MSK - Drugs for Arthritic Disorders

Question 1

What does SY|SA|D|OA stand for?

Answer 1

Symptomatic SLOW-acting Drug for Osteoarthritis

Question 2

Name an evidence-based SYS ADOA for osteoarthritis

Answer 2

Intra-articular hyaluronic acid

Question 3

Briefly explain the mechanisms of action of intra-articular hyaluronic acid

Answer 3

● 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

Question 4

List TWO supplements commonly used for osteoarthritis for which there is limited medical evidence

Answer 4

Chondroitin sulphate and glucosamine

Question 5

Name the 4 compartments and 3 things of immune cell reponses

Answer 5

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

Question 6

List anti-inflammatory drugs used to control acute gouty attacks

Answer 6

1. Nonselective NSAIDs (e.g., naproxen, indometacin)
2. COX‐2 selective NSAIDs (e.g., celecoxib)
3. Glucocorticoids (e.g., prednisolone)
4. Colchicine

Question 7

List TWO classes of drug used to reduce uric acid levels

Answer 7

1. Xanthine Oxidase Inhibitors
   = cannot produce uric acid (aka. Uric acid synthesis inhibitors)

• Purine analogue = allopurino
• Non-purine analogue = febuxostat

2. Uricosuric agents
   = inhibit anion transport at proximal tubule
   = inhibit uric acid reabsorption at proximal tubule
   = increase uric acid excretion

• probenecid
• sulfinpyrazone

Question 8

Briefly explain the mechanisms of action of colchicine

Answer 8

1. Binds to tubulin
2. Prevent tubulin polymerization into microtubules
3. Inhibits leukocyte migration and phagocytosis
4. Inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production
5. Relieves pain and inflammation of acute gouty attack within 24-36 hours

Question 9

What is the dose-limiting adverse effect of colchicine?
(aka. what happens if you take too much colchicine)

Answer 9

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.

Question 10

List adverse effects of colchicine

Answer 10

diarrhoea, nausea & vomiting, abdominal pain,

muscle weakness (myalgia)

unusual bleeding, pale lips

change in urine amount

Question 11

List THREE risk factors for allopurinol causing severe cutaneous adverse reaction [M2 CA2 ALREADY TESTED]

Answer 11

1. Renal impairment
2. HLA‐B*58:01 genotype
3. Thiazide therapy

Question 12

What measures can be taken to reduce the risk of kidney stones when probenicid is prescribed

Answer 12

Precautions:
● Plenty of fluid to minimize renal stone formation
● Administer alkalina potassium citrate = keep urine pH >6.0

Question 13

Which drugs should not be started during an acute gouty attack? [TESTED ALREADY]

Answer 13

1. Uricosuric agents
2. Uric acid synthesis inhibitors
   ● Reduction of plasma urate levels can increase mobilisation ftom joints and hence recognition and attack by immjne cells
3. 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

Question 14

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]

Answer 14

Combine with low dose NSAID or colchicine

Question 15

What is the first-line csDMARD?

Answer 15

Methotrexate

Question 16

List FOUR examples of csDMARDs

Answer 16

Methotrexate (first-line)
Sulfasalazine Leflunomide Hydroxychloroquine (best tolerated) Ciclosporin

Question 17

Name a tsDMARD

Answer 17

Tofacitinib or any other jakinib DMARD

Question 18

List THREE examples of bDMARDs

Answer 18

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)

Question 19

Briefly explain the mechanisms of action of methotrexate

Answer 19

● 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

Question 20

How can methotrexate-induced nausea/vomiting, mouth and GI uclers, and hair-thinning be reduced?

Answer 20

Concomitant folic acid (high dose) or folinic acid given 12‐24hr after methotrexate decreases toxicity

Question 21

List adverse effects and cautions for jakinibs in the treatment of rheumatoid arthritis

Answer 21

● 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

Question 22

Name an example of a TNF signalling blocking bDMARD

Answer 22

● Mabs against TNF:
Infliximab, adalimumab, golimumab
● Decoy TNFR2 receptor‐IgG1 fusion protein intercepts TNF:
etanercept

Question 23

Name an example of a bDMARD blocking IL-1 signalling

Answer 23

Anakinra - Modified version of human interleukin-1 receptor antagonist protein.

Question 24

Name an example of a bDMARD blocking IL-6 signalling

Answer 24

Tocilizumab - mab against IL-6 receptor

Question 25

Explain why toc ilizumab has drug-drug interactions with drugs undergoing hepatic metabolism

Answer 25

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