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.

Occasionally, drugs are actually targeted to the fetus. This is a growing area of research and therapeutics, but one of the early examples of this is the use of corticosteroids to facilitate lung maturation in fetuses that are expected to be born prematurely.

Neonates, Infants, and Children

Neonates, in particular, have several differences in their pharmacokinetics that may be of clinical significance. The neonatal period is typically defined as the time from birth to 4 weeks of age. The neonatal information that follows is typically for full-term births unless otherwise indicated. Preterm births require special considerations and will generally not be considered here.

Pharmacokinetics

Pharmacodynamics

Pharmacodynamic differences among neonates, infants, and adults have not been well studied. It is not known, for example, whether increased sensitivity to opioids in the newborn results from pharmacokinetic or pharmacodynamic differences or both.

Lactation

An important consideration when assessing the ability of neonates to eliminate drugs is exposure through breast milk. Data on the safety of drugs in breastfeeding mothers are generally inadequate, as are the data on pregnancy. Therefore it is important to understand some general principles about the passage of drugs from the mother into breast milk. These factors include the following:

Size of the drug molecule: Smaller drugs are able to cross into milk more easily.

Lipophilicity: The more lipophilic a drug, the more likely it is to pass into breast milk.

Percent of the drug ionized (based on pH of blood and milk): Breast milk has a lower pH than plasma; therefore alkaline drugs, once they reach the milk, become ionized and are trapped in the breast milk.

Extent of plasma protein binding: Drugs bound to plasma proteins are unable to cross membranes into the milk.

Elderly

The definition of elderly varies depending on the source but is often considered to be 65 years of age or older. It is also important to note the distinction between biologic and chronologic age. As the worldwide population ages, and with advances in preventative medicine, there will likely be an ever-widening biologic gap between patients of the same age, based on their lifestyle choices and genetics, among other considerations.

Pharmacokinetics

As with the very young, the impact of age on the very old is broken down here using the ADME system.

Absorption

Impaired GI motility and blood flow, both common effects of aging, will impair absorption to an extent. As with infants, the elderly tend to have a higher gastric pH, and this may affect absorption in a manner similar to that described earlier.

GI motility in general tends to be slowed, leading to delayed gastric emptying. This may reduce the rate of drug absorption, which may become clinically significant with drugs such as analgesics, in which delayed efficacy has an impact on the patient.

Distribution

Humans tend to dry out with age, so the elderly have a lower proportion of total body water than adults. Conversely, the elderly have a higher proportion of body fat. This means that hydrophilic drugs have a higher plasma concentration, and lipophilic drugs have a lower concentration, than in adults.

The elderly also tend to have lower albumin levels. However, they tend to have higher α1-acid glycoprotein levels, and the overall impact of plasma protein binding changes with age is not considered to be clinically significant in the healthy senior. However, in disease states, including liver failure, changes in plasma protein levels can be large enough to have clinical significance.

Metabolism

Compared with adults, the elderly have impaired hepatic metabolic function for some drugs. This is because of a combination of a reduction in liver mass, hepatic blood flow, and activity of phase 1 enzymes (Box 5-2). Drugs that are metabolized by phase 2 enzymes appear to be less affected by advancing age.

BOX 5-2 Drugs with an Age-related Decrease in Hepatic Metabolism

Excretion

Declining renal function is a consistent but not universal consequence of the aging process. In many patients this decline in renal function begins in the early 20s and is a continuous process throughout life.

It is important to note, however, that it appears that not all patients experience a clinically significant decline in renal function with age. Again, a distinction must be made between biologic and chronologic age.

As in infants, this reduced renal function will prolong the elimination half-life of drugs that rely on the kidney for their clearance.

Pharmacodynamics

The influence of advancing age on pharmacodynamics has not been as comprehensively studied, probably an indication of the much greater complexity and variety of receptors involved. Studies have suggested alterations in receptor density or in second messenger activity in the elderly. Some notable examples include the following:

Reduced cardiac β receptor activity. Although findings for receptor density have not been consistent, coupling of β₁ adrenoceptors to G proteins appears to be impaired with age. Remember from the introductory pharmacodynamics chapter that G proteins mediate the cellular actions of a receptor (Figure 5-3).

Benzodiazepines. Elderly people appear to be more sensitive to the central nervous system (CNS) effects of benzodiazepines, and although this has been attributed to pharmacokinetic changes with age, studies also suggest that the clinical impact of aging is greater than would be expected from changes in pharmacokinetics alone. It is therefore hypothesized that pharmacodynamic responses to these drugs may be altered.

Figure 5-3 G protein–coupled receptors.

Summary and Clinical Context

Perhaps the most important factors in determining the impact of age on drug efficacy and toxicity are polypharmacy, health of the patient, and adherence to therapy.

Elderly patients are far more likely to be taking multiple medications, predisposing them to drug interactions.

The elderly are far more likely to have kidney or liver disease, each of which would greatly accelerate the normal age-related reduction in the capacity of these organs to eliminate medications.

The elderly are also far more likely to have cognitive deficits and are more likely to live alone, both of which would increase the risk of nonadherence to drug regimens.

The combination of all these limitations has increased focus on the issue of appropriate prescribing in the elderly. Lists of inappropriate drugs used in elderly patients have been generated and updated by several groups. One of the early lists consisted of the Beers criteria; some examples of the most harmful drugs from this list are in Table 5-2.

TABLE 5-2 List of Drugs That Are Inappropriate for Elderly Patients (Beers Criteria)

Drug	Class	Description of Concern
Indomethacin	NSAID	CNS side effects worse than other NSAIDs
Methocarbamol Cyclobenzaprine

Muscle relaxants Anticholinergic side effects, sedation, weakness; questionable effectiveness Flurazepam BZD Extended elimination t_1/2 in elderly (days), leading to falls Amitriptyline TCA Strong anticholinergic and sedative BZDs BZDs Increased sensitivity to BZDs requires lower dosage

Chlordiazepoxide

Diazepam

BZDs Prolonged elimination t_1/2 and therefore prolonged sedation, increasing risk of falls Digoxin — Reduced renal clearance requires dosage adjustments

Dicyclomine

Hyoscyamine

Antispasmodics Anticholinergics with significant side effects

Antihistamines Anticholinergic side effects Barbiturates except phenobarbital — Cause more side effects than other sedatives or hypnotics in elderly Ticlopidine Antiplatelet No more effective than aspirin but much more toxic

Naproxen

Oxaprozin

Piroxicam

NSAIDs (longer t_1/2 full dose) Potential for GI bleeding, renal failure, hypertension, heart failure Fluoxetine (daily) SSRI Long elimination t_1/2; excess CNS stimulation, sleep disturbances, agitation

Bisacodyl

Cascara sagrada

Neoloid

Stimulant laxatives Long-term use may exacerbate bowel dysfunction Nitrofurantoin Antibiotic Potential for renal impairment Methyltestosterone Steroid Potential for prostatic hypertrophy and cardiac problems

BZD, Benzodiazepine; CNS, central nervous system; GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; t_1/2, half-life; TCA, tricyclic antidepressant.