‫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 overthe-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
TRIDIONE®

(Anticonvulsant)
◦ 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
DEPARENE®

(Anticonvulsant)

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

Drugs affecting Development : Medications

defects of the lungs

Busulfan
MYLERAN ®

(Chemotherapy)

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

(RHEUMATREX ®)

effects are found with Methotrexate

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

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