Pharmacology

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Forth stage Dr. Enass Najem

2nd semester Lec. 4

Drugs Used to Treat Osteoporosis

Background:-

Osteoporosis literally translate as porous bones.

Osteoporosis occurs when holes between bone become bigger making bone fragile and

liable to break easily.

Osteoporosis results from an unhealthy imbalance between two normal activities of

bone: bone resorption and bone formation

These activities rely on two major types of cells: osteoclasts for bone resorption and

osteoblasts for bone formation. The combined processes of bone resorption and bone

formation allow the healthy skeleton to be maintained continually by the removal of old

bone and its replacement with new bone.

It occurs in the elderly of both sexes but is most pronounced in postmenopausal women.

Osteoporosis is characterized by frequent bone fractures, which are a major cause of

disability among the elderly.

Osteoporosis is called the "silent disease" because bone is lost with no signs. You may not

know that you have osteoporosis until a strain, bump, or fall causes a bone to break.

Risk factors for osteoporosis:

• Unchangeable risk factors:-

• Sex, age, Race, family history, Body frame size.

• Hormone levels:-

• Sex hormones:- Low estrogen levels due to missing menstrual periods or to

menopause can cause osteoporosis in women. Low testosterone levels can bring on

osteoporosis in men.

• Thyroid conditions - over active thyroid or parathyroid.

• Dietary factors:- Low calcium intake, Low vitamin D levels.

• Medication use:- Corticosteroids, Anticoagulants (heparin) and Some medicines

for breast cancer, prostate cancer, epilepsy and some antidepressants

• Lifestyle factors:- Sedentary lifestyle, Excessive alcohol consumption, smoking.

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How menopause influences osteoporosis

There is a direct relationship between the lack of estrogen after menopause and the

development of osteoporosis.

Peak bone mass is reached around the age of 25 to 30 years, when the skeleton has

stopped growing and bones are at their strongest and thickest. The female sex hormone

oestrogen plays an important role in maintaining bone strength.

Oestrogen levels drop during menopause, at around the age of 45-55 years, resulting in

increased bone loss. If a woman’s peak bone mass before menopause is less than ideal,

any bone loss that occurs during menopause may result in osteoporosis.

Research suggests that about half of all women over the age of 60 years will experience at

least one fracture due to osteoporosis.

How Is Osteoporosis Diagnosed?

A bone mineral density (BMD) test is can provide a snapshot of your bone health.

Dual-energy x-ray absorptiometry (DEXA) measurement of the hip and spine is the

technology now used to establish or confirm a diagnosis of osteoporosis, predict future

fracture risk and monitor patients by performing serial assessments.

The results of your test are usually reported as a T-score and Z-score:

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• T-score compares your bone density with that of a healthy 30-year-old adult

• Z-score compares your bone density with that of other people of your age,

gender, and race.

With either score, a negative number means you have thinner bones than average. The

more negative the number, the higher your risk of a bone fracture.

Who Should Be Tested?

Women age 65 and older and men age 70 and older, regardless of clinical risk factors.

people over age 50 with any of the following: previous bone fracture from minor trauma,

rheumatoid arthritis, low body weight, a parent with a hip fracture.

Individuals receiving, or planning to receive, long-term glucocorticoid (steroid) therapy.

Individuals with primary hyperparathyroidism.

Individuals being monitored to assess the response or efficacy of an approved

osteoporosis drug therapy.

Osteoporosis Treatments

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Lifestyle Changes

Calcium and Vitamin D :-

Advise all individuals to obtain an adequate intake of dietary calcium (at least 1,200 mg

per day, including supplements if necessary.

Also recommend an intake of 600 to 1,000 international units (IU) of vitamin D per day

for adults age 50 and older.

Physical Activity:-

Osteoporosis Drugs

Bisphosphonates:

These analogs of pyrophosphate, including etidronate, risedronate , alendronate,

ibandronate, pamidronate, tiludronate, and zoledronic acid, comprise an important drug

group used for the treatment of disorders of bone remodeling, such as osteoporosis and

Paget's disease, as well as for treatment of bone metastases and hypercalcemia of

malignancy. Zoledronic acid is also approved for the treatment of postmenopausal

osteoporosis.

The aim is for treatment to be taken correctly and regularly for a minimum of 5 years in

the first instance and for the patient to remain calcium and vitamin D replete during this

time

The bisphosphonates decrease osteoclastic bone resorption via several mechanisms,

including 1) inhibition of the osteoclastic proton pump necessary for dissolution of

hydroxyapatite, 2) decrease in osteoclastic formation/activation, 3) increase in

osteoclastic apoptosis (programmed cell death), and 4) inhibition of the cholesterol

biosynthetic pathway important for osteoclast function. The relative importance of the

mechanisms may differ among the individual bisphosphonates.

The decrease in osteoclastic bone resorption results in a small but significant net gain in

bone mass in osteoporotic patients, because the bone-forming osteoblasts are not

inhibited. The beneficial effects of alendronate persist over several years of therapy, but

discontinuation results in a gradual loss of its effects. Bisphosphonates are preferred

agents for the prevention and treatment of postmenopausal osteoporosis.

Pharmacokinetics:

Alendronate, risedronate, and ibandronate are orally active agents for osteoporosis,

although less than one percent of the administered dose is absorbed. Alendronate and

risedronate may be dosed once daily or once weekly, whereas ibandronate is

administered once monthly. Food significantly interferes with absorption.

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Bisphosphonates should be administered with 6 to 8 ounces of plain water at least 30

minutes (60 minutes for ibandronate) before eating breakfast or taking other

medications. The bisphosphonates are rapidly cleared from the plasma, primarily because

they avidly bind to the hydroxyapatite mineral of bone. Once bound to bone, they are

cleared over a period of hours to years. the bisphosphonates should not be given to

individuals with severe renal impairment. Intravenous ibandronate is administered once

every 3 months, and zoledronic acid is administered once yearly.

Adverse effects:

These include diarrhea, abdominal pain, and musculoskeletal pain. Alendronate and

ibandronate are associated with esophagitis and esophageal ulcers. To minimize the risk

of esophageal irritation, patients should remain upright for at least 30 minutes (60

minutes for ibandronate) after taking a bisphosphonate. Etidronate is the only member of

the class that causes osteomalacia following long-term administration.

Selective estrogen-receptor modulators

. Estrogen replacement is an effective therapy for the prevention of postmenopausal bone

loss. When initiated in the immediate postmenopausal period. [Note: Estrogen-

progestogen therapy is no longer the therapy of choice for the treatment of osteoporosis

in postmenopausal women because of increased risk of breast cancer, stroke, venous

thromboembolism, and coronary disease.].

Raloxifene is a selective estrogen-receptor modulator approved for the prevention and

treatment of osteoporosis. It increases bone density without increasing the risk of

endometrial cancer. In addition, raloxifene may reduce the risk of invasive breast cancer.

Raloxifene is a first-line alternative for postmenopausal osteoporosis in women who are

intolerant to bisphosphonates. The risk of venous thromboembolism appears to be

comparable to that with estrogen. Other adverse effects include hot flashes and leg

cramps

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Calcitonin

Calcitonin (also known as thyrocalcitonin) is a hormone that is produced in humans

primarily by C-cells of the thyroid. calcitonin lowers blood Ca2+ levels in four ways:

Inhibits Ca2+ absorption by the intestines, Inhibits osteoclast activity in bones, Stimulates

osteoblastic activity in bones and Inhibits renal tubular cell reabsorption of Ca2+ allowing

it to be excreted in the urine

Salmon calcitonin, administered intranasally, is effective and well tolerated in the

treatment of postmenopausal osteoporosis. A unique property of calcitonin is the relief of

pain associated with osteoporotic fracture. Therefore, calcitonin may be beneficial in

patients who have recently suffered a vertebral fracture. Side effects from nose sprays

may include runny nose or nosebleeds. Calcitonin is considered a second or third line of

treatment for patients unable to tolerate bisphosphonates.

Teriparatide

Teriparatide is identical to a portion of human parathyroid hormone (PTH) and

intermittent use activates osteoblasts more than osteoclasts, which leads to an overall

increase in bone. Parathyroid hormone given continuously leads to dissolution of bone,

but when it is given subcutaneously once daily, bone formation is the predominant effect.

Teriparatide has been associated with an increased risk of osteosarcoma in rats.

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Drugs Used to Treat Obesity

Two classes of drugs are used in treating obesity: the anorexiants (appetite suppressants)

phentermine, diethylpropion, and sibutramine, and a lipase inhibitor, orlistat.

Phentermine and diethylpropion are indicated for short-term management of obesity.

Sibutramine and orlistat have been approved for up to 2 and 4 years of use, respectively.

Phentermine, diethylpropion, and sibutramine

Phentermine exerts its pharmacologic action by increasing release of norepinephrine and

dopamine from the nerve terminals and by inhibiting reuptake of these

neurotransmitters, thereby increasing levels of neurotransmitters in the brain.

Diethylpropion has similar effects on norepinephrine. Sibutramine inhibits central

reuptake of serotonin, norepinephrine, and to a lesser extent, dopamine. Unlike the other

agents, sibutramine does not cause the release of neurotransmitters.

Pharmacokinetics: phentermine and Diethylpropion is excreted via the kidney.

Diethylpropion undergoes extensive first-pass metabolism. Many of the metabolites are

active. The half-life of the metabolites is 4 to 8 hours. Sibutramine undergoes first-pass

demethylation to active metabolites, which are primarily responsible for its

pharmacologic effects. The half-life of the active metabolites is about 15 hours.

Adverse effects and contraindications: All of the appetite suppressants are Schedule IV

controlled agents due to potential for dependence or abuse. Dry mouth, headache,

insomnia, and constipation are common problems. Heart rate and blood pressure may be

increased with these agents, and they should be avoided in patients with a history of

hypertension, CVD, arrhythmias, congestive heart failure, or stroke. Concomitant use of

appetite suppressants and monoamine oxidase inhibitors should be avoided. Sibutramine

should also be avoided in patients who are taking selective serotonin inhibitors such as

fluoxetine, serotonin agonists for migraine such as sumatriptan. Drug interactions can

occur when sibutramine is administered with drugs that inhibit CYP3A4, such as

ketoconazole, erythromycin, and cimetidine.

Orlistat

Orlistat is the first drug in a class of antiobesity drugs known as lipase inhibitors. Orlistat

is a pentanoic acid ester that inhibits gastric and pancreatic lipases, thus decreasing the

breakdown of dietary fat into smaller molecules that can be absorbed. Fat absorption is

decreased by about 30 percent. Orlistat is administered three times daily with meals. The

most common adverse effects associated with orlistat are gastrointestinal symptoms,

such as oily spotting, flatulence with discharge and fecal urgency. It interferes with the

absorption of fat-soluble vitamins and -β carotene. The vitamin supplement should not be

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taken within 2 hours of orlistat. Orlistat is contraindicated in patients with chronic

malabsorption syndrome or cholestasis.

Drugs Employed in the Treatment of Gout

Gout is a metabolic disorder characterized by high levels of uric acid in the blood.

Hyperuricemia can lead to deposition of sodium urate crystals in tissues, especially the

joints and kidney. Hyperuricemia does not always lead to gout, but gout is always

preceded by hyperuricemia. In humans, sodium urate is the end product of purine

metabolism.The deposition of urate crystals initiates an inflammatory process involving

the infiltration of granulocytes that phagocytize the urate crystals . This process generates

oxygen metabolites, which damage tissues, resulting in the release of lysosomal enzymes

that evoke an inflammatory response. The cause of hyperuricemia is an overproduction of

uric acid relative to the patient's ability to excrete it. Most therapeutic strategies for gout

involve lowering the uric acid level below the saturation point (<6 mg/dL), thus

preventing the deposition of urate crystals.

This can be accomplished by

1) interfering with uric acid synthesis with allopurinol,

2) increasing uric acid excretion with probenecid or sulfinpyrazone,

3) inhibiting leukocyte entry into the affected joint with colchicine, or

4) administration of NSAIDs.

acute gout

Acute gouty attacks can result from a number of conditions, including excessive alcohol

consumption, a diet rich in purines, or kidney disease. Acute attacks are treated with

indomethacin to decrease movement of granulocytes into the affected area; NSAIDs other

than indomethacin are also effective at decreasing pain and inflammation. [Note: Aspirin

is contraindicated, because it competes with uric acid for the organic acid secretion

mechanism in the proximal tubule of the kidney.]. and then reduced over the next few

days. Intra-articular administration of glucocorticoids (when only one or two joints are

affected) is also appropriate in the acute setting.

B. chronic gout

Chronic gout can be caused by 1) a genetic defect, such as one resulting in an increase in

the rate of purine synthesis; 2) renal deficiency; 3) Lesch-Nyhan syndrome or 4)

excessive production of uric acid associated with cancer chemotherapy. Treatment

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strategies for chronic gout include the use of uricosuric drugs that increase the excretion

of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol,

which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid.

Colchicine

Colchicine , a plant alkaloid, has been used for the treatment of acute gouty attacks as well

as chronic gout. It is neither a uricosuric nor an analgesic agent, although it relieves pain

in acute attacks of gout. Colchicine does have a suppressive, prophylactic effect that

reduces the frequency of acute attacks and relieves pain.

Mechanism of action: Colchicine binds to tubulin, a microtubular protein, causing its

depolymerization. Availability of tubulin is essential to mitosis Therefore colchicine

blocks cell division by binding to mitotic spindles.

Also disrupts cellular functions, such as the mobility of granulocytes, thus decreasing

their migration into the affected area. Furthermore, Colchicine also inhibits the synthesis

and release of the leukotrienes . leading to a net anti-inflammatory effect. This has proven

useful in the treatment of acute gout flares.

Therapeutic uses: The anti-inflammatory activity of colchicine is specific for gout,

usually alleviating the pain of acute gout within 12 hours. (Note: Colchicine must be

administered within 24 to 48 hours of onset of attack to be effective).

Adverse effects: Colchicine treatment may cause nausea, vomiting, abdominal pain, and

diarrhea. Chronic administration may lead to myopathy, neutropenia, aplastic anemia,

and alopecia. The drug should not be used in pregnancy. The fatal dose has been reported

as low as 7 to 10 mg.

Allopurinol

Allopurinol is a purine analog. It reduces the production of uric acid by competitively

inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine

oxidase . [Note: Uric acid is less water soluble than its precursors. When xanthine oxidase

is inhibited, the circulating purine derivatives (xanthine and hypoxanthine) are more

soluble and, therefore, are less likely to precipitate.]

Therapeutic uses: Allopurinol is effective in the treatment of primary

hyperuricemia of gout and hyperuricemia secondary to other conditions, such as

that associated with certain malignancies or in renal disease.

Pharmacokinetics: Allopurinol is completely absorbed after oral administration.

The primary metabolite is alloxanthine (oxypurinol), which is also a xanthine

oxidase inhibitor with a half-life of 15 to 18 hours; the half-life of allopurinol is 2

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hours. Thus, effective inhibition of xanthine oxidase can be maintained with once-

daily dosage.

Adverse effects: Hypersensitivity reactions, especially skin rashes, are the most common

adverse reactions, occurring in approximately 3% of patients. The reactions may occur

even after months or years of chronic administration. Acute attacks of gout may occur

more frequently during the first several weeks of therapy; therefore, colchicine or NSAIDs

should be administered concurrently. Allopurinol interferes with the metabolism of the

anticancer agent 6-mercaptopurine and the immunosuppressant azathioprine, requiring

a reduction in dosage of these drugs.

Uricosuric agents: Probenecid and sulfinpyrazone

The uricosuric drugs are weak organic acids that promote renal clearance of uric acid by

inhibiting the urate-anion exchanger in the proximal tubule that mediates urate

reabsorption. Probenecid blocks the tubular secretion of penicillin and is sometimes used

to increase levels of the antibiotic. It also inhibits excretion of naproxen, ketoprofen, and

indomethacin.