This is Nurse 615, and we are going to be talking about Special Populations in Prescribing.
What are the issues in pediatric prescribing? There is a potential for adverse drug events within the pediatric and patient population that is three times as high as among hospitalized adults, and what are the reasons for that? There are several reasons. One is that most medications used in the care of children are formulated and packaged primarily for adults, so those medications have not been tested for side effects or actions on the pediatric population. We just use the medication that has been tested for adults and then just does it for, off label use, pediatric patients. That is one reason. Another is that children, especially young, small, sick children, are usually less able to physiologically tolerate a medication error due to still developing renal, immune, and hepatic functions. So that makes them more at risk for adverse drug events. This becomes really obvious when we look at the fact that 25% of all of the drugs approved by the FDA have any specific indications for children, so a lot of drugs are being approved by the FDA and used in children but only 25% have any indications for children in general. In the past 10 years 12% of all prescriptions written in the US were prescribed for children less than 9 years of age.
When we think about prescribing for the pediatric population, we need remember that children differ from adults in the following ways: absorption, distribution, biotransformation (or metabolism), and excretion. In the ways we have learned about last week in terms of pharmacokinetics, the pediatric population differs from adults in all of those ways, and that can certainly affect the way they metabolize or handle the drugs and it can certainly make them more at risk for adverse drug events and medication errors.
In terms of pharmacokinetics, we need to also think about doses in children are typically based on weight—they are based on weight—milligrams per kilogram, and some physiologic differences are that infants have more water and less fat so that of course becomes an important factor when we start to think about metabolism and distribution of medications. Their liver is immature, so it is going to make fewer serum proteins which is an important piece in drug distribution and metabolism. The blood-brain barrier is less well-developed in infants and renal function is not fully developed until 30 months. Drugs known to be dangerous to children should not be given.
Now pediatric absorption, the gastric pH levels do not reach adult levels until 1 year of age, so that is really significant if an acidic environment is needed to absorb the medication. It is not going to be absorbed as well. They have a greater body surface area, so topical medications need to be taken into consideration because they will have greater skin absorption. They have increased hydration and thinners stratum corneum as well, so that is an issue for topical medications.
In terms of distribution, we already talked about the fact that they have differences in body water and fat and that the immature liver function is a factor. Until about age of 6 months they will have fewer liver plasma proteins, so that gives them fewer binding sites, so we have to be very careful with medications because the pediatric patients with medications could result in higher blood concentrations if you are getting multiple drugs. There might be a competition for receptor binding sites.
Now we also talked about the immature blood-brain barrier. It is not well-developed, so you have an increased risk of drugs entering the CNS.
Phase I drug metabolism is important to remember. In phase I drug metabolism, if you can remember, it is the cytochrome P-450 system. Remember that the 3A system is an important one, a major one in drug metabolism. The 3A system, 3A4 is low in neonates, and it does not reach adult levels until about 6-12 months, so if you give an infant less than a year old any medication that is required to be metabolized in this enzyme system, they are not going to be able to metabolize it effectively. You can see here I have listed several of the enzymes and when they develop; 3A7 is present in utero but rapidly declines after birth, so that is one that neonates do have at birth. One that is especially important and is the reason why we don’t give children aged 2 up to about 5 anymore, why it is not recommended to give them cold medicine, is 2D6. It is absent in the neonatal and does not reach adult levels until age 3-5. Cytochrome P-450 2D6 is the pathway that metabolizes Robitussin and some of the other ingredients in over-the-counter cold medicines, so this helps explain why those medications to toddlers and small children. It doesn’t reach adult levels, this iso-enzyme, until about age 5, so you can see why children were having adverse drug effects with those over-the-counter cold medicines. It is a really good example—I think that is a really good example of where some of those adverse effects come into play and why.
Now we go on to pediatric excretion. We know that infants and small children, especially infants, have immature kidneys. They have a reduced GFR, and it doesn’t really reach levels close to adulthood until at least after 6 months, so what does that mean in terms of pharmacokinetics? Drugs are going to have an extended half-life, so again these little guys (6 months or less) we really have to be very careful in giving them any kind—any medications at all, and certainly renal function is one reason.
Now when we talk about medication errors in the pediatric population, the number one group of medications that are involved in medication errors are immunizations, and #2 are antibiotics. I think if we were to guess just off the top of our heads we would’ve said antibiotics because of how frequently they are prescribed in the pediatric population and the need for weight-based dosing, but immunizations are the #1 group of medications that are involved in medication errors, and it is probably because they are given—some visits they get multiple immunizations, and many of these look very similar in terms of the pediatric and the adult vaccines. They are very similar in the packaging and the way they look, so that is—I just make that point to say be careful if you are a provider who is going to be treating pediatric patients and be involved in immunizing them. It is always a good idea to have more than 1 person checking the vaccine before administering it because you can’t take that back, so just be careful.
Pregnant or breast-feeding women—drug therapy in pregnant women, you know it is targeted at treating either a pre-existing medical condition or pregnancy-related complications, and during lactation we really try (and during pregnancy obviously also) we are really trying to use drugs only if necessary, and during lactation if you do need to give medications to the breast-feeding mother, it is best to have them take it immediately after breast-feeding the infant to lower the concentration of the drug at the next meeting.
Now the FDA in 2014 replaced the old pregnancy categories which were the A, B, C, D, X. Those were the risk categories that all medications were assigned. The new information is called Pregnancy and Lactation Labeling Rule, and it is more of a narrative that each medication is assigned. In the hope was that it would clear up some of the confusion about the letter categories. From what I have read and seen, it has only kind of created more confusion, so I think in most of the resources, you will still see the old A, B, C, D, X kind of categories used, and they are still very helpful. I think your book still talks about them. I don’t think there is a lot of confusion. Typically if you see a category B—you are never going to see an A—but if you see a B you can feel pretty comfortable that this is a medication that you can prescribe during pregnancy.
What happens in pregnancy in terms of pharmacokinetics? You will see that progesterone decreases gastric tone and prolongs emptying time (stomach emptying time) which can really cause a lot of the discomfort (the GI discomfort) that pregnant women will experience. Progesterone causes a lot of things in pregnant women, but it also does cause some respiratory changes as well.
What does it do in metabolism? This has some things that don’t really have to do with metabolism. It does cause your heart rate to go up, but the plasma lipids are increased so the drug transport and distribution are affected. What will happen is there are more—drugs will compete for receptor sites occupied by the hormones which results in more unbound and free drug.
Now, during lactation, with increased lipid solubility and low protein binding such as CNS, we have to think about those are going to pass easily into the breast milk and anything with a low molecular weight is going to pass into the breast milk, so by and large, anytime you are going to prescribe medication to a woman who is breast-feeding, you really want to look at medication up to look at the lactation category. It will be assigned a category to let you know how well it does or does not pass through the breast milk. The biggest rule of thumb to think about, too, is we try not to prescribe a lot of medications to lactating women, but if we have to we try to find a medication that is least likely to pass through the breast milk, although we know that many of them do, and then as we talked about we want to have them take it right after a feeding to decrease the dose in the next feeding.
All right, let’s move on to the geriatric patient. Let’s talk about some aging changes that happen to us all. I think the sad thing to think about is that we really start to notice some of these aging changes at 45, so we are not talking about really elderly people. We are talking about—that sounds young now but not even middle-aged. What happens? The blood-brain barrier starts to increased brain to drug sensitivity, especially for drugs like benzodiazepines and opioids. We have change in the baroreceptor responsiveness so that there is increased risk for orthostatic hypotension, so that is something that is very important, especially as—maybe not so much a 45 but definitely at 70 to 75 when our risk for fall increases. We have decreased renal and hepatic blood flow because our vessels are getting stiffer and we have increased atherosclerosis. A process called immunosenescence develops where there is gradual deterioration of the immune system which is brought on by just the natural advancement of age. What this means is we have increased risk of infections and malignancy, which we all really know that that occurs with the aging process. However, presentations aren’t always real dramatic. Immunosenescence is the reason—pneumonia is the #1 cause of morbidity in the elderly. They just don’t really have the same immune system that they did when they were 30 or even 40. It is a gradual deterioration, and then just the pharmacodynamic aging changes. We have changes in receptors, changes in number of receptors, or receptor responsiveness. This all occurs as we get older. To get good impact from a drug we may need to increase the dose, but we can’t always do that because of renal and hepatic function, so it is a catch 22 when it comes to the pharmacodynamic aging changes. We may not have as many receptors or receptor responsiveness but we may not be able to push the dose because of our renal and hepatic function.
All right, so drug absorption in the elderly—what are some factors that we need to think about? We have decreased gastric acid, so we all know that drugs require an acidic environment to dissolve. If we don’t have that it will take longer to be absorbed. We have reduced blood flow to the organs, and we have overall slower GI motility.
Distribution in the elderly can be a significant issue because of decreased body mass, reduced albumin—all of those factors that you see there. The three most problematic drugs in terms of distribution for the elderly are warfarin, Dilantin, and the SSRIs. You know, the likely factors are probably the reduced albumin, decreased body mass—all of the things that we need to ensure proper drug distribution, but those are the three most problematic medications for the elderly.
What are some other distribution concerns that we need to think about in our geriatric patients? They have increased body fat compared to younger adults, and lipophilic medications will have a greater time to excretion, so that makes sense thinking about the physiology behind that. They will have a particular problem with benzodiazepines, and if you look at this country, who takes a lot of benzodiazepines? Little elderly people, so that can be a really big problem; if they are not excreting them on a regular basis, as they should be, they are hanging onto that drug and we could be looking at some significant side effects. They have less water in their body so you could have increased levels of hydrophilic medications. That is not going to be as much of an issue as the lipophilic medications, however.
Drug metabolism in the elderly, what are we looking at there? Decreased blood flow results in less drug clearance, so that makes sense. The liver size declines because we have a decreased in hepatocytes. That happened to all of our organs. They start to just have smaller mass. We have first pass effect will be reduced, and we know that aging affects the efficiency of phase I metabolism, so what’s phase I? That is our cytochrome P-450. We are going to get slowed metabolism, so all of those enzymes (3A4, 2D6) it’s going to be there but it’s going to work slower. There is reduced oxidation, so we are going to get increased drug blood levels and extended half-lives. All of that makes sense when we think about a slower metabolism, slower phase I metabolism of drugs. None of that is good when you have more drugs hanging on board for longer. Phase II metabolism is not as affected.
Drug excretion in the elderly, what do we need to think about there? We know that aging can decrease renal function, right? We know that. Abnormal renal function effects about two thirds of the elderly population. When you have decreased blood flow to the kidneys, it will definitely affect your GFR. If your GFR is less than 60 you need to be cautious because if that person gets sick then it is likely lower, so even though it is 60 on a good day, if they get sick and you are prescribing medications it is probably lower than that. Even with a seemingly normal renal function, there is a risk with any medications. Patients are asymptomatic until there GFR is less than 35, so we really need to be monitoring creatinine clearance and renal function in our elderly patients.
Let’s look at medication safety in older adults. Our elderly patients take 34% of all prescription medications. Two out of five of them take five or more prescription medications, so when we think about all of the things that we just talked about in terms of the changes in their body, changes in the plasma proteins and how that can affect binding sites and risk for drug to drug interactions, that is a little scary. They also take 30% of all over-the-counter medications and they may not be telling you all of that. Most medications for older adults are for hypertension, coronary artery disease, analgesics, sedatives, and GI medications.
When we talk about adverse drug effects in elderly patients, accidental overdoses are often related to pain medications, and you can see the 4 medications that cause two thirds of hospitalizations. Warfarin is up there, and then you see interestingly insulin and oral hypoglycemics, which are probably sulfonylureas. Insulin is there because really with elderly patients it is hard for them to tell that they are having a hypoglycemic reaction.
What are some causes of adverse drug effects in older adults? Medication factors, which are really drug to drug or drug to food interactions, the physiologic aging changes they really can’t hear when we are giving them instructions. They can’t hear as well. Hopefully they will tell us that, but sometimes they just get tired of telling everyone ‘I can’t hear you,’ or they tell us but they don’t tell us every time they can tear. They may not have their hearing aid in that day or they can’t see the label. They just simply can’t see it. Patient errors which are cognitive, sensory, and system errors. This can happen a lot. Multiple pharmacies, polypharmacy (too many drugs, too many different pharmacies filling them) and provider errors which is over prescribing. It is that 5+ which is sometimes is needed. I’m not saying that it is always an error when older adults have multiple prescriptions, but there could be a way to potentially decrease some prescriptions. It is not always a good thing. Sometimes we are just giving them prescriptions for a medicine for symptom rather than treating the cause.
Risk factors for adverse drug effects—certainly greater than 85 years of age, low BMI. The low BMI typically is less than 22. The creatinine clearance less than 50, more than 6 comorbid disorders—so you can see that, #1, what that would do would be to make you a very sick individual but also typically if you have 6 comorbid disorders you are going to have multiple medications as well. More the 9 meds or more than 12 doses a day, that is just asking a lot for anyone. I feel like if I have 3 or 4 medications to take, I’m probably going to mess that up, especially if it is 3 times a day. Imagine if you had 9 meds or more than 12 doses a day in your elderly. You add in sensory deficit or you have arthritis in your hands can’t open those bottles as well. That’s a risk factor, or if you have had a previous adverse drug event or effect.
What can we do to hopefully help us not unnecessarily or inappropriately prescribed medications for older adults? The Beers criteria is one way that providers can check to make sure they are not over prescribing. It was first developed in 1991 by Mark Beers who was a geriatrician. It was then updated in 2011 by the American Geriatric Society. It is by an interdisciplinary task force that determine quality of evidence of potentially inappropriate meds for older adults, and then there is a 2015 update. You can download this criteria. It goes through a set of questions that help you determine if a medication is potentially inappropriate for a patient, so that is one way.
Another way is to use STOPP and START criteria. The STOPP criteria stands for Screening Tool of Older Persons’ Potentially Inappropriate Medication basically. The START criteria is the Screening Tool to Alert Doctors to Right Treatment. These are—the STOPP is actually of Older Persons’ Potentially Inappropriate Prescriptions, and that the START criteria is the Screening Tool to Alert Doctors to Right Treatment. You can get these easily on the Internet. They are a little bit—STOPP is one, START is another—can be a little bit lengthy, but they go through and assign points and they are really very helpful, especially if you have a patient with a long list of medications and you are really trying to weed through them.
That is the end of this presentation.