202406221435

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Tags: pharmacology, Paed

Developmental pharmacology

Growth follows three typical curves

• Rapid growth occurs during the first 3 years
• slowly decelerating childhood component
• rapid growth phase in adolescence

neonatal CO

• at term may > 200 ml/kg/minute
  • almost 3x that of adults
• by 2 years, still 50% > adult
  Cardiac index:
• Changes of CI mirror the growth curves
• ↑CI affect drug distribution & elimination clearance
  • ↑ hepatic extraction drugs w/ perfusion limited clearance are particularly affected

As growth rates decline, children over the age of 3 years behave more like little adults, and predicting pharmacokinetic variation becomes easier.

Clearance and elimination are not related linearly to weight, metabolic rate or cardiac output

Absorption

GI

At birth, gastric pH is higher due to amniotic fluid in the stomach. Gastric pH drops steadily and approaches a fasting value of around pH 3.5 within a week. Subsequently, it slowly decreases until about 3 years of age when the intraluminal pH reaches adult values.
Gastric pH influences drug stability, dissolution and ionization and impacts drug absorption

Although age influences intestinal transit time, gut mobility is more dependent on food type. The gastric emptying time for infant formula is approximately double that for human milk in term babies (6-4-2 rule see Paediatric preoperative fasting)

Premature infants demonstrate longer emptying times in comparison with term neonates

Bile salt and bile acid concentrations are lower in the intestinal lumen at birth, and neither enterohepatic bile circulation nor transporter-mediated uptake is fully functional.

Successful bacterial colonization of the gastrointestinal tract is necessary to produce secondary bile acids, and until this occurs, absorption of lipophilic compounds remains impaired.

Premature infants have a low first-pass effect by intestinal and hepatic metabolism by CYP3A. The result is a high bioavailability of CYP3A substrates such as Midazolam

Cutaneous

A newborn’s skin is immature at birth, and the dysfunctional barrier is predisposed to trans-epidermal fluid loss and absorption of chemicals. Preterm infants’ skin is thinner with increased cutaneous permeability of the stratum corneum and immature vasomotor control

Increased permeability is present in the axillae, groin and flexor surfaces of the limbs, increasing topical absorption of drugs. The high body surface area to mass ratio in neonates further enhances drug and chemical absorption

Absorption of iodine-containing disinfectants such as povidone-iodine by immature skin and can result in iodine toxicity and subsequent hypothyroidism in neonates

Prilocaine applied topically as a component of Emla® cream may result in methaemoglobinaemia in neonates; the presence of fetal haemoglobin increases this propensity.

Distribution

Developmental changes in cardiac index, regional blood flow, plasma protein concentrations and body composition affect the volume of distribution.

Body composition

Body water content

Total body water content may approach 85% in neonates, and rapid postnatal changes in body composition occur as neonates adapt to the extrauterine environment.

Contraction of extracellular water by the first week of life results in a loss of 7% loss of body weight in term infants

Preterm infants, however, may exhibit a weight loss of up to 15%.

Extracellular water steadily declines to 55–60% in adulthood

This increase in total body water enlarges the volume of distribution for some hydrophilic drugs (e.g. gentamycin) and may necessitate a larger loading dose to achieve adequate plasma concentrations.

Fat & muscle

Neonates consist of low quantities of fat and muscle. The fat component increases rapidly during the first year and gradually declines to adult proportions by 3 years of age. These changes explain the reduced volume of distribution of lipophilic compounds in the newborn compared to older infants

Lipophilic drugs that redistribute rapidly to fatty tissue may display higher and prolonged plasma concentrations in neonates. The volume of distribution of propofol is 3.14 litres/kg in a premature neonate compared to 7.1 litres/kg in an older child. Other lipophilic drugs like thiopentone and fentanyl undergo similar changes.

Plasma proteins

Neonates have lower total concentrations of plasma proteins (albumin, α-1 acid glycoprotein (AAG) and plasma globulins) and a reduced ability of these proteins to bind to drugs

As plasma proteins do not readily leave the intravascular space, reductions in circulating proteins will increase the volume of distribution of highly protein-bound drugs. A higher free fraction of drugs in neonates results in increased therapeutic effect and toxicity in highly protein-bound drugs

Several medications used perioperatively, including propofol, phenytoin, diazepam and ibuprofen, undergo competitive binding by bilirubin for albumin. Competition for protein binding sites may result in increased free-drug or bilirubin concentration, increasing the risk of kernicterus in neonates

At birth, the plasma concentration of AAG is between 20% and 50% of adult levels. AAG is the principal protein to which the amide local anaesthetic agents bind, resulting in neonates having high unbound fractions of the drug, potentially increasing the risk of local anaesthetic toxicity. AAG acts as a stress protein with extrahepatic synthesis occurring in response to surgical stress. The increased AAG binds free local anaesthetic, decreasing hepatic metabolism and clearance of the drug

Plasma protein concentrations reach adult values in infancy.

Regional blood flow

Cardiac index changes affect the redistribution of a drug by changing intercompartmental clearances

Changes in hepatic blood flow may affect metabolism and elimination clearance, particularly of high hepatic extraction drugs

Cardiac index influences initial and steady-state arterial drug concentrations by redistribution clearance and plasma concentrations are inversely related to the cardiac index. A high cardiac index (often linked to increased metabolic rate) results in a high venous return, diluting intravenously administered drugs and producing lower-than-expected plasma arterial concentrations. The need for increased doses to offset this may result in a prolongation of the context-sensitive half-life of the drug

Metabolism

Drug metabolism may occur in many tissues (gastrointestinal epithelial, renal, skin and lung tissues), with the liver being the predominant site

Phase I hepatic metabolism converts drugs into inactive, partially active or active metabolites. Phase II metabolism usually converts drugs to water-soluble compounds. These compounds are subsequently easily excreted by the renal route

Reduced metabolism and clearance result in an increased risk of drug accumulation and toxicity needing reduced doses or prolonged dosing intervals.

Drug elimination in neonates and infants is slower than in older children and adults

Phase I reactions increase the polarity of the compound by introducing or exposing functional groups on the molecule. Quantitatively, the most significant phase I reactions are processed by the cytochrome P450 system, part of the microsomal proteins.

The ratio of hepatic mass to body mass decreases with age. Liver mass represents 5% of body weight at birth and declines to 2% in adults

hepatic metabolic capacity is a function of both the liver mass and the concentration of microsomal proteins. Hepatic microsomal protein concentration increases from 26 milligrams per gram of liver at birth to 40 mg per gram in adulthood

Each CYP450 isoform has a unique maturation pattern. CYP3A7 is the predominant active isoform in the neonatal period, and there is a progressive shift from CYP3A7 to CYP3A4 during the first year of life

Drug metabolizing enzyme ontogeny classifies into three groups: (i) Enzymes that are mature and expressed at their highest levels in the fetus and decline after birth; (ii) enzymes that are mature at birth and maintain constant expression; and (iii) enzymes with low expression in the fetus and increase expression after birth. The third category, the largest, has the most profound impact on developmental metabolism

In humans, only seven isoenzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 CYP3A4) are responsible for the metabolism of more than 95% of drugs

CYP3A accounts for the metabolism of at least 50% of therapeutic drugs given

Overall, the CYP-dependent metabolic capacity at birth is 30–60% of adults

Exposure to benzyl alcohol may result in the so-called ‘gasping syndrome’
grey-baby syndrome with chloramphenicol administration

At birth, CYP1A2, responsible for caffeine-3-demethylation, has negligible activity. The half-life of caffeine may exceed 100 hours in premature neonates compared with 5 hours in older children. CYP1A2 activity increases quickly after birth with age, resulting in a decrease in half-life and an increase in clearance

CYP3A4 is essentially functionally immature at birth. Enzyme activity rapidly increases at 2 weeks of age, approaches 40% of adult values by the end of the neonatal period, and reaches adult levels by about 3 years

Neonates rely on CYP3A4 for clearance of levobupivacaine and midazolam and CYP1A2 for ropivacaine clearance. The reduced metabolic clearance of local anaesthetic results in potentially increased toxicity in this age group and necessitates reduced infusion rates

Midazolam, in neonates, is also cleared by CYP3A4, and the immature enzyme may result in an increased duration of sedation

Table 2. Developmental expression of selected drug-metabolizing enzymes in the neonate

Phase II products are usually hydrophilic and readily eliminated from the body.

Conjugation reactions are reactions that include glucuronidation, sulphation, methylation or acetylation

Phase II enzyme maturation occurs at a less predictable rate than phase I reactions

Some phase II pathways like sulphate conjugation are mature at birth and can compensate for other immature pathways. Other pathways like acetylation, glycation, glucuronidation are immature.

Sulphate conjugation is an active metabolic pathway in neonates for morphine and paracetamol.

Glucuronidation activity for morphine reaches adult values by the end of the first year of life with subsequent increases in clearance. Glucuronidation is the predominant metabolic pathway for propofol however, contributions by CYP2A6, CYP2B6 and CYP2C9 accelerate its maturation profile

Elimination

References

Developmental Pharmacology - BJA Ed