Final- Van Rijn Learning Objectives Flashcards
Pain Transmission Pathway:
Ascending Pathway?
Periphery –> Spinal Cord –> CNS
Pain Transmission Pathway:
Descending Pathway?
CNS –> Spinal Cord –> Periphery/Site of injury
What receptors are involved in pain signaling of the PERIPERHY?
Temperature sensitive (TRP/TRPM/TRPV) Acid Sensitive (ASIC) Chemical Irritant Sensitive (Histamine/Bradykinin)
Periphery Signaling:
What channel is involved with temperature sensitive
TRP
(TRPV - Vanniloid - HEAT)
(TRPM - Melastatin - COLD)
Periphery Signaling:
what ions are involved in the ASIC?
activated by H+
and
conducts Na+
Periphery Signaling:
what chemicals are involved with the chemical irritant sensitive
histamine
and
bradykinin
______ nerve goes toward spinal cord
and
_______ nerve goes toward muscle (from spinal cord)
afferent
efferent
Nerve Transmission from periphery to spinal cord:
involves _____ and _____ channels along the nerve to propagate the action til it reaches nerve terminal
Na+; K+
Nerve Transmission from periphery to spinal cord:
at nerve terminal ____ channels are present to further facilitate neurotransmitter release
Ca2+
Nerve Transmission from periphery to spinal cord:
release of neurotransmitters (main one is _______) and they work on ______ receptors/channels
(but also ______ neurons exist too..)
glutamate
glutametergic (AMPA, NMDA, mGlu)
GABA
there are how many different pain fibers (for us to know)?
3
what are the names of the 3 diff pain fibers
A-beta
A-delta
C-fibers
Rank the pain fibers from slowest to fastest
C fiber —> A-delta —> A-beta
slow —————————fast
which pain fiber is known as “second pain”
c fiber
which pain fiber is known as non-noxious
A-beta
which pain fiber is myelinated
A-delta and A-beta
which pain fiber is known as first pain
A-delta
which pain fiber is related to touch/pressure
A-beta
which pain fiber is known to have sharp/prickly feeling
A-delta (first pain)
which pain fiber is known to have dull aching pain
C-fiber (second pain)
which pain fiber is unmyelinated
C-fiber (why it is the slowest one!)
with pain transmission —- repeated stimuli will reduce firing threshold — thus _______ is used to heighten pain responding
substance P
what 4 things does substance P do to heighten pain response
vasodilation
degranulation of mast cells
release of histamine
inflammation and prostaglandins
What opioid drugs are phenanthrene structure
morphine codeine hydrocodone buprenorphine levophanol naloxone
what opioid drugs are non-phenanthrenes
tramadol
meperidine
fentanyl
methadone
what opioid is a partial agonist
buprenorphine
what opioid is an antagonist
naloxone
phenanthrene potency is altered mainly by changing substituents at the ____ and ____ position
3;6
Opioid antagonists (like naloxone) are created by having a ________ group
bulky side
T or F: Opioids do not experience much first pass metabolism
false!! hella first pass
since opioids do experience a lot of first pass metabolism… what is a concern about using the drugs
cant use same dose for IV and oral!!
Opioids are mainly _______ eliminated
renally (90%)
also CYP 2D6 and 3A4 stuff
what opioids are prodrugs
heroin codeine and tramadol
which opioid drugs are not prodrugs (the ones vanrijn points out…)
fentanyl and methadone
aka good if hepatic or renal dysfunction
what drugs are good for anesthesia (because reach peak plasma levels fast)
remifentanyl
sufentanil
CYP_____ makes opioids into inactive metabolites
CYP3A4 into NOR_______
Opioids are primarily metabolized by what CYPs
2D6 and 3A4
all opioid receptors are (Gs or Gi) couple
Gi (aka will inhibit adenylyl cyclase!)
what are 4 opioid receptors
Mu
Kappa
Delta
Nociceptin/orphanin
opioid receptors can be activated by the endogenous opioids —- these are known as?
endorphin
dynorphin
enkephalin
nociceptin
what receptor used to be known as an opioid receptor but actually isnt…
sigma receptor
all opioid receptors are Gi coupled but they also activate ________ channels to cause even more hyperpolarization
GIRK
opioid receptors are found presynaptically, postsynaptically, or both?
both!
Presynaptic inhibition happens via _______
and
Postsynaptic inhibition happens via_____
pre: inhibit Ca2+
post: induce hyperpolarization by GIRK
for mu opioids: _________ is assoc. w/ side effects
beta-arrestin (side effect of respiratory depression)
if a drug doesn’t use beta arrestin signaling - less/no chance of respiratory depression
______ is a natural ligand that binds to kappa opioid receptor
Dysnorphin
______ is a natural ligand that binds to delta opioid receptor
Enkephalin
Kappa or Delta Opioid Receptor?
Which one as potential use for treating addiction (because it may have a role in causing addiction…)
kappa
Kappa or Delta Opioid Receptor?
which one has role in preventing hypoxia/ischemia/stroke
delta
Kappa or Delta Opioid Receptor?
which one counterbalances the mu opioid receptor effects
kappa
Kappa or Delta Opioid Receptor?
which one reduces anxiety/depression
delta
Kappa or Delta Opioid Receptor?
which one may be involved in alcoholism
delta
list the drugs that are opioids but are non-analgesic
Dextromethorphan
Diphenoxylate w/ atropine
Loperamide
Eluxadoline (Viberzi)
sufentanil, remifentanil, alfetanil have v short half lives and are used for anestheia/sedation…
they have a short life because …?
they are broken down by esterases due to ester linkage
what Non-phenanthrene opioids are beneficial because they have SNRI antidepressant activities
tramadol
and
tapentadol
what opioid drugs have NMDA antagonism
methadone
levorphanol
what non phenanthrene opioid is not recommended due to being neurotoxic
meperidine
has active metabolite!!
Pentazocine and Butorphanol are
______ agonists and _____ partial agonists/antagonist
kappa
mu
Nalbuphine is a
full agonist at _____ and antagonist at ____
kappa
mu
Buprenorphine is a partial agonist at \_\_\_\_\_\_ weak agonist at \_\_\_\_\_ and antagonist at \_\_\_\_\_
mu
kappa
delta
what does inflammatory pain feel like
throbbing / pulsating
what does neuropathic pain feel like
burning
tingling
shooting
electrical
what does visceral pain feel ike
deep
squeezing
compression
what does breakthrough pain feel like (??)
spontaneous
iodopathic
incidental
what pain is known as throbbing/pulsating
inflammatory
what pain is known as burning/tingling/shooting
neuropathic
what pain is known as deep/squeezing
visceral
what condition is known to be allodynia pain
fibromyalgia
Substance P or NMDA/AMPA are more related to peripheral sensitization?
Substance P
it heightens pain response
Substance P or NMDA/AMPA are more related to nerve transmission from periphery to spinal cord?
NMDA/AMPA(mGlur too)
these are the receptors at the spinal cord — receptors for the neurotransmitters that Ca2+ help release)
what pain related disease state is an example of central sensitization
fibromyalgia
tx options for fibromyalgias
Ca2+ blockers/TCAs/Anti-convulsants
Chronic pain is typiclly enhanced by _______ sensitization
central
opioid receptors are found in high expression in the ______ along the _______ pathway
brain stem
descending pathway
When opioid receptor is activated in brain — what are the results
altered mood
sedation
reduced emotional reaction
When opioid receptor is activated in brain stem — what are the results
increase activity of descending fibers
When opioid receptor is activated in spinal cord — what are the results
inhibit vesicle release
hyperpolarize postsynaptic membrane
When opioid receptor is activated in periphery — what are the results
reduce activation of primary afferent nerves
modulate immune activity by modulating inflammatory mediators
what drugs are known as “peripherally restricted mu opioid antagonists”
Relistor (Methylnaltrexone)
Entereg (Alvimopan)
Movantik (Naolxegol)
Symproic (naldemedine)
what are the “peripherally restricted mu opioid antagonists” drugs used for?
for opioid induce constipation
what is the MOA of drugs that are used for treating opioid induced constipation
they antagonize the mu opioid receptor in the ileus (peripherally restricted to the gut!)
preventative/acute management of opioid induced constipation?
senna
polyethylene glycol (Miralax)
Docusate
Therapeutic Use of the Mu Opioid Receptor
Analgesia (not chronic pain tho??)
sedation
antitussive
Kappa opioid receptors may have role in _______ and are typically known to cause ______
role in addiction
dysphoria
Delta opioid receptors are known to decrease _______ and ______
Delta opioid receptor will also treat ________
decrease anxiety/depression
treat alcoholism
mu, kappa, or delta is more related to chronic pain?
delta
what NSAID is a salicylate
aspirin
what NSAIDs are arylpropionic acids
ibuprofen
what NSAIDs are arylacetic acids
indomethacin diclofenac ketorolac etodolac sulindac
what NSAIDs are Enolic acids
meloxicam
piroxicam
________ are the mediators of inflammatory pain – thye recruit inflammatory cells
Eicosanoids (aka arachidonic acid metabolites)
Prostaglandins, Thromboxanes, Leukotrienes, Cytokines
What are the types of eicosanoids?
Prostaglandins,
Thromboxanes,
Leukotrienes,
Cytokines
Inflammatory Response/Arachadonic Acid Pathway:
_______ are suggested to be the contributor to the painful response
prostaglandins
Inflammatory Response/Arachadonic Acid Pathway:
Inhibiting ________ leads to reduction in thromboxane
COX1
Inflammatory Response/Arachadonic Acid Pathway:
________ induces platelet aggregation
thromboxane
Inflammatory Response/Arachadonic Acid Pathway:
Inhibiting thromboxane = blood thinning or clotting?
thinning
duh, NSAIDS inhibit COX enzymes = decrease thromboxane = less aggregation = more bleeding
COX 1 or COX2 leads to protective mucosa effects?
COX1
why selective COX2 is good because then don’t worry about GI bleeds as much
Thromboxane or Prostacyclin will reduce platelet aggregation?
Prostacyclin
COX 1 or COX2 is induced when there is inflammation?
COX2
Thromboxane or Prostaglandins promote uterine motility?
prostaglandins
thromboxane causes vasodilation or vasoconstriction?
constriction!
Thromboxane = thrombosis = platelet aggregation AND constriction - aka asking for a thrombus..
COX 1 or COX 2 has bigger rule in nociception
cox 2!
PGI2 causes vasodilation or vasoconstriction?
vasodilation!
acts opposite of thromboxane
Aspirin Overdose/Poisoning looks like??
Metabolic Acidosis!! (seen when severe ASA toxicity)
(look at ABG and BMP)
N/V/sweating/fever
delirium
respiratory alkalosis (seen when moderate toxicity)
To treat Aspirin Overdose - what do you do?
want to get ASA excreted….
thus give dextrose, or Na+HCO3- or dialysis
what NSAID irreversibly inhibits COX?
ASA
Ibuprofen or Naproxen has longer half life
naproxen!(~14 hr)
[Ibuprofen (~2 hr)]
Diclofenac has increased risk for ________ and renal dysfunction with prolonged use
For protective effect —- use ________
risk: peptic ulcer
give: Misoprostol (PGE1 analog)
Arylacetic acid NSAIDs are really weak or strong inhibitors of prostaglandins?
strong!! why hella peptic ulcer risk
Enolic Acid NSAIDs have great ______ penetration
joint
At low doses of meloxicam it is __________ seletive
cox 2
Enolic acids — short or long half life?
long!
Meloxicam (~20 hours)
Piroxicam (~ 57 hours)
why should NSAIDs be avoided in pregnancy?
it inhibits uterine motility!!
when are NSAIDs sometimes helpful in pregancy?
used to DELAY preterm labor
because they inhibit uterine motility
NSAIDs cause diuresis or Peripheral edema?
edemaaaa (because NSAIDs lead to Na+ reabsorption)
why CV risk
Peripheral Edema risk with NSAIDs increase with shorter or longer acting NSAIDs?
longer!!
Advantages of APAP?
no GI toxicity
no effect on platelet aggregation
no reye’s syndrome crap
CAN still be used in liver disease – just do < 2 g/day
Disadvantages of APAP
hepatic necrosis if acute overdose
no anti-inflammatory effect
APAP is converted to _______ by _____ enzymes (which can form toxic reactions)
NAPQI; CYP
explain how APAP overdose happens
APAP –> NAPQI (which is a toxic fella)
NAPQI usually not a problem because it gets conjugation with GSH
BUT overdose = run out of GSH = more NAPQI
how does APAP and Alcohol a bad interaction?
Alcohol increases CYP Enzymes aka more NAPQI is made (still not enough GSH present to make NAPQI not a problem)
Biggest pro with COX2 Selective Inhibitors?
reduced ulcers and GI bleeds
Biggest con with COX2 Selective Inhibitors?
High chance of blood clots/strokes/heart attacks
because COX 1 not inhibited = more thromboxane (not in balance with PGI2) = hella more thrombosis/platelet aggregation
ALL NSAIDs should be avoided in patients with what 3 PMH/disease states?
- CKD
- Peptic Ulcer Disease
- Hx of GI bleed
T or F: Not all NSAIDs carry a CV risk in pts with coronary heart disease in the short term
FALSE!!! they do!
(Diclofenac - highest risk
lowest risk - naproxen)
NSAIDs or APAP can cause asthma exacerbation
NSAIDs
what channel is an analgesic target (GOF and LOF mutations are big in this)
Na+
NaV1.7 and NaV1.8
Local anesthetics are _____channel blockers
Na+
what drugs are local anesthetics/Na+ channel blockers
lidocaine
Bupivicaine
Benzocaine
SNRIs w/out Na+ channel blocking properties can be used to treat chronic pain conditions because why?
they increase NE
more NE = able to activate alpha2 receptors in spinal cord = inhibit neutrotransmission bc receptors are GI coupled
*also why clonidine can work — works at alpha 2 receptor
(from VanRijn lectures)
which SNRIs have Na+ channel blocking power (#2)
and
which SNRIs do NOT have Na+ channel blocking power (but will still help with pain_
have Na+: Duloxetine and venlafaxine
No Na+: Milnacipran; Tapentadol
(from VanRijn lectures)
what drugs are Ca2+ blockers that can be possible analgesics
Gabapentin and PRegabalin
Ziconotide
Levetiracetam
Main points about general anesthesia
loss of consciousness
endotracheal tube needed
main points of Neuraxial anesthesia
placed into spinal area/epidural
used for abdomen and lower back surgeries
main points of peripheral nerve block (PNB)
local anesthetic
used for surgeries on extremities
3 Main Components for Anesthesia
Muscle Relaxant
induce amnesia (loss of consciousness)
Analgesia/Sedation
(May need anxiolytic too)
Propofol is a _________ modulator of ______ channels
Propofol is also a ______ agonist so it causes ______ at injection site
positive allosteric; GABA
TRPA; pain
T or F: when trying to cause peripheral nerve block you should inject the drug directly into the nerves
Falseeee. NEVER inject directly into a nerve
what drugs are typically used for peripheral nerve block
mepivacaine
ropivacaine
which Na channel isoforms are expressed in the PNS in the afferent neuron?
Nav 1.7, 1.8, 1.9
aka have limited side effects because only in PNS
which Na channel isoforms are expressed in the CNS?
Nav 1.1, 1.2, 1.3, 1.6
which Na channel isoforms are expressed in the cardiac muscle?
Nav1.5
which Na channel isoforms are expressed in the skeletal muscle
Nav1.4
Cell Physiology:
At rest — Na+ is _____ of the cell and K+ is ______ the cell
Na+ – outside
K+ inside
Process of Local Anesthetic (LA) Entering the Cell:
LA binds to ________ side of ______ channel
intracellular;
Na+
Process of Local Anesthetic (LA) Entering the Cell:
LA is a weak acid or base?
weak base
Process of Local Anesthetic (LA) Entering the Cell:
LA is a weak base thus it is or is not protonated at pH < 7.4
it is partly not protonated at a pH < 7.4 (thus can penetrate cells)
LA’s pKa = ~ 7.5 - 9..
what are the 3 different moieties that make up local anesthetic?
lipophillic group (aromatic ring( intermediate linkage ionizable group (terminal amine)
Bicarbonate helps or inhibits Local anesthetics from penetrating the cell
helps!
since LA’s are weak bases - the higher the pH the increasing percentage that the LA is non-ionized and is more capable of crossing the membrane
Local Anesthetics have a higher affinity for Nav channels when it is the non-ionized or ionized form?
ionized
when intracellular - pH is lower than extracellularly aka will be protonated
Intracellular pH is lower or higher than the extracellular pH
LOWER aka more acidic aka will protonated local anesthetics (da weak bases)
4 main factors that influence local anesthetics
frequency of transmission
size/class of peripheral axons
pH
Vascularity of target tissues
______ pH reduces efficacy of LA
acidic
Local anesthetics have faster/higher absorption when the blood flow is _______
greater
LAs bind to the closed or open state of the Nav channel
open
LAs work (aka block pain) better on small myelinated or large unmyelinated nerves
small/myelinated
because fire better and can move it faster
Potency of LA is better when it is hydrophillic or lipophillic?
lipophillic
For LA: lower or higher pKa leads to longer half life
lower pKa
lower pKa = more it resides in non-protonated form = cross plasma membrane faster also evades degradation
Duration of action of a LA is is determined by _______ and _______
protein binding
hydrophobicity
Adrenergic agonists or antagonists are used as adjuncts to local anesthetics — and why?
agonists!
they cause vasoCONSTRICTION and that prolongs duration of action by limiting diffusion of the drug
Amide or Ester based LAs?
have fast onset
amide
Amide or Ester based LAs?
have short to long duration
ester
Amide or Ester based LAs?
have med to long duration
amide
Amide or Ester based LAs?
have variable onset
ester
Amide or Ester based LAs?
slow t1/2 (hours)
amides
Amide or Ester based LAs?
rapid t1/2 (minutes)
esters
Amide or Ester based LAs?
has fast hydrolysis by esterases
ester
Amide or Ester based LAs?
has hydrolysis by CYP system
amide
Amide or Ester based LAs?
caution of giving this kind of LA in hepatic disease
amide
bc its metabolized by CYPs
Ester bond or amide bond is more rapidly metabolized
ester
Metabolism of _____ bond containing LAs leads to formation of ______ which can cause an allergic rxn/dermatitis/asthmat attacks
ester bond
PABA (para-aminobenzoic acid)
Main Local Anesthetic Toxicities
Neurotoxicity
Cardiovascular
Methemoglobinemia
Local Anesthetics: Neurotoxicity
First CNS _______
then at high doses CNS _______
first: stimulation
high doses: depression
Local Anesthetics: Neurotoxicity
When at first CNS is stimulated what is the result?
inhibit GABA neurons (aka = stimulation)
will induce seizures!!! ahhhh. treat w/ benzos
Local Anesthetics: Cardiovascular
what are the outcomes of this toxicity?
Vasodilation/hypotension
Depress cardiac AP/Dysrhytmias
Cardiac arrest
neuromuscular blockers work by blocking _______ or _________
block Ach transmission
or
block nicotinic receptors on skeletal muscle
what are the 2 types of neuromuscular blockers
depolarizing
and
non-depolarizing
what is an example of a depolarzing neuromuscular blocker
succinylcholine
Avoid using depolarizing neuromuscular blockers in ______ because it could cause ______
HYPERkalemia;
cardiac arrest
Succinylcholine is metabolized fast or slow and by what?
fast!!
by Butrylcholinesterase
why should depolarizing agents be avoid if a patient has hyperkalemia
depolarizing agonists cause influx of K+ — adds to the current hyperkalemia = at high risk of cardiac arrest
Non-depolarizing neuromuscular blockers MOA?
ACH/Nicotinic receptor ANTAGONIST
example of non-depolarizing neuromuscular blocker
pancuronium
Non-depolarizing neuromuscular blockers are _____-like
curare
Non-depolarizing neuromuscular blockers are reversible or irreversible
reversible!! easily!
how can you reverse non-depolarizing neuromuscular blockers
AchE inhibitors (neostigmine)
Cyclodextrin Scavenger (Suggamadex)
naloxone or naltrexone?
has limited bioavailability
naloxone
why we do nasal spray
naloxone or naltrexone?
has medium half life?
naltrexone (taken PO daily for abuse…)
naloxone or naltrexone?
has faster onset?
naloxone
what are the 3 main drug categories (for drugs that are abused)
stimulants
depressants
psychedelics
what drugs of abuse are known as depressants
opioids alcohol cannabis GHB inhalants
what drugs of abuse are known as stimulants
cocaine amphetamine meth bath salts ectasy nicotine
what drugs of abuse are known as psychedelics
LSD psilocybin PCP mescaline ketamine
per DEA: what schedule is this drug?
heroin
I
per DEA: what schedule is this drug?
ketamine
III
per DEA: what schedule is this drug?
BZDs
IV
per DEA: what schedule is this drug?
lomitil
V (antidiarrheal - its an opioid used as an antidiarrheal)
per DEA: what schedule is this drug?
marinol
III (its THC in capsule form)
per DEA: what schedule is this drug?
Cocaine
II (!!!!!)
per DEA: what schedule is this drug?
Ritalin
II
per DEA: what schedule is this drug?
Marijuana
I
per DEA: what schedule is this drug?
MDMA
I
per DEA: what schedule is this drug?
PCP
II (!!!!!)
per DEA: what schedule is this drug?
LSD
I
per DEA: what schedule is this drug?
heroin
I
per DEA: what schedule is this drug?
buprenorphine
III
per DEA: what schedule is this drug?
psilocybin
I
T or F: DEA drug scheduling is permanent
hell nah
what 5 groups does VanRijn mention that are substances of abuse that act DIRECTLY on GPCRs?
Opioids LSD/mushrooms Marijuana/K2/spice GammaHydroxyButyyric ACid (GHB) Caffeine
Substances of abuse work on GPCRs:
Opioids work on what specifically?
opioid receptors (mu)
Substances of abuse work on GPCRs:
LSD/mushrooms work on what specifically?
5HT receptors! (2A and 2C)
*LSD and Mushrooms aka psilocybin and psilocin?
Substances of abuse work on GPCRs:
Marijuana/K2/Spice work on what specifically?
cannabinoid receptors (CB1)
Substances of abuse work on GPCRs:
GHB works on what specifically?
GABA (B)!! receptor
GABA(A) is not a GPCR but is a channel
Substances of abuse work on GPCRs:
caffeine works on what specifically
adenosine
Substances of abuse work on GPCRs:
The drugs binding to their respective GPCR can modulate _______ or _______ channels — leads to increase or inhibiting release of excitatory/inhibitory neurotransmitters
Ca2+; K+
what substances of abuse work INDIRECTLY on GPCRs
Cocaine/ampheamine
MDMA/Ectasy
Alcohol
Substances of abuse work on GPCRs:
Cocaine/Amphetamine work on what specifically?
dopamine transporter (remember it is INDIRECTLY working on GPCRs)
Substances of abuse work on GPCRs:
MDMA/Ecstasy work on what specifically?
Monoamine transporter (DA/5HT) (remember it is INDIRECTLY working on GPCRs)
Substances of abuse work on GPCRs:
Alcohol works on what specfically?
GABA Channels!! (also 5HT, NMDAR, NACHR, KIR3) — WILL CAUSE ENDOGENOUS RELEASE OF OPIOIDS —
what substances of abuse act on ION CHANNELS
Nicotine
PCP/Ketamine
BZDs/Barbitruates
Substances of abuse working on Ion channels:
Nicotine works how?
AGONIST of ionotropic Ach receptors (Na+)
Substances of abuse working on Ion channels:
PCP and Ketmaine work how?
ANTAGONIST to ionotropic NMDA receptor (Ca2+, K+, Na+)
Substances of abuse working on Ion channels:
BZDs and Barbiturates work how?
Postive allosteric modulators (PAMs) for ionotropic GABA receptors (Cl-)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Cocaine
indirect on GPCRs (dopamine transporter)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Nicotine
ion channels (Ach receptor agonist)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Caffeine
direct on GPCRs (adenosine receptors)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
BZDs
ion channels (PAM for GABA receptors)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
MDMA/Ecstasy
indirect on GPCRs (monoamine transporter - DA and 5HT)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Alcohol
indirect on GPCRs (causes release endogenous opioids – GPCR)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
amphetamine
indirect on GPCRs (dopamine transporter)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
opioids
direct on GPCR (mu opioid receptor)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
marijuana/K2/spice
direct on GPCRs - cannabinoid receptors (CB1)
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
GHB
direct on GPCRs (works on GABA(B))
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
LSD/mushrooms
direct on GPCRs (works on serotonin receptors)
Circuit related to dopamine neurons and abuse of drugs?
Limbic pathway!! (VTA –> Amygdala/Prefrontal cortex/Hippocampus)
what brain region is important in reward sensation/valuation
nucleus accumbens
what brain region is important in memory/learning
hippocampus
what brain region is important in emotion/fear
amygdala
what brain region is important in planning/judgement
prefrontaol cortex
what brain region is the “source of dopamine”/dopamine neurons originate here
VTA (ventral tegmental area)
drugs of abuse of diff. classes all are habit forming/addictive b/c they act on the same pathway of _______ release in the _______
dopamine;
nucleus accumbens
(they just may do it through different pathways that lead to DA release)
why is the limbic system important for survival in humans?
limbic system makes you want to find food and procreate
2 main hypothesis of addiction
dopamine hypothesis
and
glutamate hypothesis
idea behind dopamine hypotehsis of addiction?
1) pleasurable events lead to release of DA
2) parkinson disease pts less likely to suffer from addiction – unless they are taking L-DOPA then they are more likely
3) dopamine is important in assigning “incentive salience”
what is incentive salience
a particular item is a higher priority than other other things (ex: that dude dove in dirty toilet for opioid suppository b/c seemed like a v high priority for him)
limits of dopamine hypothesis of drug abuse?
1) there is a distinction b/w like and want..
2) monkey experiment shows that DA neurons can fire in anticipation and evoke a drive to action (not always a response)
Glutamate hypothesis of addiction?
1) Glu can increase DA activity in NAcc
2) destruction of Glu pathway to VTA = reduce drug reward
Hypothesis of Addiction
______ controls_____ activity in amygalda
DA; Glu
drug use iduces long term ______
plasticity
what is LTP stand for (about drug use) and what does it mean
long term potentiation
means: persistent increase in synaptic strength following intense stimulation
Drug Use: LTP:
Persistent stimulation causes strong release of ______ - this causes an enhanced expression of _______ receptors on post-synaptic membrane:
This leads to the ratio of _______ being increase
stimulation = major increase in Glu release
enhanced AMPA receptor expression
leads to higher ratio of: AMPA/NMDA
(higher ratio is known as CELLULAR MEMORY)
T or F: Only unnatural substances lead to longer cellular memory (aka increase in AMPA/NMDA)
false!! natural (food, sucrose, sex) AND unnatural (cocaine, heroin, alcohol) both cause the increase ratio/longer prolonger memory
BUUUUUUUT
unnaturals’ ratio increase lasts longer!!
T or F: when abstinence from a drug (after cellular memories have formed for the drug) - the drug addiction memories are not erased
truuue. - why people can relapse easily
BUT during abstinence time period — new cellular memories about abstinence are being created and are competing with the drug abuse cellularmemories
Substance used disorder criteria: (how many pts?)
Mild:
Moderate:
Severe:
Mild: 2 - 3
Moderate: 4 - 5
Severe: > 6
what are some of the emotional withdrawal symptoms
anxiety/depression restlessness/insomnia irritability poor concentration (HA - vanrijn put this here but maybe physical??)
what are some of the physical withdrawal symptoms
sweating racing heart goose bumps muscle spasms tremors N/VD
what are some of the more dangerous withdrawal symptoms?
Grand Mal seizures
heart attacks/strokes
hallucinations/delirium tremens (DTs)
*these are seen a lot with alcohol and tranquilizers (bzds and barbiturates)
difference/definitions of positive and negative reinforcements?
positive: keep taking because it is rewarding/pleasurable/giving satisfaction
negative: taking to escape a negative/painful stimulus or event
3 main ways for pathway to addiction
1) Therapeutic use
2) recreational use
3) self medication
Pathways to addiction:
Therapeutic use — (-) or (+) reinforcement?
(-) –> (+) –> (-)
Pathways to addiction:
Recreational Use — (-) or (+) reinforcement?
(+) –> (-)
Pathways to addiction:
Self Medication — (-) or (+) reinforcement?
(-)
what are the primary psychoactive compounds in marijuana
THC
cannabidiol
cannabinol
Cannabidiol oil — has low or high activity at CB receptors (thus also has low or high psychoactive effects)
low activty @ receptors
and low psychoactive activity (why starting to be used for seizures/legalized)
Scheduling of Marijuana:
Plant: ____
Nabilone (synthetic cannabinoid): _____
Marinol (THC formulation) _____
I
II
III
how is K2/Spice made?
synthetic marijauna/cannabinoids are sprayed onto plant material
what are the physical effects of marijuana use?
sedation red eye tachycadria angina (if hx of coronary insufficiency) reduction in pulmonary vitality
why does marijuana cause red eye
it dilates conjunctival vessels
what are sxs of marijauna withdrawal
dysphoria
anxiety/depression
decreased appetite
what is “cannabinoid hyperemesis syndrome” and how do you treat it?
it is N/V
relieved by hot shower and is dose dependent (so no smoking = no syndrome)
overdose is uncommon but what are possible things seen with overdose on marijuana
anxiety/panic attacks
convulsions
why can a fatal overdose not really happen with marijauan
there are no CB receptors in respiratory centers of brain stem
PK of THC:
quick or slow absoprtion?
metabolized by ______
short or long half life?
quick absorption
liver (CYP2C9)
long 1/2 life
PK of THC:
is an agonist to ______ which are GPCRs
are they Gi or Gs?
CB1/CB2
Gi
since CB receptors are Gi – whent hey are activated they will _____ Ca2+ channels and _____ GIRK channels
inhibit Ca2+
activate GIRK
THC will _____ release of GABA
inhibit
CB1 or CB2 is of higher expression in brain?
CB1
CB actions in the _______ lead to locomotor effects
cerebellum
CB actions in the _______ lead to appeteite increase
hypothalamus
CB actions in the _______ lead to effects on memory and coping with stress
hippocampus
CB actions in the _______ lead to effects with pain
PAG, LC (locus coeruleus), SC (spinal cord)
With marijuana ingestion: psyhcoactive cannabinoids will bind to _____ receptors found (pre or post) synaptically on _____ neurons
CB1 receptors
PRE-synapse
GABA neurons
psychoactive CBs will promote or inhibit release of GABA neurotransmitters
INHIBIT
with CBs inhibiting GABA release — the GABA receptors post synaptically have reduced activity — the post synaptic ones NORMALLY do what?
normally inhibit DA neurons
aka CB receptor activation leads to DISINHIBITION on DA neurons
CB receptor activation leads to DISINHIBITION on DA neurons – this leads to dopamine _______ in the ______
release; nucleus accumbens
CB1 or Cb2 is found in higher expression in the periphery
CB2
CB1 or CB2 receptors are expressed on lymphocytes (B and T cells)
CB2
Anandamide and 2-arachidonylglycerol (2-AG) are what ?
endogenous cannabinoids
endogenous cannabinoids: for 2-AG
DAG lipase does _____ and is found ____
MAG lipase does ____ and is found _____
synthesis; post-synaptically
degradation; pre-synaptically
(not sure on locations 100% bc i think he contradicts himself later in the notes ………)
endogenous cannabinoids: Anandamide
AEA does ______
FAAH does _______
AEA: synthesis
FAAH: degradation
what route of marijuana ingestion is seen to be th emost efficacious
vaping
what are the 2 FDA approved cannabinoid drugs
marinol
nabilone
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
acts as an anti-emetic
nabilone
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
is used to increase appetite (helpful for chemo pts o pts with HIV/AIDS)
Marinol
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
is synthetic THC in seasme oil
marinol
Cannabinoids and Increasing Appetite:
activation of CB1 —> inhibits _____ neurons in the ______
POMC neurons
in hypothalamus
Cannabinoids and Increasing Appetite:
NORMALLY when POMC neurons get stimulated (they are inhibited when CB is activated..) it leads to ________ which activates _______ which is involved in appetie suppression
release of alpha-MSh
activate MC4R (melanocortin)
Cannabinoids and Increasing Appetite:
Normally POMC leads to appetite suppression or heightened
appetite suppression
POMC inhibited when marijuana in system thus leads to appetite being heightened
Cannabinoids and Increasing Appetite:
when POMC is inhibited it shifts gene transcription of _____ (up or down) which leads to increase in appetite
beta endorphins (up!)
Cannabinoids can reduce N/V:
CB1 receptors where allow this to happen?
CB1 in GI tract and in brain stem
super detailed:
in GI: submucsal plexus and myenteric plexus
in Brain stem:
NTS and AP
NTS: Nucleus of solitary tract; AP: Area Postrema
CB1 presence in brain stem helps with reduce nausea with chemotherapy because it works at the NTS which affects ______ and AP which controls ______
NTS: gag reflex
AP: controls vomiting
how do cannabinoids help with glaucoma?
CB1 receptors are on ciliary muscles can relax the muscle and reduce the fluid build up to reduce sxs of glaucoma
Cannabinoids can help with MS: Ways that it helps:
Activating CB2 receptors on ____ cells
moving shift from _____ to _____ cells
there are also CB2 receptors on_____
on T cells
TH1 –> TH2 (aka goes towards anti-inflammatory)
glial cells
how can cannibinoids be helpful in pain?
CB1 and Cb2 receptors are expressed in spinal cord and they can inhibit the release of substance P, inflammatory cytokines, and glutamate = reduce central pain sensitization
psychedelics:
3 main classes?
hallucinogens
dissociateies
delirants
t or f: hallucinogens are typically very addictive
false actually (biggest issue with these drugs is that they might hurt themselves while taking them)
PCP and ketamine are usually used as?
veterinarion anestheetics
Psilocybin and Psilocin:
these are in magic mushrooms
(less or more) potent than LSD
which one is a prodrug of the other?
less potent
Psilocybin is prodrug of psilocin
Salvia:
acts fast or slow?
is a ____ opioid receptor agonist
works v fast
kappa
what hallucinogen is known to be helpful in treating drug abuse because it allows for introspection?
*it is NOT legal in US
ibogaine
what molecule is thought to be the cause of hallucinations
serotonin
Serotonin Receptors:
G____?
Gi/o, Gs, AND Gq!!
Presynaptic serotonin receptors tend to be G____
and
Postsynaptic serotonin receptors tend to be G____
Pre: Gi
Post: Gq
LSD works on what serotonin G receptor?
Gq - 5HT2A
serotonin/serotonin receptor binding molecules tend to have what common moiety?
tyrptamine
Mescaline is found in peyote - it combines the action of what 2 other hallucinogens
LSD; MDMA
LSD and MDMA (aka mescaline too) are known as _________ or ______ which makes these more hallucinogenic (rather than stimulatory)
empathogens; entactogens
Mescaline has a ____ potency and _____ half life (and has cross tolerance with LSD)
LOW; long
what hallucinogenic drugs are known to be glutamatergic NMDA receptor antagonists (this lead to inhibiting GABA release –> more glutamate release..)
Ketamine
PCP
most of the dissociative psychedelics have what MOA?
NMDA receptor antagonist
what are the 3 main medical uses of ketamine
anesthesia
chronic pain analgesia
anti-depressant (good for tx resistant)
what are examples of dissociative psychedelics
Ketamine
PCP
Dextrmetorphan
Muscimol
ketamine or PCP - which one has severe dissociation
PCP!
remember the PCP face being disgusting
what is the MOA of muscimol
it is a true GABA(A) agonist
what are examples of synthetic/designer drugs of psychedelics — of opioid class
krokodil (can cause gangrene)
Codeine derivs.
what are examples of synthetic/designer drugs of psychedelics — of cannabinoid class
K2
Spice
what are examples of synthetic/designer drugs of psychedelics — of stimulant class
Bath salts
designer steroids
what are examples of synthetic/designer drugs of psychedelics — of psychedelics class
PCP
NBOMe
NBOMe is a designer LSD like drug —- does this drug have a lower or higher chance of overdose
higher chance
most psychedelics don’t have this problem but this designer drug does
Main ADEs with Inhalants
cerebral degradation/brain shrinkage
hypoxia
respiratory depression
MOA of inhalants
inhibit excitatory transmission- NMDA antagonism
AND
stimulate inhibitory NTs
