08/06/2018 Drug Distribution and Excretion

What does ADME stand for again and what is it used to describe?
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What does ADME stand for again and what is it used to describe?
It is used to describe pharmokinetics (what the body does to the drug) and it stands for Absorption, Distribution, Metabolism, and Excretion
What is drug distribution? How is a drug typically distributed? What does it have to do to get to a pharmacological site of action?
it is how the drug moves through the body.
typically through the blood circulation.
it has to cross multiple biological barriers typically to reach the site of action
Explain how blood flow rate will affect the distribution of a drug.
The blood flow to adipose tissue and bone have very low levels of perfusion compared to the organs for example the lungs and the brain. So the ability of blood to get to the tissue in a set amount of time will determine if that tissue gets the drug that is in the blood. So it is dependent on perfusion rate.
Explain what volume of distribution is
What does it tell you most basically?
it is a conceptual idea. the volume into which the total amount of drug would be uniformly distributed to give the observed plasma concentration.
it basically tells you whether a drug is in the plasma or not
A low volume of distribution means what
the lower the number the more likely the drug is to be in the plasma aka not absorbed by tissues.
What is the formula for volume of distribution
Vd= D/Cp0
D is dose
Cp0 is the plasma concentration of drug at time zero.
where does the Cp0 value come from for the volume of distribution equation
so this is the theoretical time the plasma concentration and the tissue compartment concentration is equal.
ok so on the Iv dose curve you look at the point when the tissue compartment is full (when the curve starts to level out), then back extrapolate to when time equals zero.
What are the common volumes for compartments in the body. E.g. total body water, ECF compartment, ICF compartment, blood plasma etc.
We have a total body water compartment of 42 Liters. 14 liters of that is extracellular fluid (blood plasma 3 L and interstitial fluid 11 L). And 25 liters of intracellular fluid.
What if we have a volume of distribution that is extremely high, like higher than 42 which is the total volume of fluid in the body?
it means the drug is in very very very low concentration in the plasma. it will readily be taken up by the tissue
how is the volume of distribution so high 15,000 Liters of chloroquine
because it is found IN the red blood cells so when you are doing your thing with testing the blood you throw away the red blood cells so it looks like none of the drug was in the blood when it actually was.
So if a drug is bound to a plasma protein what does this meanit won't be able to diffuse across a membrane to interact with tissue, nor is it able to be filtered by the kidney. so it remains in the blood.What are factors that affect distribution? three of themwhether the drug is ionized or not, blood flow, and plasma protein bindingExplain plasma protein binding and what it does to the free drug level in the blood, distribution of the drug, and elimination of the drug.So, it will lower the free drug level in the blood right because the drug is bound to the protein and unable to go do its thing. It would not be distributed at all because the bound protein would not be able to cross a membrane (typically). And it would not be able to be eliminated (or eliminated more slowly) because it is bound by a protein. It is eliminated more slowly because you would just slowly chip away a little bit of the drug at a time for each pass the bound protein goes through the kidney.What are the two proteins in the blood that are commonly used as drug binding proteins? what types of drugs do they like?Albumin and they like acidic drugs and alpha 1-acid glycoprotein and they like basic drugs.There are a finite number of binding sites on drug binding proteins for the drugs, what does this mean and what can it result in (clinical application as well)?so this means that the drugs can saturate the protein which would cause competitive nature between drugs. if you were to have a drug saturating a protein and it has filled all of the binding sites and then added another drug that competed with that drug it would knock off the original drug, raising the free drug concentration in the blood and causing toxicityExplain why, if filtration is the primary route of elimination for a drug, binding to a protein can decrease the rate of elimination. Note: acrtive processes such as secretion in the kidney that utilize active transporters are not slowed by protein bindingso the kidney is working like mad with their pumps, it is pumping the drug into the urine. and because of this it is making a concentration gradient to where the drug flies off the protein in the blood and into the urine.Explain some of the clinical relevance of drugs binding to proteinsImportant to remember that most drug doses account for how much the drug is going to be bound to the protein. Can change free drug concentrations as discussed above, potential for drug interactions, decrease drug binding to plasma albumin seen in renal failure, hypoalbuminemia may alter intensity and duration of drug action (albumin levels decrease with age). Injury may increase the levels of AAG resulting in decrease of drug intensity and prolonged drug action.If a drug is typically bound to proteins what are some things that you can do as a physician that will cause toxicity of that drug in your patient explain each.if the drug is very highly protein bound, like over ninety percent, you can easily overdose that patient with a small dosage. if the drug has a very low therapeutic index the same applies a small change in dosage may cause toxicity. if the drug has low hepatic extraction. this means the protein that the drug is attached to isn't metabolized well that means the drug stays in the blood longer and could cause toxicity. and lastly if you give the drug intravenously. you will have a huge dose of that drug at one place at one tissue that is free and not bound and may cause toxicity.most drugs are what kinds of acids and bases what does this mean at physiological pHweak acids and bases. but we know this right this means a drug is partially ionized at physiological pH rightexplain capillary escape of free drugs and how it affects drug distributionwater soluble drugs escape slower from the blood. thus molecular size and ionization are important. so it depends in the capillaries if the drug is hydrophilic or lipophillicwater soluble drugs are _______ limited when it comes to capillary escapeare solubility or diffusion limited. so the flow of the blood is not important.For lipophillic compounds and capillary escape what factors are important? so lipid soluble drugs are ____________ limited when it comes to capillary escapethe rate of perfusion is so since the lipohillic compound wants to cross the membrane anyway how fast it gets there is what determines the rate of distribution. they are limited by flow or perfusion limited.explain the non-equilibrium steady state, and what is it caused byit is due to differing rates of tissue perfusion. some tissues get a lot of blood and others not so much. a rapidly perfused organ will obtain equilibrium quickly for a lipid based drug while organs that aren't perfused as much will slowlywhat is redistribution, what does it deal with and how does it workit deals with the non-equilibrium state caused by perfusion differences in tissue so a redistribution of drug occurs from rapidly perfused tissue to slowly perfused tissues whenever the dosage of drug is no longer occurring.give an example of redistribution that involves a drug and tell what it causesso this drug thiopental is used to put people to sleep. it will quickly go to the brain and put you to sleep in no time. but it takes a good long while to get to the muscles and fat. so the highly perfused brain will dump all of its drug into the plasma after like 10 minutes and it will be redistributed to tissue with lower rates of perfusion. the pt can then wake up.What protective mechanism does the brain have and what does it accomplishthe blood brain barrier, it can act to limit drug penetration into the CNS and prevent drugs from reaching therapeutic levels (or toxic levels).what is the blood brain barrier essentially made up ofjust layer and layer and layer of different types of cells that have various uses and cell membranes.What is P-glycoprotienit is an ABC transporter found in the BBB that can transport drug outside of the CSFSome general characteristics of the BBB when it comes to drug limitationtight junction limit drug movement out of capillaries. glial wrapping makes lipid solubility even more important (highly lipid soluble drugs can rapidly reach the brain). ABC transporters can rapidly transport drug out of the CNS and back into the systemic circulation.what are the three essential jobs of the kidneyfiltering the blood, maintaining homeostasis by regulating fluids status etc, and hormone production.what force moves filtrate from the glomerulus through bowman's capsule?hydrostatic pressure or blood pressurethe filtrate produced by the kidney is a lot more what than the blood in the capillaries around it with this being said, what does the kidney readily eliminate then in terms of drugsionic it is a lot more polarized because we are getting ride of all the electrolytes we don't need it will readily eliminate polar drugswhat is re absorption in the kidneysit is the transport or movement of molecules out of the tubular filtrate back into the blood stream.if your drug is lipophilic will it be reabsorbed by the blood in the kidneyyes it would be because the filtrate would have it at a much higher concentration than the concentration of it in the bloodhow much filtrate is produced per dayabout 180 liters of filtrate is made a day and we only excrete about 1-2 liters per day, so a lot is reabsorbed.what is secretion in the kidneyit is the active transport of substances from the peritubular capillaries into the tubular fluid. it is the opposite direction of reabsoroptionwhat is the definition of eliminationit is a general term for removal of drug from the body, so it refers to all processes that it can be like urinary excretion or metabolism by the liverwhat is drug clearanceit is a quantitative measures of elimination (mL/min). it CAN involve different organs but typically involves renal excretion.what is drug excretionit is the process of drug elimination. the main organ that does it is the kidney. so like getting rid of it in the body but not by metabolism (renal,pulmonary, salivary) etc.pumonary excretion primarily eleminates what kind of drugfor gaseous anesthetics and volatile compounds. some etOH is lost through the lungs.biliary excretion of a drug what organ is it associated withit is associated with the liver and it is the active transport of polar molecules into the bile, often conjugated with metabolites. also they tend to be really large.what is enterohepatic recirculation and what does it do for drugsit tends to prolong the duration of drug in the body so is absorbed by the intestine and it goes on to the liver, and the liver can conjugate it, then it goes into the bile duct and then back into the intestinal tract. some of it will then be excreted yeah but certain bacterial phophatases will recognize the conjugate and cleave the conjugate and then you hve free drug again. which can then be reabsorbed into the systemic circulation and do its action again.what types of drugs are reabsorbed by the kidneyslipid soluble drugs, and un-ionized drugs.so as a physicain what can you do to the kidney to try and get rid of a drug or to keep it in the blood longeryou can alter the urine pH.why is the ionized form of a drug often the one urinated outthe ionized form is favored thus it is ion trapped. it is only reabsorbed if the non-ionized form is favored.so active secretion of the drug from the capillary circulation. what two transporters mostly do this tis this process saturableorganic anion transporter OAT. and organic cation transporter. ca carrier mediated transport is saturable and is specific.give an example where competition occurs for active secretion in the tubulesthis drug you used for gout and PCN compete for the same transporter. normally the pcn is transported through it really quickly that is why we have to take it so often bc it just readily goes through to the tubules. but the gout medication will compete for it and will keep the PCN in the blood longer causing toxicity.tubular reabsorption is greatly affected by what factor If the urine is to become more acidic what would it mean for weak acid excretion?urine pH. if the urine is acidic, then a weak acid is more likely to be reabsorbed right because more of it will be in the deprotonated state it will have its hydrogen because it is in an acidic environment. the unionized will be reabsorbed.if a drug is eliminated entirely by filtration its max clearance would be ____120 ml/minif a drug is cleared by filtration but some tubular reabsoption of the drug also occurs, the clearance would be whatit would be less than 120 right. some of it is coming back incan renal clearance of a drug ever be greater than the GFRyes if the drug is being actively transported back into the filtrate.