NR 566 NR566 Advanced Pharmacology for

NR 566 / NR566 Advanced Pharmacology for Care of the Family Week 1 Chapter 21 Notes| Drugs Affecting the Endocrine System | Chamberlain College

Bisphosphonates

Pharmacokinetics ❖ Absorption and Distribution

• All oral bisphosphonates potentially cause esophagitis and gastric irritation
• Absorption and bioavailability of oral doses are significantly reduced by the presence of food in

the gut or other preparations containing divalent cations.

• To enhance absorption, the patient takes the drug with 8 oz of water, No other food or drink

should be ingested, and the patient must remain upright for at least half an hour (1 hour with ibandronate).

• all mainly distributed to bone.
• Their terminal half-life in bone is exceedingly long, varying from more than 10 years for

alendronate to more than 90 days for etidronate.

• The half-life of risedronate is much shorter, at 480 hours; ibandronate is 220 hours; zoledronic

acid is 167 hours; and tiludronate is 150 hours→ these times are thought to represent the dissociation of the drug from the bone surface, rather than its time within the bone.

• Most bisphosphonates are Pregnancy Category C. Pamidronate and zoledronic acid are Category

D

• All bisphosphonates are used with extreme caution during breastfeeding; zoledronic acid binds to

bone for long periods so is never used in lactating mothers.

• Safety and efficacy in children have not been fully established, but children have been treated

with etidronate (Pregnancy Category B) at doses recommended for adults to prevent heterotopic ossifications or soft tissue calcifications ❖ Metabolism and Excretion

• no evidence that any are systemically metabolized.
• Drug that is not distributed to bone is largely excreted in the urine.

• these drugs are not recommended for patients with moderate to severe renal impairment (serum

creatinine greater than 4.9; creatinine clearance (CCr) less than 30 to 35 mL/min). Dosage adjustments may be necessary if the drug must be given Pharmacodynamics (MOA) ❖ adhere tightly to bone and, by inhibiting osteoclastic activity, are potent inhibitors of both normal and abnormal bone resorption.❖ Etidronate (Didronel) reduces both bone resorption and bone formation because formation is coupled with resorption.❖ Pamidronate (Aredia) and risedronate (Actonel) inhibit bone resorption without inhibiting bone formation and mineralization ❖ Alendronate (Fosamax) is a highly selective inhibitor of bone resorption and is 100 to 500 times more potent than the other drugs.

• does not interfere with osteoclast recruitment or attachment,
• does inhibit osteoclastic activity

❖ Tiludronate (Skelid) inhibits osteoclastic activity through two different mechanisms.

• It inhibits protein-tyrosine-phosphatase, resulting in detachment of osteoclasts from the bone

surface,

• It inhibits the osteoclastic proton pump.

❖ 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 released by tumors.❖ Ibandronate (Boniva) inhibits osteoclast activity and reduces bone resorption and turnover based on its affinity for hydroxyapatite, which is part of the mineral matrix of the bone ❖ All reduce vertebral fractures ❖ only aldendronate, risedronate, and zoledronic acid have demonstrated nonvertebral fracture reductions; it cannot be assumed the others can achieve the same endpoint

• these three have been have been studied in men, but transferability of results with other

medications is considered a safe assumption.❖ pamidronate and zoledronic acid are available only for parenteral use, they are (not discussed in detail except to alert the primary care provider about monitoring the drug and its place in the total treatment regimen of the patient.) Pharmacotherapeutics ❖ Precautions and Contraindications

• no absolute contraindications except uncorrected hypocalcemia, documented Barrett's esophagus,

and renal insufficiency

• Cautious use is recommended for patients with gastrointestinal (GI) disorders.
• The risk for severe esophageal adverse reactions is greater in patients who lie down after taking

these drugs or who fail to swallow them with a full glass (8 oz) of water.

• Etidronate has been withheld from patients with enterocolitis because diarrhea has occurred in

some patients, particularly at high doses.

• Etidronate has also been associated with fractures in patients with Paget's disease when they are

given high doses or when therapy lasted longer than 6 months.▪ These patients must be carefully monitored with x-rays and laboratory work to assess for these lesions.

• IV formulations associated with higher renal toxicity risk, especially with rapid infusion.
• Checking serum creatinine prior to every dose is required.
• Forcing fluids before and after infusion is also recommended

Adverse Drug Reactions ❖ musculoskeletal pain. → more common for patients with Paget's disease and in those taking risedronate and higher doses of etidronate.❖ Rare→ osteonecrosis of the jaw ❖ If elective dental procedures are planned, drug cessation for 3 months pre- and post-procedure may decrease the risk, → no evidence to support this plan ❖ Some concerns have arisen about increased risk of atrial fibrillation.Drug Interactions ❖ Because of these drugs' adverse reactions on the GI tract, drug interactions are most common with other drugs that also affect the GI tract.❖ Histamine2 blocking agents double alendronate bioavailability→impact is unknown ❖ Calcium supplements and antacids interfere with bisphosphonate absorption when taken within 1 hour of each other.❖ The risk of GI bleeding is increased when aspirin and NSAIDs are concomitantly taken ❖ Aspirin may decrease the bioavailability of tiludronate by up to 50% when taken 2 hours after the tiludronate.❖ each NSAID must be considered individually

• indomethacin increases the bioavailability of tiludronate by 2- to 4-fold, the bioavailability is

not significantly altered by diclofenac ❖ Concurrent use of bisphosphonates and other drugs known to build bone density, such as estrogens and SERMs, prove to have additive bone density, but fracture reduction potential is unknown. The safety of combination therapy appears to be the same as the use of each drug separately

• reserved for extreme cases where one drug is inadequate.

Clinical Use – Osteoporosis ❖ prevention and treatment of osteoporosis and its risk for fractures in men and postmenopausal women, especially vertebral fractures.❖ The best trials have been done with alendronate, risedronate, and zoledronic acid with hip fracture reductions → have received FDA approval for this indication.❖ Ibandronate is considered a second-line drug

• Ibandronate and zoledronic acid come in an IV form and alendronate has an oral solution

(Binosto) for those patients unable to take tablets.

• Among these alternative forms, only the zoledronic acid shows evidence of hip fracture

reduction.❖ Initial doses for prevention of bone loss for alendronate and risedronate are 5 mg/day or 35 mg/week.For treatment of existing osteoporosis, the dose of alendronate doubles to 10 mg/day or 70 mg/week, and the dose of risedronate increases to 75 mg for 2 consecutive days or 150 mg once a month ❖ Therapy with 10 mg daily can increase bone density by up to 10% after 3 years and can decrease vertebral and hip fractures by 50% ❖ Use for more than 4 years is currently under review concerning its efficacy or safety. A “drug holiday” for up to 3 years may be considered for lower-risk patients; higher-risk patients are encouraged to remain on therapy due to a better risk versus harm profile ❖ The initial and maintenance dosage of ibandronate for both prevention and treatment is one 2.5 mg tablet taken daily or one 150 mg tablet taken once monthly on the same date of each month.

• The IV dose is 3 mg given over 30 seconds and repeated every 3 months, a schedule that must be

closely maintained for best results.❖ Another IV osteoporosis treatment and fracture prevention medication is zoledronic acid (5 mg), which is taken only yearly. The 4 mg dosing is typically reserved for monthly cancer metastasis prevention and treatment.❖ All bisphosphonates are used to treat Paget's disease when the alkaline phosphatase is at least twice the upper limit of normal. They may also be used for those who are asymptomatic or at risk for future complications from their disease ❖ When heterotopic ossification is a complication of total hip replacement, etidronate may be used at 20 mg/kg daily for 1 month pre-operatively and 20 mg/kg daily for 3 months post-operatively.

• Etidronate is also used when heterotopic ossification occurs secondary to spinal cord injury. The

dosage then is 20 mg/kg daily for 2 weeks, followed by 10 mg/kg daily for 10 weeks, begun as soon as possible after the injury and prior to evidence of heterotopic ossification.Use for early osteopenia related to long-term use of medications that contribute to bone loss (what drugs increase the risk of osteopenia?)