Non-opioid analgesics Flashcards
Advantages of non-opioid analgesics
- Analgesic and antipyretic properties
- Wide availability
- Familiarity to patients
- Effectiveness for milder pain condictions
- Ease of administration
- Additive analgesia when combined with other analgesics
- Relatively low cost
Disadvantages of non-opioid analgesics
- Ceiling effect for pain relief
- Risk of side effects (especially GI, renal, and cardiovascular for NSAIDs and hepatotoxicity for acetominophen)
Prostaglandins
- Lipid soluble molecules produced by enzymatic breakdown of arachidonic acid
- Produced from cell-membrane phospholipids
- Produced as either mediators of physiologic effects or as part of the inflammatory cascade
COX-1 and COX-2
COX-1
- Enzyme that produces prostaglandins that protect gastric mucosa, maintain normal kidney function, and promote platelet aggregation
- Constitutive (exists and acts continuously in many tissues)
COX-2
- Enzyme induced as part of the inflammatory cascade
- Constitutive to a more limited extent
Overall large variation in relative effects of NSAIDs on COX-1 and COX-2
Positive effects of NSAIDs
Inhibition of PG synthesis
- Reduced inflammation
- Reduced pain
Adverse effects of NSAIDs: Overview
- Disrupt normal physiologic processes of prostaglandins
Disruption to gastric mucosa
- GI bleeding or PUD
Renal blood flow
- Normally, prostaglandin synthesis is low and role in modifying renal blood flow is minimal (typically causes vasodilation and increases renal blood flow to an extent)
- When NSAIDs are used, lack of vasodilatory effect of prostaglandin in context of volume depletion may result in AKI
- Reduction of renal blood flow may also result in higher concentration of lytes and water retention
- Results in higher blood pressure
Bleeding risk (esp GI)
- NSAIDs temporarily decrease thromboxane A2 (pro-thrombotic) and prostacyclin (anti-thrombotic)
- In general less selective COX inhibition increases bleeding risk
- More COX-2 inhibition relative to COX-1 increases risk of thrombosis
Cardiovascular risk
- When COX-2 is inhibited relative to COX-1, the pro-thrombotic/antithrombotic balance on the endothelial surface shifts in favour of thrombosis
- Other factors include blood pressure elevation, reduced renal perfusion, fluid retention, and exacerbation of heart failure
Coxibs
- Developed in an effort to target COX 2 (inducible) rather than COX 1 (source of most bad side effects - GI, renal impairment, BP, etc.)
- In general, however, increase cardiovascular risk when COX-2 is inhibited relative to COX-1 due to shift of pro-thrombotic/antithrombotic balance on the endothelial surface in favour of thrombosis
- Includes Celecoxib
Pharmacology of NSAIDs: Absorption
Absorption
- Most taken orally and absorped in the upper GI tract
- When taken PO, effects typicaly begin within 30 minutes with peak effects within 120 minutes
Injectable
- Ketorolac (Toradol) is available as an IM or IV injection
Pharmacology of NSAIDs: Pharmacokinetics
- Highly protein bound (range 90-99%)
- Predominantly metabolised by the liver through the P450 system
- Generally rapidly distributed in all tissues of the body
- Eliminated in the urine
NSAIDs for cancer pain
- No good evidence to determine comparative efficacy or safety across NSAIDs for cancer pain
- Seems to be more effective than placebo for cancer related pain
- Long term safety not established
Side effects of NSAIDs GI
- Pain
- Nausea
- Gastric erosion and ulceration (may be seen in up to 30% of patients on NSAIDs)
- Lower GI bleeding (not as significant a risk as upper GI)
- Bleeding
- Perforation
Risk higher with non-selective COX1/COX2 NSAIDs
- Ibuprofen appears to be least harmful non-selective
Lower risk of GI toxicity with COX-2 selective inhibitors, but does not eliminate risk (halved)
Higher risk of GI effects in:
- 65
- PUD in the last year
- H. pylori infection
- simultaneous use of corticosteroids, ASA, or anticoags
- advanced disease
- CV disease
- renal or hepatic impairment
- DM
- smoking
- ETOH use
Gastroprotective strategies:
- Evidence limited
- PPIs often used
- Patients at high risk should receive COX-2 selective (celecoxib) or non-selective and PPI (thought to be more effective)
Side effects of NSAIDs: Renal
- Water and sodium retention
- Edema
- Hyperkalemia
- Reduced effectiveness of antihypertensives and diuretics
- renal papillary necrosis (vascular supply dependent on local renal PG production, risk especially high with volume depletion)
Pathophys:
NSAIDs inhibit rate-limiting enzymes involved in the production of prostaglandins
- Prostaglandins are mediators of vascular tone, salt and water balance, and renin release
In conditions where there is decreased renal perfusion (e.g. dehydration, CHF, cirrhosis, diuretic use, blood loss, restricted sodium intake), absence of a compensatory prostaglandin mechanism can result in AKI
In conditions where there is high salt intake or volume expansion, NSAIDs may result in further sodium retention and HTN
Choice of agent:
Risk likely with either non selective or COX-2 inhibitors, as renal effects depend on activity of COX-2.
Side effects of NSAIDs: CNS
- Dizziness
- Headache
- Confusion
- Vertigo
- Depression
Side effects of NSAIDs: Platelets
- Inhibition of activation (bleeding) - increased risk of hemorrhage
Bleeding risk (esp GI)
- NSAIDs temporarily decrease thromboxane A2 (pro-thrombotic) and prostacyclin (anti-thrombotic)
- In general less selective COX inhibition increases bleeding risk
- More COX-2 inhibition relative to COX-1 increases risk of thrombosis
Side effects of NSAIDs: Cardiac
CHF
- Risk especially high in frail and elderly patients
CAD and Thrombosis
- Particularly with more COX-2 inhibition relative to COX-1 (greater relative activity of thromboxane A2, pro-thrombotic)
- Results in increased risk of CAD and stroke
- Highest risk with celecoxib and ibuprofen, lower risk with naproxen
- All NSAIDs constitute some risk as all inhibit COX-2
