Section 1
Basics of Pharmacotherapy in Neonates, Infants, and Children
INTRODUCTION
According to a dictum, “the child is not a mini adult.” Likewise, the neonate is not a mini child. This holds good at least from the angle of drug therapy and dosage that are based on not only the indication but also on the pharmacokinetics and pharmacodynamics. As a result of studies related to developmental pharmacokinetics, today we know that:
- Pharmacokinetics are quite immature in the neonates, especially in the according to preterm, low birth weight (LBW) infants and infants suffering from intrauterine growth restriction (IUGR)
- During age 1 to 12 months, there is an improvement in the maturity
- During age 1 to 4 years, these are nearly stabilized
- During age 5 to 11 years, these are even somewhat above the status in adults
- During adolescence, these are fully matured.
The old practice of drug prescribing in neonates, infants and children just by arbitrary modification of the adult dose was by all means erroneous and ill-founded.2
As a rule, most of the factors influencing the drug disposition are unique in neonates and infants who represent the most fragile group due to physiological instabilities and increased potentials for toxic effects as compared to children and adults. However, only limited work has been done in these areas in pediatric age group, leaving quite a few gray areas for elucidation. This age group should, therefore, receive special attention for pharmacokinetic, pharmacodynamics, and toxicologic research.
CERTAIN DEFINITIONS
The term, pharmacokinetics, implies the quantitative evaluation of various components of a drug's disposition, e.g. absorption, distribution, metabolism and excretion. Precisely, pharmacokinetics refers to what the body does to the drug. It is, thus, a mathematical expression of the time course of movements in the body. A drug's pharmacologic effects, toxic effects or both correlate best with its concentration in blood or some other biologic fluid rather than the administered absolute dose. The dose and dose interval to attain a defined target concentration for the desired pharmacological effect is based on pharmacokinetics.
The term, pharmacodynamics, denotes the correlation of pharmacological response to a measured drug concentration in blood or some other body fluid that reflects the drug concentration at the receptor site. In short, pharmacokinetics refers to “What the drug does to the body?”
Rational prescribing is dictated by the pharmacokinetics and pharmacodynamics of the drug. An additional factor of paramount importance is age of the subject.
APPLIED CLINICAL PHARMACOKINETICS AND DRUG THERAPY
The drug's pharmacologic effects, toxic effects or both correlate well with its concentration in a biologic fluid rather than the absolute dose administered.
As a rule, amount of drug in the body (usually measured in terms of serum concentration) is determined by the dose administered. This is called principle of linear or first order pharmacokinetics.3
Some such drugs as phenytoin, salicylates and alcohol do not follow this principle. Though they exhibit first order or linear principle at low dose, with increasing dose, their elimination pathway becomes saturated and the drug concentration in blood changes disproportionately to the dose administered. Such drugs are, therefore, said to follow the principle of zero order (the so-called Michaelis-Menten kinetics).
Drug Absorption and Bioavailability
The drug's bioavailability is the fraction of the amount absorbed following extravascular drug administration relative to intravenous (IV) administration, the drug administered by latter route being considered as 100% bioavailable. It is calculated as the ratio of the area under drug concentration time curve (AUC) determined after extravascular drug administration to the drug AUC obtained after IV administration as shown below:
Volume of Distribution
The distribution of drugs in blood depends mainly on its lipid solubility, ionization, pH of blood, available protein-binding capacity and difference in the regional blood flow.
Whereas lipid-soluble drugs are, as a rule, distributed throughout the extracellular and intracellular spaces, the water-soluble drugs are distributed mainly in the extracellular space and hardly in the cerebrospinal fluid (CSF) or other body fluids.
As far as the selective distribution of drugs is concerned, it occurs as a result of protein-binding in blood (penicillins) and in tissues (mepacrine). In case of such drugs as are not bound to proteins (insulin), distribution remains confined to the extracellular space. Obviously, these drugs can be utilized to measure extracellular space.
The drugs which get speedily absorbed from the gastrointestinal tract on account of their lipid solubility readily diffuse into the CSF and brain tissue.
The drugs which get poorly absorbed from the gastrointestinal tract (streptomycin, neostigmine), demonstrate poor penetration into various body fluids.4
A noteworthy point is that, in case of inflamed meninges, there is a remarkable elevation in the penetration of all drugs into the CSF.
The initial dose or loading dose is not influenced by the drug clearance or elimination from the body. Thus, the initial dose remains the same for subjects with normal renal function as for those with compromised renal function.
Metabolism
Once the drug has performed its action (effectively or otherwise), it has got to be metabolized and finally excreted. Liver is the major site of drug metabolism which occurs in two phases:
- Conversion to pharmacologically-inactive substances.
- Conversion to pharmacologically-active substances (prednisone, cortisone, imipramine, cyclophosphamide).
Drugs are chiefly metabolized by enzymes in hepatic microsomes and to some extent, by the enzymes in blood and elsewhere in the body. In the nonsynthetic reaction, the molecule is changed by oxidation, reduction or hydrolysis. In the synthetic reaction, the molecule is conjugated with other substances like glucuronic acid (glucuronidation), acetic acid (acetylation), sulfate (ethereal sulfate formation), etc.
Just a word about enzyme induction. Such drugs as phenobarbital, phenytoin, alcohol, DDT and phenylbutazone (often called “bute”) are examples of enzyme-inducers. Enzyme induction by alcohol consumption causes excessive breakdown of phenobarbital. As a result alcoholics develop tolerance to it. On the other hand, isoniazid (INH), anticoagulants and phenylbutazone depress enzyme induction and, thus, the phenytoin metabolism. Phenytoin toxicity even with recommended doses may, therefore, occur in such subjects.
Elimination Half-life
The term, half-life, denotes time required for half the amount of drug present in body fluid to be cleared. It is expressed as t½ and is frequently employed to determine a drug's dosage intervals. It may also be employed to find the time required to attain the steady-state concentration. By the latter term is meant the point at which the amount of drug dose is equivalent to the amount of drug cleared from the body.5
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Table 1 shows the relationship between different half-lives and steady-state concentration.
Clearance
It means the amount of drug removed from the body per unit of time. It is influenced by the integrity of blood flow and by the functional ability of the organs involved in removing the drug from the body.
Renal excretion: Plasma protein-binding of drug, glomerular filtration rate (GFR), back diffusion from glomerular filtration, active renal tubular reabsorption and active renal tubular secretion influence the renal excretion of drugs.
Biliary excretion: Penicillin, rifampicin, erythromycin and tetracycline are examples of drugs excreted in bile. An important feature of such drugs is that they are often reabsorbed into circulation (the so-called “enterohepatic cycle”), thereby prolonging their half-life. Finally, they are excreted in urine.
Pulmonary excretion: The examples of drugs excreted through lungs are volatile lipid-soluble anesthetics and metabolites.
Excretion in breast milk: Drugs ingested by lactating mother and excreted in breast milk so as to harm the baby include antithyroid agents (propylthiouracil is an exception), cytotoxic agents, radioactive substances, lithium, bromocriptine and phenelzine.
Drug-drug Interaction
The term drug-drug interaction is applied when two or more drugs administered to a particular patient modify the pharmacokinetic and pharmacodynamics properties of each through combined interaction.6
The resultant effects may be unpredictable clinical responses or toxic effects. Box 1 lists the different types of drug-drug interactions.
Therapeutic Drug Monitoring
Adjustment of the dose on the basis of clinical response and measurement of concentration of the drug in serum or plasma is called therapeutic drug monitoring. Such an approach is termed target concentration strategy. In this strategy, a drug's pharmacologic or toxicologic response can be directly related to a specific serum concentration range.
Therapeutic drug monitoring is neither necessary not feasible for all drugs.
For more details, see Chapter 3.
CHARACTERISTICS OF VARIOUS ROUTES OF DRUG ADMINISTRATION
Intravenous Route
Absorption: Effect is large immediate.
Special indication: Excellent for emergency situations, for administering large amounts and for irritating agents that can be given in a diluted form.7
Limitations: Expensive, requiring assistance of an expert for administration; unsuitable for oily preparations; boosts vulnerability to superimposed infection.
Oral Route
Absorption: Most drugs are absorbed by passive diffusion, only some by active transport or facilitated diffusion; preferred route; influenced by a number of factors (Table 2).
Special indication: Most natural, convenient, economical and safe route.
Limitations: There usually is a considerable lag period before action at the target level starts; it cannot be employed in uncooperative subjects; bioavailability is somewhat erroneous since some drugs may be inactivated by gastric juices whereas most drugs are metabolized in the liver after absorption.
Intramuscular Route
Absorption: Quite fast for aqueous solutions.
Special indication: Most suitable for oily preparations (vitamin A) and some irritating substances (iron-dextran complex).
Limitations: May cause local necrosis, induration or even abscess; may precipitate otherwise abortive poliomyelitis; not advisable in bleeding 8diathesis and for such drugs as phenytoin and chloramphenicol which have erratic absorption.
Subcutaneous Route
Absorption: Quite fast for aqueous solutions.
Special indication: Appropriate for certain insoluble suspensions and implantation of solid pellets.
Limitations: Not appropriate when large volumes are to be administered; local pain and induration may occur.
Sublingual Route
Absorption: Quite fast absorption of lipid-soluble agents.
Specific indication: When it is desirable to bypass liver.
Limitations: Utility limited to drugs requiring direct effect on heart (nitroglycerine).
Rectal Route
Absorption: Quite prompt absorption.
Specific indication: Appropriate for subjects with persistent vomiting and in unconscious state; very effective for controlling acute seizures (rectal diazepam).
Intrathecal
Absorption: Prompt action at targeted site central nervous system (CNS).
Special indication: For prompt local effect in meningitis and other CNS infections.
Limitations: Not practicable for administering large doses of drugs; may cause chemical or iatrogenic meningitis.
Pulmonary (Aerosol, Nebulization)
Absorption: Quite prompt local as well as systemic effect.
Limitations: Particle size has got to vary between 1 micron and 7 microns (<1 micron is likely to be exhaled whereas >7 microns is unlikely to reach small bronchi); poor ability to regulate dose; not always practicable in small children.
DRUG DOSING AND ITS CALCULATION
The best way of calculating drug dose is in terms of surface area. However, it is quite cumbersome and not always practicable. Therefore, in practice, drug dose is usually calculated according to body weight in children. This approach is practical but not ideal because even within a population of similar age and weight, drug requirement may differ on account of maturational differences in absorption, metabolism and elimination.
According to the famous Clark's rule, pediatric drug dose can be calculated if we know the adult dose and child's weight. Fred's rule is similar, in place of weight in pounds, age in months employed. Now, both are infrequently employed because of their limitations. Box 2 lists pediatric dose and the surface area formulas.
NEONATAL PHARMACOTHERAPY
Notwithstanding the advances in the basic science research that have improved our understanding of use of pharmacological agents in the neonate, neonatal pharmacotherapy remains an area that has not received the attention that it indeed deserves. Today, several drugs are used in the newborn in spite of the lack of specific clinical research in this vulnerable age group.
In fact, present day pharmacotherapy in neonates is mainly based on the individual clinical expertise of specialized neonatologists and pediatricians. Around 60–70% drugs used in neonates and infants are unlicensed, the so-called “off-label drugs”. These continue to be employed in neonatal drug therapy without the recommended regulatory phases of drug development.
Let's have some idea about the peculiarities of the neonate in relation to drug therapy.
- In the newborn, the individual response to a drug in terms of efficacy and safety is highly variable. Predicting drug dosing is complex since rapid physiological changes occurring during the perinatal and early postnatal periods affect the pharmacokinetic profile of several drugs
- Neonatal disorders such as renal and hepatic diseases may also have significant implications for drug pharmacokinetics
- Pharmacotherapy in the newborn poses difficulties in accurate drug delivery and, consequent upon that a high risk of adverse drug reactions
- The neonates, especially in neonatal intensive care unit (NICU), are highly exposed to the risk of medication errors, with potentially serious adverse events.
In other words, the extensive variability in pharmacokinetics and pharmacodynamics because of its fast maturation is a glaring feature of the newborn. This together with the newly-evolving treatment modalities, environmental issues and pharmacogenetics renders clinical pharmacological research in neonates utmost important though cumbersome.
Obviously, all this is challenging too. Why? This is understandable on account of quite a few reasons. First and foremost, the pharmacological trial in neonates are more difficult to perform. Secondly, appropriate dosing is hampered by the rapid physiological changes occurring at this stage of development, and the selection of proper end-points. Thirdly, biomarkers are complicated by the limited knowledge of the pathophysiology of the specific neonatal diseases. Fourthly, there are many ethical challenges in planning and conducting drug studies in the newborns.
These “pharmacological” challenges add to the ethical challenges that are always present in planning and conducting clinical studies in neonates. These challenges justify that clinical research in neonatology should be evaluated by ad hoc ethical committees with specific expertise.11
How to overcome the challenges? Tailored tools and legal initiatives, combined with clever trial design are likely to result in more robust information on neonatal pharmacotherapy. This necessitates collaborative efforts between clinical researchers, sponsors, and regulatory authorities. Additionally, patient representatives and society need to make their contribution.
The regulatory framework for model-based neonatal medicinal development needs to be streamlined and initiated wherever it does not exist. In trials, success is assured by the implementation of specific pharmacokinetic assessments as a result of accurate drug dosing achieved with a combination of dose validation, population pharmacokinetics and mathematical models of drug clearance and distribution.
Further, age-specific pharmacodynamics need to be considered via appropriate evaluations of drug efficacy with end-points adapted to the peculiar pathophysiology of diseases in this age group.
Tailoring research tools is urgently needed. Development of dried blood spot techniques and the introduction of micro-dosing and tracer methodology in neonatal drug studies as well as building research networks and clinical research skills for neonates must take precedence and that too on priority. Both techniques can be combined with sparse sampling techniques through population modeling. Building the initiatives to build and integrate knowledge on neonatal pharmacotherapy through dedicated working groups, research networks and clinical research skills can go a long way in meeting the aims and objectives.
All in all, new innovations in pharmacokinetic research, like population pharmacokinetic modeling, present opportunities to conduct clinical trials in neonates aimed at improving the safety and effectiveness of the drugs in this vulnerable population.
Untoward Effects of Drugs
- The term, side effects, denotes undesirable effects, e.g. drowsiness caused by antihistamines, dryness of mouth because of decongestant therapy or diarrhea secondary to ampicillin therapy.
- The term, idiosyncrasy, means that a genetic abnormality [glucose-6-phosphate dehydrogenase (G6PD) deficiency, porphyria] predisposes an individual to a qualitative abnormal reaction to certain drug(s).
- The term, secondary effects, denotes indirect consequences following a prolonged use of certain drugs.
- The term, hypersensitive, relates to anaphylactoid shock (penicillin, serum), urticarial rash, angioneurotic edema, serum sickness syndrome and pulmonary reactions (antigen-antibody reaction).
Maternal Medication and Fetus
As a rule, the pregnant woman should receive no medication as all medication is potentially risky to the fetus, especially during the first trimester of pregnancy. A drug apparently safe for the mother may be harmful for her growing baby in utero. The golden rule is to prescribe for the pregnant woman only when its beneficial effect outweighs the risk for the fetus. Even in such a situation, attempt should be to prescribe a drug that has withstood the test of time or a drug which is likely to be least risky.
Table 3 provides a list of drugs that are likely to have a teratogenic effect on the fetus.
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Maternal Medication and Breastfeeding
Many drugs are excreted to some extent into the breast milk and, naturally, ingested by the nursing infant. Some of them may have adverse effects on the neonate and the infant (Table 4). The nursing mother must, therefore, never consume any medication without obtaining an approval of the pediatrician.14
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In certain special situations, a sample of breast milk may be analyzed to get an idea about the amount of drug the infant is receiving or about the likely drug effects on the infant.
There is a fair consensus that breast-feeding should be continued in most cases even when the mother is receiving psychotropic drugs. Mind you, the benefits of breast feeding outweigh the risk associated with small amount of drug that may be excreted in milk. The only contraindication is when mother is on chemotherapeutic agents or receiving radiation therapy.