drug categories of concern in elderly

Some drug categories (eg, analgesics, anticoagulants, antihypertensives, antiparkinsonian drugs, diuretics, hypoglycemic drugs, psychoactive drugs) pose special risks for elderly patients. Some, although reasonable for use in younger adults, are so risky as to be considered inappropriate for the elderly. The Beers Criteria are most commonly used to identify such inappropriate drugs (see Table 5: Drug Therapy in the Elderly: High-Risk Drugs in the Elderly (Based on the Beers Criteria)). The Zhan expert panel further categorized some inappropriate drugs from the Beers Criteria into 3 groups:

Table 5

High-Risk Drugs in the Elderly (Based on the Beers Criteria)

Class
Drug
Prescribing Concern

Analgesics
Indomethacin

*
Of available NSAIDs, indomethacin

has the most CNS adverse effects and therefore should be avoided in the elderly.

Ketorolac

Immediate- and long-term use should be avoided in the elderly because many of them have asymptomatic and undiagnosed GI disorders.

Meperidine


Meperidine

is not an effective oral
analgesic and has many disadvantages compared with other opioids. It should be avoided in the elderly.

Non–COX-selective NSAIDs (naproxen

,
oxaprozin

,
piroxicam

)
Long-term use of the maximum dosage may cause GI bleeding, renal failure, hypertension, and heart failure.

Pentazocine


Pentazocine

is an opioid analgesic
that has CNS adverse effects (eg, confusion, hallucinations) more commonly than other opioids; it is a mixed agonist/antagonist. For both reasons, it should usually be avoided in the elderly.

Propoxyphene

‡ and
combination products that contain it
Propoxyphene

should usually be
avoided in the elderly. It has few analgesic advantages over acetaminophen

but has the adverse
effects of other opioids.

Antidepressants
Cyclic antidepressants (eg, amitriptyline

,*
doxepin

*)
Because of strong anticholinergic and sedating effects, amitriptyline

or
doxepin

is rarely the antidepressant
of choice for the elderly.

Fluoxetine

(taken
daily)
Fluoxetine

has a long half-life, may
cause excessive CNS stimulation and sleep disturbances, and may increase agitation. Safer alternative SSRIs exist.

Antihistamines
Chlorpheniramine

*

Cyproheptadine

*

Dexchlorpheniramine

Diphenhydramine

*

Hydroxyzine

*

Orphenadrine

Promethazine

*

Tripelennamine
All OTC and many prescription antihistamines have potent anticholinergic properties. Antihistamines are commonly included with other drugs in cough and cold preparations. However, many cough and cold preparations without antihistamines are available; they are safer alternatives for the elderly.

Antipsychotics
Mesoridazine

Thioridazine

Risk of CNS and extrapyramidal adverse effects is increased. When used to treat dementia-related behaviors, 2nd-generation (atypical) antipsychotics may increase mortality risk.

Cardiovascular drugs
Amiodarone

Adverse effects include QTc prolongation and risk of provoking torsades de pointes.

Clonidine

Adverse effects include orthostatic hypotension and CNS effects.

Digoxin

Because renal clearance of digoxin

is decreased in the elderly, doses should rarely exceed 0.125 mg/day, unless the patient is monitored.

Dipyridamole

*
Immediate-release dipyridamole

frequently causes orthostatic hypotension in the elderly (the controlled-release formulation in combination products may be acceptable). The immediate-release formulation is beneficial only in patients with artificial heart valves. If possible, it should be avoided in the elderly.

Disopyramide

*
Of all antiarrhythmics, disopyramide

is the most potent negative inotrope and therefore may induce heart failure in the elderly. It is also strongly anticholinergic. If antiarrhythmics are needed, others should be used.

Doxazosin

Adverse effects include hypotension, dry mouth, and urinary problems.

Ethacrynic acid

Adverse effects include hypertension and fluid imbalances.

Guanethidine

Guanadrel
Adverse effects include orthostatic hypotension.

Methyldopa

*
Methyldopa

may cause bradycardia
and exacerbate depression in the elderly. Alternate treatments for hypertension are generally preferred.

Nifedipine

(short-
acting)
Adverse effects include hypotension, constipation, and reflex tachycardia.

Reserpine

*
Doses > 0.25 mg pose unnecessary risks in the elderly by inducing depression, impotence, sedation, and orthostatic hypotension. Safer alternatives exist.

Ticlopidine

Ticlopidine

is no better than
aspirin

in preventing clotting and is
considerably more toxic. It should be used only as a 2nd-line drug in the elderly.

GI antispasmodics
Belladonna alkaloids†

Clidinium/chlordiazepoxide

Dicyclomine

Hyoscyamine

Propantheline


GI antispasmodics are highly anticholinergic and usually cause substantial toxicity in the elderly. Efficacy at doses tolerated by the elderly is questionable. All of these drugs are best avoided in the elderly, especially for long-term use.

Hypoglycemics
Chlorpropamide


Chlorpropamide

has a prolonged
half-life in the elderly and can cause prolonged, serious hypoglycemia. It is the only oral hypoglycemic that causes SIADH. It should be avoided in the elderly.

Laxatives (stimulant)
Bisacodyl

Cascara

Neoloid except when used with opioids
With long-term use, stimulant laxatives may exacerbate bowel dysfunction.

Muscle relaxants
Carisoprodol

Chlorzoxazone

Cyclobenzaprine

Metaxalone

Methocarbamol

Oxybutynin

*
Most muscle relaxants and antispasmodics are poorly tolerated by the elderly, resulting in anticholinergic effects, sedation, and weakness. Efficacy at doses tolerated by the elderly is questionable. If possible, they should not be used in the elderly. For extended-release oxybutynin

, the patch is better
tolerated.

Sedative-hypnotics
Alprazolam

*, § 2 mg

Lorazepam

3 mg

Oxazepam

60 mg

Temazepam

15 mg

Triazolam

0.25 mg
Because sensitivity to benzodiazepines is increased in the elderly, smaller doses may be effective as well as safer; total daily doses should rarely exceed those listed.

Barbiturates† (except phenobarbital

)
Barbiturates have more adverse effects in the elderly than most other sedative-hypnotics and are highly addictive. They should not be started as new therapy in the elderly except to control seizures.

Chlordiazepoxide

Chlordiazepoxide

/
amitriptyline

Clorazepate

Clidinium/chlordiazepoxide

Diazepam

Flurazepam

Halazepam

Nitrazepam

Quazepam

These long-acting benzodiazepines have a long half-life in the elderly (often days), causing prolonged sedation and increasing risk of falls and fractures. Short- or intermediate-acting benzodiazepines are preferred if a benzodiazepine is required.

Diphenhydramine

Diphenhydramine

is potently
anticholinergic and usually should not be used as a hypnotic in the elderly. When used to treat or prevent allergic reactions, it should be used in the smallest possible dose and with great caution.

Meprobamate

Meprobamate

is a highly addictive
and sedating anxiolytic. It should be avoided in the elderly. Elderly patients who take it for long periods may become addicted, and the drug may need to be withdrawn slowly.

Other
Amphetamines

Anorexics
These drugs may cause dependence, hypertension, angina, and MI. Amphetamines have CNS stimulant adverse effects (methylphenidate

may be useful for certain elderly patients).

Cimetidine

Cimetidine

has CNS adverse
effects, including confusion.

Cyclandelate

Ergot mesylates
These drugs in the doses studied have not been shown to be effective for treatment of dementia or any other disorder.

Desiccated thyroid
Cardiac effects are a concern. Safer alternatives exist.

Estrogens

only (oral)
Evidence suggests that estrogens

increase risk of breast and endometrial cancer and may increase risk of pulmonary embolism, stroke, and coronary artery disease in older women.

Ferrous sulfate

Doses > 325 mg/day do not substantially increase total absorption and are more likely to cause constipation.

Isoxsuprine

Isoxsuprine

is not effective in the
elderly.

Methyltestosterone

Adverse effects include benign prostatic hypertrophy and cardiac problems.

Mineral oil
Mineral oil may result in aspiration.

Nitrofurantoin

Nitrofurantoin

is ineffective in
patients with moderate to severe renal insufficiency; metabolites may cause peripheral neuropathy. Long-term use for UTI prevention can cause pulmonary fibrosis.

Trimethobenzamide


Trimethobenzamide

is one of the
least effective antiemetics and can have extrapyramidal adverse effects. When possible, it should be avoided in the elderly.
*Sometimes indicated but often misused according to the Zhan panel.
†Always to be avoided according to the Zhan panel.
‡Rarely appropriate according to the Zhan panel.
§Doses of alprazolam

may be higher when used to treat panic disorders.
COX = cyclooxygenase; SIADH = syndrome of inappropriate antidiuretic hormone secretion.

Adapted from Fick DM, Cooper JW, Wade WE, et al: Updating the Beers criteria for potentially inappropriate medication use in older adults. Archives of Internal Medicine 163:2716–2724, 2003.

Always to be avoided

Rarely appropriate

Sometimes indicated but often misused

Analgesics: NSAIDs are used by > 30% of people aged 65 to 89, and half of all NSAID prescriptions are for people > 60. Several NSAIDs are available without prescription.

The elderly may be prone to adverse effects of these drugs, and adverse effects may be more severe because of the following:

NSAIDs are highly soluble in lipids, and because adipose tissue increases with age, distribution of the drugs is extensive.

Plasma protein is often decreased, resulting in higher levels of unbound drug and exaggerated pharmacologic effects.

Renal function is reduced in many of the elderly, resulting in decreased renal clearance and higher drug levels.

Serious adverse effects include peptic ulceration and upper GI bleeding; risk is increased when an NSAID is begun and when dose is increased. Risk of upper GI bleeding increases when NSAIDs are given with warfarin

, aspirin

, or other antiplatelet drugs (eg,
clopidogrel

). NSAIDs may increase risk of cardiovascular events and can cause fluid
retention and, rarely, nephropathy.

NSAIDs can also increase BP; this effect may be unrecognized and lead to intensification of antihypertensive treatment (a prescribing cascade). Thus, clinicians should keep this effect in mind when BP increases in elderly patients and ask them about their use of NSAIDs, particularly OTC NSAIDs.

Selective COX-2 (cyclooxygenase-2) inhibitors (coxibs) cause less GI irritation and platelet inhibition than other NSAIDs. Nonetheless, coxibs have a risk of GI bleeding, especially for patients taking warfarin

or aspirin

(even at a low dose) and for those who have had GI
events. Coxibs, as a class, appear to increase risk of cardiovascular events, but risk may vary by drug; they should be used cautiously. Coxibs have renal effects comparable to those of other NSAIDs.

Lower-risk alternatives (eg, acetaminophen

) should be used when possible. If NSAIDs are
used in the elderly, the lowest effective dose should be used, and continued need should be reviewed frequently. If NSAIDs are used long-term, serum creatinine and BP should be monitored closely, especially in patients with other risk factors (eg, heart failure, renal impairment, cirrhosis with ascites, volume depletion, diuretic use).

Anticoagulants: Aging may increase sensitivity to the anticoagulant effect of warfarin

.
Careful dosing and scrupulous monitoring can largely overcome the increased risk of bleeding in elderly patients taking warfarin

. Also, because drug interactions with warfarin

are
common, closer monitoring is necessary when new drugs are added or old ones are stopped; computer drug interaction programs should be consulted if patients take multiple drugs.

Antidepressants: Tricyclic antidepressants are effective but should rarely be used in the elderly. SSRIs and mixed serotonin/dopamine

reuptake inhibitors are as effective as
tricyclic antidepressants and cause less toxicity; however, there are some concerns about some of these drugs:

Fluoxetine

: A possible disadvantage is the long elimination half-life, especially of its
active metabolite.

Paroxetine

: This drug is more sedating than other SSRIs, has anticholinergic effects,
and, like some other SSRIs, can inhibit hepatic cytochrome P-450 2D6 enzyme activity, possibly impairing the metabolism of several drugs, including some antipsychotics, antiarrhythmics, and tricyclic antidepressants.

Sertraline

: This drug is more activating; diarrhea is a common adverse effect.

Doses of these drugs should be reduced by up to 50%. Many SSRIs are available, but data on their use in the elderly are sparse.

Antihyperglycemics: Doses of antihyperglycemics should be titrated carefully in patients with diabetes mellitus. Risk of hypoglycemia due to sulfonylureas may increase with age. Chlorpropamide

is not recommended because elderly patients are at increased risk of
hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and because the drug’s long duration of action is dangerous if adverse effects or hypoglycemia occurs. Risk of hypoglycemia is greater with glyburide

than with other oral
antihyperglycemics because like chlorpropamide

, it is eliminated by the kidneys, and
clearance can be reduced when renal function is impaired.

Metformin

, a biguanide excreted by the kidneys, increases peripheral tissue sensitivity to
insulin and can be effective given alone or with sulfonylureas. Risk of lactic acidosis, a rare but serious complication, increases with degree of renal impairment and with patient age. Heart failure is a contraindication.

Antihypertensives: In many elderly patients, lower starting doses of antihypertensives may be necessary to reduce risk of adverse effects; however, for most elderly patients with hypertension, achieving BP goals requires standard doses and multidrug therapy. Initially, a thiazide-type diuretic is usually given alone or with one of the other classes shown to be beneficial (ACE inhibitors, angiotensin II receptor blockers, β-blockers, Ca channel blockers). Short-acting dihydropyridines (eg, nifedipine

) may increase mortality risk and should not be
used. Sitting and standing BP can be monitored, particularly when multiple antihypertensives are used, to check for orthostatic hypotension, which may increase risk of falls and fractures.

Antiparkinsonian drugs: Levodopa clearance is reduced in elderly patients, who are also more susceptible to the drug’s adverse effects, particularly orthostatic hypotension and confusion. Therefore, elderly patients should be given a lower starting dose of levodopa and carefully monitored for adverse effects (see Movement and Cerebellar Disorders: Levodopa). Patients who become confused while taking levodopa may also not tolerate newer dopamine

agonists (eg, pramipexole

, ropinirole

). Because elderly patients with
parkinsonism may be cognitively impaired, anticholinergic drugs should be avoided.

Antipsychotics: In nonpsychotic, agitated patients, antipsychotics control symptoms only marginally better than placebos and can have severe adverse effects. Antipsychotics should be reserved for psychosis.

When an antipsychotic is used, the starting dose should be about one quarter the usual starting adult dose and should be increased gradually. Clinical trial data relating to dosing, efficacy, and safety of these drugs in the elderly are limited.

Antipsychotics can reduce paranoia but may worsen confusion (see also Schizophrenia and Related Disorders: Conventional antipsychotics). Elderly patients, especially women, are at increased risk of tardive dyskinesia, which is often irreversible. Sedation, orthostatic hypotension, anticholinergic effects, and akathisia (subjective motor restlessness) can occur in up to 20% of elderly patients taking an antipsychotic, and drug-induced parkinsonism can persist for up to 6 to 9 mo after the drug is stopped.

The FDA has issued a warning regarding the use of 2nd-generation (atypical) antipsychotics, once thought to be safer, in the treatment of behavioral disorders in elderly patients with dementia; a review of placebo-controlled studies has shown a higher mortality rate associated with their use. Extrapyramidal dysfunction can develop when 2nd-generation antipsychotics (eg, olanzapine

, quetiapine

, risperidone

) are used, especially at higher doses. Risks
and benefits of using an antipsychotic should be discussed with the patient or the person responsible for the patient’s care.

Anxiolytics and hypnotics: Treatable causes of insomnia should be sought and managed before using hypnotics (see also Sleep and Wakefulness Disorders: Hypnotics). Nonpharmacologic measures and sleep hygiene (eg, avoiding caffeinated beverages, limiting daytime napping, modifying bedtime) should be tried first. If they are ineffective, nonbenzodiazepine hypnotics (eg, the imidazopyridines, alpidem and zolpidem

) are
options. These drugs bind mainly to a benzodiazepine receptor subtype. Imidazopyridines disturb the sleep pattern less than benzodiazepines and have a more rapid onset, fewer rebound effects, fewer next-day effects, and less potential for dependence. Short- or intermediate-acting benzodiazepines with half-lives of 0.8 ng/mL are associated with increased mortality risk.
Adverse effects are typically related to its narrow therapeutic index. One study found digoxin

to be beneficial in women when serum levels were 0.5 to 0.9 ng/mL but possibly
harmful when levels were ≥ 1.2 ng/mL. A number of factors increase the likelihood of digoxin

toxicity in the elderly. Renal impairment, temporary dehydration, and NSAID use (all common among the elderly) can reduce renal clearance of digoxin

. Furthermore, digoxin

clearance
decreases an average of 50% in elderly patients with normal serum creatinine levels. Also, if lean body mass is reduced, as may occur with aging, volume of distribution for digoxin

is
reduced. Therefore, starting doses should be low (0.125 mg/day) and adjusted according to response and serum digoxin

levels (normal range 0.8 to 2.0 ng/mL). However, serum
digoxin

level does not always correlate with likelihood of toxicity.

Diuretics: Lower doses of thiazide diuretics (eg, hydrochlorothiazide

or chlorthalidone

12.5 to 25 mg) can effectively control hypertension in many elderly patients and have less risk of hypokalemia and hyperglycemia than other diuretics (see also Hypertension: Diuretics). Thus, K supplements may be required less often.

K-sparing diuretics should be used with caution in the elderly; the K level must be carefully monitored, particularly when these diuretics are given with ACE inhibitors.

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