Analgesics Flashcards
What is the MOA of NSAIDs?
Blocks COX enzyme from producing prostaglandins
→ Prostaglandins mainly cause acute pain, while leukotrienes mainly cause chronic pain
→ Prostaglandins, depending on situation, cause: Vasodilation/constriction, Inhibit/Stimulate platelet aggregation, Pain (nociceptive fibre sensitisation), Vascular permeability
→ Typical NSAIDs thus: Block vasodilation – ↓heating, redness, swelling; ↓ vascular permeability – ↓swelling; Block pain associated with inflammation
What are NSAIDs effective for?
Mild pain – Inhibition of prostaglandins is enough to reduce the pain signals from nociceptors such that the brain stops interpreting the sensation of pain
→ Block of sensitisation rather than direct nociceptive activation may explain why NSAIDs have an “analgesic ceiling”
→ Not good for chronic/severe pain – bradykinin and/or leukotriene effect outweighs prostaglandins
Antipyretic – prostaglandin PGE2 (which causes additional heating) production is blocked
What are the adverse effects of NSAIDs
→ GI – e.g. gastric ulcer and haemorrhage risk in chronic use; dyspepsia, nausea, vomiting
→ Renal - AKI
→ Pseudo-allergic Reactions – rashes, swelling itching, nasal congestion, anaphylaxis
→ Asthma – can trigger bronchospasm in some asthmatics
→ Bleeding
Why do NSAIDs cause GI SE?
- Prostaglandins reduce gastric acid secretions, increase mucosal blood flow and secretion, and increase secretion of bicarbonate
- Risk of peptic ulcers greatly increased if used for >5 days – usually administered w/PPI
Why do NSAIDs cause renal SE
Inhibition of PGE2 production causes:
* Sodium retention
* Water retention
* Peripheral oedema
* Hypertension
Inhibition of PGI2 production causes:
* Suppression of renin and aldosterone secretion
* Hyperkalaemia
* Acute renal failure
What are the risk factors for NSAID-induced AKI?
Increasing age (>65yo), chronic HTN, atherosclerosis – narrowing of renal arterioles decreases capacity for renal afferent function
Pre-existing glomerular disease or renal insufficiency – renal afferent dilation likely needed to maintain GFR
Volume depletion – ↓ afferent arteriolar pressure, stimulates secretion of angiotensin II
ACEi or ARBs – prevent efferent arteriole vasoconstriction
Triple Whammy – ACEi/ARB + diuretic + NSAID
- NSAID – blocks vasodilation of afferent arteriole (i.e. vasoconstricted)
- ACEi/ARB – blocks vasoconstriction of efferent arteriole (i.e. vasodilated)
- Diuretics – reduce renal blood flow
- As a result, GFR and CrCl reduced
Why can NSAIDs trigger bronchospasm in asthmatics?
COX inhibition results in build up of arachidonic acid – spills over to inc 15- and 5-Lipoxygenase
What are coxibs?
Are more selective for COX-2 than COX-1 – can use W CAUTION in asthmatics
→ COX-1 is a constitutive enzyme (always active) – inhibiting COX-1 thus has greater AEs from stopping other essential processes
→ COX-2 is an inducible enzyme (only activated when needed) in some systems (constitutive in CNS, kidneys, female reproductive tract, synovium) – can inhibit with less AEs
What are the unwanted effects of COX-2 inhibition?
Renal toxicity
Effects on ovulation in long term (incl delayed follicular rupture)
Premature closure of of ductus arteriosus (fetal lung bypass) in late pregnancy
Impaired wound healing – complete GI tract sparing doesn’t actually happen (just lesser, not zero)
→ Thus on PUD, shouldn’t use coxibs (nor NSAIDs)
Increased thrombosis risk (except for aspirin)
→ Inhibition of COX-2 results in build up of arachidonic acid that spills over to COX-1 instead
→ Results in increased stimulation of platelet aggregation by TXA2 (outweighs the decrease in inhibition of platelet aggregation by PGI2)
What are the risk factors that are contraindicated with NSAIDs?
- Severe kidney impairment (eGFR < 30ml/min)
- Severe heart failure
- Active GI ulcer or bleeding
- Bleeding disorders
- Use of systemic corticosteroids, antiplatelets or anticoagulants
- Multiple risk factors for NSAID toxicity
- Third trimester of pregnancy
What are the actions that should be taken before prescribing an NSAID for patients with risk of renal toxicity?
Discuss with patient’s managing Dr before prescribing
What are the actions that should be taken before prescribing an NSAID for patients with risk of CV toxicity?
Avoid diclofenac and COX-2 selective NSAIDs (except celecoxib)
Use of celecoxib or ibuprofen for ≤5 days
Otherwise consider paracetamol monotherapy
What are the actions that should be taken before prescribing an NSAID for patients with risk of GI toxicity?
Avoid non-selective NSAIDs
Use COX-2 selective NSAIDs with caution
Consider co-prescribing PPI
What are the risk factors that warrant using a PPI with NSAIDs?
At least 3 out of 4
- >65yo
- Hx of ulcer
- Use of high dose/chronic NSAID
- Concurrent glucocorticoids, antiplatelets or anticoagulants
OR Hx of complicated ulcer
What are the actions that should be taken before prescribing an NSAID for patients with risk of NSAID-related bronchospasm or pseudoallergic reaction?
Avoid non-selective NSAIDs
Use COX-2 selective NSAIDs with caution
What are the effects of paracetamol?
Analgesic and antipyretic effects, but not anti-inflammatory
When are patients at risk of liver damage from paracetamol?
→ Increased risk of harm with doses ≥4g per 24h
→ Shouldn’t occur at therapeutic dose, but may be exacerbated by chronic alcohol use or alr poor liver function (accumulation of paracetamol, leads to more NAPQI than detoxification can handle)
→ Refer to A&E if ≥10g per 24h
When do paracetamol doses need to be decreased?
Underweight, significant liver disease
How should opioid analgesics be used?
SHOULD NOT BE 1st LINE FOR PAIN – Use NSAIDs and/or paracetamol where possible first
If opioids are deemed appropriate:
→ Use lowest effective dose of weakest effective opioid for shortest duration
→ Ensure patient is well-educated on use, storage and risk of adverse effects – risk of unused prescribed opioids being misused by others, contributing to increased risk of addiction
What are the adverse effects of opioid analgesics?
→ GI – C, N, V
→ Sedation/Drowsiness
→ Falls and fractures (esp elderly)
→ Tolerance, physical dependence, addiction, and/or withdrawal
→ Hormonal effects
→ Depression
→ Respiratory effects
→ Overdose and death
→ Opioid-induced hyperalgesia
What are the risk factors of note when prescribing opioid analgesics?
Combination with other CNS depressants (e.g. alcohol, benzodiazepines, antidepressants)
Other comorbidities (e.g. mental health conditions)
Renal or hepatic insufficiency, age > 65 years
Pregnancy (risk to both mother and fetus)
Personal or family history of substance use disorder
Already prescribed an opioid
→ Increased risk with increased dose and duration of use
→ Risk of diversion – unused opioid used by others
→ Risk of opioid use disorder
What is the MOA of orphenadrine?
Muscarinic receptor antagonist – acts at muscarinic receptors in the basal ganglia to reduce muscarinic cholinergic neurotransmission, resulting in central muscle relaxant effects
Also a H1 antihistamine, NMDA receptor antagonist, norepinephrine and dopamine reuptake inhibitor and a Na channel blocker
What are the adverse effects of orphenadrine?
→ Common: N/V, flushing, dilated pupils, dry mouth
→ Higher doses: tachycardia, ataxia, nystagmus, drowsiness, delirium, agitation, visual hallucinations
