Musculo-Skeletal

Question 1

NSAIDs: Mechanism and Indications

What is the mechanism and indications for NSAID use?

Answer 1

1. Mechanism: reduce prostaglanding production by inhibiting COX; vary in selectivity for COX → COX-2 selectivity improves GI tolerance, but does not decrease adverse effects
2. Indications:
   
   1. For single doses, comparable to paracetamol but paracetamol preferred on safety grounds (particularly in elderly)
   2. Useful for **continuous, regular pain **associated with inflammation → particularly useful in inflammatory arthritis

Question 2

NSAIDs: Options

Which are the commonly used NSAIDs?

Note: pain relief starts soon after dose, with full analgesic effect within 1 week. Anti-inflammatory effect not achieved for 3 weeks

Answer 2

1. Ibuprofen: propionic acid derivative anti-inflammatory, analgesic and antipyrectic. Lower GI and cardiovascular risk than non-selective NSAIDs, but less anti-inflammatory (therefore less suitable in inflammatory predominant conditions e.g. gout)
2. **Naproxen: **propionic acid derivative → combines good efficacy and low incidence of side effects; good first choice
3. Diclofenac: similar to naproxen but ↑CV risk. Combined with misoprostol (synthetic PGE1) → used in those at risk of GI ulceration
4. Indomethacin: superior pain relief to naproxen, ↑S/E (headache, dizzinesss, GI disturbance)

Question 3

COXIBs: Options

Which drugs act through selective inhibition of COX-2? What is the mechanism of aspirin?

Answer 3

1. COX-2 selective inhibitors celecoxib and etoricoxib: equally effective as non-selective inhibitors, may have ↓ serious UGI events, but reduced cardiovascular safety. Contraindicated in PVD, CVD, CAD and moderate / severe HF.
2. **Aspirin: **anti-inflammatory when used >3g/day, but other NSAID better tolerated - used in lower doses for antiplatelet effects. In high doses may cause toxicity:
   
   1. Dizziness, tinnitus, deafness
   2. Metabolic acidosis and respiratory alkalosis
   3. Pulmonary oedema

Question 4

NSAIDs: Cautions and Contraindications

In which situations should NSAIDs be used cautiously, and when are they contraindicated?

Answer 4

1. Cautions:
   
   1. Elderly
   2. Breast feeding and Pregnancy
   3. Coagulation defects
   4. Renal, cardiac, hepatic impairment → impair RF, therefore use with low dose monitoring renal function
2. Contraindications:
   
   1. Severe heart failure → increase Na and H20 retention
   2. ​Allergic disorders → contra-indicated if aspirin / NSAID hypersensitivity, including precipitation of asthma, angiooedema, urticaria or rhinitis

Question 5

NSAIDs: Cardiovascular Events

What are the cardiovascular risks associated with NSAID and COXIB use?

Answer 5

1. Non-selective NSAIDs: small ↑ risk of thrombotic events; best to use low doses of ibuprofen and naproxen over diclofenac where possible.
2. COXIBs: ↑ risk thrombosis (myocardial and stroke) → not used in preference of NSAIDs unless strongly indicated (e.g. after DU bleeding with reasonable cardiovascular risk profile)

Question 6

NSAIDs: Ulceration

What are the risks associated with NSAIDs in relation to gastro-intestinal bleeding

Answer 6

1. ↑ risk of ulceration, variable between individuals. Where-ever possible, NSAID should be withdrawn if ulcer occurs
2. High risk for ulceration:
   
   1. Age > 65
   2. Previous PUD / serious GI complication
   3. Concurrent medicines with ↑GI risk
   4. Serious comorbidity
3. Strategies for ↓ risk of peptic ulceration on NSAID:
   
   1. Add PPI
   2. Add H2RA → ranitidine, twice normal dose
   3. Add misoprostol (colic + diarrhoea more common)
   4. Switch to COXIB ± PPI

Question 7

NSAIDs: Adverse Effects

What are the adverse effects associated with NSAID use?

Answer 7

1. Common: GI discomfort, nausea, diarrhoea, occasionally bleeding and ulceration
2. Occasional:
   
   1. **Renal failure: **especially if renal impairment due to afferent arteriolar constriction
   2. **Fluid retention **rarely precipitating CCF
   3. Colitis
   4. ​Hypersensitivity → rash, angioedema, bronchospasm
   5. Headache, dizziness, nervousness, depression

Question 8

NSAIDs: interactions

What are the relevant interactions of NSAIDs?

Answer 8

1. **Anticoagulants → **may potentiate warfarin; NSAID induced GI bleeding more severe in warfarinised patients
2. ACEi, ARB, diuretics: risk of renal failure due to decreased flow (ACEi vasoconstrict efferent arteriole, NSAIDs vasoconstrict afferent)
3. ↓ renal flow → increased levels of renally excreted drugs; lithium toxicitiy particular hazard

Question 9

Gout

What are the management options in acute gout?

Note: no evidence exists to support one being more effective than any of the others

Answer 9

1. **NSAIDs → **Naproxen best choice; better anti-inflammatory than ibuprofen, but safer CV profile than diclofenac
2. Colchicine → may be used in patients with heart failure, asthma, or on anticoagulants where NSAIDs are contraindicated
3. **Corticosteroids → **given either intra-articular or systemic

Question 10

Colchicine

What is the mechanism, indications and adverse effects of colchicine? How is it dosed?

Answer 10

1. Mechanism: provides pain relief by binding tubulin dimers → prevents macrophage and leukocyte migration and phagocytosis, reducing inflammation and pain of gout
2. Indication: used in both acute gout, and during initial therapy with allopurinol and uricosuric drugs
3. Adverse effects:
   
   1. ​Common: nausea, vomiting, diarrhoea, abdominal pain. Profuse diarrhoea + GI haemorrhage in excessive doses
   2. Rare: peripheral neuropathy, myositis
4. **Dosing: **500micrograms, TDS, until symptoms relieved. Higher doses predictably cause GI s/e

Question 11

Recurrent and Chronic Gout

What are the NICE recommendations for patients with recurrent gout?

Note: prophylaxis not indicated for asymptomatic hyperuricaemia or isolated episodes

Answer 11

1. Start uric acid lowering drugs if second attack of uncomplicated gout, or further attacks in 1 year
2. Offer uric acid lowering to people with:
   
   1. Toephi
   2. Renal insufficiency
   3. Uric acid stones and gout
   4. Need to continue on diuretic therapy
3. Wait until 1 - 2 weeks after acute attack before initiating → precipitates attacks in acute phase
4. Use uricosuric agents (e.g. sulphinpyrazone) as second line in those resistant / intolerant to allopurinol
5. Co-prescribe colchicine for 6 months

Question 12

Allopurinol

What is the mechanism, indication, adverse effects and interations of allopurinol?

Answer 12

1. **Mechanism: **inhibits xanthine oxidase, catalysing breakdown of xanthine and hypoxanthine derived from purines to uric acid
2. Indications:
   
   1. Prophylaxis of gout, and uric acid and calcium oxoalate renal stones.
   2. Prophylaxis of hyperuricaemia associated with cancer chemotherapy
3. Adverse effects:
   
   1. ​Occasional: rash → withdraw treatment. May re-introduce cautiously if mild, but discontinue immediately if recurrence
   2. Rare: hypersensitivity and SJS, drug fever thrombocytopenia and leukopenia
4. Interactions:
   
   1. ​Renally excreted → reduce in renal failure
   2. ↑ levels of azathioprine; reduce dose to avoid toxicitiy

Question 13

Osteoarthritis: General Measures

What are the general / non-pharmacological measures taken in management of OA?

Answer 13

1. Application of heat or cold to site of pain
2. Transcutaneous electrical nerve stimulation (TENS)
3. Manipulation and stretching (particularly hip OA)
4. Assessment for bracing / joint support / insoles if biomechanical joint pain or instability
5. Assistive devices (e.g. walking sticks, tap turners)

Question 14

Osteoarthritis: Pharmacological Measures

What are the pharmacological options for patients with OA?

Note: generally older → higher risk from NSAIDs, and trial evidence has shown ≃ efficacy between NSAID and paracetamol, so paracetamol and topical NSAIDs preferred before oral

Answer 14

1. **Paracetamol **(regular dosing may be required)
2. Topical NSAIDs → particularly for hand or knee OA
3. Oral NSAIDs, COXIBs or opiates → third line, used **in addition **to paracetamol
4. Topical capsaicin may be used for knee / hand OA (applied to an area pre-treated with anaesthetic. Overwhelms nerves by calcium influx, preventing nociception for an extended period)
5. Intra-articular corticosteroids may be used for moderate / severe pain

Question 15

Hydroxychloroquine

For hydroxychloroquine, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 15

1. Toxic effects: macular degeneration, ↓ visual acuity
2. Baseline evaluation: None, unless > 40 or previous eye problems
3. Clinical / Lab follow up: visual acuity and fundoscopy yearly

Note: usually used as add on DMARD → limited efficacy as single agent

Question 16

Sulfasalazine

For sulfasalazine, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 16

1. Toxic effects: oligospermia, neutropenia, myelosuppression
2. Baseline evaluation: FBC
3. **Clinical / Lab follow up: **caution of fever or bruising. Perform FBC

Question 17

Methotrexate

For methotrexate, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 17

1. Toxic effects: Myelosuppression, hepatic fibrosis, pneumonitis
2. Baseline evaluation: FBC, CXR, LFTs, creatinine
3. Clinical / Lab follow up: check for mouth ulcers and respiratory symptoms. Follow up with FBC and LFTs

Folic acid antagonist → prescribe with folic acid 5mg weekly. Contraindicated in pregnancy, liver disease and alcohol use. Reduce dose in renal disease (renally excreted)

Question 18

​Leflunomide

For leflunomide, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 18

1. Toxic effects: hair loss, myelosuppression, hepatic fibrosis
2. Baseline evaluation: FBCs, LFTs
3. Clinical / Lab follow up: FBCs and LFTs

Note long half life. Pregnancy contraindicated, and alcohol intake should be limited.

Question 19

Azathioprine

For azathioprine, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 19

1. Toxic effects: myelosuppression
2. Baseline evaluation: FBC, LFT, creatinine
3. Clinical / Lab follow up: caution of fever or bruising. Perform FBC

Less effective as single agent → often used as part of combination therapy

Question 20

Cyclosporine

For cyclosporine, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 20

1. Toxic effects: renal failure, anaemia, HTN, hyperkalaemia
2. Baseline evaluation: FBC, U&Es, creatinine, BP
3. Clinical / Lab follow up: check for oedema and HTN, follow up with FBC and creatinine

Question 21

Penicillamine

For penicillamine, what are the:

1. Toxic effects
2. Baseline evaluation
3. Clinical and laboratory follow up

Answer 21

1. Toxic effects: proteinuria, myelosuppression, rashes, loss of taste, lupus like syndrome
2. Baseline evaluation: FBC, creatinine, dipstick urine for protein
3. Clinical / Lab follow up: caution of fever or bruising. Perform FBC, creatinine and dipstick.

Poorly tolerated, therefore used infrequently

Question 22

Anti-TNFα

For anti-TNFα, what are:

1. Examples
2. Toxic effects
3. Baseline evaluation
4. Clinical and laboratory follow up

Answer 22

1. Examples: etanercept, infliximab, adalimumab
2. Toxic effects: infection, particularly reactivation of TB
3. Baseline evaluation: screen for previous TB → CXR
4. Clinical / Lab follow up: check for symptoms of infection, CHF, or demyelination.

Discontinue during severe infections. Relatively contra-indicated if recurrent sepsis, history of demyelinating disease, or severed CHF.