CME-Article Submitted: 16.2.2014 Accepted: 2.4.2014 Conflict of interest None.
DOI: 10.1111/ddg.12365
Dermatologic therapy in geriatric patients
Dorothea Kratzsch, Regina Treudler Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig A.ö.R., Germany Section Editor Prof. Dr. Jan C. Simon, Leipzig
Summary Demographic changes in our society will lead to an increasing proportion of elderly people. Age-associated multimorbidity often results in polypharmacy and elevates the risk of adverse drug reactions. Decisive alterations in pharmacokinetics and pharmacodynamics are detectable in old age, primarily a decrease in total body water, an altered ratio of muscle mass to fatty tissue, and decreased renal function. Changes in gastrointestinal transit, plasma protein binding, hepatic drug metabolism, and an increased susceptibility to drug-induced cognitive decompensation have also been reported. All these alterations should be considered in geriatric dermatotherapy to minimize drug-related complications caused by over- or underdosage and drug interactions.
Introduction The population structure in Germany, as well as in the rest of the European Union (EU), has been undergoing significant changes for many years. In 1990, about 15 % of the German population was aged 65 or older; by 2011, that figure was already 21 % [1]. The percentage of people over 65 years of age is the highest of all EU countries. This demographic change is the result of a persistently low birth rate, along with increasing life expectancy. As a person ages, the organs – especially the kidney and the liver – are increasingly subject to functional limitations. Multimorbidity is also more prevalent among older adults, who often are taking several prescription drugs. The resulting polypharmacotherapy presents the treating physician with increasingly difficult treatment challenges, as the complex interactions between different medications and competing treatment regimens become more complicated and unpredictable. This is reflected by the number of hospitalizations due to adverse drug events. In general hospitals, about 5 % of hospitalizations are due to adverse drug events, while in geriatric units the number is 10–15 % [2]. This trend is also evident in dermatology, as dermatologists are seeing growing numbers of older patients. The goal of this paper is to highlight strategies for systemic dermatologic therapy in older patients, taking into account the physiological changes that occur in advanced age.
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Figure 1 Pharmacokinetic changes in geriatric patients.
Reason of adverse drug events and the PRISCUS list In older patients, age-related changes in pharmacokinetics and pharmacodynamics are a major cause of increased susceptibility to adverse drug events.
Older adults are generally not included in clinical studies.
The PRISCUS list identifies potentially inadequate medication use in older adults.
In older patients, age-related changes in the pharmacokinetics and pharmacodynamics of various medications must be taken into account for proper dosing; these are a major cause of the increased susceptibility to adverse effects in advanced age. Impaired vision and hearing among older adults can also compromise their ability to follow their doctor’s instructions. Many adverse effects are also the result of using drugs which are no longer necessary in old age, as well as the difficulty of detecting drug interactions in polypharmacy. Another problem is that current treatment approaches do not adequately address the needs of older patients with multimorbidity and chronic illness. One reason is that older adults are largely excluded from clinical studies. Current treatment guidelines are usually based on studies done on younger patients who have a single disease. Therefore, the results may not necessarily apply to geriatric patients. To avoid potentially inadequate medication in older patients, the PRISCUS research group has drawn up a list of recommendations for pharmacotherapy in advanced age [3]. Not only does it identify potentially inadequate pharmaceuticals, it also cites treatment alternatives and appropriate measures in the event that one of the drugs cannot be avoided. Unfortunately, only a few of the most common dermatologic drugs are included in the PRISCUS list.
Absorption, distribution volume, and plasma protein binding Pharmacokinetics is defined as the sum of the processes by which a medication is handled by the body. These include drug absorption, distribution, metabolism, and excretion. Figure 1 presents an overview of pharmacokinetic changes occurring in advanced age. With the exception of slowed gastrointestinal transit, drug absorption is largely unchanged in geriatric patients [4, 5]. Slower gastrointestinal transit means that, given a consistent level of absorption, the absorption rate is somewhat diminished. Diseases such as atrophic gastritis, as well as prior surgical interventions involving the gastrointestinal tract, can also significantly decrease medication a bsorption.
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The distribution volumes in older adults differ significantly from those in younger people, due to loss of muscle mass and increase of fatty tissue with age. In advanced age, there is also a decrease in body water.
Diminished plasma protein binding in older people leads to an increase in free-circulating levels of the drug, and thus its pharmacologically active portion.
The distribution volumes in older adults are vastly different from those in younger people, because the ratio of muscle mass to fatty tissue decreases with age [2]. Body water also decreases in advanced age. The decrease in extracellular volume leads to a decrease in the volume of distribution of water-soluble substances, such as aminoglycosides or morphine. Higher plasma concentrations of the drug lead to increased potency, making reduced dosages necessary in older patients. In addition, more fatty tissue means an increased volume of distribution of fat-soluble substances such as hydroxyzine. Lipophilic drugs can have prolonged or hangover effects in older patients. The dosages for such medications must therefore also be adjusted accordingly. The circulating portion of a drug is significantly influenced by plasma protein binding. In advanced age, the concentration of plasma proteins decreases; albumin levels may drop by 10–12 % [2]. The resulting diminished plasma protein binding leads to an increase in free-circulating levels of the drug, and thus its pharmacologically active portion.
Hepatic metabolism
Reduced liver function in geriatric patients results in increased bioavailability. This is especially true of those drugs which are subject to significant firstpass metabolism in the liver. Yet, reduced hepatic function plays a much smaller role than age-related loss of renal function.
In advanced age, there is reduced hepatic clearance due to a decrease in liver mass, hepatic circulation, and liver enzyme activity [2]. Two important phases may be distinguished in the biotransformation of drugs. Phase 1 reactions include the introduction of polar, functional groups into nonpolar molecules. A well-known example is the cytochrome P450 enzyme, which metabolizes 80 % of all drugs, including cyclosporine, statins, and beta blockers [4]. There is some evidence that, in advanced age, there is a decrease in phase 1 reactions, perhaps in conjunction with reduced hepatic blood flow (blood volumes) [6]. In phase 2 reactions, the molecules are conjugated via functional groups with water-soluble molecules, and are then excreted via the kidneys or the gall bladder. These reactions do not seem to be influenced by normal processes of aging [5]. All of the processes described here lead to diminished liver function in geriatric patients. Reduced liver function in geriatric patients results in increased bioavailability. This is especially true of those drugs which are subject to significant first-pass metabolism in the liver. Yet, reduced hepatic function plays a much smaller role than age-related loss of renal function.
Renal excretion Reduced renal function, as a part of normal senescence, is caused by decreased renal circulation, a decline in the number of functioning glomeruli, and diminished tubular secretion [2]. The glomerular filtration rate (GFR) can drop by about 30% between the ages of 30 and 80 [7]. Exogenous factors, such as diabetes mellitus, arterial hypertension, and chronic medication abuse (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), can exacerbate renal insufficiency. This is a very important consideration when prescribing drugs which are eliminated by the kidneys and which have a narrow therapeutic range. About 50 % of the most commonly prescribed drugs either partly or fully undergo renal excretion, including beta-lactam antibiotics, antiviral agents, and antifungal medications.
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50 % of the most commonly used drugs either partly or fully undergo renal excretion. Given that muscle mass decreases with age, older and/or undernourished p atients may have normal or only slightly elevated creatinine levels, in spite of renal insufficiency.
Creatinine levels depend on muscle mass. Given that muscle mass decreases with age, older and/or undernourished patients may have normal or only slightly elevated creatinine levels, in spite of renal insufficiency. Thus, use of the usual formulas for calculating GFR, such as the Modification of Diet in Renal D isease (MDRD), may lead to a slight overestimate of renal function in older adults (especially with a GFR exceeding 60 ml/min). Recommended alternatives for estimating GFR in older patients with beginning renal insufficiency include the Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI), as well as formulas based on the endogenous marker cystatin C. None of these formulas has been validated in large geriatric samples, however. In very advanced age, and in undernourished patients, a 24-hour urine specimen should be collected to measure creatinine clearance. Serum creatinine levels do not increase until a reduction in GFR of around 50 %, and thus they are unsuitable as early markers for kidney disease.
Changes in the central nervous system
Older patients have an increased risk of a drug-induced cognitive disorder as a result of taking benzodiazepine, tricyclic antidepressants, first-generation antihistamines, anticholinergic medications, ciprofloxacin, or acyclovir.
Older adults are particularly susceptible to drug-induced cognitive disturbances [4]. Delirium refers to an acute, often fluctuating brain dysfunction marked by cognitive disorders, abnormal vigilance, hallucinations, delusions, and psychomotor symptoms such as extreme agitation. Unlike dementia, the mental changes associated with delirium are reversible. The risk of delirium, or another psychiatric or paradoxical reaction, increases in older patients, especially with the use of narcotics, benzodiazepine, tricyclic antidepressants, first-generation antihistamines, and anticholinergic medications [3]. Side effects affecting the central nervous system have also been reported for ciprofloxacin and acyclovir. These drugs should only be prescribed after carefully weighing the benefit-risk ratio.
Changes in pharmacodynamics Pharmacodynamics refers to the biological effects of a medication in the organism. It describes the influence of pharmaceuticals on the organism, including dose-response relationships, mechanisms of action, side effects, and toxicology. The effects of a drug are based on interactions with receptors, as well as the influences of enzyme activity, voltage-dependent ion channels, and transport systems. These interactions may change in advanced age. Medications may thus be weaker or stronger without any evident alteration in pharmacokinetics. Older people are presumed to have increased sensitivity to certain drugs, including benzodiazepine and opioids [2, 7]. In older adults, beta receptor stimulants do not elevate heart rate as much as in younger patients, perhaps due to a decrease in the number of beta receptors. Yet older adults are more sensitive to morphine and diazepam; the former may cause respiratory depression, while the latter may have myotonolytic effects, with a risk of falling. In older people, the antihistamine hydroxyzine is presumed to enhance suppression of H1 receptor activity [8].
Common dermatologic drugs Antihistamines The large group of agents known as H1 receptor blockers may be divided into two generations based on their lipophilicity and their ability to enter the CNS [9].
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Table 1 Dosage reduction for cetirizine depending on renal function [10]. Form of renal insufficiency
Creatinine clearance (ml/min)
Recommended dose
≥80
10 mg 1x daily
Mild
50–79
10 mg 1x daily
Moderate
30–49
5 mg 1x daily
Severe
< 30
5 mg 1x daily every 2 days
Terminal
< 10
Contraindication
Normal
Because first-generation anticholinergic antihistamines hydroxyzine ( Atarax®), clemastine (Tavegil®), and dimetindene (Fenistil®) have been associated with reduced cognitive functioning in older patients, they have been classified in the PRISCUS list as potentially inadequate.
When administering terfenadine or hydroxyzine in combination with other drugs that may prolong the QT interval, it is important to recall the risk of life-threatening cardiac arrhythmias. ECG studies should be performed, if needed.
First-generation preparations are lipophilic, and can penetrate the blood-brain barrier, producing a sedative effect. Given their low H1 receptor specificity, first-generation antihistamines also have anticholinergic, antiadrenergic, and anti-serotonergic properties. Side effects include dry mouth, tachycardia, mydriasis, and urinary or gastrointestinal disorders. Second-generation preparations are less lipophilic and cannot enter the CNS. They have limited or no sedative effects. Given their greater H1-receptor specificity, they do not trigger anticholinergic side effects. Because first-generation anticholinergic antihistamines hydroxyzine (Atarax ®), clemastine (Tavegil®), and dimetindene (Fenistil®) have been associated with reduced cognitive functioning in older patients, they have been classified in the PRISCUS list as potentially inadequate. Therapy alternatives for older patients include other sedatives and hypnotic agents, or non-sedating antihistamines without anticholinergic properties, such as cetirizine, desloratadine, and loratadine. These are also a good option given that they do not interact with other drugs [10]. Yet, due to renal clearance, for cetirizine a dosage reduction is needed in patients with renal insufficiency (Table 1). Desloratadine should be used with caution in patients with renal insufficiency; there is no need to modify the dosage of loratadine in geriatric patients or in people with renal insufficiency [10]. Should hydroxyzine, clemastine, or dimetindene need to be used in an older patient, the PRISCUS list advises clinical tests such as controlling CNS function as well as measuring liver and kidney function. When administering terfenadine or hydroxyzine in combination with other drugs that may prolong the QT interval, it is important to recall the risk of life-threatening cardiac arrhythmias. ECG studies should be performed, if needed.
Immunosuppressants
Important side effects of corticosteroids in geriatric patients include diabetogenic effects, myopathies, skin atrophy, cataracts, osteoporosis, cushingoid habitus, increased risk of thrombosis, elevated blood pressure, gastric and duodenal ulcers, and an elevated risk of life-threatening infections.
Corticosteroid use is associated with numerous, relevant side effects, especially in older patients [9, 10]. Along with their diabetogenic effects, increased catabolism may lead to myopathy, skin atrophy, cataracts, or osteoporosis. The redistribution of fat leads to a cushingoid habitus with adrenocortical obesity and a moon face appearance. Relevant side effects of prolonged corticosteroid treatment include an elevated risk of thrombosis, increased blood pressure resulting from sodium retention, and decreased mucus production in the gastrointestinal tract. There is a significantly higher risk of stomach or duodenal ulceration, especially if taken together with NSAIDs. Due to the inhibition of chemotactic substances, and thus the suppression of B-cell and especially T-cell function, there is a risk of life-threatening infection. In advanced age, corticosteroids should only be prescribed after carefully weighing the benefit-risk ratio.
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Table 2 Dosage reduction for methotrexate depending on renal function [10].
In older patients, lower dosages should be selected due to reduced kidney and liver function, as well as diminished folate reserves.
MTX is contraindicated in patients with creatinine clearance < 60 ml/minute.
When administering cyclosporine to older patients, the initial dosage should be in the low range, and kidney tests should be performed.
In older patients with impaired renal function, and mild to moderately impaired liver function, the dosage should be maintained at the low end of the normal range.
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Creatinine clearance (ml/min)
Recommended dose
> 80 ml/min
Standard dose
= 80 ml/min
75 % of standard dose
= 60 ml/min
63 % of standard dose
< 60 ml/min
Contraindication
Methotrexate (MTX) is a folic acid antagonist which is mainly used to treat severe psoriasis vulgaris, especially plaque psoriasis and psoriatic arthropathy. To avoid severe toxic side effects, folic acid substitution should be given about 24 hours after moderate-to-high dose MTX therapy (about 100 mg/m 2 BSA or more) [9, 10]. In older patients, lower dosages should be selected due to reduced kidney and liver function, as well as diminished folate reserves [10]. Table 2 shows the dose reductions which are advised in the product information on MTX and broken down by renal clearance. MTX is primarily eliminated by the kidneys. Diminished renal excretion, especially in combination therapy with MTX and NSAIDs, leads to a marked increase in toxicity [9]. The toxic effects of MTX are increased when used in combination with cotrimoxazole, penicillin, or other cytostatic agents, as well as in patients with folic acid deficiency. MTX is contraindicated in patients with creatinine clearance < 60 ml/min; other treatment alternatives should be considered [10]. Cyclosporine A is an immunosuppressant which mainly acts via inhibition of interleukin-2 production to suppress the cellular immune response. In dermatology, cyclosporine A is used to treat severe psoriasis vulgaris and atopic dermatitis. Cytochrome P450-dependent oxidation occurs in the liver and the drug is excreted through the gall bladder. It is essential to modify the dosage of cyclosporine A and to thoroughly understand potential interactions, given that elevated levels are associated with increased nephrotoxicity and neurotoxicity. Elevated blood pressure, including manifest hypertension, is one possible side effect. When administering the drug to older patients, initial dosages should be in the lower range, and kidney tests should be performed [10]. Table 3 contains recommended dosage reductions for cyclosporine in patients with elevated creatinine levels. Combination use with other nephrotoxic drugs, such as aminoglycosides or amphotericin B, is not advised [4, 9]. Combination therapy with macrolides, itraconazole, amphotericin B, or calcium antagonists increases the risk of cyclosporine toxicity, due to enzyme inhibition. In addition, in older patients, cyclosporine can lead to elevated digitoxin levels. Azathioprine is a cytotoxic and immunosuppressive agent which primarily inhibits the cellular immune response. It is used in patients with autoimmune skin disorders. It is metabolized as a prodrug (via intrahepatic activation) to 6-mercaptopurine [9]. 6-mercaptopurine is transformed by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanine nucleotides, which are incorporated into DNA and inhibit signal transduction and de novo synthesis of purine. The enzymes thiopurine methyltransferase (TPMT) and xanthine oxidase lead to inactivation of 6-mercaptopurine. If xanthine oxidase is inhibited by allopurinol, increased toxicity of 6-mercaptopurine may be induced with bone marrow suppression (Figure 2). If allopurinol is given simultaneously, it is thus advisable to reduce the dosage of azathioprine to 25 %. In older patients with impaired renal function, and mild to moderately impaired liver function, the dosage should be kept at the low end of the normal range [10].
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Table 3 Dosage reduction for cyclosporine depending on renal function [9]. Increased creatinine with cyclosporine
Recommended dose
Increased creatinine > 30 % of baseline (also if in normal range)
Reduce dose by 25–50 %
Increased creatinine > 50 % of baseline
Reduce dose by 50 %
Figure 2 Drug interaction between azathioprine and allopurinol: inhibition of xanthine oxidase could increase the risk of nephrotoxicity through azathioprine [9].
Antiviral drugs
Acyclovir is eliminated by the kidneys. It may have nephrotoxic effects, due to crystallization within renal tubules. Given that renal function is often impaired in older patients, adequate fluid intake must be ensured.
Acyclovir is a common antiviral drug which is used to treat herpes simplex and varicella zoster infections. It is phosphorylated by viral thymidine kinase as well as cellular kinases, and thus acts selectively on infected cells [9, 10]. As a nucleoside analogue, it disrupts synthesis of the viral DNA. Acyclovir only has this effect on virus reproduction and not on latent infections without virus replication. Antiviral therapy should begin promptly, no later than 72 hours after the onset of skin symptoms. Acyclovir is eliminated by the kidneys. It may have nephrotoxic effects, due to crystallization within renal tubules. Given that renal function is often impaired in older patients, adequate fluid intake must be ensured. In intravenous acyclovir administration, when GFR ≤ 50 ml/min, the dosage interval should be prolonged to 12 hours; when GFR ≤ 25 ml/min, it should be increased to 24 hours. When GFR < 10 ml/min, half of the single dose should be infused once every 24 hours, after hemodialysis. In older patients, and those with impaired renal function, higher dosages are associated with a greater risk of neurological side effects (e.g., dizziness, confusion, psychotic symptoms, and somnolence). Table 4 gives an overview of the pharmacokinetics and pharmacodynamics of commonly used dermatologic drugs, as well as important aspects in regard to treating older patients.
General information on pharmacotherapy in advanced age Given multimorbidity, and thus the use of multiple medications, treating geriatric patients is a particular challenge for physicians. This is evidenced by the fact that uniform recommendations on pharmacotherapy are lacking for the treatment of geriatric patients. The following tips may be useful when treating older patients [2, 4, 7, 11]:
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Table 4 Common dermatologic drugs and important aspects when prescribing this medications to elderly people [2, 4, 7, 9, 10]. Agent
Pharmacokinetics/-dynamics
Important aspects in older patients
Acyclovir
Renal clearance
Nephrotoxicity
Adjust dosing interval to renal function Adequate hydration Dizziness, confusion
Acitretin
Lipophilic, hepatic metabolism, renal excretion
Prolonged elimination half-life Contraindicated in patients with severe renal or liver
insufficiency, manifest diabetes, or severe metabolic disorders Azathioprine
Brivudine
Intrahepatic activation to form 6-mercaptopurine, renal excretion
Reduce dose in liver or kidney insufficiency
Accumulation increased toxicity of 5-fluoropyrimidine (5-fluoropyrimidine)
Combination use with 5-fluoropyrimidine (5-Fluorouracil,
Renal excretion
Dose reduction in renal insufficiency
Dose reduction to 25% with concomitant use of allopurinol Lowers warfarin levels
capecitabine, floxuridine, tegafur, flucytosine) No dosage modification in advanced age, required for renal
or liver insufficiency Cetirizine
Contraindicated if GFR < 10 ml/min
Cephalosporin
Primarily renal excretion
Dose adjustment in renal insufficiency Certain cephalosporins increase warfarin levels
Cyclosporine
Hepatic metabolism via CYP3A3/3A4, biliary excretion, nephro- and neurotoxicity
Start in low range of dosage, control kidney values and
blood pressure Dose optimization based on serum levels Numerous drug interactions Elevates digitoxin levels
Ciprofloxacin
Renal excretion, CYP1A2 inhibitor
Dose reduction in renal insufficiency Increases warfarin levels Risk of prolonged QT time, tendon rupture,
and delirium Dapsone
Metabolism via CYP3A3/3A4
Contraindicated in patients with severe liver
insufficiency Dimethyl fumarate
Hydrolysis to form methyl hydrogen fumarate, animal studies show excretion via respiration
Dose reduction in renal and liver insufficiency
Dimetindene
Lipophilic, renal and biliary excretion
Sedation, anticholinergic side effects
Famciclovir
Renal excretion
Increases warfarin levels
Contraindicated in patients with gastrointestinal ulcers
Disorientation, somnolence
Fluconazole
CYP2C9/3A4 inhibitor, renal excretion
Increases warfarin levels In advanced age, dosage adjustment only with renal
insufficiency Contraindicated in patients with severe liver insufficiency
Hydroxyzine
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Strongly lipophilic, metabolism via CYP3A4, renal excretion
Sedation, anticholinergic side effects Prolonged elimination half-life Dose reduction in renal and liver insufficiency
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Table 4 Continued. Agent
Pharmacokinetics/-dynamics
Important aspects in older patients
Isotretinoin
Hepatic metabolism via C YP enzymes
Contraindicated in patients with severe liver insufficiency
or serious metabolic disorder In kidney insufficiency start with low dose
Itraconazole
CYP3A4/3A5 inhibitor
Elevates digitoxin levels Dose reduction in renal and liver insufficiency
Macrolides
Inhibitors and substrates of CYP3A4
Elevates warfarin and digitoxin levels Prolongs QT time Hepatotoxicity
Methotrexate
Penicillin
10 % of the dose undergoes hepatic metabolism, primarily renal excretion
In advanced age, administer in low range
Primarily renal excretion
In patients with severe renal insufficiency, reduce
Contraindicated in patients with liver damage,
greater alcohol use, and renal insufficiency (GFR < 60 ml/min) maintenance dose or dosing intervals (see Table 5)
Prednisone
Hepatic metabolism via CYP3A4
Due to numerous side effects, only use after carefully
weighing benefit-risk ratio In patients with liver insufficiency elimination half-life is
prolonged Use caution in combination with NSAIDs, oral diabetes drugs,
insulin, and coumarin Terbinafine
CYP2D6 inhibitor, renal e xcretion
No dosage adjustment needed in advanced age Not advised if creatinine clearance < 50 ml/min Contraindicated in patients with liver insufficiency Loss of appetite or anorexia
Tetracycline
Primarily renal excretion
Dosage reduction in renal insufficiency (except for
doxycycline) Contraindicated in patients with severe liver
insufficiency Elevates digitoxin levels
Abbr.: GFR, glomerular filtration rate; Crea-Cl, creatinine clearance
Table 5 Reduction of maintenance dose for benzylpenicillin depending on renal function [10]. GFR (ml/min)
Serum creatinine (mg/100 ml)
Dosage mill. IU benzylpenicillin (mg benzylpenicillin sodium)
Dosing interval (hrs.)
120
0.8
5 (3,000)
6
45
2.0
5 (3,000)
8
18
3.5
4 (2,400)
8
8
6.0
5 (3,000)
12
2
15.5
3 (1,800)
12
–
2 (1,200)
12
Under 2
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1. Strict indications for treatment with a clear treatment goal Before prescribing any drug, doctors should critically weigh the need for its use, the indications in older patients, and possible alternatives which have fewer side effects. In postoperative pain treatment, for instance, the use of a cold pack may provide adequate analgesia, rendering the use of NSAIDs – which have numerous side effects – unnecessary. In general, it is a good idea to avoid medications with a long half-life. In addition, clear treatment goals should be established and weighed against potential side effects of the medication. 2. Low initial dosage, carefully increasing (start low, go slow) In general, for older patients, the dosage should be lower than the adult dosage recommended in the product information. One may begin at 50 % of the recommended dosage and then slowly increase it. Slowly increasing the dosage is especially important for drugs with a narrow therapeutic range, such as methotrexate and aminoglycosides. 3. Adjust the dosage for impaired renal function Older patients often have impaired renal function, in spite of having normal serum creatinine levels. Renal function should be estimated based on age-adjusted creatinine clearance or by measuring creatinine levels in a 24-hour urine specimen. About half of all commonly prescribed medications are eliminated via the kidneys and require a dosage adjustment. This may be accomplished by giving a smaller single dose or by prolonging the dosing interval. 4. Adjusting the prescription to the patient’s life situation and comorbidities Older patients often have problems such as presbycusis and impaired vision, which may severely limit communication between the doctor and the patient. In order to improve patient compliance, the instructions for taking the drug should be printed in large and legible print. Doctors should double-check whether patients have understood their instructions and are able to follow them. For instance, osteoarthritis of the hand may make it difficult for some patients to open drug packaging alone. Establishing set times for taking medication, or using pill dispensers which allow drugs to be sorted in advance, can help if the patient is forgetful. 5. Routine control of drug effectiveness and observance of adverse drug events Regular controls should be performed to check the effectiveness of the medication and to critically evaluate the indications for its use. Given that older, multimorbid patients are often under the care of several physicians, the patient's medication list should be regularly controlled in regard to new drugs and potential interactions.
Summary Pharmacotherapy in older adults presents special challenges for the dermatologist, due to comorbidities, drug interactions, and compliance issues. Doctors should adhere to narrow indications for pharmacotherapy and establish clearly defined treatment goals. Especially when administering drugs with a narrow therapeutic range, the initial dosage should be low and then gradually increased. In addition, many systemic agents used in dermatology require dosage modifications for patients with impaired renal function. Routine controls and critical evaluation of the prescribed medication can significantly reduce the risk of adverse events.
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References
Correspondence to Dr. med. Dorothea Kratzsch Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Leipzig A.ö.R. Philipp-Rosenthal-Straße 23 04103 Leipzig E-mail: dorothea.kratzsch@ medizin.uniklinik-leipzig.de
1 Statistisches Bundesamt, Wiesbaden 2012, www.destatis.de 2 Wehling M. Klinische Pharmakologie, Georg Thieme Verlag, Stuttgart, 2005. 3 www.priscus.net 4 Endo JO, Wong JW, Norman RA, Chang AL. Geriatric pharmacology for the dermatologist. J Am Acad Dermatol 2013; 68: 521e1–10. 5 Hutchison LC, Sleeper RB. Fundamentals of geriatric pharmacotherapy: an evidencebased approach. Bethesda (MD): American Society of Health-System Pharmacists; 2010. 6 McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163–84. 7 Flammiger A, Maibach H. Dermatological drug dosage in the elderly. Skin Therapy Lett 2006; 11: 1–7. 8 Simons KJ, Watson WT, Chen XY, Simons FE. Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther 1989; 45: 9–14. 9 Karow T, Lang-Roth R. Allgemeine und spezielle Pharmakologie und Toxikologie, 20. Auflage, Thomas Karow (Verlag), Köln, 2012. 10 Fachinformationen der Medikamente. 11 Hilmer SN, McLachlan AJ, Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007; 21: 217–30.
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Fragen zur Zertifizierung durch die DDA 1.
Welcher Faktor kompliziert die
systemische Pharmakotherapie im Alter nicht? a) veränderte Pharmakokinetik b) veränderte Pharmakodynamik c) Einschränkungen beim Sehvermögen d) Verbesserung des Hörvermögens durch Hörgeräte e) Einschränkungen kognitiver Funktionen
2. a)
Was ist die Priscus-Liste? Ein pharmakologisches Nachschlagewerk, in dem ausführlich auf Pharmakokinetik und -dynamik von im Alter problematischen Arzneimitteln eingegangen wird. b) Eine Auflistung potenziell inadäquater Pharmaka im Alter, einschließlich möglicher Therapiealternativen. c) Eine Liste, welche konkrete Empfehlungen für die dermatologische Pharmakotherapie im Alter gibt. d) Eine Leitlinie zur topischen Therapie im Alter. e) Dermatologische Pharmaka werden von der Priscus-Liste nicht erfasst.
3.
Welche Aussage bezüglich der
Pharmakokinetik im Alter trifft zu? a) Die enterale Resorption ist erhöht. b) Das Fettgewebe nimmt zu Gunsten des Körperwassers ab. c) Die Plasmaeiweißbindung ist erhöht. d) Die Nierenfunktion bleibt unverändert. e) Kreatinin kann trotz altersbedingter Niereninsuffizienz normal oder nur leicht erhöht sein.
4. Die Einnahme welcher Medikamente erhöht das Risiko für kognitive Störungen nicht wesentlich? a) selektive Serotonin- Wiederaufnahmehemmer (SSRI)
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b) Narkotika c) Benzodiazepine d) trizyklische Antidepressiva e) Antihistaminika der ersten Generation
5.
Welches Antihistaminikum
wurde von der Priscus-Liste als im Alter p otenziell inadäquat klassifiziert? a) Dimetinden b) Cetirizin c) Loratadin d) Desloratadin e) Mizolastin
6. Was ist keine Nebenwirkung einer systemischen Glukokortikosteroidtherapie? a) Erhöhung des Blutzuckers b) Zunahme der Knochendichte c) Erhöhtes Thromboserisiko d) Magen-Darm-Ulzerationen e) Erhöhte Infektanfälligkeit
7.
Ab welcher Kreatinin-Clearance
ist Methotrexat kontraindiziert? a) 80 ml/min b) 60 ml/min c) 40 ml/min d) 20 ml/min e) 10 ml/min
8. Welche Aussage zu I mmunsuppressiva trifft zu? a) Die Elimination von Methotrexat erfolgt überwiegend hepatisch. b) Bei Methotrexat ist im Alter keine Dosisanpassung erforderlich. c) Erhöhte Spiegel an Ciclosporin gehen mit Nephro- und Neurotoxizität einher. d) Ciclosporin kann bei älteren Patienten die Digitoxinwirkung abschwächen.
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e)
Bei Kombination von Azathioprin mit Allopurinol ist eine Dosisreduktion um 60 % notwendig.
9. Bei welchem Medikament ist bei Niereninsuffizienz keine Dosisanpassung erforderlich? a) Brivudin b) Cetirizin c) Aciclovir d) Penicillin e) Ciprofloxacin
10. Welcher allgemeine Hinweis zur Pharmakotherapie im Alter trifft nicht zu? a) Nebenwirkungsärmere Therapiealternativen sollten bevorzugt werden. b) Start low, go slow. c) Die Dosis sollte an eingeschränkte Organfunktionen angepasst werden. d) Regelmäßige Kontrolluntersuchungen sollten vermieden werden. e) Die Verordnung sollte an die Lebenssituation des Patienten angepasst sein.
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 18. September 2014. Die richtige Lösung zum Thema „Kutane Lymphome“ in Heft 1 ( Januar 2014) ist: (1d, 2b, 3e, 4a, 5a, 6b, 7b, 8c, 9a, 10d).
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DOI: 10.1111/ddg.12365
Dermatologic therapy in geriatric patients
Dorothea Kratzsch, Regina Treudler Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig A.ö.R., Germany Section Editor Prof. Dr. Jan C. Simon, Leipzig
Summary Demographic changes in our society will lead to an increasing proportion of elderly people. Age-associated multimorbidity often results in polypharmacy and elevates the risk of adverse drug reactions. Decisive alterations in pharmacokinetics and pharmacodynamics are detectable in old age, primarily a decrease in total body water, an altered ratio of muscle mass to fatty tissue, and decreased renal function. Changes in gastrointestinal transit, plasma protein binding, hepatic drug metabolism, and an increased susceptibility to drug-induced cognitive decompensation have also been reported. All these alterations should be considered in geriatric dermatotherapy to minimize drug-related complications caused by over- or underdosage and drug interactions.
Introduction The population structure in Germany, as well as in the rest of the European Union (EU), has been undergoing significant changes for many years. In 1990, about 15 % of the German population was aged 65 or older; by 2011, that figure was already 21 % [1]. The percentage of people over 65 years of age is the highest of all EU countries. This demographic change is the result of a persistently low birth rate, along with increasing life expectancy. As a person ages, the organs – especially the kidney and the liver – are increasingly subject to functional limitations. Multimorbidity is also more prevalent among older adults, who often are taking several prescription drugs. The resulting polypharmacotherapy presents the treating physician with increasingly difficult treatment challenges, as the complex interactions between different medications and competing treatment regimens become more complicated and unpredictable. This is reflected by the number of hospitalizations due to adverse drug events. In general hospitals, about 5 % of hospitalizations are due to adverse drug events, while in geriatric units the number is 10–15 % [2]. This trend is also evident in dermatology, as dermatologists are seeing growing numbers of older patients. The goal of this paper is to highlight strategies for systemic dermatologic therapy in older patients, taking into account the physiological changes that occur in advanced age.
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Figure 1 Pharmacokinetic changes in geriatric patients.
Reason of adverse drug events and the PRISCUS list In older patients, age-related changes in pharmacokinetics and pharmacodynamics are a major cause of increased susceptibility to adverse drug events.
Older adults are generally not included in clinical studies.
The PRISCUS list identifies potentially inadequate medication use in older adults.
In older patients, age-related changes in the pharmacokinetics and pharmacodynamics of various medications must be taken into account for proper dosing; these are a major cause of the increased susceptibility to adverse effects in advanced age. Impaired vision and hearing among older adults can also compromise their ability to follow their doctor’s instructions. Many adverse effects are also the result of using drugs which are no longer necessary in old age, as well as the difficulty of detecting drug interactions in polypharmacy. Another problem is that current treatment approaches do not adequately address the needs of older patients with multimorbidity and chronic illness. One reason is that older adults are largely excluded from clinical studies. Current treatment guidelines are usually based on studies done on younger patients who have a single disease. Therefore, the results may not necessarily apply to geriatric patients. To avoid potentially inadequate medication in older patients, the PRISCUS research group has drawn up a list of recommendations for pharmacotherapy in advanced age [3]. Not only does it identify potentially inadequate pharmaceuticals, it also cites treatment alternatives and appropriate measures in the event that one of the drugs cannot be avoided. Unfortunately, only a few of the most common dermatologic drugs are included in the PRISCUS list.
Absorption, distribution volume, and plasma protein binding Pharmacokinetics is defined as the sum of the processes by which a medication is handled by the body. These include drug absorption, distribution, metabolism, and excretion. Figure 1 presents an overview of pharmacokinetic changes occurring in advanced age. With the exception of slowed gastrointestinal transit, drug absorption is largely unchanged in geriatric patients [4, 5]. Slower gastrointestinal transit means that, given a consistent level of absorption, the absorption rate is somewhat diminished. Diseases such as atrophic gastritis, as well as prior surgical interventions involving the gastrointestinal tract, can also significantly decrease medication a bsorption.
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The distribution volumes in older adults differ significantly from those in younger people, due to loss of muscle mass and increase of fatty tissue with age. In advanced age, there is also a decrease in body water.
Diminished plasma protein binding in older people leads to an increase in free-circulating levels of the drug, and thus its pharmacologically active portion.
The distribution volumes in older adults are vastly different from those in younger people, because the ratio of muscle mass to fatty tissue decreases with age [2]. Body water also decreases in advanced age. The decrease in extracellular volume leads to a decrease in the volume of distribution of water-soluble substances, such as aminoglycosides or morphine. Higher plasma concentrations of the drug lead to increased potency, making reduced dosages necessary in older patients. In addition, more fatty tissue means an increased volume of distribution of fat-soluble substances such as hydroxyzine. Lipophilic drugs can have prolonged or hangover effects in older patients. The dosages for such medications must therefore also be adjusted accordingly. The circulating portion of a drug is significantly influenced by plasma protein binding. In advanced age, the concentration of plasma proteins decreases; albumin levels may drop by 10–12 % [2]. The resulting diminished plasma protein binding leads to an increase in free-circulating levels of the drug, and thus its pharmacologically active portion.
Hepatic metabolism
Reduced liver function in geriatric patients results in increased bioavailability. This is especially true of those drugs which are subject to significant firstpass metabolism in the liver. Yet, reduced hepatic function plays a much smaller role than age-related loss of renal function.
In advanced age, there is reduced hepatic clearance due to a decrease in liver mass, hepatic circulation, and liver enzyme activity [2]. Two important phases may be distinguished in the biotransformation of drugs. Phase 1 reactions include the introduction of polar, functional groups into nonpolar molecules. A well-known example is the cytochrome P450 enzyme, which metabolizes 80 % of all drugs, including cyclosporine, statins, and beta blockers [4]. There is some evidence that, in advanced age, there is a decrease in phase 1 reactions, perhaps in conjunction with reduced hepatic blood flow (blood volumes) [6]. In phase 2 reactions, the molecules are conjugated via functional groups with water-soluble molecules, and are then excreted via the kidneys or the gall bladder. These reactions do not seem to be influenced by normal processes of aging [5]. All of the processes described here lead to diminished liver function in geriatric patients. Reduced liver function in geriatric patients results in increased bioavailability. This is especially true of those drugs which are subject to significant first-pass metabolism in the liver. Yet, reduced hepatic function plays a much smaller role than age-related loss of renal function.
Renal excretion Reduced renal function, as a part of normal senescence, is caused by decreased renal circulation, a decline in the number of functioning glomeruli, and diminished tubular secretion [2]. The glomerular filtration rate (GFR) can drop by about 30% between the ages of 30 and 80 [7]. Exogenous factors, such as diabetes mellitus, arterial hypertension, and chronic medication abuse (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), can exacerbate renal insufficiency. This is a very important consideration when prescribing drugs which are eliminated by the kidneys and which have a narrow therapeutic range. About 50 % of the most commonly prescribed drugs either partly or fully undergo renal excretion, including beta-lactam antibiotics, antiviral agents, and antifungal medications.
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50 % of the most commonly used drugs either partly or fully undergo renal excretion. Given that muscle mass decreases with age, older and/or undernourished p atients may have normal or only slightly elevated creatinine levels, in spite of renal insufficiency.
Creatinine levels depend on muscle mass. Given that muscle mass decreases with age, older and/or undernourished patients may have normal or only slightly elevated creatinine levels, in spite of renal insufficiency. Thus, use of the usual formulas for calculating GFR, such as the Modification of Diet in Renal D isease (MDRD), may lead to a slight overestimate of renal function in older adults (especially with a GFR exceeding 60 ml/min). Recommended alternatives for estimating GFR in older patients with beginning renal insufficiency include the Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI), as well as formulas based on the endogenous marker cystatin C. None of these formulas has been validated in large geriatric samples, however. In very advanced age, and in undernourished patients, a 24-hour urine specimen should be collected to measure creatinine clearance. Serum creatinine levels do not increase until a reduction in GFR of around 50 %, and thus they are unsuitable as early markers for kidney disease.
Changes in the central nervous system
Older patients have an increased risk of a drug-induced cognitive disorder as a result of taking benzodiazepine, tricyclic antidepressants, first-generation antihistamines, anticholinergic medications, ciprofloxacin, or acyclovir.
Older adults are particularly susceptible to drug-induced cognitive disturbances [4]. Delirium refers to an acute, often fluctuating brain dysfunction marked by cognitive disorders, abnormal vigilance, hallucinations, delusions, and psychomotor symptoms such as extreme agitation. Unlike dementia, the mental changes associated with delirium are reversible. The risk of delirium, or another psychiatric or paradoxical reaction, increases in older patients, especially with the use of narcotics, benzodiazepine, tricyclic antidepressants, first-generation antihistamines, and anticholinergic medications [3]. Side effects affecting the central nervous system have also been reported for ciprofloxacin and acyclovir. These drugs should only be prescribed after carefully weighing the benefit-risk ratio.
Changes in pharmacodynamics Pharmacodynamics refers to the biological effects of a medication in the organism. It describes the influence of pharmaceuticals on the organism, including dose-response relationships, mechanisms of action, side effects, and toxicology. The effects of a drug are based on interactions with receptors, as well as the influences of enzyme activity, voltage-dependent ion channels, and transport systems. These interactions may change in advanced age. Medications may thus be weaker or stronger without any evident alteration in pharmacokinetics. Older people are presumed to have increased sensitivity to certain drugs, including benzodiazepine and opioids [2, 7]. In older adults, beta receptor stimulants do not elevate heart rate as much as in younger patients, perhaps due to a decrease in the number of beta receptors. Yet older adults are more sensitive to morphine and diazepam; the former may cause respiratory depression, while the latter may have myotonolytic effects, with a risk of falling. In older people, the antihistamine hydroxyzine is presumed to enhance suppression of H1 receptor activity [8].
Common dermatologic drugs Antihistamines The large group of agents known as H1 receptor blockers may be divided into two generations based on their lipophilicity and their ability to enter the CNS [9].
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Table 1 Dosage reduction for cetirizine depending on renal function [10]. Form of renal insufficiency
Creatinine clearance (ml/min)
Recommended dose
≥80
10 mg 1x daily
Mild
50–79
10 mg 1x daily
Moderate
30–49
5 mg 1x daily
Severe
< 30
5 mg 1x daily every 2 days
Terminal
< 10
Contraindication
Normal
Because first-generation anticholinergic antihistamines hydroxyzine ( Atarax®), clemastine (Tavegil®), and dimetindene (Fenistil®) have been associated with reduced cognitive functioning in older patients, they have been classified in the PRISCUS list as potentially inadequate.
When administering terfenadine or hydroxyzine in combination with other drugs that may prolong the QT interval, it is important to recall the risk of life-threatening cardiac arrhythmias. ECG studies should be performed, if needed.
First-generation preparations are lipophilic, and can penetrate the blood-brain barrier, producing a sedative effect. Given their low H1 receptor specificity, first-generation antihistamines also have anticholinergic, antiadrenergic, and anti-serotonergic properties. Side effects include dry mouth, tachycardia, mydriasis, and urinary or gastrointestinal disorders. Second-generation preparations are less lipophilic and cannot enter the CNS. They have limited or no sedative effects. Given their greater H1-receptor specificity, they do not trigger anticholinergic side effects. Because first-generation anticholinergic antihistamines hydroxyzine (Atarax ®), clemastine (Tavegil®), and dimetindene (Fenistil®) have been associated with reduced cognitive functioning in older patients, they have been classified in the PRISCUS list as potentially inadequate. Therapy alternatives for older patients include other sedatives and hypnotic agents, or non-sedating antihistamines without anticholinergic properties, such as cetirizine, desloratadine, and loratadine. These are also a good option given that they do not interact with other drugs [10]. Yet, due to renal clearance, for cetirizine a dosage reduction is needed in patients with renal insufficiency (Table 1). Desloratadine should be used with caution in patients with renal insufficiency; there is no need to modify the dosage of loratadine in geriatric patients or in people with renal insufficiency [10]. Should hydroxyzine, clemastine, or dimetindene need to be used in an older patient, the PRISCUS list advises clinical tests such as controlling CNS function as well as measuring liver and kidney function. When administering terfenadine or hydroxyzine in combination with other drugs that may prolong the QT interval, it is important to recall the risk of life-threatening cardiac arrhythmias. ECG studies should be performed, if needed.
Immunosuppressants
Important side effects of corticosteroids in geriatric patients include diabetogenic effects, myopathies, skin atrophy, cataracts, osteoporosis, cushingoid habitus, increased risk of thrombosis, elevated blood pressure, gastric and duodenal ulcers, and an elevated risk of life-threatening infections.
Corticosteroid use is associated with numerous, relevant side effects, especially in older patients [9, 10]. Along with their diabetogenic effects, increased catabolism may lead to myopathy, skin atrophy, cataracts, or osteoporosis. The redistribution of fat leads to a cushingoid habitus with adrenocortical obesity and a moon face appearance. Relevant side effects of prolonged corticosteroid treatment include an elevated risk of thrombosis, increased blood pressure resulting from sodium retention, and decreased mucus production in the gastrointestinal tract. There is a significantly higher risk of stomach or duodenal ulceration, especially if taken together with NSAIDs. Due to the inhibition of chemotactic substances, and thus the suppression of B-cell and especially T-cell function, there is a risk of life-threatening infection. In advanced age, corticosteroids should only be prescribed after carefully weighing the benefit-risk ratio.
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Table 2 Dosage reduction for methotrexate depending on renal function [10].
In older patients, lower dosages should be selected due to reduced kidney and liver function, as well as diminished folate reserves.
MTX is contraindicated in patients with creatinine clearance < 60 ml/minute.
When administering cyclosporine to older patients, the initial dosage should be in the low range, and kidney tests should be performed.
In older patients with impaired renal function, and mild to moderately impaired liver function, the dosage should be maintained at the low end of the normal range.
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Creatinine clearance (ml/min)
Recommended dose
> 80 ml/min
Standard dose
= 80 ml/min
75 % of standard dose
= 60 ml/min
63 % of standard dose
< 60 ml/min
Contraindication
Methotrexate (MTX) is a folic acid antagonist which is mainly used to treat severe psoriasis vulgaris, especially plaque psoriasis and psoriatic arthropathy. To avoid severe toxic side effects, folic acid substitution should be given about 24 hours after moderate-to-high dose MTX therapy (about 100 mg/m 2 BSA or more) [9, 10]. In older patients, lower dosages should be selected due to reduced kidney and liver function, as well as diminished folate reserves [10]. Table 2 shows the dose reductions which are advised in the product information on MTX and broken down by renal clearance. MTX is primarily eliminated by the kidneys. Diminished renal excretion, especially in combination therapy with MTX and NSAIDs, leads to a marked increase in toxicity [9]. The toxic effects of MTX are increased when used in combination with cotrimoxazole, penicillin, or other cytostatic agents, as well as in patients with folic acid deficiency. MTX is contraindicated in patients with creatinine clearance < 60 ml/min; other treatment alternatives should be considered [10]. Cyclosporine A is an immunosuppressant which mainly acts via inhibition of interleukin-2 production to suppress the cellular immune response. In dermatology, cyclosporine A is used to treat severe psoriasis vulgaris and atopic dermatitis. Cytochrome P450-dependent oxidation occurs in the liver and the drug is excreted through the gall bladder. It is essential to modify the dosage of cyclosporine A and to thoroughly understand potential interactions, given that elevated levels are associated with increased nephrotoxicity and neurotoxicity. Elevated blood pressure, including manifest hypertension, is one possible side effect. When administering the drug to older patients, initial dosages should be in the lower range, and kidney tests should be performed [10]. Table 3 contains recommended dosage reductions for cyclosporine in patients with elevated creatinine levels. Combination use with other nephrotoxic drugs, such as aminoglycosides or amphotericin B, is not advised [4, 9]. Combination therapy with macrolides, itraconazole, amphotericin B, or calcium antagonists increases the risk of cyclosporine toxicity, due to enzyme inhibition. In addition, in older patients, cyclosporine can lead to elevated digitoxin levels. Azathioprine is a cytotoxic and immunosuppressive agent which primarily inhibits the cellular immune response. It is used in patients with autoimmune skin disorders. It is metabolized as a prodrug (via intrahepatic activation) to 6-mercaptopurine [9]. 6-mercaptopurine is transformed by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanine nucleotides, which are incorporated into DNA and inhibit signal transduction and de novo synthesis of purine. The enzymes thiopurine methyltransferase (TPMT) and xanthine oxidase lead to inactivation of 6-mercaptopurine. If xanthine oxidase is inhibited by allopurinol, increased toxicity of 6-mercaptopurine may be induced with bone marrow suppression (Figure 2). If allopurinol is given simultaneously, it is thus advisable to reduce the dosage of azathioprine to 25 %. In older patients with impaired renal function, and mild to moderately impaired liver function, the dosage should be kept at the low end of the normal range [10].
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Table 3 Dosage reduction for cyclosporine depending on renal function [9]. Increased creatinine with cyclosporine
Recommended dose
Increased creatinine > 30 % of baseline (also if in normal range)
Reduce dose by 25–50 %
Increased creatinine > 50 % of baseline
Reduce dose by 50 %
Figure 2 Drug interaction between azathioprine and allopurinol: inhibition of xanthine oxidase could increase the risk of nephrotoxicity through azathioprine [9].
Antiviral drugs
Acyclovir is eliminated by the kidneys. It may have nephrotoxic effects, due to crystallization within renal tubules. Given that renal function is often impaired in older patients, adequate fluid intake must be ensured.
Acyclovir is a common antiviral drug which is used to treat herpes simplex and varicella zoster infections. It is phosphorylated by viral thymidine kinase as well as cellular kinases, and thus acts selectively on infected cells [9, 10]. As a nucleoside analogue, it disrupts synthesis of the viral DNA. Acyclovir only has this effect on virus reproduction and not on latent infections without virus replication. Antiviral therapy should begin promptly, no later than 72 hours after the onset of skin symptoms. Acyclovir is eliminated by the kidneys. It may have nephrotoxic effects, due to crystallization within renal tubules. Given that renal function is often impaired in older patients, adequate fluid intake must be ensured. In intravenous acyclovir administration, when GFR ≤ 50 ml/min, the dosage interval should be prolonged to 12 hours; when GFR ≤ 25 ml/min, it should be increased to 24 hours. When GFR < 10 ml/min, half of the single dose should be infused once every 24 hours, after hemodialysis. In older patients, and those with impaired renal function, higher dosages are associated with a greater risk of neurological side effects (e.g., dizziness, confusion, psychotic symptoms, and somnolence). Table 4 gives an overview of the pharmacokinetics and pharmacodynamics of commonly used dermatologic drugs, as well as important aspects in regard to treating older patients.
General information on pharmacotherapy in advanced age Given multimorbidity, and thus the use of multiple medications, treating geriatric patients is a particular challenge for physicians. This is evidenced by the fact that uniform recommendations on pharmacotherapy are lacking for the treatment of geriatric patients. The following tips may be useful when treating older patients [2, 4, 7, 11]:
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Table 4 Common dermatologic drugs and important aspects when prescribing this medications to elderly people [2, 4, 7, 9, 10]. Agent
Pharmacokinetics/-dynamics
Important aspects in older patients
Acyclovir
Renal clearance
Nephrotoxicity
Adjust dosing interval to renal function Adequate hydration Dizziness, confusion
Acitretin
Lipophilic, hepatic metabolism, renal excretion
Prolonged elimination half-life Contraindicated in patients with severe renal or liver
insufficiency, manifest diabetes, or severe metabolic disorders Azathioprine
Brivudine
Intrahepatic activation to form 6-mercaptopurine, renal excretion
Reduce dose in liver or kidney insufficiency
Accumulation increased toxicity of 5-fluoropyrimidine (5-fluoropyrimidine)
Combination use with 5-fluoropyrimidine (5-Fluorouracil,
Renal excretion
Dose reduction in renal insufficiency
Dose reduction to 25% with concomitant use of allopurinol Lowers warfarin levels
capecitabine, floxuridine, tegafur, flucytosine) No dosage modification in advanced age, required for renal
or liver insufficiency Cetirizine
Contraindicated if GFR < 10 ml/min
Cephalosporin
Primarily renal excretion
Dose adjustment in renal insufficiency Certain cephalosporins increase warfarin levels
Cyclosporine
Hepatic metabolism via CYP3A3/3A4, biliary excretion, nephro- and neurotoxicity
Start in low range of dosage, control kidney values and
blood pressure Dose optimization based on serum levels Numerous drug interactions Elevates digitoxin levels
Ciprofloxacin
Renal excretion, CYP1A2 inhibitor
Dose reduction in renal insufficiency Increases warfarin levels Risk of prolonged QT time, tendon rupture,
and delirium Dapsone
Metabolism via CYP3A3/3A4
Contraindicated in patients with severe liver
insufficiency Dimethyl fumarate
Hydrolysis to form methyl hydrogen fumarate, animal studies show excretion via respiration
Dose reduction in renal and liver insufficiency
Dimetindene
Lipophilic, renal and biliary excretion
Sedation, anticholinergic side effects
Famciclovir
Renal excretion
Increases warfarin levels
Contraindicated in patients with gastrointestinal ulcers
Disorientation, somnolence
Fluconazole
CYP2C9/3A4 inhibitor, renal excretion
Increases warfarin levels In advanced age, dosage adjustment only with renal
insufficiency Contraindicated in patients with severe liver insufficiency
Hydroxyzine
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Strongly lipophilic, metabolism via CYP3A4, renal excretion
Sedation, anticholinergic side effects Prolonged elimination half-life Dose reduction in renal and liver insufficiency
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Table 4 Continued. Agent
Pharmacokinetics/-dynamics
Important aspects in older patients
Isotretinoin
Hepatic metabolism via C YP enzymes
Contraindicated in patients with severe liver insufficiency
or serious metabolic disorder In kidney insufficiency start with low dose
Itraconazole
CYP3A4/3A5 inhibitor
Elevates digitoxin levels Dose reduction in renal and liver insufficiency
Macrolides
Inhibitors and substrates of CYP3A4
Elevates warfarin and digitoxin levels Prolongs QT time Hepatotoxicity
Methotrexate
Penicillin
10 % of the dose undergoes hepatic metabolism, primarily renal excretion
In advanced age, administer in low range
Primarily renal excretion
In patients with severe renal insufficiency, reduce
Contraindicated in patients with liver damage,
greater alcohol use, and renal insufficiency (GFR < 60 ml/min) maintenance dose or dosing intervals (see Table 5)
Prednisone
Hepatic metabolism via CYP3A4
Due to numerous side effects, only use after carefully
weighing benefit-risk ratio In patients with liver insufficiency elimination half-life is
prolonged Use caution in combination with NSAIDs, oral diabetes drugs,
insulin, and coumarin Terbinafine
CYP2D6 inhibitor, renal e xcretion
No dosage adjustment needed in advanced age Not advised if creatinine clearance < 50 ml/min Contraindicated in patients with liver insufficiency Loss of appetite or anorexia
Tetracycline
Primarily renal excretion
Dosage reduction in renal insufficiency (except for
doxycycline) Contraindicated in patients with severe liver
insufficiency Elevates digitoxin levels
Abbr.: GFR, glomerular filtration rate; Crea-Cl, creatinine clearance
Table 5 Reduction of maintenance dose for benzylpenicillin depending on renal function [10]. GFR (ml/min)
Serum creatinine (mg/100 ml)
Dosage mill. IU benzylpenicillin (mg benzylpenicillin sodium)
Dosing interval (hrs.)
120
0.8
5 (3,000)
6
45
2.0
5 (3,000)
8
18
3.5
4 (2,400)
8
8
6.0
5 (3,000)
12
2
15.5
3 (1,800)
12
–
2 (1,200)
12
Under 2
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1. Strict indications for treatment with a clear treatment goal Before prescribing any drug, doctors should critically weigh the need for its use, the indications in older patients, and possible alternatives which have fewer side effects. In postoperative pain treatment, for instance, the use of a cold pack may provide adequate analgesia, rendering the use of NSAIDs – which have numerous side effects – unnecessary. In general, it is a good idea to avoid medications with a long half-life. In addition, clear treatment goals should be established and weighed against potential side effects of the medication. 2. Low initial dosage, carefully increasing (start low, go slow) In general, for older patients, the dosage should be lower than the adult dosage recommended in the product information. One may begin at 50 % of the recommended dosage and then slowly increase it. Slowly increasing the dosage is especially important for drugs with a narrow therapeutic range, such as methotrexate and aminoglycosides. 3. Adjust the dosage for impaired renal function Older patients often have impaired renal function, in spite of having normal serum creatinine levels. Renal function should be estimated based on age-adjusted creatinine clearance or by measuring creatinine levels in a 24-hour urine specimen. About half of all commonly prescribed medications are eliminated via the kidneys and require a dosage adjustment. This may be accomplished by giving a smaller single dose or by prolonging the dosing interval. 4. Adjusting the prescription to the patient’s life situation and comorbidities Older patients often have problems such as presbycusis and impaired vision, which may severely limit communication between the doctor and the patient. In order to improve patient compliance, the instructions for taking the drug should be printed in large and legible print. Doctors should double-check whether patients have understood their instructions and are able to follow them. For instance, osteoarthritis of the hand may make it difficult for some patients to open drug packaging alone. Establishing set times for taking medication, or using pill dispensers which allow drugs to be sorted in advance, can help if the patient is forgetful. 5. Routine control of drug effectiveness and observance of adverse drug events Regular controls should be performed to check the effectiveness of the medication and to critically evaluate the indications for its use. Given that older, multimorbid patients are often under the care of several physicians, the patient's medication list should be regularly controlled in regard to new drugs and potential interactions.
Summary Pharmacotherapy in older adults presents special challenges for the dermatologist, due to comorbidities, drug interactions, and compliance issues. Doctors should adhere to narrow indications for pharmacotherapy and establish clearly defined treatment goals. Especially when administering drugs with a narrow therapeutic range, the initial dosage should be low and then gradually increased. In addition, many systemic agents used in dermatology require dosage modifications for patients with impaired renal function. Routine controls and critical evaluation of the prescribed medication can significantly reduce the risk of adverse events.
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References
Correspondence to Dr. med. Dorothea Kratzsch Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Leipzig A.ö.R. Philipp-Rosenthal-Straße 23 04103 Leipzig E-mail: dorothea.kratzsch@ medizin.uniklinik-leipzig.de
1 Statistisches Bundesamt, Wiesbaden 2012, www.destatis.de 2 Wehling M. Klinische Pharmakologie, Georg Thieme Verlag, Stuttgart, 2005. 3 www.priscus.net 4 Endo JO, Wong JW, Norman RA, Chang AL. Geriatric pharmacology for the dermatologist. J Am Acad Dermatol 2013; 68: 521e1–10. 5 Hutchison LC, Sleeper RB. Fundamentals of geriatric pharmacotherapy: an evidencebased approach. Bethesda (MD): American Society of Health-System Pharmacists; 2010. 6 McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163–84. 7 Flammiger A, Maibach H. Dermatological drug dosage in the elderly. Skin Therapy Lett 2006; 11: 1–7. 8 Simons KJ, Watson WT, Chen XY, Simons FE. Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther 1989; 45: 9–14. 9 Karow T, Lang-Roth R. Allgemeine und spezielle Pharmakologie und Toxikologie, 20. Auflage, Thomas Karow (Verlag), Köln, 2012. 10 Fachinformationen der Medikamente. 11 Hilmer SN, McLachlan AJ, Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007; 21: 217–30.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1208
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CME Article
Fragen zur Zertifizierung durch die DDA 1.
Welcher Faktor kompliziert die
systemische Pharmakotherapie im Alter nicht? a) veränderte Pharmakokinetik b) veränderte Pharmakodynamik c) Einschränkungen beim Sehvermögen d) Verbesserung des Hörvermögens durch Hörgeräte e) Einschränkungen kognitiver Funktionen
2. a)
Was ist die Priscus-Liste? Ein pharmakologisches Nachschlagewerk, in dem ausführlich auf Pharmakokinetik und -dynamik von im Alter problematischen Arzneimitteln eingegangen wird. b) Eine Auflistung potenziell inadäquater Pharmaka im Alter, einschließlich möglicher Therapiealternativen. c) Eine Liste, welche konkrete Empfehlungen für die dermatologische Pharmakotherapie im Alter gibt. d) Eine Leitlinie zur topischen Therapie im Alter. e) Dermatologische Pharmaka werden von der Priscus-Liste nicht erfasst.
3.
Welche Aussage bezüglich der
Pharmakokinetik im Alter trifft zu? a) Die enterale Resorption ist erhöht. b) Das Fettgewebe nimmt zu Gunsten des Körperwassers ab. c) Die Plasmaeiweißbindung ist erhöht. d) Die Nierenfunktion bleibt unverändert. e) Kreatinin kann trotz altersbedingter Niereninsuffizienz normal oder nur leicht erhöht sein.
4. Die Einnahme welcher Medikamente erhöht das Risiko für kognitive Störungen nicht wesentlich? a) selektive Serotonin- Wiederaufnahmehemmer (SSRI)
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b) Narkotika c) Benzodiazepine d) trizyklische Antidepressiva e) Antihistaminika der ersten Generation
5.
Welches Antihistaminikum
wurde von der Priscus-Liste als im Alter p otenziell inadäquat klassifiziert? a) Dimetinden b) Cetirizin c) Loratadin d) Desloratadin e) Mizolastin
6. Was ist keine Nebenwirkung einer systemischen Glukokortikosteroidtherapie? a) Erhöhung des Blutzuckers b) Zunahme der Knochendichte c) Erhöhtes Thromboserisiko d) Magen-Darm-Ulzerationen e) Erhöhte Infektanfälligkeit
7.
Ab welcher Kreatinin-Clearance
ist Methotrexat kontraindiziert? a) 80 ml/min b) 60 ml/min c) 40 ml/min d) 20 ml/min e) 10 ml/min
8. Welche Aussage zu I mmunsuppressiva trifft zu? a) Die Elimination von Methotrexat erfolgt überwiegend hepatisch. b) Bei Methotrexat ist im Alter keine Dosisanpassung erforderlich. c) Erhöhte Spiegel an Ciclosporin gehen mit Nephro- und Neurotoxizität einher. d) Ciclosporin kann bei älteren Patienten die Digitoxinwirkung abschwächen.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1208
e)
Bei Kombination von Azathioprin mit Allopurinol ist eine Dosisreduktion um 60 % notwendig.
9. Bei welchem Medikament ist bei Niereninsuffizienz keine Dosisanpassung erforderlich? a) Brivudin b) Cetirizin c) Aciclovir d) Penicillin e) Ciprofloxacin
10. Welcher allgemeine Hinweis zur Pharmakotherapie im Alter trifft nicht zu? a) Nebenwirkungsärmere Therapiealternativen sollten bevorzugt werden. b) Start low, go slow. c) Die Dosis sollte an eingeschränkte Organfunktionen angepasst werden. d) Regelmäßige Kontrolluntersuchungen sollten vermieden werden. e) Die Verordnung sollte an die Lebenssituation des Patienten angepasst sein.
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 18. September 2014. Die richtige Lösung zum Thema „Kutane Lymphome“ in Heft 1 ( Januar 2014) ist: (1d, 2b, 3e, 4a, 5a, 6b, 7b, 8c, 9a, 10d).
Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg. akademie-dda.de ein.
