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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

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pediatric drug therapy

Pediatric Drug Therapy

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

pharmacogenetics
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
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 terms1
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
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 biotransformation1
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)
    • Glucuronosyltransferases (UGTs)
    • Epoxidehydrolase
    • Glutathione S-transferases (GSTs)
    • Sulfotransferases (SULTs)
    • Methyltransferases (catechol O-methyltransferase, thiopurine S-methyltransferase, several N-methyltransferases).
current and future applications
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 applications1
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
pharmacokinetics
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
Pharmacodynamics
  • Relationship between drug dose or drug concentration and response.
  • Effectiveness  desirable
  • Toxicity  untoward
drug distribution
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 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 th e ff
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 binding1
Drug Binding
  • Most important circulating proteins responsible for drug binding in plasma
    • Albumin
    • α1-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.
  • α1-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
Drug Metabolism
  • The overall rate of drug removal is described by the pharmacokinetic parameter clearance (Cl)
  • Primary organs
    • liver
    • kidney
drug metabolism1
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
Drug Excretion
  • Filtration of drugs in the glomerulusper 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
  • Glomerularfiltration 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.
drug kinetics
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
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
slide29

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 (Clrenal, Clhepatic, Cllung).
drug drug interactions
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
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 medications1
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
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).