Dermatological Drug Dosage in the Elderly

A. Flammiger and H. Maibach, MD
University of California at San Francisco, San Francisco, USA

ABSTRACT

The elderly population is increasing and drug dosing requires special considerations for efficacy and decreasing toxicity. This overview provides algorithms for adjusting drug and dosage based on current evidence-based knowledge with emphasis on drugs prescribed in dermatological practice.

Key Words: elderly, drug dosing, dermatological drugs

The proportion of elderly people in the general population continues to grow rapidly¹ and dermatological diseases are common in this group,² making drug dosage and administration particularly important. Furthermore, the elderly are vulnerable to adverse drug reactions (ADRs).³ Some dermatological drugs, such as methotrexate (MTX), may result in serious toxic effects in the elderly if the dosage is not reduced.⁴ Evaluating the factors that could influence drug pharmacokinetics and pharmacodynamics is worthwhile in order to improve drug treatment in this population.

Adverse Drug Reactions in the Elderly

Anti-Infective Agents

Infections are a common problem among the elderly, and anti-infective agents are frequently prescribed to them.⁵ In elderly patients, ADRs, as well as drug interactions, should be considered when selecting an anti-infective regimen. Common drug interactions with anti-infective agents involve macrolide antibacterials and fluoroquinolones.⁶

Erythromycin and troleandomycin are strong inhibitors of the cytochrome P450 enzyme CYP3A4, and may therefore be responsible for toxicity of coadministered drugs by decreasing their clearance (Table I).⁶ Example substrates of CYP3A4 include benzodiazepines, calcium channel antagonists, immunosuppressive agents (e.g., cyclosporin, tacrolimus [Protopic^®, Astellas]), and anticoagulants.⁷ Elderly patients receiving macrolides should be monitored for adverse events resulting from drug interactions.

Fluoroquinolones are antibacterials that are frequently used in infections affecting the elderly.⁸ One of the most important drug interactions of fluoroquinolones is the ability of ciprofloxacin (Cipro^®, Bayer) and enoxacin to inhibit the metabolism of theophylline by CYP1A2, resulting in theophylline accumulation and toxicity.⁶ Seizures may occur at therapeutic theophylline levels as a result of its additive effects on the central nervous system (CNS).⁶

Corticosteroids

Corticosteroids have adverse effects on many organ systems,⁹ ranging from those that are not necessarily serious (e.g., Cushingoid appearance), to those that are life-threatening (e.g., serious infections). Some of these adverse effects may be aggravated in the elderly. Patients receiving prednisolone 5–40mg/day for at least 1 year had a partial loss of explicit memory, and elderly patients may be more susceptible to memory impairment with less protracted treatment (Table 1).¹⁰ The risk of developing diabetes mellitus more than doubles in elderly patients who are newly initiated on oral corticosteroid therapy.¹¹

A higher risk for peptic ulcer disease was reported in corticosteroid users who were receiving nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently (Table 1).¹² Those receiving NSAIDs and corticosteroids showed a risk for peptic ulcer disease 15 times greater than that of nonusers of either drug.¹²

Antihistamines

Elderly persons treated with first-generation histamine H1 receptor antagonists (antihistamines) may be at greater risk of adverse effects involving the CNS, such as sedation or impaired cognitive function.¹³

Diphenhydramine administration in hospitalized patients =70 years of age was associated with a higher risk of cognitive decline compared with nonexposed patients (Table 1).¹⁴ These findings strongly suggest caution when prescribing this drug to the elderly. Reports by Mann, et al. of sedation with second-generation antihistamines loratadine, cetirizine (Zyrtek^®, Pfizer), fexofenadine (Allegra^®, sanofi-aventis) and acrivastine (Sempra^®, GlaxoSmithKline) were infrequent, but this study did not focus on the elderly. Affrime et al.¹⁵ studied pharmacokinetics and adverse events of desloratadine (Aerius^®, Schering) in different age groups and suggested that no dosage adjustment of desloratadine is required in the elderly.

Immunobiological Agents

Three immunobiological agents have been approved by the US FDA for the treatment of moderate-to-severe psoriasis: alefacept (Amevive^®, Astellas), efalizumab (Raptiva^®, Genentech), and etanercept (Enbrel^®, Amgen Wyeth).¹⁶ A recent study found alefacept to be well tolerated and effective in elderly, obese, and diabetic patients with moderate-to-severe plaque psoriasis.¹⁷ Accidental injury, headache, and pharyngitis were among the most common adverse events. Infections were primarily colds, with no opportunistic infections being reported. In psoriatic patients =65 years of age treated with efalizumab, the overall rates of adverse events were comparable to those seen in patients < 65 years of age, although a higher rate of serious adverse events was observed in the older group.¹⁸

A recent study evaluated the safety profile of etanercept in patients with chronic, moderate-to-severe plaque psoriasis.19 Pooled safety results from the first 12 weeks of treatment suggest that short-term etanercept treatment is generally safe and well tolerated. No overall differences in safety were observed between older and younger patients.

Changes in Pharmacokinetics

Absorption

There appear to be no major alterations in intestinal drug absorption in the elderly.²⁰ However, percutaneous absorption of hydrocortisone, benzoic acid, acetylsalicylic acid, and caffeine was significantly lower in the elderly when compared with younger subjects, whereas absorption of testosterone and estradiol was not.²¹ These results suggest that aging can affect percutaneous drug absorption and that relatively hydrophilic compounds are particularly sensitive.

Physiological age-related changes in the skin may impair percutaneous drug absorption (see Table 2).²¹ The diminished lipid content of aged skin implies a diminished dissolution for percutaneous administered drugs, and the reduced water content may make aged skin less attractive to more hydrophilic compounds. Furthermore, comprised microcirculation may lead to poorer absorption capability.

Distribution

Changes in body composition in the elderly may lead to altered drug distribution. Lean body mass and total body water decrease with age, whereas fat as a percentage of body weight increases with age.^22,23 As a result, the volume of distribution is lower for hydrophilic drugs leading to potentially higher plasma concentrations. In contrast, the volume of distribution is higher for lipophilic drugs, often resulting in retention and prolonged half-life, as shown for hydroxyzine.24 When considering volume of distribution, elderly patients may have significantly reduced body weight,²⁵ which is a major risk factor for overmedication.²⁶

Drugs may be bound to plasma proteins with only the free fraction being pharmacologically active. The two plasma proteins to which drugs can bind are albumin and á-1-acid glycoprotein, and these may change with age.²⁷ Albumin levels tend to decrease with advancing age, whereas á-1-acid glycoprotein may increase.^28,29 Thus, the ratio of bound to free drug may be altered. However, the extent to which these changes in plasma protein binding are clinically relevant is controversial. Changes of >50% in the free fraction were documented for only a few drugs, such as naproxen, salicylates, and valproic acid,30 and greater drug elimination may counterbalance the increase in free drug concentration.³¹

Elimination

Decreased renal function can result in prolongation of the half-life of many drugs, which can accumulate to toxic levels if the dosage is not reduced.³² Thus, to avoid excessive drug dosing, renal function assessment is essential in elderly patients, especially when prescribing drugs with a low therapeutic index, such as MTX,³³ which is mainly eliminated by the kidney.³⁴ Studies have described a significant increase in its half-life in patients with impaired renal function, as defined by creatinine clearance (CLcr).^35,36 Patients with renal impairment have a higher overall rate of toxicity and are at higher risk of severe and respiratory toxicities than those with normal CLcr.⁴

Like MTX, the second generation antihistamine cetirizine is predominantly eliminated unchanged in the urine.³⁷ In elderly subjects with impaired renal function, the elimination half-life of cetirizine was significantly prolonged (i.e., an increase of 159% in patients with a mean CLcr of approximately 44mL/min) and apparent total body clearance was significantly reduced by 64%.³⁸ Therefore, Kaliner suggested that cetirizine dosage be reduced by 50% in patients with renal disease.¹³ Prescribing the second generation antihistamine fexofenadine may be considered in this setting, as the pharmacokinetics of fexofenadine are not affected by decreased renal function.³⁹

Renal function generally declines with age. Specifically, renal blood flow is reduced and tubular function is impaired, thus reducing the kidney’s ability to maintain homeostasis under stressful conditions.⁴⁰ The glomerular filtration rate (GFR), measured by creatinine clearance (CLcr), declines by approximately 30% between 30–80 years of age in about two thirds of the population.^41,42 It is important to remember, however, that CLcr provides only a rough estimate of the GFR because creatinine is also secreted in small amounts by the kidney.⁴³

CLcr can be estimated utilizing the Cockcroft and Gault equation44 by correcting the serum creatinine for age, sex, and weight:

Using this equation is probably the easiest way to estimate a patient’s renal function. However, CLcr estimated using this method can significantly differ from true CLcr, particularly in elderly patients.⁴⁵ Moreover, their serum creatinine might be lower because of lower muscle mass, and as a result, it might not rise significantly even when renal function is significantly impaired.⁴¹ This could lead to an overestimation of CLcr as has been shown by Goldberg and Finkelstein ⁴⁵.

CLcr measurement should be performed; however, even with this test, unreliable results are possible. Urine collection by patients might be incomplete, perhaps because of a forgotten urine specimen,⁴⁵ and CLcr might exceed the true GFR. An EDTA clearance or insulin clearance test should be performed, if available, because it provides a more accurate assessment of renal function.³³

Degrees of renal impairment can be classified as mild (GFR 20–50mL/min), moderate (GFR 10–19mL/min), or severe (GFR < 9mL/min) and therapeutic drug levels may be maintained either by reducing the dose, by increasing the interval between doses, or by doing both.³³

Metabolism

The hepatic clearance of many drugs is lower in the elderly, mainly because of a reduction in liver size of approximately 20%–40%⁴⁶ and a reduction in liver blood flow.⁴⁷ Drug metabolism proceeds via Phase I and Phase II reactions. While there may be changes in Phase I reactions with aging,48 Phase II reactions seem to be less affected.⁴⁹

Hepatic drug metabolism in the elderly is a controversial matter. Sotaniemi, et al.⁴⁸ showed a reduction of CYP-P450-linked drug metabolism by approximately 30% after 70 years of age in an investigation of CYP-P450 content and microsomal enzyme activity in the human liver. Conversely, other studies found no significant age-related differences in the activities and contents of human liver microsomal enzymes.^50,51

Drug-induced liver disease seems to occur more frequently in the elderly.⁵² For example, isoniazid-induced hepatitis, which is uncommon in younger age groups, occurred in approximately 2% of persons =50 years of age.⁵³ No studies have been published that evaluate whether elderly patients are more susceptible to potentially hepatotoxic drugs used in dermatological practice. However, caution may be indicated for this group.

Several commonly prescribed dermatological drugs, such as MTX, can potentially cause liver damage,⁵⁴ and the age at onset of therapy has been shown to be one risk factor.⁵⁵ Close attention should be paid to the recommendations for monitoring elderly patients taking MTX.

Itraconazole (Sporanox^®, Janssen Pharmaceutica) should be used with caution in patients with history of liver impairment.⁵⁶ Itraconazole users are at a higher risk of liver damage, which is associated with a cholestatic pattern of injury.^57,58 Although serious liver problems, including liver failure and death, are rare with the use of this drug,⁵⁸ liver function tests should be conducted in patients who have pre-existing hepatic dysfunction.⁵⁶

Severe hepatic injury with the use of acitretin (Soriatane^®, Connetics) has been reported,⁵⁷ but appears to be a rare side-effect of treatment with this drug. However, in patients with liver disease, the dose of acitretin should be reduced and liver function tests monitored closely.⁵⁸ Other potentially hepatotoxic drugs used in dermatology include agents such as tetracyclines, erythromycin, flucloxacillin, ketoconazole, azathioprine, synthetic androgens, and dapsone.⁵⁸

Changes in Pharmacodynamics

Pharmacodynamic considerations include receptor number and affinity, signal transduction mechanisms, cellular responses, and homeostatic regulation.⁵⁹ Sensitivity to certain drugs may be either increased or decreased in the elderly, e.g., sensitivity to benzodiazepines is greater in older patients,⁶⁰ as is the response to some opioids and anticoagulants.

Conversely, the elderly seem to be less responsive to certain â-adrenoceptor agonists and antagonists.²⁷ Simons, et al. studied H1-receptor sensitivity to hydroxyzine by measuring changes in suppression of histamine-induced wheal and flare and suggested an enhanced suppression of H1-receptor activity in the elderly.²⁴

Prescribing in the Elderly: General Considerations

How a drug is handled by the body may change in the elderly. Alterations in drug metabolism and elimination, and a higher prevalence of multidrug regimens make this population more susceptible to ADRs. What makes prescribing to the elderly even more challenging is the fact that they are known to tolerate a number of drugs less well, but they handle other drugs as well as younger individuals. In addition, drug response in the elderly shows a large inter-individual variability.31 There are no simple rules for prescribing that can apply to the elderly population in general; the right dosage must be determined for every elderly person individually.31 A general approach when prescribing drugs to this population would be to:

1. Start, when possible, with a small initial dose and titrate this dose to a clearly defined therapeutic response (dosage guidelines may help you find out about initial dosage reduction).
2. Reduce the number of drugs administered simultaneously as much as possible.
3. Take a careful drug history.
4. Check for possible ADRs or drug interactions.^27,31,32

Noncompliance with drug therapy regimens is a common reason for hospital admission for elderly patients.61 Risk factors include the patients’ inability to recall their medication regimen, medication costs, using several physicians, polypharmacy, and complicated drug regimens.⁶¹ Cognitive impairment and physical dependency are additional risk factors for poor medication management in this group.⁶² To enhance drug management in the elderly, it is crucial to simplify the drug regimen as much as possible, e.g., try to use drugs that can be taken at the same time of day.³²

Conclusions

Some commonly prescribed dermatological drugs such as MTX and cetirizine are likely to be eliminated more slowly in the elderly. Dosage reduction is recommended not only with these agents, but with any drug that is predominantly eliminated by the kidney. Potentially hepatotoxic drugs such as MTX, itraconazole, and acitretin should be used with caution in the elderly, and liver function tests should be performed when these drugs are given in order to lower the risk of hepatotoxicity. Absorption of percutaneously administered drugs may be lowered in the elderly and altered distribution may lead to prolonged half-life, as shown for hydroxyzine, or to a higher plasma concentration of hydrophilic drugs. Further research is needed in order to determine how specific dermatological drugs are handled by the elderly so that pharmacotherapy in this part of the population can be improved.

*Modified with permission from: Drugs Aging 23(3):203-15 (2006).

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