Triphasic 2-4 9-18 over 50 28-44


h h t1/2, elimination half-life.

Because of their vasodilator action, ACEIs reduce cardiac work and improve cardiac performance. They also protect heart, kidney, and possibly brain from hypoxic tissue damage. These effects are highly beneficial for heart failure patients. ACEIs are now indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis. Some ACEIs are also approved for the treatment of hemodynamically stable patients within 24 h of myocardial infarction to improve survival. The mechanism of the cardioprotective action of ACEIs is not well understood, but is considered to be the consequence of their major pharmacological action, reduction of formation of Ang II, which has also profibrotic and proapoptotic properties.

After the discovery of captopril several ACEIs were developed. With the exception of captopril and lisinopril, all are prodrug esters being hydrolyzed in the liver to the active metabolites that are identified by the suffix 'at,' e.g., the active metabolite of enalapril is enaprilat. Prodrugs, unlike their active metabolites, are well absorbed and are orally bioavailable. ACEIs differ in potency, tissue specificity, and pharmacokinetics. Their differences are mostly determined by their physicochemical properties, e.g., lipophilicity. Differences in their ability to cross cellular membranes determine tissue specificity, while duration of action often depends on the ability of an ACEI to dissociate from the enzyme. The ACE-ramipril complex dissociates much slower than the ACE-captopril complex. According to US Food and Drug Administration recommendations, antihypertensive drugs should have a trough-to-peak ratio of at least 50%. This means that, if they are to be administered once a day, they should retain at 24 h more than 50% of their activity at the time of their peak effect. At the recommended therapeutic doses enalapril, fosinopril, ramipril, and trandolapril have higher trough-to-peak ratios than 50% and higher than those of other ACEIs.38

The relative potency of ACEIs is first estimated in vitro by their affinity for the binding site of the enzyme in tissue (e.g., rabbit lungs) homogenates, expressed as an IC50 value in nanomolar. The IC50 value for one drug can vary substantially depending on the species and tissue used. Among the ACEIs listed in Table 5, ramipril has the greatest in vitro affinity for the enzyme. Its clinical doses are also low, but are higher than those of trandolapril, so that in vitro and in vivo relative potencies of ACEIs do not always correlate. ACEIs do not differ from each other in efficacy. Their maximal obtainable antihypertensive effects are identical. It is likely that any differences in efficacy claimed in the literature are based on a trial in which the drugs were compared at noncomparable dose levels.

The pharmacokinetic parameters account for the major differences among ACEIs. Drugs with longest elimination half-lives (ti/2) are expected to have the longest duration of action. It is difficult, however, to establish such a correlation for ACEIs, in part due to biphasic or even triphasic declines in their blood levels, which are determined by differences in the rate of release of ACEIs from different organs and/or tissues.

All ACEIs lower blood pressure in renal hypertensive (2K1C) rats as well as in SHRs. Their relative potency in hypertensive rats is usually comparable to that in hypertensive patients. In normotensive animals ACEIs have little or no hypotensive activity. However, ACEIs can be assayed in normotensive animals on the basis of their ability to block pressor effects of Ang I, but not of Ang II.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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