NSAIDs, Gout, and Osteoporosis Drugs

Question 1

What is the primary side effect of NSAIDs and why?

Answer 1

Gastrointestinal bleeding / peptic ulcers - Nonselective NSAIDs will block COX-1 activity and thus stop the production of prostaglandins which are needed to stimulate secretion of protective mucus and increased mucosal blood flow in the stomach.

Question 2

What drug greatly increases your risk of NSAID induced ulcers? What drug can be given to prevent this complication?

Answer 2

Corticosteroids - block arachidonic acid metabolism entirely. Anticoagulants also increase bleeding risk.

Complications can be prevented by giving with proton pump inhibitors to prevent stomach acid from ripping thru the stomach.

Question 3

Why are COX-2 inhibitors potentially preferred, and why are they not actually preferred?

Answer 3

Preferable because they do not block COX-1 and thus are less upsetting to the GI tract.

Not actually preferred because increased AA flux through the COX-1 pathway increases the synthesis of TXA2 which leads to increased cardiovascular risk (exactly what aspirin is trying to block)

Question 4

In what demographic of patients does taking NSAIDs precipitate renal failure and why?

Answer 4

Prostaglandins are needed to maintain the patency of the afferent arteriole

Particularly important in patients with heart failure, cirrhosis, chronic kidney disease, and hypovolemia who have decreased renal perfusion.

NSAIDs can lead to edema / fluid retention (stop the effectiveness of diuretics by decreasing RBF)

Question 5

What NSAIDs can be used in acute gout? Can aspirin be used?

Answer 5

Ibuprofen, naproxen should be used first line. Indomethacin is okay but is worse tolerated

Aspirin cannot be used because it needs too high of a dose for effective pain relief. It is only used low-dose as an anti-platelet agent.

Question 6

What is colchicine’s mechanism of action? Does it affect serum uric acid levels? What is the dosing regimen in acute gout?

Answer 6

Decreases leukocyte motility and phagocytosis by binding microtubules.

Does not affect serum uric acid level

Give 2 doses at first sign of flair, and repeat in 1 hour. Best if done earlier.

Question 7

What are the possible side effects of colchicine?

Answer 7

1. Bone marrow suppression
2. Neuropathy and myopathy
3. Diarrhea - if taken repeatedly like old regimen

Question 8

What are the dose adjustment considerations which should be made with colchicine?

Answer 8

Decrease dose in severe renal impairment, and don’t give with CYP3A4 inhibitors
-> metabolized by P-glycoprotein system of kidney and CYP3A4

Question 9

What other drug can be used in acute gouty attack other than colchicine and NSAIDs?

Answer 9

Corticosteroids -> systemic or intra-articular

Question 10

What patients require gouty prophylaxis? What is the goal uric acid level? Should you treat asymptomatic hyperuricemia?

Answer 10

Patients with >2 gouty attacks per year
Tophi or joint damage seen on radiography
Severe attacks or polyarticular attacks
Urate nephropathy / interstitial nephritis or nephrolithiasis

Goal is <6 mg/dL. Do not treat if asymptomatic

Question 11

Give the three broad classes of drugs used in gout prophylaxis and an example of each.

Answer 11

1. Xanthine oxidase inhibitors - allopurinol / febuxostat
2. Uricosurics - i.e. probenecid
3. Colchicine

Question 12

What should be done when starting allopurinol? What are the possible side effects?

Answer 12

Do not start during acute attack, and give colchicine prophylaxis for the first 6-12 months.

Side effects include GI upset and rash. Start low to prevent rash which can become Allopurinol hypersensitivity syndrome (AHS): progression to SJS or DRESS syndrome.

Question 13

What is one benefit febuxostat may have over allopurinol? Why is it not often used?

Answer 13

Febuxostat does not require dose adjustment for mild to moderate renal impairment (allopurinol does)

Not often used because it may be cardiotoxic and is also more expensive

Question 14

How long is colchicine prophylaxis generally continued, and what is the drug interaction of worry?

Answer 14

Generally 6 months until urate level is dropped by a XO inhibitor, or until tophi disappear.

Interaction of worry: statins, especially in renal disease -> neuromyopathy is common

Question 15

What is probenecid’s role in gout therapy? Where else is it used clinically?

Answer 15

Generally used second line as an adjunctive agent to xanthine oxidase inhibitors for patients who were unable to get uric acid levels <6 mg/dL.

Also used clinically to increase serum levels of penicillin and cidofovir by inhibiting their excretion

Question 16

What are the contraindications to probenecid?

Answer 16

1. Impaired renal function: CrCl<50 mL/min
2. History of renal calculi or nephrolithiasis -> will increase uric acid excretion thru urine and precipitate stones
3. Overproducers of uric acid causing gout -> stones are likely

Question 17

Is pegloticase effective? Why is it not given first line?

Answer 17

Very effective -> reduction in uric acid of up to 90% of patients who have failed other treatment.

It is costly, may cause anaphylaxis and infusion related reactions, and its treatment duration is not well studied

Question 18

What should be given before giving pegloticase, and what is the one definite contraindication?

Answer 18

Give corticosteroids and antihistamines to prevent infusion reaction

Contraindication: G6PD deficiency -> precipitates hemolytic anemia

Question 19

What is the primary indication for rasburicase? Contraindication?

Answer 19

Hyperuricemia in tumor lysis syndrome

Contraindication: G6PD deficiency.

Question 20

How should patients be getting their calcium everyday?

Answer 20

Give calcium as calcium carbonate, separate the doses by several hours to increase absorption. Older people need even extra calcium to prevent PTH release and bone mineral density loss.

Calcium from foods is technically safer but like we take what we can get.

Question 21

What is the definition of vitamin D deficiency and when should it be given?

Answer 21

Vitamin 25-D3 deficiency at <20 ng/day. Need to give IV vitamin D if less than this. Treat with daily vitamin D3 until at 30 ng/day

Question 22

What is the mechanism of action of bisphosphonates? How should they be taken?

Answer 22

Reduce osteoclast activity by mimicking pyrophosphate and interfering with farnesyl pyrophosphate synthase.

They should be taken without food and with 8 oz of plain water only. Do not ingest other foods for at least 60 minutes (poorly absorbed) and must sit upright after taking (otherwise GI damage may occur).

Question 23

What are the side effects of bisphosphonates?

Answer 23

Dyspepsia, acid reflux, esophagitis

Can cause bone pain atypical fractures such as fractures of the femur

Question 24

What is the contraindication of bisphosphonates and what could be used instead in this case?

Answer 24

Contraindicated in renal insufficiency (<35 ml/min)

Can use denosumab instead

Question 25

What are the risk factors for osteonecrosis of the jaw due to bisphosphonates and how can it be prevented?

Answer 25

Chemotherapy, corticosteroid use, and poor oral hygiene

Preventative dentistry and dental work should be done prior to starting the medication -> that way you don’t have the issue of needing proper bone turnover when using a bisphosphonate

Question 26

How long do bisphosphonates continue working after you stop using them? How long should you continue taking them?

Answer 26

Several years -> they have high affinity for bone tissue

Studies have shown no increased risk for nonvertebral fractures several years after stopping.

Generally: stop taking after 5 years unless a high risk patient (i.e. past vertebral fractures)

Question 27

What is the use for calcitonin and what are its side effects?

Answer 27

Side effects: rhinitis, epistaxis, and flu-like symptoms since given as a nasal spray

There is no use for calcitonin now because it increases risk of malignancy

Question 28

How is teriparatide given and who is it used in?

Answer 28

Given as a once daily subQ injection

used in those with h/o fracture, high risk of fracture, or failed previous osteoporosis therapy

Stimulates osteoblasts if you give PTH in bursts.

Question 29

Who should teriparatide be avoided in and how long can it be used?

Answer 29

Avoid in patients with Paget disease

Increased risk of osteosarcoma due to increased osteoblast activity -> limit therapy to 2 years

Question 30

What is raloxifene’s mechanism of action? Why other side benefit does this make?

Answer 30

SERM which is an estrogen agonist in bone but antagonist in breast and uterus

This also makes it pretty good at preventing breast cancer

Question 31

What is the primary indication for raloxifene? What are the side effects?

Answer 31

Best in those who are intolerant to bisphosphonate

Side effects include hot flashes (vasomotor symptoms), and increased risk of thromboembolic disease (since an estrogen agonist)

Question 32

What are the contraindications for raloxifene?

Answer 32

1. Acute or previous thromboembolism

2. Prolonged immobilization (bed rest increases risk of thrombosis, and therapy should be stopped).

Question 33

What is the mechanism and therapeutic role of denosumab? What patients should it be used with caution in?

Answer 33

Useful for those with renal impairment who cannot take bisphosphonates. Inhibits osteoclast formation by binding RANKL on osteoblasts.

Should be used with caution in patients with hypocalcemia -> osteoclasts will be suppressed, can’t raise Ca+2 levels

Question 34

What are the side effects of denosumab?

Answer 34

Same as bisphosphonates. Suppression of bone turnover predisposes to osteonecrosis of the jaw. Also some dermatologic reactions