Pharmacology of Agents Treating CKD Mineral and Bone Disorders PDF

Pharmacology of agents treating CKD Mineral and Bone Disorders Pharmacotherapeutics IV Renal Disorders and Electrolytes/Fluids PHAR 4245 January 2025 Dr. Helen E. Smith  Outline and Objectives Bone Mineral Homeostasis  Explain how the hormones presented...

Pharmacology of agents treating CKD Mineral and Bone Disorders Pharmacotherapeutics IV Renal Disorders and Electrolytes/Fluids PHAR 4245 January 2025 Dr. Helen E. Smith  Outline and Objectives Bone Mineral Homeostasis  Explain how the hormones presented in class help maintain bone mineral homeostasis as they act in the bone, kidney, and gut  Explain the role plasma Ca++ concentrations play in bone mineral homeostasis CKD Contribution to Bone Mineral Disorders  Explain how CKD contributes to bone mineral disorders in the context of Vitamin D production, Ca++ plasma concentrations, phosphate retention, PTH levels, and hyperparathyroidism  Explain how hyperparathyroidism affects bone health Pharmacology of therapies for CKD-Related Bone Disease  List the pharmacological categories of medications used in treating CKD mineral and Bone disorders  Explain how Vitamin D is produced in the body and how renal and hepatic health affect it  Explain the mechanisms of action of each medication presented in class used to treat CKD mineral and Bone disorders  List side effects of the medications presented in class; explain mechanisms of side effects presented in class Bone Mineral Homeostasis  Primary Endogenous Regulators Basic and Clinical Pharmacology, 16th Edition, Table 42-2: Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney. PTH Vitamin D FGF23 Increased calcium and Decreased calcium and Increased calcium and phosphate absorption (by phosphate absorption by Intestine phosphate absorption by increased 1,25[OH]2D decreased 1,25(OH)2 1,25(OH)2D production) production Decreased calcium excretion, Calcium and phosphate Increased phosphate increased phosphate excretion may be Kidney excretion, decreased excretion, stimulation of decreased by 25(OH)D 1,25(OH)2D production 1,25(OH)2D production and 1,25(OH)2D1 Increased calcium and Calcium and phosphate Decreased mineralization phosphate resorption by resorption increased by high due to Bone 1,25(OH)2D; bone doses. Low doses increase hypophosphatemia and formation may be bone formation. low 1,25(OH)2D levels. increased by 1,25(OH)2D Serum calcium increased, Serum calcium and Net effect on serum Decreased serum serum phosphate phosphate both 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.  Hormone Effects Basic and Clinical Pharmacology, 16 th Edition Fig. 42-1 Mechanisms contributing to bone mineral homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations are controlled principally by three hormones, 1,25- dihydroxyvitamin D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on renal excretion. PTH and 1,25(OH)2D increase the input of calcium and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D also increases calcium and phosphate absorption from the gut. In the kidney, 1,25(OH)2D decreases excretion of both calcium and phosphorus, whereas PTH reduces calcium but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical regulator of calcium homeostasis, but in pharmacologic concentrations can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, 1,25(OH)2D increases urinary calcium excretion indirectly through increased calcium absorption from the gut and inhibition of PTH secretion and may increase urinary phosphate excretion because of increased phosphate absorption from the gut and stimulation of FGF23 production. Hormone Interactions Basic and Clinical Pharmacology, 16 th Edition Fig. 42-2A Ca++ influence on PTH Golan Fig. 30-4 CKD Contribution to Bone Mineral Disorders CKD Contribution to Bone Mineral Disorders  CKD can be a primary cause of bone disease  CKD impacts bone mineral homeostasis due to  Loss of 1,25(OH)2D production  Retention of phosphate that reduces ionized calcium levels  Resulting secondary hyperparathyroidism CKD Contribution to Bone Mineral Disorders Golan Fig. 30-8 Pharmacology of therapies for CKD- Related Bone (Mineral) Disease Treatment of CKD Bone Mineral Disorders: Vitamin D Treat with active Vit D products Golan Fig. 30-8  Treatment of CKD Bone Mineral Disorders: Vitamin D  A cholesterol derivative transported in the circulation by vitamin D–binding protein  Several forms synthesized in the body  25(OH)D usually measured to diagnose vitamin D deficiency  MOA:  Binds to the vitamin D receptors (VDRs) located in parathyroid glands, intestine, bone, kidney, heart, nervous, and immune systems  When vitamin D binds to VDR, this complex binds to retinoid X receptor (RXR)  The VDR–RXR complex binds to DNA sequences in target genes to either promote or inhibit transcription depending on the organ system  Suppresses PTH synthesis  Stimulates GI calcium absorption  Treatment of CKD Bone Mineral Disorders: Activation of Vitamin D Cholecalciferol (Vit D3) is produced endogenously in skin Ingest cholecalciferol (Vit D3) and ergocalciferol (Vit D2) in diet These Vit D precursors are hydroxylated to calcifediol (25(OH)D) in liver 25(OH)D further hydroxylated in proximal convoluted renal tubular cells to calcitriol Golan Fig. 30-5 (1,25(OH)2D) Treatment of CKD Bone Mineral Disorders: Activation of Vitamin D  Treatment of CKD Bone Mineral Disorders: Active Vitamin D Products  Calcitriol  Enhances small intestine absorption of dietary Ca2+  Affects other target organs  Available PO or IV  Can elevate serum Ca++ in 24-48 hours  Should not be administered to CKD patients unless hyperphosphatemia is controlled because an increase plasma Ca2+ and phosphate binding  Need to monitor patients for serum Ca++ and phosphate levels  Treatment of CKD Bone Mineral Disorders: Active Vitamin D Products Calcifediol  The 25(OH)D form of Vitamin D  Enhances small intestine absorption of dietary Ca2+  Available as an extended-release oral formulation  Indicated for patients with  CKD stages 3 or 4 with low 25(OH)D levels  secondary hyperparathyroidism  not limited to dialysis patients  Need to monitor patients for serum Ca++ and phosphate levels  Treatment of CKD Bone Mineral Disorders: Active Vitamin D Products  Analogs of 1,25(OH)2D:  Paricalcitol  19-nor-1,25(OH)2Vit D  Doxercalciferol  1α-hydroxylated form of Vit D2; 25-hydroxylated to active form in liver  Approved for treatment of secondary hyperparathyroidism of CKD, usually only for dialysis patients  Less likely to cause hypercalcemia for any given reduction in PTH  For patients for whom calcitriol will cause hypercalcemia Treatment of CKD Bone Mineral Disorders: Phosphate Binders Treat with Phosphate Binders Golan Fig. 30-8 Treatment of CKD Bone Mineral Disorders: Phosphate Binders  Aluminum hydroxide  One of first agents used  Al precipitates with phosphate in GI tract to form non-absorbable complexes  Effective at lowering plasma phosphate concentration  Significant risk for Al toxicity  Chronic use may cause chronic anemia, osteomalacia, and neurotoxicity  Not usually used now except for refractory hyperphosphatemia  Treatment of CKD Bone Mineral Disorders: Phosphate Binders  Iron based  sucroferric oxyhydroxide  Effectively lowers phosphorus over a long-term (1-year) period  May have a lower pill burden compared to other agents  Available as a chewable tablet  Adverse effects: GI distress  Remember drug interactions that inhibit absorption of object drug  ferric citrate  Effectively lowers phosphorus  Increases iron indices (TSat and ferritin) while lowering IV iron and ESA use  Adverse effects: GI distress and risk of iron overdose  Remember drug interactions that inhibit absorption of object drug  Treatment of CKD Bone Mineral Disorders: Phosphate Binders  Calcium carbonate & Calcium acetate  Bind to dietary phosphate and inhibit its absorption (must be given with meals)  Often used  Doses required may cause iatrogenic hypercalcemia and increase risk of vascular calcifications  Sevelamer carbonate  Non-absorbable cationic ion-exchange resin  Binds dietary phosphate  Also binds bile acids interrupting enterohepatic circulation and decreasing cholesterol absorption  Treatment of CKD Bone Mineral Disorders: Phosphate Binders Lanthanum carbonate  Mechanism of Action:  Disassociates to La3+ which binds dietary phosphate resulting in insoluble lanthanum phosphate complexes  Decreases serum phosphate and calcium levels  Adverse Reactions  >10%: Diarrhea, nausea, vomiting  1% to 10%: Hypocalcemia, Abdominal pain 