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179 Cards in this Set
- Front
- Back
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Streptomycin (antibiotic)
teratogens |
hearing loss
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tetracycline (antibiotic) teratogen
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Exposure in the second or third trimester: yellow-stained teeth, other tooth enamel defects
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Valproic acid (anticonvulsant used in epilepsy treatment)
teratogen |
Neural tube defects, craniofacial anomalies, heart defects, limb defects
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Isotretinoin (Rentinoic acid or vitamin A used in acne treatment )
teratogen |
Exposure at three to five weeks: pregnancy loss, neural tube defects, brain defects, small or absent thymus, heart defects, craniofacial abnormalities (small ears, small jaws, cleft palate)
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Antithyroid drugs and potassium iodide found in cough mixtures
teratogen |
Hypothyroidism (cretenism), goiter
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Androgens and high doses of nor-progesterone
teratogen |
Exposure in the first trimester: masculinization of external female genitalia
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ACE inhibitors (anti-hypertension agents)
teratogen |
Low volume of amniotic fluid, fetal death, renal dysfunction, skull ossification defects
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Lithium (manic-depression treatment)
teratogen |
Heart and major blood vessel anomalies
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pregnancy category A
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Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm remains remote.
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pregnancy category B
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Animal studies do not indicate a risk to the fetus and there are no controlled human studies, or animal studies do show an adverse effect on the fetus but well controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Also no risk in later trimesters.
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pregnancy category C
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Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
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pregnancy category D
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Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may make use of the drug acceptable. There will be an appropriate statement in the "warning" section of the labeling.
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pregnancy category X
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Studies in animals or humans have demonstrated fetal abnormalities or there is 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. There will be an appropriate statement in the "contraindications" section of the label
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thalidomide
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In the 1950's and early 1960's thalidomide was used to treat morning sickness. Originally sold over the counter, dose was between 50-200 mg/day.
Retrospective studies demonstrate that approximately 5-10,000 were affected. Most cases were reported in Germany because the drug was quite popular. In the United States the number of infants born with thalidomide embryopathy was very low because the drug was never approved by the FDA. Ironically this was because of its potential side effects such as peripheral neuropathy, rather than concerns regarding teratogenicity |
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Teratogenic Outcome of Thalidomide (know #s)
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The major defects were limb defects. The sensitive period of exposure was between 20-40 days
27-30 days mainly arms affected >30 days, arms and legs Also defects in the kidney, eyes, ears, GI tract, and heart. |
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Mechanisms of Teratogenic Action of Thalidomide?
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The mechanism by which thalidomide induces a spectrum of birth defects is largely unknown.
Three mechanistic levels have been explored: biochemical, tissue-organ and cellular mechanisms. The cellular mechanisms under investigation include induction of inappropriate cell death, chromosome damage, and cell-cell interactions involved in morphogenesis. Cell-cell interaction is an intriguing hypothesis because of its importance in morphogenesis. In short, we still do not know. |
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MOA and teratogenic affects
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Why is it so difficult to identify the underlying mechanism of action?
Need a suitable animal model. Animal models show different levels of sensitivity to malformations. Sensitivity range is between 1 and 100 mg/kg. Human is near the 1 mg/kg value. Humans are the most sensitive to drugs compared to most animals rats and mice are nor sensitive rabbits and hamsters are somewhat sensitive primates are the most sensitive animal models |
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Thalidomide: New Era
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Thalidomide has recently been approved by the FDA for the treatment of Leprosy.
Also being studied as a medication- for the treatment of wasting that characterize diseases like cancer and AIDS. Thalidomide appears to moderate immune system reactions and is very effective for the treatment of mouth, throat, and rectal ulcers in people with AIDS |
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Diethylstilbestrol (DES)
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A non-steroidal estrogen. Widely used between the 40s-70s to prevent miscarriage by stimulating estrogen and progesterone synthesis. Works via an endocrine mechanism.
1966-1969: 7 women (15-22 years old) at Mass General had vaginal adenocarcinoma. This had never been seen before in women younger than 30 years old. This is a monumental discovery, for the first time the induction of a specific cancer by a specific agent taken by the mother several years earlier. DES < 18th week appeared to be responsible for genital tract anomalies in offspring. X classification also causes problems in males |
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females and DES
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Females offspring: mainly vaginal adenocarcinomas, perhaps reduced pregnancy rates, greater frequency of premature deliveries and spontaneous abortions. Overall risk was as high as 75% of exposed individuals.
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males and DES
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Male offspring: genital anomalies (not cancers) epididymal cysts, reduced semen volume and quality (fertility problems?)
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MOA of teratogenic affects of DES
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The precise mechanism is unknown -‘endocrine disruption’. Animal models now available.
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Valproic Acid (Depakote) (know dose)
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This drug was first prescribed in Europe 1967 and later in the US (1978) as an anticonvulsant.
Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day). |
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valproic acid and teratogenic affects and pregnancy class
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These children were born with lumbosacral spina bifida with menigomyelocele or menigocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heard disease and decreased postnatal growth
Problem is the most critical period for this defect is 30 days post conception. This drug is classified as D. |
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antigoagulation and pregnancy
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Anticoagulant therapy during pregnancy presents a substantial risk to both mother and fetus.
Intra-uterine exposure to warfarin between 6 to 9 weeks gestation is associated with up to 10 percent risk of deformities known as warfarin syndrome. Exposure to warfarin at other stages of pregnancy may cause CNS defects, spontaneous abortion, stillbirth or neonatal death. Use of warfarin and heparin later in late pregnancy increases the risk of maternal and fetal bleeding complications at delivery. |
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what anti-coag to use in pregnancy
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Heparin does not cross placenta and is the anticoagulant of choice in pregnancy.
Long-term (greater than 6 months) heparin administration may cause maternal osteoporotic changes. All women of childbearing potential who are taking anticoagulants should be counseled about the risks to the fetus if they should become pregnant. If a woman becomes pregnant inadvertently while taking warfarin she should be strongly advised to visit her MD as soon as possible |
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warfarin and teratogenic affects
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The primary teratogenic effect of warfarin is in the axial and appendicular skeleton. Effected children also have a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly and scoliosis
The effect of warfarin is time and dose dependent. The embryopathy described above results from maternal use during early pregnancy The central nervous system disorders are due to dosage at a later stage in pregnancy. The teratogenic mechanism of warfarin is unknown It has been proposed that an alteration in post-translational carboxylation of proteins may result in the chondrogenic disorders. |
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is the teratogenic effects of warfarin time dependent
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yes
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lithium and teratogenic effects
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Has been used to treat patients with manic-depressive psychosis since 1947.
Under some circumstances, cardiovascular anomalies are produced. Increased incidence of Ebstein's anomaly (the tricuspid valve is displaced into the right ventricle). In animal models, cleft palate is produced at human therapeutic doses. This drug is therefore classified as D. Therapy of bipolar disorders during pregnancy is difficult. Lithium (D), Valproate (D), and carbamazepine (C). |
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ACE inhibitors
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Hypertension is very common during pregnancy and angiotensin-converting enzyme (ACE) inhibitors have been used effectively used for more than a decade.
However, there have been numerous reports of severe fetal and neonatal morbidity and mortality in women who received ACE inhibitors for hypertension during pregnancy. |
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is the combo of an ACE and an ARB ok in pregnancy
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no it is very toxic to the fetus
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ACE inhibitors and teratogenic affects
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Agents such as captopril do not seem to present an increase risk the 1st trimester.
Use later in pregnancy is associated with significant adverse effects on the fetal kidney. Decrease fetal kidney function and urine production, which reduces the volume of amniotic fluid (oligohydraminois). Speculated that this may allow uterine musculature to put pressure on fetus. Leading to skull defects |
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Accutane (Retinoic acid)
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It has been reported since 1954 that excess retinol (Vitamin A) can induce malformations.
Affect face, limbs, heart, CNS and skeleton. 1-cis-retinoic acid (Accutane) prescribed for recalcitrant acne. Very high risk for developmental malformation. Since its introduction in September of 1982, an estimated 160,000 women of child bearing age have ingested the drug. Between 1982 and 1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions and 5000-7000 elective abortions are due to Accutane exposure. |
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does the dose of accutane have to large to induce teratogenic affects
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no
RA is teratogenic in humans at very low doses. The critical exposure time is between 3-5 weeks of pregnancy. Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ. Fifty percent of affected children have an IQ below 85 (average intelligence being an IQ of 110-100). |
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pregnancy category of accutane
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Accutane carries a pregnancy category X warning.
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affects associated with accutane and the fetus
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Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ.
Fifty percent of affected children have an IQ below 85 (average intelligence being an IQ of 110-100). |
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Cocaine
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An estimated 45% of urban pregnancies and 6% of suburban pregnancies involve cocaine exposure.
Approximately 375,000 children are born each year to mothers who use cocaine during pregnancy. It is difficult to get reliable dose information and it is often taken in conjunction with other drugs. Still, the number of defects (or deficits) associated with cocaine exposure are numerous. Reduced birth weight; CNS and cardiac defects, microcephaly, genitourinary defects, SID, irritability seizures, attention deficits. |
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MOA of Cocaine
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Cocaine is thought to induce birth defects by disrupting the vasculature in the placenta thereby inducing intrauterine hypoxia and malnutrition. More work needed in this area.
remember hypoxia |
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Alcohol
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In humans, these disorders are termed foetal alcohol syndrome (FAS), or foetal alcohol effect (FAE) if abnormalities are of lesser degree.
In the general population, the incidence of FAS has been estimated to be approximately 10-20 per 10,000 live births. The incidence of FAE is difficult to estimate, but ranges between 17 to 900 per 10,000 life births in the general population, therefore ethanol is the major human teratogen in Western Society (Department of Health and Human Services 1993). remember: major human teratogen in Western Society |
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acohols outcomes and pregenancy
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Outcome: The most obvious anomalies include craniofacial effects. The most devastating outcomes are severe intellectual and behavioral deficits. Learning and memory functions have been localized to the hippocampus and there is considerable evidence that this brain region is most sensitive to ethanol
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acohols MOA in pregnancy
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Mechanism: Precise mechanism is unknown. The structural and mental deficiencies are likely a consequence of altered brain structure and function. This is a very active area of research.
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nicotine and pregnancy
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Nicotine/Cigarettes: associated with low birth weight, premature birth, an increase in prenatal mortality
can induce CPY P450 enzymes in the placenta and fetus |
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Caffeine and pregnancy
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Caffeine: there is no evidence that caffeine is teratogenic.
There is some concern that caffeine may leads to behavioral effects that are not detectable in our current screens (controversial, and no evidence). Nonetheless, it is advisable to moderate intake during pregnancy. |
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what maternal conditions can affect the outcome of a pregnancy
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Disease
Maternal Infection (Viruses) Maternal Age |
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disease states that affect pregnancy
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Autoimmune disorders
Hypertension DM (if poorly controlled) Hypo/hyperthyroidism phenyketonuria (PKU) if left untreated |
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afftects of DM in pregnancy
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Congenital heart defects, neural tube defects, limb defects, vertebral anomalies, pregnancy loss
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afftects of DM in pregnancy
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Congenital heart defects, neural tube defects, limb defects, vertebral anomalies, pregnancy loss
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afftects of DM in pregnancy
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Congenital heart defects, neural tube defects, limb defects, vertebral anomalies, pregnancy loss
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affects of hyper/hypothyroidism in pregnancy
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Goiter, growth and developmental retardation
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affects of hyper/hypothyroidism in pregnancy
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Goiter, growth and developmental retardation
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affects of hyper/hypothyroidism in pregnancy
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Goiter, growth and developmental retardation
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affects of PKU in pregnancy
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Pregnancy loss, small brain, mental retardation, facial abnormalities, congenital heart defects
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affects of PKU in pregnancy
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Pregnancy loss, small brain, mental retardation, facial abnormalities, congenital heart defects
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affects of PKU in pregnancy
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Pregnancy loss, small brain, mental retardation, facial abnormalities, congenital heart defects
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affects of HTN in pregnancy
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Intrauterine growth retardation
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affects of autoimmune disorders and pregnancy
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Congenital heart block, pregnancy loss
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affects of HTN in pregnancy
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Intrauterine growth retardation
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affects of HTN in pregnancy
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Intrauterine growth retardation
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affects of autoimmune disorders and pregnancy
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Congenital heart block, pregnancy loss
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affects of autoimmune disorders and pregnancy
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Congenital heart block, pregnancy loss
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maternal infections and pregnancy
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Rubella virus (german measles)
Toxoplasmosis (a parasite that commonly affects cats) varicella (chicken pox) syphillis (microorganism) cytomegalovirus Herpes |
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affects of rubella and pregnancy
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Exposure in the 1st trimester: heart and blood vessel anomalies, small brain, hearing loss, eye defects (glaucoma and cataracts), post-natal growth delay
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afffects of toxoplasmosis and pregnancy
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Various brain defects, blindness, mental retardation
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affects of varicella and pregnancy
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Exposure in the first four months: skin scarring, limb reduction defects, muscle atrophy, mental retardation, rudimentary digits
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affects of syphillis and pregnancy
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Abnormal teeth and bones, mental retardation
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affects of cytomegalovirus and pregnancy
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Exposure in the first trimester: fatal to most embryos
Exposure later in pregnancy: growth and developmental retardation, small brain, hearing loss, occular abnormalities, cerebral palsy |
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affects of Herpes and pregnancy
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Pregnancy loss, growth retardation, eye abnormalities, transmission to infant most commonly occurs at delivery
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advanced age and pregnancy
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Increased Risk for Chromosomal Anomalies and increased risk for other malformations (ex. anencephaly)
> 35 |
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adolescent and pregnancy
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Reduced gestational weight, increased risk for malformations (ex. Anencephaly) and also increased infant mortality.
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toxoplasma
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Toxoplasma gondii is a protozoan parasite which is able to cross the placenta.
Fetal infection may result in hydrocephaly, microphthalmia, chorioretinitis, brain lesions and multiple organ damage and dysfunction. Twenty-five percent of reproductive age women have antibodies against toxoplasma yet fetal infection occurs only in 0.1% of all live births (approximately 1 in 4,000 pregnancies). |
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toxoplasma and time of exposure
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The severity of fetal damage directly relates to time of exposure to the teratogen.
If a mother is infected in the first trimester, 15-20% of infected fetuses acquire severe manifestations. Second trimester maternal infection yields 25-30% of infected newborns with severe malformation. Third trimester infection results in 60% of infected newborns with severe malformation, 90% of which will be asymptomatic at birth |
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DM II
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Insulin-dependent diabetes has been linked to multiple congenital malformations such as cardiac and skeletal malformations, central nervous system alterations, and caudal dysgenesis.
25% of all cases of hydramnios (excess amniotic fluid) are due to maternal diabetes. The risk of malformation is 3-4 times that of a normal pregnancy. |
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Controlled DM and pregnancy
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Diabetes controlled by insulin severely reduces the risk of congenital malformation.
Therapy should begin well before conception to ensure a normal fetus. Mammalian embryo is critically dependant upon maternal glucose levels. Even brief periods of decreased glucose concentrations are teratogenic |
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Common Drugs Initially Thought To Be Teratogenic - Now Safe
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diazepam
oral contraceptive spermicides salicylates bendectin |
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Bendectin
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Demonstrates the complexity of the social aspects of identifying a drug as a teratogen - if only transiently.
Once prescribed to alleviate morning sickness. It was estimated that at least 25% of all pregnant women were taking the drug. The vast majority of evidence supports the conclusion that this drug is nonteratogenic in humans. Controversy began with a single case report of a child born with limb reduction and the mother had used the drug |
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A famine
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A famine is a widespread shortage of food that may apply to any faunal species, which phenomenon is usually accompanied by regional malnutrition, starvation, epidemic, and increased mortality.
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Malnutrition and Development
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During the 20th century, an estimated 70 million people died from famines across the world, of whom an estimated 30 million died during the famine of 1958–61 in China.
The other most notable famines of the century included the 1942–1945 disaster in Bengal, famines in China in 1928 and 1942, and a sequence of famines in the Soviet Union, including the Holodomor, Stalin's famine inflicted on Ukraine in 1932–33. A few of the great famines of the late 20th century were: the Biafran famine in the 1960s, the disaster in Cambodia in the 1970s, the Ethiopian famine of 1983–85 and the North Korean famine of the 1990s |
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breastfeeding: The quantity of agent in the milk relative to the infant capacity to clear it.
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Pharmacokinetics of agent in milk
Maturity of the infant Health of Infant Quantity of milk consumed/day |
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Pharmacokinetics of agent in milk
Maturity of the infant Health of Infant Quantity of milk consumed/day |
The risk of dose related effects of the agent is determined by actual intake and the ability of the infant to absorb, detoxify and eliminate it. The sensitivity of the infant to the same exposure may vary with age and health. Premature infants may tolerate a given exposure differently, generally less well
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breastfeeding: Experience with use by nursing mothers
Demonstration of idiosyncratic effects on nursing in clinical use |
Clinical use can reveal unexpected or previously undocumented effects on nursing or the infant. For example, an agent that reduces milk flow may be perceived as causing infant “fussiness”.
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breastfeeding: Inherent toxicity and adverse effects profile of the agent
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Adverse effect of the agent on lactation
Severity of uncommon effects i.e.carcinogenicity Incidence of less severe adverse effects |
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Adverse effect of the agent on lactation
Severity of uncommon effects i.e.carcinogenicity Incidence of less severe adverse effects |
These factors require a value judgment about the risks of drug exposure at the estimated level relative to the known benefits of breastfeeding.
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breastfeeding: Existence of therapeutic alternatives
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Most agree that the safest therapeutic alternative for which there is reasonable amount of experience with use by nursing mother should be chosen. For example, the use of insulin rather than tolbutamide or chlorpropamide because insulin would not be present in the milk at high levels, and is not bioavailable through oral ingestion
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breastfeeding: Anticipated duration of breastfeeding
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Most physicians think of breastfeeding as the sole means of infant feeding until weaning and estimate risk on that basis. In many cases, breastfeeding constitutes only part of the infant diet or is planned as a short-term, emotionally meaningful experience. The acceptability of such shorter exposures may be higher.
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breastfeeding: Naiveté of the baby to exposure
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If an infant has been exposed to the same substance throughout gestation, the risk is very likely much lesser because the dose provided through milk is not a new risk.
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breastfeeding: Tolerance of the parents regarding unknown risks
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Certain families have an exceptionally low tolerance for risk for their child. The importance of the concerns or anxiety should not be overlooked. It often requires guidance and may be a major factor in deciding on the advisability of nursing.
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breastfeeding: Reliability of the parents for monitoring and reporting potential adverse effects
(methadone) |
Methadone-treated mothers , for example, may be motivated no to report apparent oversedation or withdrawal
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breastfeeding: Availability of pediatric follow-up
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If the parents prefer to avoid traditional medical care, the use of an agent that may require regular blood tests may be less acceptable.
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breastfeeding: Other factors that make nursing detrimental to maternal health
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For example, borderline nutritional status and high nutritional demands, as in a new mother with advanced cystic fibrosis. The risk of antibiotic medications present in the milk to the infant may be less than the risk of nursing to the mother, unless adequate supplementation can be ensured.
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agents to be avoided in pregnancy
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Cancer chemotherapy drugs,
--amethopterin, --cyclophosphamide, ---doxorubicin, ---methotrexate Androgens (e.g. testosterone) Cocaine Heroin Indomethacin Iodides Lead Marijuana Mercury Pesticides PCB PBB |
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Estimation of a infant's dose in breastmilk
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Concentration in milk] X [volume milk consumed]*
*(approximately 200 ml/kg/day) This value then can be compared to the recommended therapeutic and the toxic doses. |
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is the concentration in the infant of a drug the same as the mother
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The concentration of many drugs is similar in the mother's plasma and in the milk, but others are very different. An important value is the milk:plasma ratio.
Example: Cimetidine has a ratio of 7-12 (i.e. concentrated into milk). Mother is not recommended to nurse if taking this drug even though it is classified as a B drug. |
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The duration of the drug in the milk
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The time required to eliminate 90-95% of an agent (equally distributed in the plasma and milk) is 3-5 plasma elimination half-lives. This is only a general rule
Duration of time until selected agent falls below measurable milk concentrations or calculated to equal 3.3 milk elimination half-lives |
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is drug more difficult to eliminate from plasma or milk
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milk
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Bioavailability and breastfeeding
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Requirement for GI tract absorption. Therefore, some potent drugs in milk may pose little risk.
A point to consider when deciding the best drug for a condition. Example: Although not absorbed, cisplatin poses a local carcinogenic risk to the infant GI tract |
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the human challenge
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Manufacturers never test their products in pregnant women to determine fetal effects.
Lack of testing leads to significant fear "warning labels”. The public believes every drug has thalidomide-like effects Fewer than 30 drugs are known human teratogens. Regulation by labeling was not completely effective (accutane-isotretinoin). Every human teratogen is teratogenic in animal models (except misoprostol). |
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Testing Requirements for Drugs in pregnancy
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In 1966, the FDA published the Guidelines for Reproductive Studies for Safety Evaluation of Drugs for Human Use.
Segment I: Premating through mating in males Premating through implantation in females Segment II: Pregnant female, treatment during organogenesis Segment III: Pregnant female, treatment from end of organogenesisthrough lactation. Usually one rodent and one non-rodent species |
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omeprazole
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Significant differences in various countries, but harmonization of regulations are underway
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How Predictive Are Animal Models?
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Very predictive in general. Concordance is strongest when positive data exists from more than one species.
38 compounds demonstrated or suspected human developmental toxicants. All but tobramycin were positive in at least one other animal. 76 percent of them were positive in more than one. 85% were predictive in the mouse. 80% in the rat. 60% rabbits. 40% hamsters. |
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thalidomide and animal model predictability
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It is important to note that thalidomide teratogenicity was not easily picked up by the rat model.
Almost every drug since has been found to be teratogenic in humans has been shown to be teratogenic in at least one animal. Furthermore, high doses of other agents will cause teratogenic effects in animals, but therapeutic doses in humans have no effect |
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alternative testing
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Why do we need alternatives to the segment testing? Thousands of chemical with no know developmental toxicology data.
Some successful “alternative tests”. Three in vitro embryotoxicity tests. The rat embryo limb bud micromass assay. The mouse embryonic stem cell test. The rat embryo culture test. What’s the problem? Validation of the alternative tests is a problem |
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elelments of risk assesment
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The purpose of Risk assessment for noncancer endpoints is to define the dose, route, timing and duration of exposure which induces the effects at the lowest level in the most relevant laboratory animal.
The exposure associated with this critical critical effect is then modified by the use of “uncertainty factors”. One factor for interspecies extrapolation (10X) One factor for variability in the human population (10X) An agent that produces adverse developmental defects in animals will potentially pose a hazard to humans at some dose. All developmental toxicity endpoints death, malformations, growth alteration, functional deficits are of concern. Endpoints in animals and humans not necessarily the same. Use the most appropriate model if we have data, or use the most sensitive. A threshold is assumed for dose-response curve for reagents that produce developmental toxicity. |
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drugs to use for acne in pregnancy
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topical: erythromycin, clindamycin, benzoyl peroxide
alternative drugs: systemic erythromycin, topical tretinoin |
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Teratgenesis depends on the genotype of the conceptus and the manner in which it reacts with environmental factors
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Differences in genetic makeup lead to differences in responses by mother or conceptus
ex: Isotretinoin is highly teratogenic in humans, much less in mice (species differences). The same human mother can give birth to heteropaternal twins with very different drug syndrome effects |
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Susceptibility to teratogenic agents varies with developmental stage
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Preimplantation versus organogeneisis
ex: Thalidomide defects |
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The access of adverse environmental influences on developing tissue depends on the agent
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Pharmacokinetic characteristics of absorption, distribution, biotransformation and elimination influences the amount of agent that reaches the embryo or fetus
ex: The relative lesser susceptibility of mice than humans to isotretinoin may be related to metabolism |
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The final manifestation of abnormal development are death, malformations, growth retardation, and functional disorders
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The type of response is determined by the individual characteristics of the exposure, particularly dosage and timing, and by the organism’s susceptibility to it.
ex: A drug such as ethanol may cause growth retardation and malformations at moderate levels and fetal loss at higher concentrations |
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Teratogenic agents act in specific ways (mechanism)” to initiate abnormal embryogenesis
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The same defect may be produced by agents acting via different mechanisms. One agent can also lead to multiple defects by the same mechanism
ex: CNS cyst formation may occur as a result of anticoagulant-induced hemorrhage to hypoxic damage as a result of carbon monoxide poisoning. Phenytoin impairment of normal cell division can produce cleft palate and growth retardation |
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The manifestation of deviant development increases with increasing dose. From no-effect level to totally lethal
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The higher the dose, the more likely effect will be seen. A threshold dose exist below which defects are absent
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505 of acute liver failure is due to
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APAP
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CYP enzyme inducers
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rifampin
phenobarbital isoniazid phenytoin carbamazepine ethanol tobacco |
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ASA modified COX2
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`poduces lipoxins which ar eanti-inflammatory
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COX2 inhibitors that were withdrawn from the market
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Viox
Bextra |
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the leading cause of calls to poison control
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is APAP
>100,000 per year and accounts for more than 56,000 ER visits and 2,600 hospitalizations and an estimated 458 deaths due to acute liver failure |
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torcetrapid
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inhibits conversion of HDL--> LDL
i nphase 3 showed excessive all cause mortalityin patients taking atrovastatin |
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ADR
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adverse drug reaction is ranked the 4-6th leading cause of death in US in 94
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Deleterious (toxic effects) can be
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pharmacological (drug interactions)
genotoxic: (mutations, teratogens) pathological: effects tissue |
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selective toxicity
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a drug may affecyy a particular cell type because of uptake, metabolism or inherent properties of the cell
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absorption rate depends on
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lipid solubility (log p) and % ionization
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If GSH is depleted
|
the intermediate of APAP, N-acetyl-p-benzoquinone eimine interacts with DNA and proteins causing liver damage (acute)
|
|
|
3 types of free radicals
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cation
anion neutral |
|
|
Fenton reactions
|
need a metal to generate a free radical
ther is usally a balance of free radicals and anti-oxidants when there is an imbalance of (+) free radicals-->oxidative stress-->toxicity |
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|
the most reactive free radical
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OH
|
|
|
adriamycin and free radical damage
|
metabolism generates a hydroquinone that interacts with DNA causing toxicity
|
|
|
Redox cycling can damage DNA by
|
hydroxyl radicals reacting with sugar bacbone and breaking the DNA
ROS |
|
|
Lipid peroxidation
|
chain reaaction of free radicals with lipids
can generate many species of an aldehyde (an electrohlie) which can cause toxicty |
|
|
Consequeces of lipid peroxidation
|
chain reaction of polyunstaturate fatty acids (PUFA) and cholesterol
most reactive aldehyde generated= 4- hydroxynonenal aldehyde produced in highest concentration= malondialdehyde |
|
|
do you need GST for GSH
|
no they can be direct reactions either displacing or addition
|
|
|
through redox cycling a _______ is created
|
semiquinone that can damage proteins and DNA
|
|
|
Redox cycling generates
|
superoxide anion
perthydroxyl radical hydrogen peroxided and an OH radical all of which can cause lipid peroxidation |
|
|
NADPH regenerating systme
|
glucose 6-phosphate dehydrogenase
isocitrate dehydrogenase 6-phosphogluconate dehydrogenase malic enzyme |
|
|
enzymatic antioxidants
|
superoxidee disutase, catalase, glutathione peroxidase
GSH peroxidase/GSSG reducttase system |
|
|
what can the ration of GSSG and GSH tell us
|
it can be indicative of oxidative stress if GSSG is high
|
|
|
other antioxidants
|
bilirubin and biliverdin
beta carotene uric acid glutathione |
|
|
an ideal chealating agent should be
|
water soluble, resistent to metabolism, able to reach sites of metal storage
capable of forming non-toixc complexes with the metals have a low affinity for essential metals particularly Ca and Zinc |
|
|
tetracycline is a chelates with
|
Ca and Mg
|
|
|
what percentage of drugs are withdrawn becasue of hepatotoxicity
|
21%
|
|
|
what is the most important function of the liver
|
respiration
|
|
|
stellate cells
|
fat storage
|
|
|
types of drug induced liver toxicities are 1 of 2
|
predictable or idiosyncratic
|
|
|
can APAP cause kidney toxicity
|
yes, it is not due to the quinone emine
|
|
|
what is a proposed biomarker of liver toxity
|
ROS
|
|
|
the most effective treatment of APAP toxicity
|
NAC, it replenishes the levels of glutathione
|
|
|
APAP overdose impairs
|
beta oxidation through PPAR alpha the quinone emine blocks it
|
|
|
what drugs casue cholestatis
|
chlorpromazine, sulfonamides, sulfonylureas, erythromycin, captipril
|
|
|
what has long term estrogen therapy been implicated with
|
cholestatic jaundice
|
|
|
allergic hepititis
|
less common form of toxicity but more serious implications
both hepatocellular injury and cholestasis can occur |
|
|
covalent binding of the acitrve intermeidate of a drug can cause
|
injury=necrosis
haptan=antigen mutation=cancer |
|
|
Steatosis
|
fatty liver
|
|
|
normal liver-->
|
fatty liver--> fibrosis --> cirrhosis
|
|
|
characteristics of a liver with chronic injury
|
high density matrix in subendothelial space containing fibril--> forming collagen
activated lipocytes, which are proliferating fibrogenic and devoid of vitamin A loss of hepatocyte microvilli and sinusoidal fenestrations |
|
|
activated fat cell/stellate
|
proliferate
lose retinoid droplets and activate collagen production |
|
|
Methotrexate and cirrhosis
|
bioactivation of P450 enzymes causes fibrosis
decrease the dose decrease the risk of toxicity |
|
|
Vitamin A
|
usually stored in the space of disse and can cause significant fibrosis if taken for a periond of time
|
|
|
most common drugs that cause vascular disorders
|
pyrrolizidine alkaloids (azathioprine, comfrey), sex hormones
|
|
|
Process of drug approval (know #s)
|
phase 3 involves 3000 patients
IR are expected to occure in less than 1 in 10000 patients detecting a single drug IR would require testing of 30,000 patients many drugs complete phase 3 and are approved before IR is identified |
|
|
drugs recently removed from the market
|
bromfenec
troglitazone lumiracoxib permolin xielagatral trovafloxacin |
|
|
the kidney receives ____% of CO
|
25
|
|
|
kidney metabolic capacity
|
CYP 450 is predominantly in the cortex
GSH and related enzymes are in high concentration in the cortex Prostoglandin H synthatse in high in the medulla |
|
|
____% of patients in the ICU will develop drug induced ARF
|
15
|
|
|
acute interstitial nephritis is caused by
|
antibiotics: methicillin, sulphonamides, rifampicin
diuretics: thiazides, furosemide MISC: phenytoin, cimetidine, mefenamic acid |
|
|
drugs that commonly cause acute tubular necrosis
|
amionglycoside antiobiotics (to avoid give once daioly)
amphoterecin B APAP cisplatin (accumulates in the kidney--> selective toxicity) tetracycline cephlosporins |
|
|
how do you minimize kidney toxicity of cisplatin
|
vigorous hydration prior to therapy
|
|
|
how do you avoid kidney obstruction with methotrexate and acyclovir
|
give allupurinal
|
|
|
A teratogen
|
a agent that induces structural malformations
|
|
|
Teratogenesis, stems from
|
teras, meaning malformation or monstrosity
|
|
|
Developmental Toxicity:
|
Any structural or functional alteration, reversible or irreversible, caused by environmental insult, which interferes with homeostasis, normal growth, differentiation, development and or behavior.
Growth retardation Embryolethality Functional Impairment malformations |
|
|
Malformations-
|
teratogen either increases the frequency of spontaneous malformation, or they may induce rarely seen malformation.
|
|
|
Functional Impairment
|
For example behavior effects, with no obvious anatomical changes. Not well studied but potentially very important. These outcomes rarely screened in drug trials (requires postnatal studies).
|
|
|
What Controls the Developmental Process?
|
All cells carry essentially the same genetic information. Differences in gene expression distinguish cell types from one another.
Cell-cell interactions lead to differential gene expression. Differential gene expression leads to differences in cell fate. Key is that normal development depends on sequential programmed and locally signaling events. The cell-cell communications ultimately involve molecular and chemical interactions. Precise series of events are required to achieve a “normal and complete organism”. |
|
|
How Do Chemicals Produce Teratogenic Effects?
|
They disrupt the developmental program
|
|
|
Dose-effect relationship
|
Teratogenicity is governed by dose-effect relations, and the curve is often quite steep.
The dose response relationship determines whether or not an agent is teratogenic. All known teratogens have No Observed Adverse Effect Level (NOAEL). Teratogenic induction is a threshold, not a stochastic phenomenon. Frequency and severity of malformations increase with dose. Therefore, not all doses of a given teratogen are teratogenic, only doses sufficient to interfere with specific developmental events are. |
|
|
Frequency of dose is important.
|
Four injections of cortisone, each 0.625 mg for a total of 2.5 mg gives a higher incidence of cleft palate in mice than does a single dose of 2.5 mg.
|
|
|
Drug combinations and teratogenicty
|
In animal model syngerism or potentiation of malformation frequency has been observed between two drugs.
Example: Cyclophosphamide and fluoruracil given individually to rat produce 26 and 10 % offspring with malformations respectively. Given together at the same doses, produces 100 % malformations. So, synergism may be a significant concern. |
|
|
Changes in Pregnancy and ADME
|
Physiological changes.
Difficult to predict ADME of a drug which occurs as a result of pregnancy. We do know: Increased body mass (25% by term), increased body water by 7-8 liters, increased body fat by 21%. |
|
|
Absorption & Distribution (terogenic)
|
Oral: Decrease in GI motility and delayed stomach emptying. Therefore agents that are normally poorly absorbed from the stomach will tend to exhibit increased absorption.
Topical: May be enhanced since circulation to the skin in increased and the skin is thinner/softer. Distribution: Increased Vd in pregnancy because of the dramatic increase in maternal fatty and aqueous compartments. However, build up of fat and water in pregnancy is not uniform throughout gestation so Vd can vary considerably |
|
|
elimination and pregnancy
|
Elimination:
GFR is increased as much as two-fold in pregnancy. In general, renal excretion is more rapid. |
|
|
Fetal Exposure
|
Fetal circulation via umbilical vein, passes through fetal liver
Excretion < 20 weeks, fetal skin is very permeable therefore amniotic fluid has same composition as fetal extracellular fluid. Waste products are returned to maternal system via umbilical blood flow. > 20 weeks, skin is keratinized to form a barrier. Major route of excretion are via fetal urine, trachea and to some extent skin into amniotic fluid. Then can be swallowed by fetus, and waste products are returned to maternal circulation via umbilical blood flow. Therefore, primary route of excretion of fetal waste products is via maternal blood flow. |
|
|
Drug Transport Across Placental “Barrier”
|
The traditional view of the placenta as a barrier to drug transport is overrated. The issue is usually how fast molecules will cross rather than whether they’ll get across.
Drugs > MW 1000 DO NOT easily cross the placental membrane. Those less than <600 DO cross the placental membrane. Most chemical drugs have a MW of 250-400. Transport also depends on transport, charge, and lipophilicity. |
