Neonatal Pharmacology

Primary moral, legal and ethical duty for patient care places primary responsibility for providing safe drug administration on nursing. In neonatal care units, many different drugs are used daily. 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 drug to the neonate is in the ideal position to evaluate issues related to drug administration, make observations, and act in the area where it counts most – the bedside. The study and clinical application of specific knowledge related to neonatal pharmacology can facilitate safe drug administration in the neonatal population. The principles that govern the use of drugs in the neonatal population are no different from those in other age groups. However, the neonate is significantly different physiologically from other populations, and this physiology affects how the neonate responds to drug therapy. Failure to recognize the physiologic differences of neonates, both term and preterm, opens the door to inappropriate and potentially harmful use of drugs. Failure to acknowledge and track the rapidly changing physiologic processes characteristic of the neonatal period can impact drug effectiveness. Lower doses of drugs and longer intervals between doses may be necessary to allow for lower clearance. Without these adjustments, sub-therapeutic or, conversely, toxic drug levels can result.

One of the most important considerations, when one prescribes or administers drugs to any patient is understanding what is expected from administering the drug. 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 (Ku and Smith, 2014).

The prevention of drug-related morbidity and mortality is the responsibility of all patient care providers. Health care providers should evaluate drug therapies and ensure that drug-related problems do not exist. Drug-related problems can be divided into eight categories:

1. The patient has a medical problem that requires a drug but is not receiving a drug for that indication.
2. The patient has a drug indication but is taking the wrong drug.
3. The patient has a medical problem treated with a sub-therapeutic dose of the right drug.
4. The patient has a medical problem resulting from the patient not receiving the drug (drug-delivery or formulation problem).
5. The patient has a medical problem resulting from an adverse drug reaction or side effect.
6. The patient has a medical problem treated with too much of the right drug.
7. The patient has a medical problem resulting from a drug-drug, drug-food, or drug-laboratory interaction.
8. The patient has received the drug for no medically valid indication.

Drugs gradually accumulate in the body over time. When there is an immediate need to achieve a desired therapeutic concentration to elicit an effect and accumulation of drug is expected, a loading dose may be necessary. This fact is true of drugs, including antiarrhythmic drugs, phenobarbital, caffeine, gentamicin, and theophylline (Lodha et al., 2015). If a loading dose is not given, it may take hours to days to achieve the desired therapeutic concentration.

Pharmacokinetic constants for the patient under treatment for similar patients may calculate infusion doses to reach specific concentrations of free drugs in the circulation (Feld et al., 2018).

Effective treatment requires an accurate diagnosis and accurate assessment of the symptoms to be relieved. Although this applies to all therapeutic areas, the neonate presents a particular diagnostic challenge since the small size and fragility of the patient may preclude usefully but invasive diagnostic procedures.

Effective treatment requires the selection of the appropriate drug for the diagnosis. An accurate diagnosis is critical to drug selection since the drug should be selected according to the specific physiologic variable guided by microbes' sensitivities. The severity and acuteness of the patient's illness and symptoms should also be considered. For example, infections require an educated guess for initial drug selection based on available information.

Because it is challenging to test drugs on infants, many drugs are used without FDA approval for use in the infant. The provider must consider all options, risks, and benefits when selecting the drug (Hsieh et al., 2013).

Drug therapy aims to produce an effective concentration of free or unbound drugs at a specific site to achieve the therapeutic effect. Both acidic and basic drugs are bound to various serum and tissue proteins. Albumin binds primarily to acidic drugs, whereas basic drugs are usually bound to other plasma proteins. Only free, unbound drug is active and available to interact with tissue receptors, produce the therapeutic effect, and be metabolized and excreted. 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 sited 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 have to 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 arithmetic description of the movement of a substance through the various body compartments. It reflects a time-dependent relationship between drug dosage and the measurable concentration of a drug, usually in the serum or plasma. Measurement of blood levels is usually easier than the measurement of tissue levels.

Pharmacodynamics is the study of how chemicals produce their pharmacologic effects on living tissue when a drug is administered. 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.

• Receptor concept: the principle that assumes drugs act by forming a complex with a specific macromolecule in a way that alters that molecule's function. This alteration in function may include inhibition or potentiation of the macromolecule's activity in a way that creates the desired drug effect. The drug's affinity for binding to the receptor plays a large part in determining the concentration of the drug required to achieve the desired response. The individual characteristics of the receptor are responsible for the selective nature of drug response. The receptor theory of drug action allows an explanation of drug antagonists. The antagonist drug may alter the characteristics of the receptor molecule to limit or inhibit the response to the original drug. Some drugs do not appear to act through receptors. Their action is related to direct response in the recipient.
• General mechanisms of drug actions are based on the nature of the receptor/drug complex.
  • There are receptor/drug complexes that regulate gene expression. They mediate a response that ultimately involves gene expression and new protein synthesis. These drugs do not generally have an immediate effect after initial administration.
  • There are receptor/drug complexes that change cell membrane permeability. These drugs have a very short time lag between administration and response.
  • There are receptor/drug complexes that increase the intracellular concentration of a second messenger molecule. These drugs increase the production and activity of enzyme systems within the cell. They can stimulate a rapid response to changing cell characteristics.
• The relationship between drug dose and clinical response may be very different. Idiosyncratic drug response is an abnormal response to a drug that is not usually observed and may include:
  • Low sensitivity – usual dose results in a less intense response than usual.
  • Extreme sensitivity – more intense than expected.
  • Unpredictable adverse reaction – drug reaction is substantially different than expected or not usually seen.
  • Tolerance – diminished response to drug-related to long-term administration of the drug.
  • Tachyphylaxis – rapidly diminished drug response without drug dosage change.
• Desired versus undesired effects of drugs can be grouped as desired or therapeutic effects, side effects, and toxic effects. It is the responsibility of the health care provider to weigh the benefits against the undesirable side effects or toxic risks and adjust accordingly (Marc, 2008).

The volume of distribution refers to an imaginary space into which a drug distributes once it reaches the bloodstream and assumes equal distribution of the drug throughout all body compartments. The volume of distribution is the mathematical relationship between the dose administered and the serum concentration of the drug. The volume of distribution for a drug depends on the drug's chemical properties and the patient's physiologic state. Some physiologic factors can alter the volume of distribution:

• The extent of plasma and tissue binding
• Lipid solubility
• Increased volume of distribution for a drug that distributes into body water
• Increases in a patient's intravascular and extravascular fluid
• Changes in protein concentration and binding capacity
• Fat content in the body

If a drug is already present in the circulation, the volume of distribution is calculated from the change in concentration produced by the dose.

If a 2.5 mg dose of gentamicin raises the serum trough concentration of 1.5 mg/L to a peak of 3.5 mg/L the volume of distribution can be calculated from the following equation:

Dose adjustments are dependent upon knowledge of the volume of distribution. If the desired peak concentration is 6.0 mg/L, and the same trough level occurs after the current dose, the volume of distribution can be used to calculate the appropriate change in the next dose to reach the desired concentration.

Half-life describes the time it takes for the serum concentration of a drug to decrease by one-half of its original concentration. Half-life may be influenced by other drugs, tissue perfusion, and organ function (Mansoor & Mahabadi, 2019).

Clearance refers to the amount of drug cleared from the bloodstream per unit of time. The clearance of a drug depends on many factors, including the volume of distribution, the half-life, the physiologic status of the patient, blood flow to the organs, organ function, and the properties of the drug itself. In clinical practice, clearance is generally referred to as linear or nonlinear. For a drug whose clearance follows linear pharmacokinetics, an increase in the dose will proportionately and predictably increase the serum proportional to the drug concentration achieved at a steady state. The majority of drugs used in neonates follow this type of elimination.

A drug that follows nonlinear pharmacokinetics may rapidly raise serum concentration in response to a small increase in dose. This unpredictable dose-response is a result of enzyme saturation in the liver. Elimination now becomes dose-dependent. All drugs cleared hepatically follow nonlinear pharmacokinetics; however, elimination may appear linear over the therapeutic range and change to nonlinear elimination when levels exceed the therapeutic range. An increase in dose yields a predictable increase in serum concentration unless the serum concentration exceeds what is normally considered therapeutic.

Steady-state refers to the point in time at which, for each dosing interval, the patient is receiving the same amount of drug that is being excreted by the body; the rate of drug administration equals the rate of drug elimination. In clinical practice, the steady-state is achieved after about four to five half-lives of the drug have passed. Although drug concentrations will be the same after each dose at a steady-state, constant drug concentration does not define a steady state. The loading dose may lead to rapid attainment of constant circulating drug concentrations, but drug equilibration continues among body compartments for at least five half-lives. The collection of the drug eliminated from the body or sampling of tissue compartments will reveal this continued equilibrium. The time required to reach steady-state concentration depends on the elimination rate, which is inversely related to the half-life. Concentration increases with increasing infusion rate or dose and decreases with a larger distribution volume. Doubling the infusion rate doubles the steady-state concentration, but the time to reach the steady-state concentration remains constant (Guzman, 2020).

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: toxicity and 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:

• Analytic–drug assay is accurate, precise and requires small blood volumes.
• Pharmacokinetic – large interindividual variability exists in drug absorption, elimination, and distribution. Adequate pharmacokinetic data about the drug are available.
• Pharmacologic – pharmacologic effect is proportional to plasma drug concentrations. A narrow range exists between effective and toxic drug concentrations. The pharmacologic effect is constant over an extended period.
• Clinical – studies have provided information regarding the therapeutic and toxic ranges of drug concentrations.

A therapeutic range is a definable range of drug concentrations in which the drug is expected to exert 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 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 distribution phase. Samples drawn during the distribution phase overestimate the peak concentration; sampling 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 drugs, 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.
• Shortening the dosage interval 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 health care provider with the most accurate information about how the patient may handle the drug long-term. 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 (Kang & Lee, 2009)

Certain drugs are highly protein-bound. There are two types of tests available for highly protein-bound drugs: total and free serum concentrations. Free levels indicate the amount of free, unbound drug available to exert its effects on target tissues. 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 expected, or laboratory values are inconsistent with clinical findings, it is important to consider a 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. Drugs that decrease gastrointestinal transit time may reduce the time available for drug absorption of other drugs.

Altered tissue and protein binding can cause drug-drug interactions. One drug may interfere with the metabolism or excretion of another drug, thereby increasing effectiveness, creating toxicity, or producing sub-therapeutic levels. 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, can decrease the metabolism of drugs that require hepatic biotransformation (Lewis, 2010).

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 amount 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.

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. Careful assessment of vital sign parameters and clinical responses may assist in the evaluation of desirable or undesirable drug responses. Careful observation for therapeutic and toxic drug effects will allow safe drug administration, minimizing toxic responses while achieving maximal desired responses. Monitoring renal functions through intake and output measurements 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. Facilitation of drug serum level monitoring with absolute accuracy makes the safe administration of drugs with a narrow margin 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. Drugs known to have very specific recommendations for safe administration should be given under a defined protocol for administration. Any drug or drug preparation known to have a high risk of adverse effects in the neonate should be removed 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.

An infant was born with sluggish respirations. During labor, the infant's mother had received meperidine, a narcotic with a half-life of 2.5-4.0 hours in adults and 12-39 hours in neonates. The physician started resuscitation and ordered naloxone. Shortly after administering the drug, the infant's condition began to deteriorate further.

Prompted by the proximity of the deterioration to the administration of the naloxone, the physician checked the drug's packaging. The syringe had inadvertently been filled with digoxin, a cardiac drug instead of naloxone. The packages of both drugs, made by the same manufacturer, were almost identical. ECG revealed bi-directional ventricular tachycardia, consistent with digoxin toxicity.

Approximately 1 hour later, the infant died. A post-mortem digoxin level was 17 ng/ml (therapeutic range 0.8 to 2 ng/ml).

The brand name of digoxin is Lanoxin®, and in this case, both drugs were made by the same manufacturer and presented in similar packaging. Both are drugs that would be stocked on a typical neonatal unit, and the doses used are similar. The intravenous dose of naloxone recommended for use in newborn babies is ten mcg/kg every 2-3 minutes, and a digoxin loading dose is ten mcg/kg to 17.5 mcg/kg depending on the age of the baby and whether he was full term. If whoever administered the drug confused naloxone with Lanoxin, either because she thought this was the brand name for naloxone or simply because the name on the packaging was misread, there would be few cues to suggest that the wrong drug had been selected until after it had been administered.

Observational studies in hospitals have reported administration errors in 3%-8% of doses in the United Kingdom (UK) and 0.6%-14.6% in the United States (US), excluding wrong time errors. Methods and definitions vary, so it is difficult to compare studies directly, but it is clear that administration errors are not uncommon. Wrong drug errors are typically a smaller proportion of these, occurring in about 0.2% of all doses. Fortunately, most administration errors do not result in outcomes as tragic as in this case.

Errors in drug administration occur. Packaging and look-alike/sound-alike drugs are thought to be important contributing factors. Risk assess look-alike and sound-alike products and consider how they are stored. Improving communication between medical and nursing staff may help to prevent errors. Patients and their families want disclosure of errors and information on how similar errors will be prevented in the future.

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