Chapter 3 Pharmacokinetics: How the Body Acts on Psychotropic Medications PDF

C H A P T E R T H R E E Pharmacokinetics: How the Body Acts on Psychotropic Medications Pharmacokinetics is what your body does with a drug SECTION ONE: DRUG ABSORPTION once you ingest...

C H A P T E R T H R E E Pharmacokinetics: How the Body Acts on Psychotropic Medications Pharmacokinetics is what your body does with a drug SECTION ONE: DRUG ABSORPTION once you ingest it. Pharmacokinetics are the processes by which drugs are absorbed by the body, distributed within the body, and then metabolized, and excreted Learning Objectives (Carlson, 2012). Obviously, to be effective a drug Be able to describe the various routes of drug must reach its intended site of action. For psychotro- administration. pic drugs, this intended site is the central nervous sys- Understand why some methods of administration may tem, so the primary barrier that a drug must somehow be optimal for particular clients. get across is the blood–brain barrier. Pharmacokinetics Understand the concept of Lipophilicity. also involves understanding the time course of a drug’s effects (the intensity of the drug effect on the body across time). Understanding how a drug moves How a drug gets into the bloodstream and is dis- through the body and the length of time it takes to tributed throughout the body is referred to as drug exert therapeutic effects can help clinicians understand absorption. In psychopharmacology, the primary what the client can and cannot expect from the drug. aim is for drugs to get across the blood–brain barrier It is also important to understand that there is more and into the central nervous system, the brain spe- than the drug involved in pharmacokinetics. For cifically. How do we determine how fast a drug example, most of us know that grapefruit juice inter- gets to the brain? How do we know how much feres with a large number of drugs making them less of the drug ingested reaches the brain? The answers effective if they are taken around the same time as the to these questions depend on multiple variables grapefruit juice (Kiani & Imam, 2007; Marchetti & (Ettinger, 2011). Some of the answers are found Schellens, 2007). by examining routes of administration. This chapter is divided into five sections. Section One discusses how drugs are absorbed into the Routes of Administration body and the various routes of administration. Sec- What is the first thing you must do with a drug for tion Two covers what happens when drug mole- it to have its desired effect? Take it, of course. cules get to the bloodstream. In Section Three, we There are several ways you can do this that we discuss drug distribution and important concepts call routes of administration, although not all are like half-life and maintenance dose. In Section commonly used for administering psychotropic Four, we introduce drug binding and the various medications. The most common route is oral. For types of drug tolerance that one may develop. a drug to be taken orally, the drug must be capable Finally in Section Five, we give an overview of of being dissolved (soluble) and must retain its how drugs are eliminated from the body. integrity in the stomach fluids. This is one reason 42 Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER THREE Pharmacokinetics: How the Body Acts on Psychotropic Medications 43 there are no psychopharmacologically effective nic- route with different rates of absorption based on the otine products one swallows. Nicotine cannot body type, age, sex of the client and of course withstand stomach fluids and breaks down before gastrointestinal side effects. it can get to the central nervous system to exert The fat solubility of the drug molecule also plays a its effects. So if you hear of an energy drink adver- role. Lipophilicity (think: “liposuction”) refers to tising nicotine for the “extra jolt,” save your the fat solubility of a compound. Because the walls money. The closest to an oral administration one of the intestines, blood vessels, and neurons are com- can get with nicotine is through gum, dissolving posed of fats called lipids. The more fat soluble a tabs or mouth spray (Bolliger, van Biljon, & Axels- drug is, the more easily it crosses these barriers. Some son, 2007). The speed with which a substance drugs, such as lithium, are not at all fat soluble (lipo- moves from the site of administration to the blood- philicitous) and must attach to another molecule and stream is called absorption and this rate varies be carried across the barriers. depending on the route of administration. Follow- ing are summaries of the more common routes of Inhalation administration some of which will not be as rele- Inhalation is a predictable and direct route of admin- vant to psychopharmacology but which we include istration with many applications. Inhalation is a fast here for the sake of thoroughness.1 and efficient delivery system because the lungs (part of the pulmonary system) constitute a large surface Oral Administration for absorption that is rich with capillaries that send The most common route of drug administration for substances directly to the brain without going psychotropic medications is oral administration. through the heart first (Meyer & Quenzer, 2005). Drugs taken orally can be in the form of tablets, cap- Recreational drug users such as cigarette smokers sules, liquid, and other types of pills. Some of the learn early on how efficient and rewarding this deliv- delivery systems are designed to be time-released ery system can be. Although we know of no psycho- (such as capsules for time-released methylphenidate/ tropic compounds taken by inhaler (other than Concerta/Focalin). These drugs have to dissolve in experimental nicotine mouth sprays), cannabis stomach fluid and pass through the walls of the diges- (which has psychotropic properties) inhalers have tive tract to reach capillaries. Then the molecules been examined by the United Kingdom and Canada enter the bloodstream and will eventually cross the for administration of medical marijuana through blood–brain barrier. Obviously the drug must also be vaporization. Vaporizers like the “Volcano” seem to able to withstand stomach acids and other substances be able to deliver cannabis with fewer harmful toxins that break down food. Many drugs are not fully like carbon monoxide, benzene, and other known absorbed until they reach the small intestine. How carcinogens (Frood, 2007a). At the time of this writ- quickly the contents of the stomach move into the ing, the states of Washington and Colorado decrimi- small intestine depends on whether food is fatty (fatty nalized marijuana although federal laws still prohibit foods slow movement), the amount of food in the its use. Time will tell if this drug will make its way system, the amount of physical activity the person into the licit psychotropic substances (Frood, 2007b). engages in all make it difficult to predict how long it will take for an orally administered drug to reach its Injection intended site of action (Meyer & Quenzer, 2005). There are several types of injection: Subcutaneous, Advantages of oral administration include safety and intramuscular, intravenous, and epidural. Subcuta- ease-of-use. Disadvantages include being a slower neous is an injection just below the skin. The absorption depends on the rate of blood flow to 1 the area of injection but the absorption rate is usu- Some less common methods include intracranial (into the brain) and intra- peritoneal (into the cavity surrounding the abdominal organs) which are not ally slow and prolonged. Drugs that are injected used for psychotropic medications. subcutaneously include hormones, birth control Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 44 PART ONE An Overview of the New Edition drugs, and drugs for migraine headaches like Suma- of no rectally administered psychotropic medica- triptan/Imitrex. Intramuscular injections are slow tions. Although this route of administration would acting but produce more even absorption. Depend- be faster acting than oral, the disadvantages are obvi- ing on the injection site and the blood flow to that ous to most people. area absorption usually occurs within an hour. Drugs can be mixed with substances (e.g., oils) Mucus Membrane (transmucosal) Administration that can slow the absorption. Many antipsychotics Drugs can be administered via the mucus mem- are now administered intramuscularly because dis- branes (mouth or nose), which result in fairly direct orders such as Schizophrenia frequently disrupt absorption into the bloodstream. Drugs commonly cognitive functions and interfere with routines administered this way include nicotine (gum), and remembering to take medications. Intravenous decongestants, and nitroglycerine for cardiac injections are directly into the bloodstream and are patients (Advocat, Comaty, & Julien 2014). This the most rapid and precise ways to administer a can be advantageous for clients like children who drug (Ettinger, 2011). In this method, the drug have trouble swallowing pills. does not pass through the lungs or digestive system. The downside to intravenous administration is that complications can prove lethal because the drug is Review Questions getting into the system so quickly and directly. Epi- Explain three routes of drug administration and dural injections are used primarily for spinal anes- some advantages and disadvantages of each. thetics. In these cases, the drugs are administered What route of administration would be directly into the cerebrospinal fluid surrounding good for a client who suffers from cognitive the spinal cord bypassing the blood–brain barrier. symptoms and why? The most common use of these is for facilitating analgesia in childbirth but no psychotropic medica- Why is it important that psychotropic tions are administered in this manner. medications be highly fat soluble? Transdermal Administration Transdermal administration is done through a “patch” technology where the drug to be administered is on a SECTION TWO: GETTING TO patch that is then attached via adhesive to the skin. THE BLOODSTREAM Because the skin is resistant to water passing through but allows fat soluble molecules through this can be a useful formulation. Nicotine patches, opioids for pain, Learning Objectives and contraceptives are all examples of drugs that Understand what a protein transporter is and the role may be administered this way. Recently, (Azzaro, it could play in medications getting to their intended Ziemniak, Kemper, Campbell, & VanDenBerg, site of action. 2007) the antidepressant selegiline (an MAO inhibi- Be able to describe the process of drug diffusion. tor) was approved in a transdermal formulation. Be able to describe the blood–brain barrier, its func- Although transdermal administration is a way to get tion and how drugs pass through it. controlled rates of absorption, it can cause skin irritation in some clients. Cell Membrane Permeability Rectal Administration Once administered, a drug must pass through mul- Rectal administration is less efficient than oral or tiple membranes to reach the site of action which inhaler administrations but can be useful for patients for psychotropic medications is the brain. The route who have digestive tract difficulties. Again, we know of administration will determine which membranes Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER THREE Pharmacokinetics: How the Body Acts on Psychotropic Medications 45 the drug must pass through. Regardless of the route brain requires more protection from foreign sub- of administration, the cells lining the stomach, stances than other organs so the capillary walls do lungs, and the cells making up skin, muscle, and not have gaps. The gaps are surrounded by a type of fat cells are composed of a phospholipid biolayer glial cell called an astrocyte. These make up the (two layers of lipid molecules that form a polar blood–brain barrier. Over 100 years ago, Paul membrane). Phospholipids are the major compo- Ehrlich discovered that if blue dye is injected into nents of cell membranes (so named because they an animal’s bloodstream (in his case a rabbit’s contain an organic molecule from the phosphate bloodstream), all the tissues are tinted blue except group). Remember that lipids are molecules includ- the brain. You must inject the dye into the brain ing fats and it is fats that we are interested in here. ventricles to get that tissue to turn blue. Although As written above, the drug molecules must be fat- Ehrlich was working for a dye company on a dif- soluble enough to pass through these membranes. ferent project, he thus unwittingly discovered the The head of a phospholipid is positively charged blood–brain barrier. This barrier blocks many sub- and the tail negatively charged (thus “polar” mem- stances from entering the central nervous system. In brane). Although the head attracts water, the tails some areas, the barrier is weaker than others, to repel water and prevent water-soluble elements allow specific functions that have developed from getting through. Embedded in these phospho- through evolution. One example of such an area lipid molecules are proteins that act as transporters. is the area postrema, which signals vomiting. The For something to pass through the cell membrane, barrier is weak here, so toxins in the blood can be they must be carried through by the transporter or detected. Once it detects toxins, the brain triggers be fat soluble, which, as stated, most psychotropic the vomiting response to preserve the organism. medications are (Ettinger, 2011). The blood–brain barrier serves an important sur- Drugs must also pass in and out of capillaries vival function by keeping foreign elements such as which are a route into the bloodstream. They are toxins out of the brain. But what about things such made of a single layer of cells that, though tightly as nutrients? Nutrients such as glucose must be packed, have gaps in them. Drug molecules transported through the capillary walls by special can move through these gaps in a process called proteins. This is very important, because to exert diffusion. This is how organisms exchange food, their effects all current psychotropic medications waste, gasses, and heat with their surroundings. The must reach the central nervous system. To do so, rate of diffusion is represented by Fick’s law, which they must pass through the blood–brain barrier. states that diffusive flux goes from regions of high The glial cells that make up the blood–brain barrier concentration to regions of low concentration. This have a high fat content. The myelination of the is affected by the thickness of the membrane brain in infancy is one reason babies need a lot of through which molecules are diffusing, the surface fat in their diet. area for gas exchange, and the mass and fat solubil- Drugs will also cross the placental barrier. The ity of the molecule. Movement across membranes is placental barrier allows nutrients and oxygen from in the direction from higher to lower concentra- the mother’s blood to cross into the baby’s blood. tions. The larger the concentration gradient (the Mothers taking medications are also passing some of difference between levels of the molecule between those medications on to the baby. The evidence on the two sides of the membrane) the more rapid the psychotropic medications used during breast- diffusion. Drugs that are lipid soluble move through feeding is at the time of this writing limited for cell membranes via passive diffusion, which leaves most drugs but particularly antipsychotics, hypno- the water in the blood or stomach and moves into tics, and anxiolytics. Because we cannot formulate the membrane (Meyer & Quenzer, 2005). any generalizations about the use of these medica- As noted in Chapter Two, psychotropic medica- tions due to the dearth of data there is inherent risk tions must also cross the blood–brain barrier. The for breast-feeding mothers who choose to use Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 46 PART ONE An Overview of the New Edition psychotropics. Fortinguerra, Clavenna, and Bonati nausea by their effects on the serotonin receptors in (2014) analyzed 183 peer-reviewed papers that the digestive tract. studied 62 psychotropic drugs. Of these only 30% Your entire blood volume circulates through were thought to be safe during lactation according your body approximately once per minute. Usually to an evidence-based approach. Genung (2013) within this minute the drug taken is distributed concluded that “medications have the same, though throughout the bloodstream. The route of admin- exaggerated, targets and side effects on infants as on istration will affect how much of the drug actually adults. Therefore, each prescribed medication must makes it into the bloodstream. For example, after be researched individually. Even small amounts of oral administration the drug is reduced by enzymes medications can accumulate to toxic amounts in in the digestive tract. Then veins leading away from breastfed infants” (p. 217). the digestive tract flow through the liver further metabolizing part of the drug. This is called first- pass metabolism and may require that more of Review Questions the drug be administered than if it were given intra- What is the role of transporters in drugs venously (Advokat et al., 2014). getting to the brain? A drug’s half-life tells us how long it stays in the body. The half-life is what the words sound like— What is the process of drug diffusion? the length of time it takes for the blood level of a Describe the blood–brain barrier, its function, drug to fall by half. So at one half-life, 50% of the what it is made of, and how it affects initial dose is out of the bloodstream (much of it psychotropic medications. redistributed to the tissues of the body). At two half-lives, 75% of the initial dose is out of the blood- stream. At three half-lives, 87.5% of the drug is out SECTION THREE: DRUG DISTRIBUTION of the bloodstream. So for each half-life, half of the drug remaining is redistributed out of the blood- stream. Advokat et al. (2014) estimate that the Learning Objectives drug persists at low levels for at least six half-life Be able to describe the concepts of half-life and cycles. Even though a drug half-life can be estimated steady state. it can vary person to person. Elderly people are Understand what the cytochrome P450 enzyme sys- going to take longer to metabolize a drug than a tem is and why it is important for drug metabolism. young person in their 20s. Half-life only applies to Be able to describe what titration and a maintenance blood plasma levels, not the presence of the drug in dose are. other places like the central nervous system. Half-life is also used to gauge what is called the steady state of the drug in the patient’s body. This is Once a drug is absorbed into the bloodstream it is roughly the amount of the drug in the patient’s distributed through the body in the circulating blood with regular dosing. The goal is to match a blood. In many cases most of the drug will not particular level of the drug with therapeutic results reach the intended site (in the case of psychotropic and then match dosing to achieve that level. This medications the receptors in the brain) but is active latter then becomes the maintenance dose, the dose in other parts of the body. Advokat, Comaty, and needed to maintain levels of the drug linked to Julien (2014) note that most of any dose of a psy- therapeutic response. The process of arriving at an choactive drug is circulating outside the brain and is optimal maintenance dose is called titration. When not contributing directly to the pharmacological a doctor increases or decreases the amount of the effects. This widespread distribution may contribute drug to maximize therapeutic response we say she is to side effects, for example, antidepressants causing titrating the dose up or down. Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER THREE Pharmacokinetics: How the Body Acts on Psychotropic Medications 47 TABLE 3.1 Five Important Pharmacokinetic Terms Half-life Amount of time required for plasma concentration of a drug to decrease by 50% after a person stops taking it. Steady state The state when the concentrations of a drug in a person’s bloodstream reach a plateau so that the amount being taken in each dose is roughly equivalent to the amount being eliminated. Loading dose An initial dose of drug that is higher than subsequent doses, given for the purpose of achieving therapeutic levels rapidly. Maintenance The regular dose of the medication that maintains the steady-state plasma concentration dose in the therapeutic range. Titration The art and science of balancing a drug dose against the patient’s symptoms. Upward titration is gradually increasing the dose, and downward titration is gradually decreasing the dose. © Cengage Learning® Whenever you put a drug into your system, your important in understanding how long it takes a body begins metabolizing it and trying to get rid of it. drug to clear out of a person’s system. This concept Drugs leave the body through the urine, perspiration, is helpful in explaining to clients why they are still and exhalation. The hepatic system (liver) is one of the experiencing side effects days after discontinuing main metabolizers of drugs. Enzymes break down the medication. drugs and the most common enzyme family is the Cytochrome P450 enzyme system about which more will be said later. The liver enzymes turn the Review Questions drug into less active or inactive water soluble metabo- What is the relationship between a drug half- lites that are then sent to the renal system and filtered life and a steady state of the same drug? out by the kidneys. There are some terms related to drug metabolism that are helpful to know. The first is Describe the function of the cytochrome P450 elimination half-life. The drug’s half-life is the enzyme system and its affects on psychotropic amount of time it takes for half of the drug’s initial medications. blood level to decrease by half or 50%. A drug’s half- What is meant by a maintenance dose? life may range from hours to days. The prescribing doctor’s goal is to prescribe a dose of the drug that, based on the half-life, will result in a steady blood SECTION FOUR: DRUG BINDING AND level of the drug sometimes called steady state. Table 3.1 defines concepts related to pharmaco- TYPES OF TOLERANCE kinetics: half-life, steady state, loading dose, mainte- nance dose, and titration. These terms are frequently Learning Objectives used in medical practice and may be confusing to the layperson. Clients often ask questions about Be able to recite the primary flaws in the theory that mental disorders were caused by a chemical imbal- these terms. One client mistakenly thought he ance in the brain. could stop taking medication after the loading Understand depot binding and the effects on the dose because he interpreted “loading” in a manner plasma levels of medications. akin to computer software—once loaded, no fur- Be able to describe the types of drug tolerance. ther loading needed. The half-life is particularly Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 48 PART ONE An Overview of the New Edition Once in the blood plasma, drugs then are redistrib- important to note that drugs may also bind at sites uted to various tissues including the central nervous where there appear to be no measurable effects. system (a process labeled redistribution). The mole- These sites are called drug depots and they include cules then bind to particular target sites. In the case plasma protein, fat and muscle. Depot binding does of psychopharmacology, these sites have typically effect drug action in that it decreases the concentra- been neurotransmitter receptor sites. As we will tion of the drug at sites of action because only freely illustrate throughout this book, in the 20th century circulating drugs can pass across membranes. Also it was long believed (and the belief was perpetuated because these molecules will eventually unbind and by billions of dollars in advertising and planned re-enter bloodstream it can lead to higher- publications from pharmaceutical companies) that than-expected plasma levels and in some cases mental disorders were caused by a chemical imbal- drug overdose (Meyer & Quenzer, 2005). ance in the brain. We now have enough evidence to know that, in fact, is not the case and the idea has been Types of Tolerance falsified. The fact that a chemical intervention alle- It is important to generally understand the types of viates or decreases symptoms in no way means the tolerance clients can develop to drugs. Please note chemicals affected by the intervention were imbal- that in this book we avoid using the word anced to begin with anymore than if someone feels “addiction.” The emotional hysteria around this better after smoking marijuana it means they have a word, and the lack of operational definitions, cannabinoid imbalance. make it too inexact to be helpful. Physical depen- In the past few years, pharmaceutical companies dence is linked with the term addiction and implies are closing their neuroscience research facilities that withdrawal signs are “bad” and only linked to (Greenberg, 2013). In part this has been because drugs of abuse. This is far from the truth because despite the belief that psychotropic medications cor- severe withdrawal signs can follow cessation of such rected a chemical imbalance, the success rate of therapeutic drugs such as SSRI antidepressants. many of these drugs is modest at best. [For example, Instead, we discuss types of tolerance and depen- meta-analyses suggest antidepressants are only better dence. Advokat et al. (2014) define tolerance as the than placebo 50% of the time (Khan, Leventahl, state of reduced responsiveness to the same dose of a Khan, & Brown, 2002).] Another problem has drug. This can be produced by a variety of mechan- been a steep increase in the number of lawsuits isms, all of which result in the person needing and amounts in settlements where companies increased doses of the drug to achieve the effects were fined for questionable practices linked to psy- previously provided by lower doses. Dependence chotropic medications. In 2012 alone, companies is defined as a physical tolerance produced by paid over $5 billion in fines related to allegations repeated administration of a drug and a concomitant of fraud including misleading claims about drug withdrawal syndrome when the drug is discontin- safety (Associated Press, 2009; Isaacs, 2013). That ued. Julien outlines three primary types of tolerance: said, it remains to be seen how much new research metabolic, cellular, and behavioral conditioning will be done on pharmacological interventions processes. because we know that mental and emotional dis- Metabolic tolerance is an increase in the orders are more complex than brain chemistry. enzymes that metabolize a drug, an increase caused Certainly current medications that target receptors by the presence of that or similarly acting drug. The sites will be used for symptom control so under- most common enzyme system for metabolizing standing binding is still important. Until we can drugs is the cytochrome P450 enzyme family. understand the etiology of mental disorders, symp- These enzymes, produced in the liver, have evolved tom control may be the best we can do. over 3.5 billion years to accomplish the detoxifica- Although we know from Chapter Two that tion (metabolism) of ingested elements such as che- drugs bind to receptors to cause main effects, it is micals and food toxins. There are several families of Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER THREE Pharmacokinetics: How the Body Acts on Psychotropic Medications 49 these enzymes, some more specific to certain sub- case is that contextual cues associated with drug stances than others. Thus, metabolic tolerance onset act as conditioned stimuli that can bring begins when you take a drug that is broken down about tolerance (Ettinger, 2011). This is one reason by any one of these families. If you take the drug that if someone addicted to drugs returns to the consistently, your body responds by elevating the same context they may have a higher chance of level of enzymes needed to break the substance relapse. Finally, behavioral tolerance is similar to down. The elevated enzyme level breaks down state-dependent learning. When animals are given the drug more efficiently, leading to the need for intoxicating doses of alcohol before a learning task, a larger dosage; thus the cycle begins. The drug, the they subsequently tend to perform that particular task amount taken, and the individual body’s response better when under the influence of alcohol than to it, all determine the pattern of metabolic toler- when sober. This is behavioral tolerance. ance. This pattern does not inevitably spiral out of control to the point where the drug cannot be used. For example, many people take benzodiazepines Review Questions such as Valium or Xanax on an “as needed” Why did people believe mental disorders were (p.r.n., from the Latin pro re nata, meaning “as caused by chemical imbalances in the brain needed”) basis. Such a person may only take 0.25 and what is the main weakness in that idea? mg of Xanax once or twice a week. Such a low What is depot binding? dose is unlikely to produce any problems with met- abolic tolerance. This raises another important List and describe the different types of drug point, though, namely that similar drugs can pro- tolerance. duce cross-tolerance. For example, if the same person who took one dose of alprazolam (brand name Xanax) once or twice a week was in the SECTION FIVE: ELIMINATION habit of drinking two to three alcoholic beverages OF DRUGS each day, probably he or she would not get as much response from the Xanax as someone who only drank two to three alcoholic beverages per week. Learning Objectives The person drinking alcohol daily has likely devel- Understand the role and relationship between the oped some metabolic tolerance to it, and the fami- kidneys and liver in drug metabolism. lies of enzymes that break down alcohol are also Understand the promise and obstacles of involved in breaking down Xanax, thus diminish- pharmacogenetics. ing the effect of the latter. For the record, anyone taking a benzodiazepine such as Xanax or Valium should not drink alcohol. The phrase “termination of drug action” refers pri- Cellular tolerance, which is more related to marily to the routes through which a drug leaves pharmacodynamics, occurs when receptors in the the body. These include bile (the fluid produced by brain adapt to the continued presence of a drug. the liver), the kidneys, lungs, and the skin. The Two common forms of cellular adaptation are down- majority of drugs are excreted by the kidneys and regulation and upregulation. In downregulation, thus have to be transformed into more water solu- neurons decrease the number and/or sensitivity of ble compounds (remember that psychotropic drugs receptors because of the presence of a drug. In upre- typically begin as fat-soluble agents). In most cases, gulation, neurons increase the number of receptors. these transformations make the drugs less active as Another type of tolerance is associative tolerance. well. In this section, we will discuss the role of the This is where one would display tolerance to a drug kidneys and liver in drug elimination as well as in some but not all settings. What seems to be the other factors that may affect elimination. Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 50 PART ONE An Overview of the New Edition The Renal System environment that find their way into our system. The renal or urinary system consists of two kidneys, The P450 enzyme family is frequently mentioned ureters (tubes that propel urine from the kidneys to in package inserts and other information about drugs the bladder), bladder, and urethra, which connects citing the effects of the drug on the P450 system. the bladder to the genitals for removal of urine. Like the brain kidneys are amazing organs. They con- Other Factors Affecting Pharmacokinetics stitute about 1% of our body weight and (similar to We have learned a great deal in the late 20th and early the brain) receive about 20% of the blood supplied by 21st centuries about variables that can affect a drug’s each heart beat. The kidneys excrete the majority of effects on the body. There are genes that can affect body metabolism products using functional units pharmacokinetics and the study of such factors is com- called nephrons, which number anywhere between ing to be called pharmacogenetics (Perlis, 2007). One 800,000 and 1.5 million. Nephrons consist of a example is a gene labeled ABCB1 that is responsible “knot” of capillaries. Our blood enters these capillar- for a protein (P-Glycoprotein) that regulates absorp- ies from the renal artery. Nephrons maintain concen- tion and elimination of many psychotropic (and other) trations of water in the blood; regulate blood volume, drugs. Variations of this gene can act as predictors of blood pressure, and the blood’s acidity (ph); and pro- treatment outcome as well as the effects of polyphar- cess secretion and reabsorption of things like ions, macy (Akamine, Yasui-Furukori, Ieiri, & Uno, carbohydrates, and amino acids. The fluids filtered 2012). Advokat et al. (2014) wrote that as genetic out of the capillaries are held in a chamber called testing becomes more common and affordable, testing “Bowman’s Capsule” from which they collect in will be accessible to determine how a person metabo- ducts and are passed into the bladder. Drugs that are lizes certain drugs anywhere on a continuum from fat soluble (lipophilicitous) can easily cross the mem- slow to fast. It should be noted that substantial ethical branes of the renal system. Because most psychotropic and financial obstacles must be dealt with before this is drugs have to be fat soluble to cross the blood–brain going to be a widespread practice (Morley & Hall, barrier, they are readily reabsorbed from the renal 2004; Mutsatsa & Currid, 2013). system and back into the bloodstream making the Another field that has grown in the 21st century kidneys only one system through which psychotropic is ethnopharmacotherapy (now more frequently medications exit the body. referred to as ethnopsychopharmacology) that explores differences in the way different groups The Liver and Drug Metabolism are affected by medications. Although we each Because the kidneys do not totally break down psy- share over 99% of our genes with all other humans, chotropic medications, another system is necessary to small differences linked to race and ethnicity may effect their elimination from the body. The liver pro- play roles in how particular people respond to a vides many functions including protein synthesis, pro- medication. For example, studies have supported duction of enzymes for digestion and detoxification. the idea that pharmacokinetics may vary in people The main tissue of the liver is made of hepatocytes of Asian descent resulting in different dosing and it is these that pick up reabsorbed psychotropic requirements and side-effect profiles (Wong, medications and transform them with enzymes that 2012). A similar area is the growing discipline of make them less fat soluble and more likely to be developmental pharmacology. One of the great excreted in the urine. There are several enzyme sys- gaps of knowledge in psychotropic medication use tems or families in the liver but the most referenced in is the long-term effects of medications in pediatric regard to pharmacokinetics is the cytochrome P450 populations. The Clinton administration passed one enzyme system. According to Advokat et al. (2014), of the first bills to offer incentives to companies for the genes involved in the development of this system running more trials with children and adolescents originated over 3 billion years ago for the purpose but our knowledge is still far from complete. of metabolizing and detoxifying elements from the Currently, we know that there are significant Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER THREE Pharmacokinetics: How the Body Acts on Psychotropic Medications 51 developmental differences in changes in drug A 53-year-old female is on a regimen of lithium absorption, distribution, metabolism, and elimina- (mood stabilizer) and an atypical antipsychotic, Ser- tion. There are also developmental differences in oquel, for Bipolar I Disorder. For six months, she the development of enzymes to break down drugs was stable and asymptomatic. Although she had sig- (van den Anker, 2010). At the other end of the nificant side effects including weight gain and seda- developmental spectrum we need more data on tion, she resolved to stay on the medications as long how psychotropic medications affect elderly clients. as they reduced her symptoms. Unexpectedly, she The same issues that are relevant in pediatric popu- developed confusion, tremor and agitation. When lations arise at the other end of the lifespan spec- her lithium level was measured, it showed a toxic trum. Concerns about impaired absorption, factors concentration level of 2.4. When the patient’s slowing distribution and variables interfering with medication regimen was analyzed, it turned out metabolism are all important aspects of what is that one week before the confusion she started tak- coming to be called geriatric psychopharmacology ing over the counter Tylenol 650 mg three times a (Grossberg, 2010; Howland, 2009b). day. She did not inform her counselor or the pre- scribing physician of the over-the-counter use of Tylenol. According to the physician, the Tylenol Review Questions was reducing urinary clearance of lithium raising lithium plasma levels leading to toxicity. Although What is the relationship between the liver and she had been warned not to use over-the-counter the kidneys in metabolizing and excreting medications without her doctor’s approval, her drugs? symptoms and mental functioning are such that What is pharmacogenetics? What are some of she claims (and we believed her) that she forgot the promises and obstacles of this new field? about the warning. Questions About the Case CASE 1. Does this case represent an example of pharmacokinetics? Why? Learning Objectives 2. In your own words try to describe what Apply an understanding of pharmacokinetics to the happened to this patient/client once she case of a person. began taking the Tylenol? Understand how changes in the body or inputs to the 3. How could a nonmedical mental health pro- body can impact how the body handles the medication. fessional assist this client with remembering restrictions related to her medication? Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.