L21 - Drugs for the management of gout and osteoporosis Flashcards
Pathogenesis of Gout?
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
What are the 2 approaches for management of gout?
Urate lowering therapy for CHRONIC GOUT
Decrease inflammation during gouty attack to manage ACUTE gout
List the three ways to lower urate levels in plasma?
Decrease formation of urate
Decrease reabsorption or urate in PCT to increase excretion
Conversion of urate to soluble allantoin
List 2 drugs that can decrease formation of urate?
Allopurinol (common, pro-drug)
Febuxostat (rarer, for intolerance to allopurionol)
List 2 drugs that can increase excretion of urate?
Uricosuric agent:
Probenecid
Benzbromarone
List 2 drugs that can iconvert urate to soluble allantoin?
Uricolytic agents
Rasburicase
Pegloticase
MoA of allopurinol/ febuxostat?
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
When is febuxostat used?
Treatment of gout if allopurinol is not tolerated
Explain what renal pathology can arise from the use of allopurinol?
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
Explain how allopurinol can cause Gout flare?
Dissolution of urate crystals from tissue deposits
> > Drastic increase in serum urate concentration
> > Gouty flare
How is gouty flare caused by allopurinol use managed?
avoided by anti-inflammatory therapy e.g. give NSAIDs along allopurinol
Over time excess plasma urate is eliminated
List side effects of Allopurinol?
- hypersensitivity reactions; risk of Stevens-Johnson syndrome [normally limited to first 2 months of therapy]
- drowsiness, malaise and myalgia
Contraindication of Allopurinol?
- contraindicated in nursing mothers and children [except those with malignancy or genetic defects of purine metabolism]
- doses reduced in patients with renal impairment
List adverse effects of febuxostat?
- liver function abnormalities
- nausea, joint pain, rash
- increased incidence of myocardial infarction and stroke
- Need liver function and cardiovascular monitoring*
MoA of probenecid/ benzbromarone (Uricosuric agents)?
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
Adverse effects of uricosuric agents?
- 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]
Contraindication and precautions of uricosuric agents?
- avoided in patients with nephrolithiasis, with overproduction of uric acid, or with renal insufficiency [except benzbromarone]
- cautious in patients with peptic ulcer
- Drug interactions
What are the drug interactions of probenecid/ benzbromarone?
- Uricosuric effect reduced by salicylates (NSAID)
- Inhibit urate - anion exchange systme = increase plasma concentration of anions (e.g. penicillin, glucuronide metabolites of NSAIDs)
MoA of rasburicase/ pegloticase?
= recombinant Urate Oxidase
catalyze the oxidation of the poorly soluble uric acid to the more soluble metabolite (allantoin)
> > decrease plasma level of uric acid
What is the composition of rasburicase and pegloticase? Which one has more adverse effects?
Rasburicase = recombinant mammalian urate oxidase
Pegloticase = recombinant mammalian urate oxidase attached to methoxy polyethylene glycol:
Pegloticase has:
- prolonged t1/2
- LOWER IMMUNE RESPONSE
Adverse effects of Uricolytic agents (Rasburicase and Pegloticase)?
- Gout flare
- Risk of methemoglobinemia (rasburicase)
- Severe allergic reaction from injection and infusion reaction
Contraindication and precautions of uricolytic agents?
- Avoided in patients with G6PD deficiency»_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
List the drugs used for management of Acute gout?
- Colchicine
- NSAIDs (except Salicylate - reaction with Uricosuric agents)
- Glucocorticoids
- IL-1 antagonist (not approved)
MoA of Colchicine?
1) Inhibit tubulin polymerization into microtubules > Inhibit leukocyte migration and phagocytosis
2) Inhibit formation of leukotriene B4 > Reduce phagocytosis of urate
Adverse effects of Colchicine?
- 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
What is the dose recommendation of Colchicine?
Acute relief = 1.2mg followed by 0.6mh after 1 hour
Prophylaxis= 0.6mg, 1-3 times daily
Contraindication of Colchicine?
Dose reduced or less frequent therapy in patients with hepatic or renal disease
What is the most common NSAID used for gout?
Indomethacin
MoA of Indomethacin?
COX - inhibitor
inhibition of prostanoid production and inhibition of urate phagocytosis
Which NSAID must not be used with certain urate lowering drugs?
Salicylate cannot be used with uricosuric agents
> > compete with urate for organic acid secretory system in proximal tubule
> > inhibits uric acid excretion
Which Glucocorticoid is commonly used for urate lowering treatment?
Prednisolone
Which anti-inflammatory drug is preferred for treatment of gout?
Glucocorticoids over NSAIDs
NSAIDs induce renal impairment
Contraindication and precautions of Prednisolone?
Glucocorticoid:
Dose tapering needed
cautions in patients with diabetes and after surgery
> > due to increased blood glucose and immunosuppressive side effects
Describe the effect of salicylate dose on uric acid excretion? Why is it not recommended?
Low dose = decrease uric acid excretion
Intermediate dose = no change
Large dose = Increase uric acid excretion but great adverse effect»_space; Sudden reduction in plasma uric acid = severe gout flare
What is the regimen for management of acute gouty attack?
e.g. colchicine, NSAIDs (not salicylates), glucocorticoids
What is the regimen for prevention of acute gouty attack?
Allopurinol + NSAID
Colchicine (prophylaxis dose 0.6mg)
Define osteoporosis?
condition of low bone mass and microarchitectural disruption
Increased risk of fracture
What are some measures to alleviate osteoporosis?
- regular weight-bearing and muscle-strengthening exercise of reasonable intensity
- adequate dietary calcium and vitamin D
- avoid smoking and excessive alcohol
What is osteoporosis commonly associated with?
Commonly associated with menopausal estrogen loss and aging
List some dietary supplements to treat osteoporosis?
- Calcium
- Vitamin D and analogs (cholecalciferol Vit. D3, Calcitriol)
- Calcitonin
MoA of calcium supplements?
suppress bone remodeling
Increase bone mineral density
MoA of Vit. D and analogs?
- improve intestinal calcium absorption, suppress parathyroid function
» suppress bone remodeling and increase bone mineral density
Adverse effect of Vit D and Calcium intake for osteoporosis?
Calcium: more than 2000mg = constipation
Vit. D = risk of hypercalcemia and hypercalciuria
MoA of Calcitonin?
Acts on receptors on osteoclasts
> Inhibit motility and induces retraction
» Inhibit bone resorption to increase bone mineral density
What is Calcitonin?
A hormone produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland
List all the drugs available for treatment of osteoporosis?
- Calcium, Vit. D and Calcitonin
- Estrogen + Progestin
- Selective Estradiol Receptor Modulators (SERMs)
- Bisphosphates/ pyrophosphate analogs
- Parathyroid hormone-related protein (PTHrP)
- Denosumab
- Romosozumab
MoA of Estrogen + Progestin for osteoporosis?
- Act on estrogen receptors on bone > Increase BMD after menopause
Adverse effects and risks of Estrogen + Progestin?
- RIsk of breast cancer and heart disease
- Limited to osteoporosis prevention in women with significant ongoing vasomotor symptoms NOT at cardiovascular disease risk
Name one SERM and its MoA?
Raloxifene (alternative to hormone replacement therapy without risk of breast cancer)
Estrogen agonist on bone > Increase BMD
Risks of SERMs?
Worsen postmenopausal vasomotor symptoms
List 3 Bisphosphates for osteoporosis?
Alendronate
Risedronate
Ibandronate
All pyrophosphate analogs, most frequently used drugs for the prevention and treatment of osteoporosis
MoA of Bisphosphate for osteoporosis?
Antiresorptive or anticatabolic agents:
Pyrophosphate analogs bind to bone matrix
> > Increase osteoclast apoptosis + Inhibit osteoclast function
> > Increase BMD
Describe the Pharmacokinetics of Bisphosphate?
Poorly absorbed from intestine, limited bioavailability
Need IV preparation or taken after overnight fast
Adverse effects of Bisphosphate?
GI disturbances (contraindicated in patients with upper GI disease)
Prolonged intake = osteonecrosis of jaw, atypical femoral fractures
Precautions of Bisphosphate?
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
What is the structure and MoA of Denosumab?
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
Adverse effects of Denosumab?
hypocalcemia, allergic reactions, infections, jaw bone osteonecrosis
Contraindications of Denosumab?
Contraindicated if pregnant / plan to become pregnant
Children/ fetus
Low blood calcium
List 2 examples of PTHrP analogs?
teriparatide, abaloparatide
MoA of PTHrP analogs?
Subcutaneous injection
Low PTH levels = permissive effect, activate parathyroid hormone receptors in bone»_space; stimulate Osteoblasts»_space; increase bone formation
LOW PTH effect not HIGH PTH*
Anabolic effect , NOT anti-resorptive
Adverse effects of PTHrP analogs?
- injection-site pain, headache, nausea, leg cramps and dizziness, palpitation
- BLACK BOX WARNING = RISK OF OSTEOSARCOMA (due to increased bone formation)
When is PTHrP given?
should be used in patients refractory to bisphosphonates or at serious risk of fracture
Contraindications of PTHrP analogs?
- children with open epiphyses
- patients with bone metastases ****
- individuals with prior skeletal/ Bone radiation *****
- individuals with elevation of the alkaline phosphatase level
MoA of Romosozumab?
Human monoclonal antibody
> > binds to sclerostin (glycoprotein secreted by bone cells) to inhibit the action of sclerostin
> > Increase bone formation and decrease bone resorption
When is Romosozumab used?
osteoporosis in postmenopausal women with a high risk of bone fracture, and who are intolerant or irresponsive to other medications for osteoporosis
Subcutaneous
Adverse effects of Romosozumab?
- hypersensitivity reactions
- headache, insomnia and paresthesia
- hypocalcemia
- arthralgia, atypical femur fractures, osteonecrosis of the jaw
- cardiac disorder and peripheral oedema
Why is Romosozumab given a black box label warning?
Increase risk of myocardial infarction, stroke and cardiovascular death
NOT given to patients with a myocardial infarction or stroke within the previous year
