Welcome to the n-Lorem podcast series. This podcast is the second in the series of podcasts, which are more lecture like in which I hope to assure that everyone has a basis by which to understand how we can use ASO technology to provide individualized treatment for free for life to patients with ultra rare diseases. In the first of the basic introductory podcasts or think of it as a lecture, I guess, I introduced
the fact that all drugs are chemicals. We discussed how chemicals behave, then how biological systems are established and maintained. I noted that a biological system such as you or me, is simply an incredibly complex set of networks of chemicals and chemical reactions, organized to do the functions of life. And we define a genotype and phenotype and concluded that the goal of drug therapy is typically to alter a disease phenotype, so that a patient reverts to a
healthier phenotype. In today's podcast, my plan is to discuss how to actually think about drugs. I know this sounds simple, but it's actually not. It's really rather remarkably complex until you dissected it into its component parts. And then I think it becomes very easy to understand and much easier to think about. So let me begin with just a brief history of intellectual basis of drug discovery. And then we'll move
on from there to how to think about drugs. So the modern drug discovery industry began in 1900, precisely 1900, we can pinpoint it. And it happened because three scientists, Langley, Barnard and Ehrlich, working independently in three different countries encountered the same basic dilemma. Each of them was studying a chemical that was far far more potent, when given to an animal or human being that can be explained by existing theories. Barnard, I guess was working on the most
interesting of these chemicals and that was Curare. You know, the poison that used on darts and South America to kill things. All of them, though, came to the exact same conclusion. The only way to explain how potent these chemicals were, had to be that they must encounter in their journey through bodies, specific chemicals with which they interact more avidly than the trillions of other chemicals in
the body. And that that chemical with which they interact must be coupled to some biological system that then greatly amplifies the effects of particular chemical. How does cure Ari causes an animal who gets a tiny little dose of Kirari to be paralyzed, could not happen if it didn't anacrusis specific substance in that animal's body, and that substance were connected to a set of networks that amplify the effects of that tiny little chemical reaction, they each
came to the same conclusion. And I think in different languages, I think they even use the same terms. They suggested that when a chemical like curare interacts in the body, it interacts with the thing they call receptive substance. And that receptive substance is a part of a biological system and a network that then exaggerates amplifies the effects of that chemical reaction. And so over time, the term receptive substance has been shortened to just receptors. And that's what we
think of always when we talk about drugs. So here's the key point. Drugs, like other chemicals bind to receptors. Receptors are designed to recognize certain chemicals, including the drugs we administer, and couple the interaction of that chemical, or drug with that receptor to biological systems that then greatly amplify the effect of that tiny little chemical reaction. This concept led to
the creation of a giant industry. Many great companies 1000s of effective drugs, major advances in health care across the board, and it was not proven until the 1980s 80 years after the concept was first proposed when the first of the receptors were called. To me, that is a demonstration of the amazing power of a single brilliant idea. Though a receptor could in principle, be any type of chemical in practice, until very, very recently, all receptors were considered to be
proteins. We now also think of specific sequences and target RNAs as being receptors for some types of drugs ASOs for example, And the study of receptors in the systems that amplify the effects and interactions of chemicals with those receptors is called receptor biology. And many scientists spend their entire career sorting out how one specific receptor is coupled to its amplification network, or signaling system, and how all that is regulated.
So, before we move on, let me introduce and define two new terms, agonist and antagonist I'm sure you've heard these terms, in your various interactions with scientists, let's be sure you have a good definition. For our purpose, we can think of an agonist as a chemical, in this case, a drug that interacts with the receptor and causes a positive activation of the signaling system. And an antagonist. Of course, blocks are prevents activation of the signaling system. And there are
many, many drugs that are agonists. And there are also even more drugs that are antagonists that are used to prevent the activation of a signaling process that's causing the patient to be expressing a disease. Okay, now, how to think about therapeutic effects? Well, it's gonna take a little while, but I think you'll enjoy this, I hope you will. Anyway, remember that drugs are chemicals. And they, as Kurt Vonnegut aptly put it on the Kurt Vonnegut would say this drugs do what they do
doodly doo, and what they must muddly must. And so that means really, that while we may be using a drug, because we have a particular desired effect, we want to produce, the drug doesn't care. And it will do what the drug does. And it always does what the drug does. Many times, that's not what you want. So the purpose for which we administer a drug is called its therapeutic effect or the desired effect. But that's a value judgment that we make. It has nothing to do with the basic
chemical that is the drug. And in fact, in one setting, a particular effect might be considered desire. And in another setting, it might be considered a side effect or an unwanted effect. Think about opiates, or narcotics, most of the time, we use them to alleviate pain. And we worry because one of their side effects is very common is sedation. On the other hand, sometimes we use narcotics to produce a coma in patients, for example, who have severe trauma,
or we use them to as the first step in anesthesia. So the desired effect is a judgment that we make. And what we want in terms of the desired effect can change fairly dramatically, depending on the nature of the patient we're treating. Okay, so now let's begin with how you have to think about drugs. And let me just say this up front, you can't think of drugs in binary terms, you can't think in a way we do in cell biology, that it's a plus or a minus. It's a good drug, a bad drug.
Those terms mean nothing. For all drugs. We're interested in two basic types of properties. And they're called pharmacodynamic, and pharmacokinetic properties. pharmacodynamic is just a big word that refers to what the drug does to the body. Okay. And pharmacokinetics is just another big word that refers to what the body does to the drug. So let's begin then understanding how to think about how drugs affect biological systems of the patient, and that we might
treat. So the pharmacodynamic properties of the drug. Since drugs are chemicals, their effects are concentration dependent, and concentration is varied by adjusting the dose. Everybody knows that you take two aspirin not 20. Take 20 You have problems. So for each effect a drug produces then it has its own dose response relationship, that is drug produces one effect, at one dose, it may produce another
effect at a different dose. So pharmacologists do not think of a drug and simple yes or no ways we just don't and you can't, otherwise you'll just be making a lot of mistakes. So what we typically do is we plot the intensity of an effect versus the dose. And that then gives us a graph that we call a dose response curve. And so we define potency as the amount of drug the dose of the drug required to produce an effect that we can
observe. And this is something that we're going to hear over and over again, the midpoint of any graph is the most accurate. And so typically when we want to compare effects or we want to compare products As we take the midpoint of the dose response curve, and that's usually called an effective dose 50 or ED 50. And so when we talk about potency, you'll often hear pharmacologist talk about ED 50, or ID 50. And all that means is that that's the best way to compare the doses required to
produce a particular effect. Each effect of every drug has its own unique dose response curve. Now, let's say we give a drug to reduce blood pressure, done every day. Well, in that case, then the desired effect is reduction in blood pressure. But let's say like most drugs, essentially all drugs, this drug also has a very undesired effect, and let's say it causes the heart rate to greatly increase, okay, so the desired
effect, the therapeutic effect, is lowering blood pressure. And the side effect or undesired effect is making heart go faster, which can be very deleterious course. So when we give our drug to a patient with high blood pressure, once again, the desired effect is to lower the blood pressure. And we'd like to do that without causing an undesired effects such as
increasing heart rate. So when we then think about how to do that, recall that since drugs, all drugs are just chemicals, and their effects, our concentration or dose dependent, we adjust the dose to get the effect that we want. So what we hope is that we can find a dose that we can give to this patient that reduces blood pressure, and has no effect on heartbeat. Said another way, we hope to produce benefit, without the patient
paying for it with a side effect or a toxic effect. So pharmacologist always think in terms of dose, and dose response relationships. Moreover, a far more important characteristic of a drug than potency is therapeutic index. So let's talk a minute about therapeutic index. This is a tremendously important concept for a therapeutic index. You can think of it this way, we want to reduce the blood pressure of that patient, but we're worried that we may produce increased
heart rate. So typically, what we do as pharmacologists is we have a look at the dose response curves for blood pressure lowering, and for causing heart rate to increase. And we typically compare the dose that's in the middle of that each of those curves, the ED 50, for reducing blood pressure to the ED 50, for increasing heart rate, and then we take the dose that we need to get 50% of the blood pressure reduction that we want done, and divide that into the dose that would give that
would cause a heart rate increase. And that is how we calculate a therapeutic index. Now, if you think about it for a second, you know, that therapeutic index is far more important than potency. Because you certainly would like to benefit the drug and you'd rather not have the negative effects. So as a general rule, the most important question for you to ask about a drug is what is its therapeutic index? And as a general rule, the bigger that number, the better the drug is
going to be for you. It's not plus or minus. It's that therapeutic index that matters. And so if you're asking yourself, should I take this medicine? The question you should ask is not whether it's potent, not potent, who cares? What you really want to understand is the therapeutic index. Okay. So once again, every drug has adverse events, there is no drug that doesn't cause some adverse event. If the dose is administered high enough, we have to constantly
think about that. Okay, now, so you now know that you want to know about potency, but you're much more interested in therapeutic index, or the dose at which you'll get some benefit versus the dose at which you may have a side effect. Pharmacologists refer to then all of that as pharmacodynamic properties of the drug. Now, in addition to those sort of static concepts, that is, what's the dose at which an effect occurs that we want versus the dose at which an effect might occur that
we don't want. We also think in terms of time related events, and we call that kinetics. And so, by definition, we're going to be interested in how fast the drug produces its effect that's called onset of action, then we want to know what's its maximum effect and that's what it's called its maximal effect, and we want to know how long it lasts, its duration of action. All of those properties are greatly influenced by how the body reacts to the drug. And those properties are called
pharmacokinetics. And so we're going to move to those properties now. So once again, pharmacokinetics refers to how the body handles the drug that we administer. Pharmacodynamics refers to what the drug does to the body, okay. So if the drug has to be used throughout the body, or systemically, it has to be absorbed from whatever site you administer, and then it has to be distributed to various organs and cells, it has to
reach, you know, its target site or receptor. And then since all drugs are seen as foreign chemicals, the body as soon as it sees the drug gets busy and tried to get rid of it. And so you're interested in how it does that, and how long it takes. So and that process of getting rid of the drug is called elimination. But we're interested in how much of the drug is absorbed, how fast the process of absorption is, we want to know how broadly the drug distributes to various
organs, and how fast that happened. And we want to know what happens when it's in those organs and how long it takes for those organs to get rid of it. Okay. And, again, you know, this, I mean, you don't take some drugs orally, because they aren't absorbed and you don't take every drug every four hours, you take drugs, at varying frequencies, because
there are differences in the way those drugs are handled. Since all chemicals are distributed by blood, and drugs, are chemicals, the first step in the process of systemic drug effects is to get into blood. And we can measure that and we do for every drug, and we measure the amount of the drug that gets into blood. And so what we want to know is the total fraction of a dose of the drug administered that gets into blood. And that's called bioavailability. And that fraction of administered dose
that becomes systemically useful is a fraction. And so we think of absorption in terms of fractions of dose administered. And then in addition to that, we want to know how long it takes. And that's the absorption time. And since you know that the midpoint of our graphs are the best, we tend to discuss the absorption half life, how long it takes to absorb 50% of the total amount that's going to be absorbed. Same thing for distribution, once absorbed, a drug is distributed by blood.
And generally, drugs distribute unevenly, depending on the blood flow, the kidney and the heart get most blood flow, other organs get less. And, again, we want to know to what organs the drug distributes a set of static concepts. And then we want to know about time, how long it takes to distribute. And finally elimination. To the body, of course, a drug is simply a foreign chemical, and the body is designed to get rid of foreigners. And so as soon as the body sees the drug, it gets
busy, and it tries to begin to get rid of it. Very often, one of the things that the body does, is degrade the drug. And it's really simple to think about the drug is, you know, relatively complex chemical. And the body says okay, I'm going to get rid of it by just breaking it down into its much smaller, simpler pieces, some of which I can use to make the molecules that I want, and some that I want to get rid of. And there
are numerous, numerous processes to degrade drugs. They vary widely, depending on the organ and different drugs are degraded by different types of pathways, and ASOs are very different sort of metabolically than, say small molecule drugs. There are a few drugs that aren't metabolized, but most really are broken down to smaller bits. And as a general rule, what the body is trying to do is to create these tiny little bits of the drug you gave, and make them water soluble so that it can be
cleared in the urine. The metabolism of each drug, as I said, is different and unique to that drug and to the organs that it goes to. And we should always understand these processes, they're understandable, they're fairly easy to figure out. So there are then three major routes by which the body uses to get rid of waste. And that would include drugs and metabolites of drugs. And most often, the drugs are either the intact drug or the or the metabolites of the drug are disposed of by the
kidney in urine. So anything just water soluble after the body gets finished with it ends up in urine. And on the other hand, there are some drugs and metabolites of the drugs that are fat soluble or lipophilic. Those typically end up in bile, and then that's excreted into the gut and we get rid of the drug in the feces, another way that you can get rid of some drugs is to break them down to very, very tiny components and breathe them out. And there are a few drugs where their
clearance is primarily by index fired air. So once again, we are interested in some static parameters. And we're interested in some time related parameters kinetics. And with elimination, what we usually do is describe the elimination half life, that is the time it takes to get rid of half of the drug from a particular organ, or from the whole body. And the elimination half life has a lot to say about how often we have to administer
the drug. So let me sum up, given that our mission at in n-lorem is to treat patients with novel medicines or drugs. And the concepts I've just discussed are just incredibly important for you to understand and for you to be able to understand me and me to be able to talk to you. So I'm going to pause for just a second and really try to be very careful and some this section up. Drugs do not need to be black boxes, they're actually fairly understandable when you think
about them the right way. First, we have to think about what the drug may do to the body. And there are several relatively constant or static properties that we want to measure. And then there's a set of time related or kinetic properties that we want to know, first step one using a drug effectively, is to decide why we're using it. What is the desired effect? And again, remember, that's just our value judgment to drug doesn't care. And then we need to know what are the other effects drug
may produce. And we'll call those the non desired undesired or side effects or toxic effects. And we need know to the dose at which the desired effect occurs, as well as the major side effects. And once we have those doses, we can then figure out how good a drug we have. And we do that using a calculation called therapeutic index. Okay. And with regard to the kinetic characteristics, we're interested in how fast the drug works, that's called onset of action, and how long the drug
lasts. That's called duration of effect. And of course, we use that information to tell us when to expect a drug effect, and how often we have to give it. We're also interested in what the body does to the drug. And once again, there are both static and kinetic properties that we want to understand the fraction of the dose that is absorbed, we refer to as bioavailability, the organs and cells to which the drug distributes, and the
concentrations achieved there. And the processes by which the body then eliminates the drug are all essential things that we can understand. And we do. And once again, we're interested in a bunch of halftimes, or half lives, absorption, halftime, distribution, halftime elimination halftime, and we use the midpoints of curves, not for any particular magic, but just because that's the most accurate part of any graph that you see. Okay, to come back to the key point, once more drugs cannot be
thought of in plus or minus terms. To say a drug is safe or toxic, good or bad, is simply frankly, a silly thing to say. drugs do not behave that way. On the other hand, they don't need to be black boxes, you can understand them. And it's pretty easy when you just think about them in the way I just laid out. And so this set of concepts is going to underwrite everything we do everything we say, all the effects that we might see in a
patient who has an ultra rare disease. And so I think they're so important that our plan is to put the summary paragraph that I just gave you actually on our website, so that you can refer to it if you forget some part of this and you're trying to ask, is this a good thing for me to do take this drug? Or is it a bad thing? I think you can use this to help you make those
decisions. I hope so anyway, so that finishes today's podcast, and in the next lecture podcast, I'd like to bring most of the sort of didactic material about drugs and so on to a conclusion. And then we'll probably have one more where I talk briefly about the history of the industry just because I think you may find some value in it.
n-Lorem is a nonprofit committed to discovering and providing personalized experimental treatments for free for life to patients with genetic diseases that affect one to 30 patients worldwide, referred to by a n-lorem. As nano rare. Many of these patients progress and die without ever achieving a diagnosis. This is where n-lorem comes in. They do the impossible by providing hope and for those that they can help free lifetime treatment. For more information about n n-lorem, or today's
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