Is a Rare Cognitive Side Effect Worth Keeping in Mind?

I have read that mental confusion and paranoia may be potential side effects of certain angiotensin-converting enzyme (ACE) inhibitors. What is the likely mechanism of these effects?
— Robert Graham, DO, MPH
    Mount Pleasant, Mich For the last few decades, ACE inhibitors have been commonly used to treat hypertension and congestive heart failure. These agents were originally isolated from peptides in snake venom. The first member of the class, captopril, became commercially available in the early 1980s, followed closely by enalapril.¹ Since that time, the FDA has approved a dozen additional closely related compounds; these are available as single agents and in combination with other cardiovascular drugs. Captopril was found to block enkephalinase, the CNS enzyme that breaks down a naturally occurring opiate similar to the endorphins.² Captopril and enalapril were tested in healthy volunteers; no differences in cognitive function were found between the groups that received ACE inhibitors and those that received placebo.^3,4 However, no formal studies were done in elderly persons, despite their greater susceptibility to cognitive problems. A few isolated cases of confusion and psychosis attributed to ACE inhibitors— in both young and old persons—have been reported in the American literature. ^5,6 Similar cases have been reported in the European literature as well.⁷ The cognitive change seems to resolve quickly when the offending drug is withheld. Administration of naloxone also leads to a prompt reversal, which suggests that an increase in enkephalin levels is the likely mechanism. This appears to be an exceedingly rare—but real—adverse effect of these medications in susceptible persons. There have been no formal studies of the newer ACE inhibitors with regard to a possible association with impairment of cognitive function; thus, it is not clear whether this reaction is associated only with the older drugs, such as captopril and enalapril, or whether it is a general class effect.
— Andrew S. Duxbury, MD
    Assistant Professor
    Division of Gerontology and Geriatric     Medicine
    University of Alabama
    Birmingham
— Paula A. Thompson, PharmD
    Associate Professor
    McWhorter School of Pharmacy
    Samford University
    Birmingham, Ala