Episode Transcript
Hello everyone. My name is Anjali Patel and I am currently a medical student at the University of Florida. Today, I’m going to discuss basic principles of pediatric pharmacology. Since this is a broad topic with a vast amount of information, for the purposes of this podcast, I am going to focus on the principles of developmental physiology and its impact on pediatric pharmacology. I will also discuss the principles of pharmacokinetics, including volume of distribution, absorption, elimination, and metabolism. Finally, I will end by discussing compartment models. Before we delve further into this topic, let’s ask ourselves: Why would we even learn about pediatric pharmacology separately from adult pharmacology? I’m sure we are familiar with the old adage “children are not miniature adults.” Well, this can certainly be applied to the subject of pediatric pharmacology. It is an oversimplification at best. However, what we do know is that the developmental changes, more specifically growth, developmental, and organ maturation, affect the clinical response to medicines.
Let’s start by discussing some important principles of developmental physiology. During growth and development, body composition changes markedly. In adults, total body water represents 60% of body weight whereas in preterm neonates total body water represents as much as 80 to 85% of body weight, but then steadily decreases with age. In a full term neonate’s total body water constitutes 75% of body weight and by five months decreases to 60% and remains relatively constant thereafter. Most of the total body water content in premature and full term infants, about 40 to 45%, is located in the extracellular fluid. This decreases to 26% by one year of age and then again to 18% during puberty. In contrast to total body water, body fat content increases with age to 3% in premature, 12% in newborns, reaching its height at one year of age to 30%. Body fat content then decreases once toddlers start walking and decreases to about 18%, which is consistent with adult levels.
Now I would like to move on to discuss the volume of distribution. First and foremost, it is important to know the volume of distribution is not an actual volume; rather it is a theoretical volume. It is best to find the volume necessary to contain the total amount of administered drug at the same concentration that it is observed in the blood. The main utility volume of distribution is in calculating the amount of drug necessary to administer in order to achieve a desired blood concentration. The amount of drug required is equal to the desired concentration multiplied by the volume of distribution. This is an important concept to understand when considering the pharmacology of drugs in pediatric patients. Generally speaking, due to increased water content and decreased fat content, neonates and infants have larger volumes of distribution for water soluble drugs and a smaller volume of distribution for fat soluble drugs. In adolescence and adults the converse is true. For example, infants require a higher dose of succinylcholine since it is a water soluble drug and therefore has a larger volume of distribution. As a result they require an increased initial dose in order to achieve a target serum concentration. Neonates and infants have a large volume of distribution for nondepolarizing relaxants, but are more sensitive to their effects because of their immature neuromuscular junctions. Therefore, no change in dose is required.
There are several things which can either increase or decrease volume of distribution. For example, tissue binding increases volume of distribution while protein binding decreases volume of distribution. Protein binding leads to a decrease in free plasma fraction, causing a decrease in volume of distribution. Decreased plasma protein binding leads to an increase in free plasma fraction, causing an increase in volume of distribution and a shorter elimination half-life. The increase in the apparent volume of distribution and the shorter elimination half-life cause a decrease in total plasma concentration. Therefore, the free drug concentration is more reliable than the total plasma concentration for therapeutic drug monitoring. However, the free amount in plasma and in tissue and the tissue bound amount remain unchanged under steady state conditions.
Acidic drugs tend to bind to albumin while basic drugs bind to alpha one acid glycoprotein. Plasma protein binding is decreased in the neonate compared to the adult due to reduced total protein and albumin. The reduced protein binding increases the fraction of free drug, and thus provides an opportunity for greater pharmacologic effect. This effect is more important for medications that are highly protein bound. The decreased protein binding in neonates and infants will increase the free drug concentration and increase the volume of distribution of highly protein bound drugs, such as phenytoin and bupivacaine. This is an especially important concept for a drug such as bupivacaine, which can be toxic with higher plasma concentrations. Local anesthetics need to be dose adjusted in neonates. In another example, a neonate receiving phenytoin should also be administered in a smaller dose to achieve the same clinical effect as an adult secondary to increased free drug concentration.
Redistribution occurs when a drug with a short onset of action ceases its effects on the body. This occurs as the medication moves from highly perfused areas of the body to less perfused areas of the body. Fat and muscle mass represent a smaller portion of body weight in neonates compared to older children and adults. Medications such as barbiturates and propofol that rely on redistribution into muscle and fat for termination of their clinical effects will have a larger initial blood concentration and more sustained blood concentrations in neonates. As a child grows, they have more muscle mass and fat and will not have larger initial peak and sustained blood concentrations of these medications. With these variations in blood concentrations, one of the primary concerns in pediatric anesthesia is the impact of pharmacologic agents on pulmonary function (AHA, 2015). Anesthetic agents can affect respiratory rate and oxygenation, which is particularly critical in infants and young children due to their higher oxygen consumption and smaller airway size (Boyer, 2023). Similarly, maintaining stable circulatory function is crucial, as children have limited cardiac reserve and are more prone to rapid changes in heart rate and blood pressure (Boyer, 2023). Recent advancements in anesthetic agents are providing new tools to address these challenges. For instance, dexmedetomidine, a selective α2-adrenergic agonist, has gained popularity in pediatric anesthesia for its sedative and analgesic properties with minimal respiratory depression (Shi, 2019). This agent helps maintain stable hemodynamics and reduces the need for additional opioids, which can have more pronounced side effects in children (Shi, 2019). Another notable agent is remimazolam, a novel benzodiazepine with an ultra-short half-life (Gao, 2023). Its rapid onset and offset of action allow for precise control over sedation levels, making it ideal for procedures requiring quick recovery (Hosokawa, 2024). This property is particularly beneficial in pediatric patients, where prolonged sedation can lead to complications like respiratory depression and delayed recovery (Gao, 2023).
Now, I’ll move onto to discuss absorption, elimination, and metabolism. Even though as Anesthesiologists, we are accustomed to administering drugs intravenously, the oral route is the most common way to administer medications to children. For the most part, neonates and small children absorb drugs more slowly than older children and adults due to delayed gastric emptying and intestinal motility. This results in delayed and lowered peak drug concentrations. When it comes to administering medications via the transdermal route, neonates have increased transdermal bioavailability due to a thinner stratum corneum, and better skin perfusion. For example, if an infant had a fentanyl patch, a higher concentration of fentanyl would be absorbed since the skin is thin regardless of the drug's properties. This also applies to drugs given intramuscularly and is due to the higher density of muscle capillaries. Due to pediatric patients’ high sensitivity to changes in preload and afterload, changes in pulmonary vascular resistance (PVR) must be monitored. Agents like sevoflurane and isoflurane, commonly used in pediatric anesthesia, are known to reduce PVR, which can be advantageous in patients with certain respiratory or cardiac conditions (Shi, 2019). However, these agents must be used cautiously to avoid myocardial depression, especially in children with compromised cardiac function (Hosokawa, 2024). Agents like milrinone, which has both ionotropic and vasodilatory effects, are commonly used to support cardiac output and maintain hemodynamic stability during procedures. (Cavigelli-Brunner, 2018). Considering a child's reduced circulating blood volume and sensitive pulmonary vascular beds is crucial, as their immature organ systems contribute to their level of tolerance for ischemia and degree of inflammatory response. (Vakamudi, 2012)
For example, in cases such as a myringotomy placement, an infant without a peripheral venous line has laryngospasm. The laryngospasm continues despite positive pressure and succinylcholine and atropine are administered intramuscularly. Assuming cardiac output has not changed, the infant will have a rapid circulation time and the intramuscular medications will work quickly. Rectal absorption of medication does not change with age. Medications administered high in the rectum are subject to first pass metabolism via the liver whereas medications administered low in the rectum skip first pass metabolism. Therefore, a drug's bioavailability is variable with rectal administration. Another important physiological parameter that changes during development is the ability to metabolize drugs. The liver is the primary site of drug metabolism. Generally speaking, hepatic metabolism is decreased during the first month of life and reaches adult levels by about one year of age. The main goal of hepatic metabolism is to convert lipid soluble drugs into more water soluble compounds to facilitate elimination. Phase 1 reactions involve oxidation, reduction, and hydrolysis reactions to modify the chemical structure of the drugs to render them more water soluble. Phase two reactions involve glucuronidation, methylation, acetylation and sulfation reactions to render molecules even more soluble for elimination. The cytochrome P450 enzyme system is the main enzyme system involved in phase 1 reactions. Even though there are more than 50 P450 enzymes, most drugs are metabolized by a few, which include CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5 and 3A7. The CYP3A family metabolizes 1/3 to 1/2 of all therapeutically used drugs. While CYP3A4 is the major player in the adult liver, CYP3A7 is a predominant form in the fetal liver until about six months of age, when CYP-3A4 expression increases dramatically.
Until this happens, however, most drugs in the neonate are metabolized by CYP3A7 which has low activity towards many drugs. For example, CYP3A is responsible for metabolizing fentanyl and its derivatives, benzodiazepines and local anesthetics and the dose should be decreased in less than six months. Though the liver is the primary side of metabolism for many drugs, extra hepatic sites of metabolism include the lungs, blood, and kidneys. For example, succinylcholine is metabolized by plasma cholinesterases, fentanyl by tissue esterases and esmolol by erythrocyte esterases.
Esterase activity in neonates is already at levels nearly equivalent to those in adults. Therefore, doses of esterase medications do not need to be altered. Metabolism and elimination are intimately intertwined since elimination refers to all processes that remove a drug from the body and includes metabolism and excretion. The kidneys are the chief organs for excretion of drugs and in preterm and term neonates, renal function is less efficient than in adults, and this is mostly because of incomplete development of the glomerular network and decreased perfusion of the kidneys. During the first two months of life, glomerular filtration and tubular function develop quickly, and by two years of age, renal function is fully mature. This means that drugs, which are excreted primarily through glomerular filtration or tubular secretion such as aminoglycosides and cephalosporin antibiotics have a prolonged elimination half-life in neonates. Glomerular filtration rate increases with age and infants older than six months of age do not require renal dose adjustment of medications assuming normal renal function.
Now I’ll move onto discussing compartment models. Compartment models allow us to explain what will happen to drugs after they are administered intravenously. Remember these compartments are theoretical constructs and not actual physical spaces. When drugs are administered they enter into a central compartment where they will remain or enter into peripheral compartments. At the same time, some of the drug is irreversibly eliminated via metabolism or excretion. In the single compartment model, a drug administered as a bolus immediately goes into the central compartment and its concentration decreases as it is eliminated. In the two compartment model, that drug enters the central compartment and the initial central drug concentration falls due to elimination or drug entry into a peripheral compartment. The peripheral compartment includes tissues, such as muscle or fat. Drugs that enter the peripheral compartment can then recirculate between the central and peripheral compartments. The central compartment refers to blood in organs or tissues that are highly perfused. It is important to know that in the two compartment model, the central compartment is a rapidly equilibrating volume while the peripheral compartment is a slowly equilibrating one. In the three compartment model, after an intravenous administration, there is an immediate distribution to the central compartment, and then from the central compartment into a peripheral compartment with rapid equilibration. There’s a third compartment, a peripheral compartment, with a slower equilibrium that is usually poorly perfused. The addition of the third compartment is used to better model changes in drug concentrations. The plasma levels of most drugs used in anesthesia do not follow the single compartment model, but demonstrate multiple compartment kinetics.
To put this all together, let us consider what happens after intravenous administration of a drug like propofol. Once propofol is administered, it immediately enters into the central compartment which consists of the blood and highly perfumed organs such as the brain. From the central compartment the drug then redistributes to the first peripheral compartment, the muscles, where it equilibrates rapidly due to moderate to high perfusion. The redistribution into this compartment is clinically relevant. In our example, the relatively rapid movement of propofol into the second compartment decreases the drug concentration in the central compartment, and thus terminates the effect on highly perfused organs like the brain. The drug will then enter a second peripheral compartment which consists of poorly perfused tissues such a fat where there's a low equilibration with the central compartment.
The field of pediatric anesthesia continues to evolve, with new agents offering more effective and safer options for young patients. As we embrace these innovations, understanding the unique pharmacological needs of children remains paramount. By optimizing drug choices and dosages, healthcare providers can enhance patient outcomes and reduce the risks associated with anesthesia in this vulnerable population. After reviewing this podcast, I hope that you will remember key points of our discussion. Now you know why that age old adage that children are just small adults does not actually apply. Neonates and infants have an increased volume of distribution necessitating an increase in the doses of water soluble drugs. Infants also have decreased protein binding which increases their free concentration of drugs. Hepatic clearance depends on plasma protein binding phase 1 and phase 2 conjugation. Renally cleared medication needs to be adjusted in infants less than six months old. Thank you for taking the time to review some pediatric pharmacology with me.
