‫بسم الله الرحمن‬

‫الرحيم وأفضل‬
‫الصلة وأتم التسليم‬
‫على محمد خير‬
 Developmental
Pharmacology and
Toxicology

Iyad ABOU RABII

BDS, OMS, MD, PhD
At present, the etiology of congenital
malformations can be divided into three
categories:
◦ Unknown ,
◦ genetic, and
◦ environmental.

Why studying Developmental

Toxicology and Pharmacology?
•Some of the fetus's blood vessels are contained in
tiny hairlike projections (villi) of the placenta that
extend into the wall of the uterus.
•The mother's blood passes through the space
surrounding the villi (intervillous space).

How Drugs Cross the Placenta

Only a thin membrane (placental membrane) separates the
mother's blood in the intervillous space from the fetus's blood
in the villi. Drugs in the mother's blood can cross this
membrane into blood vessels in the villi and pass through the
umbilical cord to the fetus.

How Drugs Cross the Placenta

 Background reproductive risks in pregnancy.

Pharmacokinetics and metabolism of

the drug or chemical
 Etiology of human congenital malformations observed during the
first year of life.

Pharmacokinetics and metabolism of

the drug or chemical
 Considerations that affect the interpretation of dose-response
relationships.

Pharmacokinetics and metabolism of

the drug or chemical
Pregnancy-related physiological alterations in the mother that affect
the pharmacokinetics of drugs.

Pharmacokinetics and metabolism of

the drug or chemical
 Pregnancy-related physiological alterations in the fetus that may
affect the pharmacokinetics of drugs.

Pharmacokinetics and metabolism of

the drug or chemical
illegal
drugs, such as heroin and cocaine,
pose dangers to a pregnant woman.
Legal substances, such as alcohol and
tobacco, are also dangerous
Medical drugs, both prescription and over-
the-counter, can be harmful.
Environmental pollutants

Which Toxics are Dangerous?

Some drugs can be harmful when used at
any time during pregnancy;
others, however, are particularly
damaging at specific stages.
◦ Stage of organ formation
◦ Stage of prenatal growth
◦ Stage of birth

Drugs and the Stages of

Pregnancy
The stage of organ formation
Most of the body organs and systems of
the baby-to-be are formed within the first
ten weeks or so of pregnancy
During this stage, some drugs and toxics
cause malformations of such parts of the
developing fetus, as the heart, the limbs,
and the facial features.

Drugs and the Stages of

Pregnancy
The stage of prenatal growth
After about the tenth week, the fetus
should grow rapidly in weight and size. At
this stage, certain drugs may damage
organs that are still developing, such as
the eyes, as well as the nervous system.

Drugs and the Stages of

Pregnancy
The stage of prenatal growth
The greatest danger drugs pose at this
stage is their potential to interfere with
normal growth.
This will result in a low-birthweight baby—
a baby born too early, too small, or both.
Low-birthweight babies require special
care and run a much higher risk of severe
health problems or even death.

Drugs and the Stages of

Pregnancy
The stage of birth
Some drugs can be especially harmful at
the end of pregnancy. They may make
delivery more difficult or dangerous, or
they may create health problems for the
newborn baby.

Drugs and the Stages of

Pregnancy
Drugs and Toxics affecting
Development : Narcotics
Cocaine and methamphetamine are
powerful stimulants of the central nervous
system.
They suppress the mother’s appetite, the
blood vessels to constrict, the heart to
beat faster, and the blood pressure to
soar.

Drugs affecting Development :

Narcotics
Heavy narcotics use increases the danger
of premature birth with such
accompanying problems for the infant as
low birth weight, breathing difficulties, low
blood sugar (hypoglycemia), and bleeding
within the head (intracranial hemorrhage).

intracranial hemorrhage

Drugs affecting Development :

Narcotics
Isotretinoin(Accutane) and etretinate
(Tegison) are used to treat chronic acne
and psoriasis. They may cause chronic
malformations during the stage of organ
development.

Drugs affecting Development :

Medications
Anticonvulsants, such as phenytoin
(Dilantin) and carbamezapine (Tegretol),
are used to prevent epileptic seizures.
They are associated with defects of the
heart and face, as well as mental
retardation.

defects
of the
face

Drugs affecting Development :

Medications
Trimethadione
(Anticonvulsant)
TRIDIONE®
◦ Increased risk of miscarriage
in the woman
◦ High (70%) risk of birth
defects, including a cleft
palate and defects of the
heart, face, skull, hands, or
abdominal organs
Cleft palate

Drugs affecting Development :

Medications
Valproate (Anticonvulsant)
DEPARENE®

High risk of birth defects, including a cleft

palate and defects of the face, skull, or
hands.
risk of miscarriage .

Drugs affecting Development :

Medications
Antimigraine drugs, such as ergotamine
and methysergide, are used to head off
migraine attacks but raise the risk of
premature labor.

Drugs affecting Development :

Medications
Anticoagulant drugs based on coumarin
are used in the treatment of heart disease
and stroke, to slow blood clotting.
Taken during early pregnancy, they are
associated with facial malformations and
mental retardation.
Later on they raise the risk of uncontrolled
bleeding.

Drugs affecting Development :

Medications
Aspirin, ibuprofen, and other non-steroidal
anti-inflammatory drugs (NSAIDs)
interfere with blood clotting and increase
the risk of uncontrolled bleeding for both
mother and baby.
Toward the end of pregnancy, they hinder
production of the hormones that stimulate
labor, so that labor may be dangerously
delayed or extended.

Drugs affecting Development :

Medications
Tetracycline
(ACHROMYCIN® TETRACYN® SUMYCIN®)
Slowed bone growth, permanent yellowing
of the teeth, and increased susceptibility
to cavities in the baby
Occasionally, liver failure in the pregnant
woman

Drugs affecting Development :

Medications
Tetracycline
Angiotensin-converting enzyme (ACE)
inhibitors (Antihypertensive)
When the drugs are taken in pregnancy,
kidney damage in the fetus, a reduction in
the amount of fluid around the developing
fetus (amniotic fluid), and defects of the
face, limbs, and lungs

defects of the lungs

Drugs affecting Development :

Medications
Busulfan (Chemotherapy)
MYLERAN ®
Birth defects such as underdevelopment of
the lower jaw, cleft palate, abnormal
development of the skull bones, spinal
defects, and ear defects

nderdevelopment of the lower jaw

Similar effects are found with Methotrexate

(RHEUMATREX ®)

Drugs affecting Development :

Medications
Alcohol is one of the most dangerous
substances for pregnant women,
especially in the early weeks.
In the mother’s body, alcohol breaks
down chemically to a cell-damaging
compound that is readily absorbed by the
fetus.
Heavy drinking during early pregnancy
greatly increases the risk of a cluster of
birth defects known as fetal alcohol
syndrome
Toxics affecting Development :
Alcohol
fetal alcohol syndrome
This syndrome includes a small skull
(microcephaly), abnormal facial features,
and heart defects, often accompanied by
impeded growth and mental retardation.
Heavy drinking in later pregnancy may
also impede growth.

Toxics affecting Development:

Alcohol
 Nicotine depresses the appetite at a time
when a woman should be gaining weight,
and smoking reduces the ability of the
lungs to absorb oxygen.
The fetus, deprived of sufficient
nourishment and oxygen, may not grow
as fast or as much as it should.

Toxics affecting Development :

Tobacco
Polychlorinated biphenyls : Poisoning has
occurred from adulteration of food
products (cola-colored babies,
◦ CNS effects,
◦ pigmentation of gums, nails, teeth and groin,
◦ hypoplastic deformed nails,
◦ intrauterine growth retardation, abnormal skull
calcification).

abnormal skull
calcification

Chemical Toxics affecting

Development
Toluene addiction : Facial dysmorphology,
mental retardation
Gasoline addiction : Facial
dysmorphology, mental retardation

Facial dysmorphology

Chemical Toxics affecting

Development
Mercury : Causes Minamata disease
consisting of cerebral palsy, microcephaly,
mental retardation, blindness, and
cerebellum hypoplasia.

microcephaly cerebellum hypoplasia

Chemical Toxics affecting

Development
Concerns about environmental chemicals
and physical agents are clearly justified
because, in most cases, not enough
information is available on the potentially
differential effects on the fetus and child
it is not possible to determine whether a
chemical or drug is safe or hazardous
unless the magnitude of the exposure is
known.

Conclusion
Such information, can only be obtained
from high-quality human and animal
toxicology and epidemiological studies
which include toxicokinetic and
toxicodynamic data.

Conclusion
All chemicals and drugs have the potential
for developmental toxicity if the exposure
is high enough
So extensive program of monitoring,
reducing, and ,eliminating the delivery of
chemicals to the environment and the
exposure of populations to chemicals is
needed

Keep in mind