For many seniors, medication is essential to maintaining good quality of life. On the other hand, seniors experience serious medication-related side effects more than any other group, with an estimated 10 to 30% of hospital admissions related to adverse drug events.^1-3

There are many reasons why some seniors experience more adverse effects. These include age-related physiologic changes that alter the distribution and elimination of some drugs, as well a pharmacologic response. Older people also tend to have more chronic diseases that require treatment. The more medications a patient takes, the higher the risk for a drug-drug interaction. Extra pills can complicate the regimen, increasing the chance of error.

Age-related physiologic changes

Two key pharmacokinetic changes tend to alter the response of older adults to drugs. First, an increase in the fat compartment affects the way lipid-soluble drugs are distributed and eliminated. Fat tissue acts as a storage reservoir for lipid soluble drugs, which are eliminated more slowly than in a younger person, prolonging the pharmacologic action. This is one of the primary reasons why long-acting benzodiazepines, such as diazepam, should be avoided in older individuals.

The other important pharmacokinetic change involves elimination of medications by the kidney. Renal function declines approximately 8-10 ml/min per decade between 30 and 80 years of age.⁴ In general, a person 70 years of age or older should be assumed to have a creatinine clearance of less than 40 ml/min unless proven otherwise. Drugs that are eliminated predominately by the kidney will require appropriate dose reductions. For example, an uncomplicated urinary tract infection can be effectively treated in many older individuals by single-strength co-trimoxazole twice daily, rather than the double-strength dosage necessary for younger patients.

A decrease in renal function can also result in therapeutic failure of some drugs. For example, the antibiotic nitrofurantoin requires excretion in the kidney to achieve therapeutic concentrations in the urine. If the creatinine clearance is less than 40 ml/min, then urinary concentrations may be insufficient to adequately treat a urinary tract infection. Instead, systemic accumulation can occur, exposing some seniors to the GI, neurological and pulmonary toxicities of this agent.⁵

When considering drug dosing, keep in mind that relying solely on serum creatinine levels to estimate renal function may be inaccurate. This is due to a decrease in muscle mass that occurs with age, which needs to be taken into account. While no single method can provide a completely accurate determination of renal function for the purpose of drug dosing, the Cockcroft-Gault equation is generally considered to give a reasonable estimate in older people.⁶

Just as drug distribution and elimination can be changed by the aging process, so is response to certain medications. In particular, older individuals are more sensitive to drug effects on the central nervous system. Agents with anticholinergic properties are especially problematic and can cause or contribute to cognitive impairment. Whether or not an individual will develop anticholinergic-related cognitive impairment depends upon several factors, the most important of which appear to be baseline cognitive status and total anticholinergic burden.

Regardless of baseline cognitive status, minimizing anticholinergic burden can help prevent drug-related cognitive decline. A list of commonly used agents exhibiting anticholinergic activity is outlined in Table 1.

Drug-drug interactions

Drug interactions result from a change in the way a medication acts in the body when taken with certain other drugs, foods or natural health products. This can result in decreased efficacy, toxicity or an unexpected or seemingly idiosyncratic reaction.

Determining whether or not a combination of drugs will interact with each other and cause a problem is challenging. Literally tens of thousands of drug-drug interactions have been described in the literature, with more added every day. It's impossible for any clinician to keep up to date in this ever-changing landscape. So how can dangerous drug-drug interactions be avoided? One technique is to develop a “short list” of common drug-drug interactions.⁷ An example of such a list is outlined in Table 2.

Computerized warnings from office-based or pharmacy drug interaction programs can also be helpful in identifying potentially serious problems, but it’s important to understand the limits of this technology. Many alert programs don't effectively differentiate between clinically important and non-important interactions. They sometimes fail to distinguish between current medications and chronically remote prescriptions.⁷ When in doubt about the clinical relevance of a potential drug interaction, a call to the Regional Drug Information Centre or discussion with a pharmacist can be helpful.

One aspect of drug interactions often overlooked in the senior population is drug-disease interactions. Drug-disease interactions occur when a medication precipitates or exacerbates an underlying disease. For example, non-steroidal anti-inflammatory agents can precipitate/worsen hypertension, heart failure or renal disease and should generally be avoided in older people. Functional decline in the frail elderly can also be related to drug-disease interactions, with medications contributing to cognitive impairment and mobility problems. Psychotropic medications, in particular, have been associated with a significantly increased risk of falls and serious injury. If such agents must be used, use them sparingly and at the lowest possible dose.

Avoiding adherence problems

Medication non-adherence is a common problem and is associated with increased morbidity and mortality.⁸ Complexity of the drug regimen is a major factor in non-adherence. A comprehensive medication review can reduce complexity; remember, though, that the purpose of such a review is not to discontinue as many meds as possible. It's to encourage the appropriate use of medications in a specific patient.

To complete a medication review it’s important to first have an accurate list, including over-the-counter and natural health products, and facts on how the person is taking them. Questions to ask include the following⁹:

• What is the indication for each drug?
• Is the use of this medication consistent with the goals of therapy?
• Is use of this medication achieving the intended treatment targets?
• Is the duration of therapy appropriate given the goals of therapy and intended treatment targets?
• Is the dosage appropriate given the individual patient-specific characteristics?
• Are the directions correct?
• Is there any duplication of therapy?

Patient understanding is also an important factor in improving adherence. When prescribing new drugs, it’s important to give clear instructions for dose and dosing interval. “As directed” instructions is a medication error waiting to happen.

Two other interventions have demonstrated effectiveness in improving adherence among seniors. These are having a family member or friend assisting or supervising medication administration, and the use of compliance packaging.⁸ When discussing medication use with older patients, it's often helpful to include an accompanying family member/caregiver in the discussion. Referral to their pharmacist for preparation of an individualized med calendar and discussion of how to take the drugs can further reinforce instructions given in the office. Pharmacists can also assess individual patients to decide whether compliance packaging is likely to be of any benefit.

Table 2: Clinically important common drug interactions in older patients^11,14

Drug	Interacting drug	Outcome	Comments
ACE inhibitors	Potassium-sparing diuretics & potassium supplements	Hyperkalemia	Patients with diabetes, renal disease or baseline hyperkalemia at greatest risk. Monitor serum potassium when initiating drug combination.
Digoxin	Amiodarone, erythromycin & clarithromycin, verapamil	↑ Digoxin level	Monitor digoxin levels & adjust dose accordingly.
Glyburide	Co-trimoxazole	Hypoglycemia secondary to ↑ glyburide levels	Monitor fasting glucose more closely when initiating combination. Educate patients regarding signs/symptoms of hypoglycemia.
Lithium	ACE inhibitors, diuretics (includes loop diuretics & thiazides), NSAIDs	↑ Lithium level	Monitor lithium levels & adjust dose accordingly.
Warfarin	Amiodarone, erythromycin, clarithromycin, co-trimoxazole, metronidazole, NSAIDs (includes COX-2 selective agents)	↑ INR*	Consider ↓ warfarin dose by 25-30% when initiating interacting drug, monitor INR & adjust dose further as necessary.
Warfarin	Phenytoin, rifampin	↓ INR	Monitor INR and adjust dose accordingly

Note: This table is not meant to be a comprehensive reference for drug interactions. Readers are referred to other drug interaction sources. *INR = international normalized ratio