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PERINATAL AND PEDIATRIC PHARMACOLOGY

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PERINATAL AND PEDIATRIC PHARMACOLOGY Dr. Manuel E. Valdez Department of Pediatrics UPHRMC Aspects of Drug Therapy During Pregnancy access of the drugs to the fetus ... – PowerPoint PPT presentation

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Title: PERINATAL AND PEDIATRIC PHARMACOLOGY


1
PERINATAL AND PEDIATRIC PHARMACOLOGY
  • Dr. Manuel E. Valdez
  • Department of Pediatrics UPHRMC

2
Aspects of Drug Therapy During Pregnancy
  • access of the drugs to the fetus
  • pharmacodynamic aspects of drug action in the
    fetus
  • Recent WHO survey showed that 89 of women take
    prescription drugs during pregnancy (avg 3
    prescription each) not including OTC preparation
    and alternative therapies

3
Access of the Drug to the Fetus
  • Lipid solubility
  • Molecular size
  • Protein binding
  • Placental and Fetal metabolism

4
Lipid solubility
  • Lipid soluble drugs readily cross the placental
    barrier ionized drugs do not
  • Example a) thiopental given as anesthetic for
    C/S. Readily crosses the placenta and can produce
    sedation and apnea in newborn
  • b) salicylates ionized at blood
    PH. However, small amount that is not ionized
    crosses the placenta and can be trapped there

5
Molecular size
  • Placenta excludes drugs of high MW
  • MW 250-500 drugs are readily permeable
  • MW 500-1000- greater difficulty in crossing the
    placenta
  • MWgt1000- excluded or diffuse very poorly
  • Exception-maternal antibody globulins cross
    placenta through poorly characterized carrier
    mechanism
  • Therapeutic implications Most important clinical
    implication of this is that Heparin (large MW) is
    the anticoagulant of choice in pregnant women

6
Protein binding
  • Plasma protein binding of a drug will inhibit
    placental transfer. Tighter binding inhibits more
    than weak binding
  • Highly lipid soluble drugs may transfer anyway
    despite avid protein binding
  • Plasma protein affinity may be different in fetal
    circulation vs. maternal . Thus free fetal plasma
    concentration may be higher than free maternal
    plasma concentration of drug at equilibrium
    (sulfonamides, barbiturates, phenytoin and local
    anesthetics)

7
Placental/Fetal drug metabolism
  • Placenta important site of drug metabolism
    especially aromatic oxidation reactions
    (hydroxylation, N-dealkylation, demethylation)
    Ex. Phenobarbital oxidized by placenta
  • Fetal drug metabolism 40-50 of umbilical
    venous blood enters fetal liver

8
Pharmacodynamic aspects of drug action on the
fetus
  • Maternal drug action
  • Therapeutic action on the fetus
  • Toxic action on the fetus
  • Teratogenic action of specific agents

9
Maternal drug action
  • Mother may need to take drugs for conditions that
    arise during pregnancy. These drugs may affect
    the fetus or fetal drug metabolism
  • Ex. Pregnancy induced heart failure (digitalis
    and diuretics) pregnancy induced diabetes
    (insulin)

10
Therapeutic action on the fetus
  • Drugs are given for fetal condition in utero
  • Ex. Corticosteroids-used to stimulate fetal lung
    maturation in expected premature birth
  • Phenobarbital used to induce fetal hepatic
    enzymes which glucorunidate bilirubin

11
Toxic action on the fetus
  • Ex. Opiates can cause dependency in newborn
    leading to neonatal withdrawal syndrome
  • ACE inhibitors produce renal toxicity in the
    developing kidney

12
Teratogenic action of specific agents
  • Teratogens result in characteristic malformation
    indicating selectivity of action of the drug
  • Act predominantly at a defined stage of fetal
    development
  • Dose dependency
  • Lists of specific teratogens

13
Teratogenic drug effects
  • Category Drug Teratogenic
    effect
  • Antibiotics Amonoglycosides
    Deafness,vestibular damage
  • Tetracyclines
    Anomalies of teeth bone
  • Quinolones
    Arthropathies (Animal studies)
  • Sulfonamides
    Hyperbilirubinemia/kernicterus
  • Anticholinergics
    Meconium ileus
  • Anticoagulants Warfarin
    Skeletal CNS defects (DWS)
  • Anticovulsants Carbamazepine Neural tube
    defects
  • Phenytoin
    Growth retardation,CNS defects
  • Valproic acid
    Neural tube defects
  • Trimethadione
    CNS and facial defects

14
Teratogenic drug effects
  • Antidepressant Lithium
    Ebstein anomaly, hypotonia

  • reduced sucking,hyporeflexia
  • Antihypertensives ACE inhibitors Renal
    failure, decreased skull

  • ossification, renal tubular

  • dysgenesis
  • B-blockers
    Growth restriction, neonatal

  • bradycardia/hypoglycemia
  • Antithyroid drugs PTU
    Fetal/neonatal goiter/hypo-

  • thyroidism
  • Methimazole
    Aplasia cutis, fetal/neonatal

  • goiter/hypothyroidism

15
Teratogenic drug effects
  • Cytotoxic drugs Amonopterin/
    CNS/limb malformations
  • methotrexate
  • Cyclophosphamide
    CNS malformations,

  • secondary cancer
  • Diuretics Furosemide
    ? uterine blood flow,

  • hyperbilirubinemia
  • Thiazides
    Neonatal

  • thrombocytopenia
  • Hypoglycemics Chlorpropamide,
    Neonatal hypoglycemia
  • glibenciamide

16
Teratogenic drug effects
  • NSAIDS Indomethacin Premature
    closure of PDA, NEC,

  • neonatal PHN
  • Salicylates
    Hemorrhage
  • PG analogues Misoprostol Moebius
    sequence
  • Recreational Ethanol
    Fetal alcohol syndrome
  • drugs Cocaine
    Growth retardation
  • Sex hormones DES
    Genitourinary defects in male/

  • female offspring
  • Danazol
    Masculinization of female fetus

17
Teratogenic drug effects
  • Sedatives Thalidomide Limb
    shortening(phocomelia)

  • hearing defect
  • Psychoactive drugs Barbiturates Neonatal
    withdrawal syndromes
  • benzodiazepines
  • opioids
  • Phenothiazines
    Neonatal effects of impaired

  • thermoregulation, extra-

  • pyramidal effects
  • Miscellaneous Vit.A
    Congenital anomalies, cleft

  • palate,eye damage,syndactyly
  • Vit K
    Hyperbilirubinemia/kernicterus

18
Effect of drug administration to lactating mother
  • Drugs affecting lactation
  • Drug concentration in breastmilk
  • Pharmacodynamics of drug ingested in breastmilk

19
Drugs affecting lactation
  • Bromocriptine,ergotamine,cabergoline,lisuride,terg
    uride, and metergoline- inhibit prolactin
  • OCP -risk of ?milk supply, N2 protein content
    of milk
  • estrogen-antagonizes the milk producing effect of
    prolactin and inhibit lactation
  • clonidine- inhibit milk ejection ?maternal
    prolactin levels
  • Thiazides- suppress lactation

20
Drug concentration in breastmilk
  • Most drugs are excreted into breastmilk by
    passive diffusion making the drug concentration
    in milk directly proportional to maternal plasma
    concentration
  • Human milk is more acidic than plasma, drugs that
    pass into milk are weak bases,water soluble,
    lipid soluble and poorly bound to proteins
  • Milkplasma (MP) ratio serves as an index of
    extent of drug excretion in the milk

21
Drug excretion in human breastmilk
  • DRUG
  • Amoxicillin
  • Atenolol
  • Carbamazepine
  • Cefotoxime
  • Diazepam
  • Digoxin
  • Lithium
  • Penicillin
  • Phenytoin
  • Propranolol
  • Theophylline
  • Warfarin
  • MP RATIO
  • 0.014-0.043
  • 1.5-6.8
  • 0.6-0.7
  • 0.029-0.16
  • 0.08-0.13
  • 0.6-0.8
  • 0.25-0.77
  • 0.02-0.2
  • 0.12-0.24
  • 0.5
  • 0.57
  • lt0.01

22
Principles that can guide management of cases of
drug exposure in a breastfed infant
  • Human milk drug concentration usually do not
    exceed the maternal plasma concentration
  • Even when the MP ratio for a given drug
    approaches or exceeds 1.0, the amount of drug
    ingested by the infant rarely is sufficient to
    attain therapeutic concentration
  • Short exposure to a drug is usually of less
    concern than given for long period of time
  • Amount of drug ingested can be minimized by
    feeding the infant just before or at the time of
    maternal administration

23
Drug concentration in breastmilk
  • Drug concentration in breastmilk difficult to
    predict and usually measured empirically. However
    effect on infant is usually lower than in mother
    since dose comes from free plasma concentration
    of the mother
  • If nursing mother must take drugs, optimal
    time is 30-60 minutes after feeding and 3-4 hrs
    before next feeding or before the next dose is
    due, when the concentration of drug in milk is
    low.

24
Pharmacodynamics of drug ingested in breast milk
  • Drugs that eventually reach the infants systemic
    circulation in any appreciable amount (gt10)
    should be avoided.

25
Pharmacodynamics of drugs ingested in breastmilk
Examples
  • Tetracyclines-70 of maternal serum
    concentration-- permanent tooth staining in
    infants
  • Diazepam( many other sedative hypnotics)--
    sedation in infants and can accumulate in infant
    due to long half life
  • Cancer chemotherapy- immunosuppresion/neutropenia
  • I tracers - thyroid cancer in infant
  • Lithium(same concentration in breastmilk as in
    plasma)- tremor and involuntary movements
  • Amiodarone- thyroid disturbance because of high
    Iodine content
  • ASA- Reye syndrome

26
Pharmacodynamics of drug ingested in
breastmilk-Examples
  • Chloramphenicol- grey baby syndrome
  • Sulphonamides- jaundice because of competition
    for bilirubin for binding to albumin
  • Quinolones- adverse effect on cartilage
    development
  • Tinidazole- risk of carcinogenicity and
    mutagenicity
  • Laxatives containing phenolpthalein- risk of
    carcinogenicity
  • Antithyroid (carbimazole,methimazole) - thyroid
    suppression
  • H2 antagonist (cemitidine )-because of their
    accumulation in breastmilk (6mg/L of milk could
    mean an average dose of 18mg /day for a newborn)-
    effect on gastric acidity and inhibition of cP450
  • Ergotamine- risk of ergotism in infants

27
Epidemiology
  • Ave. of 0.9 medication/patient contact is
    prescribed in pediatric practice vs 1.1
    drugs/patient contact for all the disciplines
    together.
  • 1st 5 years of life- 95 of children have been
    prescribed medications w/ ave. of 8.5 courses of
    prescriptions and 5.5 different medications
  • Greatest number of prescriptions is given to
    children between 7 and 12 months

28
Therapeutic use of drugs in infants and children
  • Unique aspects of
  • Drug absorption
  • Drug distribution
  • Drug metabolism
  • Drug excretion

29
Unique aspects of drug absorption in infants and
children
  • Absorption from I.M. injection sites
  • - Blood supply and flow, Muscle mass
  • - Drug related factors
  • Absorption from GIT
  • - gastric PH
  • - peristaltic rate and gastric
    emptying time
  • - diarrhea
  • - bacterial flora
  • Absorption from the rectum

30
Drug absorption at IM injection sites-Local
factors
  • a) Blood supply and flow
  • - Conditions like low CO, RDS or shock may
    compromise blood supply to muscles severely
    leading to decreased absorption from the injected
    site.
  • - Immobility slows absorption rate
  • - Exercise enhances absorption Ex. After
    IM insulin- exercise-induced hypoglycemia
  • Ex. Injected IM digoxin improves regional
    blood flow therefore drug absorption/toxicity
  • b) Muscle mass - Ex. Infants, malnourished
    children has small muscle mass, Obesity

31
Drug Absorption from IM injection sites- Drug
-related factors
  • Muscle is more acidic than blood
  • Ex. Phenytoin after IM injection is converted
    into acid form. The sodium salt of Phenytoin
    precipitates at site of injection which leads to
    erratic and slower absorption

32
Drug absorption from GIT
  • a) Gastric PH slowly rises in premature infants
  • b) Gastric emptying time is prolonged in
    neonates. May increase absorption if drug is
    absorbed in stomach or delay if absorbed in
    intestines
  • c) Peristalsis slower in neonates, could increase
    intestinal absorption
  • d) diarrhea interfere with drug absorption from
    GIT, effect is exaggerated in neonates
  • e)Bacterial flora affects hydrolysis of drug
    conjugates that are excreted in bile Ex Vit K
    other fat soluble vitamins

33
Oral drug absorption in neonates vs older children
  • DRUG Oral Absorption
  • Acetomenophen Dec
  • Ampicillin Inc
  • Diazepam N
  • Digoxin N
  • Penicillin Inc
  • Phenobarbital Dec
  • Phenytoin Dec
  • Sulfonamides N

34
Rectal administration of drugs
  • Useful in conditions such as nausea,vomiting,
    status epilepticus,for induction of anesthesia
    and for administration of drugs that have a large
    first-pass effect
  • Ex. Diazepam solutions- well absorbed from the
    rectum compared with suppositories for which
    absorption is erratic and slow
  • Other drugs- lorazepam,midazolam,atropine,
  • barbiturates have been administered rectally
    with great success

35
Unique aspects of drug distribution in infants
and children
  • Total body water content
  • Fat content
  • Protein binding

36
Drug distribution-Total body water content
  • Neonate 70-75 (premature can be up to 85) vs
    50-60 in adults)
  • ECW 40 in neonates, 20 in adults
  • Neonates undergo diuresis in 1st 48 hrs
  • Thus neonates have a larger relative plasma
    volume which affects distribution of water
    soluble drugs(Ex aminoglycosides,ampicillin)
  • Water soluble drugs are distributed throughout
    ECW, therefore the volume of ECW compartment
    determines drug concentration

37
Drug distribution-Fat content
  • Varies in neonates. Prematures can be 1, full
    term 15
  • This affects distribution of lipid soluble drugs
  • Ex. Digoxin which may accumulate in smaller
    amounts in immature infants

38
Drug distribution-Protein binding
  • Neonates esp preterm are at risk of altered
    drug protein intercation
  • - ? concentration of albumin and protein lead
    to decreased drug protein binding. Ex Higher
    cord/adult free drug ratios for salicylates,
    sulfonamides, morphine, phenobarbital and
    phenytoin-greater drug effects/toxicity.
  • - Changing affinity of albumin for different
    drugs at different stage of maturation (e.g
    acidic drug affinities for serum albumin increase
    dramatically over the first few weeks of life)

39
Drug distribution-Protein binding
  • ?concentration of FFA and B 1 affect protein
    binding. FFA and B1 have high affinity for
    albumin which can result in competition or even
    displacement of drugs from albumin binding sites
    Ex sulfonamides,phenytoin
  • CNS distribution of drugs- tighter junctions in
    the brain endothelial capillaries and the close
    approximation of glial connective tissues to the
    capillary endothelium limit drug distribution to
    brain tissues. Ex. Water soluble antibiotics
    (aminoglycosides)are less likely to cross blood
    brain barrier

40
Protein binding affect free drug
concentration-Example
  • Diazepam - 98 protein bound in older children,
    plasma drug concentration of 300 ug/ml yields a
    free concentration of 6 ug/ml
  • In neonates 90 protein
    bound and yields a free concentration of 30 ug/ml

41
Unique aspects of Drug Metabolism in infants and
neonates
  • Liver- major organ of drug metabolism
  • Other organs like lungs,GIT or blood are
    capable of metabolizing drugs
  • Drug metabolism can result in either generation
    of weaker or inactive metabolites or
    transformation of a parent compound or prodrug
    into the active compound (theophylline to
    caffeine codeine to morphine)or an even more
    active metabolite
  • Generally slower drug metabolism in infants and
    neonates

42
Drug metabolism in infants and neonates-2 major
steps
  • Phase 1 reactions (oxidation, reduction,methylatio
    n)
  • reach maximal maturity by 6 months of age.
  • Ex. Theophylline- 10 is methylated to
    caffeine, with 50 excreted unchanged in urine.
    W/ maturation of hydroxylation and acetylation of
    hepatic enzymes, the rate of clearance increases
    resulting in short half life (3-5 hrs in infants
    and children vs 8 hrs in adult)

43
Drug metabolism in infants and children
  • Hepatic Phase II reactions (glucorunidation,
    sulfation, acetylation)
  • CP450 and conjugating enzymes are reduced in
    activity in the neonates (50-70 adult values)
  • Glucorunide formation- reach adult levels in
    3rd-4rth year of life
  • Sulfation pathway-reach adult levels just days
    after birth
  • Decreased ability of neonates to metabolize drugs
    result in prolonged elimination half lives
    leading to ADR or toxicity from overdose
  • Variation in enzyme activity make it difficult to
    predict plasma values of drugs Ex. Phenytoin
  • Infants more susceptible to drug toxicity vs
    adults when drug must undergo hepatic elimination

44
Half life of Phenytoin in neonates
  • Days after birth T 1/2
  • 0-2 80
    hrs
  • 3-14 18 hrs
  • 14- 50 6 hrs
  • Compared with carbamazepine which has identical
    plasma half lives in neonates and adults

45
Unique aspects of drug excretion in infants and
children
  • i) GFR lower in neonates and children
  • a) Week 1 GFR -30-40 of adult values (even
    lower in prematures)
  • Week 3 - 50-60 of adult values
  • By 6-12 months -reaches adult values (per
    unit surface area)

46
Drug excretion
  • b) elimination is thus lower in children for
    most drugs vs adults
  • c) conditions that reduce GFR (heart failure)
    also further reduce elimination
  • ii) Tubular secretion rate is about 25-50 lower
    in newborn reaching adult levels at age 1- 3
    years

47
Drug excretion
  • Renally eliminated agents- aminoglycosides,penici
    llins, digoxin
  • Ex- Dose of gentamycin younger than 7days old
    neonate- 5mg/k x 2 Older than 7 days old- 7.5
    mg/k x 3
  • Digoxin- renal clearance increases from 33
    mL/min/BSA in neonates to 98 mL/min/BSA at 3
    months and 144 mL/min/BSA at 1.5 years

48
Drug interactions
  • Defined as clinically measurable modifications in
    either magnitude or duration of action of one
    drug caused by prior or concomittant
    administration of another substance
  • 2 types 1) Desirable -such as seen in treatment
    of HPN by using multiple drugs with different
    mechanisms of action
  • 2) Adverse- serious or life
    threatening (3 of hospitalized patient with 7
    of these caused by drug interaction.
  • Mechanism pharmacokinetic and pharmacodynamic

49
Drug interactions affecting oral bioavailability
  • GIT- Ex Tetracycline can chelate
    calcium,magnesium or iron leading to decrease
    absorption
  • Oral neomycin or antineoplastic
    agents can damage the intestinal absorptive
    surface
  • Metoclopramide,domperidone- can
    enhance gastric emtying which affects rate of
    absorption
  • Morphine,anticholinergics,antacids-can
    delay gastric emptying which affects rate of
    absorption
  • Relevance- when a rapid onset of drug effect is
    desired such as sedation or pain relief

50
Interactions affecting oral bioavailability
  • Drugs that have an extensive first-pass
    effect(i.e. those that are extracted or
    metabolized during transit across the intestinal
    epithelium or during the first pass through the
    liver) such as beta blockers,Ca channel blockers,
  • tricyclic antidepressants, morphine), the
    primary factor affecting clearance is hepatic
    blood flow
  • Coadministration of drugs that decrease hepatic
    blood flow such as cimetidine would increase free
    concentration of these drugs

51
Protein binding drug interactions
  • Serum concentration of a measured drug refers to
    the total drug concentration in the plasma (free
    protein bound).
  • Only the free drug exerts its pharmacologic
    effect
  • Drugs that are highly bound to protein are
    subject to displacement by other drugs that have
    high affinity for the same protein binding sites
    resulting to increase in the free concentration
    of the index drug Ex- salycylates, sulfonamides

52
Drug interactions affecting biotransformation
  • Many of the prescribed drugs in children may
    inhibit or enhance the metabolism of other drugs
  • Drugs that have an inhibitory effects on hepatic
    drug metabolism resulting in a functionally
    impaired or inactive enzyme that cannot oxidize,
    reduce or hydrolyze drugs (cimetidine,
    erythromycin, ciprofloxacin, omeprazole)
  • Coadministration of these drugs with
    theophylline may result in increased plasma
    concentration and toxicity of theophylline

53
Drug interactions affecting biotransformation
  • Enzyme induction can enhance the clearance of
    index drugs which can lead to decreased or even
    loss of efficacy. Drug enzyme inducers are the
    following
  • a) Rifampicin - Coadministration with
    cyclosporine or prednisone leads to graft
    rejection or with oral contaceptives leads to
    failure because of increased metabolism
  • b) Phenytoin- Coadministration with methadone
    leads to withdrawal symptoms
  • c)Phenobarbital
  • If an induction interaction is established,
    ?the dose of index drug. If the inducing drug is
    stopped, ?the index drug dose to avoid toxicity

54
Drug interactions due to altered renal function
  • Drugs excreted by GFR are unlikely to be affected
    by other drugs
  • Drugs that are actively transformed into the
    tubular lumen can be inhibited by other drugs Ex-
    Methotrexate toxicity can be induced by
    inhibition of its tubular secretion by
    salicylates
  • Renal clearance of lithium is reduced in the
    presence of thiazides
  • Probenecid enhances the tubular secretion of
    penicillin

55
Pharmacodynamic features of the neonate
  • PDA - kept open by PGE
  • - closed by Indomethacin
  • PDA-vessels connecting LPA with aorta
  • PGE infusion can be used to keep ductus
    arteriosus patent in infants with TOF or TGA

56
Drug dosage in infants and children
  • Special dosage forms for infants
  • Patient compliance
  • Calculation of pediatric drug dosage
  • FDA approval and safety assurance

57
Special dosage forms
  • Elixir - alcoholic solution in which drug is
    dissolved ( No shaking is needed)
  • Suspensions- undissolved particles of drug
    floating in thich vehicle ( Must shake, at first
    dose will contain less drug than last dose), can
    reduce efficacy in early treatment and enhance
    toxicity late in treatment (ex. Phenytoin)
  • Chewable tablets-usually drug is to be chewed not
    swallowed for optimal absorption

58
Patient compliance
  • 21 of adolescents noncompliant with AED therapy
  • 28 of asthmatic children noncompliant with
    theophylline
  • 30-40 of thalssemia major patients noncompliant
    with nightly subcutaneous infusions of
    desferrioxamine
  • To improve compliance a) take time to explain the
    nature of the illness b) provide precise
    instructions for treatment (including the names
    and purposes of the drug or drugs prescribed) and
    c) give specific instructions about dosage

59
Patient compliance
  • teaspoon- should be 5 ml but can vary from 2.5
    to 7.8 ml in common household spoons. Get a
    measuring syringe
  • dosing often spilled, spit out, forgotten (Be
    clear in patient direction-e.g wake them to give
    drug or cant wait till morning etc)
  • left over drugs- Give full dose especially
    antibiotics which are often discontinued upon
    cessation of symptoms (antibiotic resistance)

60
Calculation of pediatric drug dosage
  • Youngs rule
  • dose adult dose x (age in yrs)/ (age
    12)
  • Clarks rule (more precise than Youngs rule)
  • dose adult dose x wt (kg)/ 70
  • dose adult dose x wt (lbs)/ 150
  • BSA (Body Surface Area)
  • Neonate BSA/Adult BSA x 100 of adult dose
    needed
  • Often labeling info for manufactures contain no
    dosages for children lt 12. When using such a drug
    the dose must be started based on conversion
    factor

61
Determination of drug dosage from surface area
  • Wt Approx age SA of adult
    dose
  • 3 kg (6.6 lbs) NB 0.2
    12
  • 6 kg (13.2lbs) 3 mos 0.3
    18
  • 10 kg (22 lbs) 1 year 0.45
    28
  • 20 kg (44 lbs) 5.5 years 0.8
    48
  • 30 kg(66lbs) 9 years 1.0
    60
  • 40 kg (88 lbs) 12 years 1.3
    78
  • 50 kg (110 lbs) 14 years 1.5
    90
  • 60 kg (132 lbs) adult 1.7
    102
  • 70 kg (154lbs) adult 1.76
    103

62
Therapeutic Drug monitoring
  • Measurement of drug concentrations and the use of
    pharmacokinetic principles to individualize drug
    dosing in an attempt to maximize therapeutic
    efficacy while minimizing potential toxicity
  • Applicable for medications that possess narrow
    therapeutic indices and for agents that
    demonstrate a good correlation between serum
    concentrations and pharmacologic effect
  • Trough levels- provide accurate interpretation of
    drug concentration
  • Peak levels- less accurate because they are
    subject to significant variability due to
    differences in absorption and distribution rates.
  • Reserved for medications with short
    half-lives in which peak levels are associated
    with efficacy or toxicity

63
Therapeutic drug monitoring-Examples
  • Theophylline serum concentrations
  • 10-20 mcg/mL- clinical bronchodilation in
    asthmatic children
  • 5-10 mcg/ml- diaphragmatic stimulation
  • gt20 mcg/mL -toxicity
  • Aminoglycosides
  • Peak levels of 12-14 mcg/mL or trough levels
    gt2 mcg/mL- ototoxicity/nephrotoxicity
  • Chloramphenicol- 25 mcg/mL or higher- risk of
    reversible bone marrow suppression
  • Vancomycin- trough levels gt 30 mg/L-
    nephrotoxicity

  • 80-100 mg/L - ototoxicity

64
FDA approval and safety assurance
  • New drugs need to have studies in pediatric
    patient for safety and efficacy if they are
    likely beneficial in children
  • Certain existing classes of drugs need to be
    studied and labeled for use in children. Criteria
  • - drug would represent an improvement in
    standard therapy for children
  • - drug currently prescribed gt50,000
    times/year
  • - drug is in a class or for use where
    additional option for children are needed
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