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Patients Respond to Lower Doses of Medications

by Diane B. Crutchfield, D.Ph., C.G.P.

Geriatric Times

July/August 2001

Vol. II

Issue 4

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Health care professionals have long known the need to adjust the dose of many medications based on renal function, other medication use, concurrent medical conditions, age, weight, gender or sometimes ethnic origin. There are now indications that many of the manufacturers' recommended standard doses may be higher than necessary for effective therapy, regardless of these parameters. This is particularly important since most adverse drug reactions (ADRs) are dose-related.

In a meta-analysis, Lazarou and colleagues (1998) concluded that over 2 million ADRs occurred in hospitalized patients in the United States in 1994 and as many as 106,000 deaths occurred as a result of ADRs. Over 75% of those ADRs were dose-related. A key point made by the authors was that the guidelines used in their analysis were specifically limited to only those ADRs resulting from medications that were properly prescribed and administered.

When medications are approved by the U.S. Food and Drug Administration, the manufacturer submits information about standard doses that were used in the clinical trials. The doses used in these trials have to be high enough to demonstrate the efficacy of the drug, i.e., most patients must show a positive response. Subsequent studies may show lower doses to be as effective as the original recommended doses, but a change in the labeling would require another long and costly process for additional approval. The FDA may require the manufacturer to conduct new studies in order for package inserts to be approved. Therefore, the prerelease data may be considered standard dosing for years, even after postmarketing trials indicate that lower doses may be as effective with fewer side effects.

One of the drug references most commonly used by physicians is the Physicians' Desk Reference (PDR), which contains reprints of medication package inserts and is provided free of charge to many physician offices. Package inserts printed in the PDR may not have been updated since the original approval of the drug. While the PDR is published annually, a user cannot determine easily if the printed package insert has been updated, since, unlike the actual inserts, the printed versions usually are not dated. Therefore, it is the responsibility of the health care provider to maintain current knowledge of accepted drug doses and to individualize dosing, particularly for geriatric patients, in order to prevent adverse drug reactions. Following manufacturers' dosage guidelines does not guarantee that ADRs will be avoided. Suggested screening techniques include asking the patient if they are sensitive to alcohol, antihistamines, caffeine, decongestants or any other medications they have taken in the past. Affirmative answers may indicate that lower does of medications would be as effective, and more appropriate, for these individuals.

The PDR is just one reference among the variety of drug information that is readily available to the public in books and on the Internet. Consumers are also increasingly aware of their own health conditions and medications used to treat them. There is the risk that they heed the false notion that more is better and increase their own dose, even if their physician prescribes medication at a lower dose than the one recommended in their drug reference (i.e., package insert).

The Pharmacist's Letter recently published a summary of the concerns about unnecessary high doses of medications and a table of alternate doses for commonly prescribed medications (Table). Many of the listed medications, such as the cardiovascular agents, are frequently used by the elderly. Overdosing may lead to hypotension, falls, hypovolemia, mental status changes and other avoidable adverse reactions. The presence of ADRs may cause patient noncompliance, perpetuating the cycle of ADRs and therapeutic ineffectiveness.

Dose-related adverse reactions related to the use of antihypertensive therapy affect quality of life and compliance as reported by Cohen (2001a). Results of the report show that the doses recommended by the Joint National Commission Guidelines on hypertension (JNC VI) for initial doses were lower than the doses in the PDR for 23 (58%) of 40 drugs.

Nonsteroidal anti-inflammatory drugs are known to cause serious adverse effects in the geriatric population, including gastrointestinal toxicity. Some patients continue to receive ibuprofen at the initial recommended dose of 400 mg three to four times per day, although a dose of 200 mg three times per day is as effective and less likely to produce serious adverse reactions.

Information on low doses is difficult to locate and interpret among the millions of articles in the literature. The popularity of handheld computer software literally puts drug information at one's fingertips. The user must continue to be critical of the information, however, because even though the computer information is definitely easier to update than printed versions of drug information, it may not be done in a timely manner.

The best advice for the health care professional may be to adhere to the adage start low and go slow.

Dr. Crutchfield is president of Pharmacy Consulting Care, an independent consultant pharmacy practice located in Knoxville, Tenn.

References

Cohen JS (2001a), Adverse drug effects, compliance, and initial doses of antihypertensive drugs recommended by the Joint National Committee vs the Physicians' Desk Reference. Arch Intern Med 161(6):880-885.

Lazarou J, Pomeranz BH, Corey PN (1998), Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279(15):1200-1205 [see comments].

Pharmacist's Letter (2001), Effective Low Dose Medications: Detail-Document #170501, 17(170501).

Physicians Desk Reference, 53rd ed. (1999), Montvale, N.J.: Medical Economics Co.

Further Reading

Bates DW (1998), Drugs and adverse drug reactions: how worried should we be? JAMA 279(15):1216-1217 [comment].

Cohen JS (1999), Expert Column. Preventing adverse drug reactions before they occur. Medscape Pharmacotherapy. Available at: www.medscape.com/medscape/pharmacology/journal/1999/
v01.n12/mp1213.01/mp1213.01-01.html. Accessed June 12, 2001.

Cohen JS (2001b), Dose discrepancies between the Physicians Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events. Arch Intern Med 161(7):957-964.

Lanza FL (1998), A guideline for the treatment and prevention of NSAID-induced ulcers. Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 93(11):2037-2046.

Joint National Committee (1997), The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. [Erratum in Arch Intern Med 158(6):573.] Arch Intern Med 157(21):2413-2446 [see comments].