UNOROCK KIT 150/250MG/0.25MG TABLET

Indications

• Hypoparathyroidism
• Vitamin D-dependent rickets
• Hypophosphataemic rickets
• Persistent hypocalcaemia due to hypoparathyroidism
• Prevention of vitamin D deficiency in renal or cholestatic liver disease

Dosage

Children: In neonates, the dose is typically 20 nanograms/kg once daily, while children aged 1 month to 11 years may receive 25-50 nanograms/kg once daily, adjusted as necessary. For children aged 12-17 years, the usual dose is 1 microgram once daily, also adjusted as needed.

Adults: The typical adult dose is 0.25 to 1 microgram per day, adjusted based on calcium and phosphate levels.

Mechanism of action

Calcitriol binds to vitamin D receptors in target tissues, which leads to increased intestinal absorption of calcium and phosphate, renal tubular reabsorption of calcium, and mobilization of calcium from the bones. This activity helps to maintain serum calcium levels, which is crucial for bone mineralization and overall skeletal health.

Pharmacodynamics

The pharmacodynamic effects of calcitriol include the regulation of calcium homeostasis and promotion of bone mineralization. By enhancing calcium absorption in the intestine and increasing renal reabsorption of calcium, calcitriol helps to prevent hypocalcemia. It also influences the activity of osteoblasts and osteoclasts, thus facilitating bone remodeling.

Pharmacokinetics

Calcitriol is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 6 to 24 hours after oral administration. Its half-life is about 5 to 8 hours. It is metabolized in the liver and other tissues, and the metabolites are excreted primarily via the kidneys. Renal impairment can affect the metabolism and clearance of calcitriol, necessitating careful monitoring.

Contra-indications

• Hypercalcaemia
• Hypercalciuria
• Vitamin D toxicity
• Severe renal impairment

Adverse effects

• Hypercalcaemia
• Hypercalciuria
• Dizziness
• Weight decreased
• Confusion
• Renal impairment
• Muscle weakness
• Paralytic ileus
• Polydipsia
• Psychiatric disorder
• Sensory disorder
• Urinary disorders

Interactions

• Other vitamin D compounds
• Thiazide diuretics (may increase risk of hypercalcaemia)
• Anticonvulsants (may reduce vitamin D activity)

Precautions

• Monitor plasma calcium concentration, especially in renal impairment
• Careful dosing in infants
• Avoid excessive sun exposure and sunlamps
• Use with caution in patients with a history of nephrolithiasis

Pregnancy

Manufacturers advise avoiding unless essential due to potential risks.

Breast-feeding

No information available on safety during breastfeeding.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Calcitriol oral drops 1 microgram/mL
• Calcitriol capsules 250 nanograms
• Calcitriol capsules 500 nanograms
• Calcitriol capsules 1 microgram

Indications

• Contraception
• Regulation of menstrual cycles
• Management of dysmenorrhea
• Reduction of acne severity
• Menstrual-related disorders

Dosage

Children: Paediatric dosing for combined hormonal contraceptives is not universally established and should be determined based on individual patient needs and in consultation with healthcare providers. Refer to the BNF for Children for specific guidance.

Adults: The dosage of combined hormonal contraceptives varies by product and formulation. Patients should refer to the prescribing information or BNF for specific dosing instructions.

Mechanism of action

Combined hormonal contraceptives primarily work through the inhibition of ovarian follicular development and ovulation, as well as the alteration of the endometrial lining to prevent implantation. They contain both estrogen and progestin, which act synergistically to achieve these effects.

Pharmacodynamics

The pharmacodynamics of combined hormonal contraceptives involve the modulation of reproductive hormones. The estrogen component typically helps stabilize the endometrial lining, while the progestin component provides feedback inhibition to the hypothalamus and pituitary gland, reducing the secretion of gonadotropins (LH and FSH) necessary for ovulation. This dual action results in effective contraception.

Pharmacokinetics

Pharmacokinetics of combined hormonal contraceptives vary based on the specific formulation. Generally, they are well-absorbed orally, with peak plasma concentrations occurring within a few hours after administration. Metabolism primarily occurs in the liver, and the elimination half-lives can vary; typically, estrogen and progestin are excreted in urine and feces. The onset of contraceptive efficacy usually requires consistent daily administration for at least seven days.

Interactions

• cobicistat + combined hormonal contraceptives: Severe (decreases efficacy)
• combined hormonal contraceptives + lenalidomide: Severe (increases risk of venous thromboembolism)
• lorlatinib + combined hormonal contraceptives: Severe (decreases exposure)
• pitolisant + combined hormonal contraceptives: Severe (decreases efficacy)
• combined hormonal contraceptives + pomalidomide: Severe (increases risk of venous thromboembolism)
• combined hormonal contraceptives + thalidomide: Severe (increases risk of venous thromboembolism)
• combined hormonal contraceptives + tizanidine: Severe (increases exposure)
• combined hormonal contraceptives (containing ethinylestradiol) + voxilaprevir with sofosbuvir and velpatasvir: Severe (increases risk of increased ALT concentrations)
• combined hormonal contraceptives alter the exposure to lamotrigine and lamotrigine + combined hormonal contraceptives: Moderate (decreases efficacy)
• combined hormonal contraceptives + erlotinib: Moderate (increases exposure)

Indications

• Osteoporosis in postmenopausal women
• Prevention of osteoporosis in high-risk postmenopausal women

Dosage

Adults: For osteoporosis treatment, the usual adult dose is 150 mg orally once a month.

Mechanism of action

Ibandronate binds to hydroxyapatite in bone, where it is taken up by osteoclasts during bone resorption. This process involves local acidification that releases ibandronate, which is then internalized by osteoclasts through fluid-phase endocytosis. Once inside, it disrupts the function of osteoclasts by interfering with the mevalonate pathway and inducing apoptosis through mechanisms involving caspase-3 activation. This ultimately leads to reduced bone resorption and increased bone density.

Pharmacodynamics

Ibandronate is used to treat and prevent osteoporosis in postmenopausal women, with a long duration of action and a wide therapeutic index. Adverse effects may include upper gastrointestinal reactions, hypocalcemia, musculoskeletal pain, osteonecrosis of the jaw, atypical femoral fractures, and renal impairment. Its prolonged half-life, which can extend up to 157 hours, allows for less frequent dosing.

Pharmacokinetics

After oral administration, ibandronate is poorly absorbed, with bioavailability significantly reduced by food and certain medications (such as antacids and calcium supplements). It is extensively distributed in the bone and has a long elimination half-life due to its binding properties. The drug is primarily excreted unchanged through the kidneys. Renal impairment can affect its clearance, necessitating dose adjustments in patients with compromised kidney function.

Adverse effects

• gastrointestinal irritation
• hypocalcemia
• musculoskeletal pain
• osteonecrosis of the jaw
• atypical fractures of the femur
• severe renal impairment

Interactions

• oral antacids (decreases absorption)
• aspirin (increases risk of gastrointestinal irritation)
• NSAIDs (increases risk of gastrointestinal irritation)
• oral calcium salts (decreases absorption)
• oral iron (decreases absorption)
• oral magnesium (decreases absorption)
• oral zinc (decreases absorption)

Precautions

• Monitor calcium levels
• Assess renal function prior to initiation
• Evaluate for history of gastrointestinal disorders

Pregnancy

Ibandronate is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Caution is advised as the effects on breastfed infants are unknown.

Storage

Store at room temperature, away from moisture and light.

Formulations

• tablets
• injectable solution

Indications

• Support in energy metabolism
• Management of metabolic disorders
• Potential role in exercise performance enhancement

Dosage

Children: Refer to specific guidance in the BNF for Children.

Adults: Refer to specific guidance in the BNF.

Mechanism of action

Malate participates in the malate-aspartate shuttle, which is essential for transferring reducing equivalents across the mitochondrial membrane. This shuttle allows for the conversion of NADH produced during glycolysis to NADH within the mitochondria, thus facilitating ATP production. Additionally, malate is involved in gluconeogenesis, where it contributes to the synthesis of glucose from non-carbohydrate precursors.

Pharmacodynamics

Malate aids in energy metabolism, particularly in the conversion of nutrients to ATP. It supports the regeneration of NAD+, which is crucial for numerous metabolic reactions. By participating in the TCA cycle, malate enhances aerobic respiration and plays a role in maintaining the balance of metabolic intermediates necessary for cellular function.

Pharmacokinetics

Malate is readily absorbed in the gastrointestinal tract and is distributed throughout the body, where it enters various metabolic pathways. It is primarily metabolized in the liver and muscle tissues. The elimination of malate is through metabolic conversion, with its metabolites being further processed in the TCA cycle.

Pregnancy

There are no well-controlled studies of malate in pregnant women. Use only if clearly needed.

Breast-feeding

Malate is considered to be safe during breastfeeding, though limited data are available.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Malate salts
• Malic acid

Mechanism of action

The mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)₂-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)₂-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells. A study suggests that calcitriol plays an immunoregulatry role by suppressing the aryl hydrocarbon receptor (AhR) expression in human Th9, a pro-inflammatory CD4 T cell subset. This suppression subsequently leads to repressed expression of BATF, a transcription factor essential for Th9. Calcitriol has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes. Ergocalciferol and doxercalciferol (1-hydroxyergocalciferol); cholecalciferol and calcifediol (25-hydroxycholecalciferol); and dihydrotachysterol in their activated forms (1,25-dihydroxyergocalciferol; 1,25-dihydroxycholecalciferol [calcitriol]; and 25-hydroxydihydrotachysterol; respectively), along with parathyroid hormone and calcitonin, regulate serum calcium concentrations; in addition to conversion to the active 1,25-dihydroxycholecalciferol, calcifediol also has intrinsic activity. Calcitriol (activated vitamin D) enhances the efficiency of intestinal calcium absorption along the entire small intestine, but principally in the duodenum and jejunum. Calcitriol also enhances phosphorus absorption along the entire small intestine, but principally in the jejunum and ileum. The activated forms of ergocalciferol, doxercalciferol, and cholecalciferol may have a negative feedback effect on parathyroid hormone (PTH) production. Calcitriol appears to act in intestine in manner that is analogous to the way steroid hormones such as estrogens act on target tissues. ... Cytosol of chicken intestinal cells contains a 3.7 S protein that binds calcitriol specifically and with high affinity. Formation of complex with this receptor facilitates transfer of calcitriol to nuclear chromatin. ... Calcitriol stimulates synthesis of RNA and at least two proteins in intestinal mucosa, alkaline phosphatase and a calcium-binding protein. ... It was proposed that the calcium-binding protein is involved in transport of calcium. ... /However/, it has been reported that calcitriol-induced stimulation of intestinal transport of phosphate precedes that of calcium, and it is possible that primary effect of the vitamin is on phosphate rather than calcium transport. The effects of 1,25-dihydroxyvitamin D3 (I) on the human promyelocytic leukemia cell line HL-60 were investigated. I induces the differentiation of HL-60 into mono- and multinucleated macrophage-like cells. Phenotypic change is evident within 24 hours and reaches a plateau at 72-96 hours of incubation. The changes are metabolite-specific and include adherence to substrate, acquisition of the morphological features

Pharmacodynamics

Calcitriol is a biologically active calcitrophic hormone with anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Its main sites of action are the intestine, bone, kidney and parathyroid hormone. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal (GI) tissues, bones, and kidneys. As an active form of vitamin D₃, calcitriol elevates the plasma levels of calcium by stimulating intestinal calcium uptake, increasing reabsorption of calcium by the kidneys, and possibly increasing the release of calcium from skeletal stores. The duration of pharmacologic activity of a single dose of exogenous calcitriol is expected to be about 3 to 5 days. In addition to its important role in calcium metabolism, other pharmacological effects of calcitriol have been studied in various conditions including cancer models. Various studies demonstrated expression of vitamin D receptors in cancer cell lines, including mouse myeloid leukemia cells. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation _in vitro_ and _in vivo_ in many cell types, such as malignant cell lines carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others. In early human prostate cancer trials, administration of 1.5 µg/d calcitriol in male participants resulted in a reduction in the rate of PSA rise in most participants, however it was coincided with dose-limiting hypercalcemia in most participants. Hypercalcemia and hypercalcuria were evident in numerous initial trials, and this may be due to these trials not testing the drug at concentrations that are active in preclinical systems. Findings from preclinical data show an additive or synergistic antineoplastic action of calcitriol when combined with agents including dexamethasone, retinoids, and radiation, as well as several cytotoxic chemotherapy drugs such as platinum compounds. Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of calcitriol, 1,25-(OH)₂-D3, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of <i>Mycobacterium tuberculosis</i>. 1,25-(OH)₂-D3 has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.

Mechanism of action

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as ibandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. ibandronate also activated caspase-3 which contribute to apoptosis.

Pharmacodynamics

Ibandronate is a nitrogen containing bisphosphonate used to treat and prevent osteoporosis in postmenopausal women. The therapeutic index is wide as overdoses are not especially toxic, and the duration of action is long as the half life can be up to 157 hours. Patients should be counselled regarding the risk of upper GI adverse reactions, hypocalcemia, musculoskeletal pain, osteonecrosis of the jaw, atypical fractures of the femur, and severe renal impairment.