For many patients the average dose range for a given drug can be toxic. The purpose of this section is to describe vulnerable patient populations for which special dosing considerations must be made to protect the patient and improve clinical outcomes.
The Pediatric Patient
Most drugs prescribed to children are not approved by the Food and Drug Administration (FDA) for use in pediatric populations. This does not mean it’s wrong to prescribe these drugs to children, rather it means that the medications were not tested in children. The lack of pediatric drug information can result in patient harm or death, such as what occurred with the drug chloramphenicol. When given to very young children, chloramphenicol caused toxicity and multiple deaths. Referred to as "gray baby syndrome," this toxic reaction was eventually found to be dose dependent. The FDA now requires that new drugs that may be used in children include information for safe pediatric use.
The main reason for adjusting doses in pediatric patients is body size, which is measured by body weight or body surface area (BSA). Weight-based pediatric drug doses are expressed in number of milligrams per kilogram of body weight (mg/kg) while doses calculated on BSA are expressed in number of milligrams per meter squared (mg/m2). BSA is determined using a BSA nomogram or calculated by using formulas (Formulas Helpful for Calculating Doses ).
The neonate and the premature infant require additional adjustments secondary to immature function of body systems. For example, absorption may be incomplete or altered due to differences in gastric pH or motility. Distribution may be altered because of varying amounts of total body water, and metabolism and excretion can be delayed due to immature liver and kidney function. Furthermore, rapid weight changes and progressive maturation of hepatic and renal function require frequent monitoring and careful dose adjustments. Gestational age, as well as weight, may be needed to properly dose some drugs in the neonate.
The Older Adult Patient
Absorption, distribution, metabolism, and excretion are altered in adults over 65 years of age, putting the older patient at risk for toxic reactions. Pharmacokinetic properties in older adults are affected by (1) diminished gastrointestinal (GI) motility and blood flow, which delays absorption; (2) changes in ratios of percentage of body fat, lean muscle mass, and total body water, which alter distribution; (3) decreased plasma proteins, especially in the malnourished patient, which alters distribution by allowing a larger proportion of free or unbound drug to circulate and exert effects; (4) diminished hepatic function, which slows metabolism; and (5) diminished renal function, which delays excretion.
Older adults should be prescribed the lowest effective dose at the initiation of therapy, followed by careful titration of doses. Monitor carefully for signs and symptoms of adverse drug reactions.
Another concern is that many older adult patients are prescribed multiple drugs and are at risk for polypharmacy. As the number of medications a patient takes increases, so does the risk for an adverse drug reaction. One drug may negate or potentiate the effects of another drug (drug-drug interaction). This situation is compounded by concurrent use of nonprescription or over-the-counter (OTC) drugs, herbal supplements, and vitamins. In general, doses of most medications (especially digoxin, sedative/hypnotics, anticoagulants, nonsteroidal anti-inflammatory agents, antibiotics, and antihypertensives) should be decreased in the older adult population. The Beers List/Criteria, which appears in the Medication Safety Tools section, is a list of drugs to be used with caution in older adults.
Females of Reproductive Potential
Generally, pregnant women should avoid medications, except when necessary. Both the mother and the fetus must be considered. The placenta is a membrane which allows rapid and complete diffusion of lipid soluble drugs and protects the fetus only from extremely large molecules. The fetus is particularly vulnerable during the first and the last trimesters of pregnancy. During the first trimester, vital organs are forming, and ingestion of teratogenic drugs may lead to fetal malformation or miscarriage. Unfortunately, this is the time when a woman is least likely to know that she is pregnant. In the third trimester, drugs administered to the mother and transferred to the fetus may not be safely metabolized and excreted by the fetus. This is especially true of drugs administered near term. After the infant is delivered, he or she no longer has the placenta to help with drug excretion, and drugs administered before delivery may result in toxicity.
Of course, many conditions, such as asthma, diabetes, gastrointestinal disorders, and mental illness affect pregnant women and require long-term medication use. When the medications are used, whether over-the-counter or prescription, prescribing the lowest effective dose for the shortest period of time necessary is the rule. The Centers for Disease Control and Prevention (CDC) has a variety of resources and treatment guidelines called Treating for Two: Medicine and Pregnancy. The Web address is https://www.cdc.gov/pregnancy/meds/treatingfortwo/.
The possibility of a medication altering sperm quality and quantity in a potential father is also an area of concern. Male patients should be informed of this risk when taking any medications known to have this potential.
Renal Impairment
The kidneys are the major organ of drug elimination. Failure to account for decreased renal function is a preventable source of adverse drug reactions. Renal function is measured by the creatinine clearance (CCr), which can be approximated in the absence of a 24-hour urine collection (Formulas Helpful for Calculating Doses ). In addition, doses in patients with renal impairment can be optimized by measuring blood levels of certain drugs (e.g., digoxin, aminoglycosides).
Patients with underlying renal impairment, premature infants with immature renal function, and older adults with an age-related decrease in renal function require careful dose adjustments. Renal function may fluctuate over time and should be reassessed periodically.
Hepatic Impairment
The liver is the major organ of drug metabolism. The cytochrome P-450 (CYP450) system changes a drug from a relatively fat-soluble compound to a more water-soluble substance, which means that the drug can then be excreted by the kidneys. Liver function is not as easily quantified as renal function, and it therefore is difficult to predict the correct dose for a patient with hepatic impairment based on laboratory tests.
A patient who is severely jaundiced or who has very low serum proteins (particularly albumin) can be expected to have some problems metabolizing drugs. In advanced liver disease, portal vascular congestion also impairs drug absorption. Examples of drugs that should be carefully dosed in patients with hepatic impairment include theophylline, diuretics, phenytoin, and sedatives. Some drugs (e.g., enalapril, carisoprodol) must be activated in the liver to exert their effect and are known as prodrugs. In patients with hepatic impairment, these drugs may not be converted to the active component, thereby resulting in decreased efficacy.
Heart failure results in passive congestion of blood vessels in the gastrointestinal tract, which impairs drug absorption. Heart failure also slows drug delivery to the liver, delaying metabolism. Renal function is frequently compromised, adding to delayed elimination and prolonged drug action. Doses of drugs metabolized mainly by the liver or excreted mainly by the kidneys should be decreased in patients with chronic heart failure.
Body Size
Drug dosing is often based on total body weight. However, some drugs selectively penetrate fatty tissues. If the drug does not penetrate fatty tissues (e.g., digoxin, gentamicin), doses for the obese patient should be determined by ideal body weight or estimated lean body mass. Ideal body weight may be determined from tables of optimal weights or may be estimated using formulas for lean body mass when the patient's height and weight are known (Formulas Helpful for Calculating Doses ). If such adjustments are not made, considerable toxicity can result.
Body size is also a factor in patients who are grossly underweight. Older adults, chronic alcoholics, patients with acquired immune deficiency, and patients who are terminally ill from cancer or other debilitating illnesses need careful attention to dosing. Patients who have had a limb amputated also need to have this change in body size considered.
Drug Interactions
Use of multiple drugs, especially those known to interact with other drugs, may necessitate dose adjustments. Drugs highly bound to plasma proteins, such as warfarin and phenytoin, may be displaced by other highly protein-bound drugs. When this phenomenon occurs, the drug that has been displaced exhibits an increase in its activity because the free or unbound drug is thus available to be active.
Some drugs decrease the liver’s ability to metabolize other drugs by inhibiting the CYP450 system. Drugs capable of doing this include cimetidine and ketoconazole. Co-administered drugs that are also highly metabolized by the liver may need to be administered in decreased doses. Other agents such as phenobarbital, other barbiturates, and rifampin can stimulate the liver to metabolize drugs more rapidly by inducing the CYP450 system, requiring larger doses to be administered. Co-administered drugs that are also highly metabolized by the liver may need to be administered in higher doses.
Drugs that significantly alter urine pH can affect excretion of drugs for which the excretory process is pH dependent. Alkalinizing the urine will hasten the excretion of acidic drugs. An example of this is administering sodium bicarbonate in cases of aspirin overdose to promote the renal excretion of aspirin. Alkalinizing the urine will increase reabsorption of alkaline drugs, which prolongs and enhances drug action. Acidification of the urine will hasten the excretion of alkaline drugs. Acidification of the urine will also enhance reabsorption of acidic drugs, prolonging and enhancing drug action.
Some drugs compete for enzyme systems with other drugs. Allopurinol inhibits the enzyme involved in uric acid production, but it also inhibits metabolism (inactivation) of 6-mercaptopurine, greatly increasing its toxicity. The dose of mercaptopurine needs to be significantly reduced when co-administered with allopurinol.
The same potential for interactions exists for some foods. Dietary calcium, found in high concentrations in dairy products, combines with tetracycline or fluoroquinolones and prevents their absorption. Foods high in pyridoxine (vitamin B6) can negate the anti-Parkinsonian effect of levodopa. Grapefruit juice inhibits the enzyme that breaks down some drugs, and concurrent ingestion may significantly increase drug levels and the risk for toxicity.
Many commonly taken natural products interact with pharmaceutical drugs. St. John’s wort, garlic, ephedra, and other natural products can interact with medications and cause known or unpredictable reactions.
Nurses and prescribers should consult drug references and remember that the average dosing range for drugs is intended for an average patient. Every patient is an individual with specific drug-handling capabilities. Taking these special dosing considerations into account allows for an individualized drug regimen that promotes the desired therapeutic outcome and minimizes the risk of toxicity.