Musculoskeletal pharm Flashcards
Hydroxychloroquinine
Blocks TLR on APC
Ustekinumab
Human monoclonal antibody against IL-12 and IL-23
- Prevents Th1 cell formation
- Used in Psoriatic arthritis
Tocilizumab
Monoclonal antibody against IL-6 receptor on T-cells
- Prevents Th17 formation
- Used in RA
Infliximab, etanercept
Monoclonal antibody against TNF-alpha
Infliximab= used in RA, AS (Ankylosing spondylitis), PsA (Psoriatic arthritis)
Etanercept= used in RA, AS treatment
Adalimumab
Antibody against TNF-alpha
- Used in RA, AS
Belimumab
Anti-BLyS antibody
- used in SLE
Bisphosphonates
Mechanism of action is inhibition of osteoclast
Approved for prevention and treatment of osteoporosis
Oral forms: Alendronate, Risendronate, Ibandronate
- *Poorly absorbed and may cause esophagitis
- Daily, weekly, and monthly forms
Intravenous forms: Ibandronate and Zoledronic acid
SERMs
Raloxifene is approved for prevention and treatment of osteoporosis
Increases risk of thrombosis and fatal stroke but lowers risk of breast cancer
Increases BMD and reduces vertebral fracture but reduction is thought to not be as pronounced as those with bisphosphonates
- No direct comparison has been made
- Additive therapy does not provide much increased benefit given possible risks
Calcitonin
Binds to osteoclasts and prevents bone resorption
Available in subcutaneous, intramuscular, or intranasal formulations
Has small effect on BMD and low antifracture efficacy in comparison to bisphosphonates
Not used as first line treatment for osteoporosis
May have a role in treatment of bone pain following a fracture
PTH analogues
Teriparatide: Only PTH analogue available
- Used as subcutaneous daily injection
- Is the only anabolic therapy for osteoporosis
- Approved for prevention and treatment
Possible utility as combination therapy…
Should be used cautiously in patients with an increased risk of osteosarcoma, renal stones, gout, and renal failure
Check calcium, phosphorus, 25 hydroxy-vitamin D, alkaline phosphatase, uric acid, urine calcium prior to inititiation of medication
Denosumab
Humanized monoclonal antibody to RANK-L
Subcutaneous injection every six months
Approved in June 2010 for treatment of osteoporosis
Mediates osteoclast bone resorption
Rapid and significant increases in BMD and fracture risk reduction
Serious adverse events may be increased with Denosumab
Methotrexate
MOA: inhibits AICAR transformylase, thymidylate synthetase
- Enhances adenosine release–> antiinflammatory
- Folic acid inhibited (supplement during tx)
PK: 70% absorbed orally
- Polyglutaminiated
- Excreted in urine, bile
- 2-4 weeks to reach steady state
- 2.5-20 mg/ week; can also be given parenterally
Adverse reactions:
- GI (Nausea, mucosal ulcerations, liver enzyme elevations)
- RARE: Cirrhosis, hypersensitivity, pseudolymphomatous reaction (widespread lymph node enlargement)
Antimalarials for RA
Chloroquine
- Dose below 4 mg/kg
Hydroxychloroquine (safer, fewer side effects)
- Dose below 6.5 mg/kg
MOA: unclear
- Suppresses T-lymph response
- Decrease leukocyte chemotaxis
- Stabilize lysosomal membranes
- Inhibits DNA/RNA synthesis
- Traps free radicals in cell
PK:
- Rapidly absorbed
- 3-4 months to reach steady state
- 50% secreted unchanged in urine
- High tissue concentrations: mononucelar cells, pigmented tissue (eye), lysosomes
AEs:
- Frequent: GI, rashes
- Infrequent: retinal, neuromuscular
Sulfasalazine
Linkage of sulfapyridine, 5-aminosalicylic acid
- 30% absorbed in gut
MOA: suppresses lymphocyte/leukocyte functions
- Inhibits AICAR transformylase (like methotrexate); increases adenosine release
- Reduces activation of NF-kB (thus reducing expression of pro-inflammatory genes)
AEs:
- GI
- Sulfa allergies
RA: Combination therapy before biologics
Methotrexate + SSZ + HCQ
- (could use azathioprine, cyclosporine, leflunomide- RARE)
TNF-alpha inhibitors for RA
Adalimumab
Certolizumab- safer in pregnancy (no cytolytic activity
Etanercept- no cytolytic activity (not used in IBD)
Golimumab
Infliximab
Toclizumab
IL-6 receptor antibody (cytokine inhibitor)
- IL-6: increased neutrophil recruitment–> increased inflammation in joints
PK:
t1/2= 14-18 days
Must be dosed by weight, administered by physician/technician
Anakinra
IL-1 receptor antagonist (cytokine inhibitor)
Rituximab
CD20 monoclonal antibody (cell-depleting agent)–> B-cell destruction
- Used as salvage after all others failed
- Blocks all stages in B-cell lineage
- Can lead to decrease in Ig due to lack of plasma cell development
Dosing: infusions (2) given several months apart
- Not used on regular basis due to loss of Ig
Abatacept
Fusion protein of IgG1 (Fc portion) fused to CTLA-4 (extracellular)
- binds to CD80, CD 86
- Blocks APC co-stimulation of Native T-cell
- Used in RA
Decreases T-cell clonal expansion (naive) and T-cell activation)
Reduces signs, symptoms of RA
- Patient who have had inadequate response to 1+ DMARDS
- Used after TNF-alpha failure
- DO NOT use multiple biologics (can cause severe infections)
PK: weight-based dosing
Complications of biologics
Infections:
- Serious, opportunistic
- Malignancies (lymphoma)
Others:
- Demyelination
- Hematologic abnormalities
- Administration reactions
- CHF
- Autoantibodies, Lupus-like syndrome
Uncommon, need proper follow-up
- Liver damage: increased CRP, hepcidin
- Increased atherogeneisis (vessels)
- Increased insulin resistance in muscle
- Bone fracture (low BMD)
Tofacitinib
JAK-inhibitor (works like IL-6 receptor blocker)
- Main STAT activated in RA synovium= STAT3 (JAK1)
PK: Rapidly effective (weeks)
- 40% bound to albumen
- Renal and hepatic clearance
AEs:
- Lipid, LFT abnormalities; neutropenia
- Infections
- Malignancy
NSAIDs for acute gout attack
- Stabilize PMN lysosomal membrane (prevent spillage of contents into synovial fluid)
- Block prostaglandin synthesis
** Use if 12+ hours lapsed since symptom onset
Colchicine
- Stabilizes lysosomal membranes
- Inhibits chemotaxis of PMN (don’t move to areas of inflammation)
- Use within first 12 hours
- 0.6 mg hourly for relief on until diarrhea starts
AEs: 80% get GI toxicity
- Bone marrow depression (7 days)
- Neuromyopathy, elevated CK
- CV toxicity, arrhythmia, shock
- Liver toxicity
Allopurinol
Xanthine Oxidase Inhibitor (purine analog)
- Urate overproducers, CKD patients
Dosage: needs high dose to be efficacious
- Titrate up to 800 mg/day
- Average dose needed= 400 mg/day
- Take down dosage with elevated creatinine
- Failure often due to inadequate dosing
AEs:
Common: GI, Headache
Rare: Steven’s Johnson Syndrome (rare)- STOP if there’s a pruritic rash, eosinophilia (rashes seen in ~2%)
- Major allopurinol hypersensitivity syndrome: 0.1% with 25% mortality
** Screen for risk factors: recent initiation, renal impairment, thiazide diuretic therapies, HLA-B58
Gout flares in first 6 months: use colchicine, NSAIDs (measurement of efficacy of drug)
Febuxostat
Xanthine Oxidase inhibitor NOT purine analog - Selective - Inhibits xanthine oxidase - t1/2= 5-8 hours - 49% absorptions
Dosing:
- 40 mg/day (80-120 more potent than 300 mg allopurinol)
AEs:
- LFT
- Nausea
- Arthralgia
- Rash
- Cardiovascular thromboembolic events
- NO Steven’s Johnson
- Can be used in mild/mod renal dysfunction
Drug interactions:
- Theophylline (altered metabolism), antacids (delay absorptions), azathioprine, 6-mercaptopurine (lower dose if using Febuxostat)
Gout flares in first 6 months: use colchicine, NSAIDs (measurement of efficacy of drug)
Probenicid
Uricosuric agent (for under-excretors)
Used for Underexcretors with GFR > 50ml/min, no stone history
Dose:
- 500 mg/day; slowly increase to < 1 g/day
AEs:
Rash, nausea, urate renal stones
Limitations:
- Acidotic urine–> urolithiasis
- Contraindicated with urine uric acid > 700 mg
- Ineffective with CrCl < 50-60
- Needs bid dosing
- Drug interactions!
Goal for antihyperuricemic therapy
Serum urate t go away)
- Reduce frequency of attacks
- Reduce tophus size
- Deplete crystal stores in synovial fluid
- Improved renal function, reduction of NSAID use
- Lifelong urate-lowering therapy needed to sustain benefits
- Turn off spigot (block uric acid formation)
- Flush uric acid
- Biologic approach: directly degrade urate using uricases
Pegloticase
Pegylated uricase: severe, treatment-refractory gout treatment
- Decreased immunogenicity, increased t1/2
Works rapidly (debulk tophi)
Limitations:
- Frequent gout flares
- Infusion reactions (worsened by urate-lowering drugs)
- Antibodies formed against drug
- CV events
- Very expensive
