Analgesic agents Flashcards
what is the WHO ladder for analgesia?
3 step ladder to guide pain management
step 1 - paracetamol, ibuprofen
step 2 - weak opioids, codeine, tramadol
step 3 - strong opioids, morphine, fentanyl
adjuncts can be used along the way - steroids
what are the limitations of the WHO pain ladder?
doesnt account for type of injury e.g. chronic pain problem works for but if someone comes in with broken leg likely to need to start at step 3
doesnt account for neuropathic pain, ketamine or magnesium
Give a hollistic approach to how pain can be managed…
pain is complex can be managed via non pharm and pharmacological approaches.
non pharm - CBT, accupunture
pharm - either direct analgesics or other e.g. PPI or antidepressants
surgical - steroid injections, coeliac plexus block
how does management of visceral pain compare to neuropathic..
visceral - poorly localised, dull pain, potentially referred.
Opiates work well here. Or can consider the cause e.g. buscopan.
neuropathic - opioids dont work so well here.
gabapentin, pregabalin and amitryptilline are used.
capsascin cream - down reg VR1 receptors (substance P). baclofen for muscle spasms
what is the importance of perioperative analgesia?
Better patient experience
Prevention of other issues - early mobilisations, deeper breathing, reduced risk of pneumonias, less N&V, better nutrition and wound healing.
less stress response - risk of MI
what is meant by multimodel analgesia?
targetting pain from different receptors / modes of action
e.g. opioids, regional anaesthesia, paracetamol, ketamine.
means less of one drug has to be used so better side effect profile. opiate sparring
why might pre-emptive analgesia be useful?
better patient experience
less likely to develop chronic pain
easier to stop pain before it develops
which analgesic agents can work topically?
ibuprofen gel
fentanyl and buprenorphine patches - lipid soluble
local anaesthetic creams - EMLA or Ametop
capsaicin cream - initially burning sensation then down reg of VR1 receptors
which neurotransmitters affect descending pain pathways?
opioids - u receptor on SG
ketamine - NMDA receptor at SG
NA/5HT3 e.g. SSRIs and SNRIs , tramadol
reduces noradreanaline - clonidine
what atypical NSAIDs do you know?
paracetamol, aspirin
Tell me about the pathogenesis of paracetamol overdose
paracetamol can be metabolised by phase 1 and phase 2 metabolism within the liver.
In phase 1 - NAPQI is produced which is a toxic metabolite which is quickly conjugated with glutathione.
In phase 2 - paracetamol is glucuronidated - under normal conditions most is metabolised this way.
In OD - phase 2 becomes saturated and phase 1 metabolism increases, meaning more NAPQI produced. Glutathione stores also deplete and hence NAPQI can have toxic effects…
it causes centrolobular necrosis and can lead to fulminant hepatitis.
what factors contribute to depletion of glutathione and put patients at risk of paracetamol toxicity?
malnutrition - low BMI, starvation, malabsorption
genetic polymorphism
extremes of ages
At what level does paracetamol start to cause hepatic injury?
more than 150mg/kg
how does paracetamol OD present
N&V
RUQ pain
dearranged LFTs
after 72 hours - fulminant hepatitis and multiorgan failure
how is paracetamol overdose managed?
A to E, blood inc toxicology
accurate history
within 1 hour - activated charcoal
after than give N - acetylcysteine if - >150mg/kg, staggered overdose, acute liver injury, RUQ and jaundice with signs of liver failure.
otherwise take paracetamol level and use nonagram to decide to give NAC.
what is the dose for N-acetylcysteine?
150mg/kg in 1st hour
50mg /kg over 4 hours
100mg/kg over 16 hours
however now SNAP regime is used - 2 bags
100mg/kg in first 2 hours
200mg/kg in next 10 hours
what is the paracetamol nonagram?
guides need for NAC given levels of paracetamol post insult
not accurate under 4 hours or after 24hrs
no accurate if there is a staggeted overdose
how does N acetylcysteine work?
stimulates glutathione production
binds NAPQI and promotes its conjugation to non toxic products
reduces NAPQI back to paracetamol
any alternatives to NAC?
methionine
what are the ADRs of NAC?
rash, angioedema, flushing , N&V
can result in bronchospasm and low BP
SNAP regime has less incidence of this than classic 3 bag regime
how can the NSAIDs be classified?
Typical and atypical
Selective and non selective COX inhibitors
Typical:
* selective COX2 inhibitors = celecoxib and parecoxib
* non-selective = ibuprofen, ketorolac
atyptical
* aspirin - irreversible COX2 inhibitor
* paracetamol - Cox3 inhibitor
outline the pathway for prostaglandin production and how NSAIDs work..
tell me about COX enzymes
Cycloxygenase enzymes are a group of enzymes responsible for production of prostaglandins
different isoforms exist
COX 1 - found in most cells - particularly GIT, kidneys and platelets. responsible for GI protection, renal blood flow regulation and thromboxane synthesis in platelets
COX 2 - found in immune cells - responsible for prostaglandin production involved in pain and inflammation.
COX 3 - only in CNS - varient of COX 1, pyrexia and interpretation of pain in the brain.
why do NSAIDs exacerbate asthma?
block COX enzymes, build up of arachidonic acid which promotes leukotriene production via lipooxygenase
what role do prostaglandins have in the body
gastric protection - increase blood flow and mucus production to protect epithelium from acid
vasodilation - regulation of blood flow e.g. in kidneys
platelet aggregation - thromboxone and hence homeostasis
uterine contraction in maternity
what is reyes syndrome?
a rare life threatening condition associated with NSAIDs in children.
particularly aspirin
therefore aspirin contraindicated in under 16yrs unless kawasaki disease or juvenile arthritis
results in encephalopathy, cerebral oedema, mitochondrial failure, hepatic failure.
describe the metabolic derrangements seen in aspirin overdose..
mixed respiratory alkalosis + metabolic acidosis
aspirin stimulates resp centre - hyperventilation - resp alkalosis - drives HCO3 excretion which can worsen the acidosis…
also causes uncoupling of oxidative phosphorylation - metabolic acidosis
the acidosis results in increase in unionised form which means more can cross BBB. therefore better to be alkalotic as less toxic. hence sodium bicarb often given in overdose
what is role of sodium bicarb in aspirin OD?
alkalinsation of urine and blood
urine - ion trapping, more aspirin excreted
plasma - ionised form cant cross BBB and have toxic effects.
can also achieve this through hyperventilation if mechanically ventialtion
what are the contraindications to NSAIDs use?
allergy - anaphylaxis or other
GI ulceration / bleed
renal impairment
bleeding risk - caution if on warfarin
under 16yrs
caution in critically ill - AKI and stress ulcers.
Asthma - relative - 10% of asthmatics have an issue
pregnancy - aspirin can be used but mostly avoided due to premature duct closure.
avoid in CKD, HF
what are the indications for NSAIDs use?
pain and inflammation
pyrexia
indomethicin in neonates to help close PDA
what are the pharmacodynamics of NSAIDs..
respiratory
- bronchospasm
- hyperventilation
cardiovascular
* risk of MI - esp COX2 specific
GI:
* ulceration and bleeding
renal
* AKI risk / reduced blood flow
haem
* bleeding risk
neuro
* reyes
how are the NSAIDs classified by their relative effect on GI bleeding risk?
high risk - ketorolac
medium - naproxen, diclofenac
low risk - ibuprofen
COX 2 selective - even lower
what is the benefit of parecoxib / celexocib and risks?
selective for COX2 so target inflammatory effects of prostaglandins more
hence less GI ulceration risk
however found to be associated with thrombosis and MI
do you know any DDIs of NSAIDs…
highly protein bound and therefore displacement of others e.g. warfarin and phenytoin - bleeding risk
SSRIs - risk of bleeding increased,
ACEi - risk of AKI increased.
describe in general the pharmacokinetics of NSAIDs..
A: Oral, IV, gel, PR.
weak organic acids - at stomach pH unionised so can be absorbed, but mostly duodenem due to high S.A
mostly high BO. some 1st pass metabolism
D: highly PB - albumin, low Vd
M + E : hepatic and renal
are NSAIDS contraindicated in neuroaxial blocks?
no
what is the difference between an opiate and opiod?
opiate is naturally ocurring opioid e.g. morphine, codeine
opioids are any molecule that can bind and act on opioid receptors - diamorphine, fentanyl, remifentanil, oxycodone etc - these include synthetic opiouds too.
