DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Agents Affecting Mineral Ion
Homeostasis and Bone Turnover
Peter A. Friedman
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 Ca 2+
and phosphate metabolism, then some relevant pathophysiology,
and, finally, pharmacotherapeutic options in
treating disorders of mineral ion homeostasis.
PHYSIOLOGY OF MINERAL
ION HOMEOSTASIS
Calcium
Elemental calcium is essential for a variety of micromolecular
and macroscopic biological functions. Its ionized
form, Ca 2+ , is an important component of current flow
across excitable membranes. Ca 2+ is vital for muscle contraction,
fusion, and release of storage vesicles. In the submicromolar
range, intracellular Ca 2+ 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.
Ca 2+ 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 Ca 2+ . Unlike disulfide or sugar–
peptide cross-links, Ca 2+ 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 Ca 2+ , intracellular
free Ca 2+ is maintained at a low level, ~100 nM
in cells in their basal state, by active extrusion by
Ca 2+ –ATPases and by Na + /Ca 2+ exchange. As a consequence,
changes in cytosolic Ca 2+ (whether released
from intracellular stores or entering via membrane Ca 2+
channels) can modulate effector targets, often by interacting
with the Ca 2+ -binding protein calmodulin. The
rapid association–dissociation kinetics of Ca 2+ and the
relatively high affinity and selectivity of Ca 2+ -binding
domains permit effective regulation of Ca 2+ 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. Ca 2+ 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 Ca 2+ :
ionized (50%), protein-bound (40%), and complexed
(10%). Thus, whereas total plasma calcium concentration
is ~2.54 mM, the concentration of ionized Ca 2+ 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
bound to plasma proteins. Smaller percentages are
bound, albeit with greater affinity, to β-globulin, α 2
-globulin,
α 1
-globulin, and γ-globulin. The remaining 10% of
the serum calcium is complexed in ion pairs with small
polyvalent anions, primarily phosphate and citrate. The
degree of complex formation depends on the ambient pH
and the concentrations of ionized calcium and complexing
anions. Ionized Ca 2+ is the physiologically relevant
component, mediates calcium’s biological effects, and,
when perturbed, produces the characteristic signs and
symptoms of hypo- or hypercalcemia.