NSAIDs Flashcards
What are the 2 classes of NSAIDs?
- Non-selective COX inhibitors (target COX-1&2 but preference for COX-2)
- COX-2 selective inhibitors
- How do NSAIDs work
- What are COX-1 and COX-2 enzymes responsible for?
- NSAIDs inhibit prostaglandin synthesis by reversibly inhibiting cyclooxygenase (COX) enzymes.
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COX-1
* COX-1 produces prostaglandins that help to maintain gastric mucosal integrity and platelet-initiated blood clotting.
- COX-1 is present in most tissues.
- Inhibition of COX-1 is thought to be responsible for gastrointestinal toxicity.
COX-2
* COX-2 produces prostaglandins that mediate pain and inflammation.
* COX-2 is usually undetected in tissues and is produced in response to inflammatory cytokines.
* Inhibition of COX-2 is thought to be responsible for the anti-inflammatory action of NSAIDs.
What are examples of non-selective COX inhibitors and COX-2 inhibitors?
- Non-selective inhibitors - ibuprofen, indometacin, mefenamic acid, and naproxen. Diclofenac, etodolac, meloxicam, and nabumetone
- COX-2 inhibitors (the ‘coxibs’) – Celecoxib and etoricoxib
What are contraindications for NSAIDs?
- Active GI bleeding or ulcer
- Recurrent GI ulceration or haemorrhage (2 or more episodes)
- History of GI bleeding or perforation with NSAIDs
- Allergy or hypersensitivity to NSAIDs (e.g. asthma, rhinitis, urticaria or angioedema)
- Severe HF
- Severe renal impairment (eGFR<30)
- Severe hepatic impairment (albumin <25g/L or child-Pugh score of 10 or more)
What are additional C/I for:
- COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (>2400mg):
- Etoricoxib or high dose ibuprofen:
- COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (>2400mg):
* * IHD
* * IBD (COX-2 only)
* * Peripheral arterial disease
* * Cerebrovascular disease
* * CHF (II-IV)
2.Etoricoxib or high dose ibuprofen:
* * Uncontrolled HTN (persistently above 140/90)
What are cautions for NSAID usage
- History of peptic ulceration (non-selective contraindicated)
- Allergic disorders
- Cardiac impairment or HF – NSAIDs may impair renal function
- Cerebrovascular disease
- Coagulation disorders
- HTN – NSAIDs may impair RF
- IBD-NSAIDS may increase risk/cause exacerbations of UC or Crohn’s
- IHD
- PAD
- Risk factors for CV events (e.g. HTN, hyperlipidaemia, diabetes mellitus, smoking)
- Hepatic impairment – dose reductions may be necessary
- Renal impairment (avoid if possible) – sodium and water retention may occur leading to a deterioration in RF
Also prescribe in caution in:
* Women trying to conceive — NSAIDs may impair female fertility.
* The elderly — increased risk of cardiovascular, renal, and serious GI adverse effects (including GI bleeding and perforation, which may be fatal).
What are Adverse effects of NSAIDs?
GI Complications
Dyspepsia and other upper gastrointestinal (GI) complications are the most common adverse effects of NSAIDs — for example, ulcer, perforation, obstruction or bleeding.
Cardiovascular & Renal Complications
NSAID adverse effects — for example, myocardial infarction, stroke, cardiac failure, hypertension, and renal failure.
All NSAID use is associated with a small increased risk of thrombotic events independent of baseline cardiovascular risk factors or duration of NSAID use. However, the greatest risk may be in those receiving high doses long-term.
Other Complications
* * Prolonged bleeding (for example, after surgery) as a result of inhibition of platelet aggregation.
* * Bronchospasm — NSAIDs may exacerbate or precipitate asthma. Stop the NSAID if it is suspected to have precipitated bronchospasm.
* * Severe skin reactions and angioedema (for example, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) — stop the NSAID if these occur.
* * Anastomotic leakage. [ABPI, 2019]
* * ‘Kounis syndrome’ (allergic acute coronary syndrome). [ABPI, 2019]
* * Very rarely, NSAIDs can precipitate severe hepatic reactions (such as hepatitis, liver necrosis, or hepatic failure).
* If there are symptoms or signs of liver damage (for example, nausea, vomiting, abdominal pain, and jaundice), or persistently abnormal liver enzymes, stop the NSAID.
What are risk factors for GI adverse effects?
- Aged over 65 years.
- A high dose of an NSAID.
- A history of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation.
- Concomitant use of medications that are known to increase the likelihood of upper GI adverse events (for example, anticoagulants, corticosteroids, selective serotonin reuptake inhibitors [SSRIs]).
- A serious comorbidity, such as cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension.
- Heavy smoking.
- Excessive alcohol consumption.
- Previous adverse reaction to NSAIDs.
- Prolonged requirement for NSAIDs.
Additional risk factors for NSAID-induced GI adverse events include:
* The type of NSAID used.
* The presence of Helicobacter pylori infection.
- What are the categories of GI risk?
- What criteria needs to be filled to complete these?
- What action should be taken when prescribing NSAIDs for each of these risk categories?
- High risk if they have a history of previously complicated ulcer, or multiple (more than two) risk factors.
- Moderate risk if they have 1–2 risk factors.
- Low risk if they have no risk factors.
Managment:
How is GI risk associated with NSAID use managed?
- Avoid prescribing more than one NSAID at a time
- Avoid concomitant use of NSAID with low dose aspirin where possible - if essential monitor closely
- Use short-acting NSAID (e.g.ibuprofen) compared to long-acting (e.g. naproxen)
- Consider an alternative analgesic if appropriate
- For elderly patients co-prescribe PPI
- For OA and RA - co prescribe PPI
**High risk of GI adverse events — **prescribe a COX-2 selective NSAID (for example, etoricoxib, or celecoxib) instead of a standard NSAID, and co-prescribe a PPI.
Moderate risk of GI adverse events — prescribe a COX-2 inhibitor alone, or an NSAID plus a PPI.
Low risk of GI events — prescribe a non-selective NSAID.
What are risk factors for CV events associated with NSAID usage?
Inhibition of COX-2 leads to suppression of prostacyclin (which normally protects endothelial cells, produces vasodilation and interacts with platelets to antagonize aggregation).
Inhibition of COX-1 inhibits conversion of arachidonic acid to thromboxane A2 (a potent platelet aggregator and vasoconstrictor).
Selective COX-2 inhibition presents a CV risk, as it shifts the prothrombotic/antithrombotic balance and favours thrombosis.
How do NSAIDs relate to Renal complications?
NSAIDs inhibit prostaglandins PGE2 and PGI2 synthesis which may result in sodium retention, reduced renal blood flow, and renal failure
What are risk factors for CV and renal events associated with NSAID usage?
- Cerebrovascular disease.
- Heart failure.
- Ischaemic heart disease.
- Peripheral arterial disease.
- Renal impairment.
- People with risk factors for cardiovascular disease (for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking) and all elderly people (aged 65 years or over) are also at increased risk.
How do you manage CV risk associated with NSAID use?
For people with heart failure:
* Severe heart failure — do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs).
- Mild to moderate heart failure — do not prescribe a COX-2 inhibitor, diclofenac, or high-dose ibuprofen (2400 mg or more daily). Prescribe a standard NSAID and monitor the person closely.
Ibuprofen up to 1200 mg daily, or naproxen up to 1000 mg daily are first-line options.
For people with ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease, prescribe:
Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily are first-line options.
COX-2 inhibitors, diclofenac, and high-dose ibuprofen are contraindicated.
For people with risk factors for cardiovascular (CV) disease or the elderly, prescribe:
Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily.
Diclofenac should only be initiated after careful consideration of the associated risks in people with risk factors for CV disease.
For people with hypertension:
Avoid prescribing etoricoxib or high-dose ibuprofen in people with uncontrolled hypertension (blood pressure persistently above 140/90 mmHg).
Consider whether monitoring is needed.
How do you manage the risk of renal adverse events with NSAIDs?
For people with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute/1.73 m2):
Ideally, avoid prescribing NSAIDs.
If an NSAID is used, monitor the person closely.
