Page 798 - Basic _ Clinical Pharmacology ( PDFDrive )

784 SECTION VII Endocrine Drugs

approximately 1000–1500 mg of elemental calcium per day. Dos- of therapy that can lead to it (eg, phosphate binders, certain types
age must be adjusted to avoid hypercalcemia and hypercalciuria. of parenteral nutrition) and treated in conditions that cause it, such
as the various forms of hypophosphatemic rickets. Oral forms of
Vitamin D phosphate are listed above.

When rapidity of action is required, 1,25(OH) D (calcitriol),
3
2
0.25–1 mcg daily, is the vitamin D metabolite of choice because it SPECIFIC DISORDERS INVOLVING
is capable of raising serum calcium within 24–48 hours. Calcitriol BONE MINERAL-REGULATING
also raises serum phosphate, although this action is usually not
observed early in treatment. The combined effects of calcitriol HORMONES
and all other vitamin D metabolites and analogs on both calcium
and phosphate make careful monitoring of these mineral levels PRIMARY HYPERPARATHYROIDISM
especially important to prevent ectopic calcification secondary to
an abnormally high serum calcium × phosphate product. Since This rather common disease, if associated with symptoms, signifi-
the choice of the appropriate vitamin D metabolite or analog for cant hypercalcemia, and hypercalciuria, osteoporosis, and kidney
long-term treatment of hypocalcemia depends on the nature of disease is best treated surgically. Oral phosphate and bisphospho-
the underlying disease, further discussion of vitamin D treatment nates have been tried but cannot be recommended. A substantial
is found under the headings of the specific diseases. proportion of asymptomatic patients with mild disease do not get
worse and may be followed without treatment, although a number
of such patients do end up requiring surgery. The calcimimetic agent
HYPERPHOSPHATEMIA cinacalcet, discussed previously, has been approved for secondary
hyperparathyroidism and is in clinical trials for the treatment of
Hyperphosphatemia is a common complication of renal failure and primary hyperparathyroidism. If such drugs prove efficacious and
is also found in all types of hypoparathyroidism (idiopathic, surgi- cost effective, medical management of this disease will need to be
cal, and pseudohypoparathyroidism), vitamin D intoxication, and reconsidered. Primary hyperparathyroidism is often associated with
the rare syndrome of tumoral calcinosis (usually due to insufficient low levels of 25(OH)D, suggesting that mild vitamin D deficiency
bioactive FGF23). Emergency treatment of hyperphosphatemia is may be contributing to the elevated PTH levels, although this could
seldom necessary but can be achieved by dialysis or glucose and also be due to the stimulation by PTH of 1,25(OH) D produc-
2
insulin infusions. In general, control of hyperphosphatemia involves tion that in turn induces CYP24A1, which will increase 25(OH)
restriction of dietary phosphate plus phosphate-binding gels such D (and 1,25(OH) D) catabolism. Vitamin D supplementation in
2
as sevelamer, or lanthanum carbonate and calcium supplements. such situations has proved safe with respect to further elevations of
Because of their potential to induce aluminum-associated bone dis- serum and urine calcium levels, but calcium should be monitored
ease, aluminum-containing antacids should be used sparingly and nevertheless when vitamin D supplementation is provided.
only when other measures fail to control the hyperphosphatemia. In
patients with chronic kidney disease, enthusiasm for the use of large
doses of calcium to control hyperphosphatemia has waned because HYPOPARATHYROIDISM
of the risk of ectopic calcification.
In PTH deficiency (idiopathic or surgical hypoparathyroidism) or
an abnormal target tissue response to PTH (pseudohypoparathy-
HYPOPHOSPHATEMIA roidism), serum calcium falls and serum phosphate rises. In such
patients, 1,25(OH) D levels are usually low, presumably reflecting
2
Hypophosphatemia is associated with a variety of conditions, the lack of stimulation by PTH of 1,25(OH) D production. The
2
including primary hyperparathyroidism, vitamin D deficiency, skeletons of patients with idiopathic or surgical hypoparathyroidism
idiopathic hypercalciuria, conditions associated with increased are normal except for a slow turnover rate. A number of patients
bioactive FGF23 (eg, X-linked and autosomal dominant hypophos- with pseudohypoparathyroidism appear to have osteitis fibrosa, sug-
phatemic rickets and tumor-induced osteomalacia), other forms of gesting that the normal or high PTH levels found in such patients
renal phosphate wasting (eg, Fanconi’s syndrome), overzealous use are capable of acting on bone but not on the kidney. The distinction
of phosphate binders, and parenteral nutrition with inadequate between pseudohypoparathyroidism and idiopathic hypoparathy-
phosphate content. Acute hypophosphatemia may cause a reduc- roidism is made on the basis of normal or high PTH levels but
tion in the intracellular levels of high-energy organic phosphates deficient renal response (ie, diminished excretion of cAMP or phos-
(eg, ATP), interfere with normal hemoglobin-to-tissue oxygen phate) in patients with pseudohypoparathyroidism.
transfer by decreasing red cell 2,3-diphosphoglycerate levels, and The principal therapeutic goal is to restore normocalcemia
lead to rhabdomyolysis. However, clinically significant acute effects and normophosphatemia. Standard therapy involves the use
of hypophosphatemia are seldom seen, and emergency treatment of calcitriol and dietary calcium supplements. However, many
is generally not indicated. The long-term effects include proximal patients develop hypercalciuria with this regimen, which limits
muscle weakness and abnormal bone mineralization (osteomalacia). the ability to correct the hypocalcemia. Full-length PTH (rhPTH
Therefore, hypophosphatemia should be avoided when using forms 1-84, Natpara) has recently been approved for the treatment