Pain Management: NSAIDs/APAP Flashcards
4 types of pain
nociceptive
inflammatory
neuropathic
functional
nociceptive pain
occurs in response to noxious stimuli, in order to prevent further damage
inflammatory pain
occurs in response to tissue damage or infection in order to promote healing
neuropathic pain
occurs as the result of damage or pathological changes in either the PNS or the CNS
functional pain
occurs due to an abnormality in processing by, or functioning of, the CNS in response to normal stimuli
acute pain is typically from what types of pain?
nociceptive or inflammatory
chronic pain is typically from which types of pain?
neuropathic, inflammatory, functional.
mild/moderate acute pain
two tiers of treatment
1st tier: NSAIDs or APAP
2nd tier: opioids
severe acute pain
two tiers of treatment
1st tier: opioids
2nd tier: opioids plus NSAIDS or APAP
acute pain treatment modailities
NSAIDS, APAP, opioids
chronic pain treatment modalities (8)
TCAs AEDs lidocaine SSRI/SNRI long acting opioids clonidine or bactrim pregabalin APAP/NSAIDs (inflammatory)
nociceptor stimulation pathology:
what 6 substances does injured tissue cause the release of?
bradykinin serotonin potassium histamine prostaglandins substance P
nociceptor stimulation pathology
injured tissue causes the release of bradykinin, serotonin, potassium, histamine, prostaglandin, and substance P. they further sensitize or activate nociceptors. This results in a lowering of the pain threshold.
nociceptor activation
action potentials are produced and transmitted to the spinal cord along myelinated a-delta-fibers and unmyelinated c-fibers
pain signals are transmitted via the spinal cord to
the thalamus
after pain signals reach the thalamus,
they are transmitted to cortical regions where pain is actually perceived.
a-delta-fibers transmit
sharp and fast pain
c-fibers transmit
slower, dull, diffuse pain
modulation of pain occurs through what 3 processes?
endogenous opioids
descending pathway
cognitive behavioral treatments
pain modulation: endogenous opioids
endorphins act on opioid receptors in the CNS to inhibit pain impulses
pain modulation: descending pathway
inhibition of pain transmission in the dorsal horn of the spinal cord
pain modulation: cognitive behavioral treatments
reduce pain perception by altering pain processing in the cortex
inflammatory pathway produces
prostaglandins
arachidonic acid
liberated from CMs when cells are damaged. from there, it can convert to prostaglandins by cox enzymes
3 prostaglandins
thromboxane (TXA2)
prostaglandin e2 (PGE2)
prostacyclin (PGI2)
in response to tissue injury, nociceptors release which prostaglandins?
PGE2 & PGI2
PGE2 & PGI2 actions
Prostaglandins which facilitate inflammation and sensitize nociceptors to painful stimuli
COX inhibitor drug uses
anti inflammatory
analgesic
antipyretic
adverse effects of cox inhibitors
gastric ulceration
bleeding
renal impairment
cox inhibitor MoA
inhibit cox which is the enzyme that converts arachidonic acid into prostaglandins and related compounds.
inhibition of COX-1 also leads to
gastric ulceration
bleeding
renal impairment
which COX is good cox and which is bad cox?
COX-1 : goood
COX-2: bad
what is the one benefit of inhibiting cox 1
decreased risk for MI on low dose daily ASA
When cells are damaged and release cox2, what will be produced?
PGE2 and PGI2, sensitizing nociceptors and facilitating inflammation
cox 2 inhibition Thera effects
anti inflammatory
analgesic
anti pyretic
potential for reducing tumorigenic growth
Cox inhibiting drugs with anti inflammatory properties
NSAIDS
cox inhibiting drug that does not have an anti inflammatory property
APAP (acetaminophen)
why isn’t acetaminophen anti inflammatory?
Distributes almost exclusively in the CNS.
Binds to and inhibits cox in the CNS, leading to analgesia and antipyretic
Does not effect COX in peripheral tissues
NSAIDS are nonselective, meaning
they bind to and inhibit COX 1 and 2
only FDA approved sole cox-2 inhibitor
celecoxib
benefit of acetaminophen over nsaid
no renal impairment, gastric ulcers, or risk of bleeding.
aceta MoA
inhibits cox in the CNS
PO bioavailability of aceta
85-100%
peak plasma time of po aceta
within 1 hour
protein binding of aceta vs NSAIDs
aceta: low protein binding
NSAIDs: high protein binding
metabolism of aceta
excretion
mainly in the liver
undergoes phase I via CYP2E1 and II, but vastly done in phase II.
in phase II, aceta is conjugated to glucoronic acid, sulfuric acid, and cysteine. then excreted.
small proportion of aceta goes through phase I. If not able to complete and this metabolite builds up, hepatotoxicity can occur.
elimination of aceta in adults time
2-3 hours
acetaminophen in the setting of inflammatory pain
may be used as an analgesic adjunct but is inadequate for this type of pain as a single agent.
acetaminophen in neuropathic or functional pain
lacks efficacy
current FDA recommended daily dose of aceta
4g
can effect liver function
what dose of acetaminophen can be fatal and why?
15g
severe hepatotoxicity and potentially renal failure via acute tubular necrosis
treatment for acetaminophen overdose
acetylcysteine
NAPQI
toxic metabolite of acetaminophen
NAPQI and glutathione
glutathione binds to NAPQI, renders it harmless, and it is excreted in the urine
NAPQI with insufficient glutathione
hepatotoxicity
N-acetylcysteine will
act as glutathione, bind to NAPQI for excretion.
single and daily doses of aceta are not to exceed…
single: 1g
daily: 4g
at what adult weight must daily and single aceta doses be adjusted?
<50kg
which CYP enzyme metabolizes aceta in phase I? (3)
CYP2e1
CYP1a2
CYP3a4
Alcohol does what to CYP450?
induces it
CYP450 does what in aceta metabolism?
converts aceta to NAPQI
glutathione is effected how by alcohol?
depleted
alcohol + aceta
metabolism
CYP450 is induced by alcohol. More of the toxic metabolite, NAPQI, is produced. Alcohol reduces glutathione, which neutralizes NAPQI. this leads to too much NAPQI -> hepatotoxicity.
why are renal impaired patients susceptible to aceta toxicity?
kidney produces some degree of NAPQI because small amounts of phase I metabolism occur in the kidney. If you have impaired renal function, the NAPQI isn’t able to clear out of the nephron. the kidney is then damaged by the NAPQI.
first generation NSAIDs inhibit
cox-1 and cox-2
first generation NSAID therapeutic indications: (5)
- inflammatory disorders ie: RA
- mild/moderate pain
- antipyretic
- dysmenorrhea/heavy menstrual bleeding
- promote closure of patent ductus arteriosus
first generation of NSAIDS suppress inflammation but
pose risk of serious harm
first generation NSAIDs in dysmenorrhea
uterus SM produces prostaglandins associated with cramping. blocking cox can alleviate.
cox 2 is associated with heavy bleeding. blocking can alleviate.
prototype of 1st gen NSAID
ASA
low dose ASA indication
antithrombotic
higher dose ASA indication
antipyretic
analgesic
anti inflammatory
absorption of ASA
within 1hr
protein binding of ASA
high
traditional NSAIDS (tNSAIDs) were developed to
be safer alternatives to asa
what is the primary difference between ASA and tNSAIDs?
the way they bind to cox.
asa: irreversible inhibition
tNSAIDs: reversible inhibition
ASA inhibition of COX1&2
irreversible, meaning that the ASA binds for life. as ASA concentrations fall, ASA is still bound to the cox.
ASA prior to surgery & rationale
ASA must be stopped a week prior to surgery. the life of a platelet is 8-10 days. ASA will bind to a PLT for its entire life. you need a week to give the body a chance to make PLTs that have not been bound to ASA
tNSAID inhibition type of COX
reversible.
as the concentration of tNSAIDs decrease below therapeutic, cox are able to produce prostaglandins again. Dosing needs to be repeated to keep this effect.
two most common OTC tNSAIDs
ibuprofen
naproxen
ibuprofen vs naproxen
ibuprofen: better for dysmenorrhea
naproxen: better for joint pain but more GI effects
FDA warning for tNSAIDs
can cause MI or stroke in those treated chronically with tNSAIDs.
thromboxane prostacyclin imbalance hypothesis
We have a balance between prostaglandin signaling and plts/endothelial cells. Endothelial cells express COX 2, producing prostacyclin (required for normal vasodilation/inhibition of plt agg). that balances out thromboxane production by cox1 and plts. in plts, cox1 produces thromboxane a2, promoting vasoconstriction and plt agg. normally there is this balance between the two, promoting homeostasis.
-balance between prostaglandin signaling and plts/endo cells. endothelial cells express cox2. cox 2 produces prostacyclin which does vasodilation and prevents aggregation. so endo cells = open vessels and free flowing plts.
-thromboxane production by cox1 and plts = thromboxane 2 which = vast con and agg. so cox1-> thromboxane-> constricted vessels and sticky platelets.
when you inhibit cox2, you’re tipping the scales more towards constricted vessels and platelet aggregation.
selective cox2 inhibitors are well known for propensity to cause mi/stroke because they inhibit cox2 in endothelial cells. decrease prostacyclin signaling = thromboxane production in platelets, vasoconstriction and plt agg. this leads to mi and stroke. tNSAIDs and ASA (non selective), promote inhibition of cox2 and prostacyclin. then youre tilted toward thromboxane - vasoconstriction, htn, plt agg, clot formation.
Cox 2 selective inhibitor suffix
coxibs
cox 2 selective inhibitors were created
to be safer alternatives to tNSAIDs in terms of GI bleed/ulcerations
some tNSAIDs are now known to be cox-2-selective. they are:
meloxicam
diclofenac
etodolac
cox-2-selective inhibitors are ____ inhibitors of cox-2
reversible
T or F: cox-2-inhibitors are just as effective as tNSAIDs in suppressing inflammation and pain
true.
adverse effects of cox-2-selective inhibitors
impaired renal function
htn
edema
inc risk for MI/stroke
Vioxx
former cox-2-selective inhibitor drug which was very effective/had low GI effects but was pulled from the market because of MI/strokes after studies showed a link. The results were suppressed initially until more organizations did their own studies and the link was stronger established.
celecoxib new research is showing
higher risk for cardiac calcification and aortic stenosis
acute, mild to moderate, nociceptive and inflammatory pain treatment modality
aspirin, tNSAIDs, coxibs
chronic mild to moderate pain
ASA*
tNSAIDs
*ASA is not really used anymore in a chronic way.
NSAIDs in neuropathic and functional pain
are not effective
precision trial: celecoxib
evaluating CV safety of celecoxib compared to naproxen or ibuprofen in pts with arthritis.
suggesting that the risk, in moderate doses, is equal among these meds.
why is GI mucosa damaged in NSAID use?
Arachidonic acid is converted to prostaglandins in the GI tract.
COX 1 is expressed in GI tract, which converts arachidonic acid to PGE2 and PGI. These things have gastric protective effects like mucous secretion, bicarb, and increased mucosal blood flow. When inhibited, peptic ulcers and GI bleeding may occur.
why are kidneys damaged in NSAID use?
cox 1 and 2 are expressed in the kidney. They produce PGE2&PGI which facilitate GFR and Na/water excretion.
when these enzymes are blocked, we get edema, HTN, and kidney injury.
why are there CV effects in NSAID use?
we have a natural balance between cox 1 and 2 in the CV system’s endothelial cells and platelets. when the balance is disturbed, constriction effects become dominant, leading to MI/stroke.
GI effects of NSAIDs
pain nausea diarrhea (rare) gastic ulcers bleeding
platelet effects in NSAID use
inhibited activation, therefore a risk of hemorrhage.
renal effects in NSAID use
salt/water retention
edema
decrease FX of anti-HTN/diuretics
hyperkalemia
CV effects in NSAID use
MI
stroke
hypersensitivity effects in NSAID use
rhinitis
edema
asthma
hypersensitivity in NSAID use: rationale
arachidonic acid can be converted into lipoxygenase as well. these are known to produce inflammation. if you inhibit cox, there will be more arachidonic acid available to be converted by things like lipoxygenase, which can convert arachidonic acid into leukotrienes which promote bronchospasm, mucous plugging, and further inflammation. aka leukotriene shunt.
combining asa with any other nsaid
contraindicated.
synergistic effects on GI mucosa
risk of ulcer complications by ASA or tNSAIDs is increased by what other drugs? (3)
warfarin
glucocorticoids
SSRIs
NSAIDs and ACE inhibitors
- ACEs will be less effective
2. additive effects against renal function
Which meds that bind to albumin may be displaced due to NSAIDs binding to albumin as well?
warfarin
mtx
sulfonylureas
ibuprofen blocks the interaction of ASA with _____
cox 1
what should you do if a patient on daily ASA needs inbuprofen or another NSAID? and why?
take ASA 1-2 hours before ibuprofen.
ASA binds irreversibly to cox1 and platelets. When you introduce ibuprofen, it will have no effect because the plts will be bound to asa.
Options for preventing GI bleeding on NSAIDs/ASA
- lowest effective dose possible
- substitute acetaminophen instead
- use a cox-2 selective instead
- administer NSAID/ASA with a PPI
- reduce NSAID/ASA dose and add opioid.
Advil dual action
new drug
250mg aceta/125mg ibuprofen
