Chapter 44

### INTRODUCTION

To understand why, when, and how to employ pharmacological agents that affect mineral ion homeostasis, one must first understand some basic physiology and pathophysiology of the subject. This chapter presents a primer on mineral ion homeostasis and the endocrinology of Ca2+ and phosphate metabolism, then some relevant pathophysiology, and, finally, pharmacotherapeutic options in treating disorders of mineral ion homeostasis.

### PHYSIOLOGY OF MINERALION HOMEOSTASIS

#### Calcium

Elemental calcium is essential for a variety of micromolecular and macroscopic biological functions. Its ionized form, Ca2+, is an important component of current flow across excitable membranes. Ca2+ is vital for muscle contraction, fusion, and release of storage vesicles. In the submicromolar range, intracellular Ca2+ acts as a critical second messenger (Chapter 3). In extracellular fluid, millimolar concentrations of calcium promote blood coagulation and support the formation and continuous remodeling of the skeleton.

Ca2+ has an adaptable coordination sphere that facilitates binding to the irregular geometry of proteins. The capacity of an ion to cross-link two proteins requires a high coordination number, which dictates the number of electron pairs that can be formed and generally is six to eight for Ca2+. Unlike disulfide or sugar− peptide cross-links, Ca2+ linking is readily reversible. Cross-linking of structural proteins in bone matrix is enhanced by the relatively high extracellular concentration of calcium.

In the face of millimolar extracellular Ca2+, intracellular free Ca2+ is maintained at a low level, ~100 nM in cells in their basal state, by active extrusion by Ca2+–ATPases and by Na+/Ca2+ exchange. As a consequence, changes in cytosolic Ca2+ (whether released from intracellular stores or entering via membrane Ca2+ channels) can modulate effector targets, often by interacting with the Ca2+-binding protein calmodulin. The rapid association–dissociation kinetics of Ca2+ and the relatively high affinity and selectivity of Ca2+-binding domains permit effective regulation of Ca2+ over the 100 nM to 1 μM range.

The body content of calcium in healthy adult men and women, respectively, is ~1300 and 1000 g, of which >99% is in bone and teeth. Ca2+ is the major extracellular divalent cation. Although the portion of calcium in extracellular fluids is small, this fraction is stringently regulated within narrow limits. In adult humans, the normal serum calcium concentration ranges from 8.5-10.4 mg/dL (4.25-5.2 mEq/L, 2.1-2.6 mM) and includes three distinct chemical forms of Ca2+: ionized (50%), protein-bound (40%), and complexed (10%). Thus, whereas total plasma calcium concentration is ~2.54 mM, the concentration of ionized Ca2+ in human plasma is ~1.2 mM.

The various pools of calcium are illustrated schematically in Figure 44–1. Only diffusible calcium (i.e., ionized plus complexed) can cross cell membranes. Albumin accounts for some 90% of the serum calcium ...

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