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8/8/2019 1041171 National Institutes of Health Frederiksen 20062007
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Drug Therapy DuringPregnancy and the
Perinatal PeriodMarilynn C. Frederiksen, M.D.
Associate Professor Clinical
Ob/GyneFeinberg Medical School,
Northwestern University
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular system
– Plasma volume expansion
–Increase in cardiac output– Regional blood flow changes
• Respiratory Changes
• Decrease in albumin concentration
• Enzymatic activity changes• Increase in GFR
• Gastrointestinal changes
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
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Body Fluid Spaces in Pregnantand Nonpregnant Women
WEIGHT
(kg)
PLASMAVOLUME
(mL/kg)
ECFSPACE
(L/kg)
TBW
(L/kg)
NONPREGNANT< 70
70 – 80> 80
490.1890.1560.151
0.5160.4150.389
PREGNANT < 7070 – 80
> 80
67 0.2570.2550.240
0.5720.5140.454
Frederiksen MC, et al. Clin Pharmacol Ther1986 40:321-8.
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Cardiovascular SystemChanges
• Plasma volume expansion
– Begins at 6 - 8 weeks gestation
– Volume of 4700 - 5200 ml peaksat 32 weeks gestation
– Increase of 1200 - 1600 ml above
non-pregnant women
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Cardiovascular SystemChanges
• Cardiac output increases 30 -50%
– 50% by 8 weeks gestation
• Increase in stroke volume andheart rate
– Stroke volume in early pregnancy
– Heart rate in later pregnancy
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Regional Blood FlowChanges
• Increased blood flow to uterus- 20% of cardiac output at term
• Increased renal blood flow
• Increased skin blood flow
• Increased mammary blood flow
• Decreased skeletal muscleblood flow
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HEPATIC BLOOD FLOW IN PREGNANCY (% CARDIAC OUTPUT)
Robson SC, et al. Br J Obstet Gynaecol1990 97:720-4.
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Respiratory Changes
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Respiratory Changes
• Compensated respiratoryalkalosis
• Lowered PaCO
2
• pH 7.44
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Respiratory Changes
• Decrease in albuminconcentration
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PREGNANT POSTPARTUM
[GLOBULI
N]
[TOTALPROTEIN]
[ALBUMIN]
PROTEIN CONCENTRATIONS DURINGPREGNANCY AND POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther
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Is The Hypoalbuminemia of Pregnancy Dilutional ?
• [GLOBULIN] IS NOT REDUCED
• DISTRIBUTION VOLUME DOES NOT AFFECT CSS
• THEREFORE, ↓ [ALBUMIN] REFLECTS EITHER ↓
SYNTHESIS RATE OR ↑ CLE.
E
SS
CL
RATESYNTHESISC =
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output– Regional blood flow changes
• Respiratory Changes
• Decrease in albuminconcentration
• Enzymatic activity changes
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Enzymatic Activity Changes
• Thought to be related topregnancy hormonal changes
• N-demethylation inhibited byprogesterone, not by estrogen
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CYP3A4
• Hydroxylation
• Increased activity during
pregnancy
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CYP1A2
• Activity decreasedprogressively during
pregnancy• Progressive lengthening of
caffeine half-life
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Caffeine Clearance – CYP
1A2
BIRTH
Aldridge A, et al. Semin Perinatol-
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CYP2C9
• Activity shown to increaseduring pregnancy
• Lowered total concentration of phenytoin during pregnancy
Ph t i Pl C t ti
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Phenytoin Plasma Concentrationsduring and after Pregnancy – CYP
2C9
Tomson T, et al. Epilepsia 1994;35:122-30.
0
2
4
6
8
10
12
NONPREG 1ST Δ 2ND Δ 3RD Δ
T O T A L [ P H E N
Y T O I N ] ( μ g / m
1.2
1.0
0.8
0.6
0.4
0.2
0
F R E E [ P H E N Y T O I N ] ( μ g /
***
***
***
*
[TOTAL]
[FREE]
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CYP2D6 Activity
• Genetic determined polymorphism• Increased clearance of metoprolol
observed during pregnancy
• Increased clearance in homozygousand heterozygous extensivemetabolizers
• No change in homozygous poor
metabolizers
Wadelius M, etal. Clin Pharmacol Ther 1997; 62:
400.
h i l
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular System
– Plasma Volume Expansion
– Increase in Cardiac Output– Regional Blood Flow Changes
• Respiratory Changes
• Decrease in Albumin
Concentration• Enzymatic Activity Changes
• Increase in GFR
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GFR DURING PREGNANCY ANDPOSTPARTUM
Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw-
PREGNANT POSTPARTUM
CLCr
sitting
CLCr 24°
CLINULIN sitting
P Ph i l
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Pregnancy PhysiologyPotentially Affecting
Pharmacokinetics• Cardiovascular System
– Plasma Volume Expansion
– Increase in Cardiac Output
– Regional Blood Flow Changes
• Respiratory Changes
• Decrease in Albumin Concentration
• Enzymatic Activity Changes• Increase in GFR
• Gastrointestinal Changes
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Gastrointestinal Changes
• Decreased gastric acidity
• Gastric emptying
– Delayed in laboring women
– No difference between 1st & 3rd ∆– No difference from postpartum
• Increased orocecal transit time in 3rd ∆– Progesterone effect
– Pancreatic polypeptide inverse correlation
M t l Ph i l i
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Maternal PhysiologicChanges Altering PK of
Drugs• Volume Expansion
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CAFFEINE Vd (MARKER FOR TBW)
DURING PREGNANCY AND
POSTPARTUM
BIRTH
PREGNANT POSTPARTUM
Vd
Aldridge A, et al. Semin Perinatol
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THEOPHYLLINE Vd
DURING PREGNANCY ANDPOSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther-
Vd
UNB
OU
ND%
(f)
PREGNANT POSTPARTUM
* * P < 0.05Vd
f
M t l Ph i l i
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Maternal PhysiologicChanges Altering PK of
Drugs• Volume expansion
• Protein binding-increase in
free fraction of drugs bound toalbumin
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THEOPHYLLINE PROTEIN BINDINGDURING PREGNANCY AND
POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther-
PREGNANT POSTPARTUM
0
2
4
6
SERU
M
ALB
UMIN
(g/dL
)
f
ALBUMIN
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Theophylline Protein Binding
Connelly TJ, et al. Clin Pharmacol Ther
NONPREGNANT
PREGNANT
0
100
200
300
400
500
A F F I N I T Y C O N S T A
( m o
l / L )
0
1
3
2
4
5
BIND
IN
GCAPACI
TY
(N)
f = 61%[Alb] = 4.4
g/dL
f = 69%[Alb] = 3.2
g/dL
k a
N
M t l Ph i l i
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Maternal PhysiologicChanges Altering PK of
Drugs• Volume expansion
• Protein binding
• Clearance changes
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THEOPHYLLINE RENAL CLEARANCEDURING PREGNANCY AND
POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther-
PREGNANT POSTPARTUM
CL
Cr
(mL/ m
in)
0
50
100
150
200CLCr
CL
R
INTRINSIC RENALCLEARANCE
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THEOPHYLLINE CLH AND CLINT DURING
PREGNANCY AND POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther-
PREGNANT POSTPARTUM
CLINT
CLH
U
NB
OUND
FR
ACT
ION
(f)
f
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THEOPHYLLINE CLEARANCE DURINGPREGNANCY AND POSTPARTUM
CLE
CLNR
CLR
PREGNANT POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther-
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METHADONE CLEARANCEDURING AND AFTER
PREGNANCY (Primarily a CYP3A4 Substrate)
Pond SM, et al. J Pharmacol Exp Ther 1978;233:1-6.
0
50
10 0
15 0
20 0
25 0
30 0
35 0
E L I M I N A T I O N C L E A R A N C E
( m L / m i n )
2nd TRI 3rd TRI 1-4 wks PP 8-9 wks PP
* p< 0.05 vs.
Postpartum*
*
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Concentrations DuringPregnancy
(Primarily CYP 3A4 Substrate)
Tomsom T, et al. Epilepsia 1994; 35:122-30.
Phenytoin Plasma Concentrations
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Phenytoin Plasma Concentrationsduring and after Pregnancy – CYP
2C9
Tomson T, et al. Epilepsia 1994;35:122-30.
0
2
4
6
8
10
12
NONPREG 1ST Δ 2ND Δ 3RD Δ
T O T A L [ P H E
N Y T O I N ] ( μ g / m
1.2
1.0
0.8
0.6
0.4
0.2
0
F R E E [ P H E N Y T O I N ] ( μ g /
***
***
***
*
[TOTAL]
[FREE]
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FREE AND TOTAL PHENYTOIN LEVELS(DOSE = 300 MG/DAY)
[PH
ENYTOIN
]μg
/mL
NON-PREGNANT PREGNANT
BOUND [PHENYTOIN]
■ FREE [PHENYTOIN]
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CAFFEINE METABOLITE / PARENT DRUGRATIOS IN PREGNANT AND NON-PREGNANT
EPILEPTIC WOMEN
Bologa M, et al. J Pharmacol Exp Ther
* P < .05
*** P < .005
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CAFFEINE METABOLITE / PARENT DRUGRATIOS IN HEALTHY PREGNANT AND NON-
PREGNANT WOMEN
0
1
2
3
4
5
6
7
8
9
10
11
M e
t a b o l i c R a t i o
CYP1A2 XO NAT2 8-OH
*
** **
* P < 0.001
** P < 0.01
utsumi K, et al. Clin Pharmacol Ther 2001; 70: 121.
NS
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Betamethasone PK in Singletonand Twin Pregnancies
Parameter Singleton TwinVd (L) 67.5 ± 27.9 70.9 ± 28.4
Cl (L/h) 5.7 ± 3.1 8.4 ± 6.4 **
T½ (h) 9.0 ± 2.7 7.2 ± 2.4 *
* P < .017 ** P < .06
Ballabh P, et al. Clin Pharmacol Ther 2002; 71, 39.
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Lamotrigine Clearance inPregnancy
• Phase II biotransformation byglucuronidation
• Increased clearance in second
and third trimesters ( > 65%)• May require dose adjustment
• Rapid decrease in clearance inthe first two weeks postpartum
Tran TA, et al. Neurology 2002; 59: 251-55.
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Pharmacokinetics of Cefuroxime inPregnancy
Pt Category VD(L) CI(ml/min) T(1/2)
Pregnant 17.8+ 1.9 282+34* 44+5*
At Delivery 19.3+3.1 259+35* 52+10
Postpartum 16.3+2.1 198+27 58+8
*p<0.05 on comparison to PP
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TobramycinPharmacokinetics
• Cl higher in mid-trimester with acorresponding shorter half-life
• Cl lower in the third trimester with a
corresponding longer half-life
Bourget P, et al. J Clin Pharm Ther1991;16:167-76
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Metformin PK in Pregnancy
• Cmax
in pregnancy 81% lower than
postpartum values
• Mean metformin concentrations69% of the postpartum values
• Mean AUC for metformin duringpregnancy is 80% of the
postpartum AUC
Hughes RCE et al. Diabetes Medicine 23:323-6, 2006.
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Brancazio et al. Am J Obstet Gynecol 1995; 173: 1240.
Heparin PK duringPregnancy
• Shorter time to peak heparinconcentration and effect
• Lower peak effect
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Casele, et al. Am J Obstet Gynecol 1999; 181: 1113.
Enoxaprin PK duringPregnancy
• Tmax
shows no change
• Cmax
lower during pregnancy
• Cl decreases in late pregnancy
• Lower anti-factor Xa activity
• AUC lower during pregnancy
Maternal Physiologic
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Maternal PhysiologicChanges Altering PK of
Drugs• Volume expansion
• Protein binding
• Clearance changes
• Gastrointestinal changes
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Oral Ampicllin Pharmacokinetics inPregnancy
Parameter Pregnant Nonpregnant
AUC(cm2) 8.2+4.1 12.6+4.3*
Peak Level (µg/ml) 2.2+1.0 3.7+1.5*
Bioavailability (%) 45.6+20.2 48.1+19.3**
* P < 0.001 ** NS
Philipson A. J Inf Dis 1977;136:370-6.
PK of Oral Valacyclovir &
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PK of Oral Valacyclovir &Acyclovir
• The pro-drug Valacyclovir convertedby first pass metabolism toAcyclovir
• Non-pregnant Valacyclovir gives 3 -
5 times higher plasma level asAcyclovir
• Valacyclovir PK study in pregnancygave plasma levels 3 times higherthan Acylovir
Kimberlin DF, et al. Amer J Obstet Gynecol 1998;179: 846
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Peripartum PharmacologicConsiderations
• Increased cardiac output
• Blood flow changes
• Uterine contractions
• ? Pharmacodynamic changes
MORPHINE
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MORPHINEPHARMACOKINETICS
DURING LABOR
Gerdin E, et al. J Perinat Med 1990;18:479-
0
100
200
300
Vd(L
)p<0. 0
5
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Pharmacokinetics of Cefuroxime inPregnancy
Category VD (L) CI (ml/min) T(½)
Pregnant 17.8+ 1.9 282+34* 44+5*
At Delivery 19.3+3.1 259+35* 52+10
Postpartum 16.3+2.1 198+27 58+8
*p<0.05 on comparison to PP
P PK
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Postpartum PK Considerations
• Increased cardiac outputmaintained
• GFR increased• Diuresis
• Breastfeeding
• Great variability
P Cli d i
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Steen B, et al. Br J Clin Pharmacol 1982; 13: 661.
Postpartum ClindamycinPharmacokinetics
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Del Priore Obstet Gynecol 1996; 87: 994
D St di f
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Drug Studies forPregnancy
• Pregnancy Specific Drugs– Tocolytic agents
– Oxytocic agents– Eclampsia agents
• Drugs commonly used by womenof childbearing potential
– Antidepressants– Asthma drugs
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Technical Considerations
• Ethical and IRB concerns
• Serial studies
– Spanning pregnancy
– Specific to peripartum period
– Controls
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Study Design
• Use population PK analysis
• Incorporate in vitro protein
binding studies• Use stable isotopes for
bioavailability studies
• Use established tracer substancesas reference markers
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Teratogenesis
General Principles of
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General Principles of Teratology
• Teratogens act with specificity
• Teratogens demonstrate a dose-response relationship
• Teratogens must reach the conceptus
• Effects depend upon the developmentstage when exposed
• Genotype of mother and fetus effect
susceptibility
General Principles of
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General Principles of Teratology
• Teratogens act with specificity
PHOCOMELIA DUE TO
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PHOCOMELIA DUE TOTHALIDOMIDE
General Principles of
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General Principles of Teratology
• Teratogens act with specificity
• Teratogens demonstrate a
dose-response relationship
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DOSE-RESPONSE
RELATIONSHIP
General Principles of
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General Principles of Teratology
• Teratogens act with specificity
• Teratogens demonstrate a
dose-response relationship• Teratogens must reach the
conceptus
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Placental Transport
• Passive diffusion
• P-glycoprotein expressed ontrophoblastic cells of placenta
• Active transport of P-gpsubstrates back to the mother
• Pore system
• Endocytosis
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PHARMACOKINETIC MODEL OFMATERNAL-FETAL TRANSPORT
MPERIPHERAL MCENTRAL FETUS
DOSE
CL E
FETAL
EXCRETION+
METABOLIS
M
General Principles of
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General Principles of Teratology
• Teratogens act with specificity
• Teratogens demonstrate a
dose-response relationship• Teratogens must reach the
conceptus
•Effects depend upon thedevelopment stage whenexposed
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All or Nothing Period
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General Principles of
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General Principles of Teratology
• Teratogens act with specificity
• Teratogens demonstrate a dose-response relationship
• Teratogens must reach the conceptus• Effects depend upon the development
stage when exposed
• Genotype of mother and fetus effect
susceptibility
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Phenytoin
• Animal evidence for an areneoxide (epoxide) reactive
metabolite• Genetic susceptibility to the
Dilantin Syndrome related to
variation in Epoxide hydrolaseactivity
Prenatal Diagnosis of the Fetus at
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FET AL HY DANT OIN SY NDROMEUNAFFECT ED
AMNIO C Y T E SAMP LES
Prenatal Diagnosis of the Fetus atRisk
Buehler BA, et al. N Engl J Med-
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Genetic Polymorphisms
• Increased risk of clefting infetuses carrying atypical allele
for transforming growth factor whose mothers smoke
• Decreased risk for fetal alcohol
syndrome in African Americanwomen carrying alcoholdehydrogenase isoform 2
Mechanisms of
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Mechanisms of Teratogenesis
• All theoretical
• Most not understood well
• Implications of a geneticcomponent
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Parman T,et al. Nature Medicine 1999; 5: 582
Thalidomide
• Thalidomide causes DNA oxidation inanimals susceptible to teratogenesis
• Pre-treatment with PBN (free radicaltrapping agent) reduced thalidomide
embryopathy• Suggesting that the mechansim is free
radical-mediated oxidative DNAdamage
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Teratogen?
• Is there a specific pattern of abnormalities?
• Was the agent present during
development of that organ system?
• Is there a dose-response curve?
• Could there be a genetic component?
Evaluation of Drugs in
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Evaluation of Drugs inBreast Milk
• Measure the M / P radio
• Estimate breast milk dose
• Estimate infant dose
• Measure blood level in theinfant
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Drugs in Breast Milk
• Free drug transferred into milk
• Milk concentrations usually
less than serum concentrations• Exchange is bi-directional
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PLASMA
MILK
KINETIC ANALYSIS OFTHEOPHYLLINE
PLASMA AND MILK CONCENTRATIONS
KINETIC ANALYSIS OF PREDNISOLONE
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PLASM
A
MILK
KINETIC ANALYSIS OF PREDNISOLONE
PLASMA AND MILK CONCENTRATIONS
SHADED AREA IS EXPECTED RANGE OF UNBOUND PLASMA CONC.
Factors Effecting the Milk /
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Factors Effecting the Milk /Plasma Concentration Ratio
• Maternal protein binding
• Protein binding in milk
• Lipid solubility of drug• Physiochemical factors of drug
effecting diffusion
Drugs GenerallyC t i di t d d i
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Contraindicated during
Lactation • Antineoplastics
• Immune suppressants
• Ergot Alkaloids
• Gold
• Iodine
• Lithium carbonate
• Radiopharmaceuticals• Social drugs & drugs of abuse
• Certain antibiotics
G l d i
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General Recommendations
• Drugs considered safe forpregnancy are usually safe duringlactation
• Decrease the drug dose to theinfant by feeding just prior to adose
• Infant blood levels can bemonitored and should be less thantherapeutic