A Comprehensive Monograph on Metolazone (DB00524)

I. Executive Summary & Drug Identification

1.1. Overview

Metolazone is a quinazoline-sulfonamide derivative classified pharmacologically as a thiazide-like diuretic.[1] It is a small molecule drug primarily indicated for the management of hypertension and for the treatment of salt and water retention (edema) associated with congestive heart failure and various renal diseases.[1] While sharing a primary mechanism of action with thiazide diuretics, Metolazone possesses two distinct characteristics that define its unique and critical niche in clinical practice. First, it maintains significant diuretic efficacy in patients with advanced renal impairment, a condition where traditional thiazide diuretics are largely ineffective.[4] Second, it exhibits a potent synergistic effect when co-administered with loop diuretics, a combination therapy known as sequential nephron blockade, which is employed to overcome diuretic resistance in patients with severe, refractory edema.[4] These properties establish Metolazone as a vital therapeutic agent, particularly in complex cardiovascular and renal patient populations.

1.2. Chemical and Physical Properties

A precise understanding of Metolazone's chemical and physical nature is fundamental to its pharmacological profile and formulation characteristics.

1.2.1. Chemical Structure and Nomenclature

Metolazone is a synthetic small molecule belonging to the quinazoline class.[1] Its structure consists of a 1,2,3,4-tetrahydroquinazolin-4-one core with methyl, 2-tolyl, sulfamyl, and chloro substituents at positions 2, 3, 6, and 7, respectively.[2] The formal International Union of Pure and Applied Chemistry (IUPAC) name for the compound is 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-dihydroquinazoline-6-sulfonamide.[2]

1.2.2. Molecular Formula and Weight