2nd joint annual meeting – club phase i and agah positioning human pharmacology for the future bad...
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2nd Joint Annual Meeting – Club Phase I and AGAHPositioning Human Pharmacology for the Future
Bad Homburg v.d.H., April 26 and 27, 2007
H. W. Seyberth
Department of Pediatrics
Philipps University, Marburg/Germany
Workshop: Workshop:
Designs of human pharmacology trials forDesigns of human pharmacology trials for
paediatric populationspaediatric populations
Physiology, Diseases and
Developmental Pharmacology
Appreciation of at least
five phases
of development
Physiology:
Large body surface Increased skin permeability Reduced surfactant synthesis
Aortopulmonary shuntsImmaturity of the brain stem No ciruclatory autoregulation Incomplete retinal vascularisation
Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation
Pathophysiology:
Respiratory distressPulmonary hypertensionPatent ductus arteriosusApneaIntraventricular hemorrhageRetinopathy of prematurity (ROP)Bronchopulmonary dysplasia
Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation
Term Newborn: Phase of Adaptationage: birth up to 1 month
Physiology:
Large body surfaceIncreased skin permeabilityIncreased body water Decreased blood brain barrierIncomplete neuronal maturationIncreased hemolysis
Pathophysiology:
SepsisHyperbilirubinemiaSeizures HypocalcemiaHypoglycemiaMalformations
Term Newborn: Phase of Adaptationage: birth up to 1 month
Infants and Toddler: Phase of proliferation and growthage: 22 days to 24 months
Physiology:
Small airways Ongoing cerebral myelination Naive (incompetent) immune system
Large liver and kidney (increased clearances)
Pathophysiology:
Otitis mediaBronchiolitisFebrile seizuresRickets
Infants and Toddler:
Phase of proliferation and growth
age: 22 days to 24 months
Children:Phase of Differentiation and Trainingage: 2 to 11 years
Physiology:
Slower growth rateIncreased independenceIncreased school performanceShift to logical operations
Pathophysiology:
AccidenceDysfunctions of the immune system:
Asthma/allergyJuvenile rheumatoid arthritisAutoimmune diseasesNeoplasm
HyperkinesiaEnuresisOrgan transplantationsEpileptic syndromesObesityDiabetes
Children: Phase of Differentiation and Trainingage: 2 to 11 years
Adolescents: Sexual Maturation
age: 12 to 17 years
Physiology:
Rapid body changes:growth spurtgonadal growth
Emotional instability
Adolescents: Sexual Maturationage: 12 to 17 years
Pathophysiology:
Acne vulgarisEndocrine dysfunctionsAccidenceSexual transmitted diseasesDrug addictionDoping
Pre-term InfantPre-term Infant
< 36 weeks of < 36 weeks of gestationgestation
Term Newborn Term Newborn InfantInfant
0-27 days0-27 days
Infant/ToddlerInfant/Toddler
28 days -23 months28 days -23 months
ChildChild
2 - 11 years2 - 11 years
AdolescentAdolescent
12 - 17 years12 - 17 years
SurvivalSurvival AdaptationAdaptation GrowthGrowth TrainingTraining MaturationMaturation
Seyberth, in Pädiatrie, eds Speer/Gahr, 2005
Pharmacokinetic differences in the term and preterm infants
Absorption: Gastric HCI-production Bile flow Bacterial intestinal growth
Enterohepatic circulation
Distribution: Body water Body fat Muscular mass Plasma protein binding
Liver metabolism: Hydroxylation Glucoronidation
Renale excretion: GFR Tubular function
An important dosage-principle in the NICU
• Given:
• Result:
• Examples:
• Vd
• Clearance
• Loading dose (LD) • Maintenance dose (MD)
• Phenobarbital, Phenytoin, Methylxanthine, Digoxin, Aminoglykoside, Indometacin Chloramphenicol, Furosemide
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-
-
- - - - -
- - - - - - - - - -
- - - - -
- -
-
-
-
-
-
-
-(µg/kg/day)
(mg/kg/day)(mg/kg/day)
(ml/h/kg)Total body clearenceTotal body clearence
Maintenance doseMaintenance dose
DIGOXINDIGOXIN
GENTAMYCINEGENTAMYCINE
Preterm+ term
neonates
Youngchildren(< 8 y)
Adults(< 50 y)
Adults(> 50 y)
Preterm+ term
neonates
Youngchildren(< 8 y)
Adults(< 50 y)
Adults(> 50 y)
Preterm+ term
neonates
Youngchildren(< 8 y)
Adults(< 50 y)
Adults(> 50 y)
Preterm+ term
neonates
Youngchildren(< 8 y)
Adults(< 50 y)
Adults(> 50 y)
THEOPHYLLINETHEOPHYLLINEMaintenance dose of drugs with renal eliminationMaintenance dose of drugs with renal elimination
20
15
10
5
0
10
5
0
100
75
50
25
0
30
20
10
0
Resorption
Distribution
Excretion
Receptor
Signal transduction
Cellular reaction
PHARMACODYNAMICSPHARMACODYNAMICS PHARMACODYNAMICSPHARMACODYNAMICS PHARMACOKINETICSPHARMACOKINETICS PHARMACOKINETICSPHARMACOKINETICS
Medium analgesic dosage of morphine
in children with an age between 0 and 6 years
(Olkkola et al., CPT 1988)
0
10
20
30
40
0 - ½ year n = 5
6 year n = 4
2 - 4 year n = 5M
orp
hin
e p
lasm
a c
on
cen
trat
ion
[µg
/l]a
t tim
e p
oin
t of p
ain
re
cove
ry
p < 0.01
dosis:0.05 mg/kg/min infusionrate until painlessness
Indomethacin induces GFR reduction in young adults with volume depletion and in preterm infants with sPDA
GF
Rm
l/min
/1.7
3m2
2 mg/kg/d
0.2 mg/kg/d
91
19.5
- 12 %
- 40%
adults infants
8080
60
40
20
100
11.7
without indo
with indo
Congenital salt losing tubulopathies (SLTs)Congenital salt losing tubulopathies (SLTs)Different aDifferent age at manifestation and ontogeny of targets ge at manifestation and ontogeny of targets (Jeck et al., AJ P 2005)(Jeck et al., AJ P 2005)
Thiazid-SLT : NCCTFurosemid-SLT : NKCC2
Polyhydramnios 12/12 0/13
Postnatal leading symptoms
polyuria hyponatremiahypotension (shock) hypercalciurianephrocalcinosis
hypokalemiacarpopedal spasms hypomagnesemiahypocalciuriagrowth retardation
Age at first
presentation antenatal: 12/12
<1 year: 1/13 1-5 years: 4/13
6-13 years: 8/13
thick ascending limb distal convoluteAffected nephron segment
fluid restriction
furosemide
digoxin
NSAID´s ACE- inhibitor
Adverse effects of geriatric heart failure therapy Adverse effects of geriatric heart failure therapy applied to preterm infants with sPDA:applied to preterm infants with sPDA:
arrhythmias with cerebral bleeding
marked volume depletion renal hypoperfusion
PG-stimulationnephrocalcinosis
intestinal perforationrenal failure
Pre-renal failure in the preterm infant with sPDAPre-renal failure in the preterm infant with sPDA
filtration
v. afferens v. efferens
vasodilation vasoconstrictionprostaglandins angiotensin II
Examples on long-term adverse effects of medicines in early infancy and childhood
Target/ Organ Drug Effect
teeth tetracyclines discoloration/ enamel dysplasia
genital tract
cyclophosphamide
infertility/ovarian failure
immune system tacrolimus lymphoproliferation
diabetes
heart antracyclines
alkylating agens methylphenidate
cardiotoxicity heart failure cardiovascular events like myocard. infarct
CNS phenobarbital
glucocorticoides
methylphenidate
cisplatin
attention and memory dysfunctioncerebral palsy strokehearing loss
kidney furosemide nephrocalcinosis
bone glucocorticoids growth failure
There are marked differences in pediatric patiants with respect to:
- Pharmacokinetics
- Pharmacodynamics
- Drug toxicity
- Longterm safety