enalaprilat-anhydrous and Cough

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Cough; Dinoprostone; Enalapril; Enalaprilat; Female; Half-Life; Humans; Hypertension; Male; Middle Aged; Substance P

Angiotensin-converting enzyme (ACE) inhibitors are one of the first drugs of choice for the treatment of hypertension. However, there have been many reports of persistent chronic dry cough and inflammatory skin reactions (rash and/or angioedema, etc.) induced by ACE inhibitors. In this study, in order to evaluate the cough and inflammatory reaction, we measured the number of citric acid-induced coughs and the intradermal inflammation with ovalbumin in guinea pigs consecutively treated with ACE inhibitors (lisinopril, enalaprilat and imidapril) for 3 days. The number of citric acid-induced coughs and the inflammatory responses were significantly enhanced by treatment with lisinopril and enalaprilat, whereas imidapril produced no change in either response. These results correspond to the frequency of adverse effects in clinical practice, which suggests that imidapril has the least ability to induce the inflammatory skin response and cough. Furthermore, the enhancement produced by the ACE inhibitors in the number of coughs and the inflammatory responses were significantly reduced by pretreatment with indomethacin (prostaglandin synthesis inhibitor). This finding suggests that PGs at least participate in the mechanism for ACE inhibitor-induced cough and inflammatory skin response.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cough; Cyclooxygenase Inhibitors; Enalaprilat; Female; Guinea Pigs; Imidazoles; Imidazolidines; Indomethacin; Inflammation; Lisinopril

The first inhibitor of angiotensin converting enzyme (ACE) was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Capsaicin; Cough; Drug Eruptions; Enalapril; Enalaprilat; Guinea Pigs; Histamine Release; Humans; Injections, Intradermal; Ovalbumin; Skin; Skin Tests