MSK - Drugs for Muscle Pain (including NSAIDs revision) COPY Flashcards
Compare and contrast the clinical actions of aspirin and ibuprofen.
Both aspirin and ibuprofen are:
(1) Anti-inflammatory
(2) Analgesic
(3) Antipyretic
Aspirin but NOT ibuprofen is an irreversible cyclo-oxygenase (COX) inhibitor and so a potent:
(4) Anti-platelet
What would be the usual analgesic choice for a child with mild to moderate pain?
Paracetamol would usually be the preferred first choice. Ibuprofen may be considered if greater anti-inflammatory action and analgesia is required.
Why does indometacin have a stronger anti-inflammatory profile than other nonselective NSAIDs?
Besides being a non-selective inhibitor of cyclo-oxygenase (COX), indometacin also inhibits phospholipase A2. Thus, indometacin reduces the production of leukotrienes, in addition to prostanoids, and so has a broader spectrum anti-inflammatory effect.
Which form of cyclo-oxygenase is expressed in inflammatory cells at sites of acute inflammation.
Inducible cyclo-oxygenase-2 (COX-2)
Why should etoricoxib be used with caution in a patient with active peptic ulcers?
Etoricoxib will impair wound healing and so pre-existing peptic ulcers are likely to persist.
What is the MOST common adverse effect of paracetamol at clinical analgesic doses?
Nausea
List THREE NSAIDs with greater selectivity for cyclo-oxygenase-2 (COX-2) over COX-1.
Etoricoxib, parecoxib (pro-drug of valdecoxib), celecoxib, meloxicam, mefenamic acid
Which NSAID has the greatest risk of precipitating an asthma attack in a patient with NSAID exacerbated respiratory disease (NERD)?
Aspirin because it is an irreversible inhibitor of cyclo-oxygenase (COX)
Which NSAIDs has the strongest anti-platelet effect?
Aspirin because it is an irreversible inhibitor of cyclo-oxygenase (COX)
What is the MOST common adverse effect of non-selective NSAIDs?
Nausea and other gastrointestinal adverse effects
What is the normal function of prostaglandins in the stomach?
Protective effects:
(1) Increase bicarbonate secretion
(2) Increase mucus secretion
(3) Increase blood flow to mucosa
(4) Decrease acid secretion
Why do NSAID-induced pseudoallergic reactions occur?
Inhibition of cyclo-oxygenase (COX) causes shunting of arachidonic acid to overflow into the 5-lipoxygenase pathway for the production of leukotrienes. Leukotrienes activate cysteinyl leukotriene receptors promoting mast cell degranulation and allergic responses.
At analgesic doses, what do ALL NSAIDs have in common?
At analgesic doses, all NSAIDs inhibit cyclo-oxygenase-2 (COX-2)
For what severity of pain are NSAIDs useful as analgesics?
NSAIDs are only useful for analgesics for mild to moderate pain. NSAIDs have an analgesic ceiling as they work as analgesics by preventing prostaglandin-mediated sensitisation of nociceptive fibres.
Explain why diclofenac is useful for the management of joint pain and inflammation.
Diclofenac accumulates in synovial fluid enabling a prolonged analgesic and anti-inflammatory at the joints while it has a relatively short plasma half-life and so fewer gastrointestinal adverse effects than other non-selective COX inhibitors.
Why are ALL NSAIDs contraindicated in late pregnancy?
All NSAIDs inhibit cyclo-oxygenase-2 (COX-2) at analgesic and anti-inflammatory doses. Inhibition of COX-2 risks premature closure of the ductus arteriosus. All NSAIDs are therefore contraindicated in the third trimester.
Which form of cyclo-oxygenase (COX) do platelets predominantly express?
Platelets express cyclo-oxygenase-1 (COX-1) which makes thromboxane-2 (TXA-2)
In general, COX-1 is constitutive and COX-2 is inducible but EXCEPTIONS include…
Expression of COX-2 in the kidney, synovial joints, CNS and female reproductive system.
The renal adverse effects of NSAIDs are due to inhibition of…
Both COX-1 and COX-2
List at least THREE renal adverse effects of NSAIDs?
Increased sodium retention, water retention following sodium retention, risk of hyperkalaemia, and changes in renal blood flow dynamics.
List at least FOUR NSAIDs ranked from most strongly antiplatelet to most strongly prothrombotic.
Aspirin > Ketoprofen > Indometacin > Naproxen > Ibuprofen >Piroxicam > Diclofenac > Mefenamic acid > Celecoxib > Parecoxib > Etoricoxib
Alcohol increases the hepatoxicity of paracetamol by altering its metabolism through…
Inducing minor pathway enzymes resulting in toxic metabolites and depleting glutathione, which is required to detoxify the toxic metabolites to nontoxic metabolites
Hepatoxicity of paracetamol (acetaminophen) overdose can be treated with…
N-acetyl-cysteine helps to treat paracetamol toxicity by replenishing glutathione, which detoxifies the toxic metabolites of paracetamol to nontoxic metabolites
The coxibs are markedly safer than non-selective NSAIDs for patients…
At risk of stomach ulcers
List at least THREE adverse effects of COX-1 inhibition
Increased risk of nausea and vomiting, gastro-oesophageal reflux, stomach ulcers, bruising/bleeding, renal adverse effects contributing to hypertension and fluid retention. (Note that COX-2 inhibition also contributes to renal adverse effects).
Name an NSAID available in a patch formulation suitable for lower back pain
Ketoprofen or diclofenac
Name TWO NSAIDs available in topical gel or cream formulations
Piroxicam, diclofenac, ketoprofen
What are the mechanisms of analgesic action of tramadol?
Tramadol is (1) a weak opioid analgesic with (2) additional norepinephrine and serotonin (5-HT) re-uptake inhibition
What are the MOST LIKELY adverse effects of tramadol?
Constipation, nausea, vomiting
Which relatively common adverse effect of tramadol is it typically MOST IMPORTANT to warn patients about?
Sedation/drowsiness - can result in accidents (e.g., if driving or operating machinery) or falls and fractures in the elderly. Sedation can be more severe if tramadol is combined with other CNS depressants (e.g., alcohol).
Name TWO rare but SEVERE adverse effects of tramadol
Risk of dependence, respiratory depression at very high doses (can result in death on overdose or combination with other CNS depressants, e.g., alcohol)
Combination of NSAIDs with which two classes of drugs greatly increases the risk of acute renal injury?
Combination of NSAIDs with (1) diuretics and (2) angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) greatly increases the risk of acute renal injury.
Briefly describe the mechanism(s) of action of orphenadrine
Orphenadrine is a central muscle relaxant blocking muscarinic receptors in the basal ganglia in the brain. Additionally, it has H1 antihistamine, NMDA receptor antagonism, norepinephrine and dopamine re-uptake inhibitor and sodium channel blocker actions that may contribute to adjunct analgesic and muscle relaxant actions.
List THREE common adverse effects of orphenadrine
Nausea and vomiting, flushing, dilated pupils, dry mouth
List THREE adverse effects of orphenadrine seen only at higher doses
Tachycardia, ataxia, nystagmus, drowsiness, delirium, agitation, visual hallucinations
Name an analgesic available in a combined formulation with orphenadrine
Paracetamol, mefenaminc acid. Note that paracetamol alone is usually insufficient for acute lower back pain but in combination with orphenadrine may be effective.
Name a muscle relaxant used for acute (< 4 weeks) pain
Orphenadrine
Briefly describe the mechanism(s) of action of diazepam
Allosteric modulator of GABA-A receptors increasing the frequency of opening of chloride channels and hence the potency of endogenous GABAergic neurotransmission
Suppresses brain reticular activating system: sedation, amnesia, loss of consciousness
Increased inhibitory neurotransmission also has anticonvulsant and muscle relaxant effect
List THREE significant adverse effects of benzodiazepines
Drowsiness, impaired judgement, reduced motor skills, tolerance and high potential for dependence.
Briefly describe the mechanism(s) of action of baclofen
GABA analogue that selectively activates GABA-B receptors in CNS
? Reduces tonic neural stimulation to muscles
What is the risk associated with discontinuation of baclofen?
Abrupt cessation causes withdrawal syndrome:
- Potentially life-threatening withdrawal syndrome.
- Common effects are hyperthermia, pruritus, and increased spasticity.
Name TWO adverse effects of baclofen
Sedation, weakness, and other CNS effects. Additionally, abrupt cessation causes a potentially life-threatening withdrawal syndrome.
Name a gabapentinoid
Gabapentin, pregabalin
Briefly describe the mechanism(s) of action of gabapentionoids
GABA analogues but act at voltage-gated calcium channels rather than GABA receptors.
? Reduces tonic neural stimulation to muscles.
List TWO side effects of gabapentinoids
Somnolence, dizziness, ataxia (greater incidence if not titrated over days to weeks)
Which antidepressant commonly used as an adjunct for chronic pain has LEAST risk of adverse effects?
While all antidepressants have a risk of adverse effects, duloxetine is a more selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) than the tricyclic antidepressants (e.g., amitriptyline), which have antihistamine, anticholinergic and alpha-1 antiadrenergic adverse effects.
Which antidepressant commonly prescribed as an adjunct for chronic pain is MORE EFFECTIVE for lower back pain?
Duloxetine is usually more effective than tricyclic antidepressants (e.g., amitriptyline) for chronic lower back pain.
List THREE major mechanisms of adverse effects of amitriptyline and at least ONE example of an adverse effect caused by each mechanism
Antihistamine: Sedation, weight gain
Anticholinergic: Blurred vision, dry mouth, urinary retention, constipation, agitation, tachycardia, heating (due to block of sweating)
Alpha-1 adrenoceptor blockade: Postural hypotension, tachycardia
Briefly describe the mechanisms of action of topiramate
Inhibits excitatory neurotransmission:
- Blockade of AMPA subtype glutamate receptors
- Blockade of voltage-sensitive Na+ channels
May also potentiate inhibitory GABAergic neurotransmission
Together the above mechansims ? reduced tonic neural stimulation to muscles
List THREE adverse effects of topiramate
Dizziness, fatigue, ataxia, confusion (although note that the adverse effects are usually mild)
List the THREE major classes of drug used for muscle pain
Analgesics, muscle relaxants and adjuncts
List the THREE major classes of muscle relaxants used for muscle pain and ONE example of a drug for each class
Central muscle relaxants (e.g., orphenadrine), benzodiazepines (e.g., diazepam), GABA derivatives including GABA-B agonists (e.g., baclofen) and gabapentinoids (e.g., gabapentin, pregabalin)
List the TWO major classes of adjuncts used together with analgesics for subacute or chronic muscle pain and ONE example of a drug for each class
Anticonvulsants (e.g., topiramate or gabapentinoids such as gabapentin, pregabalin) and antidepressants (e.g., SNRIs such as duloxetine, or tricyclic antidepressants such as amitriptyline)
