Renin–Angiotensin Blockade: Therapeutic Agents

3.1.1

Pharmacokinetics

There is no evidence for systemic accumulation of the prodrugs for ramipril, enalapril, fosinopril, trandolapril, or benazepril in various stages of chronic kidney disease (CKD). This observation implies that these compounds undergo intact biliary clearance and/or that the metabolic conversion of these drugs to their active diacid form is not altered by the circumstances of renal failure. These pharmacokinetic findings relating to prodrug clearance have been offered as evidence for a dual route (hepatic/renal) of elimination for these particular compounds. A dual route of drug elimination in CKD is viewed as being advantageous in that dosage adjustment becomes a less pressing issue on a pharmacokinetic basis. For these compounds, this pharmacokinetic feature is inconsequential to their dosing in CKD since prodrugs for these compounds negligibly inhibit ACE. Actual dual route of elimination of ACE inhibitors are those whose active diacid form undergoes comparatively proportional degrees of hepatic/renal clearance. In that regard, the active diacid forms of only two ACE inhibitors, fosinopril → fosinoprilat and trandolapril → trandolaprilat, undergo comparable degrees of hepatic and renal clearance. For the remaining ACE inhibitors, systemic clearance is almost entirely renal, occurring through both filtration and various degrees of tubular secretion. The tubular secretion of an ACE inhibitor is compound specific and the organic acid transporter (OAT1) appears to play a role in the secretion of select ACE inhibitors. Being both renally and hepatically eliminated, an ACE inhibitor minimizes any systemic accumulation of such compounds when dosed to steady state in CKD. To date, a specific concentration-dependent adverse effect, attributable to an ACE inhibitor’s accumulation in CKD, has not been identified. It is probable though that the longer ACE inhibitor concentrations remain elevated—once a BP response had occurred—the longer it is that BP will remain reduced. Thus, the major adverse consequence of ACE inhibitor accumulation may be that of prolonged hypotension and the organ-specific sequelae of low BP.

3.1.2

Tissue Binding

The second unresolved pharmacologic feature of the ACE inhibitor class relates to the concept of their affinity for tissue ACE. The physicochemical dissimilarities among ACE inhibitors include binding affinity, potency, lipophilicity, and depot effect and allow for the arbitrary classification of ACE inhibitors according to a level of affinity for tissue ACE. The degree of in vivo functional inhibition of tissue ACE by an ACE inhibitor corresponds to two properties: the inhibitor’s binding affinity and the free inhibitor concentration within a designated tissue compartment. The free concentration of an ACE inhibitor, in turn, derives from a state of dynamic equilibrium, which evolves from the transport of an ACE inhibitor to various tissues and its subsequent washout and return into the vascular space. Free inhibitor tissue concentrations are influenced by customary pharmacologic variables including dose frequency/amount, absolute bioavailability, plasma half-life, tissue penetration, and ultimately the capacity for retention at the tissue level.

The bioavailability and half-life of an ACE inhibitor in blood can be readily determined and are elements guiding the selection of an ACE inhibitor dose. When blood levels of an ACE inhibitor are high—typically in the first half of a dosing period—tissue retention of an ACE inhibitor is not as critical for functional ACE inhibition. However, during the second-half of an ACE inhibitor dosing period as blood levels drop, two factors appear to be critical to extending functional ACE inhibition (1) inhibitor binding affinity for ACE and (2) tissue retention, which will have a direct influence on the free inhibitor concentration found in tissues.

The experimental order of potency for several ACE inhibitors has been ranked by competition analyses and by direct binding of tritium-labeled ACE inhibitors to tissue ACE. These studies show a hierarchal potency for their diacid metabolites with quinaprilat = benazeprilat > ramiprilat > perindoprilat > lisinopril > enalaprilat > fosinoprilat > captopril. The order of potency for several ACE inhibitors has also been ranked by competition analyses and by direct binding of tritium-labeled ACE inhibitors to tissue ACE. These studies demonstrated a ranked potency of quinaprilat = benazeprilat > ramiprilat > perindoprilat > lisinopril > enalaprilat > fosinoprilat > captopril.

Finally, the process of tissue retention of ACE inhibitors has also been explored. Isolated organ bath studies studying the duration of ACE inhibition after the removal of ACE inhibitor from the bathing milieu show that functional inhibition of ACE lasts well beyond (2–5-times longer) the time predicted solely on the basis of inhibitor dissociation rates or binding affinity. The ranking of tissue retention was quinaprilat > lisinopril > enalaprilat > captopril and this ordering reflects both the binding affinity and lipophilicity of these particular ACE inhibitors. These tissue-based studies, however, have yet to be correlated with head-to-head clinical effect studies showing superiority or for that matter inferiority between these various ACE inhibitors.

The question has been posed as to whether an ACE inhibitor exhibits tissue protective effects separate from the degree to which it might lower BP as suggested by the Heart Outcomes Prevention Evaluation (HOPE) Study. In the HOPE Study ramipril significantly reduced the rates of death, MI, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction (EF) or HF and did so in a manner that was seemingly independent of the degree to which office BP, and less so ambulatory BP monitored readings, were lowered. This quite obviously is a different issue than whether there are differences in BP lowering efficacy between various ACE inhibitors when compared head-to-head.

ACE inhibitors are diverse in their actions reducing angiotensin II levels, increasing, enhancing nitric oxide bioavailability, and lessening endothelial dysfunction, which may embody BP-independent mechanisms by which these compounds confer vascular protection. The effect of ACE inhibitors on endothelium-dependent relaxation relates to the compound being studied, the dose used, the organ system in question as well as the type of experimental design in use. It should be noted that consistent improvement in endothelial function is reported with those ACE inhibitors with a higher affinity for tissue ACE, such as quinapril and ramipril. Despite the innate appeal of these oftentimes-positive findings, there has been a dearth of head-to-head trials, which directly compare highly tissue-bound ACE inhibitors to those with more restricted tissue binding. In circumstances, where such comparisons have been undertaken, the results do not persuasively support the claim of overall superiority for lipophilic ACE inhibitors or there being benefits with ACE inhibitors that go beyond BP reduction.

3.1.3

Application of Pharmacologic Differences

Class effect is a concept often invoked to legitimatize use of a less costly RAS inhibitor when a higher priced agent within the class has been the one specifically studied in a disease state, such as for HF or diabetic nephropathy. The concept of class effect may be most appropriately applied to the use of ACE inhibitors or ARBs in the treatment of hypertension. Therein, little appears to distinguish one ACE inhibitor from another if equivalent doses are being given. Alternatively, it is less certain as to what represents actual dose equivalence among RAS inhibitors when they are being used specifically for outcomes benefits, that are at least in part BP independent, as in the case of treatment of diabetic nephropathy or reduced EF forms of HF. In the treatment of proteinuric renal disease the dose–response relationship for RAS inhibitors and proteinuria reduction is to a degree limited and not completely characterized, a situation made more complex in its interpretation by the observation that the higher the baseline urine protein excretion, the greater the antiproteinuric effect of a RAS inhibitor. Since there have been so few hard endpoint studies with RAS inhibitors in nephropathic patients, it would seem reasonable to infer interchangeability among drugs in these classes using as a treatment guide what is a suggested top-end dose for the treatment of hypertension.

In the case of reduced EF forms of HF, an ACE inhibitor is titrated to a presumed maximal tissue effect dose since any reduction in the morbidity and mortality with ACE inhibitors is dose-dependent. The utility of an ACE inhibitor in reduced EF forms of HF may derive from therapy-related neurohumoral and tissue-based changes and not solely from ACE-related inhibition of angiotensin II production. Since not all ACE inhibitors have been thoroughly studied in reduced EF forms of HF or for that matter are clinically approved for HF use, particularly relative to secondary neurohumoral response parameters, it is less likely that specific interchangeable doses of different ACE inhibitors (or ARBs) can be correctly identified in the treatment of HF.