Pharmacokinetics and Pharmacodynamics of Enalapril in Patients with Congestive Heart Failure and Patients with Hypertension

Schwartz, Janice B.; Taylor, Addison A.; Abernethy, Darrell; O’Meara, Mike; Farmer, John A.; Young, James B.; Nelson, Edward; Pool, James L.; Mitchell, Jerry R.

doi:10.1097/00005344-198507000-00023

Cited by 42 publications

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“…However, little or no change in enalaprilat disposition was noted in patients with compensated liver cirrhosis (8aba et Hayes et al 1989). Following oral doses of enalapril, the clearance of enalaprilat was impaired in patients with congestive heart failure compared with patients with hypertension (Dickstein et al 1987;Johnston et al 1984;Schwartz et al 1985). However, after repeated doses of enalapril, plasma enalaprilat concentrations were similar in patients with congestive heart failure to those observed in patients with hypertension (Johnston et al 1984).…”

Section: Enalaprilatmentioning

confidence: 90%

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

MacFadyen

Meredith

Elliott

1993

Clinical Pharmacokinetics

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The conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure. Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Enalaprilatmentioning

confidence: 90%

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

MacFadyen

Meredith

Elliott

1993

Clinical Pharmacokinetics

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“…6 - 10 Although this is likely to reflect the wide range of intersubject variability in pharmacokinetic responses, particularly when group data are evaluated, there is preliminary evidence that concentration-effect relations for ACE inhibitors can be more readily identified when individual subjects are considered.…”

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confidence: 99%

Kinetic-dynamic relations and individual responses to enalapril.

et al. 1990

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Pharmacoklnetic and phannacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (E^J and the drug concentration required to produce 50% of E M (0,50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, E^, was -46.1 ±16.5 and -19.7 ±3.8 mm Hg for systolic and dlastolic blood pressure, respectively, and the corresponding C,50 values were 66.1 ±20.2 and 61.6 ±22.5 ng/ml. For angiotensin converting enzyme inhibition, £ " , (%) and C.50 (ng/ml) were, respectively, 102.4±5 and 19.8±13 after the first dose, 103±5 and 33.4±20J after 1 week, and 101 J±2.2 and 31 J±18.9 after 6 weeks. There was no relation between the responsiveness to enalapril ( E^ or C.50) and patient age or plasma renin activity, but there was a significant positive correlation between E^ and the pretreatment blood pressure. In individual subjects, E^ (first dose) was directly correlated with E mM1 after 1 and 6 weeks. This study, which incorporated kinetic as well as dynamic information to characterize the antihypertensive response to enalapril, has identified enalaprilat concentration-effect relations in individual hypertensive subjects. 3 Qinical studies have shown large interindividual differences in the effect of an ACE inhibitor on blood pressure and the renin-angiotensin system, particularly after the first dose, but little attempt has been made to quantify and optimize the response in individual subjects. 4 There is some evidence that reduction of blood pressure and inhibition of plasma ACE activity are dose-dependent, 5 " 7 but no consistent concentrationeffect relation has been established between plasma drug (or active metabolite) concentration and blood pressure reduction or ACE inhibition. Received May 1, 1989; accepted in revised form October 30, 1989. this is likely to reflect the wide range of intersubject variability in pharmacokinetic responses, particularly when group data are evaluated, there is preliminary evidence that concentration-effect relations for ACE inhibitors can be more readily identified when individual subjects are considered. -13This study uses integrated pharmacokineticpharmacodynamic modeling 14 to investigate and characterize the antihypertensive responses and concentration-effect relations during acute and chronic treatment with enalapril in patients with esse...

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“…Half-life (h) 1-3 (6-9) 5-9 tently shown with fosinopril (64), ramipril (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63), and trandolapril (50-100) [92].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…This activation may be impaired in severe liver disease but this is rarely a major problem. There are no definite data to indicate that the hepatic congestion associated with heart failure reduces hepatic de-esterification of ACE inhibitor prodrugs, such as enalapril [54]. There are no major differences in the response between the ACE inhibitors that are in the form of prodrugs or those which are given as the active moiety, except in the time to maximum plasma concentration of the active compound and the time to maximum effect, which will usually be later with those drugs which have to undergo metabolic activation.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Prevention of Macrovascular Disease in Type 2 Diabetic Patients: Blockade of the Renin-Angiotensin-Aldosterone System

Thomas

Tomlinson²

2008

CDR

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Type 2 diabetes is reaching epidemic proportions throughout the world, which has major health implications as such patients have considerably increased risk of coronary heart disease (CHD). The renin-angiotensin-aldosterone system (RAAS) is involved in a wide range of adverse effects that contribute to the pathogenesis of CHD in diabetic patients, including vascular haemodynamic regulation, oxidative stress and hypertrophy of vascular cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. In diabetic patients ACE inhibitors and ARBs both effectively lower blood pressure, particularly in combination with low-dose thiazide diuretics, and may be considered first line therapies in the treatment of diabetic hypertension. Additionally they have important renoprotective actions independent of their blood pressure-lowering action, which is of particular benefit in diabetic patients, who are at increased risk of developing nephropathy. ARBs are generally well tolerated, but ACE inhibitor therapy is associated with some side effects such as cough and both may result in hyperkalaemia. Blockade of the RAAS with these agents appears to play an important role not only in protecting from renal disease, but it may also help to reduce morbidity and mortality from certain vascular diseases in diabetic patients.

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Pharmacokinetics and Pharmacodynamics of Enalapril in Patients with Congestive Heart Failure and Patients with Hypertension

Cited by 42 publications

References 0 publications

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Kinetic-dynamic relations and individual responses to enalapril.

Prevention of Macrovascular Disease in Type 2 Diabetic Patients: Blockade of the Renin-Angiotensin-Aldosterone System

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