MSS21 Drugs For The Management Of Gout And Osteoporosis Flashcards
Arthritis
- Degenerative: OA
- Inflammatory: Rheumatic diseases, Gout
Gout
- 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)
- ↓ inflammation during gouty attack (acute gout management)
—> Colchicine, NSAIDs, glucocorticoid
***Urate-lowering therapy
For LONG term management
- ↓ Uric acid formation
- Allopurinol, Febuxostat - ↓ Reabsorption of uric acid in ***proximal tubule –> ↑ excretion of uric acid
- Uricosuric agents e.g. Probenecid, Benzbromarone - Conversion of uric acid to soluble ***allantoin
- Uricolytic agents e.g. Rasburicase, Pegloticase - Anti-inflammatory (during initiation of therapy)
Xanthine oxidase inhibitor: Allopurinol, Febuxostat
MOA:
1. Allopurinol
—> purine analog
—> competitive inhibitor of xanthine oxidase
- 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)
Uricosuric agents: Probenecid, Benzbromarone
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
- 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 - Avoid in nephrolithiasis (***kidney stone) / overproduction of uric acid / renal insufficiency (except benzbromarone)
- Caution in peptic ulcer patient
Adverse effects:
- mild GI irritation (risk ↑ with higher dose)
- overdose –> fatal (CNS stimulation, convulsions, respiratory failure)
Uricolytic agents: Pegloticase, Rasburicase
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
***Management of acute gout
- Colchicine
- inhibit PMN —> specific action by ↓ inflammatory responses during phagocytosis of urate - Anti-inflammatory
- NSAID (NOT salicylate!!!)
- Glucocorticoid - IL-1 antagonist
- Anakinra
Colchicine
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
Anti-inflammatory
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
Osteoporosis
- 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
- Adequate dietary Ca, vitamin D
- Avoid smoking / excessive alcohol
Treatment aim:
- Restore bone strength
- Prevent fractures
***Therapies for osteoporosis
- Estrogen +/- Progestin
- act on estrogen receptors on bone –> ↑ BMD after menopause - Selective Estradiol Receptor Modulators (SERMs): Raloxifene
- estogen receptor agonist on bone –> ↑ BMD - Calcium
- suppress bone remodeling - Vitamin D and analogs: Cholecalciferol (vit D3), Calcitriol
- improve intestinal Ca absorption
- ↑ Reabsorption of Ca at distal tubule
- suppress PTH function - Calcitonin
- act on receptors on Osteoclasts
–> inhibit bone resorption - Bisphosphonates (pyrophosphate analogs): Alendronate, Risedronate, Ibandronate, Zoledronate (IV)
- bind to bone matrix
–> Inhibit Osteoclast function + ↑ Osteoclast apoptosis - Denosumab
–> bind to RANKL
–> Inhibit RANKL to bind to RANK on surface of osteoclast precursor and mature osteoclasts - Parathyroid hormone-related protein (PTHrP) analogs: Teriparatide, Abaloparatide
–> activate PTH receptors in bone (Intermittent activation!!!)
–> ↑ Bone formation
–> Anabolic effect
–> ↑ BMD - Romosozumab
–> binds to Sclerostin
–> Inhibit sclerostin action
–> ↑ new bone formation + ↓ bone resorption
Estrogen +/- Progestin
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)
Selective Estradiol Receptor Modulators (SERMs)
***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
Calcium
MOA:
- Suppress bone ***remodeling
–> ↑ BMD
- daily intake of ~1200mg for adults >50
- > = 2000mg: constipation
Vitamin D and analogs
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
Calcitonin
MOA:
- Act on receptors on ***Osteoclasts
–> inhibit bone resorption
–> ↑ BMD
Bisphosphonates (pyrophosphate analogs)
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
Denosumab
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
Parathyroid hormone-related protein (PTHrP) analogs
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)
Romosozumab
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
