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Neonatal Pharmacology

2 Contact Hours including 2 Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Saturday, June 11, 2022
Outcomes

≥90% of participants will understand how to administer drugs to a newborn.

Objectives

Upon completion of this course, the learner will be able to meet the following objectives:

  1. Describe three methods used to administer drugs to neonates.
  2. Identify four characteristics that influence the way a patient responds to a drug.
  3. Define the goal of therapeutic drug monitoring.
  4. Discuss four factors of pharmacology that are unique to neonates.
  5. Discuss the needs of special neonatal populations.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Kelly LaMonica (DNP(c), MSN, RNC-OB, EFM)

Introduction

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 pharmacologic principles, pharmacodynamic, and pharmacokinetic properties of the drug. 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 the way that 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.

General Principles

One of the most important considerations, when one prescribes or administers drugs to any patient, is the understanding of what is expected from the administration of the drug. It is important to design a monitoring plan that establishes the limits of toxicity that will be tolerated as well as 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.1

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

Drug Administration

Parenteral Administration

Intravenous (IV) drug therapy is usually recommended if not essential for the sick neonate owing to the unreliable and unpredictable gastrointestinal drug absorption. Some of the more common problems of parenteral infusion are related to the infusion rates of neonatal IV fluids. When the retrograde infusion is used, Y-injection ports may trap small volumes of the drug. In-line filters absorb certain drugs. Drugs may be diluted within the reservoir volume; they may infuse more slowly or become trapped at the bottom of the reservoir if they are much heavier than the IV solution. The hub of a syringe contains about 0.1 ml, and if IV fluid or blood from a catheter is drawn back into the syringe after infusion of a small volume dose, a potentially large extra amount of drug may be administered.

Extravasation and infiltration are terms used interchangeably in the literature; both terms reflect a misdirection of intravenous fluid or drug into the tissue surrounding the intravenous site. Infiltration or extravasation injuries occur when fluids or drugs penetrate the tissue surrounding an intravenous catheter site and are a known complication of peripheral IV use.2 Extravasation is usually defined as the inadvertent administration of a vesicant solution, while infiltration is defined as a non-vesicant solution. Both injuries result from damage to vessel endothelium, which allows the fluid to penetrate tissues surrounding an IV site. The extent of damage that follows such an event depends on the extravasated substance and the volume of the fluid that has leaked into the interstitium. The best prevention of serious damage is close attention to the intravenous site where the drug is infusing. Using guidelines for appropriate IV drug administration and completing thorough IV, site assessments can decrease infiltrations and prevent serious damage. Hyaluronidase, an enzyme that destroys tissue cement, may be useful for the treatment of extravasation.

Intramuscular (IM) administration

IM drug therapy may be used in larger, well-perfused infants. The rate of absorption of the drug from IM administration depends on the blood flow to the site and the surface area of the muscle.1 The chemical properties of the drug can also affect absorption. IM administration is not appropriate if the infant is cold or vasoconstricted. IM administration of a high dose of a drug that is caustic and burns tissue may produce a depot effect in which the drug remains in a puddle-like collection within the tissue, and absorption is delayed and often incomplete.

Enteral Administration

Enteral therapy is an integral part of long-term management for many premature infants. Enteral drug therapy may produce unpredictable circulating concentrations for drugs that undergo hepatic first-pass elimination (removal of a large portion of the drug during the first circulation through an organ). Many of the drugs that are used orally are available only as tablets or capsules. There is limited information on the bioavailability of the product as to which active ingredients are absorbed and the time at which maximum serum concentration is achieved. Drugs available in suspensions and the oral solution often have volumes that are not appropriate for the neonate. The product may be concentrated such that accurate measuring is difficult. These preparations may also contain "silent" or inert ingredients such as preservatives that are harmless to adults, but when administered frequently to neonates may result in toxicity.

Absorption of the enteral drug depends on the pH levels of the GI tract (which can vary in different segments), feeding frequency, and gastric emptying times. Generally, most drugs are absorbed more slowly in neonates. The pancreatic and biliary function may be immature in the neonate.3

Osmolality must also be considered when providing neonatal enteral drugs. Substances with high osmolality that are administered to the neonate have been associated with many adverse effects, including the development of necrotizing enterocolitis and decreased transit time. Many enteral drugs add a significant osmolar load to the formula or breast milk. It is important to stagger neonatal enteral drugs to avoid the simultaneous administration of highly osmolar drugs.

Aerosolized Drugs

The delivery of drugs to the lung would appear to be optimal because this is the desired site of action of many therapies prescribed in the neonatal population. Intrapulmonary administration via drug inhalation is used to achieve a local effect. Development of the lung influences this effectiveness of drugs delivered by this route.3 The particle size produced by various inhalers and nebulized solutions may be much larger than the airway diameter itself. This discrepancy may preclude the premature infant from receiving the most benefit from a drug administered by inhalation because the larger particles of the drug may deposit in the airway before reaching the intended site of activity.

Rectal Administration

The rectal route is an alternative site for systemic drug administration when nausea, vomiting, seizures, or preparation for surgery preclude the use of oral dosage formulations.3

Loading Doses

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 of the drug may be necessary. This is true of drugs, including antiarrhythmic drugs, phenobarbital, caffeine, gentamicin, and theophylline.4 If a loading dose is not given, it may take hours to days to achieve the desired therapeutic concentration.

Continuous Infusion Dosing

Pharmacokinetic constants for the patient under treatment for similar types of patients may be used to calculate infusion doses to reach specific concentrations of free drug in the circulation.5

Diagnosis

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

Drug Selection

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 that is guided by the sensitivities of microbes. The severity and acuteness of the patient's illness and symptoms should be considered as well. 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 and risks and benefits when selecting the drug to use.6

Drug Binding

The goal of drug therapy is to produce an effective concentration of free or unbound drug at a specific site to achieve the therapeutic effect. Many drugs, both acidic and basic, 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 and produce the therapeutic effect as well as to 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 increased metabolism or excretion.7

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

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 drug that results, 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 the determination of 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 in a way that then limits or inhibits the response to the original drug. Some drugs do not appear to act through receptors. Their action is related to a 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 act by mediating a response that ultimately involves gene expression and new protein synthesis. These drugs do not generally have a rapid 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 substantially different than would have been 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 risk and adjust accordingly.8

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 chemical properties of the drug itself and the physiologic state of the patient. Some physiologic factors can alter the volume of distribution:

  • 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 from by the dose.

Volume of distribution (Vd) =
dose (mg/kg)/Peak concentration (mg/L)

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:

3.5 - 1.5 (mg/L) =
2.5 (mg/kg)/volume of distribution (L/kg)
Volume of distribution (mL/kg) =
2.5 (mg/kg)/2.0 (mg/L)
= 1.25 (L/kg)

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.9

Half-life (t1/2)
t1/2 = .693 x VD (volume of distribution)/CL (clearance)
t1/2 = .693 x
VD/CL

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 concentration of drug achieved at steady state. The majority of drugs used in neonates follow this type of elimination.

A drug that follows nonlinear pharmacokinetics may have a rapid rise in 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.

Clearance (Cl) =
0.693 X Vd/T1/2

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 considered to be achieved after about four to five half-lives of the drug have passed. Although drug concentrations will be the same after each dose at steady-state, constant drug concentration does not define a steady state. The use of 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 is dependent upon the elimination rate, which is inversely related to the half-life. Concentration increases with increasing infusion rate, or increasing dose and decreases with larger distribution volume. Doubling the infusion rate doubles the steady-state concentration but the time to reach the steady-state concentration remains constant.10

Therapeutic Drug Monitoring

The goals of monitoring drug concentrations are to avoid concentrations that are toxic and to achieve concentrations that are effective at the site of drug action. This requires a close association between drug concentrations and these two effects: toxicity and efficacy. For many drugs, this association is not as well established 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 concentrations considered toxic. Requirements for application of a target concentration strategy include:

  • Analytic – drug assay is available that 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. Pharmacologic effect is constant over an extended period.
  • Clinical – 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 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 that distribution has ended. 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.
  • If the trough concentration is below the desired level, shortening the dosage interval is needed.
  • Sub-therapeutic or elevated peak levels require actual dosage adjustments instead of interval changes. For other drugs, it is most important to be able to determine that serum drug concentration remains within the therapeutic range throughout the dosing interval (e.g., seizure drug, 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 on 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.11

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 that is available to exert its effects on target tissues. If free serum assays are not available, caution must be used in the interpretation of 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. Whenever a patient's response to a drug is different 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.12

Factors Unique to the Neonate

Metabolism

Many drugs must be metabolized to a more highly charged, less lipid-soluble form before elimination from the body by renal, biliary, or other routes of excretion. The process of biotransformation occurs mainly in the liver. Although the liver is the major organ responsible, other organs are quite active for newborns (kidneys, intestine, adrenal, and skin). Each pathway matures at a different rate. A variety of factors after birth from nutrition to acquired illnesses may accelerate or retard the maturation of drug metabolism. These factors along with changes in hepatic blood flow, enzyme induction, renal tubular and glomerular function, protein binding, and biliary secretion prevent accurate estimations of drug metabolism after birth.1

Maternal drugs during pregnancy must also be considered. There is evidence that prenatal exposure to drugs that can induce liver enzymes may affect neonatal metabolism. During intrauterine life, the fetus depends on his own and his mother's liver to detoxify compounds.

Absorption

No absorption time is required for intravenous or intra-arterial administration. Other routes of administration require absorption of the drug from the site of administration for the drug to be recovered from the bloodstream. Absorption from an intramuscular injection is influenced by muscle tone, muscle mass, and regional blood flow to the area. Neonates have significantly decreased muscle mass and decreased tone. Blood flow to the muscle tissue can be complicated by hypoxemia, sepsis, shock, and congestive heart failure. IM injections of some drugs may result in a delay in therapy because of poor or erratic absorption. A longer duration of action and a delay in the time to peak serum levels may occur with IM drugs. IM administration should only be used if absolutely necessary for the patient to receive drug therapy.

Problems common in neonates alter enteral drug absorption. Absorption from the gastrointestinal tract depends on many variables. Most GI absorption occurs outside the stomach in the large surface of the intestine. Delayed gastric emptying or delayed peristalsis delays the distribution of the drug along the intestine and decreases drug absorption. Rapid intestinal transit due to diarrhea may prevent complete absorption. Antacids used to raise gastric pH binds with some drugs in the intestinal tract, such as digoxin, which is excreted with the stool and reduces the amount of absorption. Disease states with venous engorgement and decreased perfusion of the GI tract will decrease drug absorption.1

Neonates have a gastric pH at birth of 6 – 8. Drugs that are weak acids will be poorly absorbed. Drugs that are weak bases will be absorbed to a much greater extent. Absorption and time for peak serum concentration are influenced by the contact time of the drug with the absorptive surface. Neonates and especially premature infants, have a delayed gastric emptying. Neonates have a relative state of pancreatic insufficiency. Pancreatic enzymes are required for the intraluminal hydrolysis of some drugs—biliary function and bile acid pool increase over the first month of life. The state of bile acid depletion affects drugs administered with food. Bile acids are required for the absorption of fat-soluble vitamins, and those patients with poor biliary function have difficulty absorbing these nutrients.

The absorption of some drugs through the skin depends on the skin integrity, blood flow to the skin, and the amount of subcutaneous fat. Premature infants have skin to body surface area that is three times that of an adult. They also have decreased amounts of subcutaneous fat and overall decreased skin barrier. Topical drugs can be absorbed to a significant degree, which can lead to toxicity.

Rectal absorption may be a valuable route of administration for some drugs when other routes are not available. Rectal absorption depends on blood flow, retention of the drug in the rectum, and chemical properties of the drug.

Distribution

Distribution is the rapid transfer of drugs from a site with a high concentration to tissues with low concentrations until equilibrium is established. Immaturity and organ function alter distribution. The rate of distribution depends on tissue perfusion, the permeability of tissue to the drug, and the relative partition of drugs between tissue and blood. Some drugs are actively transported across tissues against a concentration gradient. This lowers the serum concentration and raises the calculated volume of distribution. Distribution is affected by:

  • Binding to tissue or plasma proteins
  • Nature and size of available body compartments
  • Chemical properties of the drug

Most drugs that are protein-bound bind to serum albumin. Newborns have a higher concentration of substances that compete with drugs for binding sites on albumin. Serum albumin and total protein levels decrease during infancy. Total body water and the distribution of it in the intracellular and extracellular spaces vary with the gestational age of the infant. As the fetus matures, total body water decreases to a total of 75 percent at term, with only half of that as extracellular fluid. The central nervous system and the blood-brain barrier are immature in neonates resulting in increased accessibility of drugs to the central nervous system. Neonates have an increased sensitivity to drugs that have sedative and central nervous system effects.1

Excretion

Excretion begins with the administration of the drug and ends when the drug is completely eliminated from the body. There are several important organs of excretion. Renal excretion is a major route for the elimination of both metabolized and unmetabolized drugs. This occurs by glomerular filtration and tubular secretion. The glomerular filtration rate is lower in infants than adults and significantly lower in premature infants. For some drugs, there is significant renal tubular reabsorption of the drug back into the circulating plasma. Tubular reabsorption and secretion are also decreased in the neonate. Because of changes in renal blood flow, the urinary output is not a reliable sign of renal excretion of drugs. Drugs excreted primarily by the renal route, must have extended dosing intervals. Small amounts of drugs may be excreted through salivary, sweat, and mammary glands. The lungs are an important route of excretion of gaseous anesthetics, but relatively less important for other drugs. The large lipid-soluble surface of the GI tract allows the diffusion of drugs from out of the bloodstream. The liver is the most important site of drug biotransformation and serves as an important site of drug excretion. The excretion of bile is an important route of drug elimination. Limited bile flow may limit the efficacy of this elimination.1

Specific Drug Categories

Antimicrobial drugs

The use of a larger variety of antimicrobial drugs in the newborn population has occurred in the last several years because of advancing clinical sophistication in the use of antimicrobial drugs as well as an expanding body of knowledge on the use of such drugs in the neonatal population. Antimicrobial drugs inhibit growth or kill microorganisms and include antibacterial drugs, antifungal drugs, and antiviral drugs. The choice of antimicrobial regimen must consider:

  • Microorganism sensitivity to available antimicrobial drugs
  • Relative permeability of the target tissue to the drug of choice
  • Bioactivity of the chosen antimicrobial drug in the target tissue
  • Known MIC (minimum inhibitory concentration)/MBC (minimum bactericidal concentration) in relation to the existing body of knowledge concerning side effects and toxicity in the specific population
  • Specific characteristics of the individual patient in relation to the chosen antimicrobial's pharmacokinetic (e.g., in a patient with impaired renal function, a nephrotoxic antimicrobial should be avoided if possible)13

Diuretics

Diuretics are commonly used in both acute and long-term neonatal care to encourage the removal of excessive extracellular fluid. The site of action of nearly all diuretic drugs is the luminal surface of the renal tubular cell. Diuretic use must be based on a good understanding of renal physiology and function. Diuretic drugs whose primary purpose is to cause the excretion of excess extracellular fluid commonly cause loss of electrolytes along with the water loss. The pharmacologic response is dependent on the existing level of renal function and on the drug's ability to reach the target tissue in amounts adequate to produce a diuretic effect. Any drug or therapy that increases the glomerular filtration rate may have an indirect diuretic effect. Some drugs that act on the cardiovascular system to increase cardiac output or increase renal blood flow through vasodilation may cause diuresis. Maximal water and electrolyte excretion usually occur in the first days of use. Later, decreased glomerular filtration rate and hyperaldosteronism that result from diuretic-induced hypovolemia limit these losses.14

Central Nervous System (CNS) Drugs

CNS drug use has been increasing as neurobehavioral assessment skills among caregivers increases. The value of pain control and mood alteration in the neonatal population has finally been recognized, but not much is known about neonatal neurological development. The effect that CNS drugs may have on that development is largely unknown. These drugs can cause the development of drug tolerance and dependence. Consideration must be made for the risks and benefits of the drug. Important considerations with CNS drugs include:

  • Addiction is a lifestyle change that occurs in a drug-dependent person. This lifestyle change involves a focus on drug use. It cannot occur in a neonate.
  • Tolerance is a condition that may occur with many types of drugs. Tolerance exists when larger doses and higher serum concentrations of the drug are required to achieve the desired response and commonly occurs in conjunction with physical dependence.
  • Dependence is a physiologic state in which the individual requires regular drug administration for continued physiological well-being. It can easily be remedied through a dosage tapering regimen (weaning).

There are three types of CNS drugs:

  • Analgesic drugs provide a diminished sensation of pain and help to promote a diminished response to painful events.
  • Anesthetic drugs remove pain sensation either through peripheral nerve block or through the CNS effect.
  • Sedative/hypnotic drugs provide mood alteration in patients with anxiety. They are divided into barbiturates and non-barbiturates. However, they do not provide relief from pain and careful attention to the differentiation of need for sedation, pain relief, or both.

Newborns born to mothers using CNS drugs, specifically opioids, can experience withdrawal and need to be carefully assessed for neonatal abstinence syndrome. Congenital malformations are also possible with other types of CNS drugs. These drugs can have serious consequences for the neonate.15

Cardiovascular (CV) Drugs

CV drugs are a broad group of drugs that affect the regulation, inhibition, or stimulation of the CV system. They have increased utilization in acute and long-term care of neonates. The wide range of pharmacologic action requires specific, in-depth knowledge about each drug before use. Many of these drugs have overlapping effects. Extensive knowledge and application of invasive and non-invasive cardiovascular monitoring are necessary when using these drugs.16 There are several types of CV drugs:

  • Inotropic drugs can improve cardiac output by increasing the heart rate, increasing the force of myocardial contraction, and increasing vascular tone. They are most commonly used in cardiovascular resuscitation and long-term support of the myocardium.
  • Antihypertensive drugs are used to normalize blood pressure. They may be used to inhibit pathophysiologic changes that cause increased blood pressure or directly reduce blood pressure through changes in intravascular volume or resistance.
  • Vasodilators may be used to acutely diminish blood pressure, alter vascular resistance or capacities, and reduce pulmonary vascular resistance.
  • Antiarrhythmics are used in the treatment of cardiac arrhythmias causing adverse effects on cardiac stability.

Extracorporeal Membrane Oxygenation (ECMO)

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 drugs are injected after the filter but place the infant at risk for development of air emboli and should be done with extreme caution.17 Drugs injected directly into the reservoir or prefilter usually result in a prolonged time of actual drug delivery and incomplete administration. There is often 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 drug for the patient. Once the circuit becomes saturated with these drugs, bioavailability is no longer an issue. Increased doses may be required when these drugs are started or when the circuit is changed. 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 that dosing adjustments need to be made for any drugs cleared by the kidneys.

Summary

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 response. Monitoring renal functions through intake and output measurements may alert care team members to potential changes in drug metabolism and excretion. 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 possible 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 should be specifically labeled to avoid inadvertent administration. Some drugs are introduced into the clinical area after only minimal study of specific drug response in the neonate, and early observation of potential toxic effects may avert a later disaster. The neonate is significantly different physiologically from other populations, and this affects the way that the neonate responds to drug therapy. Failure to acknowledge and track the physiologic processes can impact drug effectiveness.

Case Study18

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 the administration of 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 packaging of the drug. 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 given. 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, along with information on how similar errors will be prevented in the future.

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