Exam 5 (final) - Barker's lectures Flashcards
describe opioid induced hyperalgesia
worsened pain due to chronic opioid use
pain is an ________ and impacts mood because of this
emotion
pain begins with stimulus in _______ and signals to the _____
periphery, brain/CNS
temperature sensitive receptors and channels involved in pain
TRP (transient receptor potential cation channel)
TRPV (vanniloid) = heat (and spice like capsaicin)
TRPM (melastatin) = cold (like menthol)
glutamates’ role in pain
glutamate in the major excitatory neuron in brain
-plays a role in conduction in spinal cord
A beta fibers
non-noxious (non-pain producing)
faster (35-75m/s)
A gamma fibers
pain, cold receptors
fast (2-35m/s)
respond to “first pain” such as sharp object
C-fibers
respond to pain, temp, touch, pressure, itch
-“second pain” (dull, aching)
slow (0.5-2m/s)
what is substance P
neuropeptide released when there is an injury causing a chain of events
substance P chain of events (4 steps)
- vasodilation
- degranulation of mast cells
- release of histamine
- inflammation and prostaglandins
neuropathic pain sensitization description (spinal)
neuropeptides (CGRP and substance P) –> PLC –> PKC –> more excitable AMPA and NMDA receptors, and more expression and sensitivity
-possibly leads to ectopic action potentials
where does NSAID inhibition occur along signaling pathway
on afferent neuron just after injury signal is starting to be sent down afferent neuron
mu opioid receptor expression in the brain leads to what effects of opioids
altered mood
sedation
reduction in emotional reaction
morphine, codeine and thebaine are part of what structural class
phenanthrenes
3 position substitutions lead to _____
decreased potency - codeine
6 position substitutions lead to ______
increased activity - hydromorphone or hydrocodone (from codeine)
14 position OH leads to _______
increased potency - oxycodone
N-allyl substitutions leads to _____
antagonist activity - nalaxone or naltrexone
buprenorphine has substitution on which spot of the opioid structure to allow for partial agonism
N-allyl
what 3 opioid receptors are responsible for analgesia effects and side effects of opioids
mu
kappa
delta
presynaptically, mu agonists (opioid agonists) bind to ______ receptors causing an inhibition of _____ channels and a ______ in neurotransmitter release
mu opioid, calcium, decrease
postsynaptically, mu agonists (opioid agonists) bind to ______ receptors causing activation of ______ so that _____ can leave the neuron, preventing conduction to CNS
mu opioid, GIRK channel, potassium
efflux of K+ by GIRK is called ________
hyperpolarization
opioid induced side effects are mostly ____ effects (on-target or off-target)
on target
opioid induced side effects include (6)
-respiratory depression
-constipation
-pruritis (itch - note this is not allergic rxn but can be -bad enough to where pts must switch opioids)
-addiciton
-urinary retention
-NV
would you use opioids as an anti-diarrheal?
yes, you can, and some have been designed to stay out of the CNS so no analgesic effects occur (act only in GI tract to slow motility)
role of kappa opioid receptor
-reduce DA release, meaning reduction in abuse potential
-counterbalance mu opioid receptor effects
role of delta opioid receptor
reduce anxiety and depression
treat alcoholism
side effects: seizures
no FDA approved drugs for this yet
depressants (just like stimulants) can cause DA release. How?
- opioid drug binds presynaptic mu receptor
- less GABA to activate GABA-A
- shuts off inhibition of DA neuron activity
- increased DA release and therefore activation of DA receptors
in general, IV dosing looks like what on a conc./half life graph?
quick initial peak in about 6 minutes, then drops off quick
in general, IM/SQ dosing looks like what on a conc./half life graph?
high initial peak (not as high as IV) in about 30 minutes, then drops off (slower than IV)
in general, PO/PR dosing looks like what on a conc./half life graph?
lower initial peak in about 60 minutes, drops off slower than other forms
morphine bioavailability is ____%
25
morphine is metabolized by CYP _____ and _____
2D6 and 3A4
what three opioids are prodrugs
heroin
codeine
tramadol
codeine is metabolized to _________
hydrocodone
morphine
heroin is metabolized to _________
morphine
CYP3A4 makes opioids starting with ______
nor
-norhydrocodone
-noroxycodone
-noroxymorphone
when UM of codeine is given normal dose, they will have _______ serum concentrations of morphine
increased (by ~50%) (most common in north africa)
when PM of codeine is given normal dose, they will have _______ serum concentrations of morphine
decreased (most common in caucasian)
-no effect
tramadol may have properties similar to what other drug class?
SNRIs
meperidine has a toxic metabolite that leads to neurotoxicity (nervousness, tremors, twitching, seizures). which metabolite is it and what is it metabolized by?
normeperidine, 3A4
blocking of NMDA does what? what drug is this effect seen in?
blocks conduction of pain signals
methadone
3 drugs used to prevent constipation with opioids
Senna
-colonic contraction/increased fluid secretion
PEG (MiraLAX)
-stool softener
docusate
-stool softener
difference between opioid tolerance and opioid induced hyperalgesia
tolerance = needs increased dose to have effect on pain
induced hyperalgesia = due to prolonged opioid use, increased dose with have no effect on pain
methadone is a _____ _______
full agonist
methadone is a ______ antagonist
NMDA
methadone action is _____ and _____
slow and long
buprenorphine is a ______ ______
partial agonist
naltrexone is a ________
antagonist
effects on baby if mother was on opioids during pregnancy
baby has withdrawal up to 4-6 months after birth
-seizures seen in methadone users
-opioids present in breast milk
treatment of neonatal abstinence syndrome
non-pharm:
-more calories
-observe temp, weight (gain or loss), sleep
-rehydrate
pharm:
-morphine 0.4mg/mL
-SL buprenorphine
-methadone 0.05-0.1mg/kg/dose q6h
NSAIDs are COX inhibitors by what pathway
arachadonic acid pathway
COX-1 or COX-2 selective NSAIDs show fewer GI side effects
COX-2
-reduce ulcers
-reduce GI bleed
aspirin MOA
irreversibly inhibits COX-1/2 by acetylation
other NSAIDs MOA
competitive (reversible) inhibition of COX-1/2
which has longer half life ibuprofen or naproxen?
naproxen (14hr)
ibuprofen (2hr)
NSAID CI
CKD
PUD
Hx of GI bleed
increase CV risk
-also known to cause asthma exacerbations
opioids receptors
mu, kappa, delta
LSD, mushrooms receptors
5HT2a, 5HT2c
marijuana, K2, spice receptors
CB1
GHB receptors
GABA-B
caffeine receptors
adenosine
cocaine, amphetamine receptors
DAT
-NE, 5HT secondary
MDMA, ecstasy receptors
monoamine transporters
alcohol receptors
dirty (lots of them)
-GABA
-5HT
nicotine receptors (ion channels)
Ach R
-agonist
PCP, ketamine receptors (ion channels)
NMDA R
-antagonist
benzos, barbiturates receptors (ion channels)
GABA-A
-positive allosteric modulators
