BENG 100: Frontiers of Biomedical Engineering

Lecture 11

 - Biomolecular Engineering: General Concepts


Professor Saltzman starts the lecture with an introduction to pharmacokinetics and pharmacodynamics. Professor Saltzman talks about the concept of dose-response. He introduces different routes of drug administration and how they affect drug distribution and bioavailability (i.e., intravenous, oral, and sublingual routes). First-pass drug metabolism by the liver is also identified as an important source of drug degradation. Finally, modeling the body as a well-stirred vessel, Professor Saltzman explains the first-order rate equation: C = (M0/V)*e-kt, that can be used calculate the amount of drug in the body (M) as a function of time (t) and a rate constant (k); and the equation for drug half-life: t = ln(2/k).

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Frontiers of Biomedical Engineering

BENG 100 - Lecture 11 - Biomolecular Engineering: General Concepts

Chapter 1. Introduction to Drug Delivery [00:00:00]

Professor Mark Saltzman: So, this week we’re going to talk about drug delivery, this is Chapter 14. This is an example of what I call in the textbook Biomolecular Engineering. This is one of my favorite weeks of the course because this is my research specialty, is drug delivery. What I want to do today, Thursday, and then we’ll continue in section is today I’m going to sort of set up the problem, talk about some definitions to think about, if one is building drug delivery systems, think about some basic concepts in drug delivery. We’re going to do that by thinking about sort of common modes of drug administration and why some of them work with some drugs and not with others, sort of lay the foundations today. Then, on Thursday we’ll talk about what’s new in drug delivery and what things you can expect in the future, things that are still being built and then you’ll get to make some drug delivery systems in section on Thursday afternoon.

This is really a logical extension of what we started talking about last week when we moved from talking about the immune system and how it operates to administration intentionally of vaccines to alter the immune system or to change your body’s response. In some senses, you could think about delivery of a vaccine like delivery of a drug or introducing something not naturally in the body–into the body in order to have some kind of biological effect. It’s the same thing as delivery of a drug. And we also thought about delivery in a variety of ways: we thought about injection of vaccines like the smallpox vaccine, we thought about oral administration of vaccine, in the case of the oral polio vaccine. So, I just wanted to show you this picture to remind you that you already know something about drug delivery. What we’re going to talk about is an extension of what we started talking about last week.

Now, in the case of a vaccine, you’ll remember, that the intent was to administer either proteins, usually proteins or whole viruses, or we talked at the end of the class on Thursday about administering DNA with the intention that you’re going to bring some new molecules into a special class of cells called antigen presenting cells. That those antigen presenting cells are going to be changed as a result of their experience with this vaccine such that they present new molecules on their surface, that’s the change that comes about. Then, that change in this cell is going to stimulate changes in other cells. If humoral immune response or antibody mediated immune response is generated, then the change in antigen presenting cells is going to influence B-cells to differentiate and proliferate, etc.

This is an example of a very particular example of what happens when you administer a drug as well. Chemicals are introduced into the body, the intent is usually to make some kind of a biochemical change in cells or maybe many cells in your body such that they’re function is altered in some way that’s helpful to you. We didn’t really talk about it last week, but in some cases immunization really is like drug delivery. Particularly, in the case of what’s called passive immunization, where instead of introducing a pathogen or a piece of a pathogen to an individual you actually make antibodies outside of the individual. So, manufacture them in some ways, and we talked about ways of manufacturing antibodies a few weeks ago. Then introduce those antibodies themselves into the person to provide protection against whatever pathogen those antibodies are directed against.

If any of you have traveled to areas of the world where Hepatitis A is common, in parts of Asia for example, you might have gotten a shot of gamma globulin which is really just antibodies that are enriched for anti-Hepatitis A activity. Now, the difference between that and a vaccine is that that dose of antibodies only lasts for a certain length of time, about 30 to 60 days. So, you have to get the shot 30 to 60 days before you’re going to be in the area where you’re exposed. The same way we’re going to think a lot about the timing of drugs, how long do their effects last, what determines how long they last, and what does it mean if you still need the drug when its effect is gone, how does taking subsequent quantities of the drug effect its concentration in your body, for example.

I’m going to start with some definitions and I realize that you can read this on your own. Hopefully you already have read some of this in the chapter, but just to make sure that we have the vocabulary right, and some of these are words that you’re familiar with like drug. A drug is any molecule which can be introduced into the body, which alters body function on a molecular level. You’re used to thinking about drugs you might take for a headache like aspirin or Ibuprofen. Or if you asthma, for example, you might take drugs that affect your bronchioles or the pathways–the airways in your lung by dilating them so it’s easier to get air in and out. These are molecules which are introduced into the body; they make some kind of change in the body on a molecular level.

Pharmacology is the science of dealing with these interactions of molecules that are introduced into the body. They’re usually molecules that are generated from outside the body, maybe synthesized in some way. They might be molecules that are not ordinarily found in our bodies, but are known to have some effects. They might be derivatives of molecules that are naturally found in our bodies. For example, Parkinson’s disease is treated by a derivative of the neurotransmitter Dopamine. You’re introducing something that looks very much like a natural molecule back into the body to have an effect.

Toxicology is that branch of pharmacology that thinks exclusively about toxic effects of the drug. One of the main challenges with developing drugs and drug delivery systems is that drugs have unwanted effects. They have the effect that you desire at the tissue or within the cells that they were designed to affect, but they can also effects in other parts of the body and those effects are side-effects. Those effects are toxicities or unwanted changes in the body as a result of the drug.

Chapter 2. Relationships between Drug Dosage and Biological Response [00:07:13]

We’re going to talk about two important different but related concepts called pharmacodynamics and pharmacokinetics. Pharmacodynamics is the effect of a drug on a body and it’s usually on the body or on cells from the body. It’s usually defined by a dose-response curve. Dose response means I give a certain amount of the drug and I see what effect it has. I give more, I see what effect that has, I give more I see what effect that has. You can imagine that’s a very important thing to define for any drug because you want to deliver the minimum dose that’s needed to produce the desired effect. You don’t want to introduce any more than necessary.

So, understanding the relationship between dose delivered and biological response is very important. Often that’s done first on cells in culture, for example. You want to understand how a chemotherapy agent, a potential agent for treating tumors will affect tumors in a person. The first thing you do is you might have cultured tumor cells and you expose those cells to different concentrations of the drug and you see at what dose do I begin to see cell death or killing of the tumor cells. That’s one kind of dose response relationship. Now, you could understand, probably, that that might be very different if you administer that same dose into a person. We’re going to talk about why dose responses in people are different than dose responses in cell cultures, or in more artificial systems.

The pharmacodynamic effect of a drug, or the study of pharmacodynamics, is ‘what does the drug do to the body? ’ Usually that’s defined at specific doses, what does it do. Pharmacokinetics has to do with how your body handles the drug. The body has exquisite mechanisms for getting rid of molecules. Molecules that are produced naturally in your body only have a certain lifetime. Likewise, antibodies that we–molecules that we introduced from outside the body also have a lifetime, and that depends on the mechanism that your body uses to get rid of the compound. Well, that manner in which the body handles a drug, how the body changes the drug, how it excretes the drug is called pharmacokinetics and that has to do with what the body does to the drug, not what the drug does to the body. That’s the easiest way to think about it.

One pharmacokinetic concept that’s very important is the concept of bioavailability. If I have a dose of the drug, let’s say 100 milligrams of a drug, and I administer it to an individual, then how much of that drug actually gets into the body where it can be useful? Bioavailability is going to depend on how we administer the drug. If we administer it orally versus inject it intravenously, versus some of the other routes of administration we’ll talk about in a few minutes. The main effect of changing the route of administration is to change the bioavailability or how much of the drug actually reaches the active sites.

A related concept is biotransformation. Biotransformation refers to all the mechanisms that your body could use to convert a drug into something else. Often, that conversion of a drug into something else is an important part of how your body gets rid of a drug. Many biotransformation reactions happen in the liver. The liver is a very active site of metabolism and chemical reaction. Many drugs that we take are converted into other compounds in the liver, by cells in the liver. Often, this conversion into another compound is the first step in your body getting rid of it; sometimes it’s the only step. Sometimes your liver is able to convert a molecule into something that’s completely inactive. For example, if you take alcohol, which is a drug, it’s converted in the liver into other molecules which don’t have the biological effect of alcohol. It’s done by enzymes in liver cells, including the enzyme alcohol dehydrogenase. Sometimes–we won’t talk so much about this but I want you to at least realize it, is that sometimes we deliver molecules that are inactive but don’t have any response. Your body doesn’t have any response to them, but we deliver them knowing that your liver is going to convert them into something active, that they’re going to be biotransformed by some chemical reaction into an active compound. So, it’s another aspect of biotransformation.

Chapter 3. Injections for Drug Delivery [00:12:22]

I want to spend the next 15 or 20 minutes or so talking about how drugs are administered. In particular, that question should be why are they administered in different ways? Why is Ibuprofen taken orally, for example, but some antibiotics or chemotherapy drugs have to be injected directly into the bloodstream. Why is that do you think? Why are some drugs administered in different ways? It could be that you’re targeting different parts of the body and so you want to deliver them at their site of action, that might be one reason to do it. There what are you changing? You’re changing the potential for side-effects really, or the potential for toxicity of the drug. If you can deliver more at the site of action then less of it goes to the rest of the body where it might cause unwanted effects, so that’s a very good reason to target it.

Student: [inaudible]

Professor Mark Saltzman: Sometimes there are biological barriers to drugs entering different parts of the body. We’re going to start by talking about the body as sort of a single unit or compartment. When I introduce drugs into them those drugs are available everywhere, but that’s not true. There are some parts of the body that are protected from entry of drugs, and the brain is the most famous of those parts of the body that are protected. It makes sense that the brain is protected, because the function of the brain depends on the balance of chemical concentrations within it, the concentrations of ions and neurotransmitters, and any molecules that could potentially interfere with ions or neurotransmitters. Our brain chemistry has to be very tightly regulated in order for us to stay awake and pay attention and do the things that we normally do.

In contrast, the chemistry in our blood is changing throughout the day. After you eat chemistry changes because molecules are absorbed from the intestine, and as those molecules get processed by the body concentration in the blood changes. If your brain chemistry was changing in that same way, then you’d be slipping in and out of consciousness and you notice that you do a little bit right after lunch. It’s a little bit harder to pay attention than before lunch because the chemistry is changing, but that change in chemistry is muted by the blood brain barrier or the fact that molecules can’t get very easily into the brain. Why else might drugs be administered in different ways? Think about insulin, what do you know about insulin as a drug?

Student: [inaudible]

Professor Mark Saltzman: Speed of action is an important thing and we’re going to talk in a few minutes about some drugs where onset of action is very important. It needs to act very quickly and the way that you administer it has as big effect on how rapidly concentrations in the body rise. So, some things you need to act very rapidly, you’ll pick the mode of administration to do that. There’s another issue with insulin which we’ll come too, keep that one in mind.

This is a table that’s in the book and I want to go through it relatively quickly because I think you can read it and it’s pretty understandable on its own. I want to use these specific examples of different routes of administration to think about the answer to this question,’why are drugs administered in different ways? ’ More importantly, to think about the biology or the physiology of your body that leads to these alternate forms of administration.

One mode is intravenous injection and we’re going to talk –there are different kinds of injection. You can put a needle into different parts of the body. You can put it into a muscle, you can put it under the skin, you can put it actually into the spinal fluid that surrounds your spinal cord. Intravenous injection refers specifically to a needle that’s placed within the bloodstream–within a vein, and so drugs are introduced directly into the bloodstream. The advantages of that should be obvious. That’s what was related to Caitlin’s comment, that drug is immediately introduced into the blood, and so it’s immediately distributed throughout your body and available for action wherever it’s needed. So, onset of action is very rapid. In addition, its bioavailability is 100%. We’ve introduced the drug into the blood directly, into your circulatory flow, so all of the molecules that are administered to the patient are available for action.

Now, usually we think about bioavailability as the fraction of the drug that ends up in the blood and you might say, ‘well but that might not be where the drug acts’. The drug might act in the brain or it might act in the kidney, or it might act in your muscles and being in the blood is not the same as being in those tissues, and you’re right. It’s hard to measure those concentrations in individual tissues and so we define bioavailability as the fraction of a drug dose that gets into the blood.

Now, why wouldn’t we do intravenous administration for everything? Because if it is fast, usually you don’t want to wait for–you want the drug to act as rapidly as possible and you’d like all the drug molecules to be bioavailable, you would like all of them to be useful. So, why don’t we use intravenous administration all the time? Well, it probably is obvious that not–that it’s not so easy to do. That in general, safe intravenous administration requires trained medical personnel. So, usually you’re in a doctor’s office or a hospital, you don’t do it yourself at home.

There is a risk because you’re introducing drugs at high concentration into the blood. There’s much more risk of overdose or toxicity because the concentration’s going to change very rapidly. Even though you might know what the average response to a drug is, average among a population of people, we’re all different in ways that are important to how drugs act. You know this, if you take Ibuprofen, you read the dosage on the label, it will say something like ‘if you’re over 12 years old you take one dose and if you’re under 12 you take another dose.’ So, size of the person or age of the person is an important determinant of how much dose you take. Gender is often an important determinant, your overall state of health is an important determinant, and you can’t know those things for everybody. You could go on and on in this list and so you–one individual might be more sensitive to doses of the drug than another. If you’re introducing all the drug at one time intravenously the potential for an unwanted response is higher.

It’s a risk of infection because you’re introducing something directly into the bloodstream if it’s not done properly, and it’s not comfortable. Most people don’t want to have an intravenous injection. So, you might not do it in cases where even if it would benefit you, and so those are disadvantages. It’s a very safe and effective, and useful mode of administration for some kinds of compounds. For example, for antibiotics, if you happen to have what’s called sepsis or an infection that’s spread into your bloodstream, one of the only ways to combat those infections effectively is to introduce antibiotics directly into the bloodstream.

Intravenous infusion is a similar mode, but now instead of a onetime injection, with an intravenous injection you have a syringe full of drug, a needle in the circulatory system, and you introduce the drug all at once, in infusion you slowly pump the drug in and you might be pumping it in continuously over a long period time, maybe over hours or over days. Sometimes this is done–you’ve seen on TV shows a bag of a solution hanging up on a pole and a tube going into a patient’s arm. So, this is an infusion where the infusion is driven by the gravity flow of fluid through the tube into the patient’s blood vessel, that’s one example of an infusion.

Other examples are there might be pump involved at some point. You have a pump in between the bag of fluid and the needle that goes into the arm. In this way, you can control the flow much more carefully. One example of where that’s done in the hospital is the molecule Heparin, which is an anticoagulant. It’s needed for certain patients who are at risk of having blood clots, for example. This might be–they might be at risk for blood clots for a variety of reasons, but you introduce the molecule Heparin which reduces the likelihood that clots will form, only you need to have a continuous level of Heparin. You need to have that Heparin concentration continuously at some level, and so you continuously infuse it directly into the circulatory system. Now, this is a very effective method for administering drugs because you’re slowly adding the drug and you’re watching to see what concentration is maintained in the person, and you’re adjusting the rate by tuning the pump until you get exactly the concentration that you want. You can leave it there and as long as the patient stays roughly the same, then their concentration will remain roughly the same. So, you can expose them to a drug over a long period of time and have a biological effect that’s constant over a long period of time. That’s very useful in certain situations like this one I’ve mentioned.

Again, it’s 100% bioavailable and you have continuous control over plasma levels. For example, what if you knew that the patient was more at risk of developing blood clots at night? Well, then you’d put a programmable pump on it, and you’d program the pump so that the rate of infusion increased during the night and then went down again in the morning. In that way you could increase the concentration of drug at night and then decrease it during the day. So, you’d only be using the amount of drug that was needed for a biological effect and you’d be adjusting that biological effect for the needs of the patient in a very sort of interactive way. You can imagine, now, extending that very simple approach with a needle in the bloodstream and a pump, and a reservoir of fluid to deliver any pattern of drug that was needed for that individual. Why isn’t that done all the time? Well, for the same reasons the intravenous infusion aren’t done all the time, plus some, because this is even more complex, right? So it requires continuous monitoring and so there have to be people there in case there is some unexpected event in order to turn off the pump or to adjust the flow. So, that really requires hospitalization in most cases. Now, we’re going to get to the point next time where we talk about some examples of infusion using pumps that can be worn by individuals that can leave the hospital with these pumps either implanted within them or strapped to their belt, for example. In general, that’s done only in unusual situations.

Subcutaneous injection and intramuscular injection are similar to intravenous injection in that it’s an injection from a needle. It’s a onetime introduce the drug all at once, but you’re putting the needle in a different place. Instead of intentionally putting the needle into a vein so that you introduce drug into the blood, you put it either in a muscle, like a muscle mass of your arm, or your back side. Have you ever had an injection there? They don’t do this so commonly anymore, I’m not sure why. I can imagine why but–into a muscle mass and then the molecules are absorbed from that muscle into the blood or subcutaneously–is subcutaneous, cutaneous is skin, sub is under, this is an injection under the skin. So, you could pull up on your skin a little flap, you can sort of pull it away from the muscle and you’d insert the needle under there and introduce a little reservoir of drug solution underneath the skin.

Now, this is how diabetics administer insulin to themselves, usually. They put a needle into the muscle and they inject a volume of an insulin-containing solution into the muscle space. I say on this sheet here that bioavailability in that case is usually high, why is it–who do you think bioavailability is high for these particular modes? Why is it high for intramuscular injection? It might be 80% or 90%, so it’s not 100% but it’s pretty high, why is that? How does the drug get into the blood from there if I inject it into muscle? Justin?

Student: [inaudible]

Professor Mark Saltzman: Yeah, so your muscle is being perfused by blood all the time. It gets blood flow, there’s arteries going in, capillary networks, and veins that are collecting blood so there’s a very rich blood supply in muscle. So, you inject it into the muscle tissue and the drug just sort of percolates in or diffuses into the blood vessels that are already there. Now, the effects tend to last longer than an intravenous administration because it takes some time for the drugs to move from this reservoir where you’ve injected them, this little depot in the muscle, it takes some time for the drugs to move into your bloodstream. So, you get a prolonged effect because of that; not all the drug is available at once.

Chapter 4. Oral Drug Delivery [00:28:48]

You also don’t get all the drug in because some of it is metabolized locally or it doesn’t go into the blood vessels at all and so it doesn’t get distributed. So, bioavailabilities not 100% but it’s often pretty high. It’s not as hazardous because you’re not actually introducing a needle into a vein. It can be done by individuals at home and so diabetics can do this; they can do it several times a day. It’s still uncomfortable, most people don’t want to do it and you wouldn’t do it if there was an alternative. Why is there no alternative for insulin? Why do diabetics do it this way? Why do they inject insulin in this way? I think most of you can understand that they would prefer not to, what would they prefer to do? If you were a diabetic patient and you needed insulin what would you prefer to do? Kate?

Student: Orally.

Professor Mark Saltzman: You’d prefer to take a pill, right? You prefer to take a pill and that’s the next one on the list, is oral administration. You prefer to take a pill but you can’t with insulin because insulin is a protein. Insulin is a protein that is digested in the intestinal tract. That’s one of the functions of our gut, is to digest foods that we eat, foods that contain proteins for example. So, your intestinal system is very efficient at breaking down proteins into their constituent amino acids, and it does that so that you can extract amino acids from food and use them for other things.

If a protein is a drug, you need it to enter the bloodstream without being broken down. When it’s broken down it doesn’t have the effect any longer. So, insulin can’t be delivered orally, primarily because it’s digested within the stomach and small intestine before it’s absorbed. Another problem with developing a pill or oral forms of insulin is that large molecules like insulin, which is a protein, has a molecule weight of about 5,000 are not absorbed very easily through the intestinal wall. We talked about this several weeks ago, your intestinal wall is a–it’s a tube that the surface of the tube is made up of a continuous sheet or monolayer of cells and these cells are connected by tight junctions. Remember that picture I showed you several weeks ago? Because of that for a molecule to enter it has to be able to go through that monolayer of cells. Even if insulin wasn’t broken down to its constituent molecules it couldn’t be absorbed very easily because it’s a large molecule. Only molecules that are small and relatively lipid soluble can go through monolayers of cells like the epithelium of the intestine. There’s two reasons why insulin is not very bioavailable when it’s given orally. That’s one way of saying insulin doesn’t end up in the blood, insulin is not bioavailable when delivered orally.

Some drugs are aspirin, acetaminophen, Ibuprofen, things that you might take routinely for muscle aches or headaches are available orally. They’re small molecules, they aren’t digested appreciably or only a fraction of them are digested so that if you take ten milligrams, maybe five milligrams of them are not broken down in the gut and can be absorbed. One of the problems with oral administration is that drugs are degraded before they’re absorbed into the body. Now, we could tolerate that with aspirin, and why do you think that’s acceptable with aspirin to have some fraction of it broken down in the body–broken down in the gut before it’s absorbed? Why is that acceptable? How much does aspirin cost?

Student: [inaudible]

Professor Mark Saltzman: Not very much, you don’t think about it when you go buy a couple of tablets of aspirin, you go buy a bottle of aspirin or Ibuprofen because it costs something but it doesn’t cost so much. So, if you had to pay two times as much because you lost half of it, because it was degraded before it got absorbed, that might be okay. You’re more likely to use it because it’s a pill and not an injection and you’re willing to pay more for that convenience. Often, drugs that are orally administered, they’re not 100% bioavailable, only a fraction of it gets into your blood, but they’re molecules that can be produced cheaply enough that you can still take a dose that’s larger than what you would need, knowing that half of it is not going to enter your body. Does that make sense?

The other thing about aspirin is that it’s not–I’ll use aspirin as an example, realizing that nobody uses aspirin for headaches anymore, but it’s a good example because it’s a molecule that’s very safe. A safe drug is one in which the concentration at which it causes toxic effects is much higher than the concentration at which it causes good effects, or the effect that you want. We know in aspirin that if you get your concentration up to a certain level your headache will go away. You’d have to get a much higher level in your blood before you began to see side effects or unwanted effects. In aspirin those side effects are that your ears start to ring because it starts to effect the–your mechanisms of hearing, the cells within your cochlear start to be affected by concentrations of the drug at a certain level.

You have to take a lot in order to get up there. This difference between an effective dose and a toxic dose is very important for drugs. Drugs that have a big difference between the safe dose and the effective dose are ones that you can give to patients and trust them to take safely. You could imagine if the toxic dose was very close to the effective dose that might not be a drug that you would want to have patients administering themselves because what if they accidentally take one too many pills, or they take them too close together, they could produce toxic side effects. Aspirin is an example where you have a big window between effective and toxic. Chemotherapy drugs are drugs where there’s a very narrow window between effective and toxic and so those are usually given with the help and guidance of a physician.

There’s a similar mode of administration called sublingual or buckle. Here, the drug is not swallowed, it’s taken in the mouth but it’s–but you hold the pill or the capsule underneath your tongue and you allow it to dissolve there. So, the drug enters your body because it’s absorbed through the membranes in your mouth, particularly the membranes under your tongue. This is a common mode of administration for nitroglycerin. If you have grandparents or friends who are older that have certain kind of heart disease where they get chest pain, they might carry with them tablets of nitroglycerin. If they begin to experience pain they’ll put one of these tablets underneath their tongue and they’ll let it dissolve.

There’s a number of reasons for doing this. The most important one is that when you’re taking a drug orally, you’re taking advantage of the mechanisms that your body has for getting food and nutrients, and you’re using those mechanisms to get a drug. When molecules are absorbed through your intestine, they go through the intestinal wall, they enter the bloodstream that surrounds the intestine. Then, the way that your anatomy is set up all of the blood flow from your intestine goes directly to your liver and from your liver it goes back into the vena cava and then to the heart. Now, why would you design a system like that, where all the blood from your intestine goes right to your liver first? Justin?

Student: [inaudible]

Professor Mark Saltzman: Purifying and processing of the stuff that comes from the intestine, stuff like food, nutrients that are extracted from food, sugars, fats, proteins that are extracted from food that go to your liver. Why do they go to your liver? Because your liver is a very important metabolic organ and it is important for processing proteins and fats, and sugars. So, by sending all those molecules that are absorbed from the intestine to the liver first, you get a jump start on processing of these molecules into the substrates that you need for life. That’s a really good set up for nutrition, but I also mentioned, remember that biotransformation or breakdown of drugs often occurs in the liver. So, if drugs are absorbed the same way that food is they go right to the liver, and–I’m pointing here because that’s where my liver is, they go right to the liver and your liver starts to break it down right away before it even gets to your bloodstream really, before it circulates to the rest of your body. I lose a fraction of drug because it’s degraded within the gut, I lose a fraction because it can’t absorb very rapidly, and I lose another fraction because the liver breaks it down before it ever gets back to my heart and then your heart can circulate it.

Well, it turns out that the blood supply to the membranes in your mouth don’t go to the liver, it’s unusual. They go directly into the superior vena cava and into your heart. So, drug molecules that are absorbed in your mouth bypass the liver and they go directly to your–the rest of your body first. Then of course they’re going to end up in the liver as things get circulated around. They avoid going to the liver the first time and that’s called, here on this graph, avoiding first-pass metabolism in the liver. This metabolism that occurs on the first shot right from the intestine is called first-pass metabolism. Nitroglycerin would be very readily broken down in the liver. So this way it goes directly to the heart without ever having to pass through the liver and it can quickly treat heart disease.

Now, why don’t you do that with all sorts of things? Well, it only works for certain kinds of compounds, compounds that can be absorbed through those membranes in your mouth so they have to very lipid soluble. They also have to be very potent because one difference between your mouth and the intestine is that the surface area in your mouth is fairly small. Only a limited number of drugs can absorb through, whereas–why is your intestine so long? You know that your intestinal–you took it out and stretched it out it would be a tube, a continuous tube, that’s about 30 feet long. Why is your intestine that long, packed into this small space? So that it can have a big surface area to absorb lots of stuff; big surface area–lots of absorption, small surface area–little absorption. It has to be a very potent drug in order to be absorbed at a sufficient concentration through this limited space.

Chapter 5. Drug Bioavailability [00:41:25]

I think those are the main concepts that I wanted to introduce by thinking about these different methods of administration. There’s more of them listed here, some of them have to do with what Caitlin mentioned. If you want a drug that works in the eye, for example, a drug to treat glaucoma, why take a drug orally and expose your whole body to the drug when you could just put drops in your eye directly? And that’s how many glaucoma drugs are delivered? You might have eye drops that you just put into the space underneath your eye, for example, and that’s a more targeted delivery. Targeted because you are putting the drug at the site where it’s needed. I’m sure you have examples of that; topical ointments like antibacterial cream you might put on something if you have a cut and you want to keep it from being infected. You don’t take antibiotics by mouth and have them all over your body, you put a little topical treatment on the site because you’re targeting the drug to the site that you need.

On the next slide there’s some other more uncommon modes of administration, rectal, transdermal, vaginal. We won’t talk very much about those, and next week we’ll talk about special kinds of drug delivery systems that are useful for certain kinds of administration like what are called controlled release implants, we’ll talk about next time. I want–I’ve given you a lot of words and I’ve tried to introduce a lot of concepts by thinking about things that you know about. I want to try to put this in some framework that allows you to think about quantitatively what it means–what these factors mean. We’re going to introduce drugs into a patient and what we would like to know is how rapidly do those drugs become available, what fraction of the drugs become available, and how long does the one dose we give last? As I mentioned, that’s complicated, complicated because our anatomy is complicated, and complicated because we’re all different individuals and our anatomy and physiology differs. So, it’s a hard thing to, do to describe how even one particular kind of drug acts in a population of people is difficult.

We have to start somewhere so we’re going to start with a simplification. That simplification is that these complex things–people–can be represented by very simple constructs. The simple construct that I show here is that instead of a person we’re going to consider the person to be a well stirred vat of liquid, water for example. Now, how can you get away with that? Well, one to say you can get away with it is that we are mostly water, our bodies are 90% water and so if you wanted to describe us sort of in the simplest possible way we’re water, that’s largely what we are. We’re structured water with a particular kind of shape and form, but we’re largely water.

We could describe where drugs go in the body by just thinking about how they dissolve in water. All you’d need to know is, ‘What’s the volume of the water?’ So, if I give a dose what concentration do you get, I give ten milligrams. If your volume is five liters, what’s the concentration you achieve inside? What did I say? Ten milligrams? I forgot what number I said now, ten milligrams divided by five liters, two milligrams per liter. That’s the concentration and that’s the simplest way to define it. Now, how can I get away with saying that we’re well-stirred? I indicate that in this simple drawing by having a–this is a propeller that’s stirring the vat of liquid, how can I get away with saying we’re well-stirred? Well, in some senses we are, that’s what our circulatory system does, and I’m going to talk about that in the weeks to come, but our heart is a very effective–our heart and our blood vessels are a very effective system for distributing molecules very rapidly throughout a large volume and so we are stirred–we are well-stirred in certain senses.

Now, you could object to this simple model for lots of different reasons but we’re going to start with it because it’s a very simple place to start. We’re going to say then when we administer a drug we’re introducing a drug into this well stirred vat of water that has a particular volume. We’re going to administer some dose and we’re going to produce some concentration. Now, what happens afterwards? Does that concentration stay the same forever? No, it doesn’t because we–our body has mechanisms for getting rid of drugs. We’re going to describe that in our simple model by having an arrow pointing out that tells you how–that tells you that drugs are eliminated when they’re within your body.

We’re going to make this a very simple process also and say that drugs are eliminated in proportion to their concentration. The more drug you have the faster it gets eliminated, and as you have less and less drug it gets eliminated more slowly. Now, this–the simplest way to describe this is to say that the rate of disappearance of a drug is equal to some constant times the concentration. The rate of disappearance of a drug is equal to some constant times the concentration. This constant is called a rate constant and this is the concentration that would be within the body. This is a first-order equation. Means that the rate at which the drug is eliminated is proportional to concentration to the first-power or linear with concentration. As drug concentration goes down, since k is a constant for any particular drug. It’s one number, as the concentration drops from two milligrams per liter to one milligram per liter, the rate that your body eliminates it goes down by half as well.

I like to think about this as you could think about concentration as money in your wallet, and the rate at which I spend money anyway is proportional to the amount that I have in my wallet; when I have more I spend more, when I have less I spend less, and the last dollar goes really slowly. The same thing here, when you have a lot of concentration your body gets rid of it fast, but the last molecules go out very slowly. If we take this simple model and then apply it, and we introduce a dose directly into the body, now this well-stirred vat, and we say that it has some volume and we say that drug is eliminated with some rate constant k, we could derive a simple equation. This is derived in the book, in the box at the back of the chapter, that would tell us how concentration varies with time and that equation is shown here. The concentration is equal to the dose that I introduced which is M0 divided by the volume of the body, times e-kt, where k is this rate constant for disappearance of the drug; C = (M0/V)*e-kt.

Now, if you don’t understand when you look at the book where this equation comes from, that’s not important. Some of you will and some of you won’t, but you could trust me that this is the equation that results from those simple assumptions that I talked about. C is the concentration that’s available in your bloodstream or in this vat of fluid, that’s available for action. M0 is the amount that’s introduced, and remember I introduced it in a special way, I injected it right into the body. I injected it all into the body, the whole dose at time t equals 0. I introduced it all into the body at once so it was all available to circulate. That assumes the bioavailability is 100% and that I’ve introduced it all at one particular time. What is this really a representation of? It’s a representation of intravenous injection where I have syringe and I inject all of the drug at once.

In that case, what this equation tells you is that the concentration immediately after you inject the drug is the highest, and after that it continually goes down. It goes down in an exponential fashion with a time course that depends on this constant k. Does that make sense? If I have intravenous administration of a drug that’s eliminated by a first-order process, as soon as I administer it, the concentration is a peak. After that it goes down and the rate at which it goes down depends on this rate constant k. What I also show you here is that if I plugged into this equation I asked the question, ‘When does the concentration go down by a factor of two, when does it go down by 50%?’ I would look on this graph here and say 50% of the drug is gone by this time. I could calculate that time at which the drug concentration goes down by half and that’s equal to the ln(2/k), this rate constant here, so when this number is smaller the half life is longer.

Molecules with a high k are eliminated rapidly; molecules with a low k are eliminated slowly. That half-life is a good measure of how long the drug activity lasts in your body; it’s a good way of thinking about how long I’d have to wait before I needed another dose, for example. What this graph shows you here is just plotted on a semi-log plot. The difference between these curbs, if I had drugs with different half-life, a drug with a half-life of 600 minutes last a long time; concentration doesn’t drop until a long time, it has many, many hours. If it has a half-life of 60 minutes, concentration drops to 10% of its initial level after a few hours. If I have a drug with the half-life of six minutes concentration drops to 10% of its initial level after only a few minutes. So, we’re going to take this model and extend it next time and talk about more complicated modes of administration and talk about sort of new forms of drug delivery, forms that you can expect to see in the next few years.

[end of transcript]

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