Pharmacology: Calcium Homeostasis & Parathyroid Hormones

Calcium Homeostasis and Parathyroid Hormones

Functions of Calcium

• Essential for current flow across excitable membranes (action potential)
• Necessary for fusion and release of storage vesicles (e.g. acetylcholine)
• Involved in muscle contraction
• Acts as a second messenger intracellularly (PLC, DAG, IP3)
• Necessary for blood coagulation
• Supports the formation of bone (skeleton)

Composition of Calcium

• Ca2+ is the most abundant mineral in the human body
• Approximately 1 kg of Ca2+ is stored in bones in the form of phosphate and hydroxide salts, predominantly as hydroxyapatite
• Ca2+ exists in three forms in plasma: 50% ionized or biologically active, 45% bound to plasma proteins (mainly albumin), and 5% complexed to phosphate and citrate

Calcium Homeostasis

• The movement and regulation of Ca2+ in and out of the body, and between body compartments (fluids, bones)
• Maintained by two polypeptide hormones (parathyroid hormone, calcitonin) and a steroid hormone (calcitriol) as well as serum calcium and phosphate levels

Parathyroid Hormone (PTH)

• Secreted by the parathyroid gland in response to low calcium levels in the blood
• Regulates calcium and phosphate levels in blood circulation in conjunction with calcitriol
• Increases calcium levels and decreases phosphate levels
• Antagonistic to calcitonin
• Effects are present in bones, kidneys, and small intestines

Effects of PTH on Bones

• Stimulates the release of calcium indirectly via osteoclasts, causing resorption/destruction of bones
• Directly stimulates osteoblasts, which differentiate into osteoclasts, stimulating bone formation
• Osteoclasts activity exceeds osteoblasts activity, leading to bone resorption and release of calcium into the blood

Effects of PTH on Kidneys

• Targets the distal convoluted tubule and collecting duct, directly increasing calcium reabsorption
• Decreases phosphate reabsorption at the proximal tubule, leading to increased excretion of phosphates and decreased serum phosphate levels
• Decreased serum phosphate levels lead to decreased serum calcium-phosphate formation, increasing levels of serum ionized calcium

Effects of PTH on Small Intestines

• Stimulates the production of 1-alpha-hydroxylase in the proximal convoluted tubule of the kidney, required for the synthesis of active vitamin D (calcitriol)
• Calcitriol increases intestinal absorption of calcium, increasing serum calcium levels

Disorders of Calcium Homeostasis

Hypocalcemia

• Total serum [Ca2+] < 8.8 mg/dL (< 2.2 mmol/L) in the presence of normal plasma protein (albumin) concentrations
• Serum ionized [Ca2+] < 4.7 mg/dL (< 1.17 mmol/L)
• May be hereditary or acquired (liver disease, kidney disease, diet, medication, surgery, hypoparathyroidism)
• Treatment depends on the cause, severity, presence of symptoms, and how rapidly the hypocalcemia developed

Hypercalcemia

• Total serum [Ca2+] > 10.4 mg/dL (> 2.6 mmol/L)
• Serum ionized [Ca2+] > 5.2 mg/dL (> 1.3 mmol/L)
• Can result from excess calcium entering the ECF or insufficient calcium excretion from the kidneys
• Approximately 90% of cases are caused by hyperparathyroidism (usually mild, asymptomatic, and sustained for years) or malignancy (usually rapidly progressive)

Parathyroid Gland

Anatomy

• Four glands located posterior to the thyroid gland
• Normal function is achieved with at least two glands
• Composed of chief cells that synthesize, secrete, and store parathyroid hormone

Disorders of Parathyroid Hormone

Hyperparathyroidism

• Characterized by excessive production of PTH
• Primary hyperparathyroidism: unregulated levels of PTH usually from a hormone-secreting parathyroid adenoma or parathyroid hyperplasia or rarely parathyroid carcinoma
• Secondary hyperparathyroidism: ↑ production of PTH secondary to hypocalcemia or hyperphosphatemia, typically as a result of vitamin D deficiency and/or chronic kidney disease (CKD)
• Tertiary hyperparathyroidism: excessive secretion of PTH due to chronic secondary hyperparathyroidism (autonomous hypersecretion of PTH)