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MBBS II MSS > L21 - Drugs for the management of gout and osteoporosis > Flashcards

L21 - Drugs for the management of gout and osteoporosis Flashcards

1
Q

Pathogenesis of Gout?

A

metabolic disease:

Increased plasma concentration of urate

> > urate crystal deposits in synovial tissue of joints

> > acute inflammation in the joint

** Increased plasma concentration of urate might not necessary lead to gout/ be identified in gout

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2
Q

What are the 2 approaches for management of gout?

A

Urate lowering therapy for CHRONIC GOUT

Decrease inflammation during gouty attack to manage ACUTE gout

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3
Q

List the three ways to lower urate levels in plasma?

A

Decrease formation of urate

Decrease reabsorption or urate in PCT to increase excretion

Conversion of urate to soluble allantoin

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4
Q

List 2 drugs that can decrease formation of urate?

A

Allopurinol (common, pro-drug)

Febuxostat (rarer, for intolerance to allopurionol)

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5
Q

List 2 drugs that can increase excretion of urate?

A

Uricosuric agent:

Probenecid
Benzbromarone

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6
Q

List 2 drugs that can iconvert urate to soluble allantoin?

A

Uricolytic agents

Rasburicase
Pegloticase

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7
Q

MoA of allopurinol/ febuxostat?

A

Xanthine oxidase converts allopurinol to alloxanthene

> > alloxanthine non-competitively inhibits xanthine oxidase from converting hypoxanthine to
xanthine to uric acid

> > Decrease formation of uric acid, facilitates dissolution of urate crystals from tissues

> > mobilize urate from tissue deposits

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8
Q

When is febuxostat used?

A

Treatment of gout if allopurinol is not tolerated

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9
Q

Explain what renal pathology can arise from the use of allopurinol?

A

Increased Xanthine and Hypoxanthine concentration = form renal stones (Xanthine stones)

Avoided by increased water intake to increase urine volume (>2L/day) + give Potassium citrate to increase urine pH >6.0

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10
Q

Explain how allopurinol can cause Gout flare?

A

Dissolution of urate crystals from tissue deposits

> > Drastic increase in serum urate concentration

> > Gouty flare

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11
Q

How is gouty flare caused by allopurinol use managed?

A

avoided by anti-inflammatory therapy e.g. give NSAIDs along allopurinol

Over time excess plasma urate is eliminated

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12
Q

List side effects of Allopurinol?

A
  • hypersensitivity reactions; risk of Stevens-Johnson syndrome [normally limited to first 2 months of therapy]
  • drowsiness, malaise and myalgia
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13
Q

Contraindication of Allopurinol?

A
  • contraindicated in nursing mothers and children [except those with malignancy or genetic defects of purine metabolism]
  • doses reduced in patients with renal impairment
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14
Q

List adverse effects of febuxostat?

A
  • liver function abnormalities
  • nausea, joint pain, rash
  • increased incidence of myocardial infarction and stroke
  • Need liver function and cardiovascular monitoring*
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15
Q

MoA of probenecid/ benzbromarone (Uricosuric agents)?

A

Inhibit URAT-1 (organic anion transporter) in luminal side of renal proximal tubule

> > decrease reabsorption of uric acid

> > Increase excretion of uric acid

> > decrease plasma level of uric acid

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16
Q

Adverse effects of uricosuric agents?

A
  • Augment formation of urate renal stones
  • Gout flare
  • mild gastrointestinal irritation [risk increased with higher dosage]
  • overdose = fatal outcomes [CNS stimulation, convulsions and respiratory failure]
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17
Q

Contraindication and precautions of uricosuric agents?

A
  • avoided in patients with nephrolithiasis, with overproduction of uric acid, or with renal insufficiency [except benzbromarone]
  • cautious in patients with peptic ulcer
  • Drug interactions
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18
Q

What are the drug interactions of probenecid/ benzbromarone?

A
  • Uricosuric effect reduced by salicylates (NSAID)
  • Inhibit urate - anion exchange systme = increase plasma concentration of anions (e.g. penicillin, glucuronide metabolites of NSAIDs)
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19
Q

MoA of rasburicase/ pegloticase?

A

= recombinant Urate Oxidase

catalyze the oxidation of the poorly soluble uric acid to the more soluble metabolite (allantoin)

> > decrease plasma level of uric acid

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20
Q

What is the composition of rasburicase and pegloticase? Which one has more adverse effects?

A

Rasburicase = recombinant mammalian urate oxidase

Pegloticase = recombinant mammalian urate oxidase attached to methoxy polyethylene glycol:

Pegloticase has:

  • prolonged t1/2
  • LOWER IMMUNE RESPONSE
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21
Q

Adverse effects of Uricolytic agents (Rasburicase and Pegloticase)?

A
  • Gout flare
  • Risk of methemoglobinemia (rasburicase)
  • Severe allergic reaction from injection and infusion reaction
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22
Q

Contraindication and precautions of uricolytic agents?

A
  • Avoided in patients with G6PD deficiency&raquo_space; Hemolytic anemia because uricase formas hydrogen peroxide
  • Limited use for patients refractory to other urate lowering therapy
  • For patients with elevated plasma urate level due to anti-cancer therapy
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23
Q

List the drugs used for management of Acute gout?

A
  • Colchicine
  • NSAIDs (except Salicylate - reaction with Uricosuric agents)
  • Glucocorticoids
  • IL-1 antagonist (not approved)
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24
Q

MoA of Colchicine?

A

1) Inhibit tubulin polymerization into microtubules > Inhibit leukocyte migration and phagocytosis
2) Inhibit formation of leukotriene B4 > Reduce phagocytosis of urate

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25
Q

Adverse effects of Colchicine?

A
  • GI disturbance***Diarrhea, nausea, vomiting, abdominal pain
  • Myelosuppression*** (mainly with intravenous administration, not allowed now)
  • Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, seizures
  • Hair loss
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26
Q

What is the dose recommendation of Colchicine?

A

Acute relief = 1.2mg followed by 0.6mh after 1 hour

Prophylaxis= 0.6mg, 1-3 times daily

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27
Q

Contraindication of Colchicine?

A

Dose reduced or less frequent therapy in patients with hepatic or renal disease

28
Q

What is the most common NSAID used for gout?

A

Indomethacin

29
Q

MoA of Indomethacin?

A

COX - inhibitor

inhibition of prostanoid production and inhibition of urate phagocytosis

30
Q

Which NSAID must not be used with certain urate lowering drugs?

A

Salicylate cannot be used with uricosuric agents

> > compete with urate for organic acid secretory system in proximal tubule

> > inhibits uric acid excretion

31
Q

Which Glucocorticoid is commonly used for urate lowering treatment?

A

Prednisolone

32
Q

Which anti-inflammatory drug is preferred for treatment of gout?

A

Glucocorticoids over NSAIDs

NSAIDs induce renal impairment

33
Q

Contraindication and precautions of Prednisolone?

A

Glucocorticoid:

Dose tapering needed

cautions in patients with diabetes and after surgery

> > due to increased blood glucose and immunosuppressive side effects

34
Q

Describe the effect of salicylate dose on uric acid excretion? Why is it not recommended?

A

Low dose = decrease uric acid excretion

Intermediate dose = no change

Large dose = Increase uric acid excretion but great adverse effect&raquo_space; Sudden reduction in plasma uric acid = severe gout flare

35
Q

What is the regimen for management of acute gouty attack?

A

e.g. colchicine, NSAIDs (not salicylates), glucocorticoids

36
Q

What is the regimen for prevention of acute gouty attack?

A

Allopurinol + NSAID

Colchicine (prophylaxis dose 0.6mg)

37
Q

Define osteoporosis?

A

condition of low bone mass and microarchitectural disruption

Increased risk of fracture

38
Q

What are some measures to alleviate osteoporosis?

A
  • regular weight-bearing and muscle-strengthening exercise of reasonable intensity
  • adequate dietary calcium and vitamin D
  • avoid smoking and excessive alcohol
39
Q

What is osteoporosis commonly associated with?

A

Commonly associated with menopausal estrogen loss and aging

40
Q

List some dietary supplements to treat osteoporosis?

A
  • Calcium
  • Vitamin D and analogs (cholecalciferol Vit. D3, Calcitriol)
  • Calcitonin
41
Q

MoA of calcium supplements?

A

suppress bone remodeling

Increase bone mineral density

42
Q

MoA of Vit. D and analogs?

A
  • improve intestinal calcium absorption, suppress parathyroid function
    » suppress bone remodeling and increase bone mineral density
43
Q

Adverse effect of Vit D and Calcium intake for osteoporosis?

A

Calcium: more than 2000mg = constipation

Vit. D = risk of hypercalcemia and hypercalciuria

44
Q

MoA of Calcitonin?

A

Acts on receptors on osteoclasts
> Inhibit motility and induces retraction
» Inhibit bone resorption to increase bone mineral density

45
Q

What is Calcitonin?

A

A hormone produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland

46
Q

List all the drugs available for treatment of osteoporosis?

A
  • Calcium, Vit. D and Calcitonin
  • Estrogen + Progestin
  • Selective Estradiol Receptor Modulators (SERMs)
  • Bisphosphates/ pyrophosphate analogs
  • Parathyroid hormone-related protein (PTHrP)
  • Denosumab
  • Romosozumab
47
Q

MoA of Estrogen + Progestin for osteoporosis?

A
  • Act on estrogen receptors on bone > Increase BMD after menopause
48
Q

Adverse effects and risks of Estrogen + Progestin?

A
  • RIsk of breast cancer and heart disease
  • Limited to osteoporosis prevention in women with significant ongoing vasomotor symptoms NOT at cardiovascular disease risk
49
Q

Name one SERM and its MoA?

A

Raloxifene (alternative to hormone replacement therapy without risk of breast cancer)

Estrogen agonist on bone > Increase BMD

50
Q

Risks of SERMs?

A

Worsen postmenopausal vasomotor symptoms

51
Q

List 3 Bisphosphates for osteoporosis?

A

Alendronate
Risedronate
Ibandronate

All pyrophosphate analogs, most frequently used drugs for the prevention and treatment of osteoporosis

52
Q

MoA of Bisphosphate for osteoporosis?

A

Antiresorptive or anticatabolic agents:

Pyrophosphate analogs bind to bone matrix

> > Increase osteoclast apoptosis + Inhibit osteoclast function

> > Increase BMD

53
Q

Describe the Pharmacokinetics of Bisphosphate?

A

Poorly absorbed from intestine, limited bioavailability

Need IV preparation or taken after overnight fast

54
Q

Adverse effects of Bisphosphate?

A

GI disturbances (contraindicated in patients with upper GI disease)

Prolonged intake = osteonecrosis of jaw, atypical femoral fractures

55
Q

Precautions of Bisphosphate?

A

growing children and women of childbearing age
upper GI disease
renal insufficiency

supplements with calcium or intake of medication containing divalent cations, e.g. iron

56
Q

What is the structure and MoA of Denosumab?

A

Human monoclonal antibody subcutaneous injection

binds to “receptor for activating nuclear factor-kB ligand” (RANKL)

> > inhibit RANKL to bind to RANK on the surface of precursor and mature osteoclasts

> > block osteoclast formation and activation

> > antiresorptive effect

57
Q

Adverse effects of Denosumab?

A

hypocalcemia, allergic reactions, infections, jaw bone osteonecrosis

58
Q

Contraindications of Denosumab?

A

Contraindicated if pregnant / plan to become pregnant

Children/ fetus

Low blood calcium

59
Q

List 2 examples of PTHrP analogs?

A

teriparatide, abaloparatide

60
Q

MoA of PTHrP analogs?

A

Subcutaneous injection

Low PTH levels = permissive effect, activate parathyroid hormone receptors in bone&raquo_space; stimulate Osteoblasts&raquo_space; increase bone formation

LOW PTH effect not HIGH PTH*

Anabolic effect , NOT anti-resorptive

61
Q

Adverse effects of PTHrP analogs?

A
  • injection-site pain, headache, nausea, leg cramps and dizziness, palpitation
  • BLACK BOX WARNING = RISK OF OSTEOSARCOMA (due to increased bone formation)
62
Q

When is PTHrP given?

A

should be used in patients refractory to bisphosphonates or at serious risk of fracture

63
Q

Contraindications of PTHrP analogs?

A
  • children with open epiphyses
  • patients with bone metastases ****
  • individuals with prior skeletal/ Bone radiation *****
  • individuals with elevation of the alkaline phosphatase level
64
Q

MoA of Romosozumab?

A

Human monoclonal antibody

> > binds to sclerostin (glycoprotein secreted by bone cells) to inhibit the action of sclerostin

> > Increase bone formation and decrease bone resorption

65
Q

When is Romosozumab used?

A

osteoporosis in postmenopausal women with a high risk of bone fracture, and who are intolerant or irresponsive to other medications for osteoporosis

Subcutaneous

66
Q

Adverse effects of Romosozumab?

A
  • hypersensitivity reactions
  • headache, insomnia and paresthesia
  • hypocalcemia
  • arthralgia, atypical femur fractures, osteonecrosis of the jaw
  • cardiac disorder and peripheral oedema
67
Q

Why is Romosozumab given a black box label warning?

A

Increase risk of myocardial infarction, stroke and cardiovascular death

NOT given to patients with a myocardial infarction or stroke within the previous year

MBBS II MSS (31 decks)

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