Drug Safety

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Lilia Malkin, BSc

Adverse drug reactions (ADRs) account for a significant proportion of morbidity and mortality in the geriatric population. According to the 1993 Canadian Medical Association (CMA) Policy Summary, over 20 percent of acute care hospital admissions of Canadian seniors may result directly from ADRs. Other studies have reported the incidence of ADR-related admissions ranging from 8 to 35 percent.

The World Health Organization (WHO) defines an adverse drug reaction as "a noxious, unintended effect of a drug that occurs in doses normally used in humans for the diagnosis, prophylaxis, or treatment of disease." ADRs can be divided into two categories: predictable (Type A) and unpredictable (Type B). Predictable reactions make up the vast majority of ADRs at 80 percent. Type A reactions are frequently dose-dependent and related to the augmented pharmacologic action of the medication: toxicity, side effects, indirect effects, and drug interactions. Unpredictable ADRs are less common, and include intolerance, allergy or hypersensitivity, idiosyncrasy, and psycho-genic reactions. Recognition of the pertinent risk factors for both predictable and unpredictable ADRs has direct application to ADR prediction, prevention, and management in the geriatric population.

ADR Prediction: Risk Factors

Older Canadians have a four- to seven-fold higher risk of suffering an ADR compared to younger individuals. According to Dr.

Anna Liachenko, BSc, MSc

A large body of observational evidence suggested that estrogen replacement therapy (ERT) after menopause decreases a women's lifetime risk of death from myocardial infarction by 35 to 50 percent and increases life expectancy by 2 to 3 years. However, a recent major clinical trial concluded that estrogen plus progestin therapy did not decrease the overall risk of myocardial infarction and coronary death among postmenopausal women with previous heart disease. The main question raised by the results of the trial is whether doctors should change their prescribing patterns and which patient populations will be affected. While there is no simple answer, it is important to consider the issues involved such as, How serious were the limitations of the observational research? Did the trial look at the right group of patients? How far can we extrapolate the results? And what are the future implications?

The Heart and Estrogen/progestin Replacement Study (HERS) trial was a randomized, blinded, placebo-controlled trial designed to test the efficacy and safety of hormone replacement therapy (HRT, estrogen plus progestin) on secondary prevention of heart disease. The trial involved 2763 postmenopausal women with established coronary artery disease. In the HRT group, the rate of coronary events increased by 50% in the first year of the trial and subsequently decreased by 40% in the forth and fifth years, yielding no significant effect overall.

Michele Kohli, BSc, MSc

The persistence of influenza in the North American population has not been completely explained by epidemiologists.¹ During the last influenza season (1997-98), there were 5,148 laboratory confirmed cases of influenza in Canada (see Table 1).²The elderly population, those aged 65 years and above, are particularly susceptible to this disease. Over 95% of the deaths caused by influenza occur in this age group, in part, because of the higher prevalence of congestive heart failure and lung disease.¹ Last year, the occurrence of influenza peaked between January and March.² When the prevalence of influenza is high in a population, patients presenting with a febrile respiratory illness along with symptoms such as myalgia, headache, sore throat and cough are often diagnosed as having influenza.¹ However, the gold standard for diagnosis is laboratory detection of the virus in nasopharyngeal swabs.¹ The genes of the influenza virus mutate frequently, causing the antigenic molecules of the virus to change, resulting in the emergence of new viral sub-types. This process is known as antigenic drift. When human and swine or avian strains of influenza A recombine, the resulting new subtypes can cause pandemics.

Anna Liachenko, BSc, MSc

While non-pharmacological approaches are clearly beneficial for prevention of osteoporosis (OP), for many women these measures are not enough and a pharmacological treatment is required. Until early this decade, this meant one choice, hormone replacement therapy. Now, non-hormonal bisphosphonate treatments are also available. Both approaches are comparably efficient in preventing bone loss, at least on repeat bone mineral density testing. Some experts are also advocating slow-release fluoride, and combination therapy is also increasing. However, treatment choice is a complex decision which should only be made after careful consideration of the risks and benefits of each treatment, by the patient and her physician.

Before reviewing particular classes of drugs, physicians need to remember that all patients at risk for OP or with proven OP should be taking calcium and vitamin D in appropriate doses (see Fracture Prevention Part 1).

SMH Alibhai, MD, FRCPC

As any physician knows, stroke is a common cause of morbidity and mortality in older patients. Strokes can be divided into three major aetiological groups--haemorrhagic, thromboembolic, and lacunar. Practically speaking, if neuroimaging does not show evidence of haemorrhage, physicians will generally treat patients who present with an acute stroke (or a transient ischaemic attack (TIA), for that matter) with either antiplatelet or anticoagulant therapy. For patients with a well-documented embolic source (e.g. atrial fibrillation), warfarin is the treatment of choice. For all other patients with non-haemorrhagic stroke, the treatment is traditionally antiplatelet therapy.

However, there are several options within antiplatelet therapy. The standard drug has been acetylsalicylic acid (ASA), or aspirin. At least four large randomized controlled trials revealed Ticlopidine to be slightly more effective in reducing the incidence of strokes and TIAs than aspirin, although it was more costly and more toxic.¹ However, a later meta-analysis of 145 studies suggested ticlopidine was probably as equally effective as aspirin.²Although newer antiplatelet agents are on the horizon (e.g.

Jocalyn P. Clark, MSc

A recent article published in a special issue of the Canadian Medical Association Journal on Diversity and Women's Health described poor inclusion and representation of women in clinical drug trials for treatment of myocardial infarction (MI). Despite heart disease being a leading cause of disability and death among North American women, especially older women, less than one-quarter of the patients included in the studies were women and the average age of participants was only 62 years. The work of Rochon and colleagues at the University of Toronto extends earlier findings of Gurwitz et al. at the University of Massachusetts who reviewed the literature for a 30 year period up to 1991 and found that women represented only 20% of MI drug trial participants. Most of these trials excluded patients over the age of 75 years. Traditionally, older people have been poorly represented in clinical trials because they are more difficult to study: they tend to have coexisting illnesses, they use other medications that may interact with study drugs, and the elderly are more vulnerable to adverse drug effects. Additional reasons for explaining women's exclusion include fear of harming a fetus, hormonal fluctuations that may complicate responses to medication, and the use of estrogens which may be protective for some diseases.

Lawrence Papoff

Warfarin is an important tool in the prevention of thromboembolisms. Prescribing the drug to the elderly, and monitoring their progress while on the drug, however, are becoming increasingly complex matters, requiring careful attention to patient's blood levels, as measured by International Normalized Ratios (INRs) and in-depth knowledge of the patient.

Lilia Malkin, BSc

According to a study conducted by Dr. Elaine Hyle and associates at the Massachusetts General Hospital and Harvard Medical School in Boston and reported in the March 4, 1998 issue of the Journal of the American Medical Association (JAMA), acetaminophen significantly increases the level of anticoagulation, measured and commonly reported as the international normalized ratio (INR). Other important risk factors for increased anticoagulation identified in the study included decreased food intake, diarrhea, and increased warfarin dosage, as well as a recently initiated course of antibiotics or other medications previously known to augment the response to warfarin. Hylek and associates also identified factors that inversely affected the INR, such as alcohol and increased dietary intake of Vitamin K.

Future Treatment Options For Alzheimer's Disease

Tacrine (Cognex)--Parke-Davis
Exelon--Sandoz
Galanthamine (Reminyl)--Janssen-Ortho
Metrifonate--Bayer
Xanomilene--Eli Lilly
Milamilene--Hoechst Marion Roussel
Propentofylline--Hoechst Marion Roussel
Acetyl-L-carnitine (Alcar)
Selegiline (Deprenyl)--Draxis
Vitamin E
Ginkgo biloba
Phosphatidylserine
Estrogen
Non-steroidal anti-inflammatory drugs

Sherene Chen See is a freelance writer from Toronto, Ontario. We regret that Sherene Chen See's articles are not available on-line.

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Majority of Adverse Drug Reactions are Preventable

HRT Controversy Unresolved Until 2005

Less Than 40% of Elderly are Getting Flu Shots

Pharmacological Prevention of Fractures

An Aspirin A Day Keeps A Stroke Away--Really?

Older Women Often Excluded From Clinical Research: Age Bias or Gender Bias?

Warfarin Combats High Stroke Risk in Elderly

Diuretics First Choice for Elderly Hypertensive

Acetaminophen Risk Factor For Excessive Anticoagulation in Patients Taking Warfarin

Physicians To Have Drug Options for AD Treatment in Canada