Pediatric Pharm

Question 1

Neonate

Answer 1

< 4 weeks old

• premature: born before 37 weeks gestation
• term: born after 37 weeks

Question 2

Infant

Answer 2

4 weeks - 1 year

Question 3

Child

Answer 3

> 1 year but < 18 years

Question 4

What two things affect drug mvmt from plasma to tissues?

Answer 4

CO and VRG

• peds have a higher CO going to VRG plus higher surface area

Question 5

What organ is the primary determinant of biotransformation?

Answer 5

Liver

• high extraction ratio if drugs are flow dependent clearance (ie: propofol… if liver enzymes aren’t fully developed, drugs can accumulate)
• low extraction ratio drugs are enzyme activity dependent clearance (alfentanil and methadone)

Question 6

What is the primary excretion organ?

Answer 6

• kidneys (renal CO x extraction ratio)

– Small, unbound drugs pass from plasma to GF

– Nonionized (uncharged) drug reabsorbed in tubules

– Ionized (charged) drug is excreted.

– GFR 30-40% adult for 34+weekers; 60% by 3rd week nml @6 mos.

Question 7

t1/2 life elimination

Answer 7

• time for [] to fall 50%
• anesthesia drugs have multiple t1/2 b/c multiple compartments model

Question 8

Oral Absorption

Answer 8

• Principle site of absorption is small intestine.

– Rate at which drug leaves the stomach determines speed of absorption.

• Rate of absorption is slower in neonates and young infants than in older children due to delayed gastric emptying.

– Matures through infancy and doesn’t reach adult rates until 6-8 months.

Question 9

Rectal Absorption

Answer 9

• Absorption of drugs administered rectally is erratic and variable.
• Bioavailability of rectal acetaminophen in premature neonates and infants is variable.

– It is approximately 80% of oral dose and the rate of absorption is slower.

– Rectal bioavailability is formulation dependent and

decreases with age.

– Peak blood levels achieved at 60 to 180 minutes.

Question 10

Intranasal

Answer 10

• Rich vascular plexus of the nasal cavity provides a direct route into the blood stream for medications that easily cross mucous membranes.

• For many IN medications the rates of absorption and plasma concentrations are comparable to intravenous administration, and are typically better than subcutaneous or intramuscular routes.
• Poor patient cooperation can be a factor in absorption

Question 11

Transdermal/IM

Answer 11

• Increased cutaneous perfusion, thinner skin in neonates increases absorption of topically applied drugs in neonates.

– More tendency to form methemoglobin so use of EMLA in neonates need to be done cautiously.

• Skin thickness, perfusion, and hydration in infancy increases percutaneous absorption.
• IM in neonates/children is not altered.

Question 12

Pulmonary Absorption

Answer 12

• Pulmonary absorption is more rapid in infants and children than adults.

• Increased respiratory rate and cardiac index.

• Greater proportional distribution of cardiac output to vessel rich organs.

• Anesthetic levels can become toxic more quickly than adults

• Congenital anomalies with right to left shunting can delay the FA/FI of inhalational anesthetics.

Question 13

Distribution

Answer 13

• Children exhibit different drug distributions from adults due to

– different body composition

– altered protein binding

Question 14

Baby Fat/H2O and distribution: implications for anesthesia drugs

Answer 14

• Water soluble drugs are more diluted and have lower receptor concentrations
• The loading dose must be increased in younger children to achieve effect
• Succinylcholine dose in infants up to 4mg/kg
• Less pronounced with lipid soluble drugs

Question 15

Peds Drug Distribution

Answer 15

• Total body water is:

– 80-85% for premature infant

– 70-75% for term infants

– 50-60% adults

– 40% infants body weight is in ECF

– 20% adults body weight is ECF

– Vd H20 soluble drugs is >> in peds than adults

– Vd lipid soluble drugs is ??? In peds than adults

• Lower amounts of body muscle prolongs action of the drugs because?

– They can’t redistribute from site of action (Contact sensitive T 1/2 )

Question 16

Compartments

Answer 16

• Reduction in total body water is due to a gradual decline in ECF.
• Increased Vd for water soluble drugs

– NMBDs distribute rapidly to the ECF but into cells more slowly.

– Initial dose is higher in neonates and infants.

Question 17

Protein Binding

Answer 17

• Degree of protein binding is less in the pre-term and term infants than in older children and adults.

– Lower concentrations of total body proteins and albumin

– Many drugs that are highly protein bound in adults have less of an affinity for protein in neonates

– Bilirubin can displace protein bound drugs and vice versa

– Affects weakly bound drugs more than highly bound

Question 18

Implications of lower protein binding in infants than in children/adults

Answer 18

– Lower concentrations of total body proteins and albumin

– Many drugs that are highly protein bound in adults have less of an affinity for protein in neonates

– Bilirubin can displace protein bound drugs and vice versa

– Affects weakly bound drugs more than highly bound

– What does this mean for anesthetic drugs?

• Lower protein binding means more free medication and a greater pharmacological effect for drugs that are highly protein bound

– What are the implication for anesthesia?

• Albumin binds Benzodiazepines, Barbiturates, and ASA
• α 1 AAG binds Amide local anesthetics, α-blockers, opioids, NMBs

Question 19

Drug Metabolism

Answer 19

• Majority of drug metabolism happens in the liver, GI tract, gastric mucosa, and lungs
• Neonates have

– decreased Hepatic BF

– immature hepatic enzymes

—decreased biotransformation

– decreased GFR &

– decreased renal tubular fxn

– Lipid soluble compounds are converted to more water- soluble compounds.

• Water soluble drugs may be excreted unchanged in the kidneys.

Question 20

What are drug metabolism implications for peds?

Answer 20

• Drug doses need to be adjusted accordingly and should be reduced until liver enzymes and renal function approaches adult levels.

– GFR ~ 3 months

– Tubular fxn ~ 8-12 months

Question 21

Drugs w Prolonged t1/2 at Birth

Answer 21

– Bupivacaine-25hrs

– Meperidine-22hrs

• Diazepam-100hrs
• Phenytoin-21hrs

Question 22

Hepatic Metabolism - Maturation

Answer 22

• Hepatic blood flow also increases as infants mature.
• Phase I metabolism (oxidation, reduction, hydrolysis)
• The cytochrome P450 enzyme system is also immature in the neonate.

– Ondansetron, acetaminophen, fentanyl, ibuprofen, codeine

– Immature system decreases the formation of some toxic metabolites, like those with acetaminophen.

• Phase II metabolism processes are immature in neonates and mature within the first year of life.

– Issues with conjugation (bilirubin)

– Beware acetaminophen, sulfonamides, chloramphenicol

Question 23

Extrahepatic Elimination Implications

Answer 23

• Non Specific Esterase activity may be increased

– Remifentanil clearance:

• is greater in neonates (4.5 L/hr/kg)
• than in infants (3.7 L/hr/kg)
• or in adults (2.1 L/hr/kg) meaning what? keep remi infusions running when transporting pts!!!

Question 24

What is the implication of decreased plasma pseudocholinesterases in neonates?

Answer 24

• ester LA may have a prolonged effect!
• decrease doses
• avoid sux for undiagnosed DMD

Question 25

Renal Elimination

Answer 25

* Drug are excreted by either glomerular filtration or tubular excretion. * GFR is ≈ 30% that of adults at birth in term neonates and is 90% at one year.

Question 26

Decreased Renal Clearance

Answer 26

* Drugs such as aminogylcoside antibiotics (micin’s and some “mycins”) that are excreted primarily through glomerular filtration or tubular secretion have prolonged elimination half-life. * Whenever administering a drug to a preterm or term infant, one must consider the contribution of renal function in the termination of its action.

Question 27

Developmental Pharmacodynamics: Opioid Receptors

Answer 27

– Not fully developed in the newborn rat and mature through adulthood. – Increased human neonatal sensitivity to morphine is attributed to pharmacokinetic rather than pharmacodynamic differences.

Question 28

Developmental Pharmacodynamics: Nicotinic Receptors

Answer 28

– Neonates have an increased sensitivity to the effects of neuromuscular blocking drugs (NMBs). – Unknown why, but there is a three fold reduction in the release of Ach from the infant rat phrenic nerve

Question 29

Other Pediatric Issues Impacting Anesthesia

Answer 29

• Reduced FRC and O 2 reserves – Reduced lung compliance d/t fewer & smaller alveoli. – Compliant chest wall—collapses easily * May have profound Bradycardia and asystole with 1 st dose of Succinylcholine if not given atropine pretreatment. * Fluid management more critical

Question 30

Inhalation Agent Issues

Answer 30

* decreased alveolar ventilation relative to adults * decreased FRC relative to adults AND decreased oxygen consumption * Large VRG * MAC is higher than adults * B/P is sensitive to CV effects d/t less well developed compensatory mechanisms – Vasoconstriction; tachycardia – Very sensitive to myocardial depression

Question 31

GABA

Answer 31

– At birth the cerebellum only contains 1/3 of the number of GABAA receptors found in the adult. – Changes in receptor binding occur during postnatal development. – The GABAA receptor complex becomes more prevalent from birth to 2 years and then decrease to 50% of peak values by 17 years. – This is consistent with age related MAC changes and higher doses of oral midazolam. *less GABA receptors = less anesthetic*

Question 32

Propofol

Answer 32

* Larger Vd—why? What effect on induction? * Shorter T 1/2 E—why? * This does not really effect a single induction dose but does increase recovery rate from infusion * Induction dose 2-3mg/kg vs. 1.5-2.5mg/kg adults * Infusion rates 250 mcg/kg/min with rapid emergence * Remember Propofol infusion syndrome – Rhabdo; Metabolic acidosis; hemodynamic instability; hepatomagaly; multiorgan system failure

Question 33

ED95 of NMBs in Peds Table

Answer 33

Question 34

Dosing Calculations

Answer 34