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Physiologic Changes In Pregnancy:

Effect on Drug Disposition

Sumarno
Program Sp1 Farmasi Rumah Sakit
FFUA
Therapeutic drug use is
common and required in
pregnancy for:
• Maternal conditions
• Pregnancy-related
conditions
• Fetal conditions
Maternal conditions
commonly requiring
therapy in pregnancy
• Asthma
• Hypertension
• Psychiatric conditions
• Diabetes
• Thyroid dysfunction
• Autoimmune disorders
Pregnancy-related
conditions commonly
requiring therapy
• Gestational diabetes
• Gestational hypertension
• Preterm labor
• Preeclampsia
• Hyperemesis / morning sickness
Fetal conditions commonly
requiring drug therapy
• Cardiac conditions
– Supraventricular tachycardia
– Complete heart block
• Impending preterm delivery
Drug therapy in
pregnancy
Balancing act

maternal fetal
treatment effects

Little scientific evidence


Pregnancy Physiology
Potentially Affecting
Pharmacokinetics
• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Decrease in albumin concentration
• Enzymatic activity changes
• Increase in GFR
• Gastrointestinal changes
Pregnancy Physiology
Potentially Affecting
Pharmacokinetics
• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
Cardiovascular System Changes

• Plasma volume expansion


– Begins at 6 - 8 weeks gestation
– Volume of 4700 - 5200 ml peaks at 32
weeks gestation
– Increase of 1200 - 1600 ml above
non-pregnant women
Cardiovascular System Changes

• Cardiac output increases 30 - 50%


– 50% by 8 weeks gestation
• Increase in stroke volume and
heart rate
– Stroke volume in early pregnancy
– Heart rate in later pregnancy
Regional Blood Flow Changes

• 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 muscle blood
flow
Pregnancy:
Cardiovascular changes
• Alterations in regional blood flow
– flow to uterus
– renal blood flow
– skin blood flow
– mammary blood flow
– skeletal muscle blood flow
Pregnancy Physiology
Potentially Affecting
Pharmacokinetics
• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Respiratory Changes
Respiratory Changes

• Compensated respiratory alkalosis


• Lowered PaCO2
• pH 7.44
Pregnancy Physiology
Potentially Affecting
Pharmacokinetics
• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Respiratory Changes
• Decrease in albumin concentration
Albumin Concentration During
Pregnancy

7
6

g 5
m 4
/
d 3
l 2
1
0
2 Tri 3 Tri PP
Time Period
Pharmacokinetic Changes in
Pregnancy

• Total albumin amounts are diluted


resulting in decreased albumin
binding of drugs (more free drug
may be available for use due to
decreased number of albumin
binding sites)
Pregnancy Physiology
Potentially Affecting
Pharmacokinetics
• Cardiovascular system
– Plasma volume expansion
– Increase in cardiac output
– Regional blood flow changes
• Respiratory Changes
• Decrease in albumin concentration
• Enzymatic activity changes
Enzymatic Activity Changes

• Thought to be related to pregnancy


hormonal changes
• N-demethylation inhibited by
progesterone, not by estrogen
CYP3A4

• Hydroxylation
• Increased activity during
pregnancy
CYP2D6 Activity

• Genetic determined polymorphism


• Increased clearance of metoprolol

Wadelius M, etal. Clin Pharmacol Ther 1997; 62: 400.


Pregnancy Physiology
Potentially 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
Renal Clearance Changes

NP 15-18 25-28 35-38


Weeks Gestation
Pregnancy Physiology
Potentially 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
Gastrointestinal Changes

• Decreased gastric acidity


• Delay in gastric emptying
• Increased transit time-
progesterone effect
Maternal Physiologic Changes
Altering PK of Drugs

• Volume Expansion
• Blood volume increases 50%
• Increase in body fluid by 8 liters:
60% to placenta, fetus, and
amniotic fluid
• 40% to maternal tissues
Pharmacokinetic Changes in
Pregnancy

• This change in fluid will decrease


the total serum peak concentration
of medications administered
(increased volume of distribution)
Maternal Physiologic Changes
Altering PK of Drugs

• Volume expansion
• Protein binding-increase in free
fraction of drugs bound to albumin
Maternal Physiologic Changes
Altering PK of Drugs

• Volume expansion
• Protein binding
• Clearance changes
Tobramycin
Pharmacokinetics

• Cl higher in mid-trimester with a


corresponding shorter half-life
• Cl lower in the third trimester with
a corresponding longer half-life
• Vd / kg shows no change

Bourget J Clin Pharmacol Ther 1991; 16: 167


Enoxaprin Pharmacokinetics
during Pregnancy

• Tmax shows no change


• Cmax lower during pregnancy
• Cl decreases in late pregnancy
• AUC lower during pregnancy

Casele, et al. Am J Obstet Gynecol 1999; 181: 1113.


Maternal Physiologic Changes
Altering PK of Drugs

• Volume expansion
• Protein binding
• Clearance changes
• Gastrointestinal changes
Oral Ampicllin Pharmacokinetics in
Pregnancy
Parameter Pregnant Nonpregnant
AUC(cm2) 8.2+4.1 12.6+4.3*
Peak Level 2.2+1.0 3.7+1.5*
(ug/ml)
Bioavailability 45.6+20.2 48.1+19.3**
(%)
*p<0.001
**NS
Phillipson J Inf Dis 1977; 136:370.
PK of Oral Valacyclovir & Acyclovir

• The pro-drug Valacyclovir converted by


first pass metabolism to Acyclovir
• Non-pregnant Valacyclovir gives 3 - 5
times higher plasma level as Acyclovir
• Valacyclovir PK study in pregnancy gave
plasma levels 3 times higher than
Acylovir

Kimberlin DF, et al. Amer J Obstet Gynecol 1998; 179: 846


Pharmacokinetics of Cefuroxime in
Pregnancy
Patient 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
Transfer of Drugs Across The
Placenta
• Most transfer occurs by simple
passive diffusion
• Transport mechanisms do exist in
some instances
• Maternal drug concentration and
placental blood flow each impact
the amount of drug transfer
• Lipid soluble, non-polar, non-
ionized drugs pass easily through
the fetal membranes
• Most drugs given to the mother
will affect the fetus
Extent of Fetal Exposure

• Dependent upon:
• Physiochemical properties of the
drug
• Dose and duration of maternal
treatment
• Rate of maternal drug elimination
• Drugs that are easily diffused will
equilibrate between the maternal
and fetal compartments very
readily
Transfer of Drugs Across The
Placenta

• Drugs with molecular weights up


to 500 can pass through the pores
of the membranes

• Protein bound drugs cannot pass


through the membranes but free
(unbound) drugs can pass through
easily
Factors Affecting Transfer of
Drugs Across The Placenta
• Lipid solubility (if soluble readily pass)
• Degree of ionization (pass easier if not
ionized)
• Molecular weight (< 200 pass easily)
• Protein binding (highly protein bound
drugs less able to pass through)
Factors Affecting Transfer of
Drugs Across The Placenta

• Placental circulation
• Fetal circulation
• Placental maturation
• Drug metabolism
Fetal Clearance of Drugs

• Phase I and Phase II reactions do


occur in the fetal liver but are
generally ineffective at assisting in
the clearance of drug from the
maternal circulation
Effects of Drugs on the
Fetus
• Transient changes in clotting times
• Alterations in fetal breathing
movements
• Fetal death
• Intrauterine growth retardation
• Structural malformations
• Mental retardation
Timing

• Critical determinant of the effect of


a drug on the fetus is TIMING
• The first week after fertilization is
the period of the zygote
• Most common adverse effect of
drugs on the pregnancy is
termination of the pregnancy
which can occur prior to the
woman knowing she is pregnant
Timing: Effect of
gestational age

embryogenesis
1st 2nd 3rd

fetal development
Adverse Exposure Pre-
implantation Embryo

• May result in delayed development


by decreasing numbers of the
blastocyst
• Production of malformations
2 nd to8 week of
th

Gestation
• Period of the embryo
• Period of organogenesis and if
affected can produce dramatic and
catastrophic structural
malformations
3rd to 9th Months

• Period of the Fetus


• Differentiation of the nervous
system and reproduction system
continues
• Drugs given implicated as
behavioral teratogens
Fetal Result

• Disproportionate growth
retardation
• Differentiation of the reproductive
system or external genitalia
• The first 3 months of pregnancy is
a time of rapid development and
growth in the fetus

• This is the time that most


teratogens affect the growing
fetus
FDA Classification of Drugs
in Pregnancy
Category Interpretation

A Controlled studies showed no risk to the


fetus

B No evidence of risk in humans (animal


findings may show risk)

C Risk cannot be ruled out. Adequate human


studies are lacking and animal studies
show risk
D Positive evidence of risk to the fetus

X Contraindicated in pregnancy due to clear


risk to fetus
Thank
You