exam 5 pain Flashcards
what are the two types of pain?
acute and chronic
what are the types of chronic pain?
Nociceptive: inflammatory like OA, RA
neuropathic: central or peripheral
visceral: inflammatory like internal organs, IBS
mixed: lower back and cancer
what is opioid induced hyperalgesia?
chronic opioid use can lead to more pain
it can cause a secondary pain pathway
what is clinical assessment of pain?
pain is an emotion and impacts mood
what is the pain circuitry?
Pain starts at trauma and travels to the spinal cord
Then travels to the brain where the signal is read
Then travels back down to the spinal cord to act on CNS
what are the peripheral receptors and channels involved in pain signalling?
temperature sensitive: TRP, TRPV for heat and TRPM for cold
acid sensitive: acid sensing ion channel (ASIO) –> activated by H+ and conducts Na+
chemical irritant senstive: histamine and bradykinin
What is the main ion channel responsible for conduction of pain signal
Na 1.8
What are the three different pain fibers that transduce different pain signals?
Alpha-B fibers
Alpha-delta fibers
C- fibers
A-B fibers function?
not pain producing - so just touch and pressure
fastest, 35-75m/s
alpha-delta function?
pain and cold
myelinated
first pain, reflex arc
fast
C fibers function?
pain, temperature, touch, pressure
unmyelinated
slowest
second pain –> dull, aching
What is substance P?
Plays a role in heightening pain response
repeated stimuli reduces firing threshold
increased expression of pain receptors leads to sensitization –> since it sends more signals to spinal cord
functions: vasodilation, degranulation of mast cells, release of histamine, inflammation of prostaglandins
what is the spinal pain cicuirtry?
nerve damage causes nerve degeneration (neuroma)
neuroma causes spontaneous afferent activity and spinal sensitzation
what is spinal sensitization?
it leads to non painful stimulus becoming painful due to increased AMPA and NMDA receptor
what is spontaneous afferent activity?
it leads to spontaneous dysesthesias (shooting and burning pain)
Whtat is the brain pain circuitry?
high expression of opioid receptors in the brain stem along descending pathway
mu opioid receptor in the brain plats important role in pain signal
what are the two types of opium alkaloids?
Phenanthrenes - three ring structures
Benzylisoquinolones
what are the differences between opiates and opioids?
opiates are naturally occuring (morphine)
opioids are general term like synthetics (fentanyl)
What does 3 position substitutions ether or ester produce?
decreases the potency
seen in codeine
what is the function of 6 position?
increases activity seen in hydromorphone or hydrocodone
what is the function of the 14 position OH?
increases the potency seen in oxycodone
what type of receptors are opioid receptors?
GPCR
open GIRK postassium channels that normally maintain membrane potential
drugs hyperpolarize
what is the Mu opioid receptor and what are it’s therapuetic uses?
beta-endorphins (endogenous morphine)
uses: acute pain treatment, sedation, antitussive
not as effective for chronic pain
what is the presynaptic action of mu opioid receptors?
inhibit Ca+ channels to to decrease neurotransmitter release
what is the postsynaptic activity of mu opioid receptors?
activate GIRK channel releases efflux of K+ that causes hyperpolarization
What are opioid induced side effects?
they are on target effects
respiratory depression, constipation, addction, urinary retention, N/V, mioisis
pruritus due to opioid inducing histamine receptors
would you use opioids as anti-diarrheal?
Yes, some opioids are formulated to specifically act on the Gi
what is the kappa opioid receptor?
dynorphins are the natural ligand
activation causes dysphoric effects
why are kappa opioids thought to be less addictive?
activation of K opioid receptor causes dysphoric effects
there is a reduction in DA release
this can be used in combo with mu opioid receptor agonists to reduce addiction potential
are there any delta opioid receptor agonists approved?
none approved by FDA
what is the mechanism for opioids leading to addiction?
- Opioid binds mu receptor
- GI singaling inhibits neurotransmitter release
- Less GABA to activate GABA-a
- Less inhibition of dopamine neuron activity
- Increase in DA release
- Increased activation of DA receptors
What are the pharmacokinetics of morphine and phenanthrenes?
they are readily absorbed
go through first pass metabolism
hepatic metabolism: CYP3A4 and CYP2D6
glomerular filtration
which opioids are pro drugs?
heroin, codeine, tramadol
which opioids do not produce active metabolites?
methadone and fentanyl
Which drugs are metabolized by CYP3A4?
drugs beginning with NOR are created from 3A4
nor metabolites are deactivated and less active
What is the plasma concentration of an UM taking a prodrug?
increased plasma concentrations
higher ADRs
what is the plasma concentration of a PM taking a a prodrug?
no therapeutic effect
what is fentanyl’s potency?
very potent
100x morphine
50x heroin
what are the opioids related to fentanyl?
Sufentanil, remifentanil, alfentanil
used for anesthesia and sedation
breakdown by plasma esterases due to ester linkage
what are the common opioids?
hydromorphone: no active metabolites
morphine
hydrocodone
oxycodone
what are the non-phenanthrene opioids?
tramadol, meperidine, methadone
what is tramadol?
has SNRI properties
mild opiate analgesic
what is meperidine?
used to treat rigors (shivering)
not recommended
what is methadone?
used for opioid dependence
pronlonged QTc
NMDA antagonist to also reduce pain signal
what are other clinically used opioids that are non analgesic?
cough/antitussive: codeine and dextromethorphan
anti-diarrheal: loperamide and lomotil
what is bupennorphine?
partial mu agonist
weak K and delta agonist
used for opiod replacement therapy
what are medications used for constipation?
senna: irritates colon to force contraction
PEG
dioctyl sodium
how is methadone used for opioid dependence?
Full mu receptor agonist
Slow acting
Accumulation with repeated dose
NMDA antagonist
how is buprenorphine used for opioid dependence?
Mu opioid partial agonist
Blocks full agonist effect of heroin and oxycodone
Provides some activation
Subutex has abuse potential
how is naltrexone used for opioid dependence?
antagonist
will cause withdrawal due to antagonism
decent oral bioavailability
what is the difference between naloxone and naltrexone?
naltrexone is orally administered and has medium half life
naxolone has limited oral bioavailability and a short half-life
what is Naloxone?
Limited oral bioavailability
Short half life
Rapid onset
Repeated every 2-5 minutes if not concoius
what is neonatal abstinence syndrome?
Drug is passed through placenta and after birth, baby suffers from withdrawal
Heroin and other opiates: Serious withdrawal in baby and Seizures can occur in babies born to methadone users
what is the treatment of neonatal abstinence syndrome?
Nonpharm: swaddling, hypercaloric formula, frequent feedings, rehydration
Pharm: Morphine, SL buprenorphine, methadone, clonidine can be useful
what are the uses of NSAIDs?
Analgesia: chornic pain, myalgias, inflammation
Anti-inflammatory: bursitis, tendonitis, OA, RA, gout
Antipyretic
ASA to reduce risk of MI
What are three phases of inflammation?
Acute: vasodilation –> increased permeability
Subacute: infiltration of neutrophil
Chronic: proliferation
what are eicosanoids?
arachidonic acid metabolites
what is NSAID mechanism?
inhibit COX in AA pathway
decreases in TXA, PGE, PGI
PGI protects stomach lining –> why NSAIDs can cause upset stomach/ulcers
Which NSAID is irreversible?
aspirin
what are the therapuetics of aspirin?
prophylaxis for anticoagulation
no tolerance development to analgesic effects
risk of reyes syndrome in children
what is aspirin poisoning?
mild effects: vertigo and tinnitus
CNS effects: respiratory alkalosis and metabolic acidosis
what is the treatment of aspirin poisoning?
reduce salicylate
dextrose and sodium bicarbonate to trap and excrete
what are arylproprionic acids NSAIDs?
potent reversible COX inhibitors
ibuprofen 2hr t1/2
naproxen 14hr 1/2
what are arylacetic acid derivatives?
diclofenac: can be gel, increased risk peptic ulcer
indomethacin: potnet reversible inhibitors of PG biosynthesis, high side effects
sulindac: less toxic derivative indomethacin
what are enolic acids?
meloxicam and piroxicam
reversible competitive inhibitors
meloxicam low doses is Cox2 selective
what are the ADRs of NSAIDs?
renal function: inhibitrs PGE2 synthesis so water retention and edema
bleed risk
inhibits uterine motility
what are NSAID CIs?
Avoid: CKD, PUD, hx GI bleed
CV risk
Interfere with wound healing
Asthma exacerabtions
What are the therapuetic uses of APAP?
highly effective analgesic and antipyretic
no GI toxicity
overdose can cause hepatic necrosis
what are ADRs of APAP?
more renal toxicity than ASA + NSAIDs
dose dependent necrosis
increase in toxic metabolites NAPQI
why are COX 2 not used anymore?
they had reduce ulcer risk and GI bleeds but are no longer used due to risk of clots, stroke, and heart attacks
what are functions of sodium channel blockers?
local anesthetics
psychiatric drugs
SNRIs
what are local anesthetics?
lidocaine
bupivacaine
benzocaine: esters gave higher allergy risk
what are the sodium channel blockers that psychiatric drugs?
anticonvulsants: lamotrigine, carbamazepine
TCA: amitriptyline and nortriptyline
what are sodium channel blockers with SNRI function?
SNRIs increase NE and can act on A2 receptors to provide analgesia
duloxetine and venlafaxine
milnacipran does not have Na channel function
what are Ca channel blockers?
gabapentin and pregabalin
Cav1,2 selective
not metabolized
no drug-drug interactions
what is schedule 1?
no medical use
high abuse potential
marijuana, THC, LSD
what is a C2?
high abuse potential
has medical use
morphine, cocaine, PCP, opioids
what is C3?
medical use
moderate abuse
ketamine, buprenorphine, marinol
what is the MOA of cocaine and amphetamines?
block DAT which causes an efflux of DA into the synapse
results in accumulation of DA
what are substances that act on ion channels? and what receptors?
nicotine: ionotropic acetylcholine receptor agonist
PCP/ketamine: ionotropic NMDA receptor antagonist
BZD,BARB: GABAa PAM
what is the DA hypothesis of addiction?
pleasurable events release DA
DA is important for assigning value to reward prediction
what are limits of DA hypothesis?
DA is not required for reward learning
DA does not cause liking, is only a predictor of outcome
what is the glutamate hypothesis of addiction?
Glutamate can increase DA activity in Nuclues accumbens
DA controls glutamate activity in amygdala
why does drug use induce long term changes to neuronal plasticity?
Rewarding substances cause increases in glutamatergic AMPA receptors
What is physical dependence?
the body needs more drug and has built tolerance
body withdrawals w/o drug
what is psychological dependence?
mental urge to take drug to function
craving even without withdrawals
what are the types of withdrawal symptoms?
emotional
physical: goose bumps
dangerous: alcohol and tranquilizers, grand mal seizures, delirium tremens
substance use disoder criteria
mild 2-3
mod 4-5
severe 6+
what is drug reward and its relation to postive or negative reinforcement?
Drug is rewarding and produces positive reinforcement
Negative reinforcement: reward by escaping negative stimulus or event
