PHARM chapter 9
data
FDA plans to replace lettering category with detailed information about the effects of drugs during pregnancy -this section will give detailed evidence from human and animal studies regarding the information presented in the fetal risk summary.
clinical considerations
FDA plans to replace lettering category with detailed information about the effects of drugs during pregnancy this section will decribe the likley effects if a drug is taken before a woman knows she is pregnant. This section will also discuss the risks to the mother and fetus of the disease being treated along with dosing information and ways to deal with complications
Drug therapy during pregnancy
Common, about 2/3 of pregnant women take atleast 1 drug, majority takes more. -some used to treat pregnancy related conditions such as nausea, constipation, and preeclampsia. -some are used to treat chronis disorders such as hypertension, diabetes, and epilepsy. -some are used for infectious diseases or cancer. -some may abuse drugs such as alcohol, cocaine, and heroin presence of treatment must balance the risks. in pregnancy risks apply to fetus as well as mother. Unfortunately the risks for most drugs used in pregnancy have not been determined. health of fetus relies on health of the mother. hence conditions that threaten the mothers health must be addressed-for the sake of baby and mom.
drug therapy during breast-feeding
Drugs taken by lactating women can be excreted in breast milk. If drug concentrations in milk are high enough, a pharmacologic effect can occur in the infant, raising possibility of harm. very little systematic research has been done. Few drugs are said to be hazardous but the danger posed by many is still undetermined. Although all drugs can enter breastmilk, the extent of entry varies greatly. The factors that determine entry into breast milk are the same factors that that determine passage of drugs accross membranes.-- drugs that are lipid soluble enter breast milk readily, wheras drugs that are ionized, highly polar, or protein bound tend to be excluded. Most drugs can be detected in milk, but in concentrations are generally yoo low to be harmful. Hence breastfeeding is usually safe even though drugs are taken. prudence is always in order, if nursing mother can avoid drugs, she certainly should.
fetal risk summary
FDA plans to replace lettering category with detailed information about the effects of drugs during pregnancy -this section will describe what we know about drug effects on the fetus, and will offer a conclusion
FDA Pregnancy Risk Categories
The FDA established a system for classifying drugs according to their probable risks to the fetus. According to this system, drugs can be put into 5 categories: A, B, C, D, & X. Category A=least dangerous Category X=most dangerous, known to cuase fetal harm and their risk to the fetus outweighs any possible therapeutic benefits. Drugs is category B, C, & D are progressively more dangerous in drugs in category A an dless dangerous in category X. The law doesnt require classification of drugs before 1983 therefore many drugs arent classified.
Adverse reactions during pregnancy
drugs taken during pregnancy can adversely affect both mother and fetus. The effect of greatest concern is teratogenesis (production of birth defects). Not only are pregnant women subject to same adverse effects as everyone else, but they may also suffer effects unique to pregnancy. regular use of dependence-producing drugs (alcohol, heroin) during pregnancy can result in the birth of a drug-dependent infant. If an infant is not supplied with a drug that can support its dependence, a withdrawal syndrome will ensue.=shrill, crying, vomiting, and extreme irritability. The neonate should be weaned from dependence by giving progressively smaller doses of the drug of which he or she is dependent. Certain pain relievers used during delivery cna depress respiration in the neonate, the infant should be monitored closely until repsiration is normal.
placental drug transfer
essentially all drugs cross the placenta, although some cross more readily than others. The factors that determine drug passage across membranes of the placenta are the same factors that determine drug drug passage across all membranes.---drugs that are lipid soluble cross placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty. clinician should assume that any drug taken during pregnancy will reach the fetus.
identification of teratogens
for the following reasons, human teratogens are extremely difficult to identify: -The incidence of congenital anomalies is generally low -animal tests may not be applicable -prolonged exposure may be required -teratogenic effects may be delayed -behavioral effects are difficult to document -controlled expirements can't be done in humans Lack of proof of teratogenicity does not mean that a drug is safe, it only means that the available data are insufficient to make a definitive judgement Proof of teratogenicity does not mean that every exposure will result in a birth defect, most teratogens, the risk of malformation following exposure is only 10% to prove a drug to be a teratogen, these criteria must be met (1)-drug must cause a characteristic set fo malformations (2)-it must act only during a specific window of vulnerability (3)-the incidence of malformations should increase with increasing dosage and duration of exposure. *we cant do expirements in humans to see if a drug meets these criteria, the best we can do is systemically collect data and analyze data on drugs taken during pregnancy in hope that useful information on teratogenicity will be revealed. *lack of teratogenicity in animals is not proof of safety in humans.
teratogenesis
literally means to produce a monster. consistent with this deriviation, we usually think of birth defects in terms of gross malformations, such as cleft palate, clubfoot, and hydrocephalus. However birthdefects are not limited to distortions of gross anatomy, they also include neurobehavioral and metabolic anomalies.
physiologic changes during pregnancy
pregnancy brings on physiologic changes that can alter drug disposition. Changes in kidney, liver, and GI tract are of particular interest. Becuase of these changes a compensatory change in doasge may be needed. By 3rd trimester, renal blood flow is doubled, causing a large increase in glomerular filtration rate. As a result accelerated cleanance of drugs that are elimated by glomerular filtration. For some drugs hepatic metabolism increases during pregnancy. Tone and motility of the bowel decrease in pregnancy, causing intestinal transit time to increase. Because of prolonged transit, there is more time for drugs to be absorbed. Reduction of dosage may be needed.
gross malformations
produced by exposure to teratogens during embryonic period. This is the time when the basic shape of internal organs and other structures is being established. Hence it is not surprising that interference at this stage results in conspcious anatomic distortions. During preimplantation teratogens act in an "all-or-nothing" fashion. That is if dose is sufficiently high, the result is death of the conceptus. If dose is sublethal, the conceptus is liekly to fully recover. Becuase the fetus is especially vulnerable during the embryonic period, expectant mothers must take special care to avoid exposure to teratogens during this time. teratogen exposure during fetal period usually disrupts function rather than gross anatomy. Growth and development of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities.
minimizing risk of drug induced teratogenesis
the best way to minimize teratogenesis is to minimize use of drugs. If possible, pregnant women should avoid drugs entirely. At the least, unnessecary drugs drug use should be eliminated. Nurses and other health professionals should warn pregnant women against use of all nonessential drugs. As noted some disease states pose greater risk to fetal health than do drugs used for treatment. However even with these disorders, in which drug therapy reduces the risk of disease-induced fetal harm, we must still take steps to minimize harm from drugs. Accordingly, drugs pose a high risk of teratogenesis should be discontinued and safer alternatives substituted. Rarely a pregnant woman has a disease that requires use of drugs that have high probability of causing teratogenesis. Anticancer drugs is a big one. Woman should consider terminating the pregnancy then Reducing risk of teratogenesis also applies to patients who are not pregnant. Becuase 50% of pregnancies are unintended. Accordingly if a woman of reproductive age is taking a teratogenic medication, she should be educated about the teratogenic risk as well as the necessity of using at least one reliable form of birth control
incidence and causes of congenital anomalies
the incidence of major structural anomalies is between 1%-3%. half are obvious and reported at birth, the other half involve internal organs (heart, liver, GI tract) and are not dicovered until later in life or at autopsy. incidence of minor structural and functional abmnormalities is unknown. Congenital abnormalities have multiple causes, including genetic heritage, environmental chemicals, and drugs. -genetic factors account for %25 of all birthdefects (downsyndrome) -less than 1% caused by drugs -for majority, cause is unknown.
responding to teratogen exposure
when a pregnant woman has been exposed to a known teratogen, the first step is to determine exactly when the drug was taken and exactly when the pregnancy began. If drug exposure was not during the period of organogenesis (3-8wks) drug induced malformation is minimal. 3% of babies have some kind of conspicuous malformation independent of teratogen exposure. This is important because otherwise the drug is sure to be blamed if the baby is abnormal. if exposure did occur during organogenesis look up expected malformation. Atleast 2 ultrasounds should be done to assess the extent. If malformation is severe, termination of pregnancy should be considered. If minor, it may be correctable by surgery either shortly after birth or later in childhood.
minimize risk during breast-feeding
when drugs must be used, steps should be taken to minimize risk; -dosing immediatley after breast-feeding to minimize drug concentrations in milk at the next feeding -avoiding drugs that have a long half life -avoiding sustained release formulations -choosing drugs that tend to be excluded from milk -choosing drugs that are least likely to affect the infant -avoiding drugs that are known to be hazardous. -usuing lowest effective doage for the shortest possible time
