What is the mechanism of action of non-selective NSAIDs?
Inhibit both COX-1 and COX-2 enzymes, thereby inhibiting the production of prostaglandins (PGE2, PGI2 and TXA2)
State and explain the MOA of the broad pharmacological effects of NSAIDs (4)
1) Anti-inflammatory
- Inhibit vasodilation
- Dec vascular permeability –> dec swelling and pain a/w inflammation
2) Analgesic
- Inhibit production of prostaglandins, which sensitise nociceptive fibres to stimulation by other inflammatory mediators (decr signal amplification)
- May have some additional effects on CNS
3) Anti-pyretic
- Inhibit PGE2 synthesis by blocking COX in the hypothalamus, resetting the body’s thermostat
- Does not alter normal body temperature
4) Anti-platelet (most sig for Aspirin)
- Inhibits TXA2 production by platelets, thereby inhibiting platelet aggregation
List the adverse effects of non-selective NSAIDs (6)
1) Gi: Bleed/ulcers
2) Renal: Hypertension, AKI
3) Asthma: Bronchospasm
4) Increased bleeding risk
5) Pseudo-allergy
6) Reye’s syndrome (very rare)
Is it true that coxibs (selective COX-2 inhibitors) have no side effects, since COX-2 enzymes are involved only in inflammatory responses?
No.
- At higher doses, coxibs still have risk of adverse effects (some degree of COX-1 inhibition)
- There is constitutive COX-2 in kidneys, synovium and female reproductive tract as well
List the adverse effects due to COX-2 inhibition (5).
1) Renal toxicity
- Expression of COX-1 and COX-2 in kidney
- Renal effects causing HTN
2) Delayed follicular rupture
3) Impaired wound healing
- May exacerbate pre-existing ulcers
- Caution in existing ulcers/RF, post-surgical analgesia, non-union of fractures, bone repair
- Wait for wound to heal before giving coxibs
4) Increased thrombotic risk
- Relative inc in TXA2, promoting platelet aggregation
- Caution in high thrombotic risk (e.g. elderly)
5) MI and stroke
- Renal effects causing HTN + prothombotic effects
- Inc risk of heart attack, failure and stroke
- Caution in elderly, hx of CBV and CV disease
What are the contraindications for NSAIDs? (7)
- Severe renal impairment (eGFR<30)
- Severe heart failure
- Active GI ulcers/bleeds
- Bleeding disorders e.g. hemophilia
- (Relative) Concomitant use of corticosteroids, antiplatelets, anticoagulants
- Pregnancy (third trimester)
- Multiple risk factors for NSAID toxicity
Which NSAID is preferred for use in dysmenorrhea?
Naproxen
- Greater free fraction in females
- BD dosing (half-life 12-14h)
Which NSAID has long half-life in synovial fluid and can be applied topically?
Diclofenac
(Additionally has short plasma half-life, which leads to lower risk of GI effects)
Which NSAIDs are preferred and avoided in high risk of CV toxicity?
- Avoid diclofenac and COX-2 selective NSAIDs
- Use celecoxib, naproxen or ibuprofen, but limit to 5 days or less. If cannot use any of the 3, use paracetamol.
Which NSAIDs are preferred and avoided in high risk of GI toxicity?
- Avoid non-selective NSAIDs
- Use a COX-2 selective NSAID, but with caution
- Consider co-prescribing GI protectant (e.g. PPI)
Which NSAIDs are preferred and avoided in high risk of bronchospasm/pseudo-allergy?
- Avoid non-selective NSAIDs
- Use a COX-2 selective NSAID, but with caution
What is the (postulated) mechanism of action of paracetamol?
CNS-selective COX inhibition
What are the pharmacological effects of paracetamol?
- Good analgesic
- Potent antipyretic action
- NOT anti-inflammatory at clinical doses
What are some advantages of paracetamol use over other analgesics? (4)
- Low incidence of ADRs
- Spares the GIT
- Few DDIs
- Relatively safe for pediatric use
What are some disadvantages of paracetamol use compared to other analgesics? (3)
- Weak anti-inflammatory effects
- Toxicity at higher doses (nausea, vomiting, hepatotoxicity)
- Allergic skin reactions may occur
What are some cautions to be taken with paracetamol? (3)
- Hepatic dysfunction or alcohol abuse
- Dose reduction in underweight, significant liver disease, cachectic or frail
- Overdose. Refer to ED if 10g or more in 24h; increased risk of harm at 4g or more in 24h
What are some various ways of paracetamol + NSAID combination and state their beneficial effects? (2)
(Alternating) Sustain antipyretic effect
(Taken together) Synergistic effect for analgesia
Describe the clinical use of opioids as an analgesic (wrt to place in tx, presence of anti-inflammatory effect and dosing and risks involved with its use).
- NOT first-line for pain
- Not anti-inflammatory
- Use lowest effective dose of weakest effective opioid for shortest duration
- Significant risk of adverse effects, diversion and misuse
List the opioids in increasing order of strength/potency.
Tramadol < codeine < morphine < oxycodone < fentanyl
List the adverse effects of opioid analgesics (8).
- GI effects (N/V/C)
- Hormonal, respiratory effects
- Depression
- Overdose and death
- Falls and fractures
- Sedation, drowsiness
- Tolerance, physical dependence, addiction, withdrawal
- Opioid-induced hyperalgesia
80% will develop 1 or more of the above
What are the risk factors for ADRs associated with opioid analgesics? (6)
- Combi with other CNS depressants
- Other comorbidities (e.g. mental disorders)
- Renal/hepatic insufficiency, age >65
- Pregnancy
- Personal or FH of substance use
- Risk of diversion/opioid use disorder
List the 3 prostanoids and state which one inhibit platelet aggregation and which one promotes platelet aggregation
Prostacyclin (inhibit platelet aggregation), Prostaglandin, Thromboxane (promote platelet aggregation)
State the difference in prostanoids produced by COX-1 vs COX-2 and its implication
COX-1 produce thromboxane while COX-2 does not -> COX-2 selective NSAID have higher thrombotic risk
State the 2 prostanoids that have a role in kidney and the various effects caused by the inhibition of their synthesis by NSAIDs. (7)
Inhibition of PGE2:
- Inc sodium and water retention
- Edema and HTN
Inhibition of PGI2:
- AKI (cause vasoconstriction of afferent arteriole)
- Decreased secretion of renin and aldosterone -> lead to hyperkalemia (and incr sodium excretion but < than sodium reabsorption from PGE2 inhibition = overall Na retention)
