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 A_1c]) 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 angiotensin-converting 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 A_1c 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, long-term 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 NSAID-induced 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.