PT  - JOURNAL ARTICLE
AU  - Hans Peter Brunner-La Rocca
AU  - Daniel Weilenmann
AU  - Wolfgang Kiowski
AU  - Friedrich E. Maly
AU  - Ferenc Follath
TI  - Plasma Levels of Enalaprilat in Chronic Therapy of Heart Failure: Relationship to Adverse Events
DP  - 1999 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 565--571
VI  - 289
IP  - 1
4099  - http://jpet.aspetjournals.org/content/289/1/565.short
4100  - http://jpet.aspetjournals.org/content/289/1/565.full
SO  - J Pharmacol Exp Ther1999 Apr 01; 289
AB  - Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, little is known about the dosage-plasma-level relationship of ACE inhibitors in CHF and its relation to drug-induced adverse effects. We investigated 45 patients (age 55 ± 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg b.i.d. (E10,n = 16), 10 mg b.i.d. (E20, n = 18), or 20 mg b.i.d. (E40, n = 11). This dosage was changed three times to treat all patients with lower, higher, and, finally, the initial dosage for 4 weeks each. Patients were examined clinically, by questionnaire, and by spiroergometry. In addition, neurohormones (atrial and brain natriuretic peptide and norepinephrine), enalaprilat trough levels, and serum potassium and creatinine were measured. Enalaprilat trough levels differed significantly between the three groups at study entry but also varied markedly within each group. In addition to the dose of enalapril, serum creatinine, severity of CHF, basal metabolic rate, and body weight significantly influenced enalaprilat trough levels (R2=.84, p < .001). Within-patient comparisons revealed that serum creatinine (107 ± 26 versus 102 ± 20 μmol/liter) and potassium (3.8 ± 0.4 versus 3.7 ± 0.3mmol/liter) were higher, cough was more common (scored on a scale of 0–8: 1.7 ± 2.1 versus 1.4 ± 1.8), and blood pressure was lower (systolic, 112 ± 14 versus 117 ± 13 mm Hg; diastolic, 66 ± 9 versus 69 ± 11 mm Hg) on the highest than on the lowest enalaprilat trough level (all p < .05). Highly variable enalaprilat trough levels and the fact that adverse effects were more common on high enalaprilat trough levels provide a rationale for individually adjusting ACE-inhibitor dose in case of adverse effects. The American Society for Pharmacology and Experimental Therapeutics