online continuing education for nursesthe fda was started in 1906 after the passage of the pure food...

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COURSE OBJECTIVES

Upon successful completion of this course, participants will be able to:

• Differentiate between CSA drug schedules and pregnancy categories.

• List potential drug actions and identify receptors.

• Explain the four properties of pharmacokinetics.

• Discuss drug selection and the influence of patient factors.

• Identify best practices for prescribing in certain populations.

• Consider professional issues such as drug cost and the basics of Medicare.

• Recognize risk factors for adverse drug events and list ways to avoid prescription errors.

INSIDE THIS COURSE

DRUG DEVELOPMENT ................. 2 DRUG CLASSIFICATIONS ............. 3 OTC DRUGS .............................. 4 PREGNANCY CATEGORIES .......... 5 CELL ANATOMY ......................... 5 RECEPTORS .............................. 6 DRUG RESPONSES ..................... 8 PHARMACOKINETICS .................. 9 ADVERSE DRUG REACTIONS ..... 12 RATIONAL DRUG SELECTION .... 14 PATIENT FACTORS ................... 16 CULTURE & ETHNICITY ............. 17 PHARMACOGENOMICS .............. 18 PRESCRIBING TO CHILDREN ...... 19 DRUG DOSE CALCULATIONS ..... 21 PREGNANCY & LACTATION ....... 22 PRESCRIBING IN GERIATRICS .... 23 COST OF MEDICATION .............. 24 AVOIDING ERRORS ................... 25 SUMMARY & REFERENCES ....... 28 CE EXAM ................................. 31 EVALUATION ............................ 39 REGISTRATION FORM ............... 42

PHARMACOLOGY FOR THE NURSE

PRACTITIONER 8.5 Contact Hours

Written by: Heather Briere, MS, FNP-BC, CCM

You start your day as a Nurse Practitioner. Right away, your first patient reports a problem that you can see is going to need a prescription drug as part of the treatment plan. Your second patient reports a problem that you know is a common side effect of an over the counter drug that was taken incorrectly. Your third patient has a list of drug refills that are being requested. This is all before your second cup of coffee. How did you get here?

Prescribing drugs is integral to the job and life of a Nurse Practitioner. Drugs are one of the many tools in our toolbox that we can use to help our patients feel better, and the expectation of being prescribed a drug is one of the main reasons that drives a patient to come to see us. Fully understanding drug actions and interactions will allow us as Nurse Practitioners to be able to treat patients in a much more complete and competent manner.

This educational activity will review the very basics of pharmacology - everything from the very definition of a drug, through drug development, pharmacokinetics and pharmacodynamics, and adverse reactions. It will get you on your way to prescribing - or will remind you of the basics - but will not actually discuss any drugs in particular. It is intended as a review for someone who has already taken a graduate level pharmacology course. It will review all of the material from the beginning and will go into some of the more complicated concepts in depth. However, please remember that every learner is at a different comfort level, so all topics are approached as if you have not seen them previously, with some extra time being devoted to more important concepts.

Online Continuing Education for Nurses Linking Learning to Performance

https://www.corexcel.com/

https://www.corexcel.com/courses/nursing/pharmacology.htm


Pharmacology

DEFINITION OF A DRUG

A drug is any chemical substance that produces a measurable biologic response. It is that simple. This definition covers anything from caffeine, which most people would not consider a drug, to anything that you can prescribe, to anything that can be bought on the street. If you can put the chemical in your body and it produces a biological response, then it is a drug. It is important to mention that in pharmacology we don’t call something that you would prescribe a medication, we call it a drug. Therefore, you will see the term “drug” throughout this article, not the word “medication.”

DRUG DEVELOPMENT

Drug development in the United States is managed by the Food and Drug Administration (FDA). The FDA is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, cosmetics, and any products that emit radiation. The FDA also protects our nation’s food supply. Since this is an article about pharmacology, we will only further discuss the information that refers to drugs. If you are interested, you can find out much more about what the FDA does at https://www.fda.gov/AboutFDA/WhatWeDo/History/FOrgsHistory/default.htm.

The FDA was started in 1906 after the passage of the Pure Food and Drugs Act by President Theodore Roosevelt. The FDA was significantly strengthened after a major public outcry in the late 1950s and early 1960s when the drug thalidomide was approved for over the counter use in pregnant women in Germany, but was never approved in the United States. Thalidomide, unfortunately, caused many horrific birth defects, including causing multiple children to be born without limbs. The fact that this was not approved for use in the USA rallied the American people to the value of the FDA and strengthened their political power.

The FDA now holds jurisdiction over a number of different processes including standardization of nomenclature of drugs, the approval process for new drugs, the approval process for indications for drugs, the official labeling for drugs, surveillance of adverse drug events, and methods of manufacture and distribution of drugs.

When a new drug is coming to market, it goes through several phases. The first of these phases is the Preclinical Phase. This Preclinical Phase includes the studies that are the very beginning of drug development and lasts from the time that a cellular target is identified by chemists through the time that a suitable drug compound is pinpointed and then tested on cells, tissues, organs, and in lab animals.

After the Preclinical Phase are the Clinical Phases. These seek to establish the safety and efficacy of drugs in humans. Phase I studies assess the basic safety of the drug and establish how the drug moves about in the body. During phase I studies, a basic safe dose of the drug is established. Phase II studies test the efficacy of a drug. Phase II studies seek to be sure that the drug does what scientists think it is going to do. Phase III studies provide a more thorough understanding of the effectiveness of the drug, and often compare the new treatment that is being tested with the current standard treatment to see which one is better. Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug has been approved for sale. Many things are uncovered during this initial time of consumer use as the drug is now released for general use.


Pharmacology

Amazingly, only one in five thousand drugs make it from pre-clinical trials to the pharmacy shelves. This represents hundreds of thousands of lost research hours, and millions of dollars.

The goal for an ideal drug would be one that has a convenient route of administration, an established dosage, a predictable onset of action, a single desired biological action, no unwanted effects, and a convenient duration of action. This ideal drug would improve quality of life and prolong patient survival.

TYPES OF DRUG CLASSIFICATIONS

Drugs can be categorized in various ways. In this next section we will discuss two common drug categories; those based on Drug Schedules and drugs based on Pregnancy Categories.

DRUG SCHEDULES

There are a number of drugs that are considered controlled substances that are grouped into five schedules under the Controlled Substances Act (CSA). A drug that is considered a controlled substance is one that has a much higher risk of causing dependence. Drugs are placed into each category based on their abuse potential, their likelihood of causing this dependence, and whether or not they have currently accepted medical use in treatment. A complete list of the schedules is published annually in Title 21 Code of Federal Regulations (C.F.R.) §§ 1308.11 through 1308.15 which you can find at https://www.deadiversion.usdoj.gov/21cfr/cfr/2108cfrt.htm.

Schedule I Controlled Substances have no currently accepted medical use in the United States and a high potential for abuse. Some examples of substances listed in Schedule I are heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), peyote, methaqualone, and 3,4-methylenedioxymethamphetamine (Ecstasy). The discussion of why marijuana is federally listed as a Schedule I drug while it is now legalized in many states is beyond the scope of this article.

Schedule II/IIN Controlled Substances (the “N” stands for narcotics) have a high potential for abuse which may lead to severe psychological or physical dependence, but have less of a potential for abuse than the drugs in Schedule I, and have a medically accepted use. Drugs in this class cannot be refilled and can be only filled for 30 days at a time. Examples of Schedule II narcotics include hydromorphone (Dilaudid®), methadone (Dolophine®), meperidine (Demerol®), oxycodone (OxyContin®, Percocet®), and fentanyl (Sublimaze®, Duragesic®). Other Schedule II narcotics include morphine, opium, codeine, and hydrocodone. Examples of Schedule IIN stimulants include: amphetamine (Dexedrine®, Adderall®), methamphetamine (Desoxyn®), and methylphenidate (Ritalin®).

Schedule III/IIIN Controlled Substances have a potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence. Examples of Schedule III narcotics include products containing not more than 90 milligrams of codeine per dosage unit (Tylenol with Codeine®), and buprenorphine (Suboxone®). Examples of Schedule IIIN non-narcotics include benzphetamine (Didrex®), phendimetrazine, ketamine, and anabolic steroids such as Depo®-Testosterone.

Schedule IV Controlled Substances have a low potential for abuse relative to substances in Schedule III. Examples of Schedule IV substances include alprazolam (Xanax®), carisoprodol (Soma®), clonazepam (Klonopin®), clorazepate (Tranxene®), diazepam (Valium®), lorazepam (Ativan®), midazolam (Versed®), temazepam (Restoril®), and triazolam (Halcion®).


Pharmacology

Schedule V Controlled Substances have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics. Examples of Schedule V substances include cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®), and ezogabine.

Source: https://www.deadiversion.usdoj.gov/schedules/#define

Schedule VI Substances do not have an abuse potential. This schedule includes everything else that is not listed on one of the above lists but is still a prescription. Please keep in mind that the lists written above in this article are not exhaustive, and the full list can be found at the website mentioned above.

OVER THE COUNTER (OTC) DRUGS

Over the Counter (OTC) drugs are available without a prescription and are not considered to be a scheduled drug. In order to be an OTC drug, the FDA must consider the drug to be safe enough to be used without professional guidance, have a low potential for misuse or abuse, and the drug must be able to be labeled. The patient must be able to self-diagnose the condition for which the drug is being used.

Unfortunately, there are problems with OTC drugs. For instance, patients use a lot of them, and overdose (whether intentional or accidental) is frequent. Education is very important. It is not unusual to hear “I take ibuprofen and Advil® and Motrin®, and none of them work,” with the patient meaning that they have tried all of these drugs all at once.

Readability of labels and instructions is a major concern. In 2002 (and previously), the National Center for Education Statistics released the National Adult Literacy Survey which examined the literacy of nearly 13,600 Americans aged 16 years and older. In the most recent survey, they found that 21-23% of Americans demonstrated the lowest level of proficiency with reading, meaning that they were unable to find the total on a bank deposit slip or find a meeting location or time on a meeting announcement. An additional 25-28% of Americans scored in the next level up of proficiency (Level 2 out of 5 possible levels), meaning they would be able to identify the topic of a sentence and interpret simple step-by-step instructions. Thirty-one to 32% of Americans scored at Level 3, which means that they could integrate information from multiple places in a document. Only 15 to 17% scored at Level 4, meaning that they could integrate complex information from lengthy and confusing documents, and that they could make inferences based on this information. A very small 3-4% of Americans scored in the top Level 5, which allows for making complicated arithmetic calculations and searching for specific information within complex and confusing prose.

Although these literacy levels do not specifically correlate with a traditional grade level, it is easily apparent that most of the instructions that are written for our patients are fully beyond the grasp of those in Levels 1 and 2, which accounts for 46-51% of Americans.

Over the counter drugs, as all drugs, are harmful if misused or overused, or used in populations for which they were not intended. Since patients often do not understand the instructions, this type of issue happens often. Some OTC drugs, such as cough meds when combined with ETOH, pseudoephedrine, or cold preparations when taken at very high doses, can be abused. OTC drugs can have significant side effects that patients don’t always consider and can cause significant drug interactions. For example, diphenhydramine causes anticholinergic side effects, and ibuprofen causes decreased effectiveness of blood pressure lowering agents.


Pharmacology

The most important intervention for nurses is to specifically ask about OTC drugs when taking a thorough medication history, and then to follow through with a complete interaction check. Just because something is OTC does not mean that it is safe for your patient.

PREGNANCY CATEGORIES

Pregnancy categories have gotten a little confusing and are in the process of changing. Prior to 2015, drugs were assigned a category based on the danger level to the fetus as established by current scientific literature. The category was labeled with a single letter. This system has been in use since 1979.

Drugs in Category A have had adequate and well-controlled human-based studies that have failed to demonstrate a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. Example drugs in this category include levothyroxine and folic acid. There are not many drugs in this category.

Drugs in Category B have had some animal-based studies that have failed to demonstrate a risk to the fetus, but there are no adequate or well-controlled studies in pregnant women. Example of drugs in this category include metformin and amoxicillin.

Drugs in Category C have had animal studies that have shown an adverse effect on the fetus, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Example of drugs in this category include tramadol and gabapentin.

Category D drugs have shown evidence of human fetal risk based on adverse reaction data from either investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Example of drugs in this category include alprazolam and lorazepam.

Drugs in Category X have demonstrated fetal abnormalities, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Example of drugs in this category include atorvastatin and warfarin.

After 2015, the FDA Pregnancy Categories were replaced with narrative sections that include information on risks, clinical considerations, information for lactation, reproductive potential considerations for both males and females and implications for pregnancy testing, contraception and infertility. Most drug manufacturers have not yet made these new sections available.

BASIC REVIEW OF CELL ANATOMY

Drugs act on cells, which are the basic building blocks of living things. In order to have a better understanding of how these drugs work, we will quickly review selected aspects of basic cell structure in this next section.

Every cell has a cell wall, a nucleus and cytoplasm. The cell wall is the outside layer that separates the outside of the cell from the inside of the cell. The cell wall is made up of different components based on the type and needs of the cell. Most of the cell wall is made of phospholipids (a molecule of fat that has a phosphate in it); molecules that are hydrophilic (water loving) on one side and hydrophobic (water hating) on the other side. These phospholipids line up in a manner that allows the hydrophobic ends to go back to back, forming a very tight seal so that the hydrophilic ends face the intracellular (inside the cell) and extracellular (outside the cell) spaces while the hydrophobic ends face each other. This forms a tight bilayer (two layer) seal that keeps many things from easily entering or exiting the cell.


Pharmacology

Interspersed in the cell wall are large proteins that cross both layers of the phospholipids, which each have a specific job. Mostly they are associated with carrying signals or transporting water or ions (a molecule with an electrical charge, so K+ or Ca++) across the cell membrane. The proteins in the cell wall are a major target for pharmacology, as many of these proteins can be regulated to allow more or less of their particular ion or particle through the cell wall, sometimes causing drastic changes in the intracellular environment.

The nucleus of the cell contains the DNA, the chromosomes that encode the proteins that make life possible. Ribonucleic acid (RNA) controls the process of creating the proteins on which the cell will run. Obviously, this is a very large process, but we don’t need to discuss more for the purposes of this article.

There are many organelles (small organs, each with a different purpose) in the cell. While we won’t discuss any further organelles in detail here, it is important to understand that some organelles are the site of action for many drugs, and will be discussed with those drugs as appropriate.

The cytoplasm is technically the entire part of the cell that is outside the nucleus, while the cytosol is the fluid part of the cytoplasm. The cytoplasm includes the organelles. The cytosol, the fluid, is very important for pharmacology because this is a major site for enzyme activity and metabolism.

RECEPTORS

Receptors are specific places in the cell where drugs can exert their effects. There are four main types of receptors:

• Ion channel receptors

• G-protein coupled receptors

• Intracellular receptors

• Enzymes

Ion channel receptors are located outside the cell, along the cell wall. A drug that alters the ion channel receptors attaches to this receptor outside the cell and then increases or decreases the flow of ions into or out of the cell, thus altering the electrical potential of the cell. Drugs that use this approach include amlodipine and verapamil.

G-proteins are specific proteins that cross the cell wall multiple times (seven, to be precise), and then attach to a protein inside the cell. A drug that attaches to a G-protein coupled receptor (GPCR) would also attach to the receptor outside the cell, then would cause changes in the G Protein that allows the


Pharmacology

attached protein that is inside the cell to now be set free. A drug could be made to either make the protein free, or to block it from being set free. Examples of drugs that use this technology include lisinopril and aripiprazole.

You will notice that drugs that work on both ion channel receptors and receptors coupled with G-proteins do not have to cross the cell wall as both of these receptors are located outside the cell. The next two types of receptors are inside the cell itself, which means that the drugs must be able to cross the cell wall. In order to do this the drug must be lipid soluble as it needs to cross the lipid bilayer of the cell wall.

Intracellular receptors can be located in a number of different intracellular sites. Drugs that couple with intracellular receptors displace a stabilized protein that travels to the nucleus of the cell. When it arrives in the nucleus it controls the RNA, and thus changes the transcription of certain proteins. So, drugs that work on intracellular receptors control protein formation. Glucocorticoids, such as hydrocortisone, work like this.

Enzymes are biologic molecules that encourage specific chemical reactions in the body but are not necessarily located at a specific receptor site. You can consider these “roaming receptors” in that they act just like receptors but are not tied to specific areas of the body. Many drugs, such as metformin, stimulate or inhibit enzymes.

DRUG ACTION AT RECEPTORS

A drug can interact with receptors in one of three main ways:

• It can make the receptor act.

• It can make the receptor stop acting.

• It can make the receptor act just a little bit.

The term agonist is used for a drug that will produce receptor stimulation and a conformational change every time it binds to the receptor. This means that the agonist will make the receptor do whatever the receptor will normally do, every time it sees the agonist.

So, let’s say that the receptor, when activated, causes an ion channel to open. An agonist, when bound to the receptor, would cause the ion channel to open. Let’s look at another example. In our second example, the receptor, when activated, actually causes the ion channel to close. Now the agonist, when bound to the receptor, would cause the ion channel to close. So you can see from our example that the action itself is not the important part. The important piece is that the agonist is making the receptor do what it normally would have done, whatever that may be.

The second type of action a drug can have is to be an antagonist. Antagonists are drugs that bind to the receptors, but do not produce a response. They block the receptor, so that nothing happens. So, if we extend our examples from above, if the receptor would open the ion channel, then the antagonist binds to the receptor and NOTHING would happen. The ion channel would remain closed, and the receptor would not be available to be bound to anything else, so it wouldn’t be able to be opened.

If, however, the action of the receptor would normally be to close the ion channel, and the receptor was bound to an antagonist, then the channel would remain open, and would not close because, again, the antagonist would be blocking the normal action. The action itself is not the important part. It is the blocking of the action that is important. In fact, these drugs are often referred to as “blockers” or “inhibitors,” as in the case of beta blockers or leukotriene inhibitors.

The third, and final, option for drug action at a receptor is to be a partial agonist. A partial agonist is one that produces a response, but a smaller one than an agonist. Sometimes this can be only slightly smaller than a full agonist, and these drugs act basically as an agonist. Sometimes these drugs have such a small


Pharmacology

effect that they are mostly blockers and we consider them antagonists. Sometimes the effect is somewhere in between and shows a muted effect.

DRUG RESPONSES

This section is the beginning of where we will discuss how people respond to drugs. Up to this point we have been discussing how cells and receptors respond, now we will start to consider how the person responds as a whole.

A person will not start to respond to a drug until the dose of the drug is at a certain level. The dose response curve is the relationship between the dose or concentration of the drug and its biological response. In general, the higher the amount of a drug at its site of action, the more the drug will bind to the receptor and the greater the response. Most of the time, a higher dose means higher effectiveness of the drug, but also means higher risk of side effects.

(I want to take a moment to point out the “at its site of action” phrase in the previous paragraph. The implications of that phrase: a drug won’t have any effect at all if it cannot get to its site of action.)

The dose response curve is influenced by a number of things, including how many receptors are present, what type of action the receptor has, how many receptors need to be activated to create a response (the potency), and the maximum effect of a drug at the highest dose (the efficacy).

The cells themselves have a lot to say about how many receptors for a drug or chemical are present. Sometimes if your cells get too much of a signal, they will reduce the number of receptors on their cell walls to reduce the amount of signal that is getting through. This is called downregulation. The opposite can happen as well. Upregulation is the process whereby the cells will increase the number of receptors due to not getting enough signal. This process does not happen with all drugs but can be a major factor in others.

Potency is the amount of drug that is required to produce a response. Most of the time you think that you need a certain number of milligrams for a dose of a drug, but what you are really saying is that you need a certain percentage of your receptors to be exposed to the drug for the cells, and thus the person, to have a response. Every response is different and requires a different amount of stimulation.

The maximum effect that the drug has is the efficacy. Once you reach this level, giving more drug will not increase the response, because you have reached the maximum efficacy of the drug. It is doing all that it can do.

There are only two categories of drug responses available: quantal and graded. A quantal drug response is a yes/no type of response. The drug either produces a response or it does not produce a response. The other type of response is a graded drug response, which can be measured on a continuous scale. For example, the intensity of the drug response increases as the does or potency of the drug increases.

Drug selectivity, or how much the drug only chooses the intended receptors, and how much those receptors only cause the wanted effects, usually changes based on dose. Higher doses usually cause more unwanted effects. This is a major factor that is studies in Phase 1 Clinical Trials.

The placebo effect is a pharmacological effect that is not due to the active ingredient. This affects rates of both wanted and unwanted effects, while a nocebo effect is only a negative pharmacological effect not due to an active ingredient. You can see a nocebo effect when a person acts as if they are having side effects due to the suggestion that there is something wrong with what they are taking.


Pharmacology

PHARMACOKINETICS VS PHARMACODYNAMICS

Everything we have discussed to this point is under the heading of pharmacodynamics, something that is happening to the body as a result of taking a drug. Pharmacodynamics is WHY you take the drug in the first place; it is the EFFECT you are looking for. Simply put, pharmacodynamics is what the drug does to the body, and pharmacokinetics is what your body does to the drug.

ABSORPTION

Absorption is the way the drug enters the body. The route of administration affects the speed, the extent and the duration of drug absorption. The oral route of administration is the most convenient, but drugs pass a number of steps before reaching the bloodstream which can alter the drug significantly and can delay absorption. The parenteral route (administered by anything besides the alimentary canal) is the best for drugs that are not absorbed by the gut or are destroyed by acid, or when the person is unable to take anything by mouth. Parenteral administration avoids first pass metabolism (which we will discuss) and is the fastest for absorption and distribution.

Bioavailability is the percentage of the administered dose of the drug that actually enters the bloodstream. Generally, an IV administered drug’s bioavailability is 100% (since it is going directly into the bloodstream), while the bioavailability of an oral or transdermally administered drug can vary widely. When the bioavailability of an oral preparation of a drug is low, a higher dose will be given so that the amounts reaching the bloodstream are similar. However, as we will discuss, sometimes drugs would have to be given at such high doses that it is not feasible to be given orally, and other routes are better.

DISTRIBUTION

The process of drugs moving throughout the body is referred to as distribution. This can include passive diffusion, which does not require the use of energy, and active transport, which does. Distribution is affected by the molecular size of drug, the lipid solubility of drug, the acidity of the environment, and the acidity of the drug.

Some drugs will easily combine with the proteins in the blood and can travel with these proteins in a bound form. This process of protein binding allows drugs to distribute easily throughout the body. Protein bound drugs are somewhat protected from metabolism in the liver and excretion in the urine due to the properties of the protein.

There are two significant problems with protein-binding of drugs. First, only drugs that are free (unbound) can produce effect. A protein-bound drug easily moves to the site, but then must unbind before it can work. The second problem with protein binding is that sometimes a small change in the amount of drug that is bound or the amount of protein available to bind can make a drastic difference in the amount of free drug,

Four Processes of Pharmacokinetics

• Absorption

• Distribution

• Metabolism

• Excretion


Pharmacology

thus causing a large difference in the effects of the drug. One of the most plentiful proteins in the body is albumin, which is dramatically affected by a person’s nutrition status and age.

METABOLISM

The third major pharmacokinetic property is metabolism, which is the chemical alteration of the drug into metabolites. Metabolites are simply a chemical change from the original. Sometimes something is added, other times something is taken away from the drug. Sometimes it is the metabolites that are chemically active, as in the case of a prodrug. Most of the time metabolism stops the action of the drug and gets it ready for excretion. But not always - sometimes a drug is excreted in its original form, and sometimes a drug is metabolized in order to convert it to its active form.

Metabolism can occur anywhere in the body, but most commonly in the smooth endoplasmic reticulum in the cells in the liver. Other common, but much lesser, areas for drug metabolism include the small intestine, lungs, placenta, and kidneys.

A family of liver enzymes, called Cytochrome P450, or CYP450 for short, are responsible for drug metabolism. There are many different enzymes, each responsible for the breakdown of a certain group of drugs. CYP450 is only the beginning of the name, the full name having a number, a letter and then another number, such as the six enzymes that are responsible for metabolism of a majority of all drugs:

• CYP1A2

• CYP2C9

• CYP2C19

• CYP2D6

• CYP3A4

• CYP3A5

(Note that you do not have to say “450” for each one. In fact, some people say each letter, as in “C-Y-P” when pronouncing these enzymes, while others take a more abbreviated approach and refer to them as “sip” enzymes.)

It is important to recognize that these enzymes are proteins, each having been coded for in the DNA of the person they serve. It is also vitally important to know that there is marked variation in amount of CYP450 among people based on the genetics of each particular person. This will be discussed in more detail later in this article.


Pharmacology

The CYP450 system is a major source of drug interactions and many things can affect the strength of a CYP450 enzyme. A substrate is whatever the CYP450 enzyme works on. The substrate is the drug. An inducer is any substance that makes the CYP450 enzyme work harder, so it breaks down the substrate faster, while an inhibitor makes a CYP450 enzyme weaker, so it breaks down a substrate slower. Inhibitors and inducers can be foods or drugs and have drastic effects on the metabolism of drugs.

When orally administered substances (food and drugs alike) are first absorbed through the stomach and small intestine wall they are first acted on by the CYP450 enzymes in the small intestine, and then are carried by the portal vein to the liver where they are further affected by additional CYP450 enzymes before being released to general circulation. Sometimes, through this process, drugs are completely removed from the circulatory system and never reach the site of action. This process of first pass metabolism breaks down some drugs in such a complete manner that it makes them completely unable to be given in an oral form. Other drugs, however, are only affected by this process minimally, or not at all. This is one reason why, in general, oral doses of drugs have to be higher than IV doses of the same drug.

A drug will be processed by one of these two approaches to metabolism of drugs:

• First order metabolism

• Zero order metabolism

First order metabolism is characterized by a half-life, tells us that half of the drug will be removed from the system in a given amount of time. For example, a drug may have a half-life of six hours. Zero order metabolism is characterized by the specific amount of drug that is removed over a period of time. For example, a drug may be metabolized by 10mg in 12 hours.

To help understand this concept, consider you are a parent and you are picking up your child’s toys that are strewn all over the floor in the living room. In the first example, your child’s toys are tiny, and they are mostly in a pile. At first you are able to get a lot of toys in a single handful and put them into the toy box, but then after a minute you have to move around to get others and you can’t be quite as efficient. After another minute you are only picking up a single toy before you have to move to another spot to get to another location to get another toy. This is an example of first order metabolism. At first the body is really efficient at metabolizing the drug when the concentration is really high, but then when the concentration gets lower, the efficiency gets lower as well.

Let’s look at another example. For this example you are still on the floor picking up toys, but now the toys are bigger, perhaps larger doll houses. You need two hands to pick up each doll house, so no matter how close together the dollhouses are, you still need approximately the same amount of time to pick up each one. This would be an example of zero order metabolism, because there is a constant rate of metabolism, no matter what the concentration.

EXCRETION

The process by which drugs (or its metabolites) are transferred from inside the body to outside the body is excretion. Basically, excretion is the opposite of absorption. The primary organ of excretion for most drugs is the kidney, but drugs can also be secreted in bile into the GI tract, excreted into the air as we exhale, and excreted in sweat.

Every drug, after being taken consistently for long enough, will eventually reach a steady state. Steady state refers to the time when the overall intake of a drug is in dynamic equilibrium with its elimination. This will happen when the drug has been dosed appropriately and taken consistently for four to five times the half-life of the drug. Knowing if a drug has reached steady state is important for monitoring effectiveness of the drug and the drug’s side effects. Prior to reaching the steady state, the drug will be going thru periods of time where the blood levels will not be in the therapeutic level, and the drug will not be effective. It is only when steady state is reached that the drug levels are much more consistently in the therapeutic range.


Pharmacology

The last concept to discuss is that of absolute bioavailability. This starts with the same bioavailability that we discussed in the section of absorption, in which we were looking at the amount of drug that was administered versus how much drug actually makes it through to the systemic absorption, but now we add the knowledge of distribution, metabolism and excretion, so that we can determine how much drug a person is actually exposed to over time.

Absolute bioavailability reflects the actual body exposure to a drug after administration of a dose of the drug. It is dependent on the dose given to the person and the person’s ability to clear the drug. In mathematical terms it can be graphed as the area under the plasma drug concentration-time curve (or Area Under the Curve, or AUC). Think of a graph where the vertical axis is amount of drug in the blood and the horizontal axis is time. Most of the time it looks like a bell-shaped curve if a single dose of drug is given. Anything that is above the zero mark would be considered under the curve. This area under the curve has implications for drug side effects and toxicities.

ADVERSE DRUG REACTIONS

An adverse drug reaction is any undesirable or unintended event following the administration of a drug, whether or not the effect is considered related to the drug. Technically, it includes any type of medical product that the FDA covers, including any human and veterinary drugs, biological products, medical devices, cosmetics, and products that emit radiation, but for the purposes of this activity we are just going to discuss reactions to drugs. In general, there are two main categories of drug reactions:

• Pharmacological reaction

• Idiosyncratic reaction

Before we discuss drug reactions, let’s look at different types of antibodies, and how they fit into the whole picture. An antibody is a protein that is created by the immune system (the B lymphocytes, to be exact, but that’s a little beyond the scope of this article) in order to hold the memory for a heightened response during future encounters with a particular pathogen. The next time the person encounters the bacteria, virus, fungus, prion or other pathogen, the antibody will allow for such a heightened response that, most of the time, the pathogen does not cause sufficient damage to the host.

There are many types of antibodies, each doing a different type of job. An antibody is also called an immunoglobulin, and is abbreviated as “Ig”. Each of the five classes of antibodies has an additional letter after the “Ig” to differentiate the type. When you pronounce them, you say each letter, so it would be said as “I-G-G”, or “I-G-M” and so on.

The two most abundant classes of immunoglobulins are IgM and IgG. IgM is the antibody that works for a pathogen that is presenting itself currently (I think of IgM as at this moment). IgG comes in slightly later and represents a past infection (I think of IgG as gone, or in the past). IgE works for two main problems: multicellular parasites and allergies. IgA is important in the function of mucous membranes and found in skin and in GI, respiratory and GU tracts. IgD is the final class of immunoglobulin and is not well understood (I think of the IgD as developing knowledge).

Now let’s look at how different drug reactions use those antibodies in different ways.

A pharmacological drug reaction is often predictable based on the drug’s mechanism of action. Of the two types of reactions it is the more common, and it tends to be dose related. An example of a pharmacological drug reaction is a drug used to control blood pressure that works too well and causes orthostatic hypotension. A second example is an allergy medication that causes drowsiness. These are known side effects and extensions of actions. They are predictable, and we often tell our patients to watch out for them.


Pharmacology

The second main type of drug reaction is the idiosyncratic drug reaction. These are unpredictable and are more likely to result in mortality. There are many types of idiosyncratic drug reactions. Those mediated by immune responses are classified as hypersensitivity reactions, which will be discussed further below. Others include reactions due to unknown receptor abnormalities, drug-drug interactions, abnormalities of drug metabolism, pharmaceutical variations, or unmasking of abnormal biological systems. Because we cannot predict this type of reaction they tend to be very dangerous and have a high mortality rate.

Hypersensitivity reactions are the most common type of idiosyncratic drug reactions and come in four subtypes. They are an abnormal and excessive response of the activated immune system that causes injury and damage to host cells. They are more commonly referred to as allergic reactions.

Type 1 hypersensitivity is also referred to as immediate hypersensitivity. It is antibody mediated, specifically IgE mediated, and starts within minutes of the person’s encounter with the drug. In this type of reaction, whatever is causing the reaction is called an antigen. Since this type of reaction stimulates IgE, the IgE stimulates basophils which release histamine, leukotrienes and eosinophil chemotactic factor.

A type 1 sensitivity can be discrete (local) or systemic. If the antigen is confined to one spot then the reaction will be local, and will usually manifest as hives, allergic rhinitis, atopic dermatitis or bronchial asthma. These conditions tend to have a genetic base. If, however, the antigen is everywhere, then the reaction may be anaphylaxis, which is life threatening. Anaphylaxis can be associated with tiny amounts of antigen, and many antigens cross-react, meaning that a person may have a known allergy to one substance, and will now have a Type 1 hypersensitivity reaction to a similar, but different, substance. Food-induced anaphylaxis is the leading cause of ER admissions for children.

Type 2 hypersensitivity is also antibody mediated, but hypersensitivity occurs after the formation of complexes between IgM or IgG with the antigen. Unfortunately, the antigens that are targeted are already in the host’s cells, and can be either intrinsic, inherently part of the host’s cell, or extrinsic, incorporated onto the cell surface after exposure to the foreign substance or infectious agent. This type of hypersensitivity is the basis for many autoimmune disorders. Examples of this type of hypersensitivity include autoimmune hemolytic anemia and rheumatic fever.

Also mediated by IgG and IgM antibodies, type 3 hypersensitivity occurs when an antibody/antigen complex forms in the blood, but then travels to and lodges in the basement membrane of tissues and vessels. Clinically the person will show rashes, kidney damage and arthritis. Usually the symptoms will show 3-4 days after exposure to the antigen. Examples include lupus and acute glomerulonephritis.

Type 4 hypersensitivity is different from the first three types in that it is a cell-mediated disorder, not an antibody mediated disorder. It is also referred to as delayed type hypersensitivity, and usually occurs 2-3 days after exposure to the antigen. As opposed to types 1-3 hypersensitivity, which are reacting with mediators for a specific antigen, type 4 hypersensitivity reacts with non-specific cells, especially macrophages, which cause a lot of damage to the site of the initial exposure. There are many different kinds of type 4 hypersensitivity based on the T-cell that is recruited and the antigen. Examples of type 4 hypersensitivity include allergic contact dermatitis (such as poison ivy), type 1 diabetes, and Hashimoto’s Thyroiditis.

Considering the timing of the reaction will give you a clue as to the underlying cause. Type 1 hypersensitivity is usually immediate or rapid and occurs within minutes or hours of administration of the drug. However, it requires that the person has previously formed an antibody for the drug, so there may not be a reaction the first time the drug is given. Types 2-4 hypersensitivity reactions are delayed and can show more than an hour after exposure. Sometimes this can even occur after the medication is discontinued.


Pharmacology

CAUSES OF ADVERSE REACTIONS

By far, the most common cause of adverse drug reactions is medication prescribing errors, especially for high risk drugs such as insulin, opioid-containing analgesics, anticoagulants, amoxicillin-containing antibiotics, and antihistamines.

Many patient factors can contribute to adverse reactions as well, including genetics, age, gender and polypharmacy. A person’s genetics influences adverse reactions by causing hyper or hypo metabolizers, which is discussed in depth later in this article. Age and gender may also cause risks for adverse reactions

due to changes in pharmacokinetics.

Polypharmacy, or the use of many different drugs, has its own unique risks for adverse reactions. First, each added medication adds increased risk for drug-drug interactions because each medication carries its own set of risks. Polypharmacy is also an indication that there are a number of pathological processes happening in the person which may increase changes in pharmacokinetics. Polypharmacy does not have a single, well defined meaning. It is generally well accepted to mean somewhere between 5-10 drugs, including prescription drugs, OTC drugs and supplements.

If you have a person who has an adverse drug reaction, discontinue the drug immediately. The problem is that sometimes a person has been exposed to many different things at once, so you do not know if one specific drug is causing a problem. If the drug is important and the risk is low, you can consider re-trialing the drug to be sure. Always be sure to report the adverse drug reaction to the FDA at https://www.fda.gov/safety/medwatch/.

RATIONAL DRUG SELECTION

The World Health Organization defined rational drug selection as when “patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community” (2002). Unfortunately, this only happens about 50% of the time. The most common examples of irrational drug selection include polypharmacy, inappropriate use of antibiotics, overuse of injections as opposed to oral drugs, and failure to follow guidelines when prescribing.

To improve rational drug section in your own practice there are a few key things that you can do. First, be sure to accurately define the patient’s problem with a correct diagnosis. This may sound obvious, but it is estimated that one in ten diagnoses in the United States is incorrect. If you have not accurately defined the patient’s problem, you will not be prescribing a drug that is appropriate for the patient’s clinical needs. A number of great presentations are available that discuss strategies on diagnostic error reduction.

After you have accurately defined the patient’s problem, you next need to consider the therapeutic objective, or the goal of the therapy. Is your purpose curative, palliative, or preventive? A palliative goal is one that focuses on relief of pain or other symptoms instead of the underlying cause of the symptoms. A preventive goal might include the use of vaccines or therapies designed to reduce the impact of a disease, such as the use of diuretics for CHF.

After you have chosen the appropriate goal for your patient, look to the guidelines, and then individualize the treatment as needed for your patient. After you have determined which treatment would best fit your patient, discuss the options with your patient. Always remember that your patient has choices and, as their healthcare provider, you are working with your patient to provide the best treatment options available.


Pharmacology

Once the choice has been made, be sure to educate! Up to 50% of patients do not take the medications as prescribed, but that number improves with good education. Bringing your patient back to the office for monitoring will help to improve compliance and allow you to assess for side effects and effectiveness of the drug. A number of side effects are not reported as patients do not realize that they are important, or even that the problems are associated with the particular drug. Booking a follow-up appointment gives your patient a set time to come back to the office to ask questions.

DRUG FACTORS INFLUENCING DRUG SELECTION

After looking at evidence-based guidelines as the initial consideration, nurse practitioners consider each drug that is mentioned in the guideline for its clinical usefulness for each individual patient.

Pharmacokinetic factors are the first item to consider. Many different formulations of drugs exist, some offering chemical changes that affect bioavailability or duration of action. Pay attention to versions that may be IR for immediate release as opposed to XR, SR or ER for extended release. Different drugs in a class may work on different cytochrome P450 enzymes, thus creating different drug-drug interactions. Some drugs in a class may be more renally excreted than others and, therefore, less appropriate for older adults, very young infants, and those with renal disease.

Ease of titration is a pharmacodynamic principle that is affected directly by the therapeutic index (or sometimes called a therapeutic window) of a drug. The therapeutic index is the relationship between the dose needed for maximum effect of the drug without going into toxicity of the drug. If the drug has a narrow therapeutic index, then the drug needs to be monitored closely so that the levels do not become toxic. If a drug has a wide therapeutic index, then there is less concern for toxicity at standard doses. A drug with a wide therapeutic index is much easier to titrate than a drug with a narrow therapeutic index in which we are worried about toxicities.

The therapeutic index can be represented in mathematical terms as well. In human studies it is represented as:

Here, the numerator is the toxic dose in 50% of the subjects, and the denominator is the effective dose in 50% of the subjects. The safer the drug, the higher the therapeutic index.

Let’s look at two examples. In the first example, the effective dose for most people is 1mg, and the toxic dose for most people is 10mg. You would see this as:

Therefore, in our first example, we have a very safe drug.

Let’s look at another example. In this example, our safe dose is 30mg, and our toxic dose is 32mg. Now our index looks very different:


Pharmacology

You can see easily here that the difference between a safe dose and a toxic dose is very small in the second example.

It is much more important to understand the overall point than to understand the mathematics. Just remember that a drug with a wide, or high therapeutic index will be more safe and easier to titrate than a drug with a low, or narrow therapeutic index. Examples of drugs with narrow therapeutic indices include warfarin, digoxin and lithium.

The overall safety of a drug is the major concern and may change depending on the population you are working with. As many facts are learned about a drug after it hits the market, a lot of information is not in the initial studies. The FDA, however, keeps a site updated with all current safety information at https://www.fda.gov/Safety/MedWatch/default.htm. Here you can see all safety related information, and you can print medication guides - the paper handouts that come with many prescription medicines.

PATIENT FACTORS INFLUENCING DRUG SELECTION

Nurse Practitioners also have to consider cost when prescribing drugs to a patient. Insurance coverage does not necessarily cover every drug, and many prior authorizations are required for non-generic drugs. A good place to start is at the patient’s pharmacy of choice to see if they have a generics list. Many pharmacies have a list of drugs that they offer for very low cost, which do not require the use of insurance coverage.

If a preferred drug is not on this generics list, you may want to have your patient consult their pharmacy benefit formulary to see if it is a covered drug before prescribing, as many insurance companies will have you “step through” one drug before getting to your drug of choice. This means that they would like you to try one or more other, likely less expensive, drugs before getting to the one you were trying to prescribe. If this other drug is an acceptable alternative for you, you can save yourself and your office staff a lot of time by knowing this ahead of time and avoiding completing the prior authorization request that is going to be denied until you complete the requested steps. Checking ahead with their insurance company will also let your patient know what their out-of-pocket expenses will be, which will avoid the extra phone call when they get to the pharmacy and are now asking for a cheaper alternative.

There are many patient-based pharmacokinetic factors to consider, as well. But before looking at absorption, distribution, metabolism, and excretion, consider that you always need to prescribe a drug that matches what a person is willing to take. For example, you would not likely prescribe a drug that is required to be given intravenously to someone who is an outpatient. You may know that you have a patient who is willing to take a drug 4 or 5 times a day, or another patient who is only willing to time doses for once a day. You may not realize it, but this is pharmacokinetics. (Further on we will discuss prescribing in certain populations, and you will see that children, pregnant women and older adults have many differences with pharmacokinetics.)

Let’s review the differences between pharmacokinetics and pharmacodynamics for a moment. Pharmacodynamics is what the drug does, where pharmacokinetics is what the body does. Pharmacokinetics is the body’s absorption, distribution, metabolism and excretion of drugs.

Remember that absorption is the first property in pharmacokinetics. Many people have physical changes that affect the absorption of drugs. Surgeries, such as gastric bypasses, reduce the ability to absorb many


Pharmacology

drugs, and make it very difficult to absorb any extended release drugs. Gastroparesis, a condition common in diabetes, will slow the transit time in the stomach, thus exposing drugs longer to the acid environment. Sometimes this will enhance the drug absorption, sometimes this will completely degrade a drug. Absorption can be drastically affected by food, sometimes a drug needs to be taken with or without food. If a patient is able to follow instructions to take a drug at a certain time this might work well, if not, you might want to consider an alternative.

Distribution, the second principle in pharmacokinetics, is dramatically affected by dehydration, anemia or malnutrition. Kidney, heart, and liver failure all affect hydration and circulation status.

Metabolism, as discussed previously, mostly takes place in the liver, but also happens to a much lesser extent in the lungs, small intestine and kidneys. A person who has liver disease or renal disease will not be able to metabolize drugs as quickly, leaving the person with a higher level of drug in their system, and leaving them at higher risk for toxicities.

Excretion, the fourth and final principle in pharmacokinetics, mostly involves the kidneys, but can also involve the GI tract or the lungs and the skin. Kidney disease significantly reduces the body’s ability to rid itself of drug metabolites and wastes. Dehydration will temporarily reduce the body’s ability to filter wastes and can cause such a high concentration of a drug that it can cause significant kidney damage.

There are a number of other things beyond the pharmacokinetics and pharmacodynamics to consider. As the Nurse Practitioner you will also be looking at the patient’s allergies. It seems like a simple thing to say that you should not give anything that is on the allergy list, but sometimes it isn’t that simple. Sometimes a patient has so many allergies that there is nothing else to give. In this case you may need to enlist the help of an allergist. Sometimes what is perceived as an allergy is really a known side effect of the drug. This may be an opportunity for additional patient education.

Another place to always check is the current medication list. Having a go-to drug interaction checker will help with avoiding drug interactions. Some of the most common drug interactions include those based on protein binding and CYP450 enzyme interactions.

And finally, always consider your patient themselves. Consider the patient’s ability to monitor effectiveness and safety of this drug that you are prescribing. Will this particular patient be able to report any important side effects to you? Does this patient have adequate support who will be able to monitor and report if the patient cannot? Patient safety is the most important consideration of all.

ETHICAL PRESCRIBING

In order for prescribing to be ethical, your patient must be able to give informed consent. Informed consent implies that your patient is competent, or able to make decisions, that your patient was provided adequate information to make a decision, that your patient is voluntarily making this decision, and that your patient agrees to the prescription. If your patient does not meet every one of these principles, then your prescribing does not meet the criteria for ethical prescribing.

CULTURAL AND ETHNICAL DIFFERENCES IN PHARMACOLOGY

Although many people wouldn’t initially think about it, culture and ethnicity actually have a lot to do with pharmacology. Abstracted from the Merriam-Webster dictionary online, culture is the:

• Customary beliefs, social forms, and material traits of a racial, religious, or social group.

• Set of shared attitudes, values, goals, and practices that characterizes an institution or organization such as a corporate culture focused on the bottom line.


Pharmacology

• Set of values, conventions, or social practices associated with a particular field, activity, or societal characteristic such as studying the effect of computers on print culture.

• Integrated pattern of human knowledge, belief, and behavior that depends upon the person’s capacity for learning and transmitting knowledge to succeeding generations.

In 2017, according to the US census, 61.3% of Americans say that they are white, 17.8% are Hispanic, 13.3 are black alone, 1.3% are American Indian or Alaskan Native, 5.7% are Asian, 0.2% are Native Hawaiian, and 2.6% are two or more races. The culture that we come from makes a big difference in not only our willingness to prescribe drugs, but also in our patient’s willingness to take these drugs. Due to having different cultures of origin, a provider and a patient may have conflicts on many different topics, including time, personal space, body language and eye contact. A patient and provider may have very different ideas on what types of things need specific communication, and what can be left unsaid. If an interpreter is used for the visit, the provider may feel rushed, and may not completely discuss all of the potential drug side effects to report. As international travel and immigration continue to rise, providers of healthcare need to continue to become culturally competent in providing medical care that people can truly access safely.

The terms ethnicity and culture are not interchangeable. You are born into a specific ethnicity, which affects your genetics and your pharmacokinetics, whereas culture is something that is learned. Culture has to do with how a person perceives drugs and treatments and healthcare.

Culture and ethnicity can lead to disparities as well. The National Library of Medicine has put forth two definitions that are very easy to understand:

• Healthcare disparities refer to differences in access to or availability of facilities and services.

• Health status disparities refer to the variation in rates of disease occurrence and disabilities between socioeconomic and/or geographically defined population groups.

These may affect pharmacology in your ability to obtain the optimal drug choices for your patient. It is beyond the focus of this article to discuss cultural competency, however please keep in mind that both culture and ethnicity have a lot to do with disparities. You as the provider have many opportunities to help.

PHARMACOGENOMICS

Pharmacogenomics is a fascinating, and relatively new, branch of science that identifies the genetic attributes of an individual that lead to variable responses to drugs. Pharmacogenomics are easy to understand if you can grasp each of these key elements in turn. First, DNA is the source of proteins. Next, different DNA sequences produce different types of proteins. Third, proteins metabolize drugs. This last one is key. Different proteins metabolize drugs differently; therefore, people with different DNA have the potential to metabolize drugs differently.

Our genes determine which and how many proteins get made. The proteins are responsible for absorption, distribution, metabolism and excretion of drugs. Any change in the design or amount of the genes will influence how each person responds to each drug. In general, there are four possibilities: a person can be a poor metabolizer, an intermediate metabolizer, an extensive metabolizer, or an ultrarapid metabolizer. A person who is a poor metabolizer would lack any genes to metabolize a drug. Assuming we are not talking about a prodrug this person would have a high drug level and would become toxic very quickly. The next possibility is an intermediate metabolizer. This person would have one normal gene to metabolize the drug. This person would have slightly slower than normal metabolism, but may not have a problem unless drug levels are given at higher doses or for longer periods. An extensive metabolizer is a person with two normally functioning alleles (differing copies of the gene) and will have normal metabolism of drugs. The


Pharmacology

final option is a person who is an ultrarapid metabolizer. An ultrarapid metabolizer will have multiple functioning copies of the gene, which leads to very fast drug metabolism. A person who is an ultrarapid metabolizer will have trouble keeping enough drug in their system to maintain a therapeutic dose.

It is also important to understand that a person can be a poor metabolizer for one drug and an ultrarapid metabolizer for a different drug. Most of the time, however, the person will have a change that affects the metabolism of a whole group of drugs, such as in a change that affects a cytochrome P450 enzyme. Remember that CYP450 3A4 metabolizes up to 50% of all drugs. An increase or decrease in action of this important liver enzyme would have wide effects on the metabolism of a number of drugs.

Interestingly, we know that people from certain ethnic groups tend to be high or low metabolizers of certain drugs. For example, people of Swedish and Japanese descent tend to have a gene that changes the way that warfarin is metabolized.

Pharmacogenomics allows us to apply our new knowledge of the science of genes to pharmacology to prescribe the best drugs to individual patients. When used correctly, it will allow us to decrease adverse reactions. We will be able to predict if a person will need a higher dose of a drug or a lower dose, and we will be able to prescribe correctly. We will be able to maximize therapeutic effect by giving the higher dose to the ultrarapid metabolizers, who would otherwise not have enough drug in their system to have an adequate effect, or a much lower dose to a person who is a poor metabolizer.

Although pharmacogenomic science is in its infancy, there are a few places where it already makes absolute sense. In cancer patients, we know that some of the cancer therapies simply do not work in patients that do not have certain receptors. Therefore, genetic typing of the tumor is absolutely necessary before starting certain therapies. In infection control, there is a specific HIV-related drug that actually has an FDA requirement for genotyping of the HIV strain before using of the drug. In fact, the FDA is already requiring that a certain amount of pharmacogenomic information be on standard drug package insert labels.

PRESCRIBING IN CERTAIN POPULATIONS

Each person that you prescribe for is certainly unique, but there are some generalizations that can be made depending on the specific populations to which that person belongs. In the upcoming section we will discuss some aspects to consider when prescribing to children, pregnant women, and older adults.

PRESCRIBING TO CHILDREN

The first thing to remember when prescribing for children is that children are NOT simply miniature adults. There are many developmental changes that are pharmacologically significant based on the age of the child. There is much more variability among children, especially during the first year of life when growth and development are most profound.

PHARMACOKINETICS

Changes in pharmacokinetics bring some of the most challenging developmental diversities for prescribers to consider. Absorption of drugs in children has a number of confounding factors to consider. Blood flow to the site of administration is incredibly variable in infants. Neonates have very poor perfusion to muscles,


Pharmacology

leading to delayed or poor absorption if a drug is administered intramuscularly. However, if the perfusion suddenly improves, which happens if sudden movement or if warmth is applied to the area, the drug can cause sudden toxicity levels. Also associated with absorption, GI function does not even start for the first couple of hours of life (longer for premature babies) and does not reach adult levels until eight months of age. Many of the drugs that we are used to giving as oral doses will need to be adjusted in this age group. Further, gastric pH does not reach adult levels until about 20-30 months, which reduces the solubility of basic drugs. Children also have a thinner stratum corneum. The stratum corneum is the outer layer of skin. A thinner stratum corneum causes drugs to be much more readily absorbed through the skin. Adult doses of topical medications can become systemically toxic.

After a drug is administered, it needs to be distributed to the site of action. There are several issues to consider here. First, neonates have a much higher percentage of body water, which drops during the first few months. This changes the distribution of drugs so that drugs that are water soluble may not be at therapeutic doses in the serum. Also, many drugs rely on protein binding to move about in the body. Neonates have very low levels of albumin, the body’s largest plasma protein, which can allow the drug to be free to exert effect on the body. Lastly, fat stores and the ratio of fat to lean muscle mass changes drastically during growth, especially during puberty. Many medications bind to the fat stores to prolong their time in the body, thus remaining stable and elongating their half-life. During pubertal changes the stores may shift, taking needed drug out of the active serum.

Metabolism pathways develop in different ways for children until the age of one year and cannot be completely predicted. Exact development of CYP450 is unknown, but what is known is that variability is wide. In fact, certain CYP450 enzymes seem to completely disappear at certain times of the infant’s development, but then actually exceed adult levels at other times. Of the CYP450 enzymes that have been successfully mapped out, some reach adult levels as early as age four months, while others take until puberty to reach adult levels. Please keep in mind that there may also be additional ethnic variations in each individual.

In children, elimination is mostly affected by renal status, which is only 30-40% of adult value at birth but reaches adult values by age six to 12 months.

In general, there tends to be more variability in pharmacokinetics of children during times of stress, such as in the case of premature birth, the neonate period, puberty, and times of significant illness. Careful monitoring of therapeutic levels may be critical during these times.

OTHER ISSUES

Children are unique in other ways as well. They are completely dependent on the parents to administer the medication. If a parent is not available, it would be a hardship (or maybe not even possible) to give a dose of medication at school or daycare. Parents need to be taught correct procedure and timing. Remember that parents have their own limitations when being taught and need to understand the instructions they are being given.

In some cases it may not be the parent who is administering the medication. In older children it might be the adolescent who is responsible for their own dose, or in younger children it might be the caregiver (daycare provider, grandparent, or other caregiver). You may need to give written instructions.

Medication errors are very common. Give extra focus to parents with low health literacy and be sure to ask questions designed to assess their knowledge about correct drug dosing and reporting side effects. Always be sure to discuss that a patient should not stop a drug until they are told to stop, and always include a written list of side effects to report with instructions on how to report them.


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DRUG DOSE CALCULATIONS

All infants and toddlers and some school age children will need the liquid form for any oral drugs. Older children and adolescents should be given the ability to choose between tablets and liquids. This next section will discuss the procedure for calculating liquid drug doses, and then we will go through two examples.

Most drugs are prescribed based on the child’s weight, but sometimes the calculations will change based on the age. For example, there may be one calculation for an infant who is 0-3 months old, and another calculation for a child who is more than three months old.

1. The first step in calculating the drug dose is to determine the child’s weight in kg. One pound equals 2.2 kilograms, so convert their weight to kg simply divide their weight in pounds by 2.2. A child who is 22 lbs weighs 10 kg; a child who is 10 lbs weighs 4.54 kg.

2. The second step is to calculate the dose in mg. To do this, find the appropriate notation for mg/kg based on the child’s age and simply multiply the number of mg by the number of kg that you got in step one.Sometimes there will be a range, for example, the drug might be 1mg/kg to 2mg/kg. In this case make two calculations, one will be your low dose, one will be your high dose.

3. The third step is to divide the dose by the frequency. Basically, this means that step two gave you the total dose for the day, now you have to figure out how much of that total dose you would give in each individual dose. Is this a once daily drug? Well, then this step is easy. Is this a BID drug? Then you are dividing your total drug dose by two. Remember, you may have two calculations going on here.

4. The fourth step is to then convert the dose to milliliters. This one can sometimes be a little more complicated and is where the logic comes into play. Manufacturers have made drugs available in a number of different concentrations. In general, you want to use the most concentrated form available for the dose you need. This will allow the parent to give the smallest volume, which will be the easiest. However, please also keep in mind that the parent is not usually a mathematician, and simplicity is important as well. Prescribe volumes that are easy for parents to measure, for example ½ tsp is easy to measure, where .387 tsp (while technically a smaller amount) is not. When you have a drug that gives you a range, for example, the 1mg/kg to 2mg/kg from above, you may choose whichever drug concentration fits best logically.

5. Finally, make sure to look at the adult dose. Your pediatric dose should NEVER be larger than the adult dose. Sometimes, when calculating based on weight, you can come up with a dose that is higher than the adult dose. If this happens, then you give the adult dose in liquid form.

Let’s look at a case to work out some bugs.

Gary is a four-year-old boy who is 41.2lbs. You need to give him amoxicillin which is recommended at 40mg/kg per day in 3 divided doses every 8hrs for his age. Available options for concentrations include 125mg/5mL and 250mg/5mL.

1. Step 1 is to change his weight into kilograms. 41.2 pounds divided by 2.2 equals 18.72 kg.

2. Step 2 is to calculate the dose in mg. 40mg/kg means 40 times 18.72, so 748.8mg in a day.

3. Step 3 is to calculate that into a single dose measurement, which is TID dosing. 748.8 divided by 3 equals 249.6mg, so 250mg is the dose you would give three times a day.


Pharmacology

4. Step 4 is to calculate that dose into ml. If we are looking for 250mg, we can use one tsp, or 5ml, of the 250mg/5ml concentration. (We could use two tsp, or 10ml, of the 125mg/5ml concentration, but that would double the volume that the parents would need to administer and would not be preferable in this case. If we had a smaller child who needed a more precise smaller dose we would prefer the lower concentration.)

Gary’s prescription is Amoxicillin suspension 250mg/5ml 5mg TID X 10 days.

PRESCRIBING IN PREGNANCY AND LACTATION

When prescribing for a pregnant or lactating woman, always consider that you are prescribing for two patients, not one. As we have already discussed drug pregnancy categories in the “Types of Drug Classifications” section above, the remainder of this section will focus on prescribing in lactation.

PHARMACOKINETICS

The breast is considered an elimination organ in times of lactation. Sometimes the amount of drug that the infant is exposed to will be enough to cause therapeutic or even toxic effects, sometimes there won’t be any effects at all. There are several factors affecting infant exposure.

The chemical properties for the particular drug will affect how much of the drug is available in the breast milk for infant consumption. Breast milk is slightly acidic, so drugs that are slightly basic tend to have higher concentrations in breast milk, while drugs that are slightly acidic tend to remain in the serum. Drugs that are highly protein bound will not tend to be found in high concentrations in breast milk, as there is not a good way for the drugs to transfer. Drugs that are more lipid soluble will tend to be found in breast milk due to the higher fat content of milk.

In general, higher maternal serum concentrations of a drug lead to higher milk concentrations. A drug with a short half-life given right after an infant feeds will reduce the infant’s exposure. A drug with a longer half-life, or one given many times a day, will increase an infant’s exposure. Therefore, to reduce exposure give a short-acting drug just after the baby feeds.

The infant’s own pharmacokinetic properties are also important. An infant who is able to metabolize the drug without a problem will not have an issue. An infant who is lacking the CYP450 enzyme to metabolize the drug may become toxic.

The drug itself is important. Lithium, for example, reaches almost the same levels in breast milk as in maternal serum. If this is ingested by the infant, the infant may have therapeutic or toxic levels very soon.

A couple of great resources for further information on this topic include Medications and Mother’s Milk, Hale, T. & Rowe, H. (2017) and the LactMed® database. The LactMed® database is updated monthly and contains information on drugs and other chemicals to which breastfeeding mothers may be exposed. It includes information on the levels of such substances in breast milk and infant blood, and the possible adverse effects in the nursing infant. It is a free database funded by the U.S. National Library of Medicine and the National Institutes of Health that can be accessed online at https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.

PRESCRIBING IN GERIATRICS

Before we talk about the pharmacologic differences when prescribing to older adults, let’s explore some basic numbers.

In 2014, 14.5% of the US population was aged 65 or older. This represents 46.3 million people. This population is projected to reach 23.5% (or 98 million) by the year 2060. This is an astonishing number of


Pharmacology

people to care for. As you can see, most nurse practitioners are going to be responsible for prescribing to older adults at some point in their career.

In 2015, the 10 leading causes of death for all age groups (heart disease, cancer, chronic lower respiratory diseases, unintentional injuries, stroke, Alzheimer’s disease, diabetes, influenza and pneumonia, kidney

disease, and suicide) remained the same as in 2014. These 10 leading causes accounted for 74.2% of all deaths in the United States in 2015. You can see from looking at this list that these are all major concerns for older adult health.

Falls are another major risk for older adults. Falls, the leading cause of injury among older adults, are treated in emergency departments every 13 seconds and claim a life every 20 minutes. Every year, 1 out of 3 older adults fall, yet fewer than half of older adults tell their doctor. Medication is the single most common modifiable risk factor associated with falls, and minimization of medications is the top intervention to reduce falls.

PHARMACOKINETICS

There are a number of very important pharmacokinetic changes that take place as a person ages.

The gastric pH tends to be slightly higher as less acid is produced due to having fewer parietal cells in the stomach. When coupled with taking types of drugs that cause less acid to be produced, such as in the case of proton pump inhibitors (PPIs), drugs that rely on an acidic environment for absorption will no longer be absorbed as readily.

Older adults have less transdermal fat, which leads to the reduction of absorption of transdermal drugs.

Older adults have approximately 20% less lean muscle mass and about 15% less total body water than younger adults. Drugs that are normally distributed into muscle may have higher amounts of the drug left in the serum, causing stronger effects in the older adult.

Many drugs rely, at least somewhat, on protein binding to move about in the body. As an adult ages the albumin levels drop, sometimes by as much as 20%, which can allow the previously protein-bound drug to be free to exert effect on the body.

As we previously discussed, most drug metabolism occurs in the liver. As a person ages, the amount of blood that flows through the liver diminishes, and activity of the CYP450 system generally decreases with age. This effectively decreases first pass metabolism and increases the half-life of most medications. Conversely, drugs that are pro-drugs will act much more slowly in an older adult.

Most kidneys decline at a steady rate starting at about age 30, so that by about age 80 most people only have about 50% of the renal function of their younger counterparts. This drastically effects drug elimination. Decreased renal elimination allows drug or drug metabolite to build up in the blood, sometimes to toxic levels. To help reduce this, many drugs have renal doses available which are commonly used in older adults.

ADDITIONAL PROBLEMS WITH MEDICATION PRACTICES

Older adults are at risk for complications due to other issues, as well. They may have reduced vision, and they may not be able to see the prescriptions, written instructions, or preprinted lists. They may have reduced hearing which might make it difficult to adequately hear your instructions. They may have reduced health literacy or computer skills and may miss information or appointments. Of course, these issues are


Pharmacology

not completely unique to the older adult population, but this population is at much higher risk for these issues.

Another extremely important consideration for older adults is the topic of polypharmacy. Remember from above that polypharmacy is defined as the use of many drugs. Polypharmacy is much more common in older adults, as older adults tend to have more chronic problems than younger adults. This puts the older adult at higher risk for adverse drug reactions, which is very unfortunate, as the older adult also does not tend to recognize an adverse drug reaction for what it truly is.

Adverse reactions in an older adult may be blunted, as they have less of an ability to create a fever and their immune system is not as strong as the immune system of their younger counterparts. An adverse reaction may also be worsened, as the older adult has fewer reserves, such as having less body fat. An adverse reaction may also mimic other comorbidities, making the patient think that there is an alternate explanation for the symptom. Or, the patient may simply not recognize the adverse reaction as a problem at all. For example, a drug may cause constipation for a person who already has this symptom, or ankle edema in a person who is already edematous. Lastly, the person may not want to report the adverse reaction. The person may have feelings of loss of independence, or feelings of not wanting to be a burden on caregivers.

When prescribing for elders, please always consider the Beers Criteria. Originally published in 1991 by Dr. Mark Beers, the Beers Criteria have gone through at least five updates, most recently in 2015. The Beers Criteria describe medications with potential risks that may outweigh potential benefits, and it is a great place to check for drug safety prior to prescribing.

PROFESSIONAL ISSUES

COST OF MEDICATIONS

Cost of medications is a real issue. While the average annual out-of-pocket expenses for insured patients was $185 in 2014, patients who needed drugs to treat conditions such as cancer, hepatitis C and inflammatory diseases had a different story. According to one study, the top 5% of spenders in prescription drug costs were responsible for 61% of the country's total medication expenses, and more than 500,000 people spent more than $50,000 out of pocket on prescription drugs in 2014, while more than 100,000 people spent more than $100,000 (Williams, 2015).

Most of the highest paying people are baby-boomers who often take in excess of 10 medications each day. Many people have to choose between medications and items such as rent, food, and oil for heat. In fact, one study showed that 22% of Americans had either food insecurity (which was generally defined as limited availability of foods) or cost related medication underuse, and an additional 11% showed BOTH food insecurity and cost-related medication underuse (Berkowitz, 2014). This is despite the availability of programs such as WIC and Medicaid, showing that there is still a large population which is not eligible for these programs, living slightly above the calculated Federal Poverty Level (FPL), but still extremely vulnerable. Amazingly, 15% of Americans choose not to take medications or take them less than prescribed due to cost. Adults with chronic disease and adults with children are most affected.

Why are costs so high? Think back to the beginning of this primer. How many drugs do not make it through all of the many steps of research to make it to market? Only one in five thousand drugs make it from pre-clinical trials to the pharmacy shelves. The research for each of them needs to be funded. This is an expensive and very time-intensive process.

There are many other reasons, as well. Demand for prescription drugs is higher in the United States than anywhere else in the world. Since we also have one of the highest standards of living, we can presumably


Pharmacology

afford these high costs that are associated with the demand. We also have no true universal health plan, so there is no “top cost” that a pharmaceutical company has to contend with when pricing a product. In addition, the US offers pharmaceutical companies a period of time where their product is branded, during which they face no direct copycat competition.

So how can we, as Nurse Practitioners, help?

The first thing we can do is to try to understand some of the boundaries that the insurances place on our patients so that we can help them work within them. Of course it is almost impossible to understand ALL of the different types of insurances, and that is not the point of this article, but you can understand the basics of one very important type of insurance that will affect many of our patients: Medicare.

Medicare is important to understand, even if we don’t have patients who specifically have Medicare coverage, as many other types of insurance model themselves after the Medicare system. Medicare provides health insurance for people aged 65 or older, people under age 65 with certain disabilities, and people with End-Stage Renal Disease (permanent kidney failure). It is broken into a number of parts.

Medicare Part A is often referred to as “hospital insurance,” and only covers a portion of inpatient hospital care, care at a skilled nursing facility (nursing home), hospice care, lab tests, surgery, and home healthcare. Medicare Part B is often referred to as “medical insurance,” and covers a portion of outpatient costs such as healthcare providers' services and durable medical equipment (e.g. canes, wheelchairs, commodes, oxygen, etc.), home healthcare, and some preventive services.

Medicare Part C is either a Medicare Advantage Plan or a Medicare Supplement Insurance (Medigap). These Medicare Part C plans are offered by private companies, and cover different things depending on the company that offers the service. They are basically designed to reduce the out of pocket expense of the services that Medicare Part A and Part B cover. Medicare Advantage Plans will sometimes cover drugs; sometimes they will not. Medicare Supplement Insurance (Medigap) sold after January 1, 2006 does not offer prescription drug coverage.

Medicare Part D is the source of the “Donut Hole” term. One important way that we as Nurse Practitioners can help our patients is to help them avoid this gap in coverage. Part D is basically the prescription drug coverage portion of Medicare. When first enacted, the patient paid 100% of drug costs until he or she reached the original $310 deductible amount. After reaching the deductible, the patient paid 35 percent of the cost of brand-name drugs and 44 percent of generics, while the Part D plan pays the rest, until the total the patient and the plan spent on drugs reached $2,800. Once the patient reached this limit, the patient hit the coverage gap referred to as the “donut hole,” and the patient was now responsible for the full cost of the drugs until the total the patient spent for drugs reached the yearly out-of-pocket spending limit of $4,550. After this yearly spending limit, the patient was only responsible for a small amount of the cost, usually 5% of the cost of drugs.

Luckily the donut hole has been narrowing each year since March of 2010 with the passage of the Affordable Care Act by President Barack Obama. It was intended that the donut hole would be closed by the year 2020, but due to a budget deal signed in February of 2018 by President Trump it now appears that the gap will close one year early. Beginning in 2019, Part D enrollees will only pay 25 percent of the cost of all their prescription drugs from the time they enter the gap until they reach catastrophic coverage, which is defined as $5000 out-of- pocket expense per person.

Beyond insurance, one very significant way to lower costs of drugs is to try to use generic drugs when possible. Many pharmacies offer a generic drug program that will allow generic drugs to be offered at a greatly reduced price. This is not insurance, and you often do not need to be part of a program to access these rates. Many times a pharmacy will offer a 90 day prescription at an even more reduced price over a


Pharmacology

30 day prescription. In addition to being a lower cost, this is also more convenient for the patient, reducing prescription renewals and trips to the pharmacy.

Not all pharmacies are created equal. Sometimes researching different pharmacies can reveal drastically different costs for the same drug. This holds true whether you are comparing generic or brand name drugs. Please keep in mind, however, that a person may be on multiple drugs, and there is a large risk if a person goes to multiple pharmacies. The safety advantage of going to a single pharmacy cannot be overstated.

There are other cost saving techniques available, as well. Many pharmaceutical representatives will provide coupons that you can make available to your patients for brand name drugs. Sometimes this can lower the copay to $0. Rules for these programs differ by state, and cannot be used by Medicare, but there are many coupons that can be used to get the first month of a drug for free that can be used by Medicare. Please ask your drug reps for more information as they will have information that is accurate

for your state. If you don’t have a drug rep, pharmaceutical websites can put you in contact with a representative who can help you access programs that will help patients in need. Other resources such as GoodRx make price and coupon searching very easy.

AVOIDING PRESCRIPTION ERRORS

The important topic of patient safety was initially brought to light in 1999 by the Institute of Medicine with the publication of To Err is Human: Building a Safer Healthcare System (available online at https://www.nap.edu/read/9728/chapter/1). These landmark reports quickly brought patient safety to the forefront of medicine, attributing at least 44,000 deaths per year to medical errors, more than deaths due to motor vehicle accidents (43,458) or breast cancer (42,297) (Kohn, et al., 2000).

To Err is Human defines an adverse event as an injury resulting from a medical intervention, not due to the underlying condition of the patient. It defines preventable adverse events as an adverse event that is due to an error. Perhaps someone forgot to wash their hands or gave the wrong dose of a medication. This is in opposition to an adverse event that is not preventable, or not due to an error. Perhaps nothing could have prevented the poor outcome. Everything was done correctly, the patient was simply too sick to have a good outcome.

Although many of these definitions are commonplace now, To Err is Human was the first report to highlight and define many important terms in safety for drug prescription and administration. An adverse drug event (ADE) is any error at any step along the pathway that begins when a Nurse Practitioner or other provider prescribes a medication and ends when the patient actually receives the medication. The medication does not necessarily have to cause harm the patient to be considered harmful. The fact that the patient received unintended medication, or medication that did not follow the “5 Rights” is enough to consider it having caused harm. From nursing school, remember that the five rights of medication safety are administering the Right Medication, in the Right Dose, at the Right Time, by the Right Route, to the Right Patient.

A potential ADE is one that is stopped before it actually makes it to the patient because someone noticed and intervened before the process was completed. About half of ADEs are preventable.

Please note that you may also hear the term Adverse Drug Event as a term for an allergic reaction, which we have discussed previously (see section on Adverse Drug Reactions). You would have to understand the context in which the term was used to understand the meaning. In this section we are only discussing errors, not allergies.


Pharmacology

Polypharmacy is the biggest risk factor for ADEs. The more medications a person takes, the more opportunity there is for medication interactions, and for the person to not administer the medication correctly. A drug that needs to be given at multiple times a day is more likely to be forgotten, missed, or given at an incorrect time. A drug that has specific instructions, such as with or without food, is likely to be given incorrectly if there are other drugs with conflicting schedules.

Being old or young is another risk factor for ADEs. As has already been discussed, extremes of age will change a person’s pharmacokinetics. Many drugs require changes in dosing due to either infancy or renal insufficiency, which can cause complications and errors.

The ability to read and write will improve a person’s ability to understand instructions. A person who cannot read or write will tend to ask fewer questions, even if they did not understand the instructions in the first place. Reduced health literacy will significantly increase the risk for ADEs.

So, why is error reduction important, anyway? Well, Nurse Practitioners have almost 10,000 drugs available with which to treat patients, and nearly one third of adults in the U.S. take more than five drugs. It is estimated that 2-5% of hospital admissions in the United States experience a drug-related error, which makes it one of the most common types of errors.

However, there are many things that you can do to prevent errors in your own practice.

First, use two patient identifiers. This seems obvious now, but there was a long time that we were not doing this. Be sure to use something like date of birth (DOB) in addition to name.

Always verify allergies and patient reactions. Again, seems straightforward, right? Unfortunately, it is often a neglected step and is a major source of errors. It is also not as easy as it sounds. Sometimes patients misunderstand a known drug side effect as an allergy, so talking about these misperceptions can be important.

Highlight critical diagnoses that impact prescribing, such as diabetes, kidney disease, and liver disease. You can usually do this on a problem list, or in an alert section of the patient’s electronic medical record. Leaving clues like these will help cue you in the future and will help a covering provider if you are taking vacation or a sick day.

Review patient medications at each and every visit to reduce medications if possible. Basic medication reconciliation is the process of identifying the most accurate list of drugs that the patient is taking, including name, dosage, frequency, and route, by comparing the medical record to an external list of medications obtained from a patient, hospital, or other provider. You or someone in your office must do this at every single visit. You can go one step further, and offer much better patient care, by considering if your patient really needs to be on each of the drugs. Many times a patient was started on a drug many years ago for a short term problem, but then the drug was never discontinued.

Another way to reduce unnecessary drugs is to prescribe drugs with dual purposes if possible. Many drugs have more than one indication.

Give printed patient education if available, and always give a printed medication list at the end of every visit. Even if the person themselves is unable to read or write, they will often have a support person who will be able to assist at home.


Pharmacology

Encourage your patients to use a single pharmacy so that one facility has all of the information on all of the drugs that they are taking. Sometimes the patients forget that they have visited a specialist or will forget that the specialist has added or changed a drug. If they always go to the same pharmacy, however, you have a double check.

Avoid the use of sample medications as this bypasses the double-check of the pharmacy. If your patient is seeing a specialist he or she may have a new medication or a new allergy that they forgot to report to you that the pharmacist would otherwise be aware of. The pharmacist is a great teammate for error prevention.

NURSE PRACTICE ACTS

The prescriptive authority of Nurse Practitioners is based on each state’s Nurse Practice Acts. Each state has a Nurse Practice Act that establishes a Board of Nursing, which in turn establishes the specific rules for prescriptive authority for Nurse Practitioners for that state.

Nurse Practice Acts are set up to protect the public and set the standards for many aspects of nursing practice, including mandatory education and scope of practice. Nurse Practice Acts are an important step in error reduction.

SUMMARY

In this article, we have discussed the very basics of pharmacology. This is the foundation on which all other pharmacology activities build. We discussed the basic definition of a drug, the activities of a drug, and we classified drugs. We discussed drug receptors on cells and explored how people may have differences that would influence drug selection. We looked at the future through pharmacogenomics and discussed the vital importance of safety.

Prescribing in today's world as a nurse practitioner is a daunting task, but it is absolutely vital to the role. Our patients count on us to guide them through this very complex world of drug choices. With this information we are up to the task.

REFERENCES

Agency for Healthcare Research and Quality. (2017). Medication errors. Retrieved from https://psnet.ahrq.gov/primers/primer/23/medication-errors.

American Geriatrics Society. (2011). Summary of the updated Geriatrics Society/British geriatrics Society clinical practice guideline for prevention of falls in older persons. Journal of the American Geriatrics Society, 59(1), 148-57.

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. (2015). American geriatrics society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society. 63(11), 2227-46.

Aronson, J. (2009). Medication errors: what they are, how they happen, and how to avoid them. QJ Med. 102, 513-21.

Berkowitz, S., Seligman, H. & Choudhry, N. (2014). Treat or eat: food insecurity, cost-related medication underuse, and unmet needs. American Journal of Medicine. 127(4), 303-10.


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Bickley, L. & Szilagyi, P.G. Bates’ Guide to Physical Examination and History Taking. 12th ed. Philadelphia: Lippincott Williams & Wilkins; 2016.

Blum, J. (2010). What is the donut hole? The Medicare Blog. Retrieved from https://blog.medicare.gov/2010/08/09/what-is-the-donut%C2%A0hole/.

Bunis, D. (2018). Medicare ‘doughnut hole’ will close in 2019: drug companies will pay more to lower some part D costs. Retrieved from https://www.aarp.org/health/medicare-insurance/info-2018/part-d-donut-hole-closes-fd.html.

Centers for Disease Control and Prevention. (2016). Mortality in the United States, 2015. Retrieved from https://www.cdc.gov/nchs/products/databriefs/db267.htm.

Davis’s Drug Guide. (2018). Pediatric dosage calculations. Retrieved from https://www.drugguide.com/ddo/view/Davis-Drug-Guide/109514/all/Pediatric_Dosage_Calculations.

Drugs.com. (nd.) FDA pregnancy categories: FDA pregnancy risk information: an update. Retrieved from https://www.drugs.com/pregnancy-categories.html.

Graber, M., Franklin, N. & Gordon, R. (2005). Diagnostic error in internal medicine. Archives of Internal Medicine. 165(13), 1493-9.

Grossman, S., & Porth, C. Porth’s Pathophysiology: Concepts of Altered Health States. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.

Hale, T. & Rowe, H. Medications and Mother’s Milk. 17th ed. New York: Springer; 2017.

Haymarket Media. (2018). Amoxicillin suspension rx. Retrieved from https://www.empr.com/amoxicillin-suspension/drug/3435/#bacterialinfections.

HealthyPeople. (2018). Older adults. Retrieved from https://www.healthypeople.gov/2020/topics-objectives/topic/older-adults.

Jenkins, R. & Vaida, A. (2007). Simple strategies to avoid medication errors. Family Practice Management. 14(2), 41-7.

Juckett, G. (2005). Cross-culture medicine. American Family Physician. 72(11):2267-74.

Kirsch, I., Jungeblut, A., Jenkins, L. & Kolstad, A. (2002). Adult literacy in America: a first look at the findings of the national adult literacy survey. U.S. Department of Education’s 2003 National Assessment of Adult Literacy. NCES 1993-275. Retrieved from https://nces.ed.gov/pubsearch/pubsinfo.asp?pubid=93275.

Kohn, L., Corrigan, L. & Donaldson, M. (2000). To Err Is Human: Building a Safer Health System. Retrieved from https://www.nap.edu/read/9728/chapter/1 and https://www.nap.edu/read/9728/chapter/2.

Lynch, T. (2007). The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American Family Physician. 76(3), 391-6.

Marcum, Z. (2012). Commentary on the new American Geriatric Society Beers Criteria for potentially inappropriate medication use in older adults. American Journal of Geriatric Pharmacotherapy. 10(2), 151-9.

Medscape. (2018). Pediatric acetaminophen dosing. Retrieved from https://emedicine.medscape.com/article/2172407-overview.

Merriam-Webster. (nd.). Culture. Retrieved from http://www.merriam-webster.com/dictionary/culture.


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National Council of State Boards of Nursing. (2015). Nurse practice act, rules & regulations. Retrieved from https://www.ncsbn.org/1455.htm/36.htm.

National Institutes of Health. (2018). LactMed. Retrieved from https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.

Neuspiel, D. & Taylor, M. (2013). Reducing the risk of harm from medication errors in children. Health Services Insights. 6:47-59.

Rendic, S. & Guengeric, F. (2015). Survey of human oxidoreductases and cytochrome p450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chemical Research in Toxicology. 28(1), 38-42.

United States Census Bureau. (2017). Quick facts United States. Retrieved from https://www.census.gov/quickfacts/fact/table/US/PST045217.

U.S. Centers for Medicare & Medicaid Services. (nd.) Catastrophic coverage. Retrieved from https://www.medicare.gov/part-d/costs/catastrophic-coverage/drug-plan-catastrophic-coverage.html.

U.S. Centers for Medicare & Medicaid Services. (nd.) Your medicare coverage choices. Retrieved from https://www.medicare.gov/sign-up-change-plans/decide-how-to-get-medicare/your-medicare-coverage-choices.html.

Wheeler, H., Maitland, M., Dolan, M., Cox, N. & Ratain, M. (2012). Cancer pharmacogenomics: strategies and challenges. Nature Reviews Genetics. 14(1): 23-34.

Williams, S. (2015). The average American spends this much on prescription drugs each year: how does your yearly prescription drug spending stack up next to that of the average American? The Motley Fool. Retrieved from https://www.fool.com/investing/general/2015/12/12/the-average-american-spends-this-much-on-prescript.aspx.

Woo, T., & Robinson, M. Pharmacotherapeutics for Nurse Practitioner Prescribers. 4th ed. Philadelphia: F.A. Davis; 2015.

World Health Organization. (2002). Promoting rational use of medicines: core components. Retrieved from http://apps.who.int/medicinedocs/pdf/h3011e/h3011e.pdf.


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1. What is a drug?

A. A manufactured substance that is intended to change the body in a certain way.

B. An illegal substance that is bought and sold on the street by drug dealers.

C. A term that refers to prescription medications, over the counter medications are different.

D. Any chemical substance that produces a measurable biologic response.

2. Which organization in the USA is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, cosmetics, and any products that emit radiation?

A. The Agency for Healthcare Research and Quality (AHRQ)

B. National Institutes of Health (NIH)

C. The Food and Drug Administration (FDA)

D. Drug Enforcement Administration (DEA)

3. Which phase of drug studies check to be sure that the drug does what it says it is going to do?

A. Preclinical phase

B. Phase I

C. Phase II

D. Phase III

4. How many drugs make it from pre-clinical trials to the pharmacy shelves?

A. One in 50

B. One in 500

C. One in 5,000

D. One in 50,000

5. What schedule of drugs are those with the highest potential for abuse?

A. Schedule I

B. Schedule III

C. Schedule IV

D. Schedule VI

CE EXAM

PHARMACOLOGY


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6. Which schedule of drugs are over the counter (OTC) drugs?

A. Schedule I

B. Schedule IV

C. Schedule VI

D. OTC drugs are not scheduled.

7. Which of the following are NOT associated with over the counter (OTC) drugs?

A. OTC drugs have very low potential for abuse.

B. Use of OTC drugs requires the advice of a medical provider.

C. An OTC drug must be able to be labeled.

D. OTC drugs are associated with overdose.

8. In which category of drugs are those that are the safest in pregnancy?

A. Category A

B. Category B

C. Category C

D. Category D

9. Drugs that are in Pregnancy Category X are considered completely unsafe in pregnancy. Which drug listed below is in Category X?

A. Alprazolam

B. Atorvastatin

C. Gabapentin

D. Metformin

10. Which of the following is NOT one of the four main types of receptors?

A. Ion channel receptors

B. Intracellular receptors

C. Enzymes

D. Phospholipid receptors

11. Which of the types of receptors are located outside the cell and alter the electrical potential of the cell by increasing or decreasing the flow of other substances into or out of the cell?



C. Enzymes



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12. Which of the following receptors encourage specific chemical reactions, but are not necessarily located at a specific receptor site?



C. Enzymes


13. What is the difference between an agonist and an antagonist?

A. An antagonist always makes the receptor turn on, while the agonist always turns the receptor off.

B. An agonist always makes the receptor turn on, while the antagonist always turns the receptor off.

C. An agonist always produces a response, but it is not always 100%. An antagonist always turns the receptor off.

D. An antagonist and an agonist are the same thing.

14. Which of the following statements is FALSE about the dose response curve?

A. The dose response curve is the relationship between the dose or concentration of the drug and its biological response.

B. The dose response curve is influenced by a number of different factors, including how many receptors are present in/on a cell.

C. A person will not start to respond to a drug until the level of drug at the site of action is at a certain level.

D. Every patient follows the same dose response curve based on the dose of the drug given.

15. Potency is:

A. The maximum effect that the drug has.

B. How much the drug only chooses the intended receptors.

C. The amount of drug that is required to produce a response.

D. The pharmacological effect that is not due to the active ingredient.

16. Which is NOT one of the four properties of pharmacokinetics?

A. Dissemination

B. Absorption

C. Metabolism

D. Excretion


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17. Where is the most common site in the body for drug metabolism?

A. Kidneys

B. Liver

C. Lungs

D. Small intestine

18. A person is already on a drug that is metabolized by a CYP450 enzyme. This first drug is called DRUG A. A provider inadvertently prescribes a second drug that is also metabolized by the same CYP450 enzyme, this second drug is DRUG B. No changes are made to DRUG A. What is most likely to happen to the blood level of DRUG A?

A. The blood level of DRUG A will go up.

B. The blood level of DRUG A will go down.

C. The blood level of DRUG A will not be affected.

D. It is not possible to tell with the information given.

19. Sometimes orally administered drugs are so susceptible to the action of CYP450 enzymes that they are completely removed by the liver before they are even released to the general circulation. This is called:

A. Zero order metabolism

B. First pass metabolism

C. Pharmacokinetic metabolism

D. Substrate slowing

20. Which of the immunoglobulins works on a pathogen that is presenting itself currently?

A. IgG

B. IgA

C. IgD

D. IgM

21. Which of these is the most dangerous?

A. Nocebo reaction

B. Pharmacologic drug reaction

C. Idiosyncratic drug reaction

D. Discrete Type 1 hypersensitivity


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22. What is the most common cause of adverse drug reactions?

A. Medication administration errors

B. Medication prescribing errors

C. Medication transcription errors

D. Patient nonadherence

23. Which is NOT true about polypharmacy?

A. Each added drug increases the risk of drug-drug interactions because each drug carries its own risks.

B. Polypharmacy is defined as a person taking more than 8 drugs, including prescription drugs, over the counter (OTC) drugs and supplements.

C. Polypharmacy indicates that there are multiple pathological processes happening in the person, which increases the risk of adverse drug events.

D. If a person has an adverse reaction to a drug it is harder to tell which drug the person’s reaction is to if more than one drug was started at the same time.

24. Which of the following is NOT part of the World Health Organization (WHO) rational drug selection definition?

A. A drug that the person wants.

B. A drug that is appropriate to the person’s clinical needs.

C. A drug that is in the dose appropriate for the clinical requirement.

D. A drug that is at the lowest cost to the person and community.

25. How frequently do prescribing practices around the world match the World Health Organization’s (WHO) rational drug selection definition?

A. 40%

B. 50%

C. 60%

D. 75%

26. It is estimated that what percentage of diagnoses in the USA is incorrect?

A. 5%

B. 10%

C. 20%

D. 25%


Pharmacology

27. How does a drug’s therapeutic index affect its prescribing?

A. A drug with a long therapeutic index can be given at any time of day, while a drug with a short therapeutic index needs to be given multiple times a day.

B. A drug with a primary therapeutic index should be used as a first indicated drug, while a secondary therapeutic index drug is more dangerous, so should be held until safer drugs are not working.

C. A drug with a narrow therapeutic index needs to be monitored so that it does not become toxic, while a drug with a wide therapeutic index will be fine at standard doses with low risk of toxicity.

D. A drug with a low therapeutic index is safe to give with other drugs with a low therapeutic index, while drugs with a long therapeutic index can be mixed with other long therapeutic index drugs. It is not safe to mix low and long therapeutic index drugs.

28. Which is the FIRST step in pharmacokinetics?

A. Absorption

B. Dissemination

C. Excretion

D. Metabolism

29. A drug used to treat which of the following is MOST LIKELY to have problems with continued patient adherence?

A. Infection

B. Gastroesophageal reflux disease

C. Acute pain

D. Hypertension

30. What is the difference between culture and ethnicity?

A. Culture is learned, ethnicity is genetically based.

B. Ethnics is learned, culture is genetically based.

C. Culture and ethnicity are the same.

31. In pharmacogenomics, which of the following can a person NOT be?

A. Poor metabolizer

B. Normal metabolizer

C. Extensive metabolizer

D. Ultrarapid metabolizer


Pharmacology

32. According to this article, the drugs for which two diagnoses are already widely using pharmacogenomic information?

A. Schizophrenia and TB

B. COPD and asthma

C. Cancer and HIV

D. Heart failure and substance abuse

33. What is NOT something to consider when administering drugs to children?

A. CYP450 enzymes do not start being produced until one month of age, and then slowly increase until they reach adult levels at about age of 8 years old.

B. Blood flow to the site of administration in infants is incredibly variable.

C. GI function does not reach adult levels until 8 months of age.

D. Renal status reaches adult levels at about 6-12 months of age.

34. Which drug will tend to be in HIGH concentrations in breast milk?

A. One that is slightly acidic.

B. One that is highly protein bound.

C. One that is lipid soluble.

D. One with extensive first pass metabolism.

35. What is the single most common modifiable risk factor associated with falls?

A. Footwear

B. Poor vision

C. Decreased mobility

D. Medication

36. Which is NOT a concern when prescribing drugs for older adults?

A. Many drugs rely on protein binding to be well distributed. With lower albumin levels, more free drug is available to exert effects.

B. Most people’s kidneys start to decline at about age 30, leaving only about 50% of their renal function available by age 80. This decreases renal excretion of drugs.

C. Decreased blood flow to the liver and decreased activity of CYP450 decreases first pass metabolism.

D. Medicare covers the cost of most prescription drugs. Although many older adults are on a number of medications, cost is not usually an issue.


Pharmacology

37. What is the Beers Criteria?

A. A list of criteria to determine if a certain infection needs to be treated with an antibiotic.

B. A list of drugs that have potential risks that may outweigh potential benefits in older adults.

C. A way to determine if a drug can be sold as over the counter (OTC), or if it needs to stay as prescription only.

D. A way for insurance to determine if a drug should be covered on its formulary.

38. Which part of Medicare pays for prescription drug coverage?

A. Part A

B. Part B

C. Part C

D. Part D

39. Which was the first publication to bring patient safety to light in 1999?

A. Patient Safety at the Crossroads

B. The Patient Safety Congress

C. To Err is Human

D. Spotlight on Patient Safety

40. What gives a nurse practitioner the legal authority to prescribe drugs?

A. Each state’s Nurse Practice Acts

B. Each state’s Medical Board

C. The National Nurse Practice Acts

D. The National Medical Board


Pharmacology

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Pharmacology

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