Pharmacotherapy Update 2002

**sub**What’s New About Old Medications **endsub** J. Mark Ruscin, PharmD, Assistant Professor, Department of Pharmacy Practice, University of Colorado School of Pharmacy, Denver, CO, noted that the session would focus on seven studies published within the last year, several medications approved prior to 2001, and how these all fit into the practice of geriatric medicine. Dr. Ruscin first discussed the Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke (WARS) study, which compared warfarin and aspirin in secondary prevention. Dr. Ruscin stated that one could conclude from WARS that no differences existed between the two agents regarding risk of death or recurrent ischemic stroke. “Warfarin and aspirin are reasonable therapeutic alternatives, although aspirin is most easily monitored,” he added. The presenter spoke about the Losartan Intervention for Endpoint (LIFE) study, in which researchers aimed to establish whether selective blocking of angiotensin II improves left ventricular hypertrophy (LVH) beyond reducing a patient’s blood pressure, and, consequently, whether it reduces cardiovascular morbidity and death. This study compared a losartan-based  antihypertensive treatment with atenolol-based treatment. Patients were randomized to losartan 50 mg or atenolol 50 mg. “Atenolol showed significantly more adverse events overall,” Dr. Ruscin noted. “Atenolol also showed more serious drug-related adverse events. It appears that losartan is a little better tolerated than atenolol. The speaker explained that LIFE looked at persons with evidence of LVH and that the information from the study should not be extrapolated to persons without LVH. “Beta blockers and diuretics should be considered for elderly patients with hypertension but without LVH,” he stated. Dr. Ruscin next discussed data from a study looking at the risks of recurrent stroke and treatment with estrogen. He explained that when the authors of the study looked specifically at the first six months, they found significant differences between those randomized to placebo and estradiol; more total strokes and more fatal strokes occurred in the estradiol group. “Estrogen therapy should not be prescribed for the secondary prevention of cerebrovascular disease,” the speaker said. Dr. Ruscin presented the Vioxx® Gastrointestinal Outcomes Research (VIGOR) and the Celecoxib Long-term Arthritis Safety Studies (CLASS). He pointed out that there was a higher rate of MIs and cardiovascular events in those who took Vioxx versus naproxen in VIGOR. In CLASS, patients were allowed to take cardiovascular doses of aspirin throughout the study period, unlike participants in VIGOR. Those who did had a 1.4% risk of MI compared with 1.2% for those who did not take aspirin. The speaker explained that those who took aspirin were already at a higher risk, which is why they were using aspirin therapy. The speaker discussed unpublished data from the Heart Protection study, which included patients who would not typically be treated with statins; they had fairly low total cholesterol and included elderly patients, women, persons with noncoronary vascular disease, and individuals with diabetes. The study compared simvastatin 40 mg with placebo. Primary endpoints were all-cause mortality, death from coronary heart disease, and related blood vessel disease. Patients age 65 to 69 and 70 to 74 years who took simvastatin showed a 24% and a 12% decrease in primary events, respectively. The Nurses Health Study of 72,000 postmenopausal women looked at the relative risk of hip fractures for each quintile of vitamin intake compared to the lowest quintile, which was reverent quintile. The study found that long-term intake of diets high in retinol may increase the risk of osteoporotic hip fractures in women, and that the amount of retinol in fortified foods and vitamin A supplements may need to be reevaluated. “Primary sources of retinol from the diet are found in fish and liver sources,” Dr. Ruscin added. Dr. Ruscin concluded with information from a study published in the November 22, 2001, issue of The New England Journal of Medicine, which looked at the risk of Alzheimer’s disease in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs). “Concluding from this study, the long-term use of NSAIDs may protect against Alzheimer’s disease, but there was no association between NSAID use and reduced risk of vascular dementia,” the presenter stated. “I do not think this data suggests that NSAIDs should be prescribed for patients who have been diagnosed with Alzheimer’s disease. This was a primary prevention study looking at people who had not been diagnosed.” **sub**New Drugs and You **endsub** Joseph T. Hanlon, PharmD, Professor, Department of Experimental and Clinical Pharmacology, University of Minnesota, Twin Cities, Minneapolis, discussed drugs that entered the market in 2001. Dr. Hanlon focused his presentation on a new proton pump inhibitor (PPI) esomeprazole, galantamine, the beta-2 agonist formoterol, the COX-2 inhibitor valdecoxib, and general principles about good prescribing. The speaker provided information on esomeprazole, which is indicated for erosive esophagitis symptom resolution and healing, the treatment of symptomatic gastro?esophageal reflux disease, and the combination treatment with amoxicillin and clarithromycin of Helicobacter pylori. He noted that esomeprazole cannot be given with food because its absorption can be decreased by one-third to almost one-half. The agent’s half-life is about one hour to one hour and 30 minutes. A questionably significant, decreased clearance seems to exist in the elderly, according to Dr. Hanlon: “The side effects of this drug are exactly the same as all the other PPIs.” In addition, the drug interactions seen with omeprazole are not seen with esomeprazole. It can, however, decrease the absorption of ketoconazole and affect diazepam clearance. In terms of efficacy and dose equivalence a 20-mg dose of esomeprazole equals omeprazole 20 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg. The average wholesale price of the new PPI is $120 per month. However, no oral suspension or intravenous formulations exist for esomeprazole. Dr. Hanlon continued with data on galantamine, the fourth acetylcholinesterase (ACE) inhibitor to reach the market. “Galantamine is for treatment of mild-to-moderate dementia of the Alzheimer’s type, but there is some data showing effects with vascular dementia that was just published,” he explained. “One of the good things about drugs that are the third or fourth on the market is that they have to distinguish themselves somehow in terms of labeling. So, they oftentimes will increase the types of disorders they will treat.” However, Dr. Hanlon explained that physicians need to ask if galantamine would be preferential to another ACE inhibitor for vascular dementia treatment in a head-to-head trial. “The answer is that we will never know because no one will fund such a study. From a pharmacology point of view, I doubt that galantamine would be better.” The presenter explained that galantamine is well-absorbed, is not affected by food, is very low protein-binding, is primarily hepatically metabolized, has a twice-daily dosing because of a short half-life, and has a slight decrease in clearance with age. Side effects of this medication are mostly gastrointestinal in nature, and are typical of the whole drug class. “The one seen often in our geriatric clinic is anorexia and weight loss,” Dr. Hanlon noted, “which is difficult in patients with Alzheimer’s disease because they can have both even if they are not on any drugs.” The biggest concern with galantamine, according to the speaker, is what effect it has on persons with cardiovascular disease, specifically the effects that an increase of acetylcholine would have on someone’s heart. “It must be titrated slowly, dose adjustments may need to be made, and it has to be dosed twice a day,” Dr. Hanlon added. “The drugs in this class only result in a two-to-four point increase on a 70-point scale of cognition. My hope is that one of the 24 products in development now for Alzheimer’s disease will be more efficacious.” Dr. Hanlon discussed the beta-2 agonist formoterol next, which is approved for maintenance treatment of asthma, and can be used in exercise-induced bronchospasm, unlike its comparison drug, salmeterol. “Formoterol is a hybrid drug with a quick onset (three minutes vs. 10-20 minutes for salmeterol) and a long duration,” he explained. The adverse effects of this agent include tremor, dizziness, and hoarse throat, which are all dose-related. Palpitations are also seen in persons using formoterol, and there is a concern about tolerance or tachyphylaxis, which is characteristic of the beta-2 agonists. Drug interactions are mostly theoretical, as little systemic absorption occurs with formoterol.   “It clearly allows a decrease in steroid and theophylline use,” continued Dr. Hanlon, “and it might be beneficial in patients with chronic obstructive pulmonary disease who we would not typically think of as having reversible airway disease.” Formoterol is available as 12-mcg capsules for use in an inhaler twice daily. Dr. Hanlon expressed concern about the use of inhalers by elderly persons. “I know of no studies that look at community-dwelling persons who might have cognitive problems or osteoarthritis and show how they would use such a device, whether they are trained or not,” added the speaker. “There is some data with other inhaled dry powders that the actual distributor of the medication does make a difference.” The last agent Dr. Hanlon discussed was the COX-2 inhibitor valdecoxib, which is approved for osteoarthritis, rheumatoid arthritis, and primary dysmenorrhea. He explained that the COX-2 inhibitors might be preferred over NSAIDs, as NSAIDs block both COX-1 and COX-2, and COX-1 has more of an effect on GI protectivity. The presenter explained that no data have been published on valdecoxib, but discussed what is known: “It is absorbed well, food does not affect it, it is highly plasma protein-bound, it is primarily hepatically metabolized, its half-life is about eight to 11 hours, and age does seem to have an effect on its clearance. Although COX-2 inhibitors have the theoretical ability to have fewer GI effects, they do have them, especially in patients on antiplatelets for secondary prevention of cardiovascular and cerebrovascular disease. It will have approximately the same GI risk profile as an NSAID.” Valdecoxib can cause decrease in renal function, fluid retention edema, increase in blood pressure, and blockage of the anti?hypertensive effect of many drugs, such as ACE inhibitors and diuretics. An increased risk of peptic ulcer disease exists in those taking this agent with aspirin. Dr. Hanlon closed with a brief guide to good prescribing. “Figure out what a patient has, decide what you want to achieve, find out what his or her liver and renal problems are, know what other drugs are taken, and then decide if the preferred drug is reasonable for that patient,” he stated. “Give the patient some information when prescribing the drug, and monitor it over time. Also, only prescribe the drugs that have specific geriatric information.”