Recognizing, Reporting, and Reducing Adverse Drug Reactions

South Med J. 2001;94(4) 

In This Article

Historical Background

Several poignant examples of ADRs highlight the point that treating disease is not without its consequences.

Used for centuries for such conditions as syphilis, typhus, and leprosy, mercury was also used popularly in the form of calomel as a teething powder, laxative, and worming agent. By 1890, a disease called acrodynia was described and involved severe pain in the extremities, the mortality of which was 5%.[2] By 1948, a link was finally made between the use of mercury and acrodynia. It took the FDA several years thereafter to convince manufacturers to remove mercury from their products.[2]

One of the most notorious 20th-century medications, thalidomide was marketed in 1956 as a sedative for use during pregnancy. After animal testing and a large, uncontrolled clinical trial, thalidomide was said to be safe for human ingestion. In 1961, three German physicians reported a number of cases of phocomelia (congenital absence of the upper arm and/or upper leg). A connection between thalidomide and phocomelia was made, but there was a delay in removing it from all products because it was marketed under nearly 100 different trade names.[3] The tragedy caused by thalidomide, which was never approved for use in the United States, did lead to stricter regulation over testing for teratogenicity.

First approved in 1985 for treatment of ventricular arrhythmias, flecainide was used largely for premature ventricular contractions (PVCs) in patients after myocardial infarction (MI). By 1989, 200,000 people were taking the medication. After results from the Cardiac Arrhythmia Suppression Trial (CAST) were revealed, flecainide's use came into question. The CAST study found that more people with post-MI arrhythmia died taking flecainide than placebo.[4]

A significant amount of controversy has surrounded the CCB drug class. In 1995, Psaty et al[5] reported that the use of short-acting CCB for the treatment of hypertension increases the risk ratio of MI by 60%. A subsequent meta-analysis showed that short-acting nifedipine, when used in moderate to high doses in people with coronary artery disease, actually led to an increase in total mortality.[6]

This drug was introduced in 1985 as a nonsedating antihistamine. It was on the verge of becoming an over-the-counter medication in 1992 when several cases of serious arrhythmias (torsade de pointes) were associated with terfenadine use.[7] Terfenadine levels reached toxic levels when used with antifungals and macrolides. Warning letters were issued to physicians, but these lethal combinations were still being prescribed. This medication was eventually pulled from most markets.

As an isomer of fenfluramine, these nonamphetamine anorectics act by increasing serotonin levels.[3] They were heralded for their low abuse profile. In 1997, the Mayo Clinic reported 24 cases of valvular heart disease (similar to the pathogenesis of carcinoid) in patients taking these medications.[8] Redux was then linked to an increased risk of primary pulmonary hypertension and taken off the market.

Commonly used for a variety of conditions, NSAIDs clearly have proven benefit but at the same time can be deadly. Fries[9] reported that more than 70,000 hospitalizations and 7,000 deaths occur annually in the United States as a result of NSAID use. In comparison, deaths from illicit drug use (cocaine, heroin, LSD, marijuana, etc) range from an estimated annual incidence of 3,562 to 10,710.[10]

This drug showed great promise for the treatment of type 2 diabetes mellitus. Several cases of serious hepatotoxicity were reported to the FDA, which issued warnings to this effect in 1997 and 1998.[11] The drug, which was withdrawn from the market in the United Kingdom in 1997, was withdrawn in the United States in 2000.

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