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 medications 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 medication. The nurse administering the medication to the neonate is in the ideal position to evaluate issues related to medication administration, make observations, and take action 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 medication in the neonatal population are no different than 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 medication therapy. Failure to recognize the physiologic differences of neonates, both term and preterm, opens the door to inappropriate and potentially harmful use of medication. Failure to acknowledge and track the rapidly changing physiologic processes characteristic of the neonatal period can impact medication effectiveness. Lower doses of medications 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 medications 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 way that a patient responds to medication is influenced by the following characteristics:
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:
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 retrograde infusion is used Y-injection ports may trap small volumes of 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 medication into the tissue surrounding the intravenous 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 is close attention to the intravenous site where the medication is infusing. Hyaluronidase, an enzyme that destroys tissue cement, may be useful for the treatment of extravasation.
IM drug therapy may be used in larger, well-perfused infants. The rate of absorption of drug from IM administration depends on the blood flow to the site. 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. Sterile abscesses may develop from IM administration in small neonates with limited muscle mass.
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 drug during the first circulation through an organ). Many of the medications 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. Medications available in suspensions and 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.
Osmolality must also be considered when providing neonatal enteral medications. Substances with high osmolality that are administered to the neonate have been associated with many adverse effects, including development of necrotizing enterocolitis and decreased transit time. Many enteral medications add a significant osmolar load to the formula or breast milk. It is important to stagger neonatal enteral medications to avoid simultaneous administration of highly osmolar medications.
The delivery of medications to the lung would appear to be optimal because this is the desired site of action of many therapies prescribed in the neonatal population. 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 medication administered by inhalation because the larger particles of the drug may deposit in the airway before reaching the intended site of activity.
Medications 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 medication may be necessary. This is true of medications including antiarrhythmic agents, phenobarbital, caffeine, gentamicin and theophylline. If a loading doe is not given, it may take hours to days to achieve the desired therapeutic concentration.
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. If a drug is dispensed according to the weight of its salt form, the dose must be adjusted since the concentrations measured are those of the free drug.
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.
Effective treatment requires 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.
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 measure total drug concentration, including bound and free drug. Displacement of 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.
Premature infants may have circulating 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 a drug dosage and the measurable concentration of medication that results, usually in the serum or plasma. Measurement of blood levels is usually easier than measurement of tissue levels.
Pharmacodynamics is the study of how chemicals produce their pharmacologic effects on living tissue when medication 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.
Volume of Distribution refers to an imaginary space into which a medication distributes once it reaches the blood stream and assumes an equal distribution of drug throughout all body compartments. The volume of distribution is the mathematical relationship between dose administered and the serum concentration of the medication. The volume of distribution for a medication 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:
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) |
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 medication to decrease by one half of its original concentration. Half-life may be influenced by other medications, tissue perfusion and organ function.
Half-life (t1/2) =
| 0.693 |
Clearance refers to the amount of drug cleared from the blood stream per unit of time. Clearance of a medication 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 medication itself. In clinical practice, clearance is generally referred to a 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 medications used in neonates follow this type of elimination.
A drug that follows nonlinear pharmacokinetics may have 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 medications 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 increased 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 |
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 steady state. 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. 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.
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:
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-today monitoring of drug therapy. Peak and trough drug concentrations are used frequently in therapeutic drug monitoring.
The trough concentration is the lowest concentration just prior to 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 medications it is important to evaluate both peak and trough serum concentrations.
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 medication 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.
Certain medications are highly protein bound. There are two types of tests available for highly protein-bound medications: 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 interpretation of total serum concentrations for medications 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 medications but also with food and other laboratory tests is important. Whenever a patient’s response to medication 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 medications from the gastrointestinal tract. The interference can result from altered motility, altered gastrointestinal pH, altered gastrointestinal flora, and drug binding within the gut lumen. Medications that decrease gastrointestinal transit time may reduce the time available for drug absorption of other medications.
Altered tissue and protein binding can cause drug-drug interactions. One drug may interfere with the metabolism or excretion of another medication, thereby increasing effectiveness, creating toxicity or producing sub-therapeutic levels. For example, phenobarbital induces liver enzymes and increases clearance of some medications, whereas cimetidine reduces enzyme activity which decreases clearance of medications.
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 metabolism of medications that require hepatic biotransformation.
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.
Maternal medications during pregnancy must also be considered. There is evidence that prenatal exposure to drugs that have the capacity to induce liver enzymes may affect neonatal metabolism. During intrauterine life the fetus depends on his own and his mother’s liver to detoxify compounds.
No absorption time is required for intravenous or intra-arterial administration. Other routes of administration require absorption of the medication from the site of administration for the drug to be recovered from the blood stream. 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 medications 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 medications. 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 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.
Neonates have a gastric pH at birth of 6 – 8. Medications that are weak acids will be poorly absorbed. Medications 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 medication 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 medications. Biliary function and bile acid pool increases over the first month of life. The state of bile acid depletion affects medications administered with food. Bile acids are required for absorption of fat-soluble vitamins and those patients with poor biliary function have difficulty absorbing these nutrients.
The absorption of some medications through the skin depends on the skin integrity, blood flow to the skin, and the amount of subcutaneous fat. Premature infants have a 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 agents can be absorbed to a significant degree which can lead to toxicity.
Rectal absorption may be a valuable route of administration for some medications 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 is the rapid transfer of drug 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, 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:
Most medications that are protein bound bind to serum albumin. Newborns have a higher concentration of substances that compete with medications 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 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.
Excretion begins with 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 elimination of both metabolized and unmetabolized drug. This occurs by glomerular filtration and tubular secretion. 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, 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 diffusion of drugs from out of the blood stream. 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.
The use of a larger variety of antimicrobial agents 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 agents in the neonatal population. Antimicrobial drugs inhibit the growth or kill microorganisms and include antibacterial agents, antifungal agents, and antiviral agents. The choice of antimicrobial regimen must take into account:
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 agents is the luminal surface of the renal tubular cell. Diuretic use must be based on 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. Pharmacologic response is dependent on 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 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 occurs in the first days of use. Later, decreased glomerular filtration rate and hyperaldosteronism that result from diuretic-induced hypovolemia limit these losses.
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 medications can cause the development of drug tolerance and dependence. Consideration must be made for the risks and benefits of the medication. Important considerations with CNS drugs include:
There are three types of CNS drugs:
CV agents 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 prior to use. Many of these drugs have overlapping effects. Extensive knowledge and application of invasive and non-invasive cardiovascular monitoring is necessary when using these agents. There are several types of CV agents:
IV Compatibility of Common Drips
“Y” site Compatibility
TPN (no lipids)
* May co infuse if no other options available (limited data suggest that the combination is compatible)
Patients on ECMO are often treated with numerous medications, including antibiotics, sedatives, analgesics, inotropes, diuretics, and antiepleptics. Medications 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 medication depending on the site of injection. More consistent distribution and delivery of medication occurs when drugs are injected after the filter but places the infant at risk for development of air emboli and should be done with extreme caution. Medications 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 false interpretation of serum peak levels for aminoglycoside antibiotics.
Drugs such as heparin and Fentanyl bind to the ECMO circuit which results in 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 medications 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 medications 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 response. Monitoring renal functions through intake and output measurements may alert care team members to potential changes in drug metabolism and excretion. Giving the medications at the correct time and over the correct time interval is essential for many drugs to have 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 medication, a system for regular cross-checking of drug volume accuracy prior to 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 effect 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 medication therapy. Failure to acknowledge and track the physiologic processes can impact medication effectiveness.
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