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Unit 1, Principles of Pharmacology, Lesson 2a, Basic Principles of Pharmacology

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So let's start with the word pharmacokinetics. The term pharmacokinetics is derived from two Greek words, pharamacon, meaning drug or poison and kinesis, meaning motion. Therefore, pharmacokinetics is the study of drug movement throughout the body. More simply defined, it's what the body does to drugs after we give them. There are four basic pharmacokinetic processes, absorption, distribution, metabolism, and excretion. Absorption, is the movement of a drug from its site of administration into the blood. Distribution, is drug movement from the blood into the interstitial space of tissues and from there into cells. Metabolism or biotransformation, is defined as enzymatically mediated alteration of drugs structure. While excretion, is the movement of drugs and their metabolites out of the body. We'll be reviewing each of the four phases in more details shortly. But for now, I have provided a video that explains the overall concepts of absorption, distribution, metabolism, and excretion in the Notes section of this presentation, just click on the hyperlink. The diagram just simply demonstrates the four phases of pharmacokinetics from administration of an oral medication. And you can hopefully see how it moves from either the stomach or the duodenum. Most medications are absorbed from the small intestine into the bloodstream, moves out of the bloodstream to the liver, and from the liver is metabolized or biotransformed in preparation for excretion by the kidneys.

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All four phases of pharmacokinetics, absorption, distribution, metabolism, and excretion involve the movement of drugs. To move throughout the body, drugs must cross membranes. Drugs must cross membranes to enter the blood from their site of administration, unless of course, you've given a drug by intravenous route. Once in the blood, drugs must cross membranes to leave or exit the vascular system in order to reach their site of action. In addition, drugs must cross membranes to undergo metabolism, as well as excretion. Therefore, the factors that determine the passage of drugs across these membranes can have a pretty profound influence on all four phases of pharmacokinetics. So how do drugs cross membranes? There's three ways by which most drugs cross membranes. The first is through channels and pores. And while very few drugs cross membranes via channels or pores, it is one way that extremely small molecules like potassium and sodium are able to pass through membranes. Drugs may also use transport systems. Transport systems are simply carriers that move drugs from one side of a membrane to the other. Some transport systems require the expenditure of energy, while others do not. All transport systems are selective, in that they will not carry just any drug. And whether a transporter will carry a specific drug depends on the drug's structure. The third way drugs cross membranes is through direct penetration. For most drugs, movement throughout the body is dependent on the ability of the drug to actually penetrate the membrane directly. Why? Well, one, most drugs are

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much too large to pass through channels or pores. And two, most drugs lack transport systems to help them cross all of the membranes that separate them from their sites of action, metabolism and excretion. So in this case, drugs that are more lipid soluble are able to penetrate membranes quite easily. If you remember a general rule in chemistry states, like dissolves like. And since membranes are composed primarily of lipids, drugs with a high lipid solubility are able to penetrate directly quite easily.

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As I mentioned, on the previous slide there are a number of things that affect how drugs move across those plasma membranes. The size of a drug molecule is important. In order to use a channel or a pore, drugs need to be very, very small. And most drugs are much too large to use a channel and pore. Drugs that are lipid soluble have a much easier time passing through the membrane than drugs that are not lipid soluble. However, not all molecules are lipid soluble and therefore, have a difficult time penetrating membranes. This group consists of polar molecules in ions. Therefore, the ionization of a molecule is also an important consideration when thinking about how drugs pass through cell membranes. There is a nice discussion in your textbook about passive and active diffusion of drugs through membranes. I would encourage you to review the textbook for additional information.

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Let's explore each of the four phases of pharmacokinetics in a little bit more detail. As I mentioned, absorption is defined as the movement of a drug from its site of administration into the blood. The rate of absorption determines how soon its effects will begin. While the amount of absorption helps determine how intense the drug's effects will be. An important consideration in absorption is the route of administration. We're not going to get into the different routes of administration in this particular lesson. However, your textbook does an excellent job of describing the various routes, strengths, and barriers related to absorption. So please, make sure that you read. I do want to just highlight that there are a number of factors affecting a drug's absorption. The rate at which a drug undergoes absorption is very much influenced by the physical and chemical properties of the drug itself, as well as the physiologic in anatomic factors at the absorption site. For example, rate of dissolution, before a drug can be absorbed, it must first dissolve. Hence, the rate of dissolution helps determine the rate of absorption. Drugs and formulations that allow rapid dissolution have a faster onset than drugs formulated for slow dissolution. Think for example about some of the enteral or oral medications that you give. Is a drug that's administered in a form of a tablet or a capsule more likely to dissolve faster or slower than that same drug given in a liquid form? Surface area is another consideration. The surface area available for absorption is a major determinant of the rate of absorption. The larger the

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surface area, the faster the absorption will be. Be For this reason, are orally administered drugs are usually absorbed from the small intestine rather than from the stomach. Why? Because the surface area of the small intestine is much larger than the surface area of the stomach, hence, faster absorption. Blood flow is also an important consideration. Drugs are absorbed more rapidly from sites where blood flow is high. As I mentioned on the earlier slides, lipid solubility is also important. As a general rule, highly lipid soluble drugs are absorbed more rapidly than drugs whose lipid solubility is low. Why? Because these drugs with high lipid solubility can readily cross the membranes that separate them from the blood. Whereas, the drugs with low lipid solubility cannot. Last, but not least, pH partitioning is an important consideration affecting drug absorption. PH partitioning can influence drug absorption. Absorption will be enhanced when the difference between the pH of the plasma and the pH at the site of administration is such that drug molecules will have a greater tendency to be ionized in the plasma. I have included a short video with the hyperlink in the Notes section of this slide. Please, take some time to review it. It goes into absorption in more detail.

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The next step of pharmacokinetics is distribution. And distribution is simply the movement or transportation of drugs throughout the body and this occurs through the blood stream. There are a number of factors that can affect distribution, like blood flow to tissues. Tissues that have high blood flow are more likely or readily able to receive medication than tissues that have low blood flow. This is an important consideration when looking at treating pathological conditions, where blood flow is poor, like abscesses and tumors. Additionally, lipid solubility is an important consideration. If you remember from the previous slide, not only do drugs have to find their way through membranes from their site of administration into the bloodstream, they also have to find their way through membranes to get out of the bloodstream to their site of action. The higher the lipid solubility, the easier it is for drugs to do that. Another consideration is the drugs ability to accumulate in tissue. Some tissues have the ability to accumulate and store drugs in higher concentrations than other tissues, for example, adipose tissue. This is an important consideration when looking at the duration of certain medications. Because we can extend the duration of action and decrease the frequency of drug administration for certain medications. However, it's also an important consideration when considering adverse reactions of medications that have the potential to store in adipose tissue, like anesthesia in our bariatric clients. I also want to just briefly touch on drug protein binding. As you can see from the picture on the slide, certain drugs have the ability to bind with plasma albumin. And if you remember from anatomy and physiology, albumin always

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remains in the bloodstream. It's too large to squeeze through pores in the capillary wall. And there's no transport system that exists for it to leave. Leave Hence, when a drug has a high affinity or a high protein binding capacity and the drug binds to the albumin or protein molecule, less drug is available to exit the vascular system and exert its therapeutic effect. Therefore, protein binding can restrict the drug's distribution. Another important consideration with protein binding is that in addition to restricting the drug's distribution, protein binding can be a source of drug interactions. If by some chance a patient is given a medication that has a higher affinity for the protein albumin molecule, then one drug will knock another drug off that albumin molecule, resulting in the other drug blood concentration being increased and more drug being able to exit the vascular system and get to its site of action similar to absorption. I have provided you a short little video clip, hyperlinked in the Notes section of this slide, about distribution. Please, take some time to watch the video.

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Before moving on to metabolism, I do want to just spend a few moments talking about some special barriers to drug distribution. The first barrier is the blood-brain barrier. As you may recall, the blood-brain barrier are very tight junctions between cells that compose the walls of capillaries in the central nervous system. These tight junctions prevent drugs from passing between cells to exit the vascular system. Therefore, in order for a drug to reach a site of action within the brain, the drug must be able to pass directly through cells of the capillary wall. To do this the drug must be highly lipid soluble or must use an existing transport system. Presence of the blood-brain barrier is a mixed blessing. The good news is that this barrier protects the brain from injury by potentially harmful drugs and toxic substances. The bad news is that this barrier then can be a significant obstacle to treating disorders of the central nervous system and brain, by preventing the distribution of medications that are not lipid soluble or that lack a transport system. The second barrier that I want to look at is the fetal-placental barrier. As you know, there's membranes that separate maternal circulation from fetal circulation. But these membranes do not constitute an absolute barrier to the passage of drugs. The same factors that determine the movement of drugs across other membranes, determine the movement of drugs across the placenta. Therefore, drugs that are highly lipid soluble or non-ionized compounds are able to readily pass from the maternal bloodstream into the blood of the fetus. Drugs that have the ability to cross the placenta in this way can cause serious harm, including birth defects.

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Metabolism is the third step of pharmacokinetics. Drug metabolism, also known as biotransformation, is defined as the enzymatic alteration of drug structure. As you know, most drug metabolism takes place in the liver. A more simple definition, is a process that changes the activity of a drug, primarily in the liver, and makes it more likely to be excreted. Most drug metabolism that takes place in the liver is performed by the heptatic hepatic microsomal enzyme system, also known as the P450 system. The term P450 refers to cyctochrome P450, a key component of this enzyme system. It is important to appreciate that cytochrome P450 is not a single molecular entity, but rather a group of 12 closely related enzyme families. Three of the cyctochrome P450, or CYP families, designated CYP1, CYP2, and CYP3 metabolize drugs. The other nine families metabolize endogenous compounds like steroids and fatty acids. Each of the three CYP families metabolize only certain drugs. So you might be wondering. Why is it important for you as a nurse to understand these CYP families? Well, the CYPs are important to pharmacotherapy. Because they determine the speed at which most drugs are metabolized. And they contribute significantly to drug-drug interactions. I also want to spend just a few minutes talking about important variation in metabolism, known as the first-pass effect. The term first-pass effect, refers to the rapid hepatic inactivation of certain oral drugs. Key word in that definition is oral drugs. Drugs When drugs are absorbed from the GI tract they are carried directly to the liver via the hepatic portal vein. If the capacity of the

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liver to metabolize a drug is extremely high, that drug can be completely inactivated on its first pass through the liver. As a result, there is no therapeutic effect. To circumvent the first-pass effect, that drug that undergoes rapid hepatic metabolization is often administered parentally. This permits the drug to temporarily bypass the liver, allowing it to reach therapeutic levels in the systemic circulation. An example of a type of drug that we give parentally, because of first-pass effect concerns, is nitroglycerin. Similar to absorption and distribution, I have provided a video in the Note section of this slide that discusses metabolism in more detail. And for those of you that prefer more visual learning, it helps understand some of the key concepts.

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Drug metabolism has six possible consequences of therapeutic significance. The first and most important consequence of the drug metabolism is the promotion of renal drug excretion. At some point, all drugs need to leave the body. And the majority of the drugs leave the body via the kidneys. We'll talk more about excretion in a few moments. Another consequence is of drug metabolism is drug inactivation. Drug metabolism can convert pharmacologically active compounds into inactive compounds. In addition, metabolism can cause increased therapeutic action. Metabolism can actually increase the effectiveness of some drugs. The fourth consequence of metabolism in activation of pro-drugs. A pro-drug, is simply a compound that is pharmacologically inactive as administered, but undergoes conversion to its active form when it's metabolized. The fourth and fifth consequence, or excuse me, the fifth and sixth consequence of drug metabolism is either increased or decreased toxicity. By converting drugs to inactive forms, metabolism can decrease toxicity, While conversely, metabolism can increase the potential for harm by converting relatively safe compounds, for example, acetaminophen, into forms that are toxic. A couple of other special considerations related to metabolism include age. As you know, the drug metabolizing capacity of infants is limited. The liver does not develop to its full capacity to metabolize drugs until after about the first year of birth. During this time, prior to hepatic maturation, infants are especially sensitive to drugs. Therefore, you must take care to avoid injury.

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Similarly, the ability of older adults to metabolize drugs is commonly decreased. Drug doses may need to be reduced to prevent drug toxicity in our elderly population. We'll talk more about special populations, our infants, our pregnant women, and elders in an upcoming lesson. Other considerations are the induction or inhibition of CYP enzymes. Some drugs are able to inhibit or induce the action of CYP enzymes. And in doing this, they can cause either drugs to be less effective or create more CYP enzymes if they're inducers. Which can interfere with the metabolism of drugs, where inhibitors and inducers of enzymes play a role in drug, drug interactions. Last, but not least, the nutritional status of our patient can affect metabolism. Hepatic drug metabolizing enzymes require a number of co-factors to function. In a malnourished patient, these co-factors may be deficient, causing drug metabolism to be compromised.

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The fourth and final step of pharmacokinetics, is excretion. Excretion Drug excretion, is defined as the removal of drugs from the body, or a process that removes the drug from the body. As you know, the primary site for excretion is the kidney. Although drugs and their metabolites can exit the body in bile, sweat, saliva, breast milk, and even expired air. The rate of excretion of a drug determines the drug level of the blood. And while the kidneys account for the majority of drug excretion, when the kidneys are healthy they serve to limit the duration of action of many drugs. Conversely, if renal failure occurs, both the duration and intensity of drug responses may increase. Also important to remember, that some drugs undergo reabsorption after renal filtration. And that their excretion can very much be influenced by the pH of the urine, as well as any renal impairment that occurs. Similar to absorption, distribution, and metabolism, I have provided a video that explains excretion in more detail. You'll find a hyperlink in the Note section below this slide.

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I want to spend just a few moments talking about the time course of drug responses, or time response relationships. It is possible to regulate the time at which drug responses start, the onset of a medication, the time they're most intense, the peak, and the time at which they cease or the duration. In most cases, the time course of drug action bears a direct relationship to the concentration of a drug in the blood. Therefore, clinicians frequently monitor plasma drug levels in efforts to regulate drug responses. When plasma measurements indicate that drug levels are inappropriate, these levels can be adjusted up or down by changing the dose size, the dose timing, or both. The practice of regulating plasma drug levels to control drug responses might seem a bit odd, given that drug responses are related to drug concentrations at the site of action. And that the site of action of most drugs is not the blood. Therefore, the question you might be asking is, why just plasma levels of a drug, when what really matters is the concentration of that drug at the site of action? Well, the answer begins with the following observation. More often than not, it is not practical. Actually, it's impossible to measure drug concentration at the sites of action. Think about a seizure patient who's taking phenytoin o Dilantin, an anti-seizure medication. Would it be practical, even possible, to routinely draw samples from inside the patient's brain to see if the levels of medication are adequate for seizure control? Absolutely not, fortunately, in the case of phenytoin and most other drugs, it is not necessary to measure drug concentration at the actual site of action to have an objective basis for adjusting dosage.

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Research and experience has shown us that for most drugs there is a direct correlation between therapeutic and toxic responses and the amount of drug present in the plasma. Therefore, while we can't actually measure drug concentration at the site of action, we can determine plasma drug concentrations, that in turn, are highly predictive of therapeutic and toxic responses. Accordingly, the dosing objective is commonly spoke of in terms of achieving a specific plasma level of a drug. Two plasma drug levels are of special importance. And they are depicted on this diagram. The first is minimum effective concentration. And the second is toxic concentration. So let's talk about minimum effective concentration first. First The minimum effective concentration or the MEC, is defined as the plasma drug level below which therapeutic effects will not occur. Hence, to be of a benefit, a drug must be present in concentrations at or above the MEC. Conversely, toxicity occurs when plasma drug levels climb too high and the plasma levels are above the toxic concentration. Therefore, doses must be kept small enough and large enough to maintain our patient's serum plasma levels within a therapeutic range. Also, represented on this slide is the onset peak and duration of medication. And in this hypothetical exemplar, you can see that when a medication is given to a patient-- this particular medication. As the medication starts to be absorbed and distributed, it takes about two hours for that plasma drug level to reach a minimum effective concentration. Again, that point at which it's going to have a therapeutic effect. So the onset of our medication is two hours. As the medication serum levels continues to increase, the serum concentration reaches a peak level at about five hours. This is known as the peak of our medication. After which time, due to metabolism and the excretion of our medication, the medication plasma levels start to fall off. Now, that's the duration. The point at which the plasma levels will fall below the minimum effective concentration is the end of our therapeutic effect for this particular medication, somewhere around eight hours. Ideally, we dose medications to keep it within the therapeutic range. The wider the therapeutic range, the safer the medication. The more narrow the therapeutic range, the more safety concerns we have. Because there's very little room for dosing error before toxicity occurs.

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So let's talk a little bit more about a drug's half-life. Drug half-life, simply is an estimate of the duration of action for most medications. And it's defined as the time required for the amount of drug in the body to decrease by 50%. As you may be aware, some drugs have relatively short half-lifes in the order of minutes, for example, naloxone or nitroglycerin. In contrast, some drugs like amiodarone have very long half-lifes in order of a week or more. Obviously, drugs with short half-lifes leave the body very quickly. While drugs with long half-lifes are going to leave the body more slowly. Drugs with short half-lifes need to be dosed more frequently. And drugs with long half-lifes need to be dosed less frequently. It's important to understand that the definition of a half-life is a percentage not a specific amount. That is the half-life does not specify, for example, that two grams or 18 milligrams will leave the body in a given time, but rather that 50% will leave the body in a specified period of time. The actual amount of drug that is lost during one half-life depends on just how much drug is present. The more drug that is in the body, the larger the amount lost during one half-life. The concept of half-life is best understood through an example. Let's look at morphine, a drug that most of you are familiar with. The half-life of morphine is approximately three hours. By definition, this means, that body stores of morphine will decrease by 50% every three hours, regardless of how much morphine is in the body. If there are 50 milligrams of morphine in the body, 50% or 25 milligrams will be lost in three hours. If there are only two

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milligrams of morphine in the body, only one milligram, 50% of two milligrams will be lost in three hours. Note that is both cases morphine levels dropped by 50% during an interval of one half-life. However, the actual amount lost is larger, when the total body stores of the drugs are higher. So how many half-lifes does it take for most of a drug to leave the body? Well, that's easy, four. After about four days, roughly 94% to 95% of the drug has already left the body. So why is it important to understand half-life? Well, when looking at repeated dosing with medications, such as those required to control blood pressure, or to control lipid levels, or to control seizures, it's important that at some point in time that the amount going into the body through administration of new medication is equal to the amount that's leaving the body, in order to keep our patient within that therapeutic range.

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As I mentioned, repeated dosing allows a plateaued drug plasma level to be reached. And our goal is with drugs that require repeated dosing to keep our patient within that therapeutic range. We don't want them falling below the minimum effective concentration. And we don't want them going above the toxic concentration. And approximately, it takes four half-lifes in order for a plateau to be reached, where the amount lost between doses is equal to the amount being administered. Now, with certain drugs, you want to get the patient into a therapeutic range more quickly. And we might give them what we call a loading dose. And again, the loading dose might be something that is higher than a typical standard daily dose or BID dosing in order to get that therapeutic serum level up more quickly. An example would be somebody that's having a seizure. Seizure Or perhaps somebody that's having a dysrhythmia.

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Let's do a quick little Knowledge Check. A patient is given a prescription for azithromycin, trade name Zithromax, and asks the nurse why the dose on the first day is twice the amount of the dose on the next four days. Which reply by the nurse is correct?

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We're going to switch gears now and talk a little bit about pharmacodynamics. Pharmacodynamics is defined as, the study of the biochemical and physiological effects of drugs and the molecular mechanisms by which those effects are produced. Said a little bit more simply, it's what the drug does to the body and how. Similar to our unit or discussion on pharmacokinetics, I have provided you with a video. That talks about pharmacodynamics in a little bit more detail. In this lesson, I want to just touch on some of the more salient point.

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Similar to some of the other concepts we've talked about thus far, you might be asking yourself, as a nurse why it's important to understand pharmacodynamics? Well, in order to be able to help patients achieve the therapeutic objective, as a nurse, you need a basic understanding of pharmacodynamics. You must know about drug actions to educate patients about their medications, make PRN decisions, as well as to evaluate patients for potential harmful effects, as well as therapeutic effects. Have you ever had a situation where you wanted to talk with a provider or a prescriber about the patient's medication regime? Did you think maybe that there was some medications that might be inappropriate? Or believe that there was additional medications that might be helpful? Well, in that collaborative relationship isn't it important to be able to support your opinion with discussion based, at least in part, on knowledge about pharmacodynamics? Absolutely, it is. So in this next part of this lesson, we're going to talk about some of the important concepts related to pharmacodynamics. And we're going to start with a dose-response relationship. The dose-response relationship or the relationship between the size of an administered dose and the intensity of response should be fundamentally concerning to you as a nurse. Does-response relationships determine the minimum amount of a drug needed to elicit response. They also determine the maximum response a drug can elicit and help us make decisions about how much to increase the dose to produce the desired increase in response. So if you think about drug

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dosing in terms of a patient requiring a blood pressure medication, have you had patients that have only required a little bit of medication, the lowest dose possible to elicit the desired response in lowering their blood pressure? And then I'm sure you've had other patients that have required the maximum dose required or safe in order to elicit the desired reduction in blood pressure. So the range between the lowest dose and the highest dose is that dose-response relationship. Some patients will require the low end of the range. Some patients will require the high end of the range in order to get that same effect from the medication. The dose in the middle of that range is what we call the median effective dose or the ED50. And the ED50 is simply, the dose required to produce a specific therapeutic response in roughly 50% of a group of patients. And this is what is normally reported as the average or the standard dose for a drug in our drug guides. And we use this knowing that sometimes there's interpatient patient variability. Again, that some patients will need less. And some patients will need more, as at least a starting place for knowing how to dose our medications.

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I also want to spend just a few minutes differentiating between potency and efficacy. These are two concepts that are commonly misunderstood. The term potency refers to, the amount of drug we must give to elicit an effect on the body. While efficacy is defined as, the greatest maximal response produced by a drug. Potency compares the doses of two different drugs. While efficacy compares the desired therapeutic effect of two drugs. As nurses, it's important to understand that potency of a drug implies nothing about its maximal efficacy. Rarely, is potency an important characteristic of a drug. Just because one drug requires a higher dose than another drug, doesn't mean that it's any more or less effective than another drug.

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Important to understanding pharmacodynamics is also understanding drug-receptor interactions. As you know, drugs are not magic. They're simply chemicals. And because they're chemicals, the only way they can produce their effects is by interacting with other chemicals. Receptors are special chemical sites in the body that most drugs interact with to produce their effects. Most drugs activate or inhibit specific cellular receptors, such as, those for hormones, neurotransmitters, and other regulatory molecules that either enhance or inhibit a physiological process. There's four basic types of receptor families, ligand-gated ion channels, G-protein-coupled receptor systems, transcription factors in cell membrane, embedded enzymes. While these words may not mean much to you now. As we move forward in the course. You will hear these words again. when we start learning about specific drugs and how they exert their action on the body. Couple of other important things to keep in mind is that each type of receptor participates in the regulation of just a few processes. Therefore, if we have a really good understanding of anatomy and physiology and what the receptors are responsible for regulating in the body, we can understand how the drug exerts its therapeutic effect, as well as its adverse effects, based on that understanding of that receptor neurotransmitter. Additionally, understanding drug-receptor interactions help us identify ways to make drugs more selective. Meaning, that we target those receptors for only the response that we want to have happen. This helps us minimize

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adverse effects. As we learned in the first lesson, the more selective a drug is, the fewer side effects it will produce.

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Also, important to understanding drug-receptor interactions is understanding the difference between affinity and intrinsic activity. Affinity is a term that refers to, the strength of attraction between a drug at its receptor. While intrinsic activity refers to, the ability of a drug to activate our receptor upon binding. Drugs that have a high affinity and have high intrinsic activity are going to have more pronounced effect than drugs that have a low affinity or low intrinsic activity. Two other important concepts to understand, related to pharmacodynamics and drug-receptor interactions, is agonist and antagonists. And agonist is simply, a drug that binds to its receptor that mimics the action of endogenous, regulatory molecules. Drugs can also be partial agonists. Partial agonists also mimics the actions of endogenous, regulatory molecules. But they produce a response of intermediate intensity. Antagonists, however, are drugs that produce their effects by preventing receptor activation by endogenous, regulatory molecules and drugs. Antagonists have virtually no effect of their own on receptor function. They simply block the receptor so that the body cannot produce an effect through endogenous substances. Antagonist drugs are oftentimes useful in blocking excessive of endogenous activity. For example, in a beta blocker, in blocking the binding of the neurotransmitter, norepinephrine, to the beta receptors to help lower blood pressure. Antagonists drugs may also be used to reverse adverse effects associated with overdoses. Two important concepts related to that are competitive versus non-competitive antagonists.

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A non-competitive antagonist binds irreversibly to the receptor. Meaning, that there is nothing that can knock it off that receptor. As opposed to a competitive antagonist, which binds reversibly to a receptor. As their name implies, competitive antagonists produce receptor blockade by competing with agonist for receptor bindings. This is similar to the interaction that you see between morphine and naloxone in a patient suffering from an overdose.

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Just a few more important things about drug-receptor interactions. As you know, our receptors are dynamic components of the cell in response to continuous activation or continuous inhibition. The number of receptors on the cell surface can change, as can their sensitivity to agonists molecules. For example, when the receptors of a cell are continually exposed to an agonist, the cell usually becomes less responsive. When this occurs, the cell is said to be desensitized or refractory, or have undergone downregulation. Several mechanisms maybe responsible, including destruction of receptors by the cell modification receptor, such as they respond less fully. Continuous exposure to antagonists has the opposite effect, causing the cell to become hypersensitive, also referred to as supersensitive. One mechanism that can cause hypersensitivity is synthesis of more receptors.

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It's also important to note that not all drugs involve receptors. Although, the effects of most drugs result from drug-receptor interactions, some drugs do not act through receptors. Rather, they act through simple physiological or chemical interactions with other small molecules. Common examples of receptorless drugs include antacids, antiseptics, and saline laxatives. And we will discuss some of these drugs in more detail in future units.

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Woo, this was certainly a long lesson, by far the longest in the course. We have reached the end.

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Question 1 Answer Question: A patient with cirrhosis of the liver has hepatic impairment. This will require what possible changes in administration of medications? (Select all that apply.) A: A reduction in the dosage of the drugs. B: A change in the timing of medication administration. C: An increased dose of prescribed drugs. D: Giving all prescribed drugs by parenteral routes. E: More frequent monitoring for adverse drug effects. Answer: A. and E. Feedback: The liver is the primary site of drug metabolism. Patients with severe liver damage, such as that caused by cirrhosis, will require reductions in drug dosage because of the decreased metabolic activity. Even with decreased dosage, more frequent monitoring is required to detect adverse drug effects that may be related to impaired metabolism.

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Question 2 Question: A patient who is in renal failure may have a diminished capacity to excrete medications. The nurse must assess the patient more frequently for what development? A: Increased risk of allergy. B: Increased absorption of the drug from the intestines. C: Increased risk for drug toxicity. D: Decreased therapeutic drug effects. Answer: C. Feedback: Correct. The kidneys are the primary site of excretion. Renal failure increases the duration of the drug’s action because of decreased excretion. The patient must be assessed for drug toxicity.

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Question 3 Question: A patient is given a prescription for azithromycin [Zithromax] and asks the nurse why the dose on the first day is twice the amount of the dose on the next 4 days. Which reply by the nurse is correct? A: A large initial dose helps to get the drug to optimal levels in the body faster. B: The first dose is larger to minimize the first-pass effect of the liver. C: The four smaller doses help the body taper the amount of drug more gradually. D: Tubular reabsorption is faster with initial doses, so more is needed at first. Answer: A. Feedback: Correct, the initial dose helps to increase the serum drug level into therapeutic range more quickly.

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Question 4 Question: The nurse looks up butorphanol [Stadol] in a drug reference guide prior to administering the drug and notes that it is a partial agonist. What does this term tell the nurse about the drug? A: It is a drug that produces the same type of response as the endogenous substance. B: It is a drug that will occupy a receptor and prevent the endogenous chemical from acting. C: It is a drug that causes unpredictable and unexplained drug reactions. D: It is a drug that produces a similar, but weaker, action than the endogenous substance. Answer: D. Feedback: None.