INTRODUCTIONTOPEDIATRICPHARMACOLOGY

Question 1

Of current FDA approved drugs, how many are approved for pediatric use?

Answer 1

less than 50%

Question 2

What do you call the use of a medication for a non-FDA approved indication?

Answer 2

off label

60% ar ethis in peds

Question 3

How do we determine pediatric drug doses for off-label use?

Answer 3

case series, trial

Question 4

Commonly Used Age Definitions

Answer 4

Premature neonate
1 month to 1 year of age

Child
1 –11 years

Adolescent
12 –16 years

Question 5

Commonly Used Weight Definitions

Answer 5

Extremely low-birth-weight (ELBW)

90thpercentile forGA

Question 6

premature and low birth weight up

Answer 6

mortality

Question 7

HISTORICALMISTAKES

Sulfonamide: kernicterus

Answer 7

Displaces bilirubin from protein-binding sites, bilirubin deposits in the brain, results in encephalopathy

Question 8

HISTORICAL MISTAKES

Chloramphenicol: grey baby syndrome

Answer 8

Abdominal distension, vomiting, diarrhea, characteristic gray color, respiratory distress, hypotension, progressive shock

couldnt excrete

immature glucuronidating

Question 9

HISTORICAL MISTAKES

Answer 9

Congenital abnormalities; also: polyneuritis, nerve damage, mental retardation

morning sickness and sleeping aid

Question 10

OVERRIDING PRINCIPLE

Answer 10

Children are NOT just “little adults”

Cannot extrapolate dose from adult data based simply on body weight or surface area

Question 11

Oral Drug Absorption

Answer 11

Gastric volume ↓

Gastric acid ↓ (gastric pH ↑)
Increased absorption of acid labile drugs (penicillin G, erythromycin) (goes from 6-8 to 1-3 unless premautre it stays high and some drugs arent being destroyed)
Decreased absorption of weakly acidic drugs (phenobarbital, phenytoin)
Extrauterine factors (nutrition) most likely responsible for initiating acid production

Transport of bile acids ↓

Gastric emptying ↓, intestinal transit time ↑

Question 12

Intramuscular Drug Absorption

Answer 12

Absorption inconsistent due to differences in:
Muscle mass
Poor perfusion (erratic blood flow)
Peripheral vasomotor instability
Insufficient muscle contractions

Sick, immobile neonates or those receiving paralytics may show reduced absorption rates

IM dosing reserved for emergencies or when IV sites inaccessible

Exception: phytonadione IV given at birth >slow release until dietary intake adequate

wont use unless life threatening

wit k is slow release

Question 13

Transdermal Drug Absorption

Answer 13

Directly related to:
Degree of skin hydration
Relative absorptive area

Inversely related to:
Thickness of stratum corneum

Substantially increased percutaneous absorption:
Underdeveloped epidermal barrier
Compromised skin integrity
Increased skin hydration
Ratio of BSA to total body weight highest in youngest
Relative systemic exposure higher

Question 14

Rectal Drug Absorption

Answer 14

May be important alternative site when oral agents cannot be used:
Nausea
Vomiting
Seizure activity
Preparation for surgery

Erratic absorption depending on formulation and retention time

Question 15

Body Weight (%) Composed of Water

Answer 15

Premature Newborn
85%

Term Newborn
70-80%

One Year
60-65%

Question 16

Extracellular Water

Answer 16

Similar decline from 40-45% (newborn) to 20-25% (1 year)

Question 17

GentamicinVolume of Distribution

Answer 17

Premature Neonate
0.5-0.7 L/kg

One Year
0.4 L/kg

Adulthood
0.2-0.3 L/kg

have to give more drug to fill the space

Question 18

Body Fat

Answer 18

Total body water varies inversely with fat tissue

Question 19

Protein Binding IS DECREASED

Answer 19

Due to: reduced levels of albumin and α1-acid glycoprotein (+ decreased affinity)

Bilirubin non-covalently bound to albumin with lower affinity in newborn than

so increase free drug to act at receptors

bilirubin displaces drugs and vis versa causing kernictures (3rd gen cephalosporin)

Question 20

Drug Metabolism

Phase I

Answer 20

Oxidation, reduction, hydroxylation, hydrolysis
Develop at varying rates during childhood
CYP3A develop early in life
CYP2D6 similar to adult values within 2 weeks of life
CYP2C9 and 2C19 develop throughout childhood
CYP2E1 similar to adult values at 3 months
CYP1A2 negligible in newborn not exposed to caffeine
Alcohol dehydrogenase only reaches adults levels at 5 years


Question 21

CYP3A develop early in life

Answer 21

erythromycin, alprazolam, simvastatin)

Question 22

CYP2D6 similar to adult values within 2 weeks of life

Answer 22

codeine

Question 23

CYP2C9 and 2C19 develop throughout childhood

Answer 23

(warfarin, phenytoin)

Question 24

CYP2E1 similar to adult values at 3 months

Answer 24

acetaminophen)

Question 25

CYP1A2 negligible in newborn not exposed to caffeine

Answer 25

(caffeine)

Question 26

Alcohol dehydrogenase only reaches adults levels at 5 years

Answer 26

chloramphenicol

Question 27

drug metabolism phase II

Answer 27

Glucuronidation undeveloped Sulfation well-developed Acetylation see more sulfides instead of glucuronides

Question 28

Drug Elimination

Answer 28

``` Glomerular Filtration Ability to filter, excrete, reabsorb not maximized until 1 year Rapid rise in GFR: Increased renal blood flow  Increased function of nephrons  Appearance of additional nephrons ``` Tubular Secretion Reduced immediately after birth, increases over 1styear Closely monitor renal function Urine output often used diaper weights

Question 29

MEDICATION DOSINGIN CHILDREN

Answer 29

Pediatric Drug References: Lexicomp, Pediatric & Neonatal Dosage Handbook NeoFax UpToDate Weight chosen as best estimate of growth References provide doses in units per weight: mg/kg/day mcg/kg/dose Exception: chemotherapeutic agents (BSA) Doses outside of reference ranges should always be questioned Older children/adolescents transition to adult dosing when calculated weight-based dose exceeds adult doses

Question 30

PREVENTING MEDICATION ERRORS

Answer 30

Weight-based dosing may lead to mathematical errors Caution: unit conversions and decimal point errors Ten-fold overdose of narrow therapeutic window drug can be fatal(clonidine, digoxin, morphine, fentanyl) ``` Methods to Reduce Potential Medication Errors: Standard concentrations Smart pump technology Barcoding Electronic prescribing ``` Outpatient Setting: Patient specific information on Rx Appropriate medication measurement tools

Question 31

NEONATAL SEPSIS overview

Answer 31

Incidence inversely proportional to birth weight and GA | Mortality 30-50% (highest observed in neonates

Question 32

NEONATAL SEPSIS risk factors

Answer 32

``` Preterm birth Maternal GBS colonization Rupture of membranes > 18 hours Maternal signs/symptoms of intra-amniotic infection Ethnicity Male sex Low Apgar scores ```

Question 33

NEONATAL SEPSIS pathogenesis

Answer 33

Organisms ascend birth canal Organisms can also enter amniotic fluid via occult tears Chorioamnionitis: intra-amniotic infection Clinical diagnosis –maternal fever (≥ 38 ˚C; 100.4 ˚ F) Other criteria used in clinical trials (2 of the following): Maternal leukocytosis > 15,000 cells/mm3 Maternal tachycardia > 100 bpm  Fetal tachycardia > 160 bpm  Uterine tenderness Foul odor of amniotic fluid

Question 34

NEONATAL SEPSIS pathogetns early onset

Answer 34

``` Early Onset (within 5-7 days) GBS (50%) E. coli (20%) Others:  Listeria monocytogenes  Enterococcus  Gram-negative bacilli ```

Question 35

NEONATAL SEPSIS pathogens late onset

Answer 35

``` Late Onset (after 5-7 days’ PNA) CONS (68%) S. aureus Pseudomonas Anaerobes Candida ```

Question 36

NEONATAL SEPSIS antimicrobial agents

Answer 36

Ampicillin (covers gram pos) Gentamicin (gram neg) Third generation cephalosporin (dftraxone dont use bc it displaces bilirubin andyou get kernicterus) Acyclovir (not routinely used) (if viral seizures are indicative)

Question 37

NEONATAL SEPSIS treatment

Answer 37

Ampicillin MOA: inhibits bacterial cell wallsynthesis Gentamicin MOA: inhibits bacterial proteinsynthesis Third Generation Cephalosporin Cefotaxime vs. ceftriaxone MOA: inhibits bacterial cell wallsynthesis Acyclovir MOA: inhibits viral DNA synthesisand viral replication

Question 38

drug resistant gram pos use

Answer 38

vanco for late onset

Question 39

Viral myocarditis overview

Answer 39

Incidence –1:100,000 Implicated in up to 12% of sudden cardiac deaths in adolescents and young adults

Question 40

viral myocarditis pathophysiology

Answer 40

Acute phase: inflammatory cell invasion of myocardium and myocardial necrosis and apoptosis T-cell invasion: most destructive 7-14 days after inoculation Healing phase: myocardial fibrosis; continued inflammation and persistent viremia may lead to left ventricular dysfunction and dilation ; for lvh: use inotropes for afterload reduction ecmo to let heart heal

Question 41

viral myocarditis treatment

Answer 41

``` Acute phase Inotropes Afterload reduction Mechanical ventilation Extracorporeal membrane oxygenation (ECMO) Immune therapy  Intravenous immunoglobulin (IVIG) (used in myocarditis bc high rate of mortality)  Immunosuppressive agents ```

Question 42

INTRAVENOUS IMMUNOGLOBULIN

Answer 42

Sterile solution of human immune globulin > 98% gamma globulin(IGG), trace IgA and IgM MOA: protects recipient against infection and suppresses inflammatory and immune mediated processes Replacement for 1˚ and 2˚immunodeficienciesand IgG antibodies against bacteria, viral, parasitic antigens Interferes with Fc receptors for autoimmune cytopeniasand ITP Provides passive immunity by increasing antibody titer and antigen-antibody reaction potential

Question 43

IVIG PK

Answer 43

Provides immediate antibody levels Immune effect: 3-4 weeks

Question 44

IVIG AE

Answer 44

Chills, fever, flushing, myalgia, malaise, headache Tachycardia, chest tightness, dyspnea, sense of doom Thrombotic complications Acute kidney injury

Question 45

EXTRACORPOREAL MEMBRANE OXYGENATION(ECMO)

Answer 45

``` Prolonged cardio-pulmonary bypass (3-10 days)  upports patients with life-threatening respiratory or cardiac failure  Neonatal indications: Primary pulmonary hypertension Meconium aspiration syndrome Respiratory distress syndrome Group B Streptococcal sepsis Asphyxia Congenital diaphragmatic hernia ```

Question 46

ECMO CIRCUIT

Answer 46

Blood siphoned, driven by right arterial pressure  oller pump draws blood into bladder and pushes it through oxygenators and heat exchanger

Question 47

ECMO COMPLICATIONS

Answer 47

``` Clots in circuit (19%) Oxygenator failure Seizures Intracranial bleeding Hemolysis and coagulopathy Arrhythmias Oliguria (within 24-48 hours) Metabolic acidosis ```

Question 48

MEDICATION USE IN ECMO

Answer 48

Site of drug delivery Directly into patient? Proximal, distal, or directly into venous reservoir? (give proximal) Hemodilution Circulating blood volume will double (blood mixing with priming solution) affecting drugs with small volumes of distribution and those that are highly protein bound Drug binding interactions with the circuit Adsorption and sequestration onto plastic cannula and/or silicone oxygenator Altered renal, hepatic, and cerebral blood flow Non-pulsatile blood flow