Across life span

• Pregnancy


  • Physiologic changes that can alter drug disposition
  • Changes in the kidney, liver, and gastrointestinal (GI) tract are of particular interest
  • Compensatory change in dosage may be needed
• By the third trimester, renal blood flow is doubled


  Causes a large increase in the glomerular filtration rate
• Accelerated excretion


  Dosage must be increased
• Hepatic metabolism increases during pregnancy


  For some drugs
• Tone and motility of the bowel decrease in pregnancy


  Causes intestinal transit time to increase
• Prolonged transit


  More time for drugs to be absorbed
• More time for the reabsorption of drugs that undergo enterohepatic recirculation


  Possibly resulting in a prolongation of drug effects
• Reduction in dosage


  Might be needed
• Placental drug passage


  Determined by the same factors that determine drug passage across all other membranes
• Drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty
• For practical purposes, the provider should assume that any drug taken during pregnancy will reach the fetus
• Pregnant patients may suffer effects unique to pregnancy
• Effects unique to pregnancy

  • Heparin can cause osteoporosis and compression fractures of the spine
  • Prostaglandins (e.g., misoprostol) can cause abortion
  • Aspirin near term can suppress contractions in labor
  • Aspirin increases the risk for serious bleeding
• Drugs taken during pregnancy can adversely affect the patient as well as the fetus
• Regular use of dependence-producing drugs (e.g., heroin, barbiturates, alcohol) during pregnancy can result in the birth of a drug-dependent infant
• Teratogenesis


  To produce a monster
• Consistent with this derivation, we usually think of congenital anomalies in terms of gross malformations, such as cleft palate, clubfoot, and hydrocephalus
• Causes of congenital anomalies

  • Genetic predisposition
  • Environmental chemicals
  • Drugs
• Genetic factors account for about 25% of all congenital anomalies
• Down syndrome is the most common genetically based anomaly
• Less than 1% of all congenital anomalies are caused by drugs
• For most congenital anomalies, the cause is unknown
• Fetal sensitivity to teratogens


  • Changes during development
  • Effect of a teratogen is highly dependent on when the drug is given
• Stages of development


  • Preimplantation/presomite period (conception through week 2)
  • Embryonic period (weeks 3 through 8)
  • Fetal period (week 9 through term)
• Preimplantation/presomite period


  Teratogens act in an all-or-nothing fashion
• If the dose is sufficiently high, the result is death of the conceptus
• If the dose is sublethal, the conceptus is likely to recover fully
• Gross malformations are produced by exposure to teratogens during the embryonic period (roughly the first trimester)
• Teratogen exposure during the fetal period (i.e., the second and third trimesters) usually disrupts function rather than gross anatomy
• Human teratogens are extremely difficult to identify
• Reasons human teratogens are difficult to identify

  • The incidence of congenital anomalies is generally low
  • Animal tests may not be applicable to humans
  • Prolonged drug exposure may be required
  • Teratogenic effects may be delayed
  • Behavioral effects are difficult to document
  • Controlled experiments cannot 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 judgment
• Proof of teratogenicity does not mean that every exposure will result in a congenital anomaly
• Criteria to prove a drug is a teratogen

  • The drug must cause a characteristic set of malformations
  • The drug must act only during a specific window of vulnerability (e.g., weeks 4 through 7 of gestation)
  • The incidence of malformations should increase with increasing dosage and duration of exposure
• We cannot do experiments on humans to determine whether a drug meets these criteria
• Lack of teratogenicity in animals is not proof of safety in humans
• Pregnancy and Lactation Labeling Rule (PLLR)


  • FDA has done away with the lettering of the categories of drugs for pregnancy
  • Requires three sections for labeling: (1) pregnancy, (2) lactation, and (3) females and males of reproductive potential
• By 2020, all prescriptions must remove lettering labels altogether
• A first step in decreasing drug risk during pregnancy is to develop a comprehensive list of current drugs used
• If pregnancy status is unknown and a high-risk drug is recommended for management of a condition, a pregnancy test should be performed before prescribing