Greathouse agents combine drugs with synergistic mechanisms of action allowing for substantially greater reductions in BP compared with component monotherapies. For example, patients are more responsive to the BP-lowering effects of ARBs and ACE inhibitors upon the addition of HCTZ. Although the mechanism(s) involved are not clearly understood, HCTZ may activate the renin-angiotensin system (RAS), making BP more dependent on angiotensin II (Kjeldsen et al 2005). These effects on counter-regulatory processes may help to explain why the combination of an ARB or an ACE inhibitor with HCTZ reduces BP more effectively than either agent alone (Brown et al 1990; Chrysant 1994; Benz et al 1998; Kochar et al 1999; Manolis et al 2000; Chrysant et al 2004). Olmesartan medoxomil/HCTZ is the most recent fixed- dose ARB/HCTZ combination to be approved for the treatment of hypertension. This review will focus on the pharmacodynamics, antihypertensive efficacy, and tolerability of olmesartan medoxomil/HCTZ and how it compares with other currently available fixed-dose combinations. Pharmacology of olmesartan medoxomil and HCTZ The clinical effects of angiotensin II, including vasoconstriction, increasing intravascular volume, and hormone secretion are mediated by AT1 receptors (Burnier 2001). Olmesartan medoxomil is an AT1 receptor antagonist, demonstrating specificity for receptors in vascular tissue (Mizuno et al 1995; Koike et al 2001). In vitro, olmesartan medoxomil has been shown to be a competitive antagonist, displaying high affinity, slow dissociation, and a high degree of insurmountability for the AT1 receptor (Pugsley 2006). The interaction of olmesartan with the AT1 receptor is believed to occur via a two-step mechanism: the molecule first undergoes a loose “surmountable” binding followed by the formation of a tighter, “insurmountable” binding complex. The slow dissociation of olmesartan medoxomil from the AT1 receptor compares favorably with other ARBs’ dissociation, including telmisartan, and may contribute to the antihypertensive efficacy of olmesartan medoxomil in vivo (Pugsley 2006). The pressor response to exogenous angiotensin I is inhibited to a clinically relevant extent (>75%) by single doses of olmesartan medoxomil 10–40 mg, with substantial inhibition still apparent 24 hours after dosing (Brunner and Nussberger 2001). Thiazide diuretics such as HCTZ promote sodium excretion, leading to a reduction in plasma volume and peripheral resistance (Meredith 2005). The resulting 402 activation of the RAS means that the effect of blocking AT1 receptors and, therefore, the response to ARB therapy, is enhanced, providing a rationale for co-administration of agents from these two drug classes (Meredith 2005). Other synergistic mechanisms are thought to be involved but are not clearly understood. The increased efficacy resulting from the combination of HCTZ with an ARB does not greatly compromise the good tolerability profile of the ARB. The combination of these two agents may permit the use of lower doses of HCTZ and the ARB, which may be less likely to result in adverse events typically associated with HCTZ use. Olmesartan medoxomil is a pro-drug that is de-esterified to its active metabolite, olmesartan, during absorption from the gastrointestinal tract (Laeis et al 2001). Absorption is rapid, with steady-state levels reached within 5 days (Laeis et al 2001). Importantly, the long terminal elimination half- life of 10–18 hours, coupled with minimal accumulation, allows for once-daily dosing (Laeis et al 2001; Schwocho and Masonson 2001). Systemically available olmesartan is excreted via the kidneys and, after secretion in bile, in the feces (Laeis et al 2001). HCTZ is absorbed rapidly after oral administration and is eliminated unchanged in the urine (Carter et al 2004; Sweetman 2005). It has an elimination half-life of 8–15 hours after repeated doses, and the pharmacodynamic response is sufficiently long to allow once-daily dosing (Carter et al 2004). Clinically relevant pharmacokinetic interactions do not occur between these two agents (Kreutz et al 2006). Given both the pharmacokinetic and the pharmacodynamic profiles of these agents, the combination of olmesartan medoxomil with HCTZ is suitable for once- daily administration in a single tablet. Antihypertensive efficacy of olmesartan medoxomil/HCTZ A number of studies have provided evidence that the combination of olmesartan medoxomil/HCTZ is an effective option for antihypertensive therapy. Comparison with monotherapy A clinical trial using a randomized, double-blind, factorial design showed that olmesartan medoxomil/HCTZ combination therapy reduced DBP and SBP to a greater extent than monotherapy with either component (Chrysant et al 2004). In this study, hypertensive patients (n=502) with a seated DBP of 100–115 mmHg were randomized to one of 12 treatment groups for 8 weeks: olmesartan medoxomil Vascular Health and Risk Management 2006:2(4)