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

Phosphate
Phosphate is an essential component of all body tissues,
present in plasma, extracellular fluid, cell membrane
phospholipids, intracellular fluid, collagen, and bone
tissue. More than 80% of total body phosphorus is
found in bone, and ~15% is in soft tissue. Additionally,
phosphate subserves roles as a dynamic constituent of
intermediary and energy metabolism and as a key regulator
of enzyme activity when transferred by protein
kinases from ATP to phosphorylatable serine, threonine,
and tyrosine residues.
Biologically, phosphorus (P) exists in both organic
and inorganic (P i
) forms. Organic forms include phospholipids
and various organic esters. In extracellular fluid, the
bulk of phosphorus is present as inorganic phosphate in
the form of NaH 2
PO 4
and Na 2
HPO 4
; at pH 7.4, the ratio
of disodium to monosodium phosphate is 4:1, so plasma
phosphate has an intermediate valence of 1.8. Owing to its
relatively low concentration in extracellular fluid, phosphate
contributes little to buffering capacity. The aggregate
level of inorganic phosphate (P i
) modifies tissue
concentrations of Ca 2+ and plays a major role in renal H +
excretion. Within bone, phosphate is complexed with calcium
as hydroxyapatites having the general formula
Ca 10
(PO 4
) 6
(OH) 2
and as calcium phosphate.
Absorption, Distribution, and Excretion. Phosphate is absorbed from
and, to a limited extent, secreted into the GI tract. Phosphate is a
ubiquitous component of ordinary foods; thus even an inadequate
diet rarely causes phosphate depletion. Transport of phosphate from
the intestinal lumen is an active, energy-dependent process that is
regulated by several factors, primarily vitamin D, which stimulates
absorption. In adults, about two-thirds of ingested phosphate is
absorbed and is excreted almost entirely into the urine. In growing
children, phosphate balance is positive, and plasma concentrations of
phosphate are higher than in adults.
Phosphate excretion in the urine represents the difference
between the amount filtered and that reabsorbed. More than 90% of
plasma phosphate is freely filtered at the glomerulus, and 80% is
actively reabsorbed, predominantly in the initial segment of the proximal
convoluted tubule but also in the proximal straight tubule (pars
recta). Renal phosphate absorption is regulated by a variety of hormones
and other factors; the most important are PTH and dietary phosphate,
with extracellular volume and acid–base status playing lesser
roles. Dietary phosphate deficiency upregulates renal phosphate transporters
and decreases excretion, whereas a high-phosphate diet
increases phosphate excretion; these changes are independent of any
effect on plasma P i
, Ca 2+ , or PTH. PTH increases urinary phosphate
excretion by blocking phosphate absorption. Expansion of plasma volume
increases urinary phosphate excretion. Effects of vitamin D and its
metabolites on proximal tubular phosphate are modest at best.
Role of Phosphate in Urine Acidification. Despite the fact that the
concentration and buffering capacity of phosphate in extracellular fluid
are low, phosphate is concentrated progressively in the renal tubule and
becomes the most abundant buffer system in the distal tubule and terminal
nephron. The exchange of H + and Na + in the tubular urine converts
disodium hydrogen phosphate (Na 2
HPO 4
) to sodium dihydrogen phosphate
(NaH 2
PO 4
), permitting the excretion of large amounts of acid
without lowering the urine pH to a degree that would block H + transport.
Actions of Phosphate. If large amounts of phosphate are introduced
into the GI tract by oral administration or enema, a cathartic action will
result. Thus, phosphate salts are employed as mild laxatives (Chapter
46). If excessive phosphate salts are introduced either intravenously or
orally, they may reduce the concentration of Ca 2+ in the circulation and
induce precipitation of calcium phosphate in soft tissues.
HORMONAL REGULATION OF CALCIUM
AND PHOSPHATE HOMEOSTASIS
A number of hormones interact to regulate extracellular
calcium and phosphate balance. The most important are
parathyroid hormone (PTH) and 1,25-dihydroxyvitamin
D (calcitriol), which regulate mineral homeostasis by
effects on the kidney, intestine, and bone (Figure 44–3).
Kidney
Parathyroids
PTH
Calcitriol
Intestine
Bone
Urine Ca 2+ Plasma Ca 2+
Urine
phosphate
Phosphate
absorption
Ca 2+
absorption
Figure 44–3. Calcium homeostasis and its regulation by parathyroid
hormone (PTH) and 1,25-dihydroxyvitamin D. PTH has stimulatory
effects on bone and kidney, including the stimulation of
1α-hydroxylase activity in kidney mitochondria leading to the
increased production of 1,25-dihydroxyvitamin D (calcitriol)
from 25-hydroxycholecalciferol, the monohydroxylated vitamin D
metabolite (Figure 44–6). Calcitriol is the biologically active
metabolite of vitamin D.
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER