Tinjauan Farmasi Klinik

pada Ibu Hamil dan

Menyusui

The major maternal physiological

adaptation to pregnancy
1-Systemic changes:
-volume homeostasis.
-blood
-cardio vascular system.
2-Respiratory changes.
3-urinary tract and renal function.
4-Alimentary tract.
5-Reproductive organs.
6-endocrinological changes.

systemic changes

A.volume homeostasis:

fluid retention is the most

fundamental systemic changes of
normal pregnancy.
the total blood volume is increased
during pregnancy 30%.
the most marked expansion occurs in
extra cellular volume (ECV) with some
increase in intra cellular water.

The factors contributing

including:
Increase sodium retention.
Decrease in plasma osmotic
pressure.

B.Blood:
The marked increase in plasma volume
associated with normal pregnancy causes
dilution of many circulating factors.

Hematological changes
Decrease in:
o red cell count.
o hemoglobin concentration.
o haematocrit.
o plasma folate concentration.
Increase in :
o white cell count.
o fibrogen concentration.

C.Cardio vascular
changes:
Earliest changes is periphral vasodilatation
Results in decreased systemic vascular
resistence CO 6 L/ min. Max. (2228)wks.

heart rate increase (10-20%).

stroke volume increase (10%).
cardiac out put increase (30-50%).
Mean arterial blood pressure decrease
(10%).Peripheral resistance decrease (35%).-

Respiratory changes
increase O2 demand by 20 %.
tidal volume with normal respiratory rate.
po2 and pco2 with compensatory
HCO3(mild compensated respiratory
alkalosis).
Breathlessness due to hyperventilation and
elevation of diaphragm.
tissue and oxygen availability to placenta
improves.
PH alters little.

 ventilatory changes:
thoracic anatomy changes.
tidal volume increases.
vital capacity increase.
functional residual capacity
decrease.

Changes in pulmonary function

tests during pregnancy

Serial
Serialmeasurements
measurementsofoflung
lungvolume
volumecompartments
compartmentsduring
duringpregnancy.
pregnancy.Functional
Functional
residual
residualcapacity
capacitydecreases
decreasesapproximately
approximately2020percent
percentduring
duringthe
thelatter
latterhalf
halfofof
pregnancy,
pregnancy,due
duetotoa adecrease
decreaseininboth
bothexpiratory
expiratoryreserve
reservevolume
volumeand
andresidual
residualvolume.
volume.
Redrawn
Redrawnfrom
fromProwse,
Prowse,CM,
CM,Gaensler,
Gaensler,EA,
EA,Anesthesiology
Anesthesiology1965;
1965;26:381.
26:381.

The urinary tract and renal

function
blood flow increase (60-70%).
glomerular filtration increased (50%).
clearance of most substances is
enhanced.
plasma creatinine ,urea,urate are
reduced.
glycoseuria is normal.

Alimentary system changes

the gums becomes spongy.
the lower oesophageal sphincter is
relaxed (hurt burn).
gastric secretion is reduced.
the intestinal musculature is relaxed
(constipation).

Hormones produced within

uterus
human chorionic gonadotrophin (HCG):
it is secreted by trophoblast and can be
detected in serum 10 days after
conception.
there is high level of circulating HCG in
early pregnancy (to provide a suitable
environment for implantation and
development).
to support corpus luteum secretion of
oestrogen and progesterone in the first
trimester until the placenta becomes able

 constant level of HCG in late

pregnancy is useful in:
controlling placental secretion of
Estrogen progesterone.
suppressing maternal immune
system against fetus.
the human chorionic
gonadotrophine normally
disappear from urine 7-10 days
after delivery of placenta.

Estrogen
it is produce by corpus luteum in early
pregnancy.
it is produce by placenta in late pregnancy.
fetus (liver and adrenal ) provide certain
enzyme which are lack in placenta.
role of estrogen:
On connective tissue: estrogen leads to
polymerization of mucopoly saccarides of
the ground substance leads to loose
connective tissue mainly in the cervix.
On the protein: estrogen stimulate directly
RNA synthesis lead to protein synthesis.

progesterone
it is production same as estrogen.
it has effect on smooth muscle leads
to decrease muscle excitability leads
to muscle relaxation mainly in
uterus.

Diagnosis of pregnancy
History: symptoms.
Examination: signs.
Investigation : pregnancy
test and ultrasound.

symptoms of pregnancy
1-Amenorrhoea:
abrupt cessation of menses in a woman
with regular cycle is highly suggestive.
2-breast symptoms:
tenderness and fullness may be noticed .
3-frequency of micturation :
pressure on the urinary bladder by
enlarging uterus.

4-nausea with or without (morning

sickness).
5-abdominal enlargement.
6-fetal movement:
quickening is the first feels fetal
movement PG at (18-20wks).

Ultrasonography
4 weeks: pregnancy sac with
decidual reaction .
5 weeks: yolk sac.
6 weeks: fetal echo.
6-7 weeks : presence of fetal heart.
9 weeks :fetal morphology.

Teratogens
A substance, organism, physical
agents or deficiency state capable of
inducing abnormal structure or
function such as:
Gross structural abnormalities
Functional deficiencies
Intrauterine growth restriction
Behavioral aberrations
Demise

Drug Transfer to the Fetus

Placental transfer may occur by:

Passive diffusion
Facilitated diffusion
Active transport
Placental surface area
Placental metabolism

Drug Transfer to the Fetus

Placental transfer may occur by:

Passive diffusion
Facilitated diffusion
Active transport
Placental surface area
Placental metabolism

Drug Passage into Breast Milk

Diffusion from maternal plasma
into milk
Higher maternal plasma levels
mean higher breast milk
concentrations
Equilibrium will be established
with most drugs between milk and
plasma

Drug Transfer
Across Placenta Into Breast Milk
Molecular weight
Molecular
Lipid solubility
weight
Ionization
Lipid solubility
Protein binding
Ionization
Drug
Protein binding
concentration
Chemical
Drug equilibrium
Structure

Other Factors
Across Placenta Into Breast Milk
Size < 200
Size < 400
daltons
daltons
Drug pKa
High blood
Equilibration
concentration
speed
Similar
High blood
configuration
concentration

Anti-infectives

Penicillins
Cephalosporins
Carbapenems
Fluoroquinolones
Macrolides
Aminoglycosides

Sulfonamides
Miscellaneous
Antibiotics
Antivirals
Antiretrovirals
Antifungals

Kategori A
Studi control untuk menunjukan resiko pada
fetus ditrimester pertama gagal (tidak ada
buktiresiko pada trimester berikutnya)
kemungkinan aman pada fetus
Kategori B
Pada studi reproduksi hewan tidak dapat
menunjukan resiko pada fetus, pada studi
control wanita hamil / studi reproduksi hewan
tidak menunjukan efek samping (selain dari
penurunan fertilitas) yang tidak
dikonfimasikan pada studi control wanita
hamil pada trimester pertama (tidak ada
bukti pada trimester berikutnya)

Kategori C
Studi pada hewan menunjukan efek samping
pada fetus (teratogenik) / embriosidal atau yang
lainnya, tetapi belum ada studi control pada
wanita hamil, obat harus diberikan hanya jika
keuntungan lebih besar dari resiko pada fetus.
Kategori X
Studi pada hewan atau manusia telah
menunjukan ketidaknormalan fetus / terdapat
bukti terhadap resiko fetus berdasarkan
pengalaman manusia / keduanya, penggunaan
obat terhadap wanita hamil tidak ada
keuntungannya. Obat ini kontraindikasi dengan
wanita hamil

Penicillins
Category B in pregnancy
Cross the placenta easily and rapidly
Concentrations equal maternal levels

Lactation
Crosses in low concentrations
Compatible with breastfeeding

Cephalosporins
Category B in pregnancy
Cross the placenta during pregnancy
Some reports of increased anomalies with
specific cephalosporins (cefaclor,
cephalexin, cephradrine)
Primarily cardiac and oral cleft defects

Lactation
Excreted into breastmilk in low
concentrations
Considered compatible with breastfeeding

Carbapenems
(ertapenem, imipenem, meropenem)
Category B/C/B in pregnancy
Likely cross the placenta
Very little human data

Lactation
Excreted into breastmilk in low amounts
Unknown effects but likely low clinical
significance

Fluoroquinolones
(floxins)
Pregnancy Category C
Not recommended in pregnancy
Cartilage damage in animals
Safer alternatives usually exist

Lactation
Excreted into breastmilk
Limited human data
AAP says compatible with breastfeeding

Macrolides
(azithromycin, clarithromycin, erythromycin)

Pregnancy Categories B/C/B

Cross the placenta in low amounts
Limited data with azithromycin and
clarithromycin

Lactation
Erythromycin compatible
Others probably compatible

Aminoglycosides
(amikacin, gentamicin, tobramycin)

Pregnancy Category C
Rapidly cross placenta
Enter amniotic fluid through fetal
circulation

Lactation
Compatible with breastfeeding
Not absorbed through GI tract

Sulfonamides
Pregnancy Category C
Readily cross the placenta
Concerns of use at term

Lactation
Excreted into breastmilk in low levels
Use should be avoided in premature
infants

Tetracyclines
(doxycycline, minocycline,
tetracycline)
Pregnancy Category D
Can cause problems with teeth and bone
and other defects/effects
Have been linked to maternal liver
toxicity

Lactation
Compatible with breastfeeding
Serum levels in infants undetectable

Miscellaneous Antibiotics
Aztreonam
Pregnancy Category B, likely safe in
pregnancy, little human data
Lactation Compatible per AAP

Clindamycin
Pregnancy Category B, commonly
used
Lactation Compatible per AAP

Miscellaneous Antibiotics
Linezolid
Pregnancy Category C, no human data
available
Lactation unknown, myelosuppression
in animals

Metronidazole
Pregnancy Category B, carcinogenic in
animals, avoid in 1st trimester if possible
Lactation hold feeds for 12-24hrs
afterward

Miscellaneous Antibiotics
Nitrofurantoin
Pregnancy Category B, possible
hemolytic anemia with use at term
Lactation Compatible, avoid with G-6PD deficiency

Trimethoprim
Pregnancy Category C, potentially
problematic early in pregnancy
Lactation Compatible as combination
drug

Miscellaneous Antibiotics
Vancomycin
Pregnancy Category B, compatible
Lactation likely compatible, not
absorbed

Antivirals
(acyclovir, famciclovir, valacyclovir)
Pregnancy Category B
Acyclovir and valacyclovir readily cross
the placenta
Can be used for HSV treatment and
suppression

Lactation
Acyclovir and valacyclovir are
compatible
Famciclovir should be avoided

Antiretrovirals/NRTI
(abacavir, didanosine (ddI),
emtricitabine (FTC))
Pregnancy Categories C/B/B
Maternal benefit usually outweighs
fetal risk
Cross the placenta
Limited data with each do not show
increased risk of anomalies
Didanosine has been associated with
severe lactic acidosis w/ or w/o
pancreatitis

Antiretrovirals/NRTI
(lamuvidine

(3TC),

stavudine

(d4T))

Pregnancy Category C
Maternal benefit usually outweighs fetal risk
Cross the placenta by simple diffusion
Data with lamivudine show no increased risk
of anomalies
Stavudine has been associated with severe
lactic acidosis w/ or w/o pancreatitis
All NRTIs have been possibly linked to
mitochondrial dysfunction postnatally

Antiretrovirals/NRTI
(tenofivir, zalcitabine (ddC),
zidovudine (AZT))
Pregnancy Category B/C/C
Maternal benefit usually outweighs fetal
risk
Cross the placenta by simple diffusion
Limited data with zalcitabine do not show
increased risk of anomalies
Zidovudine is commonly used, but may
cause neonatal anemia
Limited data with tenofivir show low risk of
teratogenicity

Antiretrovirals/NNRTI
(delavirdine, efavirenz, nevirapine)
Pregnancy Category C
Maternal risk usually outweighs fetal risk
Likely cross into fetus (nevirapine readily)
Delavirdine has possible VSD risk, but limited
human data
Efavirenz is associated with anomalies in
monkeys, limited human data, possible NTD
Nevirapine can cause hepatotoxicity and rash
Nevirapine can be used as a single dose in
labor to prevent HIV transmission

Antiretrovirals/PI
Pregnancy Category B/C
Maternal benefit usually outweighs fetal
risk
Likely cross the placenta
All PIs can cause hyperglycemia (
GDM?)
Atazanavir can cause
hyperbilirubinemia
Indinavir can cause nephrolithiasis

Antiretrovirals/Fusion Inhibitor
(enfuvirtide)

Pregnancy Category B
Maternal benefit usually outweighs
fetal risk
Very large molecule (4492 daltons),
likely does not cross placenta
Animal data does not show risk
No human data available
Hold during first trimester if possible

Antiretroviral Combinations
Atripla (1 tab daily)

Efavirenz, emtricitabine, tenofovir

Trizivir (1 tab BID)

Abacavir, lamivudine, zidovudine

Combivir (1 tab BID)

Lamivudine, zidovudine
Truvada (1 tab daily)

Emtricitabine, tenofovir
Epzicom (1 tab daily)

Abacavir, lamivudine

Antifungals/Azoles
(fluconazole, itraconazole,
ketoconazole, posaconazole,
voriconazole)
Pregnancy Categories
C/C/C/D
Likely cross placenta
Fluconazole > 400mg/day seems to be
associated with cranio-facial abnormalities
Itraconazole appears to have low risk
Ketoconazole can impair testosterone and
cortisol synthesis
No data in humans is available for
voriconazole, increased risk in animals

Antifungals/Azoles
(fluconazole, itraconazole,
ketoconazole, posaconazole,
voriconazole)

Lactation

Fluconazole is compatible per AAP

Itraconazole could concentrate in
milk and body tissues, not
recommended
Ketoconazole is compatible per AAP
No data with voriconazole, not
recommended

Antifungals/Echinocandins
(anidulofungin, caspofungin, micafungin)

Pregnancy Category C
No data with anidulofungin
No human data with caspofungin, single
case at UVA, animal data suggests risk

Lactation
No human data, but probably
compatible

Antifungals/Polyenes
Amphotericin B
Pregnancy Category B, compatible,
lipid complexes also compatible
Lactation no data available

Migraine Headache Therapy

Triptans
Ergots
Butalbital
Caffeine
Dichloralphenazone
Isometheptene

Ergots
(Dihydroergotamine, ergotamine)

Pregnancy Category X
Oxytocic properties could cause IUGR by
vascular disruption or increased uterine tone
Early exposure appears safe, not teratogens
Chronic exposure is contraindicated

Lactation
Contraindicated

Butalbital and Caffeine

Butalbital
Pregnancy Category C, can see
neonatal withdrawal symptoms with
long-term use
Lactation not recommended

Caffeine
Pregnancy Category B, doses generally
lower than that in coffee
Lactation compatible