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

Pharmacogenetics Role of genetic factors in drug disposition and response Due to variations in human genes that can lead to variability in drug responses in individual patients

Definition of Pharmacogenetic Terms Genetic 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 HapMap

Definition of Pharmacogenetic Terms Alleles: Alternative forms of genes – Homozygous: alleles at a particular gene locus on both chromosomes are identical – Heterozygous: different alleles are present at the same gene locus Genotype: genetic make-up Phenotype: observable physical manifestation Pharmacogenetic 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 organism

Application to Drug Therapy Practice: Drug Biotransformation Phase 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 reaction Phase 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 Biotransformation Phase I enzymes: – CYPs: most important heme-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 drugs Phase IIenzymes: Arylamine N-acetyltransferases (NAT1, NAT2) Glucuronosyl transferases (UGTs) Epoxide hydrolase Glutathione 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 ALL – Patients 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 activity – Pharmacogenetic polymorphisms of several additional genes also have the potential to influence successful treatment of ALL

Current and Future Applications Best example: Progress in the treatment of ALL – 20% of patient with ALL who do not respond to chemotherapy represent an additional challenge for pharmacogenomic research

Principles of Drug Therapy

Pharmacokinetics Drug's disposition within the body ADME – 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 machines

Pharmacodynamics Relationship between drug dose or drug concentration and response. Effectiveness  desirable Toxicity  untoward

Influence of Age on Drug Therapy Physiologic Factors that influence the Oral absorption of Medications PARAMETERNeonateInfantChild Gastric Acid secretion ReducedNormal Gastric Acid Emptying Time DecreasedIncreased Intestinal Motility ReducedNormal Biliary FunctionReducedNormal Microbial FloraAcquiringAdult PatternAdult pattern

Developmental Aspects of Body Fluid Compartment Sizes AGETotal Body Water Extracellula r Fluid Intracellular Fluid <3 Months Fetus Term gestation mo mo26-30 Puberty Adult

Drug Distribution Distribution volume (Vd)  provides insight into the total amount of drug present in the body relative to its concentration in blood. Important when selecting – initial loading dose – optimal dosage regimen

Drug Binding Drug is bound to circulating plasma proteins directly influences the drug's distribution characteristics Unbound drug can be distributed from the vascular space into other body fluids and tissues, where it binds to its receptor and stimulates a response.

Drug Binding Depends on the ff. age-related variables absolute amount of proteins available binding sites affinity constant of the drug for the protein pathophysiologic conditions endogenous substances

Drug Binding Most important circulating proteins responsible for drug binding in plasma – Albumin – α 1 -acid glycoprotein – lipoproteins Influenced – Age – Nutrition – Disease Serum albumin and total protein concentrations are decreased during infancy, approaching adult values by the age of 10–12 mo. α 1 -acid glycoprotein; concentrations appear to be approximately 3 times lower in neonatal plasma compared with maternal plasma, achieving values comparable to those of adults by 12 mo of age.

Drug Metabolism The overall rate of drug removal is described by the pharmacokinetic parameter clearance (Cl) Primary organs – liver – kidney

Drug Metabolism 2 primary enzymatic processes in the Hepatocytes – Phase I, or nonsynthetic  oxidation, reduction, hydrolysis, and hydroxylation – Phase II, or synthetic reactions  conjugation with glycine, glucuronide, or sulfate.

Drug Excretion Filtration of drugs in the glomerulus per unit of time depends on the ff. – functional ability of the glomerulus – integrity of renal blood flow – extent of drug-protein binding Renal blood flow – At birth - 12 mL/min – 5-12 mo of age - approaching adult Glomerular filtration rate – Full term infants - 2–4 mL/min – 2–3 days of life - increases to 8–20 mL/min – 3–5 mo of age – adult value – Before 34 wk of gestation, glomerular filtration is markedly reduced and increases more slowly than in term infants.

Pharmacokinetics and Drug Dosing Considerations

Drug Kinetics Linear or 1st-order pharmacokinetics – The serum concentration (or the amount of drug in the body) is directly proportional to the dose administered. Zero Order or Saturation kinetics – elimination pathways become saturated – drug concentration in the blood changes disproportionately to the dose administered.

Half Life (t1/2) Time required for any given concentration in blood (or other biologic fluid) to decrease to ½ of the initial value, or the time required for ½ of the amount of drug present in the fluid to be cleared

Clearance (Cl) - estimates the theoretical volume from which a drug is removed per unit of time. Body Cl - reflects the amount of drug removed or eliminated from the body per unit of time Renal Cl - reflects the amount of drug cleared by the kidneys per unit of time. Total body Cl - summation of all Cl mechanisms for a given drug (Cl renal, Cl hepatic, Cl lung ).

Drug-Drug Interactions When 2 or more drugs are administered to the same patient, the pharmacokinetic and pharmacodynamic properties of each agent may be modified by their interaction. – Acetaminophen + alcohol = Increase hepatotoxicity – Antacid + Iron = decrease absorption – Digoxin + Cimetidine = Increase Digoxin toxicity

Prescribing Medications Factors to consider: – Taste – Smell – Color – Consistency – Dosing frequency – Cost Prescribing generically equivalent medications should be done only when it is clearly known that the generic brand affords equivalent bioavailability, bioeffectiveness, and patient acceptability.

Prescribing Medications Dispense just enough drug to treat the patient Parents should be instructed to discard all remaining doses of a prescribed medication after the completed course of therapy Patient medication instructions on the prescription should state the specific number of doses the patient should receive each day and the total duration of therapy (number of days of therapy). The number of times the prescribing physician allows the prescription to be refilled should be noted on the prescription label

COMPLIANCE WITH THE PRESCRIBED REGIMEN. A child's compliance with a prescribed therapeutic regimen is usually only as good as that of the parents. Educating the family about the nature of the child's illness, the action of the medications prescribed, and the importance of following the instructions precisely. Compliance with the therapeutic regimen is improved when the instructions are written down clearly and in detail for the family and when the regimen results in minimal interference with the daily living schedule (particularly parental sleeping habits).

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