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Transcript
Clinical Pharmacology From The Merck Manual of Geriatrics Introduction Safe, effective pharmacotherapy is one of the greatest challenges in clinical geriatrics. Special considerations are necessary when prescribing drugs (see Table 6-1). The elderly have many chronic disorders and consequently use more drugs than any other age group. Their diminished physiologic reserves can be further depleted by effects of drugs and acute or chronic disease. Aging alters pharmacokinetics and pharmacodynamics, affecting the choice, dose, and dosing frequency of many drugs. Pharmacotherapy may also be complicated by an elderly patient's inability to purchase or obtain drugs or to comply with drug regimens. In the USA, about two thirds of persons >= 65 years use prescription and over-thecounter (OTC) drugs; this age group accounts for about one third of all prescription drug use. Women use more drugs than men, especially psychoactive and antiarthritic drugs. At any time, an average elderly person uses four to five prescription drugs and two OTC drugs and fills 12 to 17 prescriptions a year. The frail elderly use the most drugs. Drug use is greater in hospitals and nursing homes than in the community; typically, a nursing home resident uses seven or eight drugs. The type of drug used most often by the elderly varies with the setting. Community dwellers use analgesics, diuretics, cardiovascular drugs, and sedative-hypnotics most often, whereas nursing home residents use antipsychotics and sedative-hypnotics most often, followed by diuretics, antihypertensives, analgesics, cardiovascular drugs, and antibiotics. According to some surveys, psychoactive drugs are prescribed for 65% of nursing home patients and for 55% of residential care patients; 7% of patients in nursing homes use three or more psychoactive drugs concurrently. Appropriateness (the potential benefits of a drug outweigh the potential risks) should guide therapy. Determining appropriateness requires an evaluation of such potential benefits and risks. Many drugs benefit the elderly, and some can save lives--eg, antibiotics and thrombolytic therapy for acute illness. Oral hypoglycemic drugs can improve independence and quality of life while controlling diabetes. Antihypertensive drugs and influenza vaccines can help prevent or decrease morbidity. Analgesics and antidepressants can control debilitating symptoms. However, adverse effects of many drugs are more common and serious in the elderly. Polypharmacy (concurrent use of many drugs) alone is not an accurate measure of appropriateness of therapy because the elderly often have many disorders requiring treatment; however, it may reflect inappropriate prescribing. Many elderly patients in hospitals and nursing homes routinely receive drugs that are not essential (eg, sedativehypnotics, analgesics, histamine [H2] blockers, antibiotics, laxatives) and can cause harm, directly or through interactions. A thorough review of drugs can often reduce the number of drugs used and, according to limited data, improve patient outcomes. Underuse of some drugs is also a significant problem among elderly patients. For example, antidepressant use in nursing homes is low compared with the high prevalence of depression. Also, the dose of antidepressants often is too low and duration of therapy too short. Drugs for incontinence and preventive treatments (eg, glaucoma drugs, influenza and pneumococcal vaccines) are also underused. Patient and caregiver issues: Increasingly, elderly patients are aware of their diagnoses and the drugs they use for treatment; however, many need to be encouraged to bring health problems and potential drug-related problems to the attention of their physician or caregiver. In particular, patients should be asked to report their use of all drugs (eg, prescription and OTC drugs, vitamins, nutritional supplements) and to report any changes at each visit. Periodically, they should be asked to bring their drugs to the office for review and for comparison with the drug record. The physician should review and update the treatment regimen at each visit. While doing so, the physician can ask about adherence (compliance). When adherence appears to be deficient, efforts should be made to simplify the regimen and to suggest useful aids to enhance adherence (eg, drug calendars, drug dispensers). The physician should also discuss how drugs should be taken (eg, with or without food, route of administration), their mechanism of action, important adverse effects, and appropriate storage. Patients should recognize the role of the pharmacist as a member of the health care team and as a resource for information. The time devoted to communicating with patients about drugs and their usage builds trust and enhances overall patient care. Pharmacokinetics The time course by which the body absorbs, distributes, metabolizes, and excretes drugs. Absorption: Despite an age-related decrease in small-bowel surface area and an increase in gastric pH, changes in drug absorption tend to be trivial and clinically inconsequential. Distribution: Total body water decreases by 10 to 15% between ages 20 and 80 years. In contrast, the percentage of body weight that is body fat increases from 18 to 36% in men and from 33 to 45% in women. The relative decrease in total body water and thus in sodium space leads to higher blood (and often tissue) concentrations of some watersoluble drugs. Increased body fat increases the volume of distribution for lipophilic drugs and may result in increased elimination half-lives. With age, serum albumin levels decrease slightly and 1-acid glycoprotein levels increase, but the clinical effect of these changes on serum drug binding is unclear. In a patient with acute disease or malnutrition, rapid decreases in the serum albumin level may enhance drug effects because serum concentrations of unbound drug are increased until metabolic excretory compensation occurs. Hepatic metabolism: With age, hepatic mass and hepatic blood flow decrease. Decreased hepatic blood flow significantly affects hepatic elimination of drugs in rare situations--eg, when a drug with high clearance, such as lidocaine, is given IV. Although expression of drug-metabolizing enzymes in the cytochrome P-450 system does not appear to decrease with age, overall hepatic metabolism of many drugs by these enzymes is reduced. For drugs with reduced hepatic metabolism (see Table 6-2), clearance typically decreases 30 to 40%. Theoretically, maintenance drug doses should be reduced by the same percentage; however, the rate of hepatic metabolism of drugs can vary greatly from person to person, and individual titration is required. In the elderly, presystemic (first-pass) metabolism of some oral drugs (eg, labetalol, propranolol, verapamil) is reduced, increasing their serum concentration and bioavailability. Consequently, initial doses of these drugs should be reduced by about 30%. However, presystemic metabolism of other metabolized drugs (eg, imipramine, amitriptyline, morphine, meperidine) is not reduced. Hepatic clearance of drugs metabolized by the cytochrome P-450 system (phase I reactions)--eg, diazepam, amitriptyline, chlordiazepoxide--is often reduced in the elderly. Age less often has been shown to affect the clearance of drugs that are metabolized by glucuronate or sulfate conjugation (synthetic or phase II reaction), such as lorazepam, desipramine, and oxazepam. Many drugs produce active metabolites in clinically relevant concentrations. Examples are some benzodiazepines (eg, diazepam, chlordiazepoxide), tertiary amine antidepressants (eg, amitriptyline, imipramine), antipsychotics (eg, chlorpromazine, thioridazine, risperidone), and opioid analgesics (eg, morphine, meperidine, propoxyphene). Accumulation of active metabolites (eg, N-acetylprocainamide, morphine-6-glucuronide) increases the risk of toxicity in the elderly due to age-related decreases in renal clearance, particularly in patients with renal disease, unless the maintenance doses are reduced. Renal elimination: With age, renal mass and renal blood flow (mainly in the renal cortex) decrease significantly. After age 30, creatinine clearance decreases an average of 8 mL/min/1.73 m2/decade in about two thirds of persons but remains the same in the rest. However, serum creatinine levels may remain within normal limits because the elderly have less lean body mass and produce less creatinine. Decreases in tubular function parallel those in glomerular function. These physiologic changes decrease renal elimination of drugs (see Table 6-2). Clinical implications depend on the contribution of renal elimination to total systemic elimination and on the drug's therapeutic index (ratio of the maximum tolerated dose to the minimum effective dose). Creatinine clearance (measured or estimated using computer programs or the Cockcroft-Gault formula) is used to guide drug dose. The Cockcroft-Gault formula uses the serum creatinine concentration to calculate creatinine clearance (Clcreat): For women, the calculated values are multiplied by 0.85. Because renal function is dynamic, maintenance doses of drugs should be adjusted if a patient becomes acutely ill or dehydrated or has recently recovered from dehydration. Also, because renal function may continue to decline with age, the dose of drugs given long-term should be reviewed periodically. Pharmacodynamics The time course and effect of drugs on cellular and organ function. In the elderly, the effects of similar drug concentrations at the site of action may be larger or smaller than those in younger persons (see Table 6-3). The difference may be due to changes in drug-receptor interaction, in postreceptor events, or in adaptive homeostatic responses; among frail patients, the difference is often due to organ pathology. Increased sensitivity due to aging must be considered when drugs that can have serious adverse effects are used. These drugs include morphine, pentazocine, warfarin, angiotensin-converting enzyme inhibitors, diazepam (especially given parenterally), and levodopa. Some drugs whose effects are reduced with normal aging (eg, tolbutamide, glyburide, -blockers) should also be used with caution in elderly patients because serious dose-related toxicity can occur and signs of toxicity may be delayed. Stimulation of receptors increases intracellular cyclic adenosine monophosphate (cAMP). This activates a protein kinase, an enzyme that phosphorylates proteins, leading to altered cellular function. In elderly persons, the cAMP response to agonists is decreased in human lymphocytes and cardiac tissue, apparently due to reduced binding affinity of agonists for the receptor and to changes in postreceptor response. Desensitization is not responsible. Up-regulation of receptors in the heart and lymphocytes after -blockade is unaltered by aging. These changes, however, are tissuespecific and differ in other tissues (eg, adipocytes). Thus, the chronotropic response to bolus administration of the agonist isoproterenol (isoprenaline) becomes blunted with age. However, sensitivity to isoproterenol is reduced in both the young and old by nonselective -blockers (eg, propranolol). The effect of propranolol may be due to blockade of receptors in the peripheral vasculature or in the heart. However, the heart rate response to isoproterenol bolus dosing is largely due to baroreflex responses of vagal withdrawal and sympathetic activation rather than to the direct effect of receptor activation. Thus, the blunted chronotropic response in the elderly is largely abolished by autonomic blockade by atropine and clonidine, which block the component of the chronotropic response due to baroreceptor reflex activation secondary to isoproterenolinduced vasodilatation. This effect shows that evaluation of drug responses must consider counterregulatory mechanisms. With age, central nervous system sedation by benzodiazepines is increased. This increase is clinically important. For effective and safe acute sedation, the dose of midazolam should be decreased by 30% in elderly patients because of pharmacodynamic changes with age. The effect of oral triazolam is also increased, but this increase is due to increased drug levels rather than to increased sensitivity. Similar pharmacokinetic and pharmacodynamic considerations apply to long-acting benzodiazepines such as chlordiazepoxide, diazepam, and flurazepam, all of which undergo oxidation to active metabolites that accumulate with chronic dosing and have a prolonged effect. The renal response to furosemide or dopamine is reduced. However, while the acute bronchodilator responses to albuterol (a 2 agonist) are reduced with age in normal subjects, the responses to albuterol or ipratropium (a muscarinic antagonist) are unaltered with age in patients with asthma or chronic obstructive pulmonary disease. Adverse Drug Reactions About one third of drug-related hospitalizations and one half of drug-related deaths occur in persons > 60. The elderly are at increased risk of toxicity from certain drugs, especially long-acting benzodiazepines, nonsteroidal anti-inflammatory drugs, warfarin, heparin, aminoglycosides, isoniazid, high doses of thiazides, antineoplastic drugs, and most antiarrhythmics (see Table 6-4). Increased risk has not been demonstrated with other drugs (eg, -blockers, antihypertensives, lidocaine, propafenone). Increased susceptibility may result from age-associated changes in pharmacokinetics or pharmacodynamics or from disorders aggravated by drugs (eg, prostatism by anticholinergic drugs, postural hypotension by diuretics). The risk of an adverse drug reaction increases exponentially with the number of drugs used, in part because polypharmacy reflects the presence of many diseases and provides an opportunity for drug-disease and drug-drug interactions. Drug-disease interactions (exacerbation of a disease by a drug) can occur in any age group but are especially important in the elderly because of the increased prevalence of disease and the difficulty in differentiating often subtle adverse drug reactions from the effects of disease (see Table 6-5). Anticholinergic drugs are a common cause of such interactions (eg, with glaucoma, benign prostatic hyperplasia, Alzheimer's disease, dry eyes, or xerostomia). Drug-drug interactions (the altered pharmacokinetics or pharmacodynamics of a drug when taken concomitantly with one or more other drugs) are myriad (see Table 6-6). Few prospective studies of drug-drug interactions in the elderly have been conducted. One study showed that 40% of ambulatory elderly patients were at risk of drug-drug interactions; 27% of these interactions were potentially serious (eg, quinidine-digoxin interaction). Inhibition of one drug's metabolism by another does not appear to change with age; eg, cimetidine and ciprofloxacin inhibit the metabolic rate of theophylline by about 30% in older and younger healthy persons. Aging's effect on induction of drug metabolism varies; eg, induction of theophylline metabolism by phenytoin is similar in older and younger persons, whereas induction of drug metabolism by dichloralphenazone, glutethimide, and rifampin may be decreased in older persons. Concurrent use of drugs with similar toxicities can result in serious adverse reactions in the elderly. For example, concurrent use of anticholinergic drugs, such as antiparkinsonian drugs (eg, benztropine), tricyclic antidepressants (eg, amitriptyline, imipramine), antipsychotics (eg, thioridazine), antiarrhythmics (eg, disopyramide), and OTC antihistamines (eg, diphenhydramine, chlorpheniramine) may cause or worsen dry mouth, gum disease, blurred vision, constipation, urinary retention, and delirium. Considerations for Effective Pharmacotherapy The principal clinical concerns include efficacy and safety, dose, complexity of regimen, cost, and patient compliance. Efficacy and safety are important considerations when prescribing drugs. Because the risk/benefit ratio of drug therapy can be less favorable in the elderly (ie, the risk of adverse effects is increased), it is important to use drugs with documented effectiveness and the lowest toxicity. Drug selection is particularly important for the very old with chronic conditions (eg, hypertension, new-onset diabetes), in whom outcomes are less certain. For example, the benefit of treatment of uncomplicated hypertension in patients >= 80 is less well established than in those < 80. Therapeutic goals (eg, reduction of blood pressure or glycosylated hemoglobin [Hb A1c]) may have to be modified to minimize the risk of dose-related adverse effects. Dose must often be reduced in the elderly, although dose requirements vary considerably (up to fivefold) from person to person. In general, starting doses of drugs with a low therapeutic index are about one third to one half the usual adult doses. If a patient has a clinical problem that may be exacerbated by a drug, the usual starting dose should be reduced by about one half, especially if elimination of the drug is reduced with age. Complexity of drug regimens (eg, multiple drugs, frequent dosing, variable doses) increases the risk of noncompliance. If a patient has more than one disorder (eg, hypertension and angina), it may be possible to treat both conditions with a single drug (eg, a -blocker or calcium [Ca] channel blocker), thus reducing the number of drugs prescribed. Drugs with once- or twice-daily dosing (long-acting or slow-release preparations) enable better compliance than do those with more frequent dosing. The drug regimen should be discussed with the patient to help form a partnership and to keep the regimen simple. Cost of drugs can impose a major financial burden, particularly for elderly patients who rely on fixed incomes. Prescribers need to be aware of drug costs and to discuss cost. When cost is a factor, the least expensive comparable therapy should first be considered (eg, thiazide diuretics for hypertension). Compliance (adherence) is affected by many factors, but probably not by age per se. However, about 40% of elderly patients do not take their drugs as directed, usually taking less drug than prescribed. Patients are more like to comply if they have a good relationship with their physician, in which they are included in the decision making and the physician shows concern that they comply. Clear prescription instructions and explanations of why the treatment is necessary and what to expect (eg, delayed benefits, general adverse effects) also help ensure compliance. Trust in the physician is crucial. Encouraging patients to ask questions and express their concerns can help them come to terms with the severity of their illness and intelligently weigh the advantages and disadvantages of a treatment regimen. Discussing the unconscious mechanism of denial of illness and how it leads to "forgetting" or otherwise not taking the drug as directed can help patients avoid that pitfall. They should be urged to report any unwanted or unexpected effects to their physician before adjusting or stopping the treatment on their own. Patients often have good reasons for not following a regimen, and their physician can make an appropriate adjustment after a frank discussion of the problem. Pharmacists and nurses may detect and help solve compliance problems. For example, the pharmacist may note that the patient does not obtain refills or that a prescription is illogical or incorrect. In reviewing prescription directions with the patient, a pharmacist or nurse may uncover a patient's misunderstandings or fears and alleviate them. Communication among all health care practitioners providing care for a patient is important. Support groups for patients with certain disorders can often reinforce treatment plans and provide suggestions for coping with problems. Drug Classes of Concern Some drug classes (eg, diuretic, antihypertensive, antiarrhythmic, antiparkinsonian, anticoagulant, psychoactive, hypoglycemic, and analgesic drugs) pose special risks for the elderly. Some individual drugs pose similar risks (see Table 6-4), and safer alternatives are often available. Diuretics: Lower doses of thiazide diuretics (eg, hydrochlorothiazide or chlorthalidone 12.5 to 25 mg) can control hypertension, with less risk of hypokalemia and hyperglycemia than higher doses. Thus, potassium supplements or potassium-sparing diuretics may be required less often. Doses > 25 mg/day have been associated with increased mortality rates. Antihypertensives: Treatment of hypertension is effective in elderly patients; treatment of only 18 elderly patients for 5 years prevents one cardiovascular event. Different classes of antihypertensives (see Table 85-3) have comparable efficacy in elderly white patients; however, in elderly black patients, -blockers and angiotensinconverting enzyme inhibitors are generally less effective, whereas diuretics and Ca channel blockers are most effective. Whether any antihypertensives are preferable because they best preserve quality of life in the elderly is unclear. If tolerated, diuretics are the first choice for elderly patients because these drugs reduce cardiovascular morbidity rates and cardiovascular and all-cause mortality rates. Long-acting dihydropyridine-type Ca channel blockers (eg, amlodipine, felodipine, sustained-release nifedipine) also appear to reduce cardiovascular events in the elderly. Short-acting dihydropyridines (eg, nifedipine) should not be used because of an increased mortality risk. The benefits of -blockers for hypertension in the elderly have been questioned. Contraindications to -blockers include chronic obstructive pulmonary disease and peripheral vascular disease; to clonidine, depression; and to vasodilators and -blockers, underlying orthostatic hypotension. Antiarrhythmics: Antiarrhythmics have the same indications and efficacy in older and in younger patients. However, because of altered pharmacokinetics, the dose of some (eg, procainamide, quinidine, lidocaine) should be reduced in the elderly. In addition, the risk of significant adverse reactions to certain drugs (eg, mexiletine; class IC drugs, such as encainide and flecainide) increases with age. Digoxin clearance decreases an average of 50% in elderly patients with normal serum creatinine levels. Therefore, maintenance doses should be started low (0.125 mg/day) and adjusted according to response and serum digoxin levels. Antiparkinsonian drugs: Levodopa clearance is reduced in elderly patients, who are also more susceptible to postural hypotension and confusion. Therefore, elderly patients should receive low starting doses of levodopa and should be monitored closely for adverse effects. Patients who become confused while taking levodopa may not better tolerate the newer dopamine agonists (eg, bromocriptine, pergolide, pramipexole, ropinirole). With long-term levodopa treatment, motor complications such as on-off fluctuations and dyskinesias occur. Whether these complications are due to disease progression or to levodopa therapy is unclear. Some neurologists advocate early use of dopamine agonists to reduce exposure to levodopa, thus avoiding or delaying these motor complications. The success of this strategy has not been demonstrated. Because elderly patients with parkinsonism may be cognitively impaired, anticholinergic drugs should be avoided when possible. Anticoagulants: Aging does not alter the pharmacokinetics of warfarin but may increase sensitivity to its anticoagulant effect (increased prothrombin time or international normalized ratio). Elderly patients generally require lower loading (< 7.5 mg) and maintenance (usually < 5 mg/day) doses of warfarin. If the drug must be stopped (eg, before surgery), the reversal to normal clotting status may be slower in elderly patients than in younger patients. Psychoactive drugs: In nonpsychotic, demented patients with behavioral disorders, antipsychotics control symptoms only marginally better than do placebos. Although antipsychotics can reduce paranoia, they may worsen confusion. Elderly patients, especially women, are at increased risk of tardive dyskinesia, which is often irreversible. Sedation, postural hypotension, anticholinergic effects, and akathisia (subjective motor restlessness) commonly occur in elderly patients using an antipsychotic. Drug-induced parkinsonism can persist for up to 9 months after the drug is stopped. One goal of the U.S. Omnibus Budget Reconciliation Act of 1987 was to reduce the use of antipsychotics as chemical restraints in nonpsychotic elderly patients. When an antipsychotic is used in the elderly, the starting dose should be about one quarter the usual adult dose and increased gradually. Risk of extrapyramidal dysfunction appears to be less with the new atypical antipsychotics (eg, olanzapine, quetiapine, risperidone)--a potential advantage in the elderly. However, experience with these drugs in the elderly is limited, and initial dose reduction is required (eg, risperidone 2 to 4 mg/day). In frail nursing home patients, a starting dose of 2 mg/day is appropriate. The elderly appear to tolerate olanzapine reasonably well. The use of anxiolytics and hypnotics is problematic. Different benzodiazepines appear equally effective in relieving anxiety symptoms; selection depends on the drug's pharmacokinetics and pharmacodynamics. Treatable causes of insomnia should be sought and managed before using hypnotics. In general, short-acting to intermediate-acting benzodiazepines with half-lives < 24 hours (eg, alprazolam, lorazepam, oxazepam, temazepam) are preferable for inducing sedation or sleep. Long-acting benzodiazepines should be avoided because the risk of accumulation and toxicity is increased, leading to drowsiness, impaired memory, and impaired balance with falls and fractures. Drug treatment of anxiety or insomnia should be limited to short-term or occasional use if possible because tolerance and dependence may develop; withdrawal may lead to rebound insomnia and anxiety. Buspirone, a partial serotonin agonist, is as effective as benzodiazepines in the treatment of general anxiety disorder; elderly patients tolerate doses up to 30 mg/day. Buspirone's slow onset of action (up to 2 to 3 weeks) can be a disadvantage in cases requiring rapid effect. Zolpidem is a nonbenzodiazepine hypnotic that binds mainly to a benzodiazepine receptor subtype; elderly patients with insomnia appear to tolerate doses of 5 to 10 mg. Zolpidem's advantages over benzodiazepines include less disturbance of the sleep profile, fewer rebound effects, and less dependence potential. H1 blockers (eg, diphenhydramine, hydroxyzine) are not recommended because of their anticholinergic effects. In general, the antidepressants of choice are the selective serotonin reuptake inhibitors (SSRIs--eg, fluoxetine, paroxetine, sertraline, citalopram). SSRIs appear to be as effective as tricyclic antidepressants but produce less toxicity, especially in overdose. One possible disadvantage of fluoxetine is its long elimination half-life, especially of its active metabolite. Paroxetine is more sedating, has anticholinergic action, and, similar to fluoxetine, can inhibit hepatic cytochrome P-450 2D6 enzyme activity, with risk of impairing the metabolism of several drugs (eg, some antipsychotics, antiarrhythmics, and tricyclic antidepressants). Sertraline is more activating, but diarrhea is a common adverse effect. Both sertraline and citalopram appear to have less drug interaction potential. The hepatic clearance of citalopram is reduced in elderly patients. Initial doses of SSRIs should be reduced by up to 50% in the elderly. Tricyclic antidepressants are effective. Those with the fewest adverse effects are best for the elderly, and those with significant anticholinergic (eg, amitriptyline, imipramine), antihistaminic (eg, doxepin), and antidopaminergic (eg, amoxapine) effects are best avoided. The norepinephrine reuptake inhibitors nortriptyline and desipramine, starting at 10 to 25 mg/day, are most suitable. Both have low anticholinergic potency, and nortriptyline has the least -blocking (hypotensive) action. However, overdose produces cardiac and neurologic toxicity, precluding the use of these drugs in patients at risk of suicide. Trazodone is now used mainly for sedation in patients with depression and insomnia. It has low anticholinergic potency. Trazodone is less cardiotoxic than tricyclics, but it can produce orthostatic hypotension and priapism. Bupropion is noncardiotoxic but, at higher doses, increases the risk of seizures. Newer drugs (eg, mirtazapine, nefazodone, venlafaxine) are useful for patients not responding to or intolerant of SSRIs. Methylphenidate can be useful in treating some elderly patients with depression who have had a stroke or who have an enervating medical illness. The drug's onset of action is rapid. Monoamine oxidase inhibitors (eg, tranylcypromine, phenelzine) should be prescribed only by psychiatrists with experience in treating elderly patients. Hypoglycemics: Recent information indicates that treatment of type II diabetes mellitus can improve outcomes, especially microvascular complications. Elderly diabetic patients with reasonable life expectancy deserve careful and aggressive treatment to reduce Hb A1c to about 7%. This reduction may be impossible because of risks of hypoglycemia or resistance to treatment. Oral hypoglycemics remain the mainstay of treatment of type II diabetes. Sulfonylureas increase insulin secretion. They are effective in and well tolerated by elderly patients. However, the incidence of hypoglycemia due to sulfonylureas may increase with age. Chlorpropamide is not recommended because elderly patients are at increased risk of hyponatremia and because the drug's prolonged duration of action is dangerous if toxicity or hypoglycemia occurs. Aging can reduce insulin clearance, but the dose of insulin depends on the level of insulin resistance, which varies widely among patients with type II diabetes. Metformin, a biguanide excreted by the kidney, increases peripheral tissue sensitivity to insulin and can be effective alone or in combination with sulfonylureas. However, longterm efficacy and safety in elderly patients are not well established. Risk of lactic acidosis, a rare but serious complication, increases with the degree of renal impairment and the patient's age. Metformin is contraindicated in patients with renal disease or renal dysfunction (ie, serum creatinine >= 1.5 mg/dL [>= 130 µmol/L] in men or >= 1.4 mg/dL [>= 120 µmol/L] in women) or in those with an abnormal creatinine clearance. Thiazolidinediones (eg, rosiglitazone, pioglitazone) improve blood glucose control by increasing peripheral tissue sensitivity to insulin's effects. They are most appropriate as reserve drugs to control blood glucose in patients taking other oral drugs or insulin. Regular monitoring of liver enzymes is advised to detect the development of hepatotoxicity. Hepatic failure with the use of troglitazone led to removal of this drug from the US market. It is not known whether aging increases the risk of hepatotoxicity. Weight gain due to edema can also occur, and for that reason these drugs should not be used in patients with poorly controlled heart failure. Acarbose, administered with food, reduces postprandial glucose elevations and, in combination with other hypoglycemics, can help improve blood sugar control in some patients. Gastrointestinal intolerance may occur. Analgesics: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, and several are available without prescription. Some data indicate that the clearance of salicylate, oxaprozin, and naproxen is decreased in elderly patients. The risk of peptic ulceration and upper gastrointestinal(GI) bleeding, which can be serious, is greater when an NSAID is begun and when the dose is increased. Ibuprofen, diclofenac, and salsalate may be slightly less likely to cause upper GI bleeding. Aging does not seem to increase the risk of NSAID-induced adverse GI effects; however, these complications, when they occur, increase morbidity and mortality rates in elderly patients. The risk of upper GI hemorrhage increases more than 10-fold when NSAIDs are combined with warfarin. For elderly patients with a high risk of NSAIDinduced gastroduodenal complications, misoprostol (a synthetic prostaglandin E1 analog), a more potent gastric acid inhibitor (eg, omeprazole, lansoprazole), or high-dose H2 blockers can be added. Such drugs can reduce the risk of peptic ulceration. The risk of NSAID-induced renal impairment may be increased in elderly patients. Monitoring the serum creatinine level is reasonable, especially in patients with other risk factors (eg, heart failure, renal impairment, cirrhosis with ascites, volume depletion, diuretic use). Because elderly persons are at higher risk of poor outcomes due to complications, NSAIDs should be tried only when less toxic analgesics (eg, acetaminophen) have failed. NSAIDs should be used at the lowest effective dose. NSAIDs nonselectively inhibit cyclooxygenase (COX)-1 (leading to gastrointestinal and renal toxicity) and COX-2 (leading to anti-inflammatory effects). Selective COX-2 inhibitors (also called coxibs) appear to have anti-inflammatory and analgesic properties similar to those of conventional nonselective NSAIDs but cause less GI toxicity. COX-2 inhibitors thus may be safer than NSAIDs for elderly patients, particularly those patients with a history of gastroduodenal ulceration or bleeding. However, one of the COX-2 inhibitors, rofecoxib (withdrawn from market), appears to increase the risk of cardiovascular events after long-term use. The risk of cardiovascular events with other COX-2 inhibitors is undergoing evaluation. Because one study has shown a 2.5-fold increase in cardiovascular events with celecoxib, FDA recommendations, pending further evidence, are to limit use of any coxib to patients who are at a high risk of GI bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well on nonselective NSAIDs. Use of coxibs for long periods or in patients with cardiovascular risk factors should be approached cautiously.