Is a Rare Cognitive Side Effect Worth Keeping in Mind?

I have read that mental confusion and paranoia may be potential side effects ofcertain angiotensin-converting enzyme (ACE) inhibitors. What is the likely mechanismof these effects?
-- Robert Graham, DO, MPH
    Mount Pleasant, MichFor the last few decades, ACE inhibitors have been commonly used to treathypertension and congestive heart failure. These agents were originallyisolated from peptides in snake venom. The first member of the class, captopril,became commercially available in the early 1980s, followed closelyby enalapril.¹ Since that time, the FDA has approved a dozen additionalclosely related compounds; these are available as single agents and in combinationwith other cardiovascular drugs.Captopril was found to block enkephalinase, the CNS enzyme that breaksdown a naturally occurring opiate similar to the endorphins.² Captopril andenalapril were tested in healthy volunteers; no differences in cognitive functionwere found between the groups that received ACE inhibitors and those thatreceived 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.⁷The cognitive change seems to resolve quickly when the offending drug iswithheld. Administration of naloxone also leads to a prompt reversal, whichsuggests that an increase in enkephalin levels is the likely mechanism.This appears to be an exceedingly rare--but real--adverse effect of thesemedications in susceptible persons. There have been no formal studies of thenewer ACE inhibitors with regard to a possible association with impairment ofcognitive function; thus, it is not clear whether this reaction is associated onlywith the older drugs, such as captopril and enalapril, or whether it is a generalclass 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

References:

REFERENCES:

1.

O’Brien AA, Bulpitt CJ. The effects of ACE inhibitors on cognitive function.

Drugs Aging.

1995;6:173-180.

2.

Sicuteri F. Enkephalinase inhibition relieves pain syndromes of central dysnociception (migraine andrelated headache).

Cephalalgia.

1981;1:229-232.

3.

Bulpitt CJ, Fletcher AE. Cognitive function and angiotensin-converting enzyme inhibitors in comparisonwith other antihypertensive drugs.

J Cardiovasc Pharmacol.

1992;19(suppl 6):S100-S104.

4.

Ebert U, Kirch W. Effects of captopril and enalapril on electroencephalogram and cognitive performancein healthy volunteers.

Eur J Clin Pharmacol.

1999;55:255-257.

5.

Ahmad S. Enalapril-induced acute psychosis.

DICP.

1991;25:558-559.

6.

Gillman MA, Sandyk R. Reversal of captopril induced psychosis with naloxone.

Am J Psychiatry.

1991;142:270.

7.

West Midlands Center for Adverse Drug Reactions Reporting. ACE inhibitors and CNS adverse sideeffects.