FARMAKOKINETIKA PADA

IBU HAMIL DAN MENYUSUI

Apt. Yanverty Idda Listyana, M.Clin. Pharm
STIKES Muhammadiyah
  Gastric emptying delayed, gastrointestinal transit
prolonged due to progesterone to smooth muscle
Pregnancy >>>bioavailability may increased
Physiology &  Gastric acid secretion decreased > pH slightly
Pharmacokinetic increased
 TBW and ECF and protein binding change >>> Vd
may be altered
 Weight Plasma ECF TBW
(kg) Vol (L/kg) (L/kg)
(ml/kg)
Nonpregn 49
ant
<70 0.189 0.516
Body Fluid
70-80 0.156 0.415
Spaces in
Pregnant & >80 0.151 0.389
Nonpregnant Pregnant 67
Women <70 0.257 0.572
70-80 0.255 0.514
>80 0.240 0.454

(Fredrickson et al., 1986, Clin. Pharmacol Ther., 40, 321-8)

Vd = ECF + fu (TBW-ECF)
 7
6
5
4
3

Total Protein 2 Albumin

& Albumin 1 Total Protein
0
 1,95 Blood Flow ml/min
37%
1,9

1,85
27%
26%
Hepatic 1,8

Blood Flow 1,75

24%

1,7

1,65

1,6
12-14 weeks 24-26 36-38 weeks10-12 weeks
weeks postPartum
Blood Flow ml/min
 Albumin concentration is reduced significantly
during pregnantcy, 2nd and 3rd trimester
 Hepatic blood flow expressed as % to cardiac
output decreased
 Metabolic capacity altered CYP 1A2 reduced Xantin
Oxidase and NAT reduced, CYP 3A4 increased, also
CYP2D6
  Ampicillin
 Caffeine

Pharmacokinetik  Theophylline
changes of some  Cefuroxime
drugs  Methadone
 Anticonvulsants
 Others
 Ampicillin pharmacokinetic in
pregnant women
• IV and PO dosering of ampicillin in 26 pregnant
women (philipson 1977, J. Infect. Dis, 136, 370-6)
serially studied
• From 13 to 33 weeks gestation, blurred assasment of
the effects of the progression of changes in maternal
physiology that occurs during pregnancy
• No difference on the tpmax between pregnant and
non-pregnan
• Peak level less in non-pregnant
• Vd increased but not normalized against maternal
body weight
• Both renal and total clearance increased ±
50% in accordance with the decreased of
plasma level
• Kubacka et al, 1983: increased Vdss in 3rd
trimester on L/kg basis
– In this study authors used male controls as an
historic reference population
Caffeine pharmacokinetics in prenancy
• Oral pharmacokinetic study Vd/F showed no
change when calculated on a basis of L/kg to
take into account the change of body weight
during pregnancy
• Caffeine is CYP1A2 substrate and elimination
clearance estimated as Cl/F, was decreased by
factor of two in 2nd trimester, by a factor of
three in the 3rd trimester compared to the
pospartum period
 9

Paired 6
Comparison of 5
Coffeine NON-PREGN
Meabolite/ 4 PREGN
Parent drug 3
Ratios
2

0
CYP1A2 XO NAT CYP3A4
  Binding to protein was reduced to 11 & 13%, in 2nd
& 3rd trimester, respectively, compared with 26%
of 6 months postpartum
Theophylline  Albumin binding site for theophylline increased
during pregnancy but binding affinity constant is
significantly lower than that of non-pregnant state
 Vdss increased during 2nd and 3rd trimester
  Renal clearance: 30% & 28% of total elimination on
pregnancy, 16% in postpartum stage
 Intrinsic clearance reduced substancially during
pregnancy (next diagram)
 Hepatic clearance less change because of the
pregnancy-associated decrease in theophylline
Theophylline binding to plasma protein
 Combined all together theophylline clearance in th
3rd trimester was 86% of its value of 6-month
postpartum
 Combined with the increased of Vd >> t1/2 change
from 4.4 h to 6.5 h in pregnancy
 Volume of distribution (n = 5)
Expected (L) Measured (L)
PREGNANT
24-26 weeks 32.0 ± 2.0 30.3 ± 6.6
36-38 weeks 37.9 ± 1.9 36.8 ± 4.2
Comparison of POSTPARTUM
Expected and
6-8 weeks 28.0 ± 1.1 28.4 ± 3.0
Measured Values
>6 months 26.9 ± 2.3 30.7 ± 4.4
of Theophylline
Vd

Vd = ECF + fu (TBW -ECF)

Fredrickson et al, 1986 Clin Pharmacol Ther, 40, 321-8

 90
80
70
60
50
40
Theophylline 30
20 Renal Cl
Clearence hepatic Cl
10
(mL/min) 0
 14

12

10

8
Plasma 6
Concentration of protein bound
Phenytoin 4 free drug
(mcg/mL)
2

0
 40

35

30

25 Subject 1
Plasma level
Subject 2
(mcg/mL) of 20
Subject 3
Clindamycin 15 Subject 4
(150 mg p.o.) Subject 5
10

0
0 1 2 4 6
 45

40

35

30
Maternal Plasma
and Milk 25
Plasma
Concentration of 20 Milk
Theophylline
(mcg/mL) 15

10

0 3.5
3.0

5.5
0
0.5

2.0
2.5

5.0

6.0
4.0
1.0

4.5
1.5
 Drug & Protei M/P Infant Detacta Report
Metaboli n dose ble in ed
tes Bindin infant infant
g (%) plasma toxicity
NE
reuptake
inhibitor
Antidepressant 95
Drugs & Breast- Amitrypt 92
Feeding yline

Nortrypty
line
10-OH-
nortrypty
lline
  Principles:
 Act with specificity
 Thalidomide (phocomelia), Valproate (neural tube
defects)
 Cortisol (cleft palate, mice), not in human

 Dose-effect relationships
TERATOGENESIS
 Much reach the developing conception in sufficient
ammount
 The effect depend on the stage of development
 Infleuenced by the genotype of mother and fetus
  Sumber US FDA
 Kategori A, B, C, D, dan X
Indeks  Berdasarkan risiko terhadap sistem reproduksi,
risiko efek samping, dan perbandingan antara
Keamanan manfaat dengan risiko
Kehamilan  Kategori A hingga X tidak berimplikasi pada
(MIMS ed 9 peningkatan risiko
2009/2010)  Obat kategori D, X dan C (bebrapa) mungkin
memiliki risiko hampir sama tetapi digolongkan
dalam kategori yang berbeda berdasarkan
besarnya perbandingan risiko dan manfaat
  Kategori A: Studi terkontrol pada wanita tidak
memperlihatkan adanya risiko terhadap janin pada
Indeks kehamilan trimester pertama, dan tidak ada bukti
Keamanan mengenai risiko pada trimester berikutnya, kecil
kemungkinan obat ini membahayakan janin
Kehamilan  Contoh Vit C, Vit B1, Vit D, dan Vit B6, bila tidak
melebihi dosis tertentu
  Kategori B: Studi pada binatang percobaan tidak
menunjukkan adanya risiko terhadap janin, tetapi
tidak ada studi terkontrol pada wanita hamil. Atau
studi terhadap reproduksi binatang percobaan
memperlihatkan adanya efek samping (selain
Indeks penurunan fertilitas) yang tidak didapati pada studi
terkontrol terhadap wanita hamil pada trimester
Keamanan pertama (dan tidak ada bukti mengenai risiko pada
trimester berikutnya)
Kehamilan
 Contoh Aciclovir (o, p, t), Acetylcystein (opt),
Cetirizin (o), Carbenicillin (o), Dexchlorpheniramine
(o), Erythromycin (opt,o,p,t), Metronidazole
(o,p,t,v), Methyldopa (o,p), Piperazine (o),
Polymyxin B (t), dll
  Kategori C: Studi pada binatang percobaan
memperlihatkan adanya efek samping pada janin
(bersifat teratogenik atau embriosidal atau yang
lainnya) dan tidak ada studi terkontrol pada wanita,
atau belum ada studi terhadap wanita atau
binatang percobaan. Obat dalam kategori ini hanya
boleh diberikan jika besarnya manfaat yang
Indeks diperoleh melebihi besarnya risiko terhadap janin
Keamanan  Contoh: Abciximab (p), Acetazolamide (o,p),
Kehamilan Acetylcholin (opt), Amantadine (o), Chloroquine
(o,p), Deferoxamine (p), Dexamethasone (opt,o,p),
Ephedrine (o,p), Imipenem (p), Imipramine (o,p),
Miconazole (t,v), Metformin + Pioglitazone (o),
Metformin + Repaglinide (o), Latanoprost (opt),
Levofloxacin (opt, o, p, pada trimester I),
Zidovudine (o), Triamcinolone (den, inh, ia,
im,n,o,p,t).....dll
  Kategori D: ada bukti positif mengenai risiko obat
ini terhadap janin, tetapi obat ini masih dibolehkan
untuk diberikan pada wanita hamil jika besarnya
manfaat yang diperoleh melebihi besarnya risiko
terhadap janin (misalnya jika obat ini sbg life-saving
Indeks drug, sedang obat yang lebih aman tidak ada)
Keamanan  Contoh: Alprazolam (o), Aminoglutetimide (o),
Kehamilan Amikacin (p), Betamethason (o,p,t pad trimester I),
Bleomycin (p), Carbamazepine (o),
Chlordiazepoxide (o,p), Doxorubicin (p), Doxicicline
(o), Gefitinib (o), Gemcitabine (p), Potassium Iodide
(o), Povidone-Iodine (t), Thiamazole (o). Thiotepa
(p), Tobramycin (inh, p), Vinblastine (p) ........dll
  Kategori X: Studi pada binatang percobaan atau
manusia memperlihatkan abnormalitas pada janin
atau terbukti berisiko terhadap janin, dan besarnya
risiko obat ini pada wanita hamil jelas-jelas
melebihi manfaat yang diharapkan.
Dikontraindikasikan pada wanita hamil atau yang
Indeks memiliki kemungkinan untuk hamil.
Keamanan  Contoh: Amlodipin + Atorvastatin (o), Atorvastatin
Kehamilan (o),, Caffeine + Ergotamine (o), Cerivastatin (o),
Ergotamin (buc, o, rect), Estazolam (o), Estradiol
(mulut/tenggorokan, o, transderm, v), Ethinyl
estradiol (o) Human menopausal gonadotrophin
(p), Methyl testosteron (o), Misoprostol (o),
Methotraxate (o,p), Pitavastatin (o), Plycamycin
(p), Pravastatin (o) ......dll
 Cause of Anomalies Percent of Total
Anomalies
Chromosomal 5
Single gene 20
Polygenic/ Multifactorial 65
Environmental 10
Human Irradiation <1
Reproductive Maternal disease 1-2
Risk Infection 2-3
Drugs & Chemicals 4-5
 Agent Teratogenic Effect
Carbamazepine Facial dysmorphogenesis, neural tube defect
Phenytoin Facial dysmorphogenesis, mental retardation,
Growth retardation, distal digital hypoplasia
Valproate Lumbosacral spina bifida, facial dysmorphogenesis
Trimethadione Facial dysmorphogenesis, intrauterine growth
retardation
Coumadine Nasal hypoplasia, optic athrophy, epiphyseal
stippling
Known Alcohol Facial dysmorphogenesis, growth n mental
Human retardation
Teratogens Diethylstilbestrol Vaginal adenosis n carcinogenesis, uterine
anomalies
Androgens Masculinization of female genitalia
Methylmercury Growth retardation, severe mental retardation
ACE inhibitors Olygohydramnios, potential lung hypoplasia,
postnatal renal failure
Folic Acid Abortion, Intrauterine growth retardation,
Antagonis microcephaly, hypoplasia of frontal bone
(aminopterin,
Methotrexate)
  All New Drug Application the must comply to FDA
rules, including the reproductive toxicology studies
Measures to
 These Studies examine the effect of the particular
Minimize agent on all aspects of reproduction:
Teratogenic organogenesis, spermatogenesis, fertility,
fecundity, as well as the effects on litter size,
Risk spontanious resorption, fetal malformation, fetal
size, newborn pup function
If an agent
does not
 Most studies are conducted in animal lab : mouse,
produce an rats, rabbits
anomaly in  Most Human teratogenic reactions of new drug
animal study, have been predicted from animal studies.
it does not  However, animal data is not always applicable to
humans, since most animals have a shorter
prove that gestational clock than humans
the agent is  Species susceptibility
innocuous in
humans.
Safety of a
 A recognizable pattern of anomalies
drug for use
 A higher prevalence of the particular anomaly
in human  Anomalies in patients exposed to an agent than in
pregnancy is acontrol population
demosntrat  Presence of the agent during the stage of
organogenesis of the organ system affected
ed by
 Increased incidence of the anomaly after
observation introduction of the agent
al studies  The production of the anomaly in experimental
animals by administration of the agent during the
after drug is appropriate stage of organogenesis.
marketed.
Adverse
 Some drugs are not teratogenic but have adverse
effects of effects on the fetus

drugs to  Includes drugs that can be given immediately

before and during labor and can cause problems in
the fetus the neonate

during the  Some of these should also be avoided during early

pregnancy
stages of  In some cases throughout the whole duration of
pregnancy
pregnancy
 1. Drugs with high risk of causing abnormalities
(teratogens) or of inducing abortion
Alcohol Fetal alcohol syndrome
Androgens Virilization; multiple congenital
deffects
Antineoplastics Multiple congenital deffects
agents
Carbimaazole Aplasia cutis
Drugs to
Corticosteroids Cleft palate
avoid during (haigh dose)
early Cyproterone Feminization of male fetus
pregnancy Diethylstilbestrol Vaginal adenosis &
adenocarcinoma in daughters
Distigmine Increases uterine tone
Ergotamine Increases uterine tone
Misoprostol Increases uterine tone
Fibrinolytic (e,.g. Placental separation
Streptokinase)
Tetracycline
 1. Drugs with high risk of causing abnormalities
(teratogens) or of inducing abortion
Tetracycline Yellow discoloration of teeth,
inhibition of bone growth
Valproate Neural tube deffects
Vit A analogues Congenital deffects
Drugs to (etretinate,..
avoid during Warfarin Multiple congenital deffects
early
pregnancy 2. Drugs under strong suspicion of producing
abnormalities (Slightly increased risk)
Amiodarone Goitre
Chloroquine Deafness (do not withhold in acute
malaria)
Phenytoin Multiple congenital deffects (do
not withhold if absolutely
necessary for control epilepsy)
 3. Other drugs to avoid (theoretical risk from animal
and other studies)
ACE inhibitors Quinolone antibiotics
Auranofin Rifampicin
Chenodeoxycholic Acid Simvastatin
Drugs to Deferoxamine Spironolactone
avoid during Diltiazem & Sulfonylureas
dihydropyridine Ca
early antagonists
pregnancy Fibrates (Clofibrate etc) Thiabendazole
Griseofulvin Tocainide
Iodoxuridine Trimetoprim (and co-
trimoxazole)
Ketokonazole Vaccines (live)
Mebendazol Vigabatrin
Mefloquine Xamoterol
Omeprazole
Drugs to be avoided or use with care during later pregnancy

Drug(s) Risk to fetus or neonate

ACE Inhibitors Impaired blood pressure control & renal function
Aminoglycoside a.b. 8th nerve danage
Antithyroid drugs Goitre and hypothyroidism
Aspirin Kernicterus; hemorrhage (also maternal)
Benzodiazepines Floppy infant syndrome
Chloramphenicol Perpheral vascular collapse
Fibrinolytic drus Fetal/maternal hemorrage
Misoprostol May induce labor
Narcotic analgesic Resp. Depression, withdrawal syndrome
NSAIDs Closure of the ductus arteriosus, delayed &
prolonged labor
Novobiocin kernicterus
Sulfonylureas Hypoglycemia
 Drugs to be avoided or use with care during later pregnancy

Drug(s) Risk to fetus or neonate

Disopyramide May induced labor
Nitrofurantoin Haemolysis
Oral anticoagulants Fetal or retroplacental haemorrhage;
microcephaly
Pethidine Respiratory depressio
Reserpine Bradycardia, hypothermia, nasal congestion with
respiratory distress
Sulfonamides Kernicterus
Tetracyclines Yellow discoloration of teeth, inhibition of bone
growth
Thiazide diuretics Thrombocytopenia
  Aspirin: suggested to be teratogenic in early
pregnancy, not proven. However, in high doses
(several grams) in late pregnancy may cause
kernicterus (displayed bilirubin from protein bond)
 Taken within 1 week of delivery: impaired maternal
haemostasis at the time of delivery and
Drug hemorrhage in the neonate
treatment  Low-doses of aspirin as antiplatelet in the hope of
preventing pre-eclampsia, but now is not
during encouraging
pregnancy  Seems no ill effects to fetus, but may slightly
increase risk of bleeding for the mother at the time
of delivery
 Aminosalicylate, for treatment inflamation on
bowel, appear to be safe in pregnancy
  Aminoglycoside antibiotic: used in pregnancy only
if absolutely esential >>> 8th nerve
 Antithyroid: used in a minimal dosage necessary to
Drug control maternal hyperthyroidism
treatment  Benzodiazepines: given at around the time of labor
can cause “floppy infant syndrome”: muscular
during hypotonia, hypothermia, respiratory difficulty, and
pregnancy difficulty with sucking
 Chloramphenicol: poorly metabilized in infant can
cause peripheral vascular collapse (ashen-grey,
flaccid, hypothermia and may die
  Oral anticoagulants: teratogenic during 1st
trimester (chondrodisplasia punctata), and cause
microcephaly or fetal or retroplacental hemorrhage
Drug at later pregnancy
treatment  They should be avoided entirely during pregnancy,
during particularly warfarin; heparin, subcutaneus, may be
given during pregnancy
pregnancy  Heparin does not cross the placenta, relatively safe,
but occassionaly cause reversible osteoporosis and
often cause subclinical bone demineralization
Drug  Sulfonylureas: cross placenta barrier, stimulate the
treatment baby islet cells to secrete insulin, and cause fetal &
neonatal hypoglycemia
during
 Used insulin, instead of, during pregnancy
pregnancy
  Pethidine: as an analgetic during labor is not
Drug contraindicative, but care should be taken not too
treatment high dose >> neonatal respiratory depression (may
be reversed by naloxon)
during
 In Addict mother: the baby may exhibit withdrawal
pregnancy syndrome
  Sulfonamides: should be avoided during 3rd
trimester
 Displayed bilirubin from plasma proteins in fetal
circulation, unbound bilirubine enters the brains
Drug and deposited at basal ganglia, causing kernicterus,
treatment in which tere can be any neurological dissorder,
including lethargy, muscular hypotonia, and poor
during feeding, progressing to spasticity and convulsion,
with extrapyramidal movement disorders on in
pregnancy those who survive
 Different sulfonamides have different affinity to
protein. Sulfalazine is relatively save during
pregnancy, in relation to treat ulcerative colitis
  Tetracycline: should be not used entirely at any
Drug time during pregnancy >>>>their effects on
growing teeth and bone
treatment
during  Thiazide diuretics can cause thrombocytopenia in
pregnancy neonate, probably by direct toxic effect on bone
marrow, and should be avoided in late pregnancy
  Folic acid and iron are geven routinely
 Folic acid may prevent neural tube deffects
 Antiemetic, meclozin and cyclizine, are most
Drug certainly safe and can be prescribed when
necessary
treatment  As mild analgesic, paracetamol is recomended
during  Penicillins are safe, except in the presence of
pregnancy hypersensitivity
 No tranquillizers or hypnotics can be said to be
complitely safe
 Insulin for diabetes and hiparin s.c. May be used
  Epilepsy
 Teratogenicity vs increasing congenital deffects
 Congenital abnormalities: 2.4% in babies of non-
epileptic mothers, 4.2% in babies of untreated
epileptic mothers, 6% in babies of treated epileptic
Common mothers

practical  Phenytoin, barbiturates, carbamazepine, and

valproate produce syndrome known as the fetal
problems of anticonvulsant syndrome: craniofacial
drug therapy abnormalities, growth retardation, digital
hypoplasia, and intellectual underfunctioning.
during
 Carbamazepine and Valproate are associated with
pregnancy an icreased risk of neural tube defects
 Newer drugs, felbamate, gabapentin, lamotrigine,
vigabatrin are still uncertain but they are not
teratogenic in animals. Currently have been used
for patient whose epilepsy is difficult to control
  For women with chronic epilepsy, counselling
before pregnancy is important
 Special caution in using contraception should also
Common be given, carbamazepine and phenytoin reduce
practical effectiveness of oestrogen
problems of  If epileptic women intend to pregnant, with
antiepileptic treatment, and has not had fit for 2-3
drug therapy years, treatment should be withdrawn, and her
during progress should be monitored carefully
pregnancy  Otherwise, treatment should be continued, making
special effort on one drug only, with dose
adjustment for altered disposition during
pregnancy
  Careful plasma concentration monitoring should be
carried out if possible
 Because chenges in protein binding, the effective
plasma concentration of phenytoin is probably in the
lower part of the usual therapeutic range: 40-60
Common mcmol/L or even lower 10-15 mcmol/L
practical  Women taking valproate or carbamazepine should
hava alpha-fetoprotein measurements and ultrasound
problems of scanning to detects neural tube defects
drug therapy  Folic acid may be prescribe although no evidence
found in prospective study in preventing neural tube
during defect by these anticonvulsats, espescially valproate
and carbamazepine.
pregnancy  Interaction between phenytoin and folic acid >>>
phenytoin dosage must be reviewed
 First fit during pregnancy, careful elucidation of the
type of seizure and any identifiable cause are of great
impotance
  The problem of adverse effects in suckling infants
through the passeage of drugs into the breast milk
is determined by:
Drugntherap  The passage of the drug from maternal blood into
the milk
y and breast-  The concentration of the the drug in the milk
feeding  The volume of milk sucked
 The pharmacokinetics of the drug in the infant,
particularly its absorption and clearance
 The inherent toxicity of the drug
 1. Some drugs to be avoided in breast-feeding
mothers
Amiodarone Chloramphenicol Isoniazid
Amphetamines Ciprofloxacin Lithium
Androgens Coticosteroids Oral
(high dose) hypoglicemics
Anthraquinone Co-trimoxazole Penicillines, in
hypersensitivities
Drugs and Antineoplastic Ciclosporin Phenobarbital
breast- Anipsychotic Diltiazem Phenytoin
feeding Antithyroid Doxazosin Radioactive
Iodine
Aspirin Ergot alkaloids Statins
Atropine Erythromycin Streptomycin
Barbiturates Fluoxetine Sulfonamides
Benzodiazepines Immunosupressiv Tetracyclines
e
Bromocriptine Indomethacin Trimetoprim
2. Some drugs that appear to be safe
ACE inhibitors Digoxin NSAIDs
Acetazolamide Disopyramide Pyrazinamide
ACTH Etambutol Pyridostigmine
Adrenaline Furosemide Rifampicin
Antiasthma (inhl) Heparin Terbutaline
Antihistamines Hydralazine Thyroid
(anti-H1) hormones
Beta-blocker Insulin TriCyclic
(monitored for antidepressants,
bradycardia & except doxepin
hypoglicemia)
Carbamazepine Methyldopa Valproate
Chloroquine Mexiletine Verapamil
Clavulanic acid Neuroleptic drugs Warfarin
(moderat dose)
Clomethiazole Nifedipine
Codeine Nortripteline