MSK - Drugs for Arthritic Disorders Flashcards
What does SY|SA|D|OA stand for?
Symptomatic SLOW-acting Drug for Osteoarthritis
Name an evidence-based SYS ADOA for osteoarthritis
Intra-articular hyaluronic acid
Briefly explain the mechanisms of action of intra-articular hyaluronic acid
● Hyaluronic acid (HA) is a large glycosaminglycan (naturally in synovial fluid)
● Shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain & stiffness
● Induces biosynthesis of endogenous HA & extracellular matrix
List TWO supplements commonly used for osteoarthritis for which there is limited medical evidence
Chondroitin sulphate and glucosamine
Name the 4 compartments and 3 things of immune cell reponses
Compartments:
Innate immunity:
(1) Complement
(2) Phagocytes
Adaptive immunity:
(3) B cells
(4) T cells
3 things immune cells do when activated:
(1) Proliferate
(2) Cytokine production
(3) Trafficking and adhesion
List anti-inflammatory drugs used to control acute gouty attacks
- Nonselective NSAIDs (e.g., naproxen, indometacin)
- COX‐2 selective NSAIDs (e.g., celecoxib)
- Glucocorticoids (e.g., prednisolone)
- Colchicine
List TWO classes of drug used to reduce uric acid levels
- Xanthine Oxidase Inhibitors
= cannot produce uric acid (aka. Uric acid synthesis inhibitors)
- Purine analogue = allopurino
- Non-purine analogue = febuxostat
- Uricosuric agents
= inhibit anion transport at proximal tubule
= inhibit uric acid reabsorption at proximal tubule
= increase uric acid excretion
- probenecid
- sulfinpyrazone
Briefly explain the mechanisms of action of colchicine
- Binds to tubulin
- Prevent tubulin polymerization into microtubules
- Inhibits leukocyte migration and phagocytosis
- Inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production
- Relieves pain and inflammation of acute gouty attack within 24-36 hours
What is the dose-limiting adverse effect of colchicine?
(aka. what happens if you take too much colchicine)
Diarrhoea and GIT disturbance.
At higher doses, binding tubulin and preventing microtubule polymerization prevents cell proliferation. As cells of the GIT walls are rapidly proliferating, diarrhoea and GIT disturbance is usually the first adverse effect seen. The colchicine dose must be titrated to control the acute gouty attack without causing intolerable diarrhoea.
List adverse effects of colchicine
diarrhoea, nausea & vomiting, abdominal pain,
muscle weakness (myalgia)
unusual bleeding, pale lips
change in urine amount
List THREE risk factors for allopurinol causing severe cutaneous adverse reaction [M2 CA2 ALREADY TESTED]
- Renal impairment
- HLA‐B*58:01 genotype
- Thiazide therapy
What measures can be taken to reduce the risk of kidney stones when probenicid is prescribed
Precautions:
● Plenty of fluid to minimize renal stone formation
● Administer alkalina potassium citrate = keep urine pH >6.0
Which drugs should not be started during an acute gouty attack? [TESTED ALREADY]
- Uricosuric agents
- Uric acid synthesis inhibitors
● Reduction of plasma urate levels can increase mobilisation ftom joints and hence recognition and attack by immjne cells - Uricosuric agents
● Use during acute attack when increased urate is mobilised to plasma and excreted pushes more urate out into urine and increases risk of kidney stones
What can be done to reduce the risk of precipitating acute gouty attack when starting uric acid synthesis inhibitors or uricosuric agents? [M2 CA2 TESTED ALREADY]
Combine with low dose NSAID or colchicine
What is the first-line csDMARD?
Methotrexate
List FOUR examples of csDMARDs
Methotrexate (first-line)
Sulfasalazine Leflunomide Hydroxychloroquine (best tolerated) Ciclosporin
Name a tsDMARD
Tofacitinib or any other jakinib DMARD
List THREE examples of bDMARDs
Anti‐TNF mAb (e.g., infliximab, adalimumab, etanercept)
IL‐1R antagonist (e.g., anakinra)
Anti-IL‐6 receptor mAb (e.g., tocilizumab)
Anti‐CTLA4Ig (e.g., abatacept)
Anti‐CD20 (e.g., rituximab)
Briefly explain the mechanisms of action of methotrexate
● Major Action: Increased adenosine levels due to ATIC inhibition
● Minor Action: Inhibits dihydrofolate reductase and thymidylate synthetase
● Overall Effects: Increase in extracellular adenosine level and activation of adenosine A2a receptor
● Anti‐proliferative effects on T cells and inhibition of macrophage functions
● Decrease in pro‐inflammatory cytokines, adhesion molecules, chemotaxis and phagocytosis
How can methotrexate-induced nausea/vomiting, mouth and GI uclers, and hair-thinning be reduced?
Concomitant folic acid (high dose) or folinic acid given 12‐24hr after methotrexate decreases toxicity
List adverse effects and cautions for jakinibs in the treatment of rheumatoid arthritis
● Cytopenia including neutrophils, lymphocytes, platelets and natural killer cells
● Immunosuppression resulting opportunistic infections [increased risk of herpes zoster infection (especially in Asian population)]
● Anaemia (affects JAK2 activitation by erythropoietin)
● Hyperlipidaemia: increases in total, LDL and HDL cholesterol and trigylcerides
● Do NOT combine with biological DMARDs
Name an example of a TNF signalling blocking bDMARD
● Mabs against TNF:
Infliximab, adalimumab, golimumab
● Decoy TNFR2 receptor‐IgG1 fusion protein intercepts TNF:
etanercept
Name an example of a bDMARD blocking IL-1 signalling
Anakinra - Modified version of human interleukin-1 receptor antagonist protein.
Name an example of a bDMARD blocking IL-6 signalling
Tocilizumab - mab against IL-6 receptor
Explain why toc ilizumab has drug-drug interactions with drugs undergoing hepatic metabolism
Like most mabs, tocilizumab is cleared by proteolytic metabolism.
But interacts with CYP450 34A, 1A2 or 2C9 substrates
IL-6 decreases expression of these CYP450 enzymes, so tocilizumab blocking IL-6 signalling increases expression
