Pediatric Drug Therapy Cortez,Anne; Cortez,Feliza; Cristi, Frances; Cruz,Denise; Cruz,Ferdinand; Cruz,Karen; Cruz,Belle; Cruz,Mary; Cua,Ronald

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Pediatric Drug Therapy

Pediatric Drug TherapyCortez,Anne; Cortez,Feliza; Cristi, Frances; Cruz,Denise; Cruz,Ferdinand; Cruz,Karen; Cruz,Belle; Cruz,Mary; Cua,Ronald

PharmacogeneticsRole of genetic factors in drug disposition and responseDue to variations in human genes that can lead to variability in drug responses in individual patients

Definition of Pharmacogenetic TermsGenetic Polymorphisms: copies of a specific gene present within a population which may not have identical nucleotide sequences Single-nucleotide polymorphism (SNP): presence of different nucleotides at a given position within a gene Haplotypes: collections of SNPs and other allelic variations that are located close to each other and when inherited together create a catalog of haplotypes, or HapMapDefinition of Pharmacogenetic TermsAlleles: Alternative forms of genesHomozygous: alleles at a particular gene locus on both chromosomes are identicalHeterozygous: different alleles are present at the same gene locusGenotype: genetic make-upPhenotype: observable physical manifestationPharmacogenetic polymorphism: monogenic trait caused by the presence (in the same population) of >1 allele (at the same locus) and >1 phenotype with regard to drug interaction with the organismApplication to Drug Therapy Practice:Drug BiotransformationPhase I: introduce or reveal (by oxidation, reduction, or hydrolysis) a functional group within the substrate drug molecule that serves as a site for a phase II conjugation reactionPhase II: Conjugation with endogenous substrates, such as acetate, glucuronic acid, glutathione, glycine, and sulfate, further increases the polarity of an intermediate metabolite and thereby enhances its renal excretion

Application to Drug Therapy Practice:Drug BiotransformationPhase I enzymes: CYPs: most importantheme-containing proteins that catalyze the metabolism of many lipophilic endogenous substances (steroids, fatty acids, fat-soluble vitamins, prostaglandins, leukotrienes, thromboxanes) and exogenous compounds, such as drugsPhase IIenzymes:Arylamine N-acetyltransferases (NAT1, NAT2)Glucuronosyl transferases (UGTs)Epoxide hydrolaseGlutathione S-transferases (GSTs)Sulfotransferases (SULTs)Methyltransferases (catechol O-methyltransferase, thiopurine S-methyltransferase, several N-methyltransferases).

Current and Future Applications Best example: Progress in the treatment of ALLPatients with ALL who have 1 wild-type allele and intermediate TPMT activity tend to have a better response to 6MP therapy than patients with 2 wild-type alleles and full activityPharmacogenetic polymorphisms of several additional genes also have the potential to influence successful treatment of ALLCurrent and Future Applications Best example: Progress in the treatment of ALL20% of patient with ALL who do not respond to chemotherapy represent an additional challenge for pharmacogenomic research

Principles of Drug TherapyPharmacokineticsDrug's disposition within the bodyADME Absorption process which drugs are made available to the body Distribution drug- specific physiochemical factors Metabolism conversion of drugs in the body to active or inactive compounds Excretion secretion of drugs involves not only the kidneys or liver, but also removal of drugs by extracorporeal systems, such as dialysis, hemofiltration, or heart-lung bypass machinesPharmacodynamicsRelationship between drug dose or drug concentration and response.

Effectiveness desirable

Toxicity untowardInfluence of Age on Drug TherapyPhysiologic Factors that influence the Oral absorption of MedicationsPARAMETERNeonateInfantChildGastric Acid secretion

ReducedNormalNormalGastric Acid Emptying TimeDecreasedIncreasedIncreasedIntestinal MotilityReducedNormalNormalBiliary FunctionReducedNormalNormalMicrobial FloraAcquiringAdult PatternAdult pattern17Developmental Aspects of Body Fluid Compartment SizesAGETotal Body WaterExtracellular FluidIntracellular Fluid