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Tumor-associated hypercalcemia is a common metabolic emergency caused by the rate of calcium metabolism in bone exceeding the calcium excretion threshold of the kidney, and one of the most common causes is that the osteoclast activity is stronger than the osteogenic activity caused by tumor with bone metastasis, which causes calcium to dissolve and release into the blood.
It can be divided into osteolytic hypercalcemia and humoral hypercalcemia. Osteolytic hypercalcemia is hypercalcemia of bone metastases, which is related to the direct destruction of bone by tumor cells. Humoral hypercalcemia is hypercalcemia without bone metastases and is mediated by a variety of different humoral mechanisms such as parathyroid hormone (PTH) or parathyroid hormone-like substances, prostaglandins, osteoclast activating factor, etc.
Clinical manifestations include gastrointestinal symptoms such as anorexia, nausea, abdominal pain, constipation, and neurological symptoms such as drowsiness, coldness, decreased reflexes, mental abnormalities, coma, etc.; In the early stage of the renal system, polydipsia and polyuria are manifested, and when renal tubular damage occurs, renal tubular acidosis, aciduria, aminoaciduria, and hyperphosphorturia are manifested; Cardiovascular reactions such as bradycardia, slowed heart rate, arrhythmias, etc.
The clinical treatment of hypercalcemia is mainly to expand the volume and promote urinary calcium excretion (normal saline expansion, loop diuretics); Drugs that inhibit bone resorption include bisphosphonates, calcitonins, and RANKL inhibitors; Drugs that inhibit PTH secretion, such as calcium-sensing receptor modulators, and glucocorticoids, which reduce intestinal calcium absorption, are drugs.
01 loop diuretics
For example, furosemide can inhibit the concentration process of urine by the kidney by selectively blocking the Na+-K+-2Cl- co-transport carrier, and produce a strong diuretic effect, which can inhibit the reabsorption of sodium and calcium and promote urinary calcium excretion, and can be used clinically for tumor-related hypercalcemia.
In acute renal failure, loop diuretics can increase urine output and K+ excretion, irrigate the renal tubules, reduce tubular atrophy and necrosis, but do not delay the progression of renal failure; High-dose furosemide can treat chronic renal failure, increase urine output, and may still be effective when other drugs are ineffective, and may be considered in patients with chronic heart failure, symptomatic volume overload, or oliguric renal failure.
In addition, the combination of loop diuretics and intravenous saline can greatly increase Ca2+ excretion, which in turn rapidly controls hypercalcemia.
Note: Thiazide diuretics are contrary to loop diuretics, which can promote the Ca2+ reabsorption process regulated by PTH in the distal convoluted tubules, reduce the urinary Ca2+ content, and then reduce the deposition of Ca2+ in the lumen, which may be caused by the reduction of Na+ reabsorption, the reduction of Na+ in the renal tubular epithelial cells, and the promotion of Na+-Ca2+ exchange in the basal membrane, which will eventually reduce the excretion of renal calcium and aggravate hypercalcemia, which is an absolute contraindication.
Notes:
Adverse reactions include water and electrolyte disorders, often caused by excessive diuresis, manifested as hypovolemia, hypokalemia, hyponasemia, hypokalemia, hypomagnesia, etc.; Ototoxicity such as tinnitus, hearing loss, temporary deafness, etc.; Others include hyperuricemia, nausea, vomiting, gastrointestinal bleeding (high dose), abnormal glucose metabolism (long-term high dose), orthostatic hypotension (long-term high dose), leukopenia, thrombocytopenia, allergic reactions, interstitial nephritis, etc.
It is contraindicated in patients with hypokalemia, sulfonamide drug allergy, thiazide drug allergy, overdose of digitalis and hepatic encephalopathy.
Combined with thiazide diuretics, it can cause severe deterioration of renal function; Combined with antimicrobial drugs such as aminoglycosides, it can increase nephrotoxicity and ototoxicity, especially to the original renal damage; In combination with glucocorticoids, it decreases the diuretic effect of furosemide and increases the risk of hypokalaemia.
02Bisphosphonates
Bisphosphonates are inhibitors of osteoclast activity, stable analogues of pyrodronate molecules, which can inhibit the lysis and destruction of bone trabeculae by osteoclasts, prevent osteolytic lesions caused by tumor metastasis, reduce bone resorption, increase bone density, reduce bone pain and hypercalcemia caused by bone metastasis and other bone-related events, and inhibit the spread, infiltration and adhesion of tumor cells to the bone matrix.
Intravenous agents such as zoledronic acid and pamidronic acid are the most commonly used drugs to correct hypercalcemia and should be used as soon as possible, especially in the setting of severe hypercalcemia. Generally, it takes 2-4 days to take effect, 4-7 days to reach the maximum effect, and it lasts for a long time (most can last more than 1 week). If the reduction of serum calcium is not ideal, it can be considered to be used again, and the time for re-use is generally 7 days after the initial dose.
Notes:
Adverse reactions include gastrointestinal reactions, transient "flu-like" symptoms, nephrotoxicity, and atypical femoral fractures (pain in the thigh or groin area). Patients with active gastric and duodenal ulcers, reflux esophagitis and functional esophageal mobility disorders should be used with caution. Not recommended for people with serious oral diseases or dental procedures. Creatinine clearance < 35ml/min is disabled. Repeated use should be suspicious of mandibular osteonecrosis.
03Calcitonin drugs
For example, salmon calcitonin and eel calcitonin can inhibit osteoclasts and inhibit bone resorption by acting on calcitonin receptors of osteoclasts, and can reduce renal tubular calcium reabsorption and increase urinary calcium excretion, which can be clinically used for tumor-related hypercalcemia. Calcitonin drugs have a rapid onset of action, but the effect is not as significant as that of bisphosphonates, and they are mostly suitable for patients with hypercalcium, which can reduce blood calcium levels in the short term, and are used for the transition period before the onset of bisphosphonates.
Notes:
Adverse reactions include nausea, facial flushing, and occasional allergies. The effect of calcitonin drugs in lowering blood calcium can occur calcitonin degeneration (mostly occurs within 72-96 hours), due to the downregulation of calcitonin receptors on osteoclasts, that is, the calcium-lowering effect is weakened after multiple injections. It is recommended to use it continuously for no more than 3 months, as it may potentially increase the risk of cancer.
04 Glucocorticoids
For example, prednisone can reduce blood calcium levels by inhibiting intestinal calcium absorption, increasing urinary calcium excretion, etc., and can inhibit the synthesis of 1,25-(OH)2-D3, and at the same time can prevent bone resorption caused by osteoclast activating factor, which can be clinically used for hypercalcemia caused by hematologic malignancies such as lymphoma and multiple myeloma, and is usually ineffective for hypercalcemia caused by solid tumors or primary hyperparathyroidism. High-dose corticosteroids are usually given for several days until a significant calcium-lowering effect, such as prednisone, takes 2 to 5 days and is not recommended for long-term use.
Notes:
- Adverse reactions include digestive tract reactions, which can stimulate gastric acid secretion and cause gastric and duodenal ulcers, and even gastrointestinal bleeding.
- It can improve central excitability, cause insomnia, agitation and even confusion, and can also induce seizures;
- Long-term use of large doses may cause osteopenia, osteoporosis and even osteonecrosis, vitamin D and calcium preparations can be appropriately supplemented to prevent osteoporosis, and anti-osteoporotic drugs can be added if necessary;
- Inhibition of protein synthesis slows down wound healing;
- Causes glucocorticoid facies, manifested as central obesity, full moon face, buffalo back, skin acne, etc.;
- Long-term use causes steroid-induced diabetes mellitus (or exacerbation of existing diabetes), myopathy, etc.;
- It can inhibit immunity and cause a decrease in body resistance, easily induce or aggravate infection, and delay viral clearance.
- It can cause edema due to water and sodium retention, and hypokalemia and hypertension can be caused by sodium preservation and potassium excretion;
- After taking glucocorticoids for a long time, when the drug is stopped or reduced, it can cause fatigue, drowsiness, poor appetite, general malaise and other withdrawal syndromes, and the drug is stopped or reduced too quickly, and may even cause the exacerbation and worsening of the original disease;
- Others include iatrogenic Cushing syndrome, congestive heart failure and atherosclerosis, thrombosis, hyperlipidemia, hormonal glaucoma, hormonal cataracts, etc.
It should be used with caution for myasthenia gravis, diabetes, congestive heart failure, gastric ulcer, gastritis or esophagitis, hypertension, hypothyroidism, osteoporosis, ocular herpes simplex, glaucoma, diverticulitis, emotional instability and psychotic tendencies, epilepsy, liver damage, hyperlipoproteinemia, renal impairment or stones, tuberculosis, etc.
It is contraindicated in patients with a history of severe psychiatric illness, active ulcers, duodenal ulcers, recent gastrointestinal anastomosis, severe osteoporosis, diabetes, hypertension, viral, bacterial, and fungal infections that cannot be controlled by antimicrobial therapy. Do not stop the drug abruptly, increase or decrease the dose at will, or change the number of doses.
05 Calcimimetic
Calcimimetic agents, such as cinacalcet, reduce PTH secretion by binding to calcium-sensitive receptors, thereby reducing serum calcium, especially for patients with obvious symptoms of hypercalcemia who cannot undergo surgery, patients with significantly elevated serum calcium, or patients with recurrent hypercalcemia after surgery. At present, the only indication in China is secondary hyperparathyroidism in patients on maintenance dialysis with chronic kidney disease (CKD).
Notes:
Adverse reactions include gastrointestinal symptoms (such as nausea, vomiting, stomach discomfort, loss of appetite and bloating, etc.), hypocalcemia, upper respiratory tract infection, gastrointestinal bleeding, QT prolongation, etc.
Caution should be used for hypocalcemia, abnormal liver function, risk of seizures or previous history of epilepsy, gastrointestinal bleeding or previous history of peptic ulcer, pregnant women and women who may become pregnant, lactating women, and people over 65 years of age.
Cinacalcet is metabolized by a variety of enzymes such as CYP3A4, CYP2D6, CYPIA2, and combined with CYP3A4 inhibitors such as azole antifungal drugs, macrolide antibacterial drugs, amiodarone, etc., which will cause the plasma concentration of cinacalcet to increase and the adverse reactions will increase; Cinacalcet is a strong inhibitor of CYP2D6, and combined with drugs metabolized by CYP2D6, such as tricyclic antidepressants and butyrylbenzene antipsychotics, may cause the blood concentration of the latter to rise; In combination with bisphosphonates, cinacalcet's effect on lowering serum calcium concentrations may be enhanced.
06 RANKL inhibitors
Denosumab is a fully human monoclonal antibody of RANKL that binds specifically to the RANK ligand to inhibit bone resorption by inhibiting osteoclast maturation, inhibiting osteoclast function, and promoting its apoptosis, thereby inhibiting bone resorption, increasing bone density and bone strength in cortical bone and trabecular bone, promoting bone remodeling, and reducing blood calcium. Clinically, it can be used for malignancy-related hypercalcemia, especially bisphosphonate-resistant hypercalcemia. Its average onset time is about 9 days and can last for 104 days.
Notes:
Adverse reactions include nausea, vomiting, decreased appetite, headache, fatigue/weakness, anemia, constipation, diarrhea, rash, itchy skin, dyspnea, hypophosphatemia, peripheral edema, hypocalcemia, severe infections (cystitis, upper respiratory tract infection, pneumonia, cutaneous cellulitis, etc.), muscle or bone pain, etc. Long-term use may over-inhibit bone resorption, leading to mandibular osteonecrosis or atypical femoral fracture. Contraindicated in patients with hypocalcemia.
07 normal saline
Hypercalcemia can cause dehydration due to renal tubular dysfunction caused by polyuria and vomiting, and conventional saline hydration can rehydrate and correct dehydration, and increase glomerular calcium filtration to promote urinary calcium excretion. According to the Expert Consensus on the Diagnosis and Treatment of Parathyroid Cancer (2019), it is recommended to give 3000-4000ml of normal saline solution daily for 24-48 hours.
Notes:
Pay attention to the load on the heart and kidneys caused by large amounts of hydration. At the same time, attention should be paid to potassium replacement to correct hypokalemia.
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The author of this article: Gao Lili Responsible editor: Sheep
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