pain 3 Flashcards
what are endorphins
endogenous opioid ligands
what are 4 types of endogenous opioid ligands
met- or leu-enkephalin
beta-endorphins
dynorphins
endomorphins
what does met and leu enkephalin come from
preproenkephalin
what do beta-endorphins come from
POMC
what do dynorphins come from
preprodynorphin
what kind of molecules are the endogenous opioid ligands
peptide hormones
how are the endogenous opioid ligands peptide hormones made
cleaved from larger precursors
what sequence do endorphins and dynorphins contiain
the leu or met enkephalin sequence
if pain is good, then why do you want this mechanism
to turn it off in VERY extreme circumstances
what kind of G protein is linked to opioid receptors
Gi
what 2 things does Gi do
inhibit adenylyl cyclase and low cAMP levels
what does Gi do to K+ conductance
increase
what channels are activated by Gi
GIRK channels
what does Gi do to membrane
hyperpolarization
what channels are suppressed by Gi - what does this cause
N-type Ca++ current - less NT release
what does Gi do to NT release
how
decrease - suppressed Ca++ current
what kinase cascade does Gi activate
MAP kinase cascade
what does the MAP kinase cascade do
changes in gene expression - addicted and dependence
what are 4 sites of actions of opioids
periphery
higher centers
dorsal horn
periaqueductal gray and rostral ventral medulla
what do opioids do at the periphery
reduce neurogenic inflammation
what do opioids do at the higher centers - which one
cingulate cortex and thalamus, alter psychological response to pain (makes less suffering)
what do opioids do at the dorsal horn and how
big one
reduce NT release from terminals of afferent Adelta and C fibres
-act on Ca++ channels to reduce release of aa and substance P)
where do opioids act to stop release of NTs (in synapse)
presynaptically
what do opioids do at the periaqueductal gray (PAG) rostral ventral medulla (RVM)
inhibit the pathway through
activation of mu receptors on GABA releasing neurons which project onto the pain inhibitory neuron
what does PAG stand for
periaqueductal gray
what does RVM stand for
rostral ventral medulla
where are PAG and RVM and what do they do
part of the descending pathway that projects to the substantia gelatinosa to inhibit pain
what happens to GABA release when opioids activate mu receptors on GABA releasing neurons
less GABA release
how do opioids allow pain inhibitory neurons to work
they activate mu receptors on GABA releasing neurons that project onto pain inhibitory neurons
where are the GABA interneurons located in the pain inhibitory pathway
PAG RVM
what causes the differences in properties of different opioids (2)
differences in
- pharmockinetics
- affinity for different opioid receptor subtypes
what are the opioid receptors
mu
delta
kappa
what are all opioids to the my delta or kappa receptors
full agonists or partial agonists
does morphine have analgesia properties
analgesia
how does morphine do analgesia (which receptors)
mu kappa
what does morphine do to your brain physiologically
sedation and mental clouding
what does morphine do to brain psychologically
euphoria and tranquility
how does morphine cause euphoria (which receptor)
delta and mu and central DA pathways
what does morphine do to respiratory center
how
depression by direct effect on brainstem resp center (prebotzinger complex)
what does morphine do to cough
how
depress, by depressing its reflex by acting in the cough centre in the medulla
what does morphine do to nausea
how
increase it, by stimulation of chemoreceptor trigger zone in medulla
what does morphine do to eye
how
miosis (pin point pupil)
excitatory action of parasympathetic nerves innervating the pupil
which receptors cause morphines act on the pupil
mu and kappa
which receptor is involved in morphine tolerance and dependence
mu
which receptor is involved in morphine constipation
mu and delta
what does morphine do to intestines
constipation by increasing colonic tone to point of spasm, increase tone of anal sphincter
what does morphine do to postural reflexes
how
postural hypotension
inhibition of baroreceptor reflex
what does morphine do to cutaneous blood vessels
dilates them, causing warm skin
why do you get sweating and itching with morphine
because cutaneous vessels are dilated which may involve the release of histamine and lead to swelling and itching
what does morphine do to peeing
makes it feel urgent but inhibits urinary voiding reflex
what does morphine do to bile duct
increase tone in sphincter of Oddi and bile duct, increase pain of gall stones (biliary colic and epigastric distress)
what is biliary colic and epigastric distress
increase tone in sphincter of Oddi and bile duct, increase pain of gall stones
what are 2 drugs used to control diarrhea
dipehnoxylate
loperamide
what is dipehnoxylate
drug used to control diarrhea
what is loperamide
drug used to control diarrhea
what is 1 drug used to suppress cough
dextromethorphan
what is dextromethorphan
drug used to suppress cough
is dextromethorphan analgesic
no
what are 4 examples of full opioid agonists
morphine
heroin
methadone
fentanyl
does everyone vomit with morphine
no
how is morphine administered which is bad
subcutaneously, IV, oral (not efficient)
why is morphine not great when oral (2 things)
first pass metabolism in liver turns it into morphine-6-glucoronide, doesnt cross BBB as well as morphien
what is the difference with heroin and morphine
heroin is more lipid soluble so it enters the brain very rapidly
what is heroin metabolized into and where
morphine in the brain
what happens to people with heroin use
tolerance and dependence
what is duration of action of methadone
long
is methadone an analgesic
yes
what is the use of methadone
suppresses opioid withdrawal syndrome for heroin addicts
also in chronic and cancer pain
how is methadone usually taken
orally
why is methadone good for chronic and cancer pain
it is a long lasting analgesic
what is the potency difference with fentanyl and morphine
fentanyl 80x more potent
what is the duration of action of fentanyl
short
where does fentanyl act
mu opioid receptor
how is fentanyl often given medically (drug combos)
can be used alone for anaesthesia induction, or sometimes in combination with inhalent or IV or neuroleptic
what are some conditions fentanyl is used for
chronic and cancer pain and painful procedures in children
what are 3 opioid agonists of lesser potency
codein
buprenorphine
oxycodone
what does codeine do
analgesia and resp depressant
does codeine do analgesia
yes
how is codeine often taken
orally
does codein have high affinities for opioid receptors
no
how is codeine activated
metabolized into morphine
how is codeine often administered (which other drugs) why
acetaminophen or aspirin
-synergistic effects between NSAIDs and opioids
what is the mechanism of action of buprenorphine
partial agonist at mu receptors
what is the duration of action of buprenorphine
long
what is the use of buprenorphine medically
alternate to methadone management of opioid withdrawal
what is the onset of action of oxycodone
fast
why does oxycodone have a high abuse potential
it has a fast onset and it is well absorbed
how is oxycodone usually administered and why
orally because it is well absorbed in GI tract
how is oxycodone often administered (which other drugs)
with acetaminophen or alone
what is the mechanism of action of tramadol
low affinity for u receptors and blocks serotonin uptake
what is the u receptor affinity of tramadol vs. that of morphine
1/16 affinity of morphine
what kind of opioid is tramadol
atypical
is tramadol an analgesic
yes
does naloxone block the analgesic effects of tramadol
not completely
why can tramadol be potentially used in opioid resistant neuropathic pain
because it blocks serotonin uptake
what does tramadol do to descending serotonergic inhibitory processes
potentiates (IDK)
what is the mechanism of action of tapentadol
mu agonist (weak), NA uptake inhibitor
compare nausea made from morphine and tapentadol
worse nausea in morphine
rate morphine tramadol and tapentadol in order of best to worst
morphine>tapentadol>tramadol
what is naloxone
antagonist, most at mu than delta and kappa
what does naloxone do to normal individuals and why
little effect unless you have your endogenous system working overdrive (ex: it will reduce acupuncture reduced analgesia)
how is naloxone used
to treat opioid overdose
what do you use to treat opioid dependence
buprenorphine + naloxone
what happens when you orally ingest buprenorphine + naloxone
why
allows absorption of buprenorphine and no withdrawal (naloxone is minimally bioavailable by oral routes)
what happens when you IV administer buprenorphine + naloxone
why
rapidly induces opioid withdrawal symptoms
because naloxone blocks mu receptors so it gives those bad symptoms
is buprenorphine or naloxone activated when taken orally
only buprenorphine
is buprenorphine or naloxone activated when taken IV
mostly naloxone will show its effects (antagonist)
what does opioid withdrawal do to BP
hypertension
what does opioid withdrawal do to pupils
dilate
what does opioid withdrawal do to poop
diarrhea
what does opioid withdrawal do to heart
tachycardia
what does opioids do to pupils
pinpoint pupils
what are 3 common things that both opioids and withdrawal cause
sweating
vomiting
hallucinations
what are 2 ways to treat opioid withdrawal
methadone or clonidine
what causes muscle fasciculation and what is it
withdrawal, muscle twitches under skin
what is clonidine used for
opioid withdrawal
what is the mechanism of action of clonidine
alpha2 agonist
