DISTRIBUTION
J!!. DRUG - PLASMA PROTEIN BINDING
NEWBORNS
Albumin ■ bound of acidic drugs (thiopental, phenytoin, diazepam), fatty acids, bilirubin
g1 - acid glycoprotein - bound of basic drugs (lidocain, alfentanil)
=> Increased Iree-drug concentration (fenytoin) => increased effect (therapeutic and toxic) =» competition for protein binding
drug- drug: drug - endogenous substances bilirubin - risk of release from a protein bound to plasma
=>
: Sulfisoxazol, fenytoin (free fraction in 1st month 11 %. adults. 3.6 % salicylates, theophylin, kofein. diazepam, thiopental, vit.K analogs
ADULT CAPACITY IS REACHED CCA IN 1 YEAR
DISTRIBUTION
bJood-brain barrier
immature BB barrier — higher permeability(morfin) more expressed in some patological conditions (hypoxia, hypotermia, acidosis, meningitis) Faster onset and increased intensity of therapeutically desirable but also undesirable/ toxic _. _ (herbal toxins, addictive substances, nicotin etc.)
DISTINCTION OF METABOLISM
Immaturity of enzymatic systems decreases liver elimination ( lipophilic drugs)
Phase I.reactions : oxidation, reduction,
hydrolysis (CYP450)
Phase II.reactions: conjugations —
glukuronidation, acetylation, sulfation, conj. with
glutation Liver blood perfusion
Mass of liver tissue - impact on liver elimination
METABOLISM
PHASE i. ENZYMES- OXIDATIVE METABOLISM_
Development and maturation of CYP450:
■ prenatal: most enzymes are functional in 30 weeks since gestation however activity is insufficient (fetus as a „ i;:: i:-r ") = insufficient detoxication of substance from mother's blood
■ postnatal:
variable maturation of individual isoforms fast maturation in first 4 weeks
Family P4S0: CYP1, CYP2, CYP3
METABOLISM
PHASE I!. ENZYMES -
CONJUGATION REACTIONS
Glucuronldation:
• UGT capacity in peri- and postnatal period i: ■ UGT activity reaches of adult values around 4th year
low of age
Consequences of low UGT activity
■  Risk of accummulation of unmetabolised drug '      y   potential higher toxicity
Cisaprid - (prokinetic drug, H4 receptor agonist:
cardiotoxicity with prolongation QT) Chloramphenicol - ,,gray baby syndrome" described in 1
METABOLISM
PHASE II. ENZYMES
CONJUGATION REACTIONS
Another types of conjugation reactions:
■ . active already in 1st month, in some drugs {paracetamol, acetaminofen) replaces insufficient activity of other conjugation enzymes
■ .        .:.:::./. (INH. sulfonamides) present at birth but low activity, as in u SM
SM - stow metaboiiser