non-opioid and opioidanalgesia Flashcards
analgesia
absense of pain in response to stimulation which would normally be painful
anagesic
pain killers
drugs that result in analgesia
maajor calsses of analgesics
opiod
non-opiod - NSAIDS, paracetomol, other
nociceptive pain
adaptive, high threshold pain
early warning system
inflammatory pain
adaptive, low threshold pain
tenderness and promotes repair
proostaglandin synthesis pathway
essential fatty acids membrane phospholipids arachidonic acid prostaglandin H2 prostacyclin, prostaglandins, thromboxane
what do NSAIDS do
block cyclo-oxygenase (COX) which is normally responsible for converting arachidonic acid into Prostaglandin H2
GI adverse effects of NSAIDS
GI irritability, inflammation, bleeding
gastric/duodenal ulceration (bleeds/peforations)
renal adverse effects of NSAIDS
no effect if normal renal function
fl;uid retention, oedema, hypertenson (significant in patients wth heart failure
renal dysfunction/failure (acute/chronic)
platelet adverse effects of NSAIDs
increase risk of bleeding (non-selectve NSAIDs)
selective COX-2 inhibition leads to increased risk of thrombotic events
respiratory adverse effects of NSAIDs
15% asthmatics get NSAID-induced asthma
3 effects of NSAIDs
- anti inflammatory
- analgesics
- anti-pyretic effects (prevent or reduce fever)
choice of NSAID depends on
- route of administration
- duration of treatment
- patient factors
- relative contraindications in renal failure, asthma, uncontrolled hypertension, previous GI ulceration/gastritis, inflammatory bowel disease, past stroke or TIA (except aspirin), upcoming surgery or other bleeding risk
non selective NSAIDs
- salicylates - aspirin
- propionic acids - ibuprofen, naproxen
- phenylacetic acids - diclofenac, ketorolac (intramuscular)
- oxicam’s - meloxicam, piroxicam
cox-2 selective
coxibs - celecoxib, parecoxib (IV), rofecoxib (withdrawn)
advantages of COX-2 selective inhibitors
coxibs lower GI adverse events reduced risk of intraoperative bleeding do not cause bronchospasm in NSAID sensitive asthmatics reduced risk of renal adverse effects
issues with selective cox-2 inhibitors
- rofecoxib was withdrawn from market in 2004 due to increased thromboembolic events
when are NSAIDS and coxibs useful
- useful as non opiod analgesics
- useful in inflammatory condtions
when are NSAIDs and coxibs less useful
- elderly
- risk of GI ulcers
- patients with CV risk factors
- patients with renal risk factors
- for prolonged use
aspirin is used for
analgesc effects
anti-inflammatory effects
analgesic aspirin dose
analgesic dose 300-900mg up to three times per day
anti platelet effects of aspirin
prevention of acute myocardial infarction and stroke
mechanism of acton of aspirin
at low dose it selectively inhibts cyclooxegenase
stops platelet activation - irreversible inhibition of platelt dependant thromboxane A2 formation - inhibits vasoconstricton and platelet aggregation
commonest toxicity of aspirin
G side effects simlar to NSAIDs
bleeding - rsk of subdural haemorrhage
long term hgh dose can cause hepatic or renal impairment
reyes syndrome
occurs at therapeutic dose of asirin
uncommon, affects mainly children
hepatic failure, encephalopathy, cerebral oedema
mortality is up to 40%
aspirin not recommended for children <12 years
aspirin in overdose
1-2% mortality
affects metabolic state - uncouples oxidative phosphorylation
respiratory alkalosis - direct stimulation of respiratory centre
metabolic acidosis - premorbid state
renal papillary necrosis
paracetamol
acetaminophen
analgesic effect
antipyretic effect
no antiinflammatory effects
paracetamol method of action
only theories
paracetamol is a recommended first line anagesic for
osteoarthritis
musculoskeletal pain in elderly
patients with renal disease
treatment of cancer pain
paracetamol is inactive at
kidney - no renal impairment
GI tract - no peptic ulcer risk
inflammation - not an anti inflammatory
oral bioavailability of paracetamol
80%
metabolism of paracetamol
hepatic metabolism via glucuronidaton to 2 inactive compounds (excreted in urine)
normally a small amount of a highly toxic compound NAPQI (N-acetyl-p-benzoquinolone imine) is produces and rapidly inactivated by the liver
paracetamol metabolism in overdose or in abnormal liver function
NAPQI levels can increase and cause hepatocellular necrosis - fulminant liver failure
risks for paracetamol toxicity
- accidental overdose
- starvation, malnutrition, low body weight
- HIV
- alcoholism
- deliberate overdose - often unaware of danger
opiate
all naturally occuring substances with morphone-like proporties
opiod
general term that also includes synthetic substances with an affinity for opiod receptors
opiod receptors
abour 400 amino acids
7 transmembrane domains
inhibitory G-protein coupled receptors
3 major classes of receptors
opiod agonists
opiod agonists binds to receptor and cause inhibition of neurotransmitter release
- leads to hyperpolarization of nuerones (peripheral psinal cord, brain)
3 classes of opiod receptors
Mu, Kappa, Delta
Mu opiod receptor
analgesia miosis - pupillary constriction euphoria respiratory depression bradycardia reduced gut motility physical dependance
kappa opiod receptor
analgesia
sedation
depression
miosis
delta opiod receptor
analgesia
physical dependance
respiratory depression
opiod receptors in the brain
brainstem - mu
limbic system - kappa > mu
cortex - kappa > delta > mu
opiod receptors in the dorsal horn of the spinal cord
presynaptic (analgesia) - mu and delta
postsynaptic - mu and kappa
opiod receptors in the PNS
on nociceptive fibres expressed after injury - analgesia - mu
morphine
naturally occuring mu receptor agonist
oral, IV, IM, SC
morphine dosing
titrate to effects - minimise life threatening adverse effects eg. sedation, respiratory depression
5-10 minute onset of action
peak effect 30-60 minutes following intramuscular administration
duration of action 3-4 hours
morphine metabolism
metabolised in the liver to
morphine-3-gluconuride
morphine-6-gluconuride
nomorphine
metabolites are renally excreted
morphine-6-glucuronide
analgesic effect
accumulates in renal failure
indications fro morphine use
moderate to severe acute pain
palliative care
used perioperatively - during anaesthesia and post operative analgesia
considerations for morphine
variable sensitivity to opiods
hepatic and renal failure
patients at risk of airway and breathing problems
side effects of the mu receptor
- miosis
- euphoria
- sedation
- respiratory depression
- reduced airway reflexes
- hypotension
- pruritis
- nausea and vomiting
- constipation
- urinary retention
- physical dependance
codeine
prodrug
inactive until metabolised in the body
often used in combination with paracetamol/ibuprofen
analgesic effect due to demethylaton to morphine
10x less potent than morphine
genetic variability for codeine
10% of patients lack the enzyme to convert codeine
genetic variability with CYP-2D6 enzyme
small proportion of people are rapid metabolisers there therefore have risk of adverse effects on normal doses
codiene bioavailability
good oral bioavalability - usualy taken orally (IM route available)
uses of codiene
mild to moderate acute pain
anttussive (cough supressant)
side effects of codeine
nausea, vomiting, constipation
oxycodone
- synthetic opiod
predominantly Mu-opiod receptor agonist
clinicala uses of oxycodone
moderate to severe pain relief
different preparations of oxycodone
immidiate release - endone, oxynorm
controlled release - OxyContin
controlled release with naloxone - Targin
naloxone
is an oopiod antagonist
reduces opdiod induced constipation and is a deterant from abuse
adverse effects with oxycodone
similar to morphine
tolerance and dependance can occur with all preparations
increasing rates of addiction, abuse and overdose
tramadol
atypical central acting analgesic with relatively weak opiod effects
has effects on non-opioid pathways as well
mechanism of action of tramadol
- metabolised in the liver to active metabolite
opioid receptor agonist mu > kappa, delta
serotonin reuptake inhibitor
noradrenaline reuptake inhibitor
tramadol compared to morphine
at equi-analgesic doses, has less respiratory depression and less constipation
serotonergic effects of tramadol
nausea, vomting and confusion
interaction with other serotonergic drugs - lowers seizure threshold, avoid in epilepsy
uses of tramadol
useful in situations to avoid opioid adverse effects
- respiratory depression, constipation, abuse, sedation, confusion
neuropathic pain
fentanyl
synthetic opioid
good parenteral, mucosal and transdermal option (good GI absorption but high first pass metabolism so not effective by oral route)
methadone
NMDA antagonist effect
good in neuropathic pain
major use is for opioid replacement in addiction (long half life over 24 hours, less sedating, less euphoria, still addictive)
pethidine
effective pain relief but side effects
short half life, increased risk of seizures especially in renal failure
avoid
opioid tolerance
developmetn of the need to increase the dose to achieve the same analgesic effects all opioid agonists usually takes 2 weeks with morphine limits clinial use does not imply addiction or abuse
physical dependance occurs with
abrupt discontinuation, substantial dose reduction or administration of antagonist
occurs with opiod use of longer than a week
opioid withdrawal symptoms
nausea, vomiting, anorexia, diarrhea, sweating, shivering, anxiety, depresion
analgesic ladder
mild pain - non opioid
mild to moderate pain - opioid for mild to moderate pain plus non-opioid
moderate to severe pain - opioid for moderate to severe pain plus non-opioid with/without adjuvant analgesic
