Drug therapy in pediatric د.شذى هاني Ph.D. candidate (pharmacology)

Administration of drugs during the first year of life can be affected by rapid changes in body size, body composition, and organ function

Physiologic processes that influence pharmacokinetic variables in the infant change significantly in the first year of life, particularly during the first few months. Therefore, special attention must be paid to pharmacokinetics in this age group.

4-Renal excretion Pharmacokinetics: 1- Absorption 2-Distribution 3-Hepatic metabolism 4-Renal excretion

Neonate – birth to 4 weeks

Infant – 5 weeks to 1 year

Child – 1 to 12 years

Adolescent- 12 to 16 years

1- Blood flow at site of administration 1- Drug Absorption: 1- Blood flow at site of administration 2- Gastrointestinal function, which changes rapidly during the first few days after birth. 3- Age after birth also influences the regulation of drug absorption

1- Blood flow at the site of administration: mainly, in neonates as in adults, depends on the rate of blood flow to the muscle or subcutaneous area to be injected.

Physiologic conditions that might reduce blood flow to these areas are: - a- cardiovascular shock. b- vasoconstriction due to sympathomimetic agents. c- heart failure.

However, sick preterm infants requiring IM injections may have very little muscle mass and a diminished peripheral perfusion to these areas. In such cases, absorption becomes irregular and difficult to predict, because the drug may remain in the muscle and be absorbed more slowly than expected.

If perfusion suddenly improves, there can be a sudden and unpredictable increase in the amount of drug entering the circulation, resulting in high and potentially toxic concentrations of drug . Examples of drugs especially dangerous in such situations are cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.

2- Gastrointestinal function: Significant biochemical and physiologic changes occur in the neonatal GIT shortly after birth. The factors affect the absorption of drugs a- pH dependent passive diffusion b- Gastric emptying c- Peristalsis of intestine d- Gastrointestinal enzyme activities

a- pH dependent passive diffusion In full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours and gastric acidity decreases during the first weeks of life. In the premature infants, gastric pH may remain elevated due to delayed and immature acid secretion, with the highest concentrations appearing on the fourth day of life. Therefore, drugs that are partially or totally inactivated by the low pH of gastric contents should not be administered orally

b- Gastric emptying Gastric emptying time is prolonged (up to 6 or 8 hours) in the first day or so after delivery. Therefore, drugs that are absorbed primarily in the stomach may be absorbed more completely than expected. In the case of drugs absorbed in the small intestine, therapeutic effect may be delayed.

- Peristalsis of intestine in the neonate is irregular and may be slow. The amount of drug absorbed in the small intestine may therefore be unpredictable. - more than, the usual amount of drug may be absorbed if peristalsis is slowed, and this could result in potential toxicity from an otherwise standard dose. -An increase in peristalsis, as in diarrheal conditions, tends to decrease the extent of absorption, because contact time with the large absorptive surface of the intestine is decreased

d- Gastrointestinal enzyme activities Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. - Activities of a-amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. - Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid- soluble drugs

Absorption from skin (Percutaneous absorption): may be drastically increased (esp. in preterm) due to immature epidermis and increased skin hydration.

2-Distribution Distribution of drugs within the body is influenced by : 1)amount and character of plasma proteins 2)relative size of fluid, fat 3)tissue compartments of the body.

a- Total body water Neonate (70-75% of body weight as water) and small preterm neonate (85% of body weight as water) have a higher percentage of its body weight in the form of water than does the adult (50-60%).

Similarly, extracellular water is 40% of body weight in the neonate, compared with 20% in the adult. Since many drugs are distributed throughout the extracellular water space, the volume of the extracellular water compartment may be important in determining the concentration of drug at receptor sites. This is especially important for water-soluble drugs (such as aminoglycosides) and less crucial for lipid-soluble agents

b- Fat content of body Preterm infants have much less fat than full-term infants. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full- term neonates. This is especially important for water-soluble drugs.

c- Plasma proteins - Albumin is the plasma protein with the greatest binding capacity. - In general, protein binding of drugs is reduced in the neonate. This has been seen with local anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital. Therefore, the concentration of free (unbound) drug in plasma is increased initially& Because the free drug exerts the pharmacologic effect, this can result in greater drug effect or toxicity despite a normal or even low plasma concentration of total drug (bound plus unbound).

d- Competition with serum bilirubin for binding Some drugs compete with serum bilirubin for binding to albumin. Drugs given to a neonate with jaundice (eg. Sulfonamide) can displace bilirubin from albumin. Because of the greater permeability of the neonatal blood-brain barrier, substantial amounts of bilirubin may enter the brain and cause kernicterus.

3- Hepatic metabolism The metabolism of most drugs occurs in the liver . Complete maturation of the liver develops by one year. Cytochrome P-450 enzyme system and the conjugating enzymes are the most important factor in drug metabolism but are substantially lower (50-70% of adult values) in early neonatal life than later

4-Renal excretion - The glomerular filtration rate (GFR) is much lower in newborns than in older infants, children, or adults, during the first few days of life. Glomerular filtration in the neonate is only 30-40% of the adult value and is even lower in premature neonate. Renal function improves substantially during the first week of life and the GFR and renal plasma flow have increased to reach the adult value; by 6-12 months

Therefore, drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life. E.g. Penicillin, aminoglycoside antibiotics, digoxin, In this situation, adjustments of the dose is needed and are best made on the basis of plasma drug concentrations monitoring at intervals throughout the course of therapy especially with a drug of low therapeutic index like digoxin.

Pediatric Drug Dosing: - Dosing in children less than 12 years is always of function of surface area, age or body weight. - Mg / kg dosing is most common calculation.

According to the body surface area (BSA): -We depends on patients height &weight. -Mainly used to calculate chemotherapy dosages Dose=SA of patient(m²)×adult dose /1.8

Age (Young's rule):