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Flashcards in Musculoskeletal pharm Deck (29)
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1

Hydroxychloroquinine

Blocks TLR on APC

2

Ustekinumab

Human monoclonal antibody against IL-12 and IL-23
- Prevents Th1 cell formation
- Used in Psoriatic arthritis

3

Tocilizumab

Monoclonal antibody against IL-6 receptor on T-cells
- Prevents Th17 formation
- Used in RA

4

Infliximab, etanercept

Monoclonal antibody against TNF-alpha

Infliximab= used in RA, AS (Ankylosing spondylitis), PsA (Psoriatic arthritis)

Etanercept= used in RA, AS treatment

5

Adalimumab

Antibody against TNF-alpha
- Used in RA, AS

6

Belimumab

Anti-BLyS antibody
- used in SLE

7

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

8

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

9

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

10

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

11

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

12

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)

13

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

14

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

15

RA: Combination therapy before biologics

Methotrexate + SSZ + HCQ
- (could use azathioprine, cyclosporine, leflunomide- RARE)

16

TNF-alpha inhibitors for RA

Adalimumab
Certolizumab- safer in pregnancy (no cytolytic activity
Etanercept- no cytolytic activity (not used in IBD)
Golimumab
Infliximab

17

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

18

Anakinra

IL-1 receptor antagonist (cytokine inhibitor)

19

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

20

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

21

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)

22

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

23

NSAIDs for acute gout attack

1. Stabilize PMN lysosomal membrane (prevent spillage of contents into synovial fluid)
2. Block prostaglandin synthesis

** Use if 12+ hours lapsed since symptom onset

24

Colchicine

1. Stabilizes lysosomal membranes
2. 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

25

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)

26

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)

27

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!

28

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

1. Turn off spigot (block uric acid formation)
2. Flush uric acid
3. Biologic approach: directly degrade urate using uricases

29

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