Module 6 Pain Flashcards
what are eicosanoids
a damily of inflamayory molcules that are dervied from arachidonic acid
where does arachidonic acid comr from
obtain in diet and stored in an esterifed form in membrane phospolipids
how is arachidonic acid released
it is released from the membrane phospholipids though the activity of the enzyme phospolipase a2
arachidonic acid serves as the prcursoe for what
all the eicosanoids
arachodonic acid is broken down into what
leukotrienes bt lipooxgenase enzyme and is metabolized by cyclooxygenase 1 and 2 enxymes ot proata glandin h2
prostaglanisn h2 is the precursoe to what
to all the other prostaglandins and thromboxane a2 which stimualtes paltelet agreggation
how do prednisode and dexamethosone work
they inhibit the phospholiupase a2 molecule which shuts down the whole pathway
what happens when prdnisode is used chronically
when used chronically there are a number of side effects such as bone and muscle breakdwon and cause hyperglycemia
what do aspirin and ibuprofen do
inhibit the cox 1 and cox2 enzymes that are expressed throughout the body inhibitng syntheiss of prostaglnaidns and thomboxanes
acetaminophen does what
inhibits cyclooxygenase enzyme expressed in the brain
what does cox 1 do
constintutive expression, physioloical housekeeping through production of prostaglandins
there is a constant level of prostagmadins that are needed for physiological housekeeping
ex prostaglamdinsm that protect gastric mucosa from stomach avcid
what does cox 2 do
inducible expression, pathological production of prostaglandins (injury and infelmmation stimuli)
what are patholoical actions of prostaglandins
-vasodilation and increase in vascular permiability - release of proinflammatory mediators
-activation of nociceptors - pain pathways
-stimulation hypothermic regulartory centers - fever
drugs taht inhibit the cox enzymes do whayt
they ahve antiinfalmmatory, analgesic and antipyretic effects
what is the mechanism of action for nsaids
inhibition of cyclooxyganse
non selective inhibition of cox 1 and cox 2
what does nsaid stand for
nonsteroidal antiinflammaotry drug
what are examples of nsaids
aspirin, ibuprofen and naproxen
salicilic acid dereviates include what and what do they do
aspirin
irreversable inhibition of cox 1 and cox2
aspririn covalently modifed both cox1 and cox2 causing an irreversible inhibition of these enzymes
propionic aids include what and what do they do
ibuporfen and naprozen
reversible inhiibition of cox 1 and cox2
aceitic acids incldue
indomethoacin
what drug does selective inhibtion of cox2
celecoxib
at normal doses celecoxib does what
it does not inhibit cox1 so there is no effect on house keeping prostaglansins mad eby cox 1
what is the pharmacology of aspirin
irreversable inhibition of cox 1 and cox 2
requires new platelet syntheiss for enzyme activity since inhibits abilitty of cells to make thromboxane a2 (incrase bleeding time for several days)
analgestic antiinflammatory and antipyrectic effects
what are therapeudic uses of aspirin
decreases in prostaglandins
mild to moderate pain - post operative, dental pain, back pain etc but other nsaids are now preferred
rheumatoid arthritis
osteoarthritis
dysmenorrhea
what si teh clotting use of aspirin
inhibitionof platelet aggregation
acute corononary syndrome (mi)
transient ischemia attacks
what are the side effects fo aspirin
salicylism: tinnitus, nausea and vomting (activation of chemorecetpor trigger zone)
associated with teh development of reyes syndrome in chiclren with febile viral illness but this is nwo less common bc we use acetominophen
what are side effects of both aspirin and other nsaids
hypersensitviity reactions similar to anaphylatic shock ebcause of increases leukotrienes
gastric ulcerations, excecerbation of peptic ulcer symptoms, gi hemorrhage, erosive gastritis
prolongationof bleeding time
caution in patinet swith asthma, gi ulcers and hemophilia
if pt has hyeprsensitivity to any nsaid then what
then all nsaids are contraindicated
hypersensitivity is particularly a problem if pt has what
if pt has asthma bc increase in leukotrienes results from inhibtion of cox enzyme
now there is more arachidonic acid that can be synthesized to leukotrienes
what is the pharmacology of the propinonic acid derivateves
ibuprofen adn naproxen
reversible inhibition of cox1 and cox2
antiinflammatory, analgesic, antipyriectic effects
preferred ove aspirin for chronic treatment - rheumatoid arthritis, osteoarthritis, etc
better side effect profile than aspirin
naproxen is often combined with what
a proton pump inhibitor - esomeprolze
why is proton pump inhibitor used with naproxin
prostaglandin 2 stimualtes the epitheltial cells of the gasttric tract to secrete mucus and bicarbonate into gastric lumen which protects against protons secreted from parietal cells but naproxen decreases teh prostaglandin E and then there is less protection which becomes destructive to gi lumen
what is the half likfe of aspirin
2 hours
what is the half life of ibuprofen
2-3 hours
what is half life of naproxen
12-14 hours
what is the pharmacology of celecoxib
inducible expression, patholoical produiction of prostaglandins (injury, inflammatory stimuli etc)
so it has antiinflammatory, analgesic and antipyreetic effects
no effects on gi tract or plateltes
treatmetn of rheumatoud arthritic, osteoarthritis and dysmenorrhea
what are side effects of celecoxib
caution in pt with hypersensitiveity to nsaids
good choice for pt with gastric ulcers
cardiovascualr conerns with long term sue
what is the pharmacology of acetominophen
acts on teh cox enzume expressed in teh brain
analgesitc and antipyretic actiosn
no antiinflammatory
used for mild to moderate pain
what are the side effects and consideratiions of acetaminophen
limited risk of hypersenstivity reactions
not assocaited with reyes syndrome
absense of gi disturbances
hepatic toxicity is major concern especially at high doses
acetophinohen undergoes what
both phase one metabolism via cyp 450 enzyme and phase 2 metabolism via glucotrhinone congugation
phase 1 of acetaminophen metabolism dose what
produces a highly reactive metabolite
at normal doses of acetaminophen this metabolite is congutated with glucathione and excreted from the body
with high doses of acetophnophen the glucothione becomes depleted and the reactiive metabolite can cause liver damage/necrosis
how is liver necrosis from acetaminophen treated
pt is given n-acetylcysteine which the body uses to restore free glucoathione thus emliminating the metabolite
opioids can be obtained in what 3 ways
opitates - from juice of opium poppy
semisynthetic - comes form morphine, codien, thebaine
synthetic - other chemical precursors
what are the opiates
morphine, codine, thebaine
what are the semisynthetics
heroine, hydrocodone, oxycodone
what are the synthetics
fetanyl, methadone, meperidine
the synthetic opiods do what
these opioids mimic the action of endogenouse opioids such as endorphiens and kephalones and dimorphins
what is the mechanism of action of opioids
opioids bind to 3 opioid receptors that include the mu, kappa and delta receptors
all opioid recetpors are gpcrs signaling through GI protein
binding of opioid to mu receptor inhibits neuronal pain pathways by producing presynaptic inhibition
opioids produce post synaptic inhibtionn by activating potassium channels and inhibtinig adenylylcyclase
the mu receptor is invloved in what
involved in pain release
also responsible for the side ffets of opidods
when the mu receptor produices presynaptic inhibtion what happens
this results from the inhibtion of calcium influx into the presynaptic neuron and the inhibtion of neruo transmitter release
what happens in the ascending pain pathway
glutamatergic neuron in the ascending pain pathway
opiod receptors are presetn at both the presynapic and postsynaptic membranes
normally when an electircal signal reaches the presynaptic neuron, voltage gated calcium channels open allowing calcium ions to move into the neruon
the calcium causes the synaptic vessicles to release glutamate into the synaptic cleft
glutamate then binds to glutamate recetpros (ligand gated channels) on the post synaptic membrane allwoing dosium ions to move into the neuron
the influx of sodium into the neurons causes membrane depolarization and the electrical signal continues along the neuronal pathway
what ahppens to teh ascenigng pain pathway in teh presence of opiods
opiods bind to the mu recetpors present in both the pre and postsynaptic membranes
first binding to the presynaptic recetpor stimualtes the G inhibitory protien that then inhibtis the calcium channel
without an influex of calcium, the vessicles do not release glutamate and the glutamate does not bind to the glutamate receptor
this is called presynaptic inhibtion
second the binding of opioids to the post synaptic recetpor causes the gihibitiory protein to open membrane potassium channels that allow k+ ions to leak
this loss of positive charge cayes membrane potential to become more negative or hyperpolar
the gi protiein inhibits the proidiction of camp
these 2 effects then prevent the eelctrical signal from continuing along the pathway
the body has what 2 pain pathways
the ascending and descrening pathwyas
what is the ascending pathway used for
used to transmit pain signals to the brain letting us know that we are heard
what is the descending pathway used for
modulates the ascending pathway reducing the pain
what are the two main effects of opioids
to shut down the ascening pathway and to activate the descending pathway providing pain relief
what ahppens when you injury your finger
primary sensory neruons in out hand are activated and send the signal to the spinal cord wher they meet secondary neurons in the doral horn
the signal continues up the spinal cord and brain stem to reach the thalamus which processes sensory information
in the thalamus, the secondary neruon synapses with tertiary neruon that activate other regionss of the rbain such as the somatosensory cortex hwere we experience pain
this is the ascneding pathway
our body can decrease how much pain we feel by activating the desending pathwy
normally neruons in teh descending pathway are inactive becayse they recieve gaba from inhibitory inter neurons in the prain stem
how does opioid activate the descending pathwya
opiod prevents and inhibitos gaba release
without gaba neurons in descrenign pathway are no logner inhibited
opioids can act directly at opioid receptors in ascenidng pathwya in spinal cord inhibtioing transmission too
what is the basis of selection of opioids
onset and duration of action is most often the basis of selection of opioids
the duration of action can range from what in opioid
4 to 72 hours
short or long
what kind of pain is usually releived by opioids
dull, constant pain is usually releived by opioids
what kind of pain is poorly controlled with opiods
sharp intermittent pain
most opioids undergo what when given orally
most undergo first pass metabolism when given orally such as morphine nad heroin so not very effective orally
what are some opioids that have reduced first pass effect adn can be given orally
methadone and oxycodone
most opioids are converted to what
most are converted to glucuronides and excreted by the kidneys
what opioid drugs must undergo cyp 450 metabolism
codine and fentanyl
codine is a prodrug meaning what
it must be comverted to morephin to be effective in pain releif
what are limitations of opioids
tolerance and drug dependance are big limitatiosn
opiod receptor agonists include what
morphine, heroine, fentanyl, methadone, oxycodone and codeine
what is the potency of fentanyl, heromine, morphine, metadone and codine when given ive
Fentylanl > heroin> morphine = methadone > codine
fentanyl is about 100 times more potent than morphine
heroine is about 2-4 times more potent than morphine
what is used for opioid use disorder
methadone
can be used orally
oxycodone is 10 time more potent than codine when given orally so what can occur
drug dependanct with controleld release formation more common
have to end up using higher doses of teh drug
what is considered safer to use than opioid full agonist
buprenorphine is a partial agonist
it has lower efficacy than morphine
considered safer to use than full agonist
what are the side effects of opioid drugs
cns - euphoria, sedation, respiratory depression, miosis and cough suppression
gi - constipation due to decrased gastric motility
pregnacy - cross fetal/placental barrier by no teratogeinc effects but can result in inflant dependance and withdrawal
facial itiching
what is used to treat diarrhea but doesnt cross bbb
loperamide (imodium)
what are opioid antagonists used for
used for opioid overdose
what are the signs of overdose
extremely low respiratory rate, pinpoint pupils and low boody temperature
what is a mu opioid recetpor antagonist that is not effective orally due to first pass effect
naloxone (narcan)
naloxone has what kind of half life
has short half life so much be injected eevvry 2-4 hours
some opiods have logn half lives (over 12 hours) requiring multiple maloxone injections
what is being used to treat opioid iduced constipatin
new antagnoists taht dont cross the bbb are being used to treat opioid induced constipation
what drugs are being used to treat opioid use disorder
methadone which is a fill agonist and buprenorphiine which is a partial agonist are used for treatment of opioid use disorder
they produce euphoria ao dont seek other opioids
what do drugs for opioid use disorder do
these drugs bind to the mu opioid receptor and rpevent abused drugs such as oxycodone and heroin from binding to the receptor
this reduces cravings for toher opioids and prevents withdrawl symptoms
the long half life of methadone allwos for what
allows for once daily dosing
what is the advantage of treatment of opioid dependence with methadone
less risk of overdoing and contracting blood borne diease through intravenous drug use
what is the disadvantage of using methadone for treatment of opioid dependence with methadone
patients may become dependent on methadone and may neeed to use it for prolonged perioids of time - substiuting one drug for another
