Impact of Age on Pharmacology

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Chapter 5 Impact of Age on Pharmacology

There are four main stages of life, which have distinct characteristics with respect to the way that the body handles drugs: fetal, neonatal and infant, adult, and elderly. These differences are largely pharmacokinetic and reflect the averages in these populations. Note that variations among individuals within these populations also exist, and this topic will be addressed in the section on pharmacogenomics. The following summarizes the key considerations in the fetal, neonatal-infant, and elderly stages of life. The adult stage of life should be considered the reference with which all others are compared. The adult stage is considered normal, and the material covered in other sections of this textbook applies to that stage of life.

Fetus

A teratogen is defined as any agent that can cause malformations in a developing fetus.

The teratogenic effects of specific drugs are discussed throughout the drug chapters. The range of effects that a drug may have on the fetus spans from temporary effects after birth to death of the fetus, and everything in between.

The placenta separates the fetal and maternal circulations and is perfused by each. In addition to this and other important functions, the placenta serves as a protective barrier against the entry of drugs into the fetal circulation. However, despite this protective function, a number of drugs will still cross from the maternal to the fetal circulation. Several factors determine whether a drug will cross the placenta:

Lipid solubility

• As with other membranes, lipophilic drugs more readily cross the placenta. Even polar (hydrophilic) drugs can cross the placenta in small amounts, if their concentrations in the maternal circulation are high enough.

Size of drug

• The larger the drug, the less likely it is to cross the placenta. Therefore larger drugs, such as proteins, are less likely to cross. However, one cannot assume that large drugs will not cross, as the placenta does have transporters that facilitate the transport of bulkier molecules.

• These transporters are typically used to transfer nutrients from the mother to the fetus and allow the fetus to transfer waste products of metabolism to the mother. Some of these transporters also facilitate transport of drugs, and in some cases, drugs can also inhibit the actions of these endogenous transporters. Examples of important substrates are listed in Box 5-1.

Plasma protein binding

• Drugs bound to plasma proteins may not cross as readily, given the added bulk, but this can be offset by drugs that are highly lipophilic, as these agents still appear to be able to cross readily despite being bound to plasma proteins.

BOX 5-1 Drugs Transported across the Placenta

The placenta itself contains some drug-metabolizing enzymes, and these enzymes may also help to detoxify drugs or in some instances may actually increase the toxicity of certain drugs. However, the relative importance of these metabolizing enzymes of the placenta to other metabolizing enzymes of either the mother or even the fetus is considered to be relatively minor.

Once a drug crosses the placenta, it enters the fetal circulation, and approximately half of it will flow through the liver. Drugs that normally undergo hepatic metabolism may also be metabolized by the fetus. It should be noted, however, that the metabolic capacity of the fetus and neonate differs from that of children and adults. In the fetus these differences result not only from a deficiency of CYP450 and other enzymes but also from the fact that much of the portal blood flow bypasses the fetal liver via the ductus venosus for up to 20 weeks of gestation.

The risk of a drug causing harm to the fetus is categorized using the system in Table 5-1, which is largely based on the evidence (or, most commonly, lack of evidence) of harm.

Note that relatively few drugs are at the extreme ends of the spectrum (either safe or absolutely contraindicated); this is typically because of a lack of good evidence. It is understandably difficult to conduct controlled trials in this population.

The fact that most drugs fall in an intermediate area between safe and unsafe makes it difficult to decide whether a given drug should be used in pregnancy, and usually the decision depends on the risk-to-benefit assessment.

In some cases, not taking the medication may be more harmful to the pregnant patient (and fetus) than taking a medication with questionable risk.

• For example, many antiseizure medications are potential teratogens. However, withdrawing an antiseizure medication during pregnancy greatly increases the risk to the mother and the fetus.

TABLE 5-1 Risk Categories and Descriptions for Use of Drugs in Pregnancy

Risk Category	Description
A	Controlled studies in humans fail to demonstrate risk to the fetus in the first trimester or later trimesters, and the possibility of fetal harm appears remote.
B	Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of risk in later trimesters).
C	Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
D	There is positive evidence of human fetal risk, but the benefits in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
X	Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Timing of exposure is also important and is correlated with the stages of fetal development (Figure 5-1).

First 14 days: Typically this is all or none, meaning that exposure results in death of the embryo or has no effect. The common feature of these two extremes is that they go undetected; if the embryo dies the patient does not realize she was ever pregnant.

Days 14-60 (organogenesis): Exposure to teratogens at this stage may lead to death of the fetus or significant malformations affecting structure or function.

Day 61 onward: Exposure does not typically result in major structural malformations unless blood supply has been disrupted. However, from this point onward the major concern is fetotoxicity.

• Fetotoxins, rather than causing malformations, typically interfere with function of organs. Although this can have serious implications, including death, the one advantage of fetotoxicity is that it might be reversible in some cases. Malformations induced by teratogens are not reversible.

One example of fetotoxicity would be angiotensin-converting enzyme (ACE) inhibitors, which can cause renal failure in the fetus. This is because the fetus appears to be much more dependent on angiotensin II to maintain glomerular filtration.

Figure 5-1 Critical periods in human development. Red color indicates highly sensitive periods when teratogens may induce major anomalies.

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