March 30, 2009 Circulatory System and Major Body Compartments Kauffman Circulatory System and Major Body Compartments Today we are going to be talking about the vascular system. The lecture is going to be divided into 2 parts just to look generally at the substance drugs are dissolved in the body mainly water. We want to talk about the distribution of water in various compartments in the body and identify what comes out. Then talk about 1compartment that particularly comes out and that’s in the (vacuuming?) the blood contained in the vascular system. That’s what we will be looking at. We left off last time with a general overview of factors influencing the ADME of drugs in the body and I think we just mentioned how drugs behave in a 1 or 2 compartment system which is generally for our purposes is to think of the body as a single, most common a 2 compartment model. That is very far displace from reality and I think we should by the end of this lecture have a better idea of what the various compartments are and how a knowledge of drug distribution in the body. One Compartment Model This is the simplest idealized one compartment behavior. We have log concentration verses time. We see that in this plot, it is decreasing in a linear matter. That is the diagram of a simple 1st order process and many drugs leaving the body will resemble the 1st order process more closely a 2 compartment model. This is really a very idealized model but it’s useful in terms of how drug concentration influences the actual rate of removal from the body at any one time. Rates of removal are described by your 1st order rate constant and that is when the concentration of the drug in the compartment is actually influencing the rate. That usually happens when some processes below saturation. There are some drugs that won’t follow this. Maybe the most common one and the one of most importance that you should hang onto as an example of something that does not follow 1st order kinetics is alcohol. Very common drug- ethyl alcohol. This appearance of that drug follows a zero order of kinetics- a linear rate. Now why might that be? Alcohol distributes in all the compartments of the body by the way. Alcohol is rapidly absorbed in the stomach. When you think of drug metabolism, you start thinking of cyp450-of course that’s the largest class of enzymes but alcohol dehydrogenase mainly metabolizes alcohol (ADH). This is right in part that that it departs from 1st order kinetics because it has a high metabolism or a not high metabolism. In the case of alcohol, alcohol is a very high compared to Km of ADH so the enzyme is following zero order kinetics because the enzyme is saturated until alcohol falls to very low levels. For all practical purposes, alcohol disappears at a zero order kinetic process- linear because its enzyme of metabolism is saturated. It is rapidly absorbed in all the water compartments of the body. Two Compartment Model In most cases, we will talk about the disappeared of drugs that follow this pattern which is strictly logarithm- the concentration log versus time. This is biphasic. Rapid. Most often, this is what you see in the blood if u give an IV injection, you will see a rapid absorption or distribution throughout the body and then it follows a bi-functional curve- second order reflecting 2 logs- 2 compartments. This is what we are usually looking at when we follow a disposition or deposition of a substance in the body. We get some idea of that simply by the pattern at which it disappears from the blood. In contrast, the second order compartment sort of follows this curve as a reverse of that but it reaches a peak and then declines. It’s like the interstitial fluid or the specific organ like liver or kidney –it goes up and then it comes down- the second compartment. This is the classical picture of 2 compartments- more often than not, drugs follow this pattern. There are departures from that. What are the major compartments of the body influencing us already have a clue of that last time we met. We saw the great importance of fat added on the body. That’s generally not a major consideration with very water soluble drugs but with lipid soluble drugs it is particularly a slow acting and will equilibrate into fat- remember fat only has a very slow blood flow- only about3% of circulation is going through fat. But still it’s a major compartment in the body for some drugs. What are some other major compartments- certainly the blood is one. What else? The liver, bone, kidneys and brain, major organs that have large vascular system in the tissue itself. Those are the major compartments we have to consider. Blood first, fat, liver, muscle, the largest organ in the body, brain, - those are the major compartments. When a drug is distributing in all of these compartments, we think of that as the profile of drug disposition in the body. It’s generally in equilibrium with the extracellular water which is largely in the vasculature- extracellular water and interstitial fluid. That’s the extracellular compartment in the body. These are some of the things we need to consider in terms of the drugs fate in the body. Remember we speak of the disappearance of drug from the blood. We don’t speak of half life because it’s not really what it is. We speak of biological half life- when the disappearance from central body. Usually when you taking this all into consideration, you are following a 2 compartment body- either the blood or everything else (interstitial fluid that will equilibrate with binding sites in the various organs.) Pathways of Drug Disposition This is a summary of all the major compartments that we are concerned about. Drug dosage equilibrates with extracellular water generally blood and fluid within tissues is at equilibrium so blood concentration reflect the concentration within the organ in the interstitial extracellular water. That’s one big compartment. The biggest water compartment in the body is intercellular water- it is the larger- that is not in equilibrium. Those 2 compartments are: extracellular and interstitial verses intracellular water and a little bit of water that is not easily assessable such as the intraocular fluid, the fluid in joints, and the fluid outside the body or intestine. Those last pools of water are often trans-cellular compartments which we don’t usually pay much attention to when we are talking about drug disposition. Here we have our various compartments in equilibrium with extracellular water or blood and interstitial fluid which of course are major determinants of the concentration of drug at the site of action specific organs, binding to receptors, and ultimately this determines some pharmacologic effect. That’s the big picture you want keep in mind when talking about drug disposition. Various Spaces (Compartments) of Body Water This is a diagram summarizing all of this. Here is the slowly accessible water which is outside- an example is water inside a bone, tendons, cartilage inside the eye- 6% of the body water is in these inaccessible or transcellular compartments. Body water that is easily accessible when a drug is introduced into the body is the extracellular fluid and the intracellular fluid. Here we are looking mainly at plasma: 16-20% on a body weight bases here. The 16-20% of this water is in either the intravascular plasma or the interstitial fluid. What’s in intravascular spaces will be in equilibrium with free and no bound in the plasma itself- capillary endothelium is here is coming from the interstitial fluid. How do you get some idea of what these compartments are? It’s very hard to get some measure of the body within each compartment- you can’t take out the fluid and measure it. So different called delusional methods which you have a known amount of some substance that when you localize the net compartment, it is measured in blood and its concentration at that time is also measured- a fluid sample that compartment. There are various chemical markers that give the size of the compartment. A measure of total body water can be obtained with things like duteraid or tritaid of water, alcohol, ethyl alcohol that distributes in all water, or some drugs- sulfanilamide and antipyrin- some drugs are known to do that and their deposition is influenced by that. These are totally in equilibrium with total body water. Some drugs like larger carbohydrates- mannitol, inulin, and sacchorose here, will not easily cross cellular membranes their restricted to the extracellular water and these compounds are also in equilibrium with intracellular so you have your extracellular and intracellular compartment here measured with things like inulin and mannitol. You get something that is strictly limited to the vascular compartment: blood plasma, a dye or some other large molecule certain proteins will give you a measure of intravascular volume. Evens blue is a common dye used to measure that. You can get some idea of the size of these compartments by using these various chemicals that are known to be restricted to those compartments- the delusional method. And these sizes are by no means fixed and they will change under certain pathological or pathological conditions- dehydration or certain diseases change the amount of fluid in these various compartments. Summary of Total Body Fluids You have a percent of total body water here. One thing you might see is that there are gender determined differences in the way this fluid is distributed. There is also age influencing various compartments. But generally, here a summary of the percentages we have been talking about. This is now a percent of the total body and they add up to 100% of the total body water eventually. Intracellular fluid- the largest compartment. Extracellular- somewhat smaller but close and so forth. This is extracellular fluid being composed of interstitial, plasma and bone, Smaller compartments like dense connective tissue and transcellular spaces- those are small amounts of water contained in various compartments like crystallized in bones or intraocular spaces- all add up to 100%. There is a slight difference between a normal adult and a normal female. Females have slightly lower concentrations in the various compartments that in the male. Why is that? Fat is a very small compartment and generally the fat content changes with the amount of adipose tissue in the body and females have a little more adipose tissue than men. The compartments are also smaller (in females). That has some relevance in terms of predicting the effects of drugs. (Slide 5) If you go back to your notes on the previous slide, I gave you an example of what happens to alcohol and what maybe the pharmacologic effects of alcohol in an adult male and an elderly obese woman. Some differences. You have this in your notes. I want to emphasize the influence of just talking about the amounts of water in the body and the pharmacological effect. With a drug that totally distributes in the body water- that’s alcohol. We have a lady and a man weighing 70 kg and have a total body water of about 50 L. body water in this case is about 70% of total weight of the individual. For the elderly obese female, where water content is only about 35 L- it has a smaller percentage. If they both take the same input of alcohol, t15g of alcohol, you will have very different concentrations in the individuals. In the male, it will be .21 g/kg- that’s going to be the same in the male and female because they both have the same dose. If you compare .3g/L for the male and you compare that same concentration to the female, because the total body water on a weight bases is a smaller percentage of total weight, the alcohol at the beginning at the exposure is going to be 40% higher than in the male. It is well known that individuals differ in their sensitivity to alcohol. This can be explained in partly by differences in the fraction of total body weight that’s water and the concentration that you can compute. That will explain differences in sensitivity between the elderly obese woman and the young male to exposure to a good stiff drink of alcohol. Subsequent neurological effects of those doses explained simply on the basis of water. In terms of emphasizing the importance of influencing drug disposition and metabolism- remember alcohol is going to be metabolized at a zero order rate- that is the rate of metabolism is going to be very similar in the individuals metabolism beginning with a higher concentration- it will be higher at the site of action and take longer to remove it from the body in the elderly obese women than in the man. So water is very important in the amounts and contained in various compartments. It is a very important determinant of drug disposition. Water Content of Body Tissues The amount of water will vary between different organs and vary with age. Here is water in different compartments. Kidney is 83%- highly vasculature-ized tissue. Above 70 in all these organs here. Adipose tissue is only 10% water. In line with the example I just gave you, the amount of water in the body is going to be indirectly proportional to the fat in the body. Fat and water vary inversely in a physiological context. Approximate Total Body Water in Normal Humans as a Percent of Body Weight I mentioned that there is a difference of water content with age. You have a gender difference with water. You also have differences in water that are very basic determinant of drug disposition in the individual. A new born either male or female more approximate total body water than humans as a percent of body weight. The newborn has a very high percent relatively speaking. Newborn is 80 and 75 percent. Why is that? Compared to 1-5 years there is a significant drop. Because they develop and change in body. Most of water in the body is intercellular water. The newborn cellular composition is increasing quite rapidly during that first year. Total number of cells and total intercellular sites is going up. So this is what’s going on here as you can see the percentages of body weight. Then it drops off in the elderly because of changes that occur in muscle mass with age. So you can relate it to changes in the cellularity – increasing or decreasing with age. Babies and adults that are fat are going to have proportionally less water as a fraction of the total body weight. Markers Used to Measure Body Fluid Compartments This is just a reiteration of what I said. We tend to use chemically to get measurements of the size of these different compartment tritiated or dueterated total body water you use substances like these that distributed throughout the body and water. Extracellular fluid- certain and there is quite a variation- these are not 100% in terms of being restricted entirely and completely to the various compartments. But extracellular fluid can be estimated from either these cations or anions or non-metabolized saccharides like inulin, mannitol or raffinose that are restricted to the extracellular space. If one wants to get an idea of just how much fluid is in the plasma itself, you can use albumin which is a large protein contained in the ___ compartment, it doesn’t really cross the vascular endothelium or you can use Evans blue dye that is restricted to the plasma body itself because it doesn’t readily cross. That’s another marker. Approximate Concentrations of Solutes in Body Fluids Different estimates of these compartments of course will be obtained depending on what your using. For most practical purpose, clinical thinking, the extracellular fluid which is very important contains approximately 1/3 of total body water so you can keep that figure in mind in terms of estimating how much of it blood level might be contained in extracellular fluid. About 1/3 of the total body fluid. What’s contained in these compartments is not just water; it’s a well established set of solutes. That is another important thing to think about in terms of deciding where water is moving in the body movement across various membranes- The osmolality. For most of the major compartments of the body, the osmolality, of the water is about the same- it is isoosmolar unless there is some physiological pathological event. Approximate concentrations on this slide here. In terms of plasma, a figure that is important is because of the solutes, plasma is only about 93% water of total volume because of the presence of these various solutes. It’s not completely pure water. If you want to know what exactly concentrations are, mol/L of water- you need to multiply the factor by .93 to have some measure of volume of blood and you want to know the exact concentration of water, just multiply that figure by .93. That’s 93% after you take the solutes out. The solutes vary a little bit across the various compartments- plasma water is divided by .93, interstitial fluid, intercellular fluid, this is plasma water which differs slightly because of the solutes and then these concentrations will change accordingly. Plasma water- major anions you find in various compartments and they change from intracellular to extracellular. The major one here is sodium and calcium and magnesium that change greatly in different compartments.