Tiêu đề 19. DRUG INDUCED BIRTH DEFECTS.pdf ✅

PHARMD GURU Page 1 TERATOLOGY:  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders present at birth are called congenital anomalies, birth defect or congenital malformation.  Congenital anomalies are of four clinically significant types: malformation, disruption, deformation and dysplasia. BIRTH DEFECTS:  3% of all live-born infants have a major anomaly.  Additional anomalies are detected during postnatal live — about 6% at 2 year-olds, 8% in 5year-olds, other 2% later.  Single minor anomalies are present in about 14% of newborns.  Major anomalies are more common in early embryos (up to 15%) than they are in newborns (3%). Most severely malformed embryos are spontaneously aborted during first 6 to 8 weeks. TERATOLOGY – TERMS:  Malformation is a primary structural defect resulting from a localized error of morphogenesis.  Disruption is specific abnormality that results from disruption of normal developmental processes. It depends on time not on agent.  Deformation is an alteration in shape / structure of previously normally formed part.  Syndrome is a recognized pattern of malformations with a given etiology. FACTORS THAT INFLUENCE TERATOGENICITY: 1) Nature of the agent. 2) Dose 3) Route 4) Frequency of exposure 5) Duration of exposure 6) Gestational timing DRUG INDUCED BIRTH DEFECTS
PHARMD GURU Page 2 7) Concurrent exposures 8) Concurrent illness 9) Genetic susceptibility  Mother  Fetus PRINCIPAL MECHANISMS OF TERATOGENESIS:  Cell growth or proliferation.  Cell death.  Cell migration.  Cell and tissue interactions.  Disruptions. MUTAGENESIS:  Principal mechanisms.  Gene mutation.  Chromosomal abnormities.  Before or after conception.  Males and females both affected. ANOMALIES CAUSED BY GENETIC FACTORS:  Chromosomal aberrations are common and are present in 6 to 7% of zygotes — (Result = abort).  Numerical chromosomal abnormalities —usually non-disjunction- error in cell division Down syndrome (21) Edwards (18) Patau (13) Turner (XO), Klinenfelter (XXY).  Structural chromosomal abnormalities —chromosome breaks = translocation, deletion (cridu chat syndrome), duplication, inversion.  Mutant genes — achondroplasia, fragile-X syndrome. ANOMALIES CAUSED BY ENVIRONMENTAL FACTORS:  Teratogens are exogenous agents that may cause developmental defects:  Drugs (warfarin, valproic acid, phenytoin, vitamin A, thalidomide, cytostatic drugs -cyclophosphamide, lithium carbonate).  Chemicals (PCBs, methyl mercury, alcohols).

PHARMD GURU Page 4 PREGNANCY RISK CATEGORIES RESPONSE:  Labeling of some prescription drugs includes information about the level of risk for the fetus and the extent of caution necessary in their use. The FDA has established five categories (A, B, C, D, and X) to indicate a drug's potential for causing teratogenicity. This format was first announced in the September 1979 FDA Drug Bulletin. Because of labeling revisions, many products now use this format.  A similar, but somewhat expanded, classification system was adopted by the Australian Drug Evaluation Committee (ADEC) in 1989. Germany set forth its own classification system. US FDA PREGNANCY CATEGORY DEFINITIONS: A - Adequate, well-controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first (second, third, or all) trimester(s), and the possibility of fetal harm appears remote. B - Animal studies do not indicate a risk to the fetus; however, there are no adequate, well-controlled studies in pregnant women. OR Animal studies have shown an adverse effect on the fetus but adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Despite the animal findings, the possibility of fetal harm appears remote, if used during pregnancy. C - Animal studies have shown that the drug exerts teratogenic or embryocidal effects, and there are no adequate, well-controlled studies in pregnant women, OR No studies are available in either animals or pregnant women. D - Positive evidence of human fetal risk exists, but benefits in certain situations (eg, life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may make use of the drug acceptable despite its risks. X - Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.