Page 792 - Basic _ Clinical Pharmacology ( PDFDrive )

778 SECTION VII Endocrine Drugs

TABLE 42–2 Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney.

PTH Vitamin D FGF23
Intestine Increased calcium and phosphate Increased calcium and phosphate Decreased calcium and phosphate
absorption (by increased 1,25[OH] 2 D absorption by 1,25(OH) 2 D absorption by decreased 1,25(OH) 2
production) production
Kidney Decreased calcium excretion, Calcium and phosphate excretion may be Increased phosphate excretion, decreased
increased phosphate excretion, decreased by 25(OH)D and 1,25(OH) 2 D 1 1,25(OH) 2 D production
stimulation of 1,25(OH) 2 D production
Bone Calcium and phosphate resorption Increased calcium and phosphate Decreased mineralization due to
increased by high doses. Low doses resorption by 1,25(OH) 2 D; bone formation hypophosphatemia and low 1,25(OH) 2 D
increase bone formation. may be increased by 1,25(OH) 2 D levels.
Net effect on Serum calcium increased, serum Serum calcium and phosphate both Decreased serum phosphate
serum levels phosphate decreased increased
1
Direct effect. Vitamin D also indirectly increases urine calcium owing to increased calcium absorption from the intestine and decreased PTH.

regulation is again appropriate. 1,25(OH) D directly inhibits PTH CALCITONIN
2
secretion (independent of its effect on serum calcium) by a direct
inhibitory effect on PTH gene transcription. The parathyroid gland The calcitonin secreted by the parafollicular cells of the mam-
expresses both the VDR and CYP27B1, so that endogenous pro- malian thyroid is a single-chain peptide hormone with 32
duction of 1,25(OH) D within the parathyroid gland may be more amino acids and a molecular weight of 3600. A disulfide bond
2
important for the regulation of PTH secretion than serum levels of between positions 1 and 7 is essential for biologic activity. Cal-
1,25(OH) D. This provides yet another negative feedback loop. In citonin is produced from a precursor with a molecular weight
2
patients with chronic renal failure who frequently are deficient in of 15,000. The circulating forms of calcitonin are multiple,
producing 1,25(OH) D due in part to elevated FGF23 levels, loss ranging in size from the monomer (molecular weight 3600) to
2
of this 1,25(OH) D-mediated feedback loop coupled with impaired forms with an apparent molecular weight of 60,000. Whether
2
phosphate excretion and intestinal calcium absorption leads to sec- such heterogeneity includes precursor forms or covalently
ondary hyperparathyroidism. The ability of 1,25(OH) D to inhibit linked oligomers is not known. Because of its chemical hetero-
2
PTH secretion directly is being exploited with calcitriol analogs geneity, calcitonin preparations are standardized by bioassay
that have less effect on serum calcium because of their lesser effect in rats. Activity is compared to a standard maintained by the
on intestinal calcium absorption. Such drugs are proving useful in British Medical Research Council (MRC) and expressed as
the management of secondary hyperparathyroidism accompany- MRC units.
ing chronic kidney disease and may be useful in selected cases of Human calcitonin monomer has a half-life of about 10 min-
primary hyperparathyroidism. 1,25(OH) D also stimulates the utes. Salmon calcitonin has a longer half-life of 40–50 minutes,
2
production of FGF23. This completes the negative feedback loop making it more attractive as a therapeutic agent. Much of the
in that FGF23 inhibits 1,25(OH) D production while promoting clearance occurs in the kidney by metabolism; little intact calcito-
2
hypophosphatemia, which in turn inhibits FGF23 production and nin appears in the urine.
stimulates 1,25(OH) D production. However, the rise in FGF23 in The principal effects of calcitonin are to lower serum calcium and
2
the early stages of renal failure remains unexplained and is not due phosphate by actions on bone and kidney. Calcitonin inhibits osteo-
to increases in either 1,25OH) D or phosphate, and appears not clastic bone resorption. Although bone formation is not impaired at
2
to be under the same feedback control as operates under normal first after calcitonin administration, with time both formation and
physiologic conditions. resorption of bone are reduced. In the kidney, calcitonin reduces
both calcium and phosphate reabsorption as well as reabsorption of
SECONDARY HORMONAL other ions, including sodium, potassium, and magnesium. Tissues
other than bone and kidney are also affected by calcitonin. Calcitonin
REGULATORS OF BONE MINERAL in pharmacologic amounts decreases gastrin secretion and reduces
HOMEOSTASIS gastric acid output while increasing secretion of sodium, potassium,
chloride, and water in the gut. Pentagastrin is a potent stimulator
A number of hormones modulate the actions of PTH, FGF23, of calcitonin secretion (as is hypercalcemia), suggesting a possible
and vitamin D in regulating bone mineral homeostasis. Com- physiologic relationship between gastrin and calcitonin. In the adult
pared with that of PTH, FGF23, and vitamin D, the physiologic human, no readily demonstrable problem develops in cases of calcito-
impact of such secondary regulation on bone mineral homeostasis nin deficiency (thyroidectomy) or excess (medullary carcinoma of the
is minor. However, in pharmacologic amounts, several of these thyroid). However, the ability of calcitonin to block bone resorption
hormones, including calcitonin, glucocorticoids, and estrogens, and lower serum calcium makes it a useful drug for the treatment of
have actions on bone mineral homeostatic mechanisms that can Paget’s disease, hypercalcemia, and osteoporosis, albeit a less effica-
be exploited therapeutically. cious drug than other available agents.