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:

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.

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).

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