Final- Van Rijn Learning Objectives Flashcards
1
Q
Pain Transmission Pathway:
Ascending Pathway?
A
Periphery –> Spinal Cord –> CNS
2
Q
Pain Transmission Pathway:
Descending Pathway?
A
CNS –> Spinal Cord –> Periphery/Site of injury
3
Q
What receptors are involved in pain signaling of the PERIPERHY?
A
Temperature sensitive (TRP/TRPM/TRPV) Acid Sensitive (ASIC) Chemical Irritant Sensitive (Histamine/Bradykinin)
4
Q
Periphery Signaling:
What channel is involved with temperature sensitive
A
TRP
(TRPV - Vanniloid - HEAT)
(TRPM - Melastatin - COLD)
5
Q
Periphery Signaling:
what ions are involved in the ASIC?
A
activated by H+
and
conducts Na+
6
Q
Periphery Signaling:
what chemicals are involved with the chemical irritant sensitive
A
histamine
and
bradykinin
7
Q
______ nerve goes toward spinal cord
and
_______ nerve goes toward muscle (from spinal cord)
A
afferent
efferent
8
Q
Nerve Transmission from periphery to spinal cord:
involves _____ and _____ channels along the nerve to propagate the action til it reaches nerve terminal
A
Na+; K+
9
Q
Nerve Transmission from periphery to spinal cord:
at nerve terminal ____ channels are present to further facilitate neurotransmitter release
A
Ca2+
10
Q
Nerve Transmission from periphery to spinal cord:
release of neurotransmitters (main one is _______) and they work on ______ receptors/channels
(but also ______ neurons exist too..)
A
glutamate
glutametergic (AMPA, NMDA, mGlu)
GABA
11
Q
there are how many different pain fibers (for us to know)?
A
3
12
Q
what are the names of the 3 diff pain fibers
A
A-beta
A-delta
C-fibers
13
Q
Rank the pain fibers from slowest to fastest
A
C fiber —> A-delta —> A-beta
slow —————————fast
14
Q
which pain fiber is known as “second pain”
A
c fiber
15
Q
which pain fiber is known as non-noxious
A
A-beta
16
Q
which pain fiber is myelinated
A
A-delta and A-beta
17
Q
which pain fiber is known as first pain
A
A-delta
18
Q
which pain fiber is related to touch/pressure
A
A-beta
19
Q
which pain fiber is known to have sharp/prickly feeling
A
A-delta (first pain)
20
Q
which pain fiber is known to have dull aching pain
A
C-fiber (second pain)
21
Q
which pain fiber is unmyelinated
A
C-fiber (why it is the slowest one!)
22
Q
with pain transmission —- repeated stimuli will reduce firing threshold — thus _______ is used to heighten pain responding
A
substance P
23
Q
what 4 things does substance P do to heighten pain response
A
vasodilation
degranulation of mast cells
release of histamine
inflammation and prostaglandins
24
Q
What opioid drugs are phenanthrene structure
A
morphine codeine hydrocodone buprenorphine levophanol naloxone
25
what opioid drugs are non-phenanthrenes
tramadol
meperidine
fentanyl
methadone
26
what opioid is a partial agonist
buprenorphine
27
what opioid is an antagonist
naloxone
28
phenanthrene potency is altered mainly by changing substituents at the ____ and ____ position
3;6
29
Opioid antagonists (like naloxone) are created by having a ________ group
bulky side
30
T or F: Opioids do not experience much first pass metabolism
false!! hella first pass
31
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!!
32
Opioids are mainly _______ eliminated
renally (90%)
| also CYP 2D6 and 3A4 stuff
33
what opioids are prodrugs
heroin codeine and tramadol
34
which opioid drugs are not prodrugs (the ones vanrijn points out...)
fentanyl and methadone
| aka good if hepatic or renal dysfunction
35
what drugs are good for anesthesia (because reach peak plasma levels fast)
remifentanyl
| sufentanil
36
CYP_____ makes opioids into inactive metabolites
CYP3A4 into NOR_______
37
Opioids are primarily metabolized by what CYPs
2D6 and 3A4
38
all opioid receptors are (Gs or Gi) couple
Gi (aka will inhibit adenylyl cyclase!)
39
what are 4 opioid receptors
Mu
Kappa
Delta
Nociceptin/orphanin
40
opioid receptors can be activated by the endogenous opioids ---- these are known as?
endorphin
dynorphin
enkephalin
nociceptin
41
what receptor used to be known as an opioid receptor but actually isnt...
sigma receptor
42
all opioid receptors are Gi coupled but they also activate ________ channels to cause even more hyperpolarization
GIRK
43
opioid receptors are found presynaptically, postsynaptically, or both?
both!
44
Presynaptic inhibition happens via _______
and
Postsynaptic inhibition happens via_____
pre: inhibit Ca2+
post: induce hyperpolarization by GIRK
45
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
46
______ is a natural ligand that binds to kappa opioid receptor
Dysnorphin
47
______ is a natural ligand that binds to delta opioid receptor
Enkephalin
48
Kappa or Delta Opioid Receptor?
| Which one as potential use for treating addiction (because it may have a role in causing addiction...)
kappa
49
Kappa or Delta Opioid Receptor?
| which one has role in preventing hypoxia/ischemia/stroke
delta
50
Kappa or Delta Opioid Receptor?
| which one counterbalances the mu opioid receptor effects
kappa
51
Kappa or Delta Opioid Receptor?
| which one reduces anxiety/depression
delta
52
Kappa or Delta Opioid Receptor?
| which one may be involved in alcoholism
delta
53
list the drugs that are opioids but are non-analgesic
Dextromethorphan
Diphenoxylate w/ atropine
Loperamide
Eluxadoline (Viberzi)
54
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
55
what Non-phenanthrene opioids are beneficial because they have SNRI antidepressant activities
tramadol
and
tapentadol
56
what opioid drugs have NMDA antagonism
methadone
| levorphanol
57
what non phenanthrene opioid is not recommended due to being neurotoxic
meperidine
| has active metabolite!!
58
Pentazocine and Butorphanol are
| ______ agonists and _____ partial agonists/antagonist
kappa
mu
59
Nalbuphine is a
| full agonist at _____ and antagonist at ____
kappa
mu
60
```
Buprenorphine is a
partial agonist at ______
weak agonist at _____
and
antagonist at _____
```
mu
kappa
delta
61
what does inflammatory pain feel like
throbbing / pulsating
62
what does neuropathic pain feel like
burning
tingling
shooting
electrical
63
what does visceral pain feel ike
deep
squeezing
compression
64
what does breakthrough pain feel like (??)
spontaneous
iodopathic
incidental
65
what pain is known as throbbing/pulsating
inflammatory
66
what pain is known as burning/tingling/shooting
neuropathic
67
what pain is known as deep/squeezing
visceral
68
what condition is known to be allodynia pain
fibromyalgia
69
Substance P or NMDA/AMPA are more related to peripheral sensitization?
Substance P
| it heightens pain response
70
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)
71
what pain related disease state is an example of central sensitization
fibromyalgia
72
tx options for fibromyalgias
Ca2+ blockers/TCAs/Anti-convulsants
73
Chronic pain is typiclly enhanced by _______ sensitization
central
74
opioid receptors are found in high expression in the ______ along the _______ pathway
brain stem
descending pathway
75
When opioid receptor is activated in brain --- what are the results
altered mood
sedation
reduced emotional reaction
76
When opioid receptor is activated in brain stem --- what are the results
increase activity of descending fibers
77
When opioid receptor is activated in spinal cord --- what are the results
inhibit vesicle release
| hyperpolarize postsynaptic membrane
78
When opioid receptor is activated in periphery --- what are the results
reduce activation of primary afferent nerves
| modulate immune activity by modulating inflammatory mediators
79
what drugs are known as "peripherally restricted mu opioid antagonists"
Relistor (Methylnaltrexone)
Entereg (Alvimopan)
Movantik (Naolxegol)
Symproic (naldemedine)
80
what are the "peripherally restricted mu opioid antagonists" drugs used for?
for opioid induce constipation
81
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!)
82
preventative/acute management of opioid induced constipation?
senna
polyethylene glycol (Miralax)
Docusate
83
Therapeutic Use of the Mu Opioid Receptor
Analgesia (not chronic pain tho??)
sedation
antitussive
84
Kappa opioid receptors may have role in _______ and are typically known to cause ______
role in addiction
dysphoria
85
Delta opioid receptors are known to decrease _______ and ______
Delta opioid receptor will also treat ________
decrease anxiety/depression
treat alcoholism
86
mu, kappa, or delta is more related to chronic pain?
delta
87
what NSAID is a salicylate
aspirin
88
what NSAIDs are arylpropionic acids
ibuprofen
89
what NSAIDs are arylacetic acids
```
indomethacin
diclofenac
ketorolac
etodolac
sulindac
```
90
what NSAIDs are Enolic acids
meloxicam
| piroxicam
91
________ are the mediators of inflammatory pain -- thye recruit inflammatory cells
Eicosanoids (aka arachidonic acid metabolites)
| Prostaglandins, Thromboxanes, Leukotrienes, Cytokines
92
What are the types of eicosanoids?
Prostaglandins,
Thromboxanes,
Leukotrienes,
Cytokines
93
Inflammatory Response/Arachadonic Acid Pathway:
| _______ are suggested to be the contributor to the painful response
prostaglandins
94
Inflammatory Response/Arachadonic Acid Pathway:
Inhibiting ________ leads to reduction in thromboxane
COX1
95
Inflammatory Response/Arachadonic Acid Pathway:
________ induces platelet aggregation
thromboxane
96
Inflammatory Response/Arachadonic Acid Pathway:
Inhibiting thromboxane = blood thinning or clotting?
thinning
| duh, NSAIDS inhibit COX enzymes = decrease thromboxane = less aggregation = more bleeding
97
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
98
Thromboxane or Prostacyclin will reduce platelet aggregation?
Prostacyclin
99
COX 1 or COX2 is induced when there is inflammation?
COX2
100
Thromboxane or Prostaglandins promote uterine motility?
prostaglandins
101
thromboxane causes vasodilation or vasoconstriction?
constriction!
| Thromboxane = thrombosis = platelet aggregation AND constriction - aka asking for a thrombus..
102
COX 1 or COX 2 has bigger rule in nociception
cox 2!
103
PGI2 causes vasodilation or vasoconstriction?
vasodilation!
| acts opposite of thromboxane
104
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)
105
To treat Aspirin Overdose - what do you do?
want to get ASA excreted....
| thus give dextrose, or Na+HCO3- or dialysis
106
what NSAID irreversibly inhibits COX?
ASA
107
Ibuprofen or Naproxen has longer half life
naproxen!(~14 hr)
[Ibuprofen (~2 hr)]
108
Diclofenac has increased risk for ________ and renal dysfunction with prolonged use
For protective effect ---- use ________
risk: peptic ulcer
give: Misoprostol (PGE1 analog)
109
Arylacetic acid NSAIDs are really weak or strong inhibitors of prostaglandins?
strong!! why hella peptic ulcer risk
110
Enolic Acid NSAIDs have great ______ penetration
joint
111
At low doses of meloxicam it is __________ seletive
cox 2
112
Enolic acids --- short or long half life?
long!
Meloxicam (~20 hours)
Piroxicam (~ 57 hours)
113
why should NSAIDs be avoided in pregnancy?
it inhibits uterine motility!!
114
when are NSAIDs sometimes helpful in pregancy?
used to DELAY preterm labor
| because they inhibit uterine motility
115
NSAIDs cause diuresis or Peripheral edema?
edemaaaa (because NSAIDs lead to Na+ reabsorption)
| why CV risk
116
Peripheral Edema risk with NSAIDs increase with shorter or longer acting NSAIDs?
longer!!
117
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
118
Disadvantages of APAP
hepatic necrosis if acute overdose
| no anti-inflammatory effect
119
APAP is converted to _______ by _____ enzymes (which can form toxic reactions)
NAPQI; CYP
120
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
121
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)
122
Biggest pro with COX2 Selective Inhibitors?
reduced ulcers and GI bleeds
123
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
124
ALL NSAIDs should be avoided in patients with what 3 PMH/disease states?
- CKD
- Peptic Ulcer Disease
- Hx of GI bleed
125
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)
126
NSAIDs or APAP can cause asthma exacerbation
NSAIDs
127
what channel is an analgesic target (GOF and LOF mutations are big in this)
Na+
| NaV1.7 and NaV1.8
128
Local anesthetics are _____channel blockers
Na+
129
what drugs are local anesthetics/Na+ channel blockers
lidocaine
Bupivicaine
Benzocaine
130
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
131
(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
132
(from VanRijn lectures)
| what drugs are Ca2+ blockers that can be possible analgesics
Gabapentin and PRegabalin
Ziconotide
Levetiracetam
133
Main points about general anesthesia
loss of consciousness
| endotracheal tube needed
134
main points of Neuraxial anesthesia
placed into spinal area/epidural
| used for abdomen and lower back surgeries
135
main points of peripheral nerve block (PNB)
local anesthetic
| used for surgeries on extremities
136
3 Main Components for Anesthesia
Muscle Relaxant
induce amnesia (loss of consciousness)
Analgesia/Sedation
(May need anxiolytic too)
137
Propofol is a _________ modulator of ______ channels
Propofol is also a ______ agonist so it causes ______ at injection site
positive allosteric; GABA
TRPA; pain
138
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
139
what drugs are typically used for peripheral nerve block
mepivacaine
| ropivacaine
140
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
141
which Na channel isoforms are expressed in the CNS?
Nav 1.1, 1.2, 1.3, 1.6
142
which Na channel isoforms are expressed in the cardiac muscle?
Nav1.5
143
which Na channel isoforms are expressed in the skeletal muscle
Nav1.4
144
Cell Physiology:
| At rest --- Na+ is _____ of the cell and K+ is ______ the cell
Na+ -- outside
K+ inside
145
Process of Local Anesthetic (LA) Entering the Cell:
| LA binds to ________ side of ______ channel
intracellular;
| Na+
146
Process of Local Anesthetic (LA) Entering the Cell:
| LA is a weak acid or base?
weak base
147
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..
148
what are the 3 different moieties that make up local anesthetic?
```
lipophillic group (aromatic ring(
intermediate linkage
ionizable group (terminal amine)
```
149
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
150
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
151
Intracellular pH is lower or higher than the extracellular pH
LOWER aka more acidic aka will protonated local anesthetics (da weak bases)
152
4 main factors that influence local anesthetics
frequency of transmission
size/class of peripheral axons
pH
Vascularity of target tissues
153
______ pH reduces efficacy of LA
acidic
154
Local anesthetics have faster/higher absorption when the blood flow is _______
greater
155
LAs bind to the closed or open state of the Nav channel
open
156
LAs work (aka block pain) better on small myelinated or large unmyelinated nerves
small/myelinated
| because fire better and can move it faster
157
Potency of LA is better when it is hydrophillic or lipophillic?
lipophillic
158
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
159
Duration of action of a LA is is determined by _______ and _______
protein binding
| hydrophobicity
160
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
161
Amide or Ester based LAs?
| have fast onset
amide
162
Amide or Ester based LAs?
| have short to long duration
ester
163
Amide or Ester based LAs?
| have med to long duration
amide
164
Amide or Ester based LAs?
| have variable onset
ester
165
Amide or Ester based LAs?
| slow t1/2 (hours)
amides
166
Amide or Ester based LAs?
| rapid t1/2 (minutes)
esters
167
Amide or Ester based LAs?
| has fast hydrolysis by esterases
ester
168
Amide or Ester based LAs?
| has hydrolysis by CYP system
amide
169
Amide or Ester based LAs?
| caution of giving this kind of LA in hepatic disease
amide
| bc its metabolized by CYPs
170
Ester bond or amide bond is more rapidly metabolized
ester
171
Metabolism of _____ bond containing LAs leads to formation of ______ which can cause an allergic rxn/dermatitis/asthmat attacks
ester bond
| PABA (para-aminobenzoic acid)
172
Main Local Anesthetic Toxicities
Neurotoxicity
Cardiovascular
Methemoglobinemia
173
Local Anesthetics: Neurotoxicity
First CNS _______
then at high doses CNS _______
first: stimulation
high doses: depression
174
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
175
Local Anesthetics: Cardiovascular
| what are the outcomes of this toxicity?
Vasodilation/hypotension
Depress cardiac AP/Dysrhytmias
Cardiac arrest
176
neuromuscular blockers work by blocking _______ or _________
block Ach transmission
or
block nicotinic receptors on skeletal muscle
177
what are the 2 types of neuromuscular blockers
depolarizing
and
non-depolarizing
178
what is an example of a depolarzing neuromuscular blocker
succinylcholine
179
Avoid using depolarizing neuromuscular blockers in ______ because it could cause ______
HYPERkalemia;
| cardiac arrest
180
Succinylcholine is metabolized fast or slow and by what?
fast!!
| by Butrylcholinesterase
181
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
182
Non-depolarizing neuromuscular blockers MOA?
ACH/Nicotinic receptor ANTAGONIST
183
example of non-depolarizing neuromuscular blocker
pancuronium
184
Non-depolarizing neuromuscular blockers are _____-like
curare
185
Non-depolarizing neuromuscular blockers are reversible or irreversible
reversible!! easily!
186
how can you reverse non-depolarizing neuromuscular blockers
AchE inhibitors (neostigmine)
Cyclodextrin Scavenger (Suggamadex)
187
naloxone or naltrexone?
| has limited bioavailability
naloxone
| why we do nasal spray
188
naloxone or naltrexone?
| has medium half life?
naltrexone (taken PO daily for abuse...)
189
naloxone or naltrexone?
| has faster onset?
naloxone
190
what are the 3 main drug categories (for drugs that are abused)
stimulants
depressants
psychedelics
191
what drugs of abuse are known as depressants
```
opioids
alcohol
cannabis
GHB
inhalants
```
192
what drugs of abuse are known as stimulants
```
cocaine
amphetamine
meth
bath salts
ectasy
nicotine
```
193
what drugs of abuse are known as psychedelics
```
LSD
psilocybin
PCP
mescaline
ketamine
```
194
per DEA: what schedule is this drug?
| heroin
I
195
per DEA: what schedule is this drug?
| ketamine
III
196
per DEA: what schedule is this drug?
| BZDs
IV
197
per DEA: what schedule is this drug?
| lomitil
V (antidiarrheal - its an opioid used as an antidiarrheal)
198
per DEA: what schedule is this drug?
| marinol
III (its THC in capsule form)
199
per DEA: what schedule is this drug?
| Cocaine
II (!!!!!)
200
per DEA: what schedule is this drug?
| Ritalin
II
201
per DEA: what schedule is this drug?
| Marijuana
I
202
per DEA: what schedule is this drug?
| MDMA
I
203
per DEA: what schedule is this drug?
| PCP
II (!!!!!)
204
per DEA: what schedule is this drug?
| LSD
I
205
per DEA: what schedule is this drug?
| heroin
I
206
per DEA: what schedule is this drug?
| buprenorphine
III
207
per DEA: what schedule is this drug?
| psilocybin
I
208
T or F: DEA drug scheduling is permanent
hell nah
209
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
```
210
Substances of abuse work on GPCRs:
| Opioids work on what specifically?
opioid receptors (mu)
211
Substances of abuse work on GPCRs:
| LSD/mushrooms work on what specifically?
5HT receptors! (2A and 2C)
*LSD and Mushrooms aka psilocybin and psilocin?
212
Substances of abuse work on GPCRs:
| Marijuana/K2/Spice work on what specifically?
cannabinoid receptors (CB1)
213
Substances of abuse work on GPCRs:
| GHB works on what specifically?
GABA (B)!! receptor
| GABA(A) is not a GPCR but is a channel
214
Substances of abuse work on GPCRs:
| caffeine works on what specifically
adenosine
215
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+
216
what substances of abuse work INDIRECTLY on GPCRs
Cocaine/ampheamine
MDMA/Ectasy
Alcohol
217
Substances of abuse work on GPCRs:
| Cocaine/Amphetamine work on what specifically?
dopamine transporter (remember it is INDIRECTLY working on GPCRs)
218
Substances of abuse work on GPCRs:
| MDMA/Ecstasy work on what specifically?
```
Monoamine transporter (DA/5HT)
(remember it is INDIRECTLY working on GPCRs)
```
219
Substances of abuse work on GPCRs:
| Alcohol works on what specfically?
GABA Channels!! (also 5HT, NMDAR, NACHR, KIR3) --- WILL CAUSE ENDOGENOUS RELEASE OF OPIOIDS ---
220
what substances of abuse act on ION CHANNELS
Nicotine
PCP/Ketamine
BZDs/Barbitruates
221
Substances of abuse working on Ion channels:
| Nicotine works how?
AGONIST of ionotropic Ach receptors (Na+)
222
Substances of abuse working on Ion channels:
| PCP and Ketmaine work how?
ANTAGONIST to ionotropic NMDA receptor (Ca2+, K+, Na+)
223
Substances of abuse working on Ion channels:
| BZDs and Barbiturates work how?
Postive allosteric modulators (PAMs) for ionotropic GABA receptors (Cl-)
224
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Cocaine
indirect on GPCRs (dopamine transporter)
225
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Nicotine
ion channels (Ach receptor agonist)
226
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Caffeine
direct on GPCRs (adenosine receptors)
227
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
BZDs
```
ion channels
(PAM for GABA receptors)
```
228
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
MDMA/Ecstasy
indirect on GPCRs (monoamine transporter - DA and 5HT)
229
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
Alcohol
indirect on GPCRs (causes release endogenous opioids -- GPCR)
230
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
amphetamine
indirect on GPCRs (dopamine transporter)
231
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
opioids
direct on GPCR (mu opioid receptor)
232
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
marijuana/K2/spice
direct on GPCRs - cannabinoid receptors (CB1)
233
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
GHB
direct on GPCRs (works on GABA(B))
234
how does it work: direct on GPCRs, indirect on GPCRs, or on ion channels?
LSD/mushrooms
direct on GPCRs (works on serotonin receptors)
235
Circuit related to dopamine neurons and abuse of drugs?
Limbic pathway!! (VTA --> Amygdala/Prefrontal cortex/Hippocampus)
236
what brain region is important in reward sensation/valuation
nucleus accumbens
237
what brain region is important in memory/learning
hippocampus
238
what brain region is important in emotion/fear
amygdala
239
what brain region is important in planning/judgement
prefrontaol cortex
240
what brain region is the "source of dopamine"/dopamine neurons originate here
VTA (ventral tegmental area)
241
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)
242
why is the limbic system important for survival in humans?
limbic system makes you want to find food and procreate
243
2 main hypothesis of addiction
dopamine hypothesis
and
glutamate hypothesis
244
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"
245
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)
246
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)
247
Glutamate hypothesis of addiction?
1) Glu can increase DA activity in NAcc
| 2) destruction of Glu pathway to VTA = reduce drug reward
248
Hypothesis of Addiction
| ______ controls_____ activity in amygalda
DA; Glu
249
drug use iduces long term ______
plasticity
250
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
251
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)
252
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!!
253
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
254
Substance used disorder criteria: (how many pts?)
Mild:
Moderate:
Severe:
Mild: 2 - 3
Moderate: 4 - 5
Severe: > 6
255
what are some of the emotional withdrawal symptoms
```
anxiety/depression
restlessness/insomnia
irritability
poor concentration
(HA - vanrijn put this here but maybe physical??)
```
256
what are some of the physical withdrawal symptoms
```
sweating
racing heart
goose bumps
muscle spasms
tremors
N/VD
```
257
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)
258
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
259
3 main ways for pathway to addiction
1) Therapeutic use
2) recreational use
3) self medication
260
Pathways to addiction:
| Therapeutic use --- (-) or (+) reinforcement?
(-) --> (+) --> (-)
261
Pathways to addiction:
| Recreational Use --- (-) or (+) reinforcement?
(+) --> (-)
262
Pathways to addiction:
| Self Medication --- (-) or (+) reinforcement?
(-)
263
what are the primary psychoactive compounds in marijuana
THC
cannabidiol
cannabinol
264
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)
265
Scheduling of Marijuana:
Plant: ____
Nabilone (synthetic cannabinoid): _____
Marinol (THC formulation) _____
I
II
III
266
how is K2/Spice made?
synthetic marijauna/cannabinoids are sprayed onto plant material
267
what are the physical effects of marijuana use?
```
sedation
red eye
tachycadria
angina (if hx of coronary insufficiency)
reduction in pulmonary vitality
```
268
why does marijuana cause red eye
it dilates conjunctival vessels
269
what are sxs of marijauna withdrawal
dysphoria
anxiety/depression
decreased appetite
270
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)
271
overdose is uncommon but what are possible things seen with overdose on marijuana
anxiety/panic attacks
| convulsions
272
why can a fatal overdose not really happen with marijauan
there are no CB receptors in respiratory centers of brain stem
273
PK of THC:
quick or slow absoprtion?
metabolized by ______
short or long half life?
quick absorption
liver (CYP2C9)
long 1/2 life
274
PK of THC:
is an agonist to ______ which are GPCRs
are they Gi or Gs?
CB1/CB2
| Gi
275
since CB receptors are Gi -- whent hey are activated they will _____ Ca2+ channels and _____ GIRK channels
inhibit Ca2+
activate GIRK
276
THC will _____ release of GABA
inhibit
277
CB1 or CB2 is of higher expression in brain?
CB1
278
CB actions in the _______ lead to locomotor effects
cerebellum
279
CB actions in the _______ lead to appeteite increase
hypothalamus
280
CB actions in the _______ lead to effects on memory and coping with stress
hippocampus
281
CB actions in the _______ lead to effects with pain
PAG, LC (locus coeruleus), SC (spinal cord)
282
With marijuana ingestion: psyhcoactive cannabinoids will bind to _____ receptors found (pre or post) synaptically on _____ neurons
CB1 receptors
PRE-synapse
GABA neurons
283
psychoactive CBs will promote or inhibit release of GABA neurotransmitters
INHIBIT
284
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
285
CB receptor activation leads to DISINHIBITION on DA neurons -- this leads to dopamine _______ in the ______
release; nucleus accumbens
286
CB1 or Cb2 is found in higher expression in the periphery
CB2
287
CB1 or CB2 receptors are expressed on lymphocytes (B and T cells)
CB2
288
Anandamide and 2-arachidonylglycerol (2-AG) are what ?
endogenous cannabinoids
289
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 .........)
290
endogenous cannabinoids: Anandamide
AEA does ______
FAAH does _______
AEA: synthesis
FAAH: degradation
291
what route of marijuana ingestion is seen to be th emost efficacious
vaping
292
what are the 2 FDA approved cannabinoid drugs
marinol
nabilone
293
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
acts as an anti-emetic
nabilone
294
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
is used to increase appetite (helpful for chemo pts o pts with HIV/AIDS)
Marinol
295
for FDA approved cannabinoid drugs:
Marinol or Nabilone?
is synthetic THC in seasme oil
marinol
296
Cannabinoids and Increasing Appetite:
| activation of CB1 ---> inhibits _____ neurons in the ______
POMC neurons
in hypothalamus
297
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)
298
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
299
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!)
300
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
301
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
302
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
303
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
304
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
305
psychedelics:
| 3 main classes?
hallucinogens
dissociateies
delirants
306
t or f: hallucinogens are typically very addictive
```
false actually
(biggest issue with these drugs is that they might hurt themselves while taking them)
```
307
PCP and ketamine are usually used as?
veterinarion anestheetics
308
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
309
Salvia:
acts fast or slow?
is a ____ opioid receptor agonist
works v fast
| kappa
310
what hallucinogen is known to be helpful in treating drug abuse because it allows for introspection?
*it is NOT legal in US
ibogaine
311
what molecule is thought to be the cause of hallucinations
serotonin
312
Serotonin Receptors:
| G____?
Gi/o, Gs, AND Gq!!
313
Presynaptic serotonin receptors tend to be G____
and
Postsynaptic serotonin receptors tend to be G____
Pre: Gi
Post: Gq
314
LSD works on what serotonin G receptor?
Gq - 5HT2A
315
serotonin/serotonin receptor binding molecules tend to have what common moiety?
tyrptamine
316
Mescaline is found in peyote - it combines the action of what 2 other hallucinogens
LSD; MDMA
317
LSD and MDMA (aka mescaline too) are known as _________ or ______ which makes these more hallucinogenic (rather than stimulatory)
empathogens; entactogens
318
Mescaline has a ____ potency and _____ half life (and has cross tolerance with LSD)
LOW; long
319
what hallucinogenic drugs are known to be glutamatergic NMDA receptor antagonists (this lead to inhibiting GABA release --> more glutamate release..)
Ketamine
| PCP
320
most of the dissociative psychedelics have what MOA?
NMDA receptor antagonist
321
what are the 3 main medical uses of ketamine
anesthesia
chronic pain analgesia
anti-depressant (good for tx resistant)
322
what are examples of dissociative psychedelics
Ketamine
PCP
Dextrmetorphan
Muscimol
323
ketamine or PCP - which one has severe dissociation
PCP!
| remember the PCP face being disgusting
324
what is the MOA of muscimol
it is a true GABA(A) agonist
325
what are examples of synthetic/designer drugs of psychedelics --- of opioid class
krokodil (can cause gangrene)
| Codeine derivs.
326
what are examples of synthetic/designer drugs of psychedelics --- of cannabinoid class
K2
| Spice
327
what are examples of synthetic/designer drugs of psychedelics --- of stimulant class
Bath salts
| designer steroids
328
what are examples of synthetic/designer drugs of psychedelics --- of psychedelics class
PCP
| NBOMe
329
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
330
Main ADEs with Inhalants
cerebral degradation/brain shrinkage
hypoxia
respiratory depression
331
MOA of inhalants
inhibit excitatory transmission- NMDA antagonism
AND
stimulate inhibitory NTs
