INTRODUCTIONTOPEDIATRICPHARMACOLOGY Flashcards
Of current FDA approved drugs, how many are approved for pediatric use?
less than 50%
What do you call the use of a medication for a non-FDA approved indication?
off label
60% ar ethis in peds
How do we determine pediatric drug doses for off-label use?
case series, trial
Commonly Used Age Definitions
Premature neonate
1 month to 1 year of age
Child
1 –11 years
Adolescent
12 –16 years
Commonly Used Weight Definitions
Extremely low-birth-weight (ELBW)
90thpercentile forGA
premature and low birth weight up
mortality
HISTORICALMISTAKES
Sulfonamide: kernicterus
Displaces bilirubin from protein-binding sites, bilirubin deposits in the brain, results in encephalopathy
HISTORICAL MISTAKES
Chloramphenicol: grey baby syndrome
Abdominal distension, vomiting, diarrhea, characteristic gray color, respiratory distress, hypotension, progressive shock
couldnt excrete
immature glucuronidating
HISTORICAL MISTAKES
Congenital abnormalities; also: polyneuritis, nerve damage, mental retardation
morning sickness and sleeping aid
OVERRIDING PRINCIPLE
Children are NOT just “little adults”
Cannot extrapolate dose from adult data based simply on body weight or surface area
Oral Drug Absorption
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 ↑
Intramuscular Drug Absorption
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
Transdermal Drug Absorption
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
Rectal Drug Absorption
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
Body Weight (%) Composed of Water
Premature Newborn
85%
Term Newborn
70-80%
One Year
60-65%
Extracellular Water
Similar decline from 40-45% (newborn) to 20-25% (1 year)
GentamicinVolume of Distribution
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
Body Fat
Total body water varies inversely with fat tissue
Protein Binding IS DECREASED
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)
Drug Metabolism
Phase I
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
CYP3A develop early in life
erythromycin, alprazolam, simvastatin)
CYP2D6 similar to adult values within 2 weeks of life
codeine
CYP2C9 and 2C19 develop throughout childhood
(warfarin, phenytoin)
CYP2E1 similar to adult values at 3 months
acetaminophen)
CYP1A2 negligible in newborn not exposed to caffeine
(caffeine)
Alcohol dehydrogenase only reaches adults levels at 5 years
chloramphenicol
drug metabolism
phase II
Glucuronidation undeveloped
Sulfation well-developed
Acetylation
see more sulfides instead of glucuronides
Drug Elimination
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
MEDICATION DOSINGIN CHILDREN
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
PREVENTING MEDICATION ERRORS
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
NEONATAL SEPSIS overview
Incidence inversely proportional to birth weight and GA
Mortality 30-50% (highest observed in neonates
NEONATAL SEPSIS
risk factors
Preterm birth Maternal GBS colonization Rupture of membranes > 18 hours Maternal signs/symptoms of intra-amniotic infection Ethnicity Male sex Low Apgar scores
NEONATAL SEPSIS
pathogenesis
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
NEONATAL SEPSIS
pathogetns early onset
Early Onset (within 5-7 days) GBS (50%) E. coli (20%) Others: Listeria monocytogenes Enterococcus Gram-negative bacilli
NEONATAL SEPSIS
pathogens late onset
Late Onset (after 5-7 days’ PNA) CONS (68%) S. aureus Pseudomonas Anaerobes Candida
NEONATAL SEPSIS
antimicrobial agents
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)
NEONATAL SEPSIS
treatment
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
drug resistant gram pos use
vanco for late onset
Viral myocarditis overview
Incidence –1:100,000
Implicated in up to 12% of sudden cardiac deaths in adolescents and young adults
viral myocarditis pathophysiology
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
viral myocarditis treatment
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
INTRAVENOUS IMMUNOGLOBULIN
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
IVIG PK
Provides immediate antibody levels
Immune effect: 3-4 weeks
IVIG AE
Chills, fever, flushing, myalgia, malaise, headache
Tachycardia, chest tightness, dyspnea, sense of doom
Thrombotic complications
Acute kidney injury
EXTRACORPOREAL MEMBRANE OXYGENATION(ECMO)
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
ECMO CIRCUIT
Blood siphoned, driven by right arterial pressure
oller pump draws blood into bladder and pushes it through oxygenators and heat exchanger
ECMO COMPLICATIONS
Clots in circuit (19%) Oxygenator failure Seizures Intracranial bleeding Hemolysis and coagulopathy Arrhythmias Oliguria (within 24-48 hours) Metabolic acidosis
MEDICATION USE IN ECMO
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
