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Principles of Drug Use in the Fetus and Neonate
Fetal Drug Disposition
The use of medications during pregnancy, prescription and over-the-counter, is a common and increasing occurrence. Multiple studies have demonstrated that approximately 90% of pregnant women take at least one medication during the pregnancy. The average number of medications used during pregnancy has increased by 68%, from 2.5-4.2, over the past 30 years, and the use of four or more medications has increased from 23%-50% of pregnant women. When interviewed, patients, physicians, and pharmacists all cite safety of the mother and fetus as a top priority when making decisions about medication use. Unfortunately, safety data for the vast majority of medications is limited.
Most of the drugs administered to the mother reach the fetus; the extent of fetal exposure depends on maternal drug disposition and placental drug transfer. The result of maternal drug disposition is the steady-state concentration of the drug in the maternal circulation, which ultimately determines the amount of the drug available for distribution to the fetal compartment. The steady-state concentration is impacted in varying degrees by maternal absorption, distribution, metabolism, and excretion of drug, all of which are altered during pregnancy.
Maternal Pharmacokinetics
Drug absorption is affected by a number of factors, including gastric emptying time and intestinal motility, which significantly change during pregnancy. Gastric emptying time is increased and intestinal motility is decreased during pregnancy. The result is a reduced rate of absorption of many medications with a potential increase in the extent of absorption due to the prolonged transit time through the intestinal tract. Intestinal metabolizing enzymes are also altered during pregnancy, which can result in either an increase or decrease in drug absorption. Together, these factors impact the oral bioavailability of a drug and ultimately the maternal steady-state concentration.
Steady-state concentration may also be altered by physiologic changes that occur during pregnancy and that influence drug distribution ( Tables 43.1 and 43.2 ). Maternal total body water, extracellular fluid, and plasma volume all increase gradually during pregnancy by about 32%, 36%, and 52%, respectively (see Table 43.2 ). Maternal cardiac output also increases by about 40%-50% as a result of increases in both heart rate and stroke volume. The increase in body water is the primary reason for the observed decreases in peak drug concentrations with standard dosing of water-soluble drugs. When the drug dose is kept constant in the presence of increasing body water, the drug's apparent volume of distribution (Vd) increases, and steady-state drug concentrations decrease. Such a decrease in steady-state concentrations may alter the therapeutic effect of the drug in the mother and influence the amount of drug available for diffusion across the placenta. Similarly, the increase in cardiac output affects drug transfer by limiting the time a drug resides in the villous space of the placenta and is available for transfer to the fetus.
TABLE 43.1
Influence of Pregnancy on the Physiologic Aspects of Drug Disposition
| Pharmacokinetic Parameter | Physiologic Change | Pharmacokinetic Impact |
|---|---|---|
| Absorption | ↑ Gastric emptying time ↓ Intestinal motility ↑ or ↓ Intestinal enzyme activity |
↓ Rate of absorption ↑ or ↓ or Unchanged extent of absorption |
| Distribution | ↑ Plasma volume ↑ Total body water ↑ Cardiac output ↑ Body fat ↓ Plasma proteins |
↑ Volume of distribution ↑ Free (active) drug fraction |
| Metabolism | ↑ or ↓ Hepatic enzyme activity (see Table 43.3 ) | ↑ or ↓ Hepatic clearance |
| Excretion | ↑ Renal blood flow ↑ Glomerular filtration rate ↑ Active renal transport |
↑ Renal clearance |
TABLE 43.2
Changes in Maternal Body Composition That Can Influence the Characteristics of Maternal Drug Distribution
Data from Mattison DR, et al. Physiologic adaptations to pregnancy: impact on pharmacokinetics. In: Yaffe SJ, et al, eds. Pediatric pharmacology: therapeutic principles in practice . Philadelphia: Saunders; 1992:81.
| Time of Gestation (wk) | Body Weight (kg) | Body Fat (%) | Plasma Volume (L) | Extracellular Fluid Volume (L) |
|---|---|---|---|---|
| 0 | 50.0 | 16.5 | 2.50 | 11 |
| 10 | 50.6 | 16.8 | 2.75 | 12 |
| 20 | 54.0 | 18.6 | 3.00 | 13 |
| 30 | 58.5 | 20.0 | 3.60 | 14 |
| 40 | 62.5 | 19.8 | 3.75 | 15 |
Coincident with the changes in body water distribution and cardiac output, the amount of maternal fat increases at a relatively constant proportion to the increase in body weight (see Table 43.2 ). The result is an increase in Vd for lipophilic drugs and the potential for accumulation within the adipose tissue. Minimal changes in drug efficacy are expected under these circumstances; however, the adipose tissue can act as a reservoir and slowly release the drug into systemic circulation. An increased half-life and prolonged drug effects may be observed.
Complicating the picture even further is the fluctuation in serum proteins during gestation. Both albumin and α 1 -acid glycoprotein are decreased during pregnancy, resulting in an increase in the free (active) fraction of various highly protein-bound drugs. For example, the free fraction of tacrolimus may increase as much as 91% during mid and late pregnancy. This unbound drug is not only the active moiety but is also the form that is available for metabolism and elimination by the mother and transfer to the fetus.
Changes in hepatic metabolism during pregnancy affect the normal rate and extent of drug transformation and ultimately renal elimination. During pregnancy, hepatic blood flow may increase, leading to increased drug metabolism in the liver; however, this is controversial. Less debated is the alteration in the activity of hepatic enzymes during pregnancy. Enzymes from the cytochrome P450 (CYP) family and those responsible for glucuronidation reactions (UGT) exhibit changes in activity as a result of pregnancy, which can potentially affect maternal and fetal drug exposure ( Table 43.3 ). For example, labetalol is a commonly used antihypertensive agent in pregnant women, and it is extensively metabolized by UGT enzymes that have increased activity during pregnancy. Therefore, as expected, the clearance of labetalol after oral administration is increased during the second and third trimester by as much as 30%, and the half-life is significantly shorter in the pregnant compared with nonpregnant patient. The consequence for the mother is an increase in total daily dose to maintain the same steady-state concentration and well-controlled blood pressure, which is critical for both mother and fetus.
TABLE 43.3
Pregnancy-Induced Effects on Metabolizing Enzymes
Modified from Anderson GD, Carr DB. Effect of pregnancy on the pharmacokinetics of antihypertensive drugs. Clin Pharmacokinet. 2009;48:161.
| Enzyme | First Trimester | Second Trimester | Third Trimester | Drugs Impacted |
|---|---|---|---|---|
| CYP1A2 | Decreased 33% | Decreased 50% | Decreased 65% | Caffeine |
| CYP2A6 | No data | Increased 54% | Increased 54% | Nicotine |
| CYP2C9 | No change | No change | Increased 20% | Phenytoin |
| CYP2D6 | No data | No data | Increased 50% | Dextromethorphan, fluoxetine |
| CYP3A4 | No data | No data | Increased 50%-100% | Nifedipine, protease inhibitors |
| UGT1A4 | Increased 200% | Increased 200% | Increased 300% | Lamotrigine |
| UGT2B7 | No data | No data | Increased 50%-200% | Digoxin, enoxaparin |
Alterations in renal elimination during pregnancy also impact mother and fetus. These changes result from the increase in renal blood flow by 10%-40% and the increase in glomerular filtration rate by about 40%. As a result, there is enhanced elimination of drugs typically excreted unchanged in the urine (e.g., penicillin, digoxin). Active renal transporters (OCT2, P-gp, OAT1) also exhibit increased activity during pregnancy, further enhancing elimination of some medications (metformin, digoxin). The net result is a lower steady-state concentration that may or may not be clinically significant for the mother but will likely result in less drug exposure to the fetus.
Placental Handling of Drug
In addition to maternal pharmacokinetics, the placenta also plays a major role in determining fetal drug exposure. From the fourth week of gestation until term, the surface area of the placenta increases dramatically to accommodate the increasing needs of the maturing fetus. The surface area of the villi, which represents the real area for exchange, is about 3.4 m 2 at 28 weeks’ gestation, compared with about 12.6 m 2 at term. In contrast, the thickness of the placental membrane decreases with advancing gestation. During late gestation (about 32 weeks), the tissue barrier separating the maternal and fetal circulations may be less than 2 mm, and the areas become specialized in the transport functions of the placenta (i.e., rapid diffusion of substances) rather than the metabolic ones. By term, the placenta has only a single cell layer of fetal chorionic tissue separating the fetal capillary endothelium from the maternal blood. This separation, with its loose intercellular connections, presents little hindrance to small molecule transfer. Both the decreasing membrane thickness and increasing surface area with advancing gestation favor the greater transfer of drugs as gestation progresses.
Very little specific information defines the mechanisms of the processes and extent of drug transfer across the placenta. A number of interdependent variables influence the rate and extent of drug transfer across the placenta from the maternal to the fetal compartment. Most investigators and clinicians believe that the vast majority of compounds found in the maternal circulation will cross the placenta and enter the fetal compartment. Therefore, the fundamental questions are about the rate and extent of this activity. Unfortunately, even today this information is only partially available for just a few chemical entities. Similarly, the mechanisms by which drugs are transferred across the placenta are not always clear, and more than one type of transfer may be involved.
The possible modes of drug transfer across the placenta are listed in order of importance in Box 43.1 . For most drugs and other compounds, it is presumed that the primary mode of transfer is by simple, passive, nonionic diffusion, which requires no energy. Pinocytosis and phagocytosis require energy and likely occur much too slowly to have any significant impact on drug transfer, whereas facilitated and active transport play a role for some drugs.
Box 43.1
Mechanisms of Drug Transfer across the Human Placenta
Corticosteroids are an example of a drug class that undergoes facilitated diffusion. No energy is required to transfer steroids across the placenta, but the steroid must form a complex with a specific carrier on the placenta to be transferred from maternal to fetal circulation. Active transport occurs in a similar way, but energy is required for active transport to take place. Metformin is thought to undergo active transport via the placental OCT3 transporter, resulting in fetal concentrations that are 70% to greater than 100% of maternal concentrations. Another important aspect of active transport involves the efflux of drugs back to maternal circulation subsequent to binding with a carrier on the placenta. Digoxin is one such drug that binds to the carrier protein P-gp. P-gp is expressed on the maternal side of the placental-trophoblastic layer, where it mediates active efflux from the fetal compartment. This efflux is unidirectional from the fetal to maternal circulation and is probably responsible for the removal of a number of highly lipid-soluble compounds and drugs from the fetal compartment. As stated, most drugs are transported across the placenta by simple diffusion, and the factors that influence this process have been more extensively evaluated than those affecting the other transport mechanisms discussed. Simple diffusion is described by the Fick equation as follows:
where K is the diffusion constant of the drug, which is dependent on the drug's physicochemical characteristics; A is the surface area of the membrane to be traversed; Cm and Cf are the concentrations of the drug in maternal and fetal blood, respectively; and d is the thickness of the membrane to be traversed. Thus, C m − C f represents the concentration gradient across the placenta, which is primarily regulated by the surface area (A) and thickness (d) of the placenta. As previously mentioned, changes in these characteristics as pregnancy progresses allow for easier transfer of drugs from maternal to fetal circulation.
The important physicochemical characteristics that influence passive drug transfer across membranes (i.e., placenta), as represented by K in the Fick equation, are outlined in Box 43.2 . The characteristics that facilitate placental transfer include high lipid solubility, the un-ionized form under physiologic and pathophysiologic conditions, low molecular weight (<500 daltons), and low protein binding. Very few clinically important drugs meet all these “ideal” characteristics, which explains the high degree of variability reported in various studies of placental transfer.
Box 43.2
Physicochemical Factors That Influence the Transfer of Compounds across the Human Placenta
Degree of Lipid Solubility
-
Lipid soluble favored over water soluble.
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