16/17 Flashcards
(90 cards)
1
Q
Ad fibers:
A
faster, myelinated axons response first to noxious mechanical stimuli. Produce the initial sensation of sharp pain
2
Q
C fibers:
A
slower, unmyelinated axons respond to thermal, mechanical and chemical assaults. Dull, aching, or burning pain.
3
Q
5x more —- fibers than —- fibers
A
C
Ad
4
Q
Nociception = the ability to
A
feel pain
5
Q
Nociceptors are molecular sensors. Different nociceptors respond to various noxious stimuli such as heat, cold, mechanical perburbations, or protons. Their activation leads to
A
local depolarization which in turn initiates action potentials.
6
Q
Allodynia
A
pain from normally painlesss stimuli
7
Q
Hyperalgesia
A
heightened sense of pain to noxious stimuli
8
Q
Hyperalgesia
A
heightened sense of pain to noxious stimuli
9
Q
Channels that let in Cl will
A
hyperpolarize
10
Q
Channels that let in Na will
A
depolarize
11
Q
Channels that let out K will
A
hyperpolarize
12
Q
PREsynaptically: Hyperpolarization
A
diminishes Ca++ influx and neurotransmitter release
13
Q
PREsynaptically: Depolarization
A
enhances Ca++ influx and neurotransmitter release
14
Q
Pro-opiiomelanocortin peptides
A
beta endorphin
15
Q
Pro enkephalin peptides
A
met-enkephalin and leu-enkephalin
16
Q
Prodynorphin peptides
A
dyn-A, dyn-B and alpha neo endorphin
17
Q
Three important opioid receptors
A
mu, kappa, delta. mu is important. All GPCRs, all widely in CNS, all activate Galphai
18
Q
Opioid receptors all activate
A
Gai
19
Q
Beta endorphin is the natural ———- of mu opioid receptor
A
agonist.
20
Q
How opioids work: in PNS and CNSGPCRs modulate nerfve activity. Don’t act as blockers, but
A
make nerve impulses difficult to conduct
21
Q
Activation of opioid receptors will also lead to activation of a particular type of —————-. This will ————– the cell.
A
potassium channel (via GbGg)
hyperpolarize
22
Q
Opioids - reduction of Ca and hyperpolarization will
A
diminish generation of AP.
23
Q
Opioids can inhibit synaptic transmission if receptros are located
A
pre or post synaptically
24
Q
Mu receptors —— important forms
A
3
25
mu receptors found in
Found in periaqueductal gray region, superficial dorsal horn of the spinal cord, nucleus accumbens, amygdala, cerebral cortex. Mainly, presynaptic.
Found in GI tract (inhibit peristaltic action, cause constipation).
26
Opioid analgesics produce
analgesia, respiratory depression, constipation, GI spasm, dependence
27
Morphine is the prototypical full agonist of
mu receptor.
28
Patients also report morphine more effective against
dull aches as opposed to sharp pains.
29
Patients also report morphine more effective against
dull aches as opposed to sharp pains.
30
Adverse effects of opioids
constipation
31
Tolerance rate for morphine
seen 5-7 days of treatment. Toxic effects remains if tolnce has developed. Mech is controversial
32
Morphine is metabolized by------ very quickly in the liver. Morphine-3glucuronide (M-3-G) is the primary product Morphine-6-glucuronide (M-6-G) is the secondary product.
UGT2B7
33
M-3-G is
inactive/useless more or less
34
Morphine as a pill is
not very useful
35
Codeine
Substitution at ---- position renders it more effective orally than morphine (probably relates to absence of 3glucuronidation in liver).
3
36
Codeine
Substitution at ---- position renders it more effective orally than morphine (probably relates to absence of 3glucuronidation in liver).
3
37
Codeine better when administered
orally, not intramuscularly
38
Codeine better when administered
orally, not intramuscularly
39
Fentanyl
pain meds with other meds. Super fast onset and offset. Effects last less than an hour or so.
40
Fentanyl danger factors
The two factors are: (1) Fentanyl is more lipid soluble than morphine or heroin. (2) Fentanyl binds tighter to the m opioid receptor than morphine or heroin.
41
Fentanyl produces more
prolonged respiratory depression than other opioids
42
mu receptor antagonists
reverse effect of opioid potentially
43
Mixed antagonists/agonists
Since activation of all the opioid receptors produce analgesia, might it be possible to produce drugs that act on kor d receptors and don’t have the major adverse effects (i.e. respiratory depression) and/or don’t produce dependence.
44
Injured cells release certain chemicals called
alarmins preceding inflammation
45
The alarmin IL-33 can produce
‘degranulation’ of resident immune cells called mast cells.
46
Histamine acts through a -------- to produce local --------------and render the capillaries ‘leaky’. This will allow more immune cells to enter the injury site and also produce ---------
G protein coupled receptor
vasodilation
edema.
47
Histamine-H1 receptor activity on vascular endothelium increases intracellular Ca++ - 2 effects
1. NO production in endothelial cells (relaxation)
| 2. MLCK mediated contraction of capillary endothelium (rendering it leaky)
48
Prostaglandins
mediate pain, accumulate inflammation.
49
Cyclooxygenases responsible for converting
arachidonic acid to prostaglandins
50
The action of the enzymes ------ sends the arachidonic acid down the path leading to production of the prostaglandins
COX1 and COX2
51
4 diff
prostaglandins, 8 diff GPCRs.
52
Prostaglandins act through
GPCRs
53
Prostaglandins (via their G protein coupled receptors) act at
peripheral nerve endings to sensitize pain responses.
54
The NSAIDS all work by inhibition of the ------, diminishing production of --------.
COX enzymes
prostaglandins
55
COX 1 if inhibited
will lead to bad effects. Goal is to inhibit cox 2, leaving cox 1 alone.
56
Platelet aggregation is mediated in part through the
autocrine production of thromboxane (TXA2 in the picture).
57
COX enzymes inhibit --------- production.
Thromboxane A2 production
58
No Advantage to Giving Preemptive NSAIDs to Improve Success of the Inferior Alveolar Nerve Block in Patients With
Symptomatic Irreversible Pulpitis.
59
Advese effect of cox enzyme inhibitors
disruption of mucosal defense in the stomach, because prostaglandins stimulate mucus and bicarbonate secretion that helps comprise mucous gel.
60
Adverse effects of cox enzyme inhibitors
```
Increases in bleeding time (acetylsalicylic acid) Kidney problems (water, Na+ retention) Increased BP
Heart failure (rare)
```
61
Adverse effects of cox enzyme inhibitors
```
Increases in bleeding time (acetylsalicylic acid) Kidney problems (water, Na+ retention) Increased BP
Heart failure (rare)
```
62
Most effective analgesia:
optimum dose of NSAID + additional opioid
63
OSteoarthritis
hyaline cart breakdown in joints.
64
-------- contributes to tissue damage in OA
Inflammation
65
Chondrocytes of inflammed cartilage:
Anabolic and catabolic activities are not balanced, the catabolic activities dominate. The extracellular matrix is not maintained in a healthy state.
One sees decreased production of collagen. Increased production of proteolytic enzymes such as matrix metalloproteases.
Inflammatory mediators produce this change. IL-1b and TNFa are particularly important
66
Proinflammatory cytokines (e.g. IL- 1b, TNFa) lead to
Reduced collagen expression, increased MMP expression, increased expression of other proteases, increased iNOS, COX-2, PEG-2
67
Esters are hydrolyzed in the plasma and liver by pseudocholinesterase into
PABA
68
Hyaline cartilage matrix is mostly made up of
type II collagen, and chondroitin sulphate, both of which are also found in elastic cartilage. It also includes keratin sulphate.
69
Synovitis is characterized by proliferation of cells of the synovial lining, increased vascularization, and infiltration by
inflammatory cells (especially lymphocytes and macrophages).
70
Eventually, synovitis leads to --------. This overgrowth is called the ------.
extension of the inflammatory tissue mass to the articular cartilage
pannus
71
Pannus is an abnormal layer of
fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface (as seen in rheumatoid arthritis), or on a prosthetic heart valve.
72
T helper 17 cells (Th17) are a subset of
pro-inflammatory T helper cells defined by their production of interleukin 17 (IL- 17). Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces, but they have also been implicated in autoimmune and inflammatory disorders.
73
Of course, Th17 cells secrete other cytokines that affect the immune response -
One of these (TNFa) is a really, really, really important therapeutic target in auto immune disorders.
74
Cardiolipin is a phospholipid that is an important component of the ----------, where it constitutes about 20% of the total lipid composition.
inner mitochondrial membrane
75
Calpastatin is an ------- (calcium- dependent cysteine protease) inhibitor.
endogenous calpain
76
Antiperinuclear factor antibodies
Stain around nucleus of neutrophils
77
Detection of --- is an important diagnostic for RA
RF
78
Cardiolipin is a phospholipid that is an important component of the ----------, where it constitutes about 20% of the total lipid composition.
inner mitochondrial membrane
79
Antibodies directed against citrullinated proteins are
frequently discovered in RA
80
Anti-citrullinated Protein Antibodies (ACPA) recognize a diverse set of proteins and are
highly cross reactive
81
Interestingly, citrullination of proteins itself might be important in the context of
tissue destruction
82
ACPAs bind and induce -------- by ------
bone resorption
osteoclasts
83
Citrullinated fibrinogen and collagen are ------- in mouse models of arthritis
arthrogenic
84
Citrullinated fibrinogen activates ---------
macrophages
85
Drugs to treat Rheumatoid Arthritis
NSAIDS, Disease-Modifying Anti-Rheumatic Drugs
3) Glucocorticoids (covered in asthma section)
4) Pain medications that aren’t NSAIDS
86
Disease-Modifying Anti-Rheumatic Drugs (DMARDS)
traditional small molecule drugs
| biologics (generally monoclonal antibodies)
87
Methotrexate: Enzyme inhibitor of
dihydrofolate reductase
| This interference with folate metabolism is the mechanism by which methotrexate acts as a chemotherapeutic agent
88
If you Inhibit DHFR, you inhibit
nucleic acid (and amino acid) synthesis
89
TNFa is a
“pleotropic cytokine” that plays a major role in the immune/inflammatory response
90
TNFa is heavily implicated in the pathogenesis of
autoimmune diseases
