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MSS > MSS21 Drugs For The Management Of Gout And Osteoporosis > Flashcards

MSS21 Drugs For The Management Of Gout And Osteoporosis Flashcards

1
Q

Arthritis

A
  1. Degenerative: OA
  2. Inflammatory: Rheumatic diseases, Gout
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2
Q

Gout

A
  • Metabolic disease
    —> ↑ urate plasma conc
  • Deposition of urate crystal in synovial joints
    —> inflammation in the joint

Treatment aim:
1. Reduce uric acid plasma level (long term)
—> Allopurinol (1st line)

  1. ↓ inflammation during gouty attack (acute gout management)
    —> Colchicine, NSAIDs, glucocorticoid
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3
Q

***Urate-lowering therapy

A

For LONG term management

  1. ↓ Uric acid formation
    - Allopurinol, Febuxostat
  2. ↓ Reabsorption of uric acid in ***proximal tubule –> ↑ excretion of uric acid
    - Uricosuric agents e.g. Probenecid, Benzbromarone
  3. Conversion of uric acid to soluble ***allantoin
    - Uricolytic agents e.g. Rasburicase, Pegloticase
  4. Anti-inflammatory (during initiation of therapy)
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4
Q

Xanthine oxidase inhibitor: Allopurinol, Febuxostat

A

MOA:
1. Allopurinol
—> purine analog
—> competitive inhibitor of xanthine oxidase

  1. Alloxanthine (Allopurinol —> metabolized by xanthine oxidase —> Alloxanthine)
    —> non-competitive inhibitor of xanthine oxidase

Overall: Hypoxanthine —X—> Xanthine —X—> Uric acid

Complications:
- may augment formation of renal stone (***Xanthine stone)
—> avoided by:
↑ urine volume (maintain daily urine output > 2L)
↑ urine pH > 6.0

Precautions:
↓ uric acid plasma level
—> facilitates dissolution of urate crystals from tissues
—> mobilization of urate from tissue deposits (from one site to deposit into another site: gouty attack)
—> ***Gout flare
- avoided by anti-inflammatory
- risk reduced after reduction of excess tissue stores of uric acid

Adverse effects:
Allopurinol:
- hypersensitivity, risk of **SJS (first 2 months)
- drowsiness, malaise, myalgia
- **CI in nursing mothers, children (except with malignancy / genetic defects of purine metabolism)
- ↓ dose in renal impairment

Febuxostat:
- ***liver function abnormalities (periodic liver function monitor)
- nausea, joint pain, rash
- ↑ incidence of MI, stroke (monitor CVS complications)

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5
Q

Uricosuric agents: Probenecid, Benzbromarone

A

MOA:
- inhibit organic anion transporter (URAT-1) which reabsorb uric acid in ***proximal tubule
–> ↑ uric acid conc in urine
–> ↓ uric acid plasma level

Complications:
- may augment formation of renal stone (***Urate stone)
–> avoided by:
↑ urine volume (maintain daily urine output > 2L)
↑ urine pH > 6.0

Precautions:
1. Gout flare
- avoided by anti-inflammatory
- risk reduced after reduction of excess tissue stores of uric acid

  1. Drug interactions
    - inhibit secretion of organic anions (by inhibiting urate-anion exchange system)
    –> ↑ anion plasma conc (e.g. **methotrexate, penicillin, gluruconide metabolites of NSAID)
    - uricosuric effect reduced by **    salicylates
  2. Avoid in nephrolithiasis (***kidney stone) / overproduction of uric acid / renal insufficiency (except benzbromarone)
  3. Caution in peptic ulcer patient

Adverse effects:
- mild GI irritation (risk ↑ with higher dose)
- overdose –> fatal (CNS stimulation, convulsions, respiratory failure)

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6
Q

Uricolytic agents: Pegloticase, Rasburicase

A

MOA:
- catalyse **Oxidation of uric acid (poorly soluble) to **allantoin (more soluble metabolite)
–> ↓ uric acid plasma level
- Rasburicase: recombinant mammalian ***urate oxidase
- Pegloticase: recombinant mammalian urate oxidase covalently attached to methoxy polyethylene glycol –> ↑ half-life and ↓ immunogenic response

Precautions:
1. Gout flare
2. Avoid in **G6PD deficiency
–> haemolytic anaemia: Uricase –> formation of **H2O2 –> Oxidative stress
–> test for G6PD deficiency in African / Mediterranean ancestry
3. Risk of methaemoglobinemia (Rasburicase)

Adverse effects:
1. Severe allergic reactions (↑ risk with higher dose)
2. Infusion reactions (Pegloticase, associated with generation of anti-pegloticase Ab)

–> Limited usage: mainly for refractory patients to other urate-lowering therapy / patients with elevated uric acid level due to ***anti-cancer therapy

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7
Q

***Management of acute gout

A
  1. Colchicine
    - inhibit PMN —> specific action by ↓ inflammatory responses during phagocytosis of urate
  2. Anti-inflammatory
    - NSAID (NOT salicylate!!!)
    - Glucocorticoid
  3. IL-1 antagonist
    - Anakinra
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8
Q

Colchicine

A

Clinical applications:
- ↓ inflammation during gouty attack
- prophylaxis of gout flare with urate-lowering therapy

MOA:
**Reduce phagocytosis of urate
1. Inhibit **Tubulin polymerization into microtubules
—> inhibit leukocyte migration and phagocytosis
2. Inhibit ***Leukotriene B4 formation
—> ↓ inflammatory response

Adverse effects (**inhibit cell division in fast-growing cells: GI tract):
- **Diarrhoea
- **N+V, **abdominal pain
- Hepatic necrosis, acute renal failure, DIC
- Seizures
- Hair loss
- ***Bone marrow depression
—> IV not accepted now
—> Lower dose recommended:
Acute relief: 1.2mg followed by 0.6mg after an hour
Prophylaxis: 0.6mg OD-TDS
—> ↓ dose / less frequent in hepatic / renal disease

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9
Q

Anti-inflammatory

A

NSAID (NOT salicylate):
- Indomethacin (COX-1 selective)
1. ***inhibit prostanoid production
2. Inhibit urate phagocytosis (additional effect)

**Salicylate and uric acid excretion:
1. Dose dependent
–> compete with urate for organic acid secretory system in proximal tubule
–> low dose will ↓ uric acid excretion
–> **high dose will ↑ uric acid excretion (but also higher SE and potentially gout flare due to sudden ↓ plasma uric acid level)
2. ***inhibit Uricosuric agents

Glucocorticoid:
- **Prednisolone
–> **Preferred over NSAID in renal impairment
–> caution in DM / after surgery
–> dose tapering needed

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10
Q

Osteoporosis

A
  • Low bone mass, microarchitectural disruption
    –> risk of fracture
    –> esp. hip, spine, wrist
  • Commonly associated with menopausal estrogen loss and aging
    –> estrogen / HRT for postmenopausal osteoporosis

Measures to ↓ fracture risk:
1. Regular weight-bearing and muscle strengthening exercise of reasonable intensity

  1. Adequate dietary Ca, vitamin D
  2. Avoid smoking / excessive alcohol

Treatment aim:
- Restore bone strength
- Prevent fractures

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11
Q

***Therapies for osteoporosis

A
  1. Estrogen +/- Progestin
    - act on estrogen receptors on bone –> ↑ BMD after menopause
  2. Selective Estradiol Receptor Modulators (SERMs): Raloxifene
    - estogen receptor agonist on bone –> ↑ BMD
  3. Calcium
    - suppress bone remodeling
  4. Vitamin D and analogs: Cholecalciferol (vit D3), Calcitriol
    - improve intestinal Ca absorption
    - ↑ Reabsorption of Ca at distal tubule
    - suppress PTH function
  5. Calcitonin
    - act on receptors on Osteoclasts
    –> inhibit bone resorption
  6. Bisphosphonates (pyrophosphate analogs): Alendronate, Risedronate, Ibandronate, Zoledronate (IV)
    - bind to bone matrix
    –> Inhibit Osteoclast function + ↑ Osteoclast apoptosis
  7. Denosumab
    –> bind to RANKL
    –> Inhibit RANKL to bind to RANK on surface of osteoclast precursor and mature osteoclasts
  8. Parathyroid hormone-related protein (PTHrP) analogs: Teriparatide, Abaloparatide
    –> activate PTH receptors in bone (Intermittent activation!!!)
    –> ↑ Bone formation
    –> Anabolic effect
    –> ↑ BMD
  9. Romosozumab
    –> binds to Sclerostin
    –> Inhibit sclerostin action
    –> ↑ new bone formation + ↓ bone resorption
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12
Q

Estrogen +/- Progestin

A

MOA:
- Act on ***estrogen receptors on bone
–> ↑ bone mineral density (BMD) after menopause

Risk of **breast cancer, **heart diseases
–> ∴ limited to osteoporosis prevention in women with ***significant ongoing vasomotor symptoms who are not at increased risk for CVS disease
–> annual individualized risk-benefit reassessment

vasomotor symptoms: hot flash, flush, vaginal dryness etc. (associated with decreased estrogen during menopause)

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13
Q

Selective Estradiol Receptor Modulators (SERMs)

A

***Raloxifene

MOA:
- ***Estogen receptor agonist on bone
–> ↑ BMD

  • Alternative to HRT
    –> inactive on uterus and anti-estrogen on breast, however ***NOT effective in reducing risk of non-vertebral fractures
  • Worsen postmenopausal vasomotor symptoms
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14
Q

Calcium

A

MOA:
- Suppress bone ***remodeling
–> ↑ BMD

  • daily intake of ~1200mg for adults >50
  • > = 2000mg: constipation
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15
Q

Vitamin D and analogs

A

Cholecalciferol (vit D3), Calcitriol

MOA:
1. Improve **intestinal Ca absorption
2. ↑ **Reabsorption of Ca at distal tubule
3. Suppress ***PTH function
–> suppress bone remodeling
–> ↑ BMD

  • Risk of hypercalcemia, hypercalciuria
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16
Q

Calcitonin

A

MOA:
- Act on receptors on ***Osteoclasts
–> inhibit bone resorption
–> ↑ BMD

17
Q

Bisphosphonates (pyrophosphate analogs)

A

Alendronate, Risedronate, Ibandronate, Zoledronate (IV)
- ***Anti-resorptive / Anti-catabolic agents
- most frequently used drugs for prevention and treatment of osteoporosis

MOA:
***Bind to bone matrix (Ca: divalent cation)
1. Inhibit Osteoclast function
2. ↑ Osteoclast apoptosis
–> ↑ BMD

PK:
- poorly absorbed from intestine and limited bioavailability
–> with full glass of water following overnight fast and >= 30 mins before breakfast

Adverse effects:
- GI irritation
- **Osteonecrosis of jaw
- **Atypical femoral fractures

Precautions:
- CI in growing children and women of child-bearing age (not certain of long-term effects on growing skeleton)
- CI in upper GI disease
- patients on Ca supplement / intake of ***divalent cation medication e.g. Iron (bisphosphonates bind to divalent cation)
- renal insufficiency patient

FDA-issued safety alert
- ***accumulated by bone and released slowly
–> ↑ risk of atypical femoral fractures if taken for > 5 years
–> drug holiday

18
Q

Denosumab

A

MOA:
- Human monoclonal Ab
–> Bind to “receptor for activating nuclear factor-kB ligand” (RANKL)
–> Inhibit **RANKL to bind to RANK on surface of osteoclast precursor and mature osteoclasts
–> Block osteoclast **formation and activation
–> ***Anti-resorptive effect

(Mimic effect of Osteoprotegerin (OPG): OPG bind to RANKL to reduce RANKL binding to RANK
–> inhibit osteoclast differentiation)

(RANKL promotes osteoclast formation and subsequent resorption of bone matrix)

Administration:
- SC once every 6 months

Adverse effects:
- ***hypocalcemia
- allergic reactions
- infections
- osteonecrosis of jaw bone (<5%)

CI:
- low blood Ca
- pregnant / plan to pregnant

19
Q

Parathyroid hormone-related protein (PTHrP) analogs

A

Teriparatide, Abaloparatide

MOA:
- First part (1-34th a.a.) of Parathyroid hormone
–> **activate PTH receptors in bone (Intermittent activation!!!)
–> ↑ Bone formation
–> **Anabolic effect
–> ↑ BMD (very effective)

Administration:
- SC OD into thigh / abdomen

Adverse effects:
- injection site pain
- headache
- nausea
- leg cramps
- dizziness
- palpitation

Black box label warning:
- ↑ ***Osteosarcoma risk
–> therapy limited to < 2 years
–> used in refractory to bisphosphonates / serious risk of fracture

CI (high risk of osteosarcoma):
- children with open epiphyses
- bone metastases
- prior skeletal radiation
- elevation of alkaline phosphatase level (regulators of bone mineralisation: secreted by osteoblasts)

20
Q

Romosozumab

A

MOA:
- Human monoclonal Ab
–> binds to ***Sclerostin
–> Inhibit sclerostin action
–> ↑ new bone formation + ↓ bone resorption

(Sclerostin: anti-anabolic protein secreted by osteocytes in response to mechanical unloading / estrogen deficiency:
1. inhibit osteogenic differentiation of mesenchymal stem cells / osteoprogenitor cells + inhibit osteoblasts proliferation
2. stimulate RANKL secretion from osteocytes for osteoclasts formation
–> inhibit osteoblastic bone formation and enhance bone loss)

Indication:
- osteoporosis in postmenopausal women with high risk of fracture
- intolerant / irresponsive to other medication

Administration:
- SC once every month for 1 year

Adverse effects:
- hypersensitivity reactions
- headache, insomnia, paresthesia
- ***hypocalcemia
- arthralgia, atypical femur fractures, osteonecrosis of jaw
- cardiac disorder, peripheral edema

Black box label warning:
- ↑ ***MI, stroke and CVS death risk
–> NOT give to patients with MI / stroke within the previous year

MSS (32 decks)

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