Donna M. Kraus, Pharm.D.
Spring 1998
Donna M. Kraus, Pharm.D.
Spring 1998
Pediatrics
Developmental Pharmacotherapeutics
Goal: To familiarize the student with the physiological differences between the adult and the pediatric patient populations with respect to alterations in pharmacokinetic parameters and pharmacotherapeutic considerations.
Objectives:
1. Define the following age-related terms:
Premature infant Term infant Post-term infant Neonate Infant Child Adolescent Adult
2. List whether the normal range for the following monitoring parameters in infants and children are higher or lower than the adult normal values:
Respiratory rate CSF cell counts Heart rate Hemoglobin/ hematocrit Blood pressure Liver enzymes Blood pH Serum creatinine
3. Describe the general dosing concepts in the pediatric patient population as they relate to weight, surface area, age and disease state.
4. Explain the special considerations which must be taken into account when using the intravenous route of administration in infants and children.
5. For each of the following kinetic parameters:
Absorption, Distribution, Protein binding, Metabolism, Excretion
A. list the specific anatomical and/or physiological changes occurring during a child's growth and development which may effect the parameter.
B. give an example of a drug and the direction in which the kinetic parameter is changed.
6. List specific age-related pharmacokinetic differences of theophylline and the aminoglycoside antibiotics.
Required Reading:
Nahata MC. Chapter 5 / Pediatrics. In Pharmacotherapy, A Pathophysiologic Approach. Third Edition. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM editors. Appleton & Lange, Stamford, Connecticut, 1997, 77 - 85.
Suggested Reading:
Kraus DM, Hatzopoulos FK. Neonatal Therapy (Chapter 96). In Applied Therapeutics: The Clinical Use of Drugs, Sixth edition. Young LY, Koda-Kimble MA, editors. Applied Therapeutics, Inc., Vancouver, WA. 1995, 96-1 to 96-7.
Milsap RL, Hill MR, Szefler SJ. Special Pharmacokinetic Considerations in Children. In Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring, Third edition, Evans WE, Schentag JJ, Jusko WJ. editors. Applied Therapeutics, Inc., Spokane, WA. 1992, 10-1 to 10-25.
Suggested Pediatric Reference:
Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook, 4th edition. Lexi-Comp, Inc., Hudson (Cleveland), OH. 1997.
A. Pediatrics --> Dynamic Patient Population
The pediatric population is a very dynamic one. Alterations of body composition, physiologic norms, pharmacokinetic parameters, and pharmacodynamics occur with maturation and growth throughout childhood.
So not only are pediatric patients very different than adults with respect to pharmacotherapy and drug dosing, but they are also very different from each other at different ages.
B. The following terms are used to define different pediatric age groups. These definitions are important to know as they are often used as dosing categories. For many drugs, different doses or mg/kg doses are recommended for these different age groups.
NOTE: Gestational age is generally thought of as the time from conception until birth. More specifically, gestational age is defined as the number of weeks from the first day of the mothers's last menstrual period until the birth of the baby. Infants born < 26 weeks gestation are generally considered to be previable.
1. Premature: born at < 37 weeks gestation
2. Term: 37 - 42 weeks gestation (Average = 40 weeks)
3. Post-term: > 42 weeks gestation
4. Neonate: 0 - 28 days old
5. Infant: 1 - 12 months old
6. Child: 1 - 12 years old
7. Adolescent: 12 - 18 years old
8. Adult: > 18 years old
9. Postconceptional age: Gestational age at birth plus postnatal age. Note: postnatal age refers to the chronological age since birth. Terms 4 through 8 refer to postnatal age.
The normal values for many monitoring parameters in the pediatric population are different compared to the normal values found in adults. In order to adequately monitor pharmacotherapy in the pediatric population, one must be aware of the differences which occur in vital signs and laboratory parameters.
A. Vital Signs 1
1. Respiratory Rate: The normal respiratory rate of infants and children is increased compared to adults, especially immediately after birth.
Hr after birth Average respiratory rate Range 1st hour 60 breaths per minute 20 - 100 2 - 6 hours 50 breaths per minute 20 - 80 > 6 hours 30 - 40 per minute 20 - 60
Age (years)
Mean RR (breaths/minute)
0 - 2
25 - 30
3 - 9
20 - 25
10 - 18
16 - 20
2. Heart Rate: The normal heart rate is increased in children of all ages compared to adults. The mean heart rate at 2 weeks of age is 148 beats per minute. The normal heart rate slowly decreases over time and adult normal values are reached by adolescence.
Age
Mean Heart Rate
(beats/minute)
Heart Rate Range
(2nd - 98th percentile)
Less than 1 day 123
93 - 154
1 - 2 days 123
91 - 159
3 - 6 days 129
91 - 166
1 - 3 weeks 148
107 - 182
1 - 2 months 149
121 - 179
3 - 5 months 141
106 - 186
6 - 11 months 134
109 - 169
1 - 2 years 119
89 - 151
3 - 4 years 108
73 - 137
5 - 7 years 100
65 - 133
8 - 11 years 91
62 - 130
12 - 15 years 85
60 - 119
3. Blood Pressure: The normal values for blood pressure in children are significantly lower than adults. Typical blood pressures for a full term newborn would be in the range of 65 - 95 systolic / 30 - 60 diastolic. Blood pressures are also slightly different for boys vs girls. Blood pressures listed by percentiles are graphed below for girls and boys 0 - 12 months and 1 - 13 years of age.
Note: Percentiles, as you recall, refer to the percent of the population which would be at that value or less. For example, the 95th percentile systolic blood pressure for a 2 year old girl is 110 which means that 95 percent of 2 year old girls have a systolic blood pressure of 110 or less.
These blood pressure graphs are used when monitoring pediatric patients in order to determine if a patient's blood pressure is normotensive or hypertensive. You'll see these again when we discuss pediatric hypertension. For now it is most important to note that blood pressures for children are lower than adults and that blood pressure increases with increasing age.
B. Laboratory Normals: In addition to different normal values for vital signs, pediatric patients also have different normal values for many laboratory parameters. Several laboratory parameters and normal values for different ages are listed below. It is important to note the general direction of these labs in comparison to adults (i.e. note if the pediatric normal values are higher or lower than adult values) as well as noting increasing or decreasing trends over time with increasing age. Most importantly, one need NOT memorize specific values for different ages, but one must be aware that different normal values exist for pediatric patients. When monitoring a pediatric patient (or evaluating a pediatric case) one needs to look up the normal laboratory value for age in order to appropriately monitor that patient in term of efficacy and toxicity of their drug therapy.
1. Hematology: Hemoglobin, hematocrit and RBC indices are different for different ages. Newborns have a relative polycythemia due to the low arterial PO2 in utero which stimulates erythropoietin production in the fetus and results in a high rate of erythropoiesis. After birth, PO2 increases and the rate of erythropoiesis decreases. This decrease in erythropoiesis, plus an increase in RBC destruction, results in a decrease in Hgb values which drop to their lowest means in term infants at approximately 6 - 12 weeks (usual nadir of 9.5 - 11.0 gm/dl at 2 months of age). This normal decrease in Hgb, which occurs earlier in premature infants, is termed "physiologic anemia". Physiologic anemia is normochromic, microcytic, and is accompanied by a low reticulocyte count. If iron stores are adequate, as oxygen demand increases, erythropoietin, reticulocyte count and hemoglobin will all increase.
Age Mean Hgb Mean Hct term (cord) 16.5 51 1-3 days 18.5 56 2 wks 16.6 53 1 month 13.9 44 2 months 11.2 35 6 months 12.6 36 6 m - 2 yrs 12.0 36 6 m - 2 yrs 12.0 36 2 - 6 yrs 12.5 37 6 - 12 yrs 13.5 40 12 - 18 yrs male
14.5 43 female
14.0 41 Adult male
15.5 47 female
14.0 41
2. Liver enzymes: Certain liver enzymes are normally higher in children compared to adults.
a. Alanine Aminotransferase (ALT) (SGPT)
Infants < 54 U/L Children/Adults 1 - 30 U/L
b. Alkaline phosphatase: As you recall, alkaline phosphatase is also found in bone and higher normal values for children probably reflect increase bone growth.
Infant 150 - 400 U/L 11 - 18 yrs male
50 - 375 U/L female
30 - 300 U/L Adult 30 - 100 U/L
c. Aspartate Aminotransferase (AST) (SGOT)
Newborn/Infant 25 - 75 U/L Child/Adult 0 - 40 U/L
3. Serum Creatinine: Serum creatine is lower in children compared to adults mostly due to the lower muscle mass seen in children. Looking at the list below, one can see that if a 1 year old child had a serum creatinine of 1.2 mg/dl (a value which would be considered normal for adults) the child would have an approximately two fold elevation in serum creatine for age and significantly decreased renal function.
Upper limits (mg/dl)
AGE (YRS) MALE FEMALE 1 0.6 0.5 2 - 3 0.7 0.6 4 - 7 0.8 0.7 8 - 10 0.9 0.8 11 - 12 1.0 0.9 13 - 17 1.2 1.1 18 - 20 1.3 1.1 ADULT 1.2 1.4
4. Blood pH: Newborn term and preterm infants have a lower blood pH during the first few days of life compared to adults (e.g., term infant 7.26 - 7.29). This lower blood pH can effect the protein binding of certain drugs.
5. Other Labs: There are many other age related differences in the normal ranges for other laboratory measurements including: serum calcium, phosphorus, iron, albumin, GGT, LDH, bilirubin, bicarbonate, TG, cholesterol, blood pH, CSF values, etc..
A. Weight
1. Pediatric doses are usually expressed as mg/kg/day or mg/kg/dose with the dosing interval specified.
2. Weight is the most commonly used patient variable to standardize pharmacokinetic parameters e.g., volume of distribution is usually expressed as liters/kg in order to compare values from patient to patient.
B. Surface Area
1. Infants have a larger surface area per kg body weight compared to adults.
2. There is a very good correlation of surface area with cardiac output, glomerular filtration rate and body organ growth and development.
3. However, since surface area is more difficult to calculate most medications are still dosed per kg body weight.
4. Some medications which require very accurate dosing are dosed upon surface area (e.g. chemotherapy)
C. Age
1. Developmental Pharmacotherapeutics: Changes in pharmacokinetic parameters and pharmacodynamic responses occur with maturation throughout childhood.
2. For most drugs, the recommended daily dose (mg/kg/day) as well as dosing interval, will vary dependent upon age group. This is usually due to changes in clearance of the drug for different age groups. Theophylline is a good example:
Age Theophylline dose1 2 - 6 months 6 - 15 mg/kg/day 6 - 12 months 15 - 22 mg/kg/day 1 - 9 years 22 mg/kg/day 9 - 12 years 20 mg/kg/day 12 - 16 years 18 mg/kg/day adults 13 mg/kg/day
D. Disease States
1. Certain disease states can effect the dose per kg weight of a medication. This can be due to an alteration in pharmacokinetics or pharmacodynamics.
Children with cystic fibrosis, for example, have an increased clearance of aminoglycosides and require more frequent dosing.
An initial gentamicin dose for a pediatric cystic fibrosis patient may be 2.5 mg/kg every 6 hours (10 mg/kg/day), while an infant without cystic fibrosis would receive 2.5 mg/kg every 8 hours (7.5 mg/kg/day).
2. Therapeutic concentrations may vary with a given disease state. In addition, certain disease states are seen only in the pediatric population. Theophylline for example, has different therapeutic ranges for different diseases. These two disease states are typically found in different age groups.
Therapeutic theophylline concentrations:
Apnea of prematurity 5 - 12 mcg/ml Asthma 10 - 20 mcg/ml
Note: Apnea of prematurity is seen in young premature infants. A lower range of theophylline concentrations is used with apnea of prematurity due to several factors:
a. A different mechanism of action is being utilized. For apnea of prematurity, theophylline's central stimulation of pCO2 receptors is important, while in asthma the main mechanism of action is bronchodilation.
b. Newborns and young infants have a higher free fraction of theophylline, so that at a given serum concentration of theophylline more of the drug is free (active).
c. Accumulation of an unmeasured active metabolite (caffeine) occurs in newborns and young infants. At a given serum concentration of theophylline the unmeasured caffeine can also be contributing to the pharmacologic as well as toxic effect.
3. As with adults, drug doses need to be adjusted for renal and liver disease depending upon the route of elimination for that specific drug.
E. Age related idiosyncratic reactions can also occur.
1. Phenobarbital, which usually causes sedation in adults, can cause hyperactivity in pediatric patients.
2. Methylphenidate (RitalinR), an amphetamine, is actually used to treat hyperactivity in pediatric patients.
F. Special Considerations: Drug Administration2,3
1. Parenteral
a. The method of IV administration can alter the peak concentration of aminoglycosides by as much as 2.5 mcg/ml (Autosyringe pump vs IVAC at Y site) and may delay the time to peak. Since peak concentrations are effected more than trough concentrations, this can result in calculation of a larger Vd and longer t1/2.
b. The syringe pump (along with delivery of the drug at the IV site closest to the patient) is the most accurate method of IV drug delivery.
c. Avoid the non-traditional "retrograde" infusion method.
d. Avoid the buretrol infusion method with very low infusion rates (especially for medications which require therapeutic drug monitoring) as serum drug concentrations can often be unpredictable.
e. Piggybacks, IV riders or IntermateR infusion devices may deliver too much free water to an infant or small child and cause hyponatremia which may lead to CNS symptoms such as seizures. Calculation of the additional fluids delivered with these methods needs to be taken into consideration in small children.
2. Oral: practical aspects of medication delivery and compliance issues
a. Infants and small children are often "uncooperative" in taking medications which makes it difficult for parents to continue to administer them as prescribed.
b. Adolescents are notorious for being non-compliant.
IV. Age Related Pharmacokinetic Differences4
Many age related differences in absorption, distribution, metabolism and elimination exist.
A. Absorption
1. Oral: Several age related factors may effect the oral absorption of drugs.
a. Gastric emptying time in neonates and premature infants is prolonged (up to 6-8 hours) with adult values being reached at 6-8 months of age. Gastric emptying time is dependent upon gestational age, postnatal age, and type of feeding. The prolonged gastric emptying time seen in neonates and young infants results in delayed drug absorption. A delay in the time to peak as well as a decrease in the peak concentration of several drugs may be seen.
b. Peristalsis in the newborn can be irregular and unpredictable. This may result in a prolonged contact time with the G.I. mucosa and possibly an increase in drug absorption.
c. Gastric pH: At birth gastric pH ranges from 6 - 8 due to residual amniotic fluid in the stomach. (Amniotic fluid is regularly swallowed during intrauterine life.) Gastric pH then falls to a pH of 1.5 to 3 within 24 to 48 hours after birth but during the first week of life returns to neutrality. Gastric pH then decreases gradually to adult values after approximately 2 years of age (range 3-7 yrs). This higher pH which normally occurs during this time is referred to as a "relative achlorhydria".
This relative achlorhydria can result in an increased bioavailability of acid labile drugs such as penicillin, nafcillin, and ampicillin and a decreased absorption of acidic drugs such as phenobarbital, phenytoin, and nalidixic acid. (Remember that a weakly acidic drug in a relatively alkaline environment will result an increase in the ionized form of the drug which would result in decreased absorption.)
d. Mucosal Absorption: Maturational changes in intestinal "permeability" and active transport rates may also be seen. This may also account for the decreased rate of absorption for digoxin and phenobarbital seen in newborns.
e. Bacterial Colonization: Changes in bacterial colonization may also effect the absorption of drugs.
f. Decreased Biliary Function: Premature infants have been shown to have a decreased bioavailability of vitamin E due to an impaired ability to synthesize bile salts and pancreatic enzymes.
g. Practical Aspects: Pediatric patient, more so than adults, may be prone to certain events which may alter the oral absorption of medications. These factors include: emesis, NG suction, severe illnesses which may decrease cardiac output and G.I. perfusion, malabsorption syndromes, gastroenteritis, diet, diarrheal episodes which may decrease intestinal transit time, and prolonged infantile diarrhea which may increase drug absorption due to mucosal changes.
2. Rectal: A proper dosage formulation is need for adequate rectal absorption of drugs in pediatric patients.
a. Rectal valproic acid absorption can be comparable to oral. (VPA must be diluted 1:1 with water for rectal use due to its mucosal irritation)
b. Theophylline has very erratic rectal absorption which has resulted in toxicities as well as fatalities in pediatric patients. Rectal use is not recommended.
3. Intramuscular
a. IM absorption may be variable or delayed in the newborn and premature infant due to:
1. Peripheral vasomotor instability with changes in relative blood flow
2. Decreased muscular contraction
3. Circulatory insufficiency
b. Neonatal reduction in I.M. absorption rate has been reported for diazepam, digoxin and gentamicin
4. Percutaneous
a. Increased absorption via the skin has been reported for newborns due to their:
1. Decreased thickness of stratum corneum
2. Increased skin hydration
3. Increased surface area per weight
b. Toxicities in newborns and young infants have been reported after the topical use of the following agents: boric acid ointment, hexachlorophene soap, salicylic acid ointment, hydrocortisone creams, and rubbing alcohol.
c. The increase in percutaneous absorption seen in newborn and premature infants may possibly be put to therapeutic use. Topical application of a theophylline gel in premature infants has been reported to result in therapeutic serum concentrations. Further studies are needed before this route of administration can be routinely used.
B. Distribution: Body composition changes with age and this can result in alterations in distribution volumes for many drugs.
1. Total body water as a percent of body weight is much higher in children less than a year of age when compared to adults and is highest in the fetus and premature infant.
Total Body Water: % Body Weight as Water Fetus 94% Premature infant 85% Full-term 78% 4-6 month old 70% One yr old 60% Adult 55% Generally, this increase in total body water results in an INCREASED VOLUME OF DISTRIBUTION FOR WATER SOLUBLE DRUGS in pediatric patients compared to adults.
2. Extracellular water (ECW) vs Intracellular water (ICW): Changes also occur in the intracellular and extracellular water compartments with age. A higher percent of total body water, as well as a higher percent of body weight, is found as extracellular water in the neonate compared to an adult. In other words, the ECW:ICW ratio is higher in newborns compared to adults.
Neonate ICW:43% Total Body Water ICW: 34% Body Weight ECW:57% Total Body Water ECW: 44% Body Weight Adult ICW:68% Total Body Water ICW: 41% Body Weight ECW:32% Total Body Water ECW: 19% Body Weight The volume of distribution for water soluble drugs which distribute to the extracellular water compartment roughly parallel ECW as a percent body weight. Aminoglycosides, for example, have a mean Vd in adults of roughly 0.2 - 0.26 l/kg which is close to the 19% body weight as ECW as listed. In neonates, however, the volume of aminoglycosides is increased and is near the 0.44 l/kg as listed above.
3. Adipose Tissue: Newborns have differences in adipose tissue compared to adults which result in alterations in drug disposition.
a. Neonates have a decreased amount of adipose tissue as a percent of their body weight compared to the average adult.
Percent Body weight as adipose tissue:
0.5% 5 month gestation fetus 12 - 16% Full term newborn (Note: this is similar to a very athletic adult) b. The adipose tissue that neonates do have contains more water than the fat of adults.
c. Both the decreased amount of adipose tissue and the higher water content of neonatal fat will decrease the volume of distribution for fat soluble drugs. Example:
Diazepam Vd:
Neonate 1.4 - 1.8 l/kg
Adult 2.2 - 2.6 l/kg
4. Compared to adults, neonates also have a decreased skeletal muscle mass which can effect drug distribution.
5. Newborns also have altered tissue affinity and membrane permeability.
a. Due to the immaturity of the brain, the neonate has an increased permeability of the CNS to certain drugs such as phenytoin. The higher brain to plasma concentration ratio which can be seen may be due to the lower myelin content and increased cerebral blood flow that occurs in the neonate compared to the adult.
b. The newborn has an increased permeability of RBC for certain drugs. For example:
RBC:Cp ratio
Newborn Adult Digoxin 3.6 1.3 Theophylline 1.0 0.5
c. This increased tissue affinity and increased permeability of drugs into neonatal tissue can result in an increased volume of distribution.
6. Ideal Body Mass (IBM) vs. Total Body Weight
a. As you know, due to distribution properties, some drugs are dosed on IBM or lean body weight (LBW) rather than total body weight. These pharmacokinetic principles should also apply in children. A problem occurs however, when trying to calculate these dosing weights in children. One cannot routinely use the LBW equations which are used in the adult population. For example:
LBWmales = 50 kg + (2.3 kg for every inch over 5 feet)
Since there aren't very many children over 5 feet, these equations cannot be used. (Note: These equations can be used in children over 5 feet)
In order to evaluate ideal body mass in children, one must first have an idea of normal physical growth in pediatric patients. On the next page, the graph on the left which is adapted from the National Center for Health Statistics1 shows the percentiles for normal physical growth for weight and height by age. These growth curves are used to evaluate a child's physical development. A child's height and weight for his/her given age is plotted on the graph and the percentile height and weight are noted. A one time measurement gives the clinician an idea of the child's body habitus.
For example, if a child is greater than 95th percentile for weight but less than 5th percentile for height, it would indicate that the child is overweight and short for their age.
Multiple plotting of a child's height and weight over time will determine if the child is following along a growth curve and growing properly.
b. The IBM for children is defined as the 50th percentile weight for a given height (irrespective of age). The graph below on the right or the following equation5 can be used in pediatric patients to calculate IBM.
IBM = 2.396 e0.01863 (Ht)
where IBM = ideal body mass in kg
Ht = height in cm
(NOTE: One must remember that IBM contains adipose tissue whereas LBW does not. In order to calculate LBW in children one must use anthropometric measurements)
C. Protein Binding: In general, neonates have decreased protein binding of many drugs compared to adults. The decrease in protein binding can result in a higher free fraction for many drugs and a higher apparent volume of distribution. The decreased protein binding in neonates is due to the following reasons:
1. Decreased concentrations of total plasma proteins
Neonates have approximately 80 % of the serum protein as that of an adult. The full adult value for plasma protein binding is not reached until end of first year of life.
a. Neonates have decreased concentrations of serum albumin
Serum Albumin
Adult 4.5 + 0.4 gm/dl Neonate 3.7 + 0.2 gm/dl
b. Neonates have decreased gamma globulin concentrations: Gamma globulin binds non-acidic drugs. Adult values of gamma globulin are reached at 7 - 12 years of age.
c. Neonates also have decreased concentrations of serum lipoproteins.
2. Decreased affinity for drugs by fetal albumin: A decreased fetal albumin affinity has been reported for ampicillin, phenytoin, phenobarbital, salicylate, propranolol, and bilirubin.
3. Lower plasma pH: The lower plasma pH seen during the first few days of life can decrease protein binding.
4. Endogenous interfering substances may exist at higher concentrations in the neonate compared to the adult. These endogenous interfering substances such as free fatty acids and bilirubin may compete with acidic drugs at albumin binding sites and may result in decreased drug protein binding (i.e., an increase in the free fraction or percent unbound of a drug). Example: Phenytoin free fraction is higher in neonates compared to adults and is increased further in infants with hyperbilirubinemia.
Unbound Phenytoin Albumin gm/dl Normal infants 10.6 + 1.4% 3.5 + 0.4 Adults 7.4 + 0.7% Hyperbilirubinemic infants: Bilirubin Total 4.5 + 0.5 mg% 15.5 + 3.3% 3.8 + 0.5 Direct < 1.9 mg% Total 20 mg% 20%
NOTE: Certain drugs such as sulfonamides may displace bilirubin from albumin binding sites and cause kernicterus. Kernicterus occurs when non-albumin-bound, unconjugated bilirubin enters and deposits in the brain. Its toxic effects include severe mental retardation.
5. Transplacental interfering substances acquired from the mother in utero may also effect protein binding of drugs in the neonate.
D. Metabolism: Varying maturational rates for different metabolic pathways exist (i.e. enzyme activity matures at different ages for different enzymes).
1. Newborns
a. Newborns have decreased activity of many enzyme pathways. Typically, if a drug's primary metabolic pathway is decreased, clearance of the drug is decreased and daily maintenance doses must be decreased or accumulation of the drug will result. This explains the decreased mg/kg/day doses which are required for many drugs in neonates.
1. Esterase (hydrolysis) activity is decreased in newborns and increases gradually over first year of life. Example: decreased hydrolysis of procaine ester anesthetics.
2. Hepatic microsomal activity (oxidative reactions) is also decreased in neonates.
In vitro evaluation of enzyme activity has demonstrated that for a term infant: Cytochrome P-450 and NADPH-Cytochrome C-Reductase Activity are approximately 1/2 that of adult values. (range: 20-70%)
Newborns have decreased hydroxylation activity which results in decreased metabolism of phenobarbital, phenytoin, lidocaine, amobarbital and diazepam.
Newborns have decreased N-demethylation activity (Dealkylation) which results in the decreased metabolism of theophylline, meperidine and diazepam.
3. Glucuronide Synthesis (Microsomal) is decreased in the newborn and reaches adult levels by 3 years of age. Due to decreased activity of UDPG - glucuronyl transferase, a decrease in the metabolism of bilirubin, morphine, and chloramphenicol is observed in neonates.
NOTE: The decreased metabolism of chloramphenicol in neonates (coupled with administration of higher than required doses) was responsible for the gray baby syndrome. Chloramphenicol accumulated and caused toxic effects including circulatory collapse, an ashen gray appearance, and death. After the recommended doses for chloramphenicol were reduced, few cases of gray baby syndrome were reported. (More recent cases of gray baby syndrome have been reported due to toxic overdoses of chloramphenicol.)
4. Glycine conjugation is decreased in neonates and reaches adult levels at approximately 8 weeks of age. Because of decreased glycine conjugation, benzoic acid can accumulate in newborns given excess benzyl alcohol or benzoic acid.
Benzyl alcohol--> benzoic acid ---->
glycine conjugation-----> hippuric acid.
This accumulation of benzoic acid results in the "benzyl alcohol gasping syndrome" with deterioration of multiple organ systems, severe metabolic acidosis and gasping respirations. This is a dose related syndrome and has been reported with doses of benzyl alcohol greater than 99 mg/kg. Because of this syndrome, the FDA now recommends that drugs containing benzyl alcohol or benzoic acid as preservatives should NOT be used in neonatal nurseries. Therefore,
USE PRESERVATIVE FREE MEDICATIONS FOR NEONATES ESPECIALLY PREMATURE NEWBORNS.
b. Adequate activity for several enzymes in neonates has been reported
1. Methylation (acetylation) can be adequate or increased at birth. Methylation is needed for neonatal surfactant synthesis. Methylation of theophylline to caffeine occurs in neonates.
2. Sulfate conjugation (sulfonation) is relatively mature at birth. Example: acetaminophen sulfonation pathway.
2. Children: Increased activity of the hepatic microsomal enzymes is seen in children, especially those 2 to 4 years of age. Hepatic microsomal activity two - six times the adult activity has been reported. This increase in activity may be due to the relatively larger liver size in comparison to total body weight seen in children vs adults. Because of this increase in hepatic microsomal activity, the maintenance doses for many drugs are higher (mg/kg/day) compared to adults. Examples: phenytoin, phenobarbital, theophylline.
3. Other factors besides enzyme activity effect metabolism.
a. Potential enzyme-substrate specificity changes may occur during development (i.e., affinity for substrates may change with maturation).
b. Effects of intrauterine or postnatal exposure to drugs may also be observed. For example, the t1/2 of diazepam may be greatly shortened if a newborn is exposed to phenobarbital.
Diazepam t 1/2 Premature infant 40-100 hours Full term newborn 20-45 hours Adult 15-25 hours Newborn with Phenobarbital Exposure 12-18 hours
E. Renal Elimination: At birth glomerular filtration, tubular secretion and tubular reabsorption are all decreased in comparison to adults. Renal function matures in the following order: first glomerular filtration, then tubular secretion, and finally tubular reabsorption.
1. Glomerular filtration:
a. Nephrogenesis occurs through 35 weeks postconceptional age with an increase in renal mass occurring throughout gestation and continuing after birth. (see figure 1)
b. At birth, glomerular filtration rate dramatically increases from what it was in utero (see figure 1). This increase in GFR at birth is due to:
-increases in cardiac output
-increases in renal blood flow
-changes in renal blood flow distribution (gradual shift from deep juxtaglomerular nephron to outer cortex with probable changes in permeability of glomerular membrane)
c. Although GFR rises at birth, it is still very much decreased in comparison to adults. A premature infant's GFR at birth is approximately 0.7 - 0.8 ml/min or about 0.5% that of an adult. A full term newborn's GFR equals approximately 2-4 ml/min (10-20 ml/min/1.73m2). (Keep in mind that an adult with a GFR < 10 would probably be on dialysis.)
d. A significant increase in GFR is seen by the 1st week of life with a two fold increase seen by about 14 days of age (figure 2). This explains why many drugs that are renally eliminated have an increase in the recommended dose after the first week or so of life.
e. GFR is approximately 70 ml/min/m2 at 1 yr of age.
f. Plasma creatinine at birth reflects maternal creatinine.
2. Tubular secretion, which transports drugs from the peritubular capillaries into the lumen of the renal tubule, is decreased at birth (20-30% of adult values).
a. The transport maximum (Tm) has been reported to be lower in newborns for PAH, glucose, phosphate and bicarbonate. Keep in mind however, that the Tm is related to GFR, i.e., Tm may be reported to be decreased due to the decrease in GFR. Tm can however, be induced in utero.
b. NOTE: Glomerular function more is more advanced than tubular function (up to 6 months of age)
3. Tubular Reabsorption is decreased at birth and is the last renal function to mature.
a. Tubular reabsorption is a passive process and is concentration dependent. Neonates have a decreased concentration gradient which can result in decreased reabsorption.
b. Tubular reabsorption is pH dependent. Neonates have a relatively lower urine pH which can also effect the reabsorption of drugs. In addition, the normal diurnal variability in urine pH is not present in the first 2 years of life.
4. Renal toxicities: The decreased renal clearance for drugs which occurs in patients < 2 years of age may increase the risk of drug toxicity due to drug accumulation. However, the decreased capacity of kidney cells to take up and store drugs may actually decrease the renal toxicity of certain drugs. Or put another way, newborns and young infants may possibly have less inherent tissue sensitivity for drug toxicity compared to adults.
5. Increased renal clearance: At 2 - 24 months of age GFR and tubular secretion are more mature than reabsorption. This can result in an increase in renal clearance of drugs. Example: digoxin.
6. Hypoxic events: Hypoxic events which may occur in premature infants and newborns can cause further decreases in renal function.
7. Determination of CrCl from SCr: Equations used in adult patients cannot be used in pediatric patients to calculate creatinine clearance from serum creatinine determinations. Due to the different ratio of muscle mass to serum creatine seen in children compared to adults, other equations must be used.
a. Equation one6: CrCl = 0.48 x Ht/SCr
CrCl = creatinine clearance in ml/min/1.73 m2
Ht = height in cm
SCr = serum creatinine in mg/dl
This equation can be used for children ages 1 - 18 years. It is less accurate with heights < 107 cm. An equal number of CrCl are over and under estimated with this equation.
b. Equation two7: CrCl = K X Ht/SCr
Units are same as above but K, a constant of proportionality, represents urinary creatinine excretion per unit of body size and is different for children of different ages. Although more complex, this equation is thought to be more accurate than equation 1.
AGE K Low birth weight < 1 year 0.33 Full term < 1 year 0.45 2 - 12 yrs 0.55 13 - 21 yrs Females 0.55 13 - 21 yrs Males 0.70
10. Adjustment of drug doses in pediatric renal failure patients1 As in adults, doses of drugs that are renally eliminated need to be adjusted in pediatric patients with renal dysfunction. The methods described here allow for initial adjustment of doses in renal failure.
a. Interval extension method (I): With this method the size of the dose is kept normal and the interval between doses is lengthened. The chart on the next page shows the number of hours between doses of normal size for different CrCl. This method is preferred for drugs such as aminoglycosides and vancomycin.
b. Dose reduction method (D): With this method the size of the individual dose is reduced, keeping the interval between doses normal. This method is recommended for drugs in which a relatively constant blood level is desired. The chart gives the percentage of the usual dose that should be given at the normal dosing interval
c. Keep in mind that dosage adjustments are approximations only. The individual patient must be followed closely for signs of drug efficacy, and toxicity. Serum levels of the drug should be measured when available and the dosage and interval modified accordingly.
d. With either the interval extension (I) or dose reduction (D) method, first calculate the dose for the child as if the patient had normal renal function. Then use the chart to either give the normal dose at an extended interval (method I) or give a reduced dose at the normal interval (method D). Either way the daily dose for the patient is reduced due to the decreased renal function.
Example: Gentamicin dosing in a 2 month old infant with CrCl = 8 ml/min, weight = 5 kg. NOTE: Normal gentamicin dose = 7.5 mg/kg/day divided every 8 hours or
2.5 mg/kg/dose every 8 hours.
The normal dose for this patient if CrCl was normal = 12.5 mg every 8 hours. (2.5 mg/dose x 5 kg = 12.5 mg/dose)
Using the interval extension method, the chart below lists an interval of every 24 hours for CrCl < 10 ml/min. Therefore, an appropriate initial dose for this patient would be 12.5 mg every 24 hours.
F. Age related pharmacodynamic differences due to alterations in receptor sensitivity and maturation of innervation also occur.
A. Theophylline
1. Absorption (oral)
a. "Fast" release preparations, preferably non-alcohol containing liquids, are usually used in children less than 1 year of age. Example: Aminophylline liquid (SomophyllineR)
b. Sustained - released preparations are designed for dosage intervals of 12 hours, however the intestinal transit time may be less than 8 hours in younger infants. As a result, use of sustained release preparations in young infants may result in incomplete and highly variable absorption (i.e., the sustained release product can be excreted in the stool before the drug is absorbed).
2. Distribution : The volume of distribution for theophylline is larger in neonates and infants compared to children and adults.
Vd (l/kg) Neonates 0.7 - 0.8 Infants 0.5 - 0.6 Children 0.45 - 0.5
3. Protein Binding
a. Approximately 60% protein bound
b. Protein binding is reduced in neonates
c. Protein binding may be altered by acidemia
4. Metabolism and Excretion 8,9,10,11
The figure on the next page (figure 32-8) depicts the metabolic pathways for theophylline. Theophylline (1,3 dimethylxanthine) can be excreted unchanged in the urine, methylated to caffeine, demethylated to 3 methylxanthine, 8-hydroxylated to 1,3 dimethyluric acid, and demethylated to 1 methylxanthine, an intermediate metabolite which rapidly converts to 1 methyluric acid.
Since theophylline hepatic metabolism (demethylation and hydroxylation pathways) is decreased in neonates, a greater percent of a dose of theophylline is excreted unchanged in the urine compared to adults (see also table 32.3). Since neonates have the capacity to methylate, they can methylate theophylline to caffeine. However, since neonates have decreased demethylation activity, the caffeine cannot be easily metabolized and therefore accumulates.
NOTE: The t1/2 of caffeine in neonates has been reported to be as long as 68 - 100 hours, while the t1/2 of theophylline in neonates is 20 - 30 hours.
Note also (Table 32-3) that both the demethylated metabolites (3 methylxanthine and 1 methyluric acid) and hydroxylated metabolite (1,3 dimethyluric acid) are decreased in premature infants and neonates compared to adults. In addition to these changes in metabolites, theophylline clearance increases approximately 5 fold over the first year of life. The basic pattern of low clearance in the neonatal period followed by rapid clearance in early childhood (see Figure 10-4 next page) is also seen with other drugs that are cleared by the hepatic microsomal P450 pathways (e.g. phenobarbital and phenytoin).
(reference 12)
a. Theophylline clearance is age-related as depicted in the above figure, i.e., theophylline clearance is related to postnatal age (PNA).
Population (mean age) ml/hr/kg Premature (7.5 days) 17.4 Premature (41 days) 38.4 Term infants < 6 m (18 weeks) 48.0 Term infants 6 - 11 m (34 weeks) 120.0 1-4 yrs (2.5 years) 102.0 4-12 yrs (9.4 years) 96.0 13-15 yrs (14 years) 54.0 Adult (non-smoker) 40-51
b. In newborns and infants, the level of hepatic maturation at birth must also be considered. In other words, the individual's gestational age at birth (GA) as well as the PNA will influence theophylline clearance. Postconceptional age (PCA), which is equal to GA plus PNA, has been found to explain the greatest amount of interpatient variability in theophylline clearance during the first year of life.13 Further studies incorporating PCA into infant theophylline dosage guidelines are needed.14
c.
Theophylline t1/2 : (hours) premature 7.5 days old 30+6.3 41 days old 20+5.3 full-term 24 Infants 0.8-8.6 Children 1-4 yrs 1.9-5.5 (mean = 3.4)
c. Urinary Excretion Patterns 11
d. Summary 11
5. Theophylline dosing guidelines
a. Therapeutic range (summary)
-Neonates (apnea of prematurity): 5 - 12 mcg/ml
-Other age groups (asthma): 10 - 20 mcg/ml
b. Usual loading dose: 5 mg/kg theophylline or 6 mg/kg aminophylline
c. Initial maintenance dosage (reference 11)
NOTE: Dose dependent pharmacokinetics due to enzyme saturation have been reported for theophylline in pediatric patients. A disproportionate increase in Cp in relation to dose has been observed. Dose dependent kinetics of theophylline have been seen with dosage increases 1.5 - 2 times the original dose. Increases > 25 to 30 % of the original dose are not usually recommended for dosage adjustments.
B. Aminoglycosides (reference 15)
1. Absorption
a. Oral: poorly absorbed
b. IM: not recommended for low birth weight (LBW) premature infants with low muscle mass or acutely ill infants with vasomotor instability.
2. Distribution
a. Distributes primarily into extracellular fluid space
b. Extracellular water (ECW)
< 3 month fetus 65% of body weight 40 weeks gestation 35 - 44 % of body weight 12 months 26 - 30 % of body weight c. Volume of distribution correlates with ECW
d. As in adult patients, physiologic and pathologic factors which effect ECW will also effect the Vd for the aminoglycosides in the pediatric population.
In fact, the volume of distribution of aminoglycosides in pediatric intensive care unit (PICU) patients has been found to be greater than non-PICU literature values. 16 This increased Vd may be the effect of certain disease states or severity of illness.
3. Elimination
a. Gentamicin clearance correlates well with creatinine clearance and postconceptional age.
b. Half-life shortens with increasing postconceptional ages.
PCA mean t 1/2 < 30 weeks 8.86 hours 30 - 37 weeks 6.62 hours > 37 weeks 5.12 hours
c. Initial dosing (gentamicin/tobramycin/netilmicin)
1. Premature infants
Postconceptional age Dose < 30 weeks 2.5 mg/kg/dose Q 24 hours 30 - 34 weeks 2.5 mg/kg/dose Q 18 hours > 35 weeks 2.5 mg/kg/dose Q 12 hours 2. Full term infants
Postnatal Age Dose < 7 days 2.5 mg/kg/dose Q 12 hours > 7 days 2.5 mg/kg/dose Q 8 hours
3. Children (Reference 17)
Few well designed studies of gentamicin dosing outside of the neonatal age group have been reported. One study proposed the following dosing guidelines for gentamicin in children.
Age Dose* Calculated Vd 0.5- 5 yrs 2.5 mg/kg 0.5 l/kg 5-10 yrs 2.0 mg/kg 0.4 l/kg > 10 yrs 1.5 mg/kg 0.3 l/kg * Dose = calculated dose required to achieve a 30 minute post-infusion level of 4-5 mcg/ml.
Using these guidelines, however, only 54% of the 60 pediatric patients studied would have obtained peak concentrations of 4 - 6 mcg/ml. None would have obtained peak concentrations > 8 mcg/ml, but 40% would have obtain peak concentrations < 4 mcg/ml. These results demonstrate the need for therapeutic monitoring of aminoglycosides in the pediatric population.
REFERENCES
1. The Harriet Lane Handbook, 11th edition. Rowe PC, editor. Year Book Medical Publishers.
2. Nahata MC et al. Effect of infusion methods on tobramycin serum concentrations in newborns infants. J Pediatr 1984;104:136-138.
3. Roberts RJ. Intravenous Administration of Medication in Pediatric Patients: Problems and Solutions. Pediatric Clinics of North America 1981;28:23-34.
4. Morselli PL. Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Clinical Pharmacokinetics 1980;5:485-527.
5. Traub SL, Kichen L. Estimating ideal body mass in children. Amer J Hosp Pharm 1983;40:107-10.
6. DeAcevedo LH and Johnson, CE. Estimation of creatinine clearance in children: Comparison of six methods. Clin Pharm 1982;1:158-161.
7. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatric Clinics of North America 1987; 34:571-590.
8. Nassif E et al. The disposition of theophylline in infancy. J Pediatr 1981;98:158-61.
9. Tserng Kou-Yi et al. Developmental aspects of theophylline metabolism in premature infants. Clin Pharmacol Ther 1983;33:522-8.
10. Gilman JT, Gal P, Levine RS et al. Factors Influencing Theophylline Disposition in 179 Newborns. Therapeutic Drug Monitoring 1986;8:4-10.
11. Hendeles L, Massanari M, Weinberger M. Theophylline. In Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring 2nd ed., Evans WE, Schentag JJ, Jusko WJ. (ed). Applied Therapeutics, Inc., Spokane, WA. pp. 1105 - 1188.
12. Milsap RL, Szefler SJ. Special Pharmacokinetic Considerations in Children. In Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring 2nd ed., Evans WE, Schentag JJ, Jusko WJ. (ed). Applied Therapeutics, Inc., Spokane, WA. pp. 294-322.
13. Kraus DM, Fischer JH, Reitz SJ et al. Alterations in theophylline metabolism during the first year of life. Clin Pharmacol Ther 1993;54:351-9.
14. Kraus DM, Hatzopoulos FK, Reitz SJ et al. Pharmacokinetic evaluation of two theophylline dosing methods for infants. Therapeutic Drug Monitoring 1994;16:270-6.
15. Besunder JB, Reed MD, Blumer JL. Principles of Drug Biodisposition in the Neonate: A critical Evaluation of the Pharmacokinetic-Pharmacodynamic Interface. Clinical Pharmacokinetics 1988; 14: 261 - 286.
16. Kraus DM, Dusik CM, Rodvold KA et al. Bayesian forecasting of gentamicin pharmacokinetics in pediatric intensive care unit patients. Pediatr Infect Dis J 1993:12:712-8.
17. Echeverria P, Siber GR, Paisley J et al. Age-dependent dose response to gentamicin. Journal of Pediatrics 1975; 87: 805-808.
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