach that is still four to five half-lives i just increase the concentration by increasing the infusion rate same thing if i wanted to decrease now i don't want to target less than 120 i want to target less than 160 systolic blood pressure so i decreased my infusion rate so it was 10 here 15 here i'm going to drop it down to 7.5 milligrams per minute so by doing that i'm going to decrease this and i'm going to try to get to a point where my steady state concentration is reached and eventually it'll kind of look like this the time it takes for me to reach steady state is still the same but the concentration at steady state is different but i'm still at steady state at the same time frame so the steady state concentration or the concentration at steady state is dependent not on the half-life but on the infusion rate if i increase the infusion rate i'll increase the concentration at steady state if i decrease the infusion rate i'll decrease the concentration at steady state but i'll still re-steady state in four to five half-lives i hope that made sense all right the next type of dosage regimen that we have to talk about which is probably one of the most common ones that most people encounter is maintenance doses and loading doses because daily people are taking medications at a particular dosage every specific you know 24 hours 12 hours eight hours and it's important to understand that we sometimes have to modify the dosage based upon renal function and liver function and so we have to talk about something called maintenance doses and loading doses and we'll talk about this graph here in a second all right so maintenance doses and loading doses so what is a maintenance dose maintenance dose is basically the dose of drug that you want to give a patient that's required to maintain steady state concentration that's all it is it's the dose required to maintain steady state concentration my friends so what how do we actually calculate maintenance doses we had to determine really what's the definition of maintenance dose it really is the dose required to maintain steady state but we could actually say it's the target plasma concentration so let's say it's the concentration of the drug in the plasma that you want to target multiplied by what's called clearance very important concept here very important one multiply by what's called the dosing interval which will represent by this like t okay and then for non-iv drugs or iv drugs divided by the bioavailability of the drug f if it's iv it's one or a hundred percent okay but if it's oral it may not have 100 bioavailability you have to determine that based upon the calculations we talked about over there but that's how we would determine maintenance dose so it's the concentration that you're trying to target within the plasma multiplied by the clearance multiplied by the dosing interval divided by the bioavailability and we know it's the dose required to maintain steady state concentration but what you also need to know is that the concentration of the drug is dependent it's proportional to the dosing interval so if you change the dosing interval for example if you want to maintain a particular concentration of the drug let's say that you want to have a particular concentration of the drug maybe you have the dosing interval to be more frequent and you'll be able to maintain a good concentration so sometimes if you think about maintenance doses we could think about like if you give a particular drug right let's say that you give a drug at this time this time this time this time and this time so every i don't know let's say every eight hours i'm giving a particular dosage of a drug when i give that what will happen is i'll see the concentration of the drug increase right it'll reach an eventual peak and what will happen is after it reaches a peak its dosing rate well what we'll start to see that the elimination rate will start to increase so we'll start metabolizing excreting the drug and we'll see the concentration of the drug dip but then right around that time where the concentration of the drug is decreasing because we're eliminating it we give another hit of the drug and then we see the concentration rise so we get another peak but then the metabolism of the drug the excretion of the drug will start to occur and we'll start to see it dip but before it hits again the complete elimination of it will give another dose and then from there we'll increase the concentration of the drug and you guys get the point we'll keep coming down hit it keep coming down hit it and eventually we'll get to this point hopefully where if you were to imagine let's actually say that it's like right around let's say that's like right around here we get to this point here where we increase it and then we increase it and then eventually we start to notice that the rate of drug administration or dosing is going to be equal to the rate of elimination you see how it's about the exact same so at this point right here where we were noticing if we're obeying first order kinetics we're seeing that as we increase the concentration of the drug we're noticing that the the the rate of elimination or we're noticing like the rate of metabolism all of these things are particularly increasing but eventually we'll start to hit a steady state once we hit that steady state that we're actually at the point where the rate of drug dosing or administration is equal to the drug elimination the rate and so at this point is where we're at steady state and that's about four to five half-lives right so this would be the doses that we're trying to be able to give to get a patient to maintain this point here this is their steady state concentration that's going to be about four to five half-lives to get their steady state concentration okay but again it's important to be able to remember it's that point where the rate of dosing is equal to the rate of elimination of the drug now that's really really important that we understand this the other thing that's really important with maintenance doses besides the dosing interval because that again the dosing interval determines the drug concentration it's the dose required to maintain steady state but there's also this other factor here which is clearance clearance has a huge role in maintenance dosing so for example if i have a patient who if you guys remember the clearance controlled by the renal system the clearance controlled by the hepatic system these were the two primary systems that were involved in clearance if there is dysfunction of the kidneys the ability to eliminate a drug from the body will decrease so the clearance will decrease and then again the hepatic system the hepatic dysfunction so if there's dysfunction of the liver the ability to metabolize and excrete particular drugs will decrease so the clearance by the hepatic system will decrease if clearance is decreasing what would that effectively need to happen what would you need to do to the maintenance dose then because if you can't clear a drug what happens to the concentration of that drug that means that the actual concentration of the drug inside of the actual blood plasma is going to be increased and if you give higher main if you keep giving high dosages and you aren't able to clear that drug then the concentration of the drug will behind you start seeing side effects or toxicity so when clearance is actually diminished in situations like renal dysfunction hepatic dysfunction what do you need to do to the maintenance dose you need to decrease the maintenance dose so remember whenever there is decreased clearance you need to modify your maintenance dose another thing that you can do to decrease the actual concentration here is think about this what if i change my time interval so if i change my dosing interval that'll also since dosing interval and drug concentration are proportional if i change my dosing interval that might also be a little bit more helpful so maybe modify the maintenance dose or change the dosing interval to actually lead to less of the concentration of the drug so these are important concepts whenever clearances decrease modify your maintenance dose change your dosing interval maybe to be less frequent and that'll actually lead to less of the actual concentration of the drug so it's important to remember that maybe decrease your time at their dosing interval and modify or decrease your maintenance dose when the patient has decreased renal and hepatic clearance all right the next thing that we have to talk about is maintenance dose we understand right it takes some time four to five half-lifes for us to be able to reach steady state but what if i have a situation where a patient is dying okay they are status epilepticus and i don't have four to five half-lives i don't have as much time to put them on a maintenance dose of kepra or phosphonotone or lucosamide or whatever the drug may be to be able to stop their seizures i need to reach rapid plasma i need to rapidly reach serum plasma concentrations that will actually allow for me to get to steady state quicker so in order for me to do that whenever i have a patient who's really really ill so let's say i have an ill patient and i want to get that plasma concentration up high really quickly i give them something called a loading dose now loading doses are basically the target plasma concentration that you're trying to achieve multiplied by the volume of distribution divided by the bioavailability and this is the important one here the volume of distribution but again the whole point of a loading dose is to rapidly reach a peak or very high serum concentration of a drug so that you can get them to steady state a little bit quicker hopefully so it helps us to reach a peak or a peak serum drug concentration rapidly so it helps us to be able to reach a very high peak serum drug concentration very rapidly and critically ill individuals so if you can imagine here look at how much time it took giving these maintenance doses to be able to get us to the peak kind of like serum concentration that we need that we want to maintain steady state at if i give this patient a loading dose so let's actually do this in like this color here what i'm going to do is is i'm going to hit them really really quickly with this very large dose and then from there we'll be able to give them their maintenance doses to maintain steady state concentration so whenever i have a patient who's very very sick oftentimes we'll give them a loading dose for example if i have a patient who's in status epilepticus i'll give them a heavy dose of a particular anti-epileptic for example let's say phosphate let's say a levatorization or keppra most commonly utilize one you can give them three grams of kapra so that's their loading dose that's going to help them to reach peak serum concentrations of the kapra to exert its effect then after that maybe a certain hours later i'll put them on a maintenance dose which is not as high as a loading dose maybe i'll instead of putting them on three grams i'll put them on 1.5 grams and i'll put it on them twice a day so it's 1.5 grams twice a day that's their maintenance dose to maintain the steady state concentration to allow for them to have anti-seizure effects so that's the significance of loading doses it helps them to reach peak serum concentrations quickly and critically ill individuals and maintenance doses helps us to maintain a steady state concentration the dose is dependent upon the dosing interval you decrease the dosing interval to be able to help with lowering potentially the drug concentration and then we also said that maintenance dose is really really heavily dependent on clearance if someone has renal dysfunction and a drug is really cleared that's going to cause them to accumulate more of that drug so you need to decrease their maintenance dose or change their dosing interval to be less frequent okay if they have hepatic dysfunction the drug is hepatically cleared you need to modify decrease the maintenance dose and again change the dosing interval to be less frequent so that you don't have toxic side effects for loading dose it's heavily dependent upon volume of distribution and i know you guys remember this volume and distribution if you have a particular volume of distribution let's say volume of distribution for this person here for the loading dose let's actually do this let's say you have a volume of distribution and it's very high and versus the volume of distribution and it's really low so high volume of distribution what does that mean for the serum concentration of the drug if a volume of distribution is high does that mean it's highly distributed so does that mean that there's much in the plasma no so that means that there is decreased plasma concentration of the drug and then for a low volume of distribution what does that mean for the plasma concentration of the drug in the serum it would be very high because it's not very distributed and so in this case there will be a very high plasma concentration of the drug if i want to reach peak serum concentrations i want to increase my serum concentration in the blood rapidly which one would i need to give a heavier loading dose for the one with a high volume of distribution or the one for a low volume of distribution i would want to give a very heavy loading dose in situations where the volume of distribution is high so these will require a very high loading dose and these will require a lower loading dose so it's very very important to remember that so again loading dose is very importantly related to volume of distribution if the volume of distribution of that particular drug is very high you're going to have to give a very very high loading dose for it to reach peak serum concentrations because it's going to try to distribute and get out of the vasculature if you have a drug that has a very low volume of distribution that means it's already pretty high in the serum and in the blood so i wouldn't need as high of a loading dose to reach that peak serum concentration same thing for maintenance doses if the clearance is reduced because of hepatic or renal dysfunction whichever route that the drug is cleared or eliminated from the body you need to decrease the maintenance dose because if there's decreased clearance you will have the patient retaining too much of the drug enough toxic side effects reduce the dose change the dosing interval to be less frequent i hope this made sense all right guys let's do some questions on dosage regimen so we got a 64 year old female patient 60 kgs treated with an experimental drug nerd for type 2 diabetes drug nerd is available as tablets with an oral bioavailability of about 90 percent if the volume of distribution is 2 liters per kg and the desired steady state plasma concentration that you want to reach is 3 milligrams per liter what is the following most appropriate oral loading dose that we should give of drug nerd to treat this patient with type 2 diabetes so you remember when we give a loading dose a loading dose is is designed to be able to help us to be able to reach peak plasma concentrations very very quickly and patients who need it very very immediately so it just helps us to be able to get up into that peak concentration very quickly so when we talked about the loading dose formula it was actually the target plasma concentration multiplied by the volume of distribution divided by the bioavailability that's our formula we said that the most important component in that is volume of distribution so we said that for volume of distribution as we increase the volume of distribution of a drug that means that less of it is going to end up in the plasma more of it is distributing into the tissues into other extravascular compartments so because of that not as much of it is going to be in the bloodstream or the plasma so the concentration of that drug in the plasma will reduce and so because of that we have to give very high loading doses and with drugs that have high volume of distributions and drugs that have a very low volume of distribution we can give very low loading doses but let's go ahead and plug all these things in it's just a plug and chug so you have to memorize this formula and know the most important relationship between loading dose is volume of distribution of the drug that is the most important factor so if we take this consideration we're going to plug 3 milligrams per liter into the target plasma concentration 2 liters per kg of this drug so that's not a ton but we're going to plug that in there into the volume of distribution and then the bioavailability is ninety percent if it was an iv drug it'd be 100 so it'd be one in this case it's going to be 0.9 so if we plug all of this in it's going to be 120 times 3 divided by 0.9 and the only reason we got 120 liters is because we're taking 2 liters per kg and multiplying it by the weight of the patient which is 60 kgs okay because the volume of distribution should be in liters all right so if we take that into consideration when we do this what's our loading dose it's 400 milligrams so that would be the potential answer here is 400 milligrams that's how much we would have to give but again again the most important relationship here that i can't stress enough is that loading dose is extremely dependent upon the volume of distribution of the drug if this increases you have to increase the loading dose to get that plasma concentration high if it's low you don't have to give as much of a loading dose because it's going to be the drug is going to be staying in the vascular compartment so you don't have to give a heavy loading dose it's a very important relationship here all right guys so in this video we definitely talked about a lot of things about dosage regimen i think it's really important i hope this stuff made sense and again don't also forget that when we talk about loading dose we understand that there's a significant importance of loading dose and volume distribution in the same way there's an extremely important relationship between maintenance dose and clearance so again remember your particular formulas for these because again if you're asked a question you just a plug and chug in these particular formulas knowing that formula is extremely important to be able to get any correct answer but also know the important relationships between loading dose and volume of distribution and maintenance dose and clearance all right engineers hope this made sense i hope that you guys enjoyed it and as always until next time [Music] [Music] you