Current Geriatric Diagnosis & Treatment, 1st Edition

Section IV - Special Situations

41. Principles of Drug Therapy: Changes with Aging, Polypharmacy, & Drug Interaction

Rebecca Boxer MD

Ronald Shorr MD

More than 80% of older adults take at least 1 medication daily. As the American population ages, more patients will be treated for acute and chronic diseases, including hypertension, arthritis, stroke, cancer, dementia, and diabetes. A larger proportion of older patients will be exposed to and consuming drug therapies. However, we have limited knowledge of age-related risks of many medications. Patients older than 75 infrequently participate in clinical trials, and if they do it is in relatively small numbers and they are often healthy.

Useful information on various medications used to treat the frail elderly has been gleaned from pharmacoepidemiological studies. For example, invaluable data on nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, hypoglycemics, and gastric motility agents have come from pharmacoepidemiological data. Because it is unlikely that large trials involving frail elderly will occur, these studies will continue to grow in value to guide therapeutic decisions for the geriatric patient.

PRINCIPLES OF PHARMACOKINETICS

Pharmacokinetics refers to the processes of absorption, distribution, metabolism, and elimination of a medication. These processes depend on the individual taking the medication and the properties of the medication. These processes can change with age but also can vary greatly between individuals. The impact is difficult to determine. The pharmacokinetic processes are also influenced by various diseases, environment, and use of other medications. In general, the impact of the individual patient's physiological status (eg, hydration, nutrition, and cardiac output) and health status on the pharmacology of a particular drug is just as important as age-related changes.

Absorption

The absorptive process includes appropriate absorptive surface, gastric pH, splanchnic blood flow, and gastrointestinal (GI) tract motility. However, the absorption of drugs seems to be relatively unaffected by age, although it can be affected by other medications, diseases, and environment.

Distribution

Drugs distribute into both intracellular and interstitial spaces. Multiple physiological changes in the elderly can affect the distribution of drugs. The rate of drug distribution will be affected by cardiac output, blood flow to various tissues, and tissue volume. Older patients have an increased fat-lean body mass ratio, decreased total body water, and often somewhat decreased serum albumin. These changes can affect the distribution of some drugs in various ways depending on the properties of the drug. Drugs that distribute in fat (eg, diazepam) will have a larger volume of distribution. Hydrophilic medications (eg, digoxin) will have a decreased volume of distribution. Drugs that bind to serum proteins reach an equilibrium between bound (inactive) and free (active) drug. Levels of serum albumin can fluctuate and often decrease during periods of illness. The amounts of free to bound drug can increase with illness, and patients can develop toxicity (eg, with warfarin). This toxicity can be compounded if the processes of metabolism and elimination are also affected by the illness. Adding a new drug that competes for protein binding (eg, thyroid hormone, digoxin, warfarin, phenytoin) with drugs the patient is already taking can also result in higher levels of free drug. When high-protein drugs are used together, drug levels and effects must be monitored.

Metabolism

The metabolism of drugs varies between individuals and with aging. Hepatic enzyme activity, mass, and blood flow can decrease with age but are highly variable. In some patients, these changes are important in metabolizing drugs that have a high first-pass metabolism (eg, propranolol) where small reductions in metabolizing ability can have a greater impact.

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There are 2 main metabolizing pathways in the liver. Phase I is catalyzed by cytochrome P450 through the process of oxidation and reduction. Phase II conjugates drugs through acetylation, glucuronidation, sulfation, and glycine conjugation. Phase II metabolism is not affected by age. The CYP groups of enzymes are predominately in the liver but also exist in the brain, kidney, and intestine. Enzyme activity varies greatly among individuals, but there also may be an age-related decline in cytochrome P450 activity. There is no way to predict which patients are affected. Metabolism is also influenced by other medications that either up- or downregulate various enzyme substrates, which can greatly change concentration of drugs. In addition, alcohol intake, smoking, diet, and illness can affect drug metabolism. Older adults tend to be on more medications, each with the potential to influence metabolism of another.

Excretion

Renal function often decreases with age, by much as 50% by age 85 compared with younger patients. Glomerular filtration rate and tubular function both decline. This can greatly affect elimination of various drugs that are renally excreted. The serum creatinine is not an accurate predictor of renal function in older adults because of their decreased muscle mass. Decreased creatinine clearance results in higher serum levels of the drug as well as a longer drug half-life. This is increasingly important for drugs with a narrow therapeutic index (eg, digoxin, aminoglycosides). To adjust the doses of these medications, the patient's creatinine clearance should be estimated using a formula such as:

Although this formula is generally helpful, it is unclear whether it accurately estimates creatinine clearance in frail elderly patients, such as those living in nursing homes.

The half-life of various medications can be prolonged in older adults because of changes in drug distribution or clearance. The half-life of a drug depends on both the volume of distribution and the clearance of the drug.

Changes in volume of distribution resulting from increased body fat and decreased body water alter the expected volume of distribution of various drugs. This, in combination with changes in creatinine clearance, will produce a concentration difference of a drug greater than that seen in a younger person.

PRINCIPLES OF PHARMACODYNAMICS

The pharmacodynamics of a drug refers to the effect the drug has on an individual at the organ site. Pharmacodynamics has not been as carefully studied in older adults as pharmacokinetics, and much information is derived from observational data. Many drugs in older adults can have an exaggerated or paradoxical effect. Older adults are more sensitive to medications that depress the central nervous system (CNS; eg, benzodiazepines), which can result in adverse effects of delirium, confusion, and agitation. Patients taking psychoactive medications need close monitoring of doses and effects. Increased sensitivity (greater response at a given concentration of drug at the organ site) to drugs can have effects such as hemorrhage with anticoagulants (especially in combination with NSAIDs, acetylsalicylic acid [ASA]); orthostatic hypotension with various blood pressure medications and α-blockers; and delirium with various psychotropics and medications with anticholinergic properties.

GERIATRIC THERAPEUTICS

Adverse Drug Reactions

Adverse drug reactions occur about twice as often in older than younger patients. Hospital admissions as a result of drug-related illness range from 2.3-27.3%. Risk of an adverse drug reaction increases with greater severity of illness, multiple comorbidities, smaller body size, changes in hepatic and renal metabolism and excretion, and prior drug reactions. The increased number of adverse drug reactions tends to correlate with age, but, when controlled for other factors such as environment and disease, age is not as important as number of medication and number of disease conditions. Patients with multiple comorbidities tend to take more medications and are at increased risk for adverse drug reactions. Medications with a narrow therapeutic index and prolonged half-life cause the most trouble for the elderly patient.

The incidence of adverse drug reactions increases sharply when the older patient uses 5 or more medications daily. The risk of adverse reactions is increased by prescribing errors and the prescribing of drugs that interfere with normal hepatic metabolism or protein binding. The symptoms of an adverse drug reaction are often nonspecific and can mimic other illnesses. Adverse reactions such as fatigue, memory loss, confusion,

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incontinence, gait instability, and parkinsonism are common and can mistakenly be attributed to age rather than medication. Adverse drug reactions misinterpreted as disease-related symptoms can result in treatment with another medication rather than discontinuation of the offending medication. Medication reactions should always be considered when evaluating an older adult with new symptoms. The physician also needs to pay close attention to drug-drug interactions when prescribing a new medication.

Polypharmacy

Polypharmacy, the use of multiple medications, correlates strongly with the incidence of adverse drug reactions. To lessen the risks of adverse reactions resulting from polypharmacy, a carefully detailed medication history is important. Patients often have to be prompted to report medications such as eyedrops, herbal medications, and vitamins. Patients who visit multiple physicians or who have been hospitalized recently are at greater risk for polypharmacy. In addition, white patients who are sicker and older also are at increased risk for polypharmacy. For example, a patient being treated for benign prostatic hypertrophy with an α-blocker, hypertension with a β-blocker, and pain or depression with a tricyclic antidepressant (TCA) is at increased risk of orthostatic hypertension and falls. Polypharmacy can be reduced by eliminating unnecessary, suboptimally effective, or ineffective medications as well as medications with duplicate effects.

Inappropriate Medications

Inappropriate prescribing occurs when the risks of the medication outweigh the benefits. The prevalence of inappropriate drug use in the elderly population ranges from 12-40%. Medications are deemed inappropriate by either their side effects or by the potential for disease-medication interactions. Expert consensus panels generated lists of inappropriate medications in the treatment of nursing home patients. These lists are now widely used in other settings but have not been evaluated in controlled clinical trials. Medications considered inappropriate for use in elderly patients include disopyramide, anticholinergic drugs (including antihistamines such as diphenhydramine for sleep), benzodiazepines with long elimination half-lives, methyldopa, chlorpropamide, and meperidine, among others. However, many other medications that are considered appropriate can cause adverse effects in vulnerable older adults. For example, antidepressants increase the risk for falls even at therapeutic doses, emphasizing the need to carefully monitor patients and inform them of potential problems arising from medications adverse effects.

Prescribing Hazards

A patient's response to a drug can be affected by multiple illnesses, hepatic and renal impairment, as well as drug-drug interactions. In general, lower doses of medications are advised compared with the usual doses used in young adults. Protocols or guidelines for drug dosaging are typically based on studies of younger and healthy older patients. For many commonly used medications, pharmacokinetic data with patients older than 75 are not available. It is prudent to consider initiating therapy at lower than published doses for many medications and slowly increasing the dosage as needed for therapeutic effect.

Discontinuing medications can also result in adverse events as a result of alterations in drug metabolism. Some medications will induce the CYP-450 enzyme system (ie, barbiturates, carbamazepine, phenytoin, primidone, rifampin, and rifabutin). Through the CYP-450 enzyme system, these drugs can increase the metabolism of other medications. For example, patients on anticonvulsants were found to have a much lower concentration of felodipine than those not on anticonvulsants. When the anticonvulsant is discontinued, the enzyme activity decreases and the level of the affected drug can become dangerously elevated. Also, a drug level may never reach a therapeutic range while a patient is on an enzyme-inducing medication. This may require prescribing very high doses of a drug to reach a therapeutic effect. For example, patients taking rifampin will usually need large doses of warfarin to achieve a therapeutic prothrombin time. When the enzyme-inducing agent is stopped, the dose of other medications will need to be adjusted to prevent excessive effects. Medication with a narrow therapeutic index should be closely monitored with all medication changes.

New Medications

Physicians should be especially aware of potential and unexpected adverse effects and disease-drug or drug-drug interactions. Physicians should be wary of using new medications without reviewing data on their use in vulnerable older adults.

Underuse of Medications

Clinicians may be overcautious in using medications that have limited data on use in older adults. Underuse of medications can increase morbidity and mortality. For example, β-blockers are underused in older patients after myocardial infarction. Other conditions that are typically undertreated are hyperlipidemia, depression, isolated systolic hypertension, iron deficiency anemia, chronic obstructive pulmonary disease (COPD) (bronchodilators),

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pain, and constipation. Elderly heart failure patients are undertreated with angiotensin-converting enzyme (ACE) inhibitors. Anticoagulants (eg, warfarin for atrial fibrillation) are still underused.

Adherence

Adherence is more difficult for patients as the drug regimen becomes more complicated. Older adults often have complicated drug regimens. Patients may not fill their prescriptions or may use them for a different use than was intended. It can be difficult to determine adequate adherence if the patient is a poor historian or has no reliable informant. Patients can have a poor understanding of disease processes and the relevance of prescribed treatment. Patient and family goals may not be expressed, and physician's goals may not be the same. Patient barriers to adherence, such as cognitive decline, illiteracy, and negative attitudes toward taking medications, need to be considered. Nonadherence could also be related to inability to open safety closure bottles or the patient's inability to afford the medication.

Risk of complications increase when a physician is unaware of nonadherence. Medications may appear to be ineffective, and dosages may be increased or a more powerful medication prescribed. Complications also arise when a patient becomes hospitalized or when supervision is increased. Patients then receive the prescribed medication and can have serious complications (eg, thyroxine dose is increased and atrial fibrillation develops). Changes in diet can have profound effects, especially for patients taking hypoglycemics, diuretics, or anticoagulants. Medications prescribed in a hospital setting may work well in the controlled environment, but outside the hospital a patient can rapidly get into trouble. Typical conditions for this scenario are congestive heart failure (CHF) with changes in salt intake and diabetes with changes in carbohydrate intake.

Adherence can improve with careful explanation of the purpose of the medication. A good patient-physician relationship and open communication can help one to realize why a patient may have trouble adhering to recommendations. Formulating a reminder system for when medication should be taken, such as setting an alarm or a receiving a reminder telephone call from a friend or family member, may be helpful. Medications can be organized in pillboxes for day and time. Medication regimens and dosing schedules should be simple with clear written and verbal instructions.

COMMON MEDICATIONS

Many valuable medications are commonly used but can cause adverse effects. Cardiovascular and psychotropic drugs are the most often associated with adverse reactions. CNS side effects of commonly used medications—α-blockers, hypnotics, and drugs with histaminic and anticholinergic effects—can result in decreased ability to perform activities of daily living, increased risk of falls, and incontinence.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are widely used for treating arthritis and chronic pain. NSAIDs provide fast and effective pain relief. However, adverse effects occur more frequently in older adults. Both age and age-related changes in NSAID pharmacokinetics increase the risk of adverse effects.

NSAIDs inhibit cyclo-oxygenase (COX) enzymes, which catalyze the conversion of prostaglandins from arachidonic acid. Prostaglandins have many roles throughout multiple organ systems and are a primary cause of pain, swelling, and inflammation. Their inhibition can also result in increased blood pressure and other adverse effects, most notably in the kidney and GI tract. Prostaglandins are vasodilators and help maintain blood flow and glomerular filtration through the kidneys, especially when blood volume is decreased. Inhibition by NSAIDs can result in decrease renal blood flow. Patients on NSAIDs who have low absolute or effective blood volume are at increased risk for renal insufficiency and renal failure. Both COX-1 and COX-2 enzymes are produced in the kidney. Inhibition of either can result in adverse renal effects, cause fluid retention, and affect sodium homeostasis. Patients who are most affected already have fluid-related morbidity (eg, CHF, liver disease, renal insufficiency). Concomitant diuretic therapy can increase risk of adverse effects. Patients with comorbidities, especially renal insufficiency and hypertension, who are given NSAIDs should be closely monitored. Preferably the lowest dose to control symptoms and intermittent shorter acting medications (eg, ibuprofen) should be used.

Infrequently, NSAIDs can also cause hyperkalemia. This is mediated though prostacyclin inhibition, resulting in decreased renin and aldosterone production, which affects potassium excretion. Patients at increased risk are those taking potassium supplements, ACE inhibitors, or potassium-sparing diuretics and those with renal insufficiency. Hyperkalemia resolves when NSAID therapy is stopped.

In the GI tract, prostaglandins have a protective effect on gastric mucosa by decreasing gastric acid production, increasing mucus production, and increasing bicarbonate production in the duodenum. COX-1 is the enzyme that catalyzes production of prostaglandin in the GI tract. Inhibition of COX-1 by nonselective NSAIDs can result in peptic ulcers and injury to the gastric mucosa. Older adults may produce less gastric

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prostaglandin at baseline, placing them at increased risk of gastropathy. In addition, comorbidity, use of multiple medications (steroids, diuretics, anticoagulants), and amount of NSAIDs consumed increase the risk. The specific COX-2 inhibitors (celecoxib, rofecoxib) have decreased toxicity of the GI tract while still providing anti-inflammatory effect.

Prostaglandins through COX-1 also play a role in platelet aggregation, which may also be a factor in GI bleeding. NSAIDs lack cardiovascular protection, unlike aspirin. NSAIDs do not replace aspirin in treating cardiovascular diseases. Patients with higher risk of adverse events from NSAIDs as a result of comorbidity (liver disease may affect hepatic metabolism, renal insufficiency CHF/edematous states, peptic ulcer disease) and multiple medication use should be monitored closely, or a different class of medication should be used to control symptoms. If an NSAID is necessary for prolonged use, COX-2 selective inhibitors should be considered. Misoprostol or proton pump inhibitors can be added to COX-1 NSAIDs to protect the gastric mucosa when costs restrict the use of the COX-2 agents.

Anticoagulants

Warfarin has been shown to decrease the risk of stroke in patients with atrial fibrillation (AF). Despite this, older adults (age 80 and older) with AF who are at the highest risk are more likely not to be receiving anticoagulation therapy. Physicians are often hesitant to start their patients on anticoagulation because of concerns of hemorrhage and difficulties controlling the therapy in an appropriate range. Regardless of age, dose response to warfarin varies among patients. Some studies have shown that effective dosing decreases with age.

The decision to start a patient on warfarin needs to be individualized. The risks and benefits of taking warfarin depend on the clinical situation and the goals of therapy. Anticoagulation will lower the risk of thromboembolic events, but older adults are at increased risk for bleeding complications. Risk of hemorrhage increases with history of hemorrhage, alcohol bingeing, use of aspirin and NSAIDs, cancer, liver disease, and renal insufficiency. Advanced age, thrombocytopenia, previous stroke, uncontrolled hypertension, and nonwhite ethnicity may also increase risk of hemorrhage.

Hemorrhagic complications are more frequent when the international normalized ratio (INR) is > 4; the therapeutic index ranges from 2.0-3.0. Older adults with acute or chronic illness taking multiple medications tend to be at the highest risk for INR fluctuations and should be closely monitored to avoid adverse events. Factors that can influence the therapeutic dose of warfarin, often requiring lower doses, include mutations in cytochrome P450, other medications (especially if highly albumin bound), low body weight, low serum albumin level, CHF, liver disease, and hyperthyroidism. In addition, warfarin can become sub- or supertherapeutic when patients experience a mild illness or changes in diet, placing them at risk for stroke or hemorrhage and necessitating close monitoring of the INR. Patients are vulnerable to complications of anticoagulation when they change settings (eg, when going from hospital to home, nursing home) and should be monitored more closely. Doses may need to be reduced in patients with CHF, COPD, liver disease, malignancy, prolonged diarrhea, or enteral feedings/poor nutritional status.

Many medications can affect the anticoagulation of warfarin by elevating or lowering the therapeutic effect. Some drugs will increase the metabolism of warfarin by induction of hepatic enzymes. This results in a lowering of the INR. Other medications will potentiate the anticoagulation effect by competing for degrading enzymes. Medications can also compete for protein-binding sites and result in more unbound warfarin. (Medication interactions with warfarin are listed in Table 41-2.) Patients must be educated about the use of warfarin and warned about use of over-the-counter (OTC) medications (no NSAIDs or ASA) and herbal remedies. Vitamin K intake should be maintained at the same level because fluctuations in intake can result in supra- or subtherapeutic INR levels (Table 41-1). The body

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stores only small amounts of vitamin K and is dependent on oral intake and gut flora to synthesize it. Impaired absorption of vitamin K or antibiotic therapy can affect gut bacterial flora and disrupt vitamin K absorption. Intracranial bleeding is the most feared adverse effect from anticoagulation; its incidence ranges from 0.3-2% per year. Risk factors of intracerebral hemorrhage are similar to those of ischemic stroke: age, prior stroke, and hypertension. A concern regarding hemorrhage from falls is often the deterrent to anticoagulation therapy. Patients and caregivers should be made aware of signs and symptoms of bleeding so they may receive prompt medical attention.

Table 41-1. Vitamin K-containing foods.

Green leafy vegetables
   Spinach
   Kale
   Lettuce
   Collard greens
   Turnip greens
   Cabbage
   Watercress
Oils
   Soybean
   Olive
   Canola
   Cottonseed
Vegetables
   Avocado
   Brussel sprouts
   Chickpeas
   Broccoli
   Cauliflower
   Asparagus
   Green beans
Meat
   Beef liver

Table 41-2. Drugs that affect warfarin.

Drugs that potentiate effect

Drugs that diminish effect

Antibiotics/antifungals

Antibiotics/antifungals

   Cephalosporins (cefamandole, cefoperazone, cefotetan, ceftriaxone)

   Griseofulvin

   Tetracyclines

   Rifampin

   Macolides

   Quinolones

   Sulfonamides (Bactrim has marked potentiating effect)

   Isoniazid

   Metronidazole

   Fluconazole

   Itraconazole

   Ketoconazole

Anti-inflammatories

Benzodiazepines

   Celecoxib

   Rofecoxib

   Piroxicam

   Fenprofen?

   Diflunisal?

   Tramadol

Anticonvulsants

Anticonvulsants

   Phenytoin

   Barbiturates

   Valproic acid

   Carbamazepine

Antidepressansts

   Selective serotonin reuptake inhibitors

Antiarrythmics

   Amiodarone (has a marked potentiating effect)

   Propafenone

   Propranolol

   Quinidine

Diruretics

   Ethacrynic acid

Gastrointestinal

Gastrointestinal

   Cimetidine

   Sulcralfate

Omeprazole

 

Lipid-lowering agents

Lipid-lowering agents

   Clofibrate

   Cholestyramine

   Gemfibrozil

   Lovastatin

   Simvastatin

Pulmonary

   Zafilukast

   Zileuton

Other

Other

   Allopurinol      Alcohol

   Vitamin K

   Danazol      Disulfiram

   Flutamide

   Methylphenidate

   Pentoxlfylline

 

Endocrine

Endocrine

   Levothyroxine

   Oral contraceptives

   Tamoxifen

   Anabolic steroids

   Sulfonylureas

Adapted from Honig PK, Gillespie BK: Clinical significance of pharmacokinetic drug interactions with over-the-counter (OTC) drugs. Clin Pharmacokinet 1998;35:167. Used with permission.

The decision to use anticoagulation is made in agreement with the patient and caregivers, weighing the benefits against the risks.

Oral Hypoglycemics

The prevalence of diabetes mellitus type 2 is increasing in the United States. Control of diabetes helps to avoid complications and maintain quality of life. However, elderly patients are believed to be at increased risk for hypoglycemia and hypoglycemic-related events while on oral hypoglycemics. Symptoms of hypoglycemia can be blunted in elderly diabetics, raising concern about optimal treatment. One must pay careful attention to various comorbidities when choosing a medication to treat diabetes.

  1. SULFONYLUREAS

Sulfonylureas act on the beta cells in the pancreas to increase insulin secretion. The second-generation sulfonylureas (glipizide, glyburide, glimeperide) are equal in efficacy, safer, and more potent than first-generation drugs (chlorpropamide, tolbutamide, tolazamide). Chlorpropamide should not be used in elderly patients because of its increased risk of hypoglycemia related to its long half-life (renal excretion). Of the second-generation medications, glyburide is the longest acting and has an increased risk of hypoglycemia compared with other agents. These drugs are metabolized by the liver and cleared by the kidney. Caution should be used in patients with renal or liver disease. Drugs should be started at the lowest dose and carefully monitored because elderly patients are at increased risk for hypoglycemia at onset of therapy and with increased dosing. Weight gain is not an uncommon side effect of this class of medication.

  1. BIGUANIDES

Biguanides (metformin) act as insulin sensitizers and decrease hepatic glucose production. They also have the added benefits of promoting weight loss and lowering low-density lipoprotein (LDL) cholesterol and triglycerides. In addition, metformin has been shown to decrease macrovascular complications, including myocardial infarction. Compared with sulfonylureas, metformin causes much less hypoglycemia.

With initiation of metformin therapy, ~50% of patients will experience GI side effects, including abdominal pain, diarrhea, and nausea. These side effects tend to decrease and resolve as patients continue therapy. To keep side effects to a minimum, dosages should be started low and slowly increased for therapeutic effect. The risk of lactic acidosis with metformin is low, but this medication should not be used in patients with renal insufficiency, heart failure, liver disease, dehydration, or alcoholism. It should be discontinued when patients become acutely ill, have major surgery, or receive radiocontrast dye.

  1. THIAZOLIDINEDIONES

Thiazolidinediones (rosiglitazone, pioglitazone) enhance insulin sensitivity by increasing skeletal muscle uptake of glucose, decreasing hepatic glucose production in the liver, and decreasing lipolysis. These drugs stimulate production of adipocytes and can cause weight gain while decreasing serum free fatty acid levels. This class of drugs can cause edema and increase plasma volume, so they should be used cautiously in patients with mild CHF and avoided in patients with class III or IV heart failure. Anemia is a rare complication. Liver enzymes should be checked periodically. Patients with liver disease should not receive this agent.

  1. α-GLUCOSIDASE INHIBITORS

α-Glucosidase inhibitors (acarbose and miglitol) inhibit the enzyme α-glucosidase in the small intestine, which decreases the breakdown of complex carbohydrates and delays absorption. These drugs work best after meals and lower glucose less than other hypoglycemic drugs. These agents are not absorbed systemically and will not cause hypoglycemia or weight loss. Side effects are mostly GI and include flatulence, bloating, loose stools, and abdominal discomfort; these tend to decrease with continued therapy. If these drugs are used in combination with other oral hypoglycemics, glucose needs to be used to reverse a hypoglycemic episode because complex carbohydrates will not be absorbed.

Nonsulfonylurea Secretagogues

Nonsulfonylurea secretagogues (repaglinide, nateglinide) are short-acting drugs that stimulate insulin secretion. These drugs are taken with meals and require the presence of glucose for action. They decrease postprandial hyperglycemia and, because of their short duration of action, have less risk of hypoglycemia compared with sulfonylureas. Nateglinide has less effect on insulin secretion in the fasting state than postprandially. Repaglinide

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has an efficacy equal to metformin and the sulfonylureas. Side effects include weight gain and hypoglycemia. They should be used cautiously in patients with renal or liver disease.

Psychoactive

The aging brain is much more susceptible to oversedation and delirium with psychoactive agents. Drugs such as neuroleptics, antidepressants, sedatives, and hypnotics are a common cause of adverse reactions and paradoxical effects. Barbiturates should be completely avoided if possible because they are very sedating and addictive, and they interact with other medications. In general, the most common adverse effects from all psychoactive drugs are oversedation, delirium, falls, and confusion. Patients on these medications need to be closely monitored.

Neuroleptic medications are often used to control behavioral problems in demented patients. Extrapyramidal side effects (EPSs), including dystonia, parkinsonism, and akathesia, are of concern. Akathesia, which can be mistaken for agitation or psychosis, is less common with the newer neuroleptics (atypical), but when it develops it often requires discontinuation of the medication. EPSs often do not manifest themselves until 1-2 weeks after initiation of therapy. The adverse affects can then appear anytime during therapy, especially with dosage increases. Patients taking these drugs should be monitored periodically for EPSs. If they are present, dosage decreases can be attempted. Changing the neuroleptic to a low potency or changing to an atypical neuroleptic are options.

Tardive dyskinesia (TD) develops with longer term use of neuroleptic drugs, and older adults are at increased risk, as much as 5-10 times that of a younger person. The risk of TD is lower with atypical drugs, clozapine, risperidone, olanzapine, and quetiapine fumarate.

  1. CLOZAPINE

Clozapine is the oldest atypical agent and is often used as a last resort when patients are not controlled on other medications. It has not been studied in patients with dementia. Clozapine has anticholinergic properties but does not cause EPSs. It can cause agranulocytosis. White blood cell count must be checked weekly for the first 6 mo and then every 2 weeks. Clozapine can also cause marked sedation, ataxia, falls, fever, delirium, and sialorrhea, weight gain, and diabetes.

  1. RISPERIDONE

Risperidone has been carefully studied in patients with Alzheimer's dementia. It is effective against both psychosis and aggression, and EPSs are less common compared with haloperidol use. The higher the dosage, the greater is the risk for extrapyramidal and other side effects. A recent black box warning was added because of a slight increased risk of stroke while on this medication.

  1. OLANZAPINE

Olanzapine has some anticholinergic and antihistaminic side effects and minimal risk of EPSs at low doses. This drug has a long half-life, and sedation is common. Sedation may not occur until 10 days after the drug has been initiated. Slow titration is advised to avoid oversedation, and it should not be used on an as-needed basis. Weight gain and an increase in triglyceride level are common.

  1. QUETIAPINE FUMARATE

Quetiapine fumarate is used to control agitation in dementia, but studies of its effectiveness are limited. EPSs are uncommon, but it has marked antihistaminic effects. Sedation, dizziness, and orthostatic hypotension are the common side effects. Patients may be at increased risk of diabetes.

  1. BENZODIAZEPINES

Benzodiazepines are used to treat anxiety and insomnia. These drugs have a high rate of adverse effects and can often result in dependency. Side effects include confusion, falls, gait impairment (ataxia), anterograde amnesia, sedation, and dizziness. Patients do build up a tolerance to these drugs over time, and a withdrawal syndrome may occur if therapy is stopped suddenly. These agents are best used on an as-needed basis for acute behavioral difficulties as a result of anxiety or drug withdrawal in order to avoid side effects. Long-acting agents should be avoided (flurazepam, diazepam), and chronic use is discouraged.

  1. ANTIDEPRESSANTS

The best tolerated antidepressants are the serotonin reuptake inhibitors (SSRIs). Unlike TCAs, there is less risk of anticholinergic side effects, orthostatic hypotension, adverse cardiac effects, or seizures. Side effects include GI disturbances, either insomnia or sedation, sexual dysfunction, and agitation (movement disorder). TCAs are, for the most part, avoided in older adults because of high rates of adverse effects. Desipramine and nortriptyline are the only recommended agents for elderly patients. Venlafaxine, a combination serotonin and norepinephrine reuptake inhibitor, tends to be activating. It can elevate blood pressure, especially in patients with hypertension. Mirtazapine has a postsynaptic serotonin effect and some serotonin and norepinephrine reuptake effect. Its effects can range from calming to sedating. Higher doses can be activating. Mirtazapine can also stimulate appetite. Doses for all antidepressants should be started low and increased slowly (weeks to months) to monitor adverse effects.

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Opioid Analgesics

Underprescribing for pain is common in older adults. Concern regarding side effects (eg, oversedation, constipation, delirium) is justified but should not prohibit use of options. Addiction/dependence can be a concern of both the physician and the patient. Elderly patients tend to clear opioids more slowly. For example, absorption from fentanyl patches can be slower and take longer to reach maximum plasma concentrations. Long-acting drugs also need to be titrated slowly to avoid accumulation. Patients should be closely monitored when this therapy is initiated and with dosage titration. Meperidine is avoided as an opioid analgesic because it has a metabolite that can cause delirium. All opioids can potentially cause delirium, and patients taking these medications should be frequently assessed. Constipation is common. A bowel regimen is usually required to avoid constipation and impaction.

Anticholinergics

Various medications have anticholinergic properties (Table 41-3). Older adults are particularly susceptible to anticholinergic side effects. The side effects for these medications can be mistaken as normal signs of aging (eg, dry mouth, constipation, tachycardia, confusion). Treatment of side effects with other medications leads to polypharmacy. Other adverse effects of anticholinergic drugs include delirium, urinary retention, orthostatic hypotension, tachycardia, seizure, constipation, exacerbation of glaucoma, and blurred vision. Patients and caregivers should be aware of potential side effects. The physician should also note whether the patient is taking multiple medications that have anticholinergic effects because the side effects are additive.

Diuretics

Concomitant use of other medications with diuretics, notably NSAIDs, can increase adverse effects on renal function. Both loop and thiazide diuretics place a patient at risk for hypokalemia, which can lead to ventricular arrhythmias. Physicians may choose to supplement potassium or change the medication to avoid hypokalemia. Potassium-sparing diuretics (eg, triamterene, spironolactone) can cause hyperkalemia. Potassium levels should be monitored periodically. Care should be taken to instruct patients on the most appropriate time of day to take diuretics to minimize disruption of daily activities (eg, because of incontinence) and to enhance compliance. Loop diuretics can cause postural hypotension or postprandial hypotension.

ACE Inhibitors

ACE inhibitors have beneficial effects on cardiac and renal function. Patients with heart failure and left ventricular systolic dysfunction benefit from ACE inhibitor therapy. Older adults may be at increased risk for related

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renal dysfunction and hypotension. Low doses are used to initiate therapy, and dose titration proceeds cautiously. Excessive diuresis at initiation or when increasing the dose of therapy may place the patient at increased risk for renal insufficiency.

Table 41-3. Common medications with anticholinergic properties.

Antibiotics

Ampicillin, cefalothin, cefamandole, cefoxitin, clindamycin, cycloserine, gentamicin, pipercillin, tobramycin, vancomycin

Antidepressants

All tricyclic antidepressants, especially amitriptyline, desiprimine, clomipramine, imipramine, and doxepin

Antipsychotics

All have some, but the strongest anticholinergics are chlorpromazine, thioridazine, and clozapine; resperidone has the least, if any, anticholinergic effects

Antihistamines

Chlorpheniramine, diphenhydramine, hydroxyzine, cryoheptadine promethazine, dexchlorpheni-ramine

Benzodiazepines

Alprazolam, chlordiazepoxide, flurazepam, oxazepam

Cardiovascular agents

Captopril, chlorthalidone, digoxin, diltazem, dipyridamole, furosemide, hydrochlorothiazide, hydralazine, isosorbide mononitrate, methyldopa, nifedipine, triamterene, warfarin

Corticosteroids

Cortisone, dexamethasone, hydrocortisone, prednisolone

Gastrointestinal agents

Atropine, cimetidine, dicyclomine, hysoscyamine, propantheline, belladonna, clidinium, ranitidine chlordiazepoxide

Immunosuppressive agents

Azathioprine, cyclosporine

Muscle relaxants

Carisoprodol, methocarbamol, cyclobenzaprine, chlorzoxazone, metaxalone, orphenadrine

Respiratory

Theophylline

Opiates

Codeine, oxycodone

Urinary agents

Oxybutynin, tolterodine

Adapted from Temple RJ, Himmel MH: Safety of newly approved drugs:implications for prescribing. JAMA 2002;287:2273. Used with permission.

ACE inhibitors render older adults at increased risk for hyperkalemia and renal insufficiency. Patients should have their renal function and potassium level monitored shortly after starting an ACE inhibitor. ACE inhibitor therapy may need to be stopped for cough, hypotension, persistent hyperkalemia, and renal dysfunction. NSAIDs used with ACE inhibitors can worsen adverse effects of renal dysfunction and hyperkalemia. Cough and angioedema can occur with any of the ACE inhibitors.

Angiotensin II Receptor Blockers

These drugs are often an option when ACE inhibitors are not tolerated. There is still a risk of renal dysfunction and hyperkalemia similar to that of ACE inhibitors. Lower doses may decrease this risk. There is no risk of cough.

β-Blockers

β-Blockers are clearly beneficial in postmyocardial infarction (MI) patients as well as in those with mild to moderate heart failure. Nonselective β-blockers (carvedilol) may have increased benefit over β1-selective β-blockers (metoprolol). Older adults may have comorbid conditions that limit their tolerance of β-blockers (eg, COPD). Older adults are at higher risk for bradycardia. However, β-blockers may have cardioprotective effects, even for patients with risk factors for complications such as pulmonary disease, heart failure, depression, and diabetes.

Topical β-blockers are used to treat glaucoma. Topical agents are readily absorbed through the lacrimal system and the nasopharyngeal mucosa. Patients on ophthalmic β-blockers should be monitored for side effects (most notably respiratory and cardiovascular effects and decreased exercise tolerance).

Digoxin

This drug has not been shown to decrease mortality, but it has been shown to reduce hospitalizations and symptoms in heart failure patients of all ages. Digoxin has a narrow therapeutic index, and older adults are at increased risk of toxicity. Decreased renal function and lean body mass are contributing factors. Digoxin interacts with many other medications, and many disease states can cause the level of the drug to become toxic (Table 41-4). Toxicity is a clinical diagnosis, and the serum digoxin level does not always predict toxicity. Digoxin is protein bound, and the level of free digoxin can fluctuate. Older adults should be monitored carefully and maintained at lower doses than might be used in younger patients (0.5 ng/mL-0.8 ng/mL). Patients should be reassessed when adding new medications, with electrolyte abnormalities, or when illness occurs.

Table 41-4. Digoxin interactions.

Drugs that increase digoxin levels

Disease states that increase toxicity

Quinidine, amiodarone

Hypoxia

Cyclosporine

Acidosis

Itraconazole, triamterene, tetracycline, erythromycin

Hypokalemia

Calcium

Hypomagnesemia

Verapamil, diltiazem

Hypercalcemia

Spironolactone

Lung disease

Propafenone

Hypothyroidism

Propantheline

Myocardial ischemia

Hepatic Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors (Statins)

Lowering LDL and increasing high-density lipoprotein (HDL) cholesterol reduces the risk of cardiovascular diseases. Statins inhibit the enzyme hepatic hydroxymethylglutaryl coenzyme A (HMG-Co) reductase in the liver. This action decreases the production of cholesterol and upregulates the LDL receptors in the liver, resulting in increased removal of LDL from the circulation. Decreasing LDL and increasing HDL decreases the risk of cardiovascular disease.

Statins should be taken at night. The risks of statin medication are the same in old and young patients alike. Older adults should start at the lowest dose, or perhaps even half of the starting dose, and be monitored for effect in 4-6 weeks. Liver transaminases should be evaluated at initiation of therapy and then again in 6-12 weeks (and every 6 mo thereafter). The drug should be discontinued when transaminases are 3 times the upper limit of normal. Patients with persistent unexplained elevations in transaminases or with chronic liver disease should not receive statin medication. The physician should carefully monitor patients who use alcohol and may choose to not prescribe a statin medication to these patients. Rhabdomyolysis is an infrequent complication of statin therapy, but the creatine kinase should be checked if muscle pain or weakness develops. Statins combined with gemfibrozil, niacin, erythromycin, or cyclosporine will increase the risk of rhabdomyolysis.

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Iron

Iron supplements can interact with many other medications. Most notably, iron can form complexes with medications in the GI tract, rendering them less effective. Drugs that most commonly interact with iron are levodopa, methyldopa, penicillamine, quinolones, tetracyclines, and l-thyroxine. Interactions can result in a 50% decrease in the concentration of these drugs. There should be at least a 2-h difference in dosing times between iron and these medications.

Herbal Medications

Herbal medications are used for a multitude of medical and psychiatric problems. Patients often erroneously assume that herbal medications can be taken without risk of adverse effects, drug interactions, or perioperative complications (Table 41-5). However, patients are often unaware that labeling of herbals can be faulty, dosing and potency can vary among manufacturers, and additives can be omitted or misidentified. The product can be tainted with pesticides, herbicides, or heavy metals.

  1. ECHINACEA

Echinacea, a member of the daisy family, has multiple uses but is best known for prophylaxis of upper respiratory tract infections. It is thought to have short-term immunostimulatory effects and can be used for various other infections as well. Evidence regarding its therapeutic effects is inconclusive. Echinacea should be avoided in patients taking immunosuppressive drugs. Prolonged use (> 8 weeks) may result in immunosuppression. Adverse effects are primarily allergic. Because of hepatotoxicity concerns, patients with liver disease should avoid using this herbal remedy.

  1. EPHEDRA

Ephedra (ma huang) has been used for a multitude of purposes, including weight loss, fatigue, treatment of asthma, and bronchitis. The active compound is ephedrine, a noncatecholamine sympathomimetic agent with activity at the α1-, β1-, and β2-receptors. Adverse events include hypertension, tachycardia/palpitations, stroke, and seizure. Multiple problems can occur perioperatively with use of this herbal (see Table 41-5) and should be discontinued before surgery. This herbal is contraindicated with use of monoamine oxidase inhibitors, causing hypertension, hyperpyrexia, and coma. This herbal should not be used with theophylline, TCAs, pseudoephedrine, cardiac glycosides, or any other drugs that may have cardiac effects. This herbal should likely be avoided in older adults. Herbal medications should be discontinued 24 h preoperatively.

  1. GARLIC

Garlic is used to decrease the risk of atherosclerosis. It has the potential to mildly lower cholesterol and blood pressure and decrease thrombus formation and platelet aggregation. Garlic may potentiate the effect of other platelet inhibitors. Use of this herbal is considered relatively safe, but it is recommended that patients discontinue use 1 week preoperatively to decrease the risk of bleeding.

  1. GINKGO BILOBA

Ginkgo biloba has been used historically for a variety of problems, most notably cognitive difficulties. It also is used for vertigo, tinnitus, headache, asthma, peripheral vascular disease, macular degeneration, erectile dysfunction, and altitude sickness. Ginkgo is believed to have multiple effects: to act as an antioxidant, free radical scavenger, vasodilator, neurotransmitter, and receptor modulator; to enhance cell use of oxygen and glucose; and to inhibit platelet aggregation. Some data indicate that its use will mildly improve memory, but there is no evidence that it improves normal cognitive function. It is unclear whether use of this herbal will improve tinnitus. The common side effects are GI upset and headache. There is concern regarding increased risk of bleeding; some studies have reported spontaneous intracranial bleeding. This herbal medication should probably be avoided in patients receiving anticoagulant therapy. Presurgical patients should stop using this herb 36 h before surgery.

  1. GINSENG

Ginseng has multiple varieties and has been used in Chinese medicine for centuries. It is thought to help maintain a sense of well-being, decrease stress, prolong life, have diuretic effects, and improve sexual functioning. This herb may also have an effect on platelet function and increase the risk of bleeding, which could be irreversible in humans. In addition, it has the potential to lower postprandial glucose by increasing glycogen storage and lipogenesis in both diabetic and nondiabetic patients. This could increase risk of hypoglycemia. It is recommended that this herb be discontinued 7 days before surgery. There are case reports of interactions with warfarin and digoxin. When used in high doses, ginseng may cause elevations in blood pressure, insomnia, diarrhea, headache, anxiety, schizophrenia, and Stevens-Johnson syndrome. It should be avoided in patients with high blood pressure. Evidence regarding its therapeutic effects is inconclusive.

  1. KAVA

Kava is used as an anxiolytic and hypnotic. Kava has multiple CNS effects, including a weak effect on the benzodiazepine-binding sites and anticonvulsant, neuroprotective,

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and anesthetic properties. Concomitant benzodiazepine use may increase effects. It potentially could have effects on any substances acting on the CNS, and concomitant use with alcohol should be avoided. Kava does have the potential for abuse and a withdrawal syndrome after long-term use, but this concern is not well established. Kava dermopathy can occur with heavy use and manifests itself as a yellow scaly eruption, which resolves when it is discontinued. It can also cause ataxia, hair loss, hearing problems, decreased appetite, and weight loss. High doses can also lead to elevation in liver enzymes or liver damage and may result

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in elevated cholesterol. Kava should be discontinued 24 h before surgery.

Table 41-5. Medicines & perioperative care: Clinically important effects & perioperative concernsof 8 herbal medicines & recommendations for discontinuation of use

Common names

Relevant pharmacological effect

Perioperative concern

Preoperative discontinuation

Echinacea, purple coneflower root

Activation of cell-mediated immunity

Allergic reactions; decreased effectiveness of immunosuppressants, potential for immunosuppression with long-term use

No data

Ephedra, ma huang

Increased heart rate and blood pressure through direct and indirect sympathomimetic effects

Risk of myocardial ischemia and stroke from tachycardia and hypertension; ventricular arrhythmias with halothane; long-term use depletes endogenous catecholemines and may cause intraoperative hemodynamic instability; life-threatening interaction with monoamine oxidase inhibitors

At least 24 h

Garlic, ajo

Inhibition of platelet aggregation (may be reversible); increased fibrinolysis; equivocal antihypertensive activity

Potential to increase risk of bleeding, especially when combined with other medications that inhibit platelet aggregation

At least 7 days before surgery

Ginkgo, duck foot tree, maidenhair tree, silver apricot

Inhibition of platelet-activating factor

Potential to increase risk of bleeding, especially when combined with other medications that inhibit platelet aggregation

At least 36 h before surgery

Ginseng, American ginseng, Asian ginseng, Chinese ginseng, Korean ginseng

Lowers blood glucose; inhibition of platelet aggregation (may be irreversible); increased PT, PTT in animals; many other diverse effects

Hypoglycemia; potential to increase risk of bleeding; potential to decrease anticoagulation effect of warfarin

At least 7 days before surgery

Kava, awa, intoxicating pepper, kawa

Sedation, anxiolysis

Potential to increase sedative effect of anesthetics; potential for addiction, tolerance, and withdrawal after abstinence unstudied

At least 24 h before surgery

St. John's wort, amber, goat weed, hardhay, hypericum, klamatheweed

Inhibition of neurotransmitter reuptake; monoamine oxidase inhibition is unlikely

Induction of cytochrome P450 enzymes, affecting cyclosporine, warfarin, steroids, protease inhibitors, and possibly benzodiazepines, calcium channel blockers, and many other drugs; decreased serum digoxin levels

At least 5 days before surgery

Valerian, all heal, garden heliotrope, vandal root

Sedation

Potential to increase sedative effect of anesthetics; benzodiazepine-like acute withdrawal; potential to increase anesthetic requirements with long-term use

No data

PT, prothrombin time; PTT, partial thromboplastin time.
From Ang-Lee MKet al:Herbal Medicines and perioperative care. JAMA 2001;286:208. Used with permission.

  1. SAW PALMETTO

Saw palmetto is effective for treating benign prostatic hypertrophy, but the mechanism is not completely understood. It has been shown to inhibit 5α-reductase as well as prostate estrogen receptors. Prostate size has not been proven to decrease with use of saw palmetto, but there have been beneficial effects on nocturia and peak urine flow. It is less effective than α-blocking agents but has fewer side effects. GI side effects, dizziness, headache, and increase in blood pressure are most common but still infrequent. There have been no reports on interactions with other drugs.

  1. ST. JOHN'S WORT

St. John's wort is currently used to treat mild to moderate depression but is not indicated for major depression. Its effect is due to inhibition of serotonin, norepinephrine, and dopamine uptake. It is considered to be safe overall. Adverse effects include insomnia, diarrhea, rare photosensitivity, and potential to unmask mania. Use with SSRIs may cause the syndrome of serotonin excess, especially in older adults. In addition, St. John's wort can induce or reduce various cytochrome P450 isoenzymes and affect levels of many drugs. Effects of warfarin can be reduced and cyclosporine levels decreased. The use of St. John's wort may affect multiple drugs used during surgery and, because of its long half-life, should be discontinued 5 days before surgery.

  1. VALERIAN ROOT

Valerian root is used as a treatment for insomnia and anxiety and is included in most herbal insomnia remedies. Side effects include morning drowsiness and headache. Effects are dose dependent. Benzodiazepines may amplify effects. Patients on long-standing doses could potentially have related withdrawal if it is stopped abruptly, justifying tapering before surgery.

OTC Medications

It is important to discuss nonprescription medication use with older adult patients because it can interfere with the effectiveness of prescription drugs and potentiate harmful effects. Many patients do not consider these therapies as part of their medication regimen, and the physician needs to ask specifically about such medications.

  1. GASTROINTESTINAL AGENTS

Antacids (eg, aluminum/magnesium hydroxide) can interfere with medication absorption, especially when absorption is pH dependent. The bioavailability of some antibiotics, notably the quinolones, and some beta-lactams as well as tetracycline can be affected.

The H2 receptor agonist cimetidine at its OTC dosage can interact with prescription medication. It affects pH-related absorption of ketoconazole, theophylline levels can be increased, and it can affect various benzodiazepines, either increasing or decreasing levels. Cimetidine and ranitidine can prolong prothrombin time during therapy with warfarin by decreasing its clearance. It also decreases the clearance of flecainide, ethmozine, procainamide, quinidine, lidocaine, propranolol, and phenytoin.

  1. NSAIDs

The physician needs to specifically inquire about the use of NSAIDs to alert patients to potential adverse effects. Aspirin can affect serum concentrations of phenytoin and valproic acid. Both ibuprofen and naproxen can increase lithium concentrations. They can reduce renal excretion of digoxin, especially in patients with renal insufficiency.

EVIDENCE-BASED POINTS

  • Drugs that are prescribed should have a clear and documented indication.
  • Patient and caregivers should be educated regarding each drug's indication and side effects so that the therapeutic effect can be monitored.
  • Medications are started at low doses and increased cautiously.
  • Changes in pharmacokinetics can occur when stopping medications.
  • Patient adherence with the medication is ensured before increasing the dose or adding a new medication.
  • New medications should be added cautiously; the medication list should be checked for potential drug-drug and drug-disease interactions.
  • Medication side effects are considered a potential cause of new symptoms.
  • Drugs that are not having the desired effect or are having adverse effects are discontinued in a timely fashion.
  • Medication lists are kept up to date and available if the patient is hospitalized or needs consultation.
  • Medications are periodically reviewed with the patient and caregiver, allowing for drugs to be stopped and drug oversights corrected.

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  • Inquiry is made about OTC and herbal medications.
  • Medications with strong anticholinergic properties are avoided, or patients and caregivers are made aware of common side effects.
  • Primum non nocere (first do no harm).

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