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SULANTO SALEH-DANU R., dr., SpFKDivisi Farmakologi-Klinik
Departemen Farmakologi & Terapi
Fakultas Kedokteran UGM
OBAT-OBATANFETUS( TERATOGENIC)
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TRIAD MATERNAL PLACENTA FOETUS
TRANSFER OBAT DARI MATERNAL KE FOETUS
PHARMACOKINETICPHARMAKODYNAMIC FOETUS
PERIODE ORGANOGENESISTERATOGENIK
PERLINDUNGAN KEMUNGKINAN KEJADIAN TERATOGEN
BEBERAPA CONTOH CACAD CONGENITAL.
BEBERAPA HAL TENTANG
OBATOBATAN & FETUS.
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- GASTROINTESTINAL TRACT :
oral cavity
motility
esophagus and stomach
intestine
liver and gallbladder
-KIDNEY and URINARY TRACT
renal dilatation
renal function
bladder
-HEMATOLOGIC SYSTEM
blood volume
red blood cellsiron
white blood cells
platelets
clotting factors
-CARDIOVASCULAR SYSTEM
heart (size, position, rhythms, murmurs)
cardiac output
blood pressureperipheral resistance
blood flow
-RESPIRATORY SYSTEM
lung volume
lung capacities
-ENDOCRINE SYSTEM,
etc.
NORMALWOMAN
PREGNANCY :
Anatomical &Physiological
changes
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PREGNANCY
1STTRIMESTER
2ndTRIMESTER
3thTRIMESTER
PARTURIENT
CHANGES :
ANATOMIC ??
PHYSIOLOGIC ??
MEDICINES &
SUBSTANCES
OUTSIDEMATERNAL
PHARMACOKINETIC ??
PHARMACODYNAMIC ??
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MOTHER FETUS
Basal Layer ?Chorion Layer ?
TRIAD MATERNAL PLACENTAFOETUS
PLACEN
TA
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OXYGEN
WATER &
ELECTROL.
HORMONES
Antibodies
DRUGS
INFECTIONS /
VIRUSES
CARBOHYDR-
ATES
LIPIDS
PROTEINS
VITAMINES
CO2
Water &
urea
Waste
product
HORMONE
S
(CERTAIN)
(Almost all )
MATERN
AL
PLACENTA
FETUS
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HARMFUL EXOGENOUSINFLUENCES FACTORS :
1. EXCHANGE PHYSIOLOGICAL CONSTITUENTS.2. RADIATION EFFECTS3. MICROORGANISM / VIRUS INFECTION4. CHEMICAL SUBSTANCES :DRUGS SERUMS VACCINES
FOREIGN SUBSTANCES5. ENVIRONMENTAL:
CLIMATE NUTRITION SMOKING ALCOHOLWORK CONDITION SICKNESS SOC-ECON.
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i.v. oral i.m TopicalTrans-
dermal
Mucosal,
buccal,
Vag., rectal,
inhalation
Localeffect
Localeffect
A B S O R P T I O N
PRESYSTEMIC METABOLISM
systemic circulation
DISTRIBUTION
Site of action METABOLISM EXCRETION
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Drug fate in the body
Absorption
Site(s) of action
Other body fluids
and tissues
ExcretionDrug-protein
Free Drug
Free Drug
Metabolism
metabolites
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How drugs act in the body ?
Drug
Drug concentration in
systemic circulation (blood)
Drug concentration
at site of action
Adverse effect Therapeutic effect
Absorption
Distribution
Metabolism
ExcretionPHARMACOKINETIK
PHARMACODYNAMIC
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FARMAKA
DRUGS/MEDICINES
PREGNANCY
FETUS MATERNAL
THERAPEUTIC EFFECT
TOXIC EFFECT
TERATOGENIC EFFECT
THERAPEUTIC EFFECT
TOXIC EFFECT
EFFECT ON PARTURITION
PLACENTA
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MATERNALPLACENTA FETUS
DRUGS
BOUND
UNBOUND UNBOUND
BOUND
EXCRETED
TISSUE
METABOLIZED
EXCRETED intoThe Amniotic Fluid
INGESTED by
the Fetus
FETAL Intestines
Model of interaction between A-D-M-E of drugs and metabolites
in the organism of mother and fetus
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FACTORS MODULATING THE PASSAGE OF DRUGS
ACROSS THE PLACENTA MEMBRANE :
1. LIPID SOLUBILITY2. MOLECULAR SIZE AND SHAPE
3. DEGREE OF IONIZATION
4. PLACENTAL BLOOD FLOW
5. STAGE OF DEVELOPMENT OF PLACENTA
6. PLACENTAL METABOLISM OF DRUGS
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Simple diffusion
Fasciliated diffusion
Active transport
Pinocytosis
Leakage
DRUGS :
lipophillic
non-ionized
non-polair
molecule size
MATERNAL :
GIT motility
pH
Blood flow
Diseases, etc
PLACENTA FETALMATERNAL
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ABSORPTION PROCESSES IN PLACENTA:
Passive diffusion down a concentration gradient
- most drugs
Cell membrane and fat-solubility of drugs
- most drugs
Active transport - few drugs
Disintegration and dissolution of tablets- many drugs
Presystemic metabolism ( first-pass metabolism )
- most drugs
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PLACENTA;
FETAL PROTECTION
FETAL FEEDING
ENDOCRINE SECRETION
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AbsorptionDistribution
Metabolism
Excretion
PHARMACOKINETIK
CLEARENCE ( CL L/hou r )
VOLUME of DISTRIBUTION ( Vd)
HALF-LIFE ( t - hou rs )
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PHARMACOKINETIK IN PREGNANCY :
DRUGS ABSORTION :
process : transfer by crossing cell membrane
construction from LIPID
lipophilic ?non-ionized ?
non polair ?
molecule size ?
crossing
cell membrane
PREGNANCY gaster pH ?intestinal motility ?
Intestinal lumen emptying ?
hepatic blood flow ?
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CLEARENCE( CL L /hour o r mL/m inute )
The eff ic iency of irreversible el iminat iono f
a drug from the body
-The excretion unchanged drug into urine
-Gut contents
-Expired air
-Sweat , etc
-The metabolic conversion of the drug
different chemical compound
The volum e of blood clear of drug per uni t t ime
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CLEARENCE
PARAMETER THAT DETERMINES THE MAINTENANCE DOSE RATE
REQUIRED TO ACHIEVE A TARGET PLASMA CONCENTRATION
AT STEADY STATE
elimination rate (mg/hour) = clearance (CL) (L/hour) x
plasma drug concentration (C) mg/L
elimination rate (mg/hour) = maintenance dose rate (DR) (mg/hour)
maintenance dose rate (DR) = clearance (CL) L/hour x
steady state drug concentration ( Css ) mg/L
DR dose (mg)CL = or CL (L/hour) =
Css AUC ( mg.hour/L )
note : AUC = Area Under the Curve
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VOLUME of DISTRIBUTION
( Vd L itre )
not a real volume parameter relat ing
the concentrat ion o f a drug in the plasma
to the total amount of the drug in the body.
tota l amount of the drug in body (A)
plasma drug concentrat ion ( C )
quick c ount a loading dose
loading dose = V x target plasma concentration
= 20 L x 10 mg/L
= 200 mg
Vd =
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HALF-LIFE
( t - hours )
is the t ime taken for the amount of dru g in the body
( or the plasma concentrat ion ) to fall by half .
0.693 x V
CLt =
1. The Duration of action after single dose2. The require to reach steady state with chronic dosing
3. The dosing frequency required to avoid too large fluctuations
plasma concentration during the dosing interval
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Pharmacokinetics:drug concentrations in plasma over time
1
10
100
0 2 4 6 8 10 12 14 16 18 20 22 24
Minimum EffectiveConcentration
Minimum ToxicConcentration
Plasma drug concentration
Time
Tmax
Cmax
AUC
Tlag
Keland T1/2 Therapeuticwindow
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Pharmacodynamics
1. Drug action in maternal body system.
Drug effects in pregnant women:- Reproductive tissues, e.g. breast, uterus, etc., are
altered the change of endocrine system according to the
stage of pregnancy;
- Other maternal organs (heart, lung, kidneys, CNS,intestine, etc.) not changed, same as the effect in non
pregnant condition.
2. Drug action in the Fetus.
Some medicine give in perinatal via maternal:- Phenobarbital when given near term, can reduce the
incidence ofjaundice baby, by inducing fetal hepatic
enzymeof the foetus.
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3. Predictable Toxic Drug Actions in the Fetus.Chronic use of medicine can produce adverse effect
after delivery, Opioidmay produce dependence in newborn babies,
(withdrawal syndrome in newborn baby).
Diethylstilbestrol (DES)produced adenocarcinoma inpubertal ages of the baby (delay reaction).
4. TERATOGENIC Drug Action.Even a single intrauterine drug exposure to a drug can
affect the fetal structure, e.g. Thalidomide ---->phocomelia.
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TERATOGEN --> to be TERATOGENIC :
substance or process should :
1. result in characteristic set of malformations,
indicating selectivity for certain target organs.
2. effects at a particular stage of fetal
development (during limited time periode of
organogenesis.
3. shows dose dependent incidence.
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New born
normal
Functional
abnormalities
Major
structuralabnormalities
Gametes Blastocyst Embryo Fetus
Fig. 4. Schematic representation of the influence of dysmorphogenic factors on
gametogenesis and various stages of prenatal development. Strongdymorphogenic agents:
wide arrows; weakagents; narow arrows(after Tuchmann-Duplessis, 1975)
Sterility
Death
Death
Death
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DANGER ZONE
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Fig.7. The stages critical for thehuman fetus. (Notethat the
developmental ages given arepostconceptionages which for
clinical purposes need to be translated intopostmenstrual
ages, ordinarily by adding 2 weeks) After Tuchmann-
Duplessis (1975).
Fig.5. The critical stages of development of the main
structures of thehuman embryo. (Notethat the
development ages given arepostconceptionages which
for clinical purposes need to be translated into
postmenstrualages, ordinarily by adding 2 weeks). AfterTuchmann-Duplessis (1975).
Days
Months
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TERATOGENIC EFFECT:
-Teratogen: a substance that lead to the birth ofmalformed baby.
The mechanism is poorly understood, possibly
multifactorial causes, may by oxygen passing ortissue nutrient for the fetus, or shown to have
important differentiation-directing in normal tissue
like vitamin A analog ( isotretinoin, etretinate ) --
powerful teratogen, or deficiency of criticalsubstance such as folic acid.
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PATHOGENESIS
( manifestation of abnormal Excessive or reduce cell interactions
development created by Fail cell interactions
above mechanism ) Reduce biosynthesisImpeded morphogenetic movement
Mechanical disruption of tissues
COMMON PATHWAYS Too few cells or cell products to
affect localized morphogenesis or
functional maturation.
Other imbalances in growth and
differentiation.
FINAL DEFECTS Death
(final manifestation of abnormal Malformation.
Development) Growth retardation
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ADVERSE EFFECTS OF FETOTOXIC EXPOSURESTAGE DEVELOPMENT
WEEK since
Ovulation Potential ADVERSE EFFECTS
1 Abortion
2-7 Fetal wastage; Structural malformations; Carcinogenesis
Intrauterine growth retardation (severe)
3 Ectopia cordis;Omphalocele; Ectomelia; Sympodia
4 Omphalocele; Ectomelia;Tracheoesophageal fistula;
Hemivertebra
5 Tracheoesophageal fistula; Hemivertebra; Nuclear cataract;
Microphtahalmia; Facial cleft; Carpal of pedal ablation
6 Microphthalmia; carpal or pedal ablation; Cleft lip; Agnathia
Lenticular cataract; Congenital heart disease; Gross
cardiac septal and/or aortic anomalies
(to be continue.)
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DRUGSWITH :SIGNIFICANT TERATOGENIC / ADVERSE EFFECTS ON FETUS
DRUG TRIMESTER EFFECT
ACE inhibitors All, espec 2nd& 3rd Renal damage
Aminopterin First Multiple gross anomalies
Amphetamines All Susp.abnomal development pattern.
decrease school performance
Androgens 2nd& 3rd Masculinization of female fetus
Antidepressants 3rd
Neonatal withdrawal symptoms havetricyclic been reported in few cases
clomopramine, desipramine, imipramin
Barbiturates All Chronic use -> neonatal dependence
Busulfan All Various congenital-malformations; LBW
Carbamazepine First Neural tube defects (eg spina bifida)Chlorpropamide All Prolonged sympt.neonatal hypoglycaemic.
Clomipramine 3rd Neonatal lethargic, hypotonia, cyanosis,
hypothermia
Cocaine All Increased risk of spontaneous abortion,
abruptio placentae, premature labor,
neonatal cerebral infarction, abnrml.dev,etc
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DRUG TRIMESTER EFFECT
Cyclophosphamide First Various congenital malformations
Cytarabine First & 2nd Various congenital malformations
Diazepam All Chronic use -> neonatal dependenceDiethylstilbesterol All Vaginal adenosis, clear cell vag. Adeno Ca
Ethanol All Risk of fetal alcohol syndr. and alc-related
neurodevelopmental defects.
Etetrinate All High risk of multiple congenital malform.
Heroine All Chonic use -> neonatal dependence
Iodide All Congenital goiter, hypothyroidism
Isotretinoin All Extremely high risk of CNSs, face, ear &
other malformations
Lithium First Ebsteins anomaly
Methadone All Chronic use -> neonatal dependence
Methotrexate First Multiple congenital malformations
Methylthiouracil All Hypothyroidism
Metronidazol First May be mutagenic (animal study;
no effidence for mutagenic/teratogenic
in humans)
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DRUG TRIMESTER EFFECT
Misoprostol First Mbius sequence
Mycophenolate First Mayor malformations of the face,
mofertil limbs, and other organs.
Organic solvent First Multiple malformations
Penicillamine First Cutis laxa, other congenital malformations
Phencyclidine All Abnormal neurologic examination, poor
suck reflex and feeding
Phenytoin All Fetal hydantoin syndromePropylthiouracil All Congenital goiter
Smoking (consti- All Intrauterine growth retardation, prematurity,
tuents of tobacco sudden infant death syndrome, perinatal
smoke) complication.
Streptomycin All 8thNerve cranialis toxicity
Tamoxifen All Increased risk of spontaneous abortion or
fetal damage
Tetracycline All Discoloration and defects of and altered
bone growth
Thalidomide All Phocomelia (shortened/absent
of long bones of the limbs) and many
internal malformations .
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DRUG TRIMESTER EFFECT
Trimethadione All Multiple congenital anomalies
Valproic acid All Neural tube defects, cardiac and limbsmalformations
Warfarin First Hypoplastic nasal bridge, chondrodysplasia.
Second CNS malformations.
Third Risk of bleeding. Discontinue use 1 monthbefore delivery
( Koren, G., Special aspects of Perinatal & Pediatric Pharmacology;
In Basic & Clinical Pharmacology, ed: Katzung, BG etals; 12thEd. 2012,
Lange McGraw Hill Medical )
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MATERNAL INFECTIONSAFFECTING THE FETUS/NEWBORN
MATERNAL INFECTION EFECTS ON FETUS/NEWBORN
VIRAL INFECTIONS :.Rubella Malformations, bleeding, hepatosplenomegaly,
pneumonitis, hepatitis, encephalitis
Cytomegalovirus (CMV) Microcephaly, chorioretinitis, deafness, mental
retardation.
Herpes simplex Generalized herpes, encephalitis, death.
Mumps Fetal death, endocardial fibroelastosis (?),
malformations (?)Chicken pox shingles Chicken pox or shingles, increase abortions and
stillbirths.
Smallpox Smallpox, increased abortions and stillbirths
Poliomyelitis Spinal or bulbar poliomyelitis
Hepatitis Hepatitis
BACTERIAL-PROTOZOAN INFECTS.:
Tuberculosis Congenital tuberculosis
Pyelonephritis Prematour labor
Gonorrhea Ophthalmitis
Toxoplasmosis Microcephajy, chorioretinitis, jaundice
Malaria Low Birth Weight (LBW), perinatal mortality (?),
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BEBERAPA BENTUK2
ANOMALI CONGENITAL
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5 CATAGORIES
DRUG USE IN
PREGNANCY
A
B
C
D
X
(US-FDA; TGA-Australia)
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CATEGORY A
Adequate and well-controlled studies have failed to
demonstrate a risk to the fetus in the first trimesterof pregnancy (and there is no evidence of risk in later
trimesters)
e.g.: almost of medicine
CATEGORY B Animal reproduction studies have failed to demonstrate
a risk to the fetus and there are no adequate and
well-controlled studies in pregnant women.
e.g.: loperamide, amoxycillin trihydrate, sulbactam+ampisillin, etc
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CATEGORY C
Animal reproduction studies have shown an
adverse effect on the fetus and there are no adequate
and well-controlled studies in humans, but potential
benefits may warrant use of the drug in pregnant
woman despite potential risks.
e. g. : salbutamol, theophyllin, aminophylline, neviparine (antiviral),
ciprofloxacine, clarithromycin, allopurinol, dipyridamole, etc.
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CATEGORY D
There is positive evidence of human fetal risk
based on adverse reaction data from investigational
or marketing experience or studies in human,
but potential benefits may warrant use of the drugin pregnant women despite potential risks.
e. g. : amikacin, amiodarone, amobarbital, atenolol,
bleomycin, busulfan, capecitabine,
carbamazepine, carboplatin, etc.
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CATEGORY X
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CATEGORY X(contraindicated in pregnancy)
Studies in animals or humans have demonstratedfetal abnormalities and/or there is positive evidence
of human fetal risk based on adverse reaction data
from investigational or marketing experience and
the risks involved in use of the drug in pregnantwomen clearly outweigh potential benefits.
e.g.: atorvastatin (statin group),
chorionicgonadotropin,
coumarine, diethylstilbestrol,
dihydroergotamine,
estazolam, estradiol, etc.
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MEDICINE /DRUGS
CHEMICAL & FOREIGN SUBSTANCES
1ST TRIMESTER : ANATOMICAL ANOMALY
2ND TRIMESTER : ANATOMICAL & PHYSIOLOGICAL ANOMALY
3RD TRIMESTER : PHYSIOLOGICAL ANOMALY & PARTURIENT
RESUME :
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