NR 566: Guide on Drugs Affecting the Endocrine System

NR 566: Guide on Drugs Affecting the Endocrine System Bisphosphonates • Drugs: etidronate (Didronel), pamidronate (Aredia), risedronate (Actonel) alendronate (Fosamax), tiludronate (Skelid), zoledronic acid (Zometa), ibandronate (Boniva) • Used for bone support, most commonly used • Pharmacodynamics  Adhere to bone, inhibit osteoclastic activity, potent inhibitors of both normal and abnormal bone resorption o Etidronate (Didronel): reduces both bone resorption and bone formation because formation is coupled with resorption o Pamidronate (Aredia) (available as IV only) o and risedronate (Actonel): inhibit bone resorption with out inhibiting bone formation and mineralization o Alendronate (Fosamax): highly selective inhibitor of bone resorption 1  100 to 500 time more potent than the other drugs  Does not interfere with osteoclastic recruitment or attachment but does inhibit osteoclastic activity o Tiludronate (Skelid): inhibits protein-tyrosine-phosphatease, results in detachment of osteoclasts from the bone surface  Inhibits the osteoclastic proton pump o Zoledronic acid (Zometa): inhibits osteoclastic activity and induces osteoclast apoptosis  Also inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors release by tumors  Only available as IV formulation o Ibandronate (Boniva): inhibits osteoclast activity and reduces bone resorption and turnover based on its affinity for hydroxyapatite (part of the bone matrix) • All drugs in this class reduce vertebral fracture however, o Only alendronate, risedronate, and zoledronic acid have demonstrated nonvertebral fracture reduction o Pamidronate and zoledronic acid: only for parenteral use • Pharmacotherapeutics o Contraindication: uncorrected hypocalcemia, documented Barrett’s esophagus, and renal insufficiency o Caution: patient with GI disorders o R/F severe esophageal adverse reactions is greater in patients who lie down after taking these drugs or fail to take with a full glass of water o Etidronate has been withheld from patients with enterocolitis r/t diarrhea particularly at high doses  Associated with fracture in patients with Paget’s disease when given high doses or when therapy lasted longer than 6 months • Monitor with x-rays and lab work to assess for lesions • Rare femur fracture in non-Paget’s patients using bisphosphonates o IV formulations associated with higher renal toxicity risk especially with rapid infusion  Check crt prior to every dose is required, force fluids before and after infusion • Clinical Use (Page 546 Dosing Chart) o Osteoporosis  Prevention and treatment of osteoporosis and its risk for fracture in men and postmenopausal women (especially vertebral fractures)  First line drugs: Alendronate, risedronate, and zolendronic acid with hip fracture reductions, FDA approved for this indication  Second-line drug: Ibandronate  Ibandronate and zoledronic acid come in IV form  Alendronate PO solution (Binosto) and PO tablets  Zoledronic acid: only alternative form that shows evidence of hip fracture reduction  Prophylactic use in patients with early osteopenia r/t long term use of medications that contribute to bone loss • Includes (thyroid hormone, aromatase inhibitors, and glucocorticoids, PPIs, SSRIs)  It is recommended that all adults taking more than 7.5 mg of prednisone or its equivalent for more than 3 weeks be given alendronate or risedrone  In very high risk patients, maximum 2-year use of teriparatide (Forteo) (bone mass benefit disappears after d/c) a parathyroid hormone, may be more efficacious • Bisphosphonates: bone mass benefit does not decline for 5 years  Alendronate and risedronate initial doses for prevention of bone loss: 5mg/day or 35mg/week  For existing osteoporosis: alendronate 10mg/day or 70mg/week  Risedronate: 75mg for 2 days or 150mg once a month o Paget’s Disease (Osteitis Deformans)  All bisphosphonates are used to treat Paget’s disease when the alkaline phosphatase is at least twice the upper limit of normal  Asymptomatic or at risk for future complications from their disease  Symptomatic Paget’s best treated with etidronate  Etidronate slows accelerated bone turnover in pagetic lesions and to a lesser extend in normal bone  Reduced turnover causes symptomatic improvement: less bone pain and decreased fractures  5-10 mg/kg daily for up to 6 months or 11 to 20 mg/kg daily for 3 months  For all drugs indications for retreatment are evidence of active disease or failure to normalize alkaline phosphatase levels  Supplemental calcium and vitamin D if dietary intake is not adequate  Space calcium supplements and bisphosphonates to prevent reduced bioavailability o Heterotopic Ossification  Complications of THR  Etidronate: first line  Heterotopic ossification r/t spinal cord injury  Use as soon as possible after injury • Drug Interactions o Adverse GI reactions, interact with drugs that affect the GI tract  Histamine 2 blocking agents double alendronate bioavailability but the impact with unknow o Calcium supplements and antacids interfere with bisphosphonate absorption when taken within 1 hr o R/F GI bleeding is increased when ASA and NSAIDs are concomitantly taken o ASA may decrease the bioavailability of tiludronate by up to 50% when taken 2 hrs after the tiludronate o Indomethacin increases the bioavailability of tiludronate by 2- to 4- fold  Diclofenac does not significantly alter bioavailability therefore each NSAID must be evaluated individually o Concurrent use of bisphosphonates and other drugs known to build bone density (estrogens and SERMs) have additive bone density however fracture reduction potential is unknown • ADRs o All bisphosphonates: musculoskeletal pain  More common in Paget’s disease  More common in those taking risedronate  High doses of etidronate  Rare reports of osteonecrosis of the jaw in active dental disease, invasive procedure, especially in CA patients • Can occur without dental issues in those receiving frequent high IV doses  R/F A-fib • Bioavailability of bisphosphonate drugs and appropriate patient education o Absorption and bioavailability of oral doses are significantly reduced by the presence of food in the gut or other preparations containing divalent cations o To enhance absorption take with 8 oz of water, no other food or drink and remain upright for at least half an hr (1 hour with ibandronate) o Histamine 2 blocking agents double alendronate bioavailability but the impact with unknow o ASA may decrease the bioavailability of tiludronate by up to 50% when taken 2 hrs after the tiludronate o Indomethacin increases the bioavailability of tiludronate by 2- to 4- fold  Diclofenac does not significantly alter bioavailability therefore each NSAID must be evaluated individually o Patient education: Take oral drugs first thing in the morning at least 30 minutes prior to other medications, beverages, or food (60 minutes for ibandronate) o Etidronate and tiludronate take 2 hours before food o Alendronate, ibandronate, risedronate, and tiludronate should be taken with 8 oz of plain water o Mineral water, coffee, OJ, and other drinks greatly reduce absorption o Supplemental calcium or antacids take the bisphosphonate at least 1 hr before these drugs o Skip missed daily doses and resume the next morning o Sit up for at least 30 mins after taking to decrease risk of esophageal irritation (1hr for ibandronate) • Adverse effects associated with long-term use o Etidronate: Fractures in patients with Paget’s disease when given high doses or when therapy lasted longer than 6 months o Oral drugs in this class: rare osteonecrosis of the jaw after 3 years of use (higher risk in IV drugs) Growth hormones • Drugs: somatropin (Nutropin and Nutropin AQ, Gentropin, Humatrope, Norditropin, Nutropin, Accretropi9n, Saizen, Serostim) and somatrem (Protropin) • Dosage of the various forms of somatropin varies by manufacturer • Pharmacodynamics o GHRH secreted by hypothalamus in response to decreased serum glucose o GHRH then binds to receptors in the anterior pituitary, secrets GH (somatotropin) o Passes through cell membrane, fosters proteins synthesis, fat breakdown, and tissue growth o Causes hyperglycemia by decreasing glucose utilization by cells and increases rate by which glycogen is broken down into glucose o Both GHRH and GH have been synthesized by recombinant DNA technology  Synthetic hormones o Administration results in an insulin like effect o Increased growth of organs and skeletal, increased cellular protein synthesis o Children with GH deficiency sometimes experience hypoglycemia and it is improved by admin of these drugs o Reduction in fat store, increased lean muscle mass, and decreased mean cholesterol o Treats lipodystrophy in HIV patients – helps to reduce wasting and cachexia o In over abundance of GH, surgical intervention is primary intervention however recurrence may require use of somatostatin analogues such as octreotide or lancreotide  GH suppressive agents • Pharmacotherapeutics o Contraindication: patients with closed epiphyses and those with evidence of active tumore growth o Caution: o intracranial tumors increased r/f tumor growth o Patients with coexisting adrenocorticotropic hormone deficiency may experience increased symptoms o Increased serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone o TH level changes have occurred  Makes managing thyroid disorders more difficult  Untreated hypothyroidism prevents optimal response to GH therapy o May induce insulin resistance o Use cautiously with diabetic patients, those with glucose intolerance, or risk for metabolic syndrome  Lipid benefits may negate this risk o Safety and efficacy of synthetic GH not established in pregnancy or lactation, Category C, only if clearly needed • Clinical Use (Dosing Schedule: Pg 551) o Growth Failure Associated with Chronic Renal Insufficiency  GH is used to treat children with growth failure up to the time of renal transplantation • Dosages are higher than normal r/t hormone resistance  After transplantation use is restricted to children 2 standard deviations below the mean for their gender without epiphyseal closure  GH increased the side effects of cyclosporine, so typically evaluated 1 year after transplant for continued use  To optimize therapy for those receiving hemodialysis, injections are given at night prior to going to sleep or at least 3 to 4 hrs after dialysis to prevent hematoma formation caused by the heparin  For those with peritoneal dialysis: take injection in the morning after dialysis is completed  Ambulatory peritoneal dialysis: injection in the evening at the time of the overnight exchange o Long-term Treatment of Growth Failure in Children who lack adequate Endogenous GH  Somatrem and all forms of somatropin (except Serostim) used for this indication  Titrated to individual patient response  Younger children respond better than prepubertal adolescents  High doses increase risk for excess human GH o Turner’s Syndrome  Somatropin is approved for long-term treatment of short stature associated with TS  Specific dosing schedule is individualized  Relative hormone resistance is common (higher doses to obtain growth) o Somatropin Deficiency  Patients must meet strict criteria to receive GH, prescribed by endocrinology team • Drug Interactions o Glucocorticoid therapy and estrogens may inhibit the growth-promoting effect of GH o Anticonvulsants may have more severe side effects o Insulin may lose its effectiveness • ADRs o 30-40 % of patients on somatrem and 2-4.7% of patients on somatropin develop persistent antibodies, making them less likely to response to the drug o Other adverse reactions are rare and include pain at the injection site, hyperglycemia, hypothyroidism, and edema secondary to retained sodium o Rare instances of death .....................