Peds Flashcards
What about growth and development makes peds a special patient poputlation? (3)
- Heterogenous population
- Maturation is a variable process
- Pathological considerations
In terms of available PK/PD information, what makes peds a special population? (3)
- Clinical studies use healthy adult subjects
- Exclusion criteria
- Therapeutic orphan
Describe the growth of an infant for the first 2 weeks after birth
5-10% weight loss from birth weight
Describe the growth of an infant from 4-6 months
Infant should double birth weight
Describe the growth of an infant from 1-5 years
Toddler gains about 2.2kg/year
What is dose normalization?
Need to consider changes in body surface area/mass
What is developmental pharmacology? (4)
- PK and PD of drugs and the clinical characteristics of neonatal and pediatric populations
- How human growth and development change PK/PD relationship in each unique patient
- Accurately determine safe and effective doses for pediatric patients
- Variability in rates of development
What are the 2 goals of developmental pharmacology?
- Understand the impact of maturation on drug’s ADME (PK)
- Describe the PD: knowing the concentration of drugs and the expected response
What are the general effects on ADME as children age? (3)
- Pharmacokinetic changes
- Anatomical and physiologcal changes
- Age-related changes in organ function are responsible for changes in PK (kidney, liver) - Rate of maturation of ADME processes is most in the first 2 years of life
- Generally slower in neonatal period, increasing into childhood
What are some developmental maturation factors affecting rate and extent of GIT absorption? (7)
- GIT surface area
- GIT perfusion
- Gastric pH
- Gastric emptying and intestinal motility
- Pancreatic exocrine and biliary function
- Bile salts
- Enzyme activity and first-pass effects
What is important to know about gastric pH at birth and as the kid ages? (3)
- Important for drug stability, dissolution, and ionization
- Birth: neutral gastric pH
- Progressive decrease over several weeks to years
(e.g., oral penicillin)
What to know about gastric emptying and intestinal motility as kids age? (3)
- Affects intestinal drug absorption
- Limited understanding of the effect of age
- Changes in Tmax in younger ages (? delayed onset of meds) - Comparable to adult values and function by 2 years
What to know about intestinal transporters and enzymes in kids? (2)
- Influx and efflux transporters (P-gp)
- CYP3A4 maturation and first-pass effect
What food considerations to be aware of in neonates and infants? (2)
- Neonates and infants are fed more often
- Types of food: breastmilk vs. formula vs. solids
Major factors governing distribution include: (3 - not even peds, just general)
- Body composition
- Plasma protein binding and tissue binding
- Hemodynamic factors
- Tissue perfusion and cardiac output
- Vd influences loading dose. Hence, larger Vd relative to body weight will require larger mg/kg doses
Should know the body water composition for the following ages:
1. Preterm neonate
2. Term neonate
3. 1-2 years
4. >2 years
- 80-90%
- 70%
- 60%
- Stabilization
How does % of lipophilic tissue change with age? (neonate until adolescence roughly)
It peaks at the end of infancy and decreases until adolescence basically.
Why does body water composition even matter? To help, think about a drug that has a relatively low Vd (<1 L/kg) (3)
- Vancomycin or enoxaparin, for example
- In an average adult we have predictable kinetics
- In neonates, they are large water containers
- Dilutional –> higher doses of drug likely required to produce therapeutic effect
- Unpredictable
What to know about protein binding in peds? (3)
- Lower concentration of plasma binding proteins
- Albumin, alpha-1 glycoprotein, plasma globulins - Binding affinity
- Presence of pathophysiologic conditions or endogenous compounds (bilirubin, free fatty acids)
Why does protein binding even matter? (3)
- Free fraction of drug exerts pharmacological effect
- Increases free drug: affect pharmacological effect and clearance
- Highly bound drugs and narrow therapeutic index
How do the following states affect distribution?
1. Obesity
2. Malnutrition
3. Sepsis
- Lipid compartment
- Albumin deficiency
- Plasma compartment
How is hepatic blood flow different at birth? (2)
- At birth: hepatic blood flow and oxygen tension change rapidly due to:
- Umbilical vein blood supply terminated
- Portal venous and hepatic arterial blood increase with closure of the patent ductus venosus - Hepatic blood flow difficult to measure
- Unlikely to affect elimination capacity in neonates
How does splanchnic blood flow change with age?
Increases rapidly postnatally to support mucosal growth and enteral nutrition
How does renal blood flow change starting from birth? (4)
- Renal perfusion at birth <20% renal perfusion adult
- Increased cardiac output (as child ages)
- Decreased renal vascular resistance
- Increased GFR
How does organ size play a role in elimination? (3)
- Elimination capacity depends on developmental changes in:
- Function
- Relative size - Higher ratio of organ/body mass in the neonate and infant relative to adult
- Age-dependent Cls may reflect liver size/body weight difference (not Clint/g liver)
How are enzymes different in peds? (2)
- Maturational differences
- Slower in infancy
- CYP development - drug-drug interactions - Sulfation and glucuronidation
What are the general patterns of hepatic enzyme ontogeny? (2)
- Developmental Switches: change in predominant metabolic pathway(s) with maturation
- E.g., CYP3A7 (predominantly in neonates) vs. CYP3A4 (predominantly in adults)
- Alteration in metabolite profiles, toxicity risk, efficiency of elimination - Variation in enzymes
- Vary in number through developmental stages
- May be different between children of the same age
Describe GFR and tubular secretion in peds
- GFR:
- Full-term newborn: 10-20 mL/min/m^2
- Rapid increase during the first weeks of life –> adult values by 3-5 months
- Schwartz equation - Tubular secretion and reabsorption are much slower
Describe the maturation of renal clearance mechanisms (2)
Developmetal changes in kidney anatomy
1. Nephrogenesis complete at 36 weeks
- Thereafter, increases in renal mass due to increase in renal tubular growth
2. Children have the fastest rate of increasing glomerular and tubular cell size
Describe the developmental changes in glomerular filtration (3 - premature infants, 6 months age, early childhood)
- Premature infants exhibit reduced GFR
- Slower pattern of GFR development in the first 1-2 weeks PNA - By 6 months of age, GFR has approached adult levels
- Early childhood to early adolescence age GFR exceeds adult levels
- Maximum relative kidney weight
Discuss renal tubular elimination in peds (3)
- Immature renal tubules compromises passive and active reabsorption and excretion processes
- 20-30% adult value at birth
- Increases slowly and variably - Reach adult values at 1-5 years of age
- Transporters: little information about development
