Neonatal Pharmacology

The primary moral, legal, and ethical duty for patient care gives primary responsibility for providing safe medication administration specifically on nurses. In neonatal care units, many different medications are used daily.

Neonatal medication administration is complicated and requires education and competency by the provider, the unit pharmacist, and the bedside nurse. New therapeutic strategies leading to further investigation, criticism, and confusion can be alleviated by understanding the drug's pharmacologic principles, pharmacodynamic, and pharmacokinetic properties.

The nurse administering the medication to the neonate is in the ideal position to evaluate drug administration, make observations, and act in the area when they see an error or determine near misses (National Association of Neonatal Nurses [NANN], 2021). The study and clinical application of neonatal pharmacology is important due to differences in neonates’ reactions to medication (Ruggiero et al., 2019). This can help to facilitate safe medication administration in the neonatal population.

The principles of medication administration are the same for all populations. However, the neonate is significantly different due to physiological immaturity, and this physiology affects how the neonate responds to drug therapy (Ruggiero et al., 2019). Failure to recognize the physiologic differences of neonates, both term and preterm, including absorption, distribution, metabolism, and excretion of drugs can lead to poor outcomes (Ruggiero et al., 2019). Knowledge about the principles of medication in regard to physiological differences in neonates can impact drug effectiveness (Le, 2022). Lower doses of drugs and longer intervals between doses may be necessary to allow for lower clearance. Without these adjustments for the size, age, and maturity of neonates, sub-therapeutic or, conversely, toxic drug levels can result.

One of the most important considerations when one prescribes or administers medications to any patient, but especially the neonate, is understanding what is expected from administering the medication. It is important to design a monitoring plan that establishes the limits of toxicity that will be tolerated and the expected therapeutic benefit of the drug treatment plan. The following characteristics influence the way that a patient responds to a drug:

• Age
• Size
• Development
• Concomitant administration of other drugs
• Concurrent disease states
• Organ function and maturity

In addition to all of these factors, many drugs have not been extensively studied in neonates (Ruggiero et al., 2019).

The prevention of drug-related morbidity and mortality is the responsibility of all patient care providers. Healthcare providers should evaluate drug therapies and ensure that drug-related problems do not exist. Drug-related problems can be divided into seven main categories (Tharanon et al., 2022):

1. Unnecessary drug therapy – The patient is receiving a drug with no specific medical reason indication.
2. Need additional drug therapy – The patient has a condition that requires either additional medication or simply the initiation of drug therapy.
3. Ineffective drug – The patient has a medical problem that needs a different drug, the drug is not effective, or the drug is contraindicated for the specific patient.
4. Dosage too low – The dose is too low, or another medication is reducing the amount of drug available in the blood.
5. Adverse drug reaction – The patient has an undesirable drug reaction, a safer drug is available, or the patient has an allergic reaction.
6. Dosage too high – The patient is receiving a medication dosage that is too high or given too frequently, resulting in toxic levels building up in the blood.
7. Non-adherence – The drug is not available for the patient, is too expensive for the patient to purchase and take, the patient does not understand the instructions for drug administration, the patient forgets to take the medication, or the patient either cannot or simply chooses not to self-administer the medication.

A thorough assessment of symptoms and an accurate diagnosis is important to be able to create an effective treatment plan.

Although this concept and priority applies to all therapeutic areas, the neonate presents a particular diagnostic challenge since the small size and fragility of the patient may preclude useful but invasive diagnostic procedures.

Effective treatment requires the selection of the suitable medication based on the presenting symptoms or diagnosis. An accurate diagnosis is critical to medication selection because the drug selection should be based on the specific physiologic variable guided by microbes' sensitivities (Korang et al, 2019).

The severity and acuity of the neonate’s illness and symptoms should also be considered. For example, infections require an educated guess for initial drug selection based on available information due to the high acuteness of potential blood infections. It is after the initial treatment with a broad-spectrum antibiotic and the collection of a blood culture that treatment can then be shifted to an antibiotic that might be better suited to treat the causative agent.

Because it is challenging to test medications on infants due to ethical considerations, many drugs are used without Food and Drug Administration (FDA) approval for use in the infant (Sivanandan et al., 2019). The provider must consider and weigh all options, risks, and benefits when selecting a drug for administration in a neonate (Korang et al., 2019).

The amount of drug binding can influence the distribution of the drug throughout the body. Both basic and acidic drugs are bound to different tissue and serum proteins. Acidic drugs predominantly bind to albumin, whereas basic drugs are usually bound to other plasma proteins. Albumin and α-1 acid glycoprotein (AAG) are 2 of the plasma proteins that most drugs bind to. These are decreased in neonates, and even more so in preterm neonates (Correia, 2020). Therefore, free, unbound drug is available to interact with tissue receptors, produce the therapeutic effect, and be metabolized and excreted (Correia, 2020).

Drugs that are more than 90% bound to protein are considered highly protein-bound. Therapeutic monitoring of plasma or serum drug concentrations usually measures total drug concentration, including bound and free drugs. Displacement of a highly protein-bound drug from its binding site does not change the total drug concentration initially but increases the amount of active drug interacting with tissue receptors, which increases the drug effects and increases metabolism or excretion (Le, 2019).

Premature infants may circulate unbound drug concentration in the therapeutic or even toxic ranges when their serum levels are less than the lower limits of the recommended range for adults because they have lower concentrations of serum proteins. Caregivers must watch for signs and symptoms of drug toxicity even though serum levels may be within a range considered nontoxic. Displacement of one protein-bound substance by another may occur in neonates with a limited capacity for protein binding, especially those with hyperbilirubinemia.

Pharmacokinetics is the study of what the body does to a drug (Le, 2022). It reflects a time-dependent relationship between drug dosage and the measurable concentration of a drug, usually in the serum or plasma (Laxxon Medical, 2023). Measurement of blood levels is usually easier than the measurement of tissue levels.

The drug’s journey through the body occurs over the course of four main stages (Laxxon Medical, 2023):

Image 4:
Pharmacokinetics Process

• Absorption is how the medication moves from the site where it is initially administered into the bloodstream.
• Distribution occurs when a medication moves through the bloodstream and into the tissues of the body.
• Metabolism is the actual breakdown of the drug, which is mainly accomplished by the liver. Newborns or infants do have immature livers, which ultimately impacts their metabolism of drugs.
• Excretion is the elimination of a drug from the body, which is typically accomplished by the kidneys, lungs, or the biliary system.

Pharmacodynamics is the study of what a drug does to the body (Le, 2022).

Drug concentrations must always be considered within the context of the therapeutic goals for which they are used. Therapeutic success or failure is not determined by drug concentrations but by the physiologic or biochemical changes produced by that specific drug in the concentration achieved at the target site. The circulation is rarely the target site but is often the route used to deliver drugs to the target site within a tissue.

The goals of monitoring drug concentrations are to avoid toxic concentrations and achieve concentrations that are effective at the site of drug action. This goal requires a close association between drug concentrations and these two effects:

1. Toxicity
2. Efficacy

This association is not as well established for many drugs in neonates as it is in adults. Therapeutic drug monitoring is not appropriate or indicated for all drugs. The importance of antibiotic concentration monitoring to ensure therapeutic concentrations is often more important to neonates than avoiding toxic concentrations. Requirements for the application of a target concentration strategy include (Husum et al., 1990):

• Analytic – Drug assay is accurate, precise, and requires small blood volumes.
• Pharmacokinetic – Large interindividual variability exists in drug absorption, elimination, and distribution. Sufficient pharmacokinetic data about the drug is available.
• Pharmacologic – The pharmacological effect is proportionate to the drug concentrations in the plasma. A limited range exists between what is an effective and what is considered a toxic drug concentration. The pharmacologic effect remains constant over an extended period of time.
• Clinical – Clinical studies have offered specific therapeutic and toxic ranges of drug concentrations.

A therapeutic drug level is a level in which the drug is expected to have the desired effect with little or low toxicity. Therapeutic drug monitoring requires an assay to be available to measure serum concentrations and is part of the day-to-day monitoring of drug therapy.

Peak and trough drug concentrations are used frequently in therapeutic drug monitoring. The trough concentration is the lowest it will be, just before the next dose. This concentration can be obtained within 30 to 60 minutes of drug administration. The peak concentration refers to the concentration immediately after the end of the drug distribution phase. Samples drawn during the distribution phase overestimate the peak concentration. Sample collection times should be selected to ensure distribution ends. In neonates with slow IV infusion rates, it is often quite hard to determine the end of the infusion.

For some medications, it is important to evaluate both peak and trough serum concentrations:

• If trough concentrations are elevated, this reflects an inability of the body to eliminate a drug, and the dosing interval should be extended (giving the medication less often).
• Shortening the dosage interval (giving the medication more often) is needed if the trough concentration is below the desired level.
• Sub-therapeutic or elevated peak levels require actual dosage adjustments instead of interval changes.

For other drugs, it is most important to determine that serum drug concentration remains within the therapeutic range throughout the dosing interval (e.g., seizure drugs, cardiac drugs, theophylline, and caffeine). In such cases, an evaluation of trough concentration will provide the most benefit. For these drugs, peak concentrations are obtained only if the patient exhibits signs of toxicity.

Obtaining drug levels once a patient achieves steady-state concentrations will usually only provide the healthcare provider with the most accurate information about how the patient may handle the drug over a long-term basis. Obtaining serum concentrations requires significant volumes of blood in the neonate, so assessment of the clinical status may provide more useful information than obtaining serum concentrations of drugs (Ku & Smith, 2015).

Certain drugs are highly protein-bound. There are two types of tests available for highly protein-bound drugs:

1. Free serum concentration
2. Total serum concentrations

Free levels indicate the amount of free, unbound drug available to exert its effects on target tissues. Total serum levels include both unbound and bound drug. If free serum assays are not available, caution must be used to interpret total serum concentrations for drugs that are highly bound to plasma protein. Levels may be falsely interpreted as low when the actual amount of active drug is adequate or toxic.

Understanding drug interactions, not only with other drugs but also with food and other laboratory tests, is important. When a patient's response to a drug differs from what is expected, or when laboratory values are inconsistent with clinical findings, it is important to consider a possible drug interaction. The potential for a drug interaction should be evaluated in all patients receiving more than one drug. It is important to look at the expected timing for potential interactions. Not all interactions occur immediately when two drugs are administered to the same patient. Each interaction has a time course of maximal risk.

Drug-drug interactions can be of several types. Some drugs may interfere with the absorption of other drugs from the gastrointestinal tract. The interference can result from altered motility, altered gastrointestinal pH, altered gastrointestinal flora, and drug binding within the gut lumen (Ruggiero et al, 2019). Drugs that decrease gastrointestinal transit time may reduce the time available for drug absorption of other drugs.

Altered tissue and protein binding can also cause drug-drug interactions. One drug may interfere with the metabolism or excretion of another drug, thereby increasing effectiveness, creating toxicity, or even producing sub-therapeutic levels (Ruggiero et al, 2019). For example, phenobarbital induces liver enzymes and increases the clearance of some drugs, whereas cimetidine reduces enzyme activity, which decreases the clearance of drugs.

Drug-disease interactions must be considered, too, when monitoring therapeutic drug levels. Concurrent disease states can interfere with drug actions. Disease states that result in blood flow alterations to the liver, such as congestive heart failure (CHF), can decrease the metabolism of drugs that require hepatic biotransformation (Ruggiero et al, 2019).

We briefly discussed the steps of pharmacokinetics. Let’s take a moment to analyze these stages a bit more and identify the factors at play that are unique to the neonate.

Extracorporeal membrane oxygenation, or ECMO, is a lifesaving means of technology that provides temporary support for both the lungs and heart when they are unable to function appropriately (Mayo Clinic, 2024).

Patients on ECMO are often treated with numerous drugs, including antibiotics, sedatives, analgesics, inotropes, diuretics, and antiepileptics. Drugs may be administered into the ECMO circuit into the venous reservoir before or after the filter. The effects of the pump may cause an incomplete admixture of the drug, depending on the site of injection. More consistent distribution and delivery of drugs occur when injected after the filter but place the infant at risk for developing air emboli and should be done with extreme caution (Van Ommen et al., 2018). Drugs injected directly into the reservoir or prefilter usually result in a prolonged time of actual drug delivery and incomplete administration. There is often a delay in peak effect for these patients resulting in a false interpretation of serum peak levels for aminoglycoside antibiotics.

Drugs such as heparin and Fentanyl bind to the ECMO circuit, which results in a reduced level of bioavailable drugs for the patient. Bioavailability is no longer an issue once the circuit becomes saturated with these drugs. Increased doses may be required when these drugs are started or when the circuit changes.

Patients on ECMO have underlying hepatic and renal dysfunction secondary to hypoxic insults, and the physiology of ECMO compounds this dysfunction. Renal function frequently deteriorates during ECMO, so dosing adjustments need to be made for any drugs cleared by the kidneys.

A 38-week gestation infant, Cindie, was born with slow respirations.

Pregnancy and labor were all normal, with no risk factors.

During labor, Cindie’s mother had received meperidine, a narcotic with a half-life of 2.5-4.0 hours in adults. Meperidine also has a half-life of 12-39 hours in neonates. Cindie’s mother had received the medication at 5 cm of dilation, but labor progressed quickly, and she delivered within 2 hours of receiving it. The nurse, along with the physician, began the initial steps of infant resuscitation. The physician also asked for naloxone. Shortly after administering the drug, the infant's condition began to deteriorate further (Franklin, 2003).

Because of the worsening of the neonate so close to the administration of the naloxone, the physician checked the drug's packaging. The physician found that the syringe had been filled with digoxin, a cardiac drug instead of naloxone. The drugs are both made by the same manufacturer and the packages were very similar. The electrocardiogram revealed a bi-directional ventricular tachycardia, an arrhythmia consistent with digoxin toxicity (Franklin, 2003).

Approximately one hour later, Cindie passed. A post-mortem digoxin level was drawn and found to be 17 ng/ml. The therapeutic range is 0.8 to 2 ng/ml (Franklin, 2003).

In this case, both drugs were made by the same manufacturer and presented in similar packaging. Both of these medications would be stocked on most neonatal units, and the doses to be given are very similar.

The IV dose of naloxone that is recommended for use in newborn babies is:

10 mcg/kg every 2-3 minutes

The IV a digoxin loading dose is:

10 mcg/kg to 17.5 mcg/kg, depending on age

If the individual who administered the drug confused naloxone with Lanoxin because of the brand name for naloxone or because the name was misread, there would be few signs to suggest that the wrong medication had been chosen until after it had been administered (Franklin, 2003).

Administration errors in hospitals have been cited to be roughly about 3%-8% of doses in the United Kingdom (UK) and about 0.6%-14.6% in the United States, excluding wrong time errors (Franklin, 2003). While methods and definitions may vary, it is clear that administration errors are not uncommon. Fortunately, most errors in medication administration do not result in outcomes as tragic as in this case (Franklin, 2003).

It is important to know that errors in drug administration do occur. Packaging and look-alike/sound-alike drugs are known to be contributing factors of these errors. Risk assessments should be completed and should assess look-alike and sound-alike products and consider how they are stored. Good communication between medical and nursing staff is known to help to prevent medical errors. Anytime an error does occur, there should be a root cause analysis to determine if there is room to make process improvements in how the medication is used and/or given. Patients and their families desire and deserve disclosure of errors and information on how similar errors will be prevented in the future (Franklin, 2003).

Primary moral, legal, and ethical duty for patient care places primary responsibility for providing safe drug administration on nursing in most cases. Nurses must have specific, in-depth knowledge about the pharmacodynamics and pharmacokinetics of the drugs they administer in the informed assessment of clinical response and potential risk. Nurses must perform accurate assessments of vital signs. They also have the opportunity to observe clinical responses to medications to determine if the medication is working or causing adverse drug responses. Nurses must observe for therapeutic and toxic drug effects to allow safe drug administration, minimize toxic responses, and achieve maximum positive results. Reporting any responses that are not expected is the responsibility of the nurse caring for the neonate.

The nurse also monitors renal function through intake and output measurements, which may alert care team members to potential drug metabolism and excretion changes. Giving the drugs at the correct time and over the correct time interval is essential for many drugs to have the maximal desired effect with minimal undesired effects. Drug serum level monitoring improves accuracy and to safely administer medications that have a small area between effective and toxic.

Because of the very small volumes of drugs, a system for regular cross-checking of drug volume accuracy before administration should be established (NANN, 2021). Drugs known to have very specific recommendations for safe administration should be given under a defined protocol for administration. Any medication known to have a high risk of adverse effects in the neonate should be removed completely from the patient care area or specifically labeled to avoid inadvertent administration. Some drugs are introduced into the clinical area after only minimal study of specific drug responses in the neonate, and early observation of potential toxic effects may avert a later disaster.

The neonate is significantly different physiologically from other populations, which affects how the neonate responds to drug therapy. Failure to acknowledge and track the physiologic processes can impact drug effectiveness.

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