Pharmacokinetics | Drug Excretion

we talk about excretion of a drug we're talking about getting rid of the drug so it's excreting the drug out of the body and there's obviously a lot of different organs that can excrete drugs out of the body right so it's whatever drugs are actually whatever organs are open to the atmosphere so the kidneys can actually be the primary way that we excrete drugs so when we talk about excretion of getting rid of a drug or eliminating it from the body the primary way would be excretion via the kidneys so we would urinate out the

drug the second one is we could take a drug and that sometimes you know drugs are actually absorbed across the gi tract they get into the bile system that will be actually conjugated with certain types of biomolecules and then excrete it out via the anteropatic circulation so sometimes we can actually excrete substances out via the bile we can also exhale so you know anesthetics so whenever people are taking certain types of inhaled like gases like anesthetics these can actually be exhaled so the lungs can also exhale specific types of inhaled gases and excrete them out

of the body in that particular way and the last one is you can have a drug that you actually take and none of it gets absorbed across the gi tract it exerts its effects within the gi tract but none of it gets absorbed and so because that you actually eliminate maybe all of the drug or portion of the drug out via the feces so we can actually eliminate drugs via the gi tract by again not absorbing the drug and then excreting out part of the drug or exhaling out particular types of inhaled gases or excreting

into the biliary system which does end up into the feces because it gets absorbed across the gi tract gets taken into the terrapatic circulation and then excrete it into the biliary system or we can excrete the drug into the urine this is going to be the most common and the most important one and whenever we're talking about excreting particular drugs that obviously since the kidneys are the primary mechanism kidney function is extremely critical and crucial to the ability to excrete particular drugs from the body if a patient has chronic kidney disease acute kidney injury just

complete destroyed up kidneys are they going to be able to excrete most of the drugs into the urine no and so the drugs can accumulate so it's important to be able to remember that so what are the different factors that are affecting excretion by the kidney since the kidneys are the primary one we're going to talk about filtration secretion reabsorption and we'll talk about how we can modify a particular excretion of drugs pretty cool concept here something called ion trapping all right so for filtration with basic concept when we actually have a drug that's moving

through the actual kidneys it'll move through the affair and arterial when it moves through the afferent arterial get to the glomerulus and then from the glomerulus via what's called the glomerular hydrostatic pressure we can excrete particular filter particular drugs across the glomerulus into the actual bowman's capsule so this is your bowman's capsule and then it'll go into what's called the proximal convoluted tubule but this process by which hydrostatic pressure pushes certain types of things out of the plasma into the bowman's capsule this is called filtration and filtration is primarily dependent upon something called glomerular filtration

rate so for example if a patient has some type of chronic kidney disease acute kidney injury for whatever particular reason and they have a decreased glomerular filtration rate what happens to the amount of drug that's filtered across the glomerulus well if there's a reduction in gfr that means that there's less plasma less volume of plasma that's actually excreted from or moved out of the plasma into the bowman's capsule that means that potentially less drug is also going to be moved from the blood into the actual bowman's capsule into the actual tubular system if that's the

case that means that we have less filtered drug and potentially higher blood drug concentration so that's an important concept to remember that as patients develop something like chronic kidney disease or they develop a very severe acute kidney injury their ability to filter particular things decreases such as drugs if there's a decreased filtration there is an increase in the actual serum concentration of that drug and more toxic side effects so important to remember that you actually should adjust particular doses of a drug in situations like ckd and acute kidney injury the next thing that we also

have to talk about here is that not only is filtration dependent upon the gfr it's also dependent upon the proteins such as albumin you know albumin is an important protein that helps to be able to bind to a particular drug so for example if we wanted the drug to be able to move out into the bowman's capsule right we know that in order for this process to take place the drug has to be able to not be heavily protein bound so if you have a drug that's like super super protein bound what do you think

the chances that you're going to be able to filter that drug across not very good so whenever you have situations where there's actually lots of albumin lots of protein binding that'll actually decrease the filtration of the drug and keep it inside of the blood so increase protein binding of drug will do what it'll actually have less drug filtered across the glomerulus and into the actual bonus capsule effectively increasing the serum or blood concentration of the drug increasing the potential like toxicity or side effects of that so that's important thing to remember whenever drugs are protein

bound there's going to be less excretion of the drug and less elimination of the drug out of the body so it's an important thing to be able to remember so again filtration is heavily dependent i say this is more important one gfr gfr the glomerular filtration rate the volume that we're actually filtering across the actual glomerulus every minute if that decreases that means that we're not going to filter as much plasma across meaning that we're not going to filter as much drug that's in that plasma across not as much is going to go into the

urine more of it's going to be retained with inside of the blood so that's important thing to remember but if you have a normal gfr a good gfr good kidneys and a decent protein binding but not heavily protein bound things what's going to happen you're going to have good amounts of drugs that will be filtered across and the same concept if you have decreased protein binding what's going to happen decreased protein binding that drug will be able to easily move across our filter across the actual glomerulus and into the actual boneman's capsule so less protein

binding in situations like what maybe if a patient has what's called cirrhosis and they have less albumin what happens they excrete a lot of the drug and maybe they can actually decrease the efficacy of the drug or in patients who have chronic kidney disease and they lose lots of albumin in their urine they have less albumin in the blood to be able to bind onto the drug and lots of drug can actually be eliminated from the body so again important to remember these concepts all right secretion this is another important concept here so let's say

that you have a drug right comes in via the affair and arterial moves into the glomerulus some of the drug is actually filtered across the glomerulus so some of the drug actually crosses over the glomerulus and into the boneman's capsule right via the filtration process but not all of it does and some of the drug actually remains in the efferent arterial and then from there you know the efferent materials move into something called the peritubular capillaries and then some of those can actually go down into the medulla of the kidney and actually cause it let's

go what's called the vasorecta but let's say that some of these actual drugs remain in the peritubular capillary blood not all of it gets filtered so this was step one filtration not all of it gets filtered some of it makes it to the peritubular capillary blood when it gets there guess what's really cool here you have the opportunity to move this drug from the peritubular capillary blood across the kidney tubular cells and into the actual lumen of the kidney tubules so that it can be easily excreted in order to do that it depends upon the

actual solubility of the drug and the concentration gradient of the drug so let's say for example i have one drug and this drug so drug one for excretion and then drug two for excretion drug one is polar it is water soluble it is large and it has to move from an area let's say that the concentration of drug one is higher more of it filtered across and so because more of it easily filtered across the concentration of drug one is higher in the tubular lumen and less in the blood so we can say high concentration

in the tubules and low concentration in the blood so in order for me to be able to move this drug here which is polar water soluble it's big and i gotta pump it from area of low concentration to high concentration am i going to be able to do that passively no not a chance it's not going to pass through the membrane it's too big to fit through small little pores in the cell membrane and it's too charged to be able to not interact with the phospholipids and it's going from areas of low to high i'm

going to need energy to be able to push it against its concentration gradient so in situations like this certain types of polar water soluble large drugs that we have to push against the concentration gradient there's no chance that it's going to move passively i need to utilize special types of transporters to move this drug across the basolateral membrane and into the actual kidney tubules and these are called organic organic anion transporters and organic cation transporters and they require atp to be able to pump this drug from area of low concentration to area of high concentration

that's one way that we can secrete a drug into the tubules and then pee that drug out effect effectively excreting the drug drug two there's another situation here it's nonpolar it's lipophilic or let's actually put this as hydrophobic so it's lipid soluble it's lipid soluble it's small and the concentration of this actual lipid soluble drug is going to be low inside of the actual kidney tubules and a high concentration inside of the blood so it's a low concentration inside of the tubules and it's a high concentration inside of the peritubular capillary blood so because of

that will this drug be able to easily move across this phospholipid yes because it's non-polar it's hydrophobic and it's small so it can do that on top of that is it going to need atp to be able to pump it into the tubular lumen no because it's going from areas of high concentration in the blood to areas of low concentration in the tubular lumen and that will effectively put the actual drug into the actual kidney tubular lumen which can be effectively removed from the body the excretion into the urine does that make sense i hope

so all right so the ways that we can affect excretion of a drug getting the drug out of the body into the urine which the most common way is filtration which is highly dependent upon the gfr or secretion which is highly dependent upon the solubility and concentration gradient of the drug this is an important concept because these transporters guess what lots and lots of drugs can interact here so for example if i had a drug that i wanted to secrete and i had another drug that i was taking for example one of them that's a

big one is like cementidine if i was taking cymetidine or if i was taking like another drug so other ones that can actually do this trimethoprim sulfamethoxazole which is an antibiotic these can directly interact with these transporters and if they inhibit these transporters they won't be able to secrete this drug via these transport processes into the tubular luminance so they'll build up inside of the blood so remember that this process of secretion is highly dependent upon the transporters and atp and if you have other drugs which can interact or inhibit these transporters can you secrete

the drugs out no so it's really important to remember that this step of excretion can be affected by not just the solubility of the drug concentration grading of the drug but by drug interactions working against these transporters don't forget that all right the third step that we need to talk about that affects excretion is reabsorption let's come down talk about that now all right so when we talk about reabsorption this is basically the drug getting back into the circulation the whole point was to excrete the drug right so we could filter the drug across right

that was the filtration process highly dependent upon the gfr low gf arms low filtration of the drug less if it's getting going to be cleared from the body the other way was that we talked about some of the drug can actually be excreted from the proximal convoluted tubular blood into the actual kidney tubular lumen this is highly dependent upon the solubility of the drug the weight of the drug the charge of the drug the concentration gradient but it also depends upon the transporters if those transporters are inhibited they won't be able to excrete the drugs

that need to be moved against their concentration gradient that are large that are charged and that are water soluble okay the last thing is let's say that some of these drugs are filtered some of them are secreted they move through the proximal convoluted tubule down the descending loop of henle through the ascending loop of henle and then it gets to the distal convoluted tubule when you get to the distal convoluted tubule there should be a decent chunk of drugs that are present in this area so the concentration of the drug via the filtration and the

secretion process should increase the concentration of the drug here and theoretically the concentration of the drug should be pretty low here in the actual peritubular capillary blood or the vasorecta blood so because of that that's a good concentration gradient for drugs to be able to move from areas of high to low but what kind of drug would move down its concentration gradient easily without any kind of transporter a small non-polar and hydrophobic drug so drugs that are nonpolar that are small so low molecular weight and hydrophobic so very lipid soluble won't require any type of

transport proteins won't require any kind of active transport process at all and they can easily passively diffuse across this into the actual bloodstream and then the point of this was to excrete the drug that's a problematic issue so now this drug is not going to be excreted as much as i want it to be excreted the whole thing that i can do with this is i can send this to who what can i do after this i can send this drug to the liver and what the liver can do is it can actually go through

what's called phase one maybe add on an oh group then it can maybe go through phase two add on some type of like conjugate like glucaronate make it more polar and if it's a more polar molecule if it's definitely more water soluble will it be able to be reabsorbed whenever it gets to that point again no it'll be way more difficult to absorb so again it's important to remember that in this situation these drugs will be reabsorbed which will decrease the excretion of the drug so what will happen is whenever they get back into the

blood they'll go to the liver they'll be metabolized further and then hopefully become a little bit more polar hydrophilic charged and more difficult for them to be reabsorbed so they can effect effectively excrete the drug from the body i hope that makes sense now here's something that's really really cool and it's very important in situations like overdose and preventing preventing reabsorption so you see how that reabsorption process is highly dependent upon the characteristics of the drug so if it's very non-polar very small very hydrophobic it's going to easily be reabsorbed there's another factor that also

affects this and this is basically the charge right so the charge so we said nonpolar which is basically that's not charged small hydrophobic if i have a drug let's say i have an overdose i take a patient who takes too much phenobarbital or i have a patient who takes too much aspirin these drugs are weak acids do you guys remember that equation so we said the let's actually do this according to the color i got to look back over here i did it in green so in this situation these are weak acids son of a

gun weak acids we go h a disassociates into protons and into this conjugate base if you will okay which one of these would be easily absorbed which one's nonpolar this one's the nonpolar one right so we'll put n p and this one is polar this is the one that would not get easily absorbed if i took a drug like phenobarbital and aspirin i took way too much of it i don't want to keep reabsorbing the dang thing i want to excrete it into the urine and make sure that i don't reabsorb the dang thing anymore

i'd want it to be in this form because in this form where it's charged it's polar it's not going to absorb easily across this it's going to need a transport protein of some kind so if i have a patient who took an overdose and they have too much of this and i don't want them to reabsorb it anymore i want them to excrete it into the urine what could i do that would increase the actual process that would shift this reaction i did it in purple there that would shift this reaction to the right if

i wanted to shift this reaction to the right to make more of this because if i make more of this molecule it will not be reabsorbed and effectively it'll be excreted okay in other words we use we'll say we'll trap it in the urine so that it can be excreted and i don't bring it into the blood what would i need to do well i would need to do what to the proton i need to decrease the concentration on that right side of the reaction so if i decrease the amount of protons so if i

decrease the amount of protons what does that mean i need to alkalinize the urine so if i make the urine alkaline that's going to do what to the actual protons that's going to decrease the protons if i decrease the protons that'll shift the reaction towards the right meaning i'll make more of this guy and it won't get reabsorbed because it's polar and i'll excrete it and trap it into the urine getting rid of it how in the heck would i alkalinize the urine what do we give to these patients to alkalinize trap the phenol barbitol

and aspirin into this form and get them excreted from the urine we give them something called bicarbonate sodium bicarbonate because it'll alkalinize the urine drop the amount of proton shift the reaction to the right make more of this guy and then you won't be able to absorb him reabsorb him and effectively excrete him into the urine take the opposite situation you have a patient who takes amphetamines and they just take a little bit too much for some particular reason so there are they have an amphetamine overdose this is a weak base if they take a

weak base i did that one in blue if they take a weak base you guys remember that this was b h positive disassociates into b and protons which one of these the b is the nonpolar one so will that be easily absorbed yeah i don't want it to be that one then this is the polar one will this be easily absorbed no so i want this to be converted into this type of molecule because if i do this one if i have more of this b h positive this thing is not going to be absorbed

it'll be effectively excreted or trapped into the urine so i need it to be in this form the only way i can get more of it going into this side is if i either do what increase the concentration on the right side of the reaction because i can't decrease this it's already there i can increase the concentration of some of the molecules on the right side of the reaction so in order to do that i need to increase the concentration of the protons so that i can shift the reaction to the left increasing the concentration

of this weak base form and if i have more of this one i won't be able to reabsorb it because it's polar it's charged harder to be able to reabsorb this and so what would i need to do if i need to increase the proton concentration i need to acidify the urine and that will increase my protons how do i acidify the urine we give these patients ammonium chloride and ammonium chloride will work to be able to increase the amount of protons acidifying the urine we give bicarb in situations like weak acid overdoses because they

decrease the amount of protons and this will effectively trap the ions inside of the actual kidney tubules and make sure that they're excreted tell me that isn't pretty cool so it's important to be able to remember this that we can modify this reabsorption process and enhance the excretion process especially in overdoses by changing the actual acidity or alkalinity of the urine to trap the ions inside of the actual urine pretty cool all right my friends we talked about excretion we're on to the next part a little bit more complicated but we're going to get through

it we're going to talk about clearance half-life and some enzyme kinetics which you probably thought you would never have to see again but it's back [Music] [Music] you