ICL 7.0, 7.1 & 8.0: Immunopharmacology Flashcards
1
Q
what is an autacoid?
A
locally acting hormone
2
Q
what are examples of autacoids?
A
- prostaglandins
- leukotrienes (LTB4, LTC4, LTD4)
- histamine, serotonin, bradykinin, NO, ATII
3
Q
what is the role of autacoids?
A
- inflammation and pain
- allergic response
- anaphylaxis
- local control of blood flow
GI motility and secretion
4
Q
why are autacoids only locally acting?
A
they’re locally acting, not systemically because they have a short half life!
they are produced in the tissue and released in that tissue so they don’t have time to get to other organs in the body
5
Q
what type of receptor do autacoids bind to?
A
they bind to G protein linked receptors in plasma membranes of target cells
G protein receptors can do 3 things: elevate cAMP, decrease cAMP, or elevate Ca
6
Q
how do autacoids induce smooth muscle contraction?
A
- autacoids bind to G protein receptors which activate G proteins, Gq
- Gq activates phospholipase Cβ (PLCβ)
- PLCβ cleaves PIP2 into DAG and IP3
- IP3 frees intracellular stores of Ca+2
DAG activates protein kinase C which opens the plasma membrane Ca+2 channel
now there’s tons of cytosolic Ca+2
- Ca+2 activates myosin light chain kinase (MLCK)
- MLCK phosphorylates MLC which causes the actomyosin to contract = smooth muscle contraction
7
Q
which autacoids when they bind to G protein receptors can cause smooth muscle contraction?
A
thromboxane (TXA2)
PGF2α
PGE2 binding to EP1
LTC4
LTD4
histamine binding to H1
8
Q
what does prostacyclin do?
A
vasodilation
9
Q
which autacoids when they bind to G protein receptors can cause smooth muscle relaxation?
A
epinephrine
PGI2
PGE2 binding to EP2
histamine binding to H2
NO
10
Q
how do autacoids induce smooth muscle relaxation?
A
- active G protein receptors activate G protein, Gs
- Gs activates adenylate cyclase (AC)
- AC converts ATP to cAMP
- cAMP activates PKA
- activate PKA leads to decrease in Ca+2
- MLCK activity decreases and MLC is dephosphorylated
- muscle relaxes
11
Q
what does NO do during muscle relaxation?
A
- NO activates soluble guanylate cyclase (GC), which converts GTP to cGMP
- cGMP activates protein kinase G (PKG)
- PKG activates MLCPase which converts MLC-P to MLC and leads to muscle relaxation
12
Q
concentration of what has to decrease in order for muscles to relax?
A
for the muscle to relax, Ca+2 must be lowered
K+ channels open and Ca+2 channels close
ATP is used to pump Ca+2 out via Na+/Ca+2 ATPase pump
13
Q
what enzyme is involved in prostaglandin synthesis?
A
arachidonic acid + O2 –> cyclo-oxygenase
COX is the enzyme that is inhibited by ibuprofen and naproxen!
14
Q
which prostaglandin is the precursor for all the other prostaglandins?
A
PGH2
it’s the precursor of PGE2, PGD2, PGF2α, PGI2, TXA2
15
Q
which prostaglandins have a really short half life and get grouped together?
A
PGE2
PGD2
PGF2α
they are very similar in structure and not extremely selective for their receptors
t1/2 = 20 seconds
16
Q
why do PGE2, PGD2 and PGF2α have short half life?
A
C15OH dehydrogenase (PGDH)
this enzyme in the lungs that oxidizes them which inactive them
17
Q
what’s another name for PGI2?
A
prostacyclin
it’s a vasodilator!
18
Q
how are prostacyclin and thromboxane connected?
A
thromboxane is a vasoconstrictor that promotes platelet activation and aggregation
prostacyclin is a vasodilator that inhibits platelet activation and aggregation
they work against each other
19
Q
why do PGI2 and TXA2 have short half lives?
A
their rings are unstable
there is just spontaneous hydrolysis into an inactive form of each
it’s not because they’re getting oxidized like the other prostaglandins
20
Q
what’s the half life of PGI2?
A
3 minutes
21
Q
what’s the half life of TXA2?
A
30 seconds
22
Q
what inactivates prostaglandins E,D and F?
A
C15OH dehydrogenase
it’s in the lungs
23
Q
how are prostaglandins synthesized?
A
- phospholipase A2 (PLA2) releases arachidonic acid from the plasma membrane
- COX metabolizes AA into PGH2
- PGH2 is the precursor for all other prostaglandins: PGD2, PGE2, PGF2α, PGI2, and TXA2
24
Q
what do glucocorticoids do in relation to prostaglandin synthesis?
A
they inhibit PLA2 and COX
25
what do NSAIDs do in relation to prostaglandin synthesis?
they block COX
26
where are PGD2, PGE2 and PGF2α found?
many tissues
27
where is PGI2 found?
aka prostacyclin
endothelial cells
28
where is TXA2 found?
aka thromboxane
platelets
29
where is COX1 found?
found *constitutively* in most tissues bound to ER -- it's being made all the time in tissues that prostaglandins are made
important sites: GI tract, platelets and renal medulla
30
where is COX2 found?
it's *induced* by cytokines (IL-1, TNFa), LPS in 2-6 hr in endothelial cells, fibroblasts and monocytes
membrane attached, ER and nucleus
involved in inflammation, pain and fever
**also found constitutively in the brain and kidney!
31
if you want to treat inflammation, would you want t inhibit COX1 or COX2?
COX2
COX2 is induced by TNFα
COX2 stimulates the synthesis of prostaglandins involved in inflammation
so if you want to treat inflammation you want to inhibit COX2
32
how are leukotrienes synthesized?
arachidonic acid --> LTA4 via 5' lipoxygenase
LTA4 is the precursor for LTB4, LTC4, LTD4, LTE4
33
what leukotriene is the precursor for all other leukotrienes?
LTA4
34
which leukotriene has glutathione on it?
LTC4
glutathione is an antioxidant! (:
35
what conditions are LTC4 and LTD4 associated with?
asthma
anaphylaxis
inflammation
36
what do LTC4 and LTD4 do?
1. contract bronchial smooth muscle
2. stimulate secretion of thick bronchial mucus
3. increase vascular permeability = induce edema
37
what condition is LTB4 associated with?
important in inflammation
38
where does LTB4 come from?
it's produced by activated neutrophils and macrophages
39
what does LTB4 do?
1. it's a chemotactic factor for leukocytes
2. helps with adhesion of neutrophils to vascular endothelium
3. promotes activation of neutrophils, etc.
40
how are leukotrienes synthesized?
1. PLA2 releases arachidonic acid from the plasma membrane
2. 5' lipoxygenase is activated by FLAP and Ca+2
3. 5' LO converts AA to LTA4
LTA4 is the precursor of the active leukotrienes: LTB4, C4, D4
adding glutathione to LTA4 gives you LTC4
removing Glu from LTC4 gives you LTD4
removing Gly from LTD4 gives you LTE4
41
how do glucocorticoids effect leukotriene synthesis?
they block PLA2, FLAP and 5' LO
42
how do NSAIDs effect leukotriene synthesis?
they don't!!!
leukotriene synthesis is NOT blocked by NSAIDs
43
what are eicosanoids?
eicosanoids are a type of autacoids
they include prostaglandins, prostacyclin, leukotrienes, and thromboxane
locally acting, short-lived modulators of inflammation and other processes
their synthesis is induced in inflammation
44
what do NSAIDs do?
they only block the synthesis of prostaglandins
they do NOT block the synthesis of leukotrienes, histamine, NO, etc.
45
what are the most common name-brand NSAIDs?
aspirin
indomethacin
ibuprofen = motrin
naproxen = aleve
46
what is hyperalgesia?
a condition where a person develops an increased sensitivity to pain
47
which prostaglandins can cause hyperalgesia? how do you treat it?
PGE2 and PGI2 sensitize nerves to pain stimuli -- they lower the threshold for sending a pain signal to the brain
ex. histamine and bradykinin
NSAIDs prevent sensitization to pain because they prevent prostaglandin production
NSAIDs don't prevent pain, they just prevent the increased sensitization caused by prostaglandins
48
what do opioids do?
they block the neurons and slow down the signals going to the brain
however, eventually if you take too much you'll be blocking so many signals, more than just pain, that you'll stop breathing all together
49
how can NSAIDs and opioids be used together to treat pain?
NSAIDs effect the PNS while opioids effect CNS
there are pros and cons of both so combining them produces an additive effect and permits use of lower doses of opioids to control pain
ex. acetaminophen + hydrocodone
aspirin + oxycodone
ibuprofen + hydrocodone
50
how do prostaglandins cause fever?
IL-1 and TNFα released from macrophages during inflammation/infection induce COX2 and PGE2 synthesis in or near the hypothalamus
prostaglandins raise the set point in the hypothalamus
normally, you don't need prostaglandins to regulate your temperature and they're not even around
51
how are NSAIDs used to treat fevers?
prostaglandins cause fevers by acting on the hypothalamus and raising the set point
NSAIDs inhibit prostaglandin production and can therefore be used to treat fevers
however, NSAIDs are NOT useful for treating hyperthermia because lets say your body temperature is high because you went on a run in the sun -- your increased temperature isn't due to prostaglandins so taking an NSAID won't do anything
NSAIDs also have no effect on your normal temperature because in a healthy individual, there are no prostaglandins around
52
what are some examples of acute inflammation?
infections
injuries
53
what are some examples of chronic inflammation diseases?
1. rheumatoid arthritis
2. asthma
3. inflammatory bowel disease
4. multiple cclerosis
5. systemic lupus erythematosus
54
which eicosanoids contribute to each inflammatory symptom?
tenderness and pain = PGE2, PGI2
redness, erythema, vasodilation = PGD2, PGE2, PGI2
swelling, edema = LTC4, LTD4
55
what do prostaglandins do during inflammation?
PGs induce relaxation of smooth muscle cells
this leads to vasodilation, redness and erythema
56
what do leukotrienes do during inflammation?
LTC4 and LTD4 induce contraction of endothelial cells
they lead to swelling and edema
57
what turns on eicosanoid synthesis?
TNFα
58
what are examples of steroidal AIDs?
prednisone
methylprednisolone
59
what do steroidal AIDs do?
they are glucocorticoid drugs that are related to hydrocortisone (cortisol) a corticosteroid – the natural anti-inflammatory agent
they are very important for treating autoimmune, inflammatory diseases and in organ transplants
but they can't be used long term at high dose without significant adverse side effects
60
what would you do to treat inflammation with non steroidal AIDs? (NSAIDs)
inhibition of COX-2 is important, but probably other factors also involved
but higher doses and longer term treatment for more than simple analgesia increases the likelihood of adverse side effects
61
what does aspirin do?
at low doses, it rapidly and irreversibly inhibits platelet TXA2 synthesis by blocking COX1 and COX2
however, it does NOT block thrombin-induced aggregation
62
what people are recommended to take a daily baby 81 mg aspirin?
prophylaxis of primary and subsequent MI and ischemic strokes in patients at high risk
ex.
- those who have already suffered MI or stroke
- stable angina, TIAs (mini-strokes)
- those who have undergone bypass surgery or angioplasty
63
which types of people should avoid aspirin?
- active bleeding
- hemophilia
- hepatic disease,
- peptic ulcer
- renal disease
64
what is epoprostenol?
PGI2 drug used to treat pulmonary hypertension
it has a very short half life -- continuous IV infusion needed through permanent central intravenous catheter
65
what are some of the side effects of epoprostenol?
flushing
hypotension
GI effects - NVD
66
what are the GI effects that prostaglandins can have?
PGE2 increases GI motility
PGE2 protects the gastric mucosa
67
why can NSAIDs lead to GI bleeding?
because PGE2 protect the gastric mucosa against acid secretion by inhibiting acid secretion and increasing bicarbonate secretion
so when NSAIDs block prostaglandin synthesis, it can lead to GI bleeding
68
what does misoprostol do?
prevents stomach ulcers that can be caused by NSAIDs
it's a PGE2 derivative!
but since prostaglandins have such a short half life, misoprostol is a derivative with a slightly different structure so that its resistant to oxidation in the lungs -- the OH group got moved to C16
it's an ester that is hydrolyzed after absorption to generate active drug
69
what is the pathway through which PGE2 protects the gastric mucosa?
PGE2 binds to EP1 receptors on mucous cell and parietal cell
mucous cell:
1. EP1 activates Gq
2. Gq activates PLC which increases Ca in the cell and activates PK
3. PK/Ca+2 causes HCO3- to be secreted from the cell which buffers against stomach acid
70
what are the side effects of misoprostol?
- nausea and vomiting
- diarrhea
- abdominal cramping
- uterine smooth muscle contraction
- cramping and diarrhea most frequent side effects of all prostaglandin drugs
71
what is the effect of prostaglandins on a pregnant uterus?
PGE2 and PGF2α have several physiological roles in normal labor
they cause uterine smooth muscle contractions
72
what is cervical ripening?
PGE2 prepares the cervix for labor and silvery by relaxing the smooth muscle in the cervix
it also activates collagenase which breaks down the collagen that makes the cervix rigid and allows the uterus to change shape and dilate! hella important for labor
PGE2 induces contractions of uterine walls
73
what is PGE2 used for?
it's used for cervical ripening prior to inducing labor
74
what is a potential side effect of PGE2?
it's used for cervical ripening prior to inducing labor
can cause potential hyper stimulation of uterus
side effects = increased GI motility --> nausea, vomiting, diarrhea
75
what two drugs are used for cervical ripening?
1. dinoprostone (PGE2)
2. misoprostol (PGE1 derivative)
PGE1 vs. PGE2 just indicates the number of C=C bonds in the structure; both forms are active
76
which brand names are dinoprostone?
1. Prepidil = PGE2 endocervical gel
| 2. Cervidil = retrievable, caginal insert PGE2
77
when is misoprostol used?
it's PGE1 derivative used for cervical ripening
it's an alternative to dinoprostone but it's not FDA approved
it works a lot faster and it's way less expensive than Pepidil or Cervidil
78
what is carboprost used for?
inhibition of postpartum bleeding
79
what does carboprost do?
it's a PGF2α that inhibits postpartum bleeding
the main mechanism is contraction of uterine smooth muscle
also causes vasoconstriction!
it's given as a single IM dose
80
what are some of the adverse effects of carboprost?
it's a PGF2α that inhibits postpartum bleeding
adverse effects are due to systemic exposure
60% of patients have NVD!!!
vasoconstriction can lead to high BP and bronchoconstriction
fevers are also common
81
when is carboprost used?
it's used for inhibition of post-partum bleeding but ONLY when oxytocin or methylergonovine fail
82
which drug is used for termination of an early pregnancy?
1-10 weeks --> misoprostol = PGE1 analog
approved for use with the antiprogestin mifepristone
83
which drug is used for termination of a 2nd trimester abortion?
1. dinoprostone = PGE2
vaginal suppository
2. carboprost = PGF2α
84
what is tocolysis?
tocolytics are also called anti-contraction medications or labor suppressants
they are medications used to suppress premature labor
85
which drug is a tocolytic?
indomethacin (it's an NSAID)
it blocks uterine prostaglandin synthesis
it's a second-line tocolytic drug; it's only used when other drugs are ineffective
it's given rectally then orally for 2-3 days
86
what drug is avoided in the last weeks of pregnancy? why?
aspirin is avoided after the 32nd week!
it can lead to unwanted tocolysis and increased post-partum bleeding
87
what is the ductus arteriosus?
a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta
it allows most of the blood from the right ventricle to bypass the fetus's fluid-filled non-functioning lungs
it is kept open by PGE2 but closes soon, hours-days, after birth
88
what is alprostadil used for?
it's a PGE1 that is used to keep the ductus arteriosus open in negates with heart defects
it's also used to treat ED
89
what is indomethacin used for in relation to patency of the ductus arteriosus?
indomethacin is an NSAID
it's used to close a patent ductus arteriosus in neonates
you have to be careful because NSAIDs can cause premature closing of the d.a. when used in the last weeks (>32) of pregnancy
90
what role do prostaglandins play in erectile dysfunction?
they can treat ED by relaxing the smooth muscle of the corpus cavernosa and blood vessels in the penis
this muscle relaxation is what allows for an erection by allowing blood to accumulate in the area
91
which drugs are used to treat ED?
alprostadil = PGE1
92
what are the three most common side effects of alprostadil in ED treatment?
1. hypotension
2. priapism = most serious
3. penile pain = most frequent
93
why can alprostadil cause hypotension?
alprostadil is a PGE1 that causes vasodilation which would cause hypotension
94
what is priapism?
the most serious side effect of alprostadil
it's a drug induced erection lasting longer than 6 hours
it's really serious because the penis has poor blood flow since the vessels are dilated
the dilated blood vessels are what's keeping the penis erect, not the blood flow
95
why is erectile pain the most common side effect of alprostadil?
it's a PGE1!
prostaglandins increase sensitivity to pain!
96
what is Peyronie's disease?
injections of caverject aka alprostadil for ED treatment
injections damage tissue and during the repair process you have fibers forming to help heal but you can get fibrosis which can lead to problems when you're having an erection
the fibrosis causes in-elasticity and can give you a bent penis!
97
what is the pathway through which prostaglandins can help with ED?
1. PGE2 binds to EP2 receptor on smooth muscle cell
2. EP2 activates Gs which activates AC
3. AC converts ATP to cAMP
4. cAMP activates PK which decreases Ca+2 levels
5. decreases Ca+2 levels decreases MLCK so MLC-P goes back to MLC which leads to smooth muscle relaxation
98
what is sildenafil?
aka viagra = treated ED
it's a cGMP phosphodiesterase inhibitor --> it raises cGMP concentration
cGMP helps with smooth muscle relaxation of the corpus cavernous which allows for an erection
99
what are the side effects of sildenafil?
aka viagra
1. vasodilation --> headache, flushing, rhinitis, hypotension
2. heartburn due to relaxation of lower esophageal sphincter
3. effect on vision
100
which drugs should you not take in combination with sildenafil?
1. organic nitrates or GC stimulators + sildenafil can produce dramatic decrease in BP
2. α-adrenergic blockers can also cause hypotension
3. inhibitors of CYP3A4 like erythromycin -- they can raise the amount of cigar in the body
101
what is tadalafil?
similar to sildenafil = treats ED
but it has a longer half-life so people only have to take it once and it lasts all day! you're always ready to go!
102
which drugs can be used to treat pulmonary artery hypertension?
both sildenafil and tadalafil have been approved for oral treatment of PAH
they are vasodilators and decrease BP by relaxing smooth muscle!
they're also used to treat ED lol
103
why can't you give NSAIDs to people in kidney failure?
if you have low BP or a condition that makes it seem like you have low BP then you're not perfusing your kidney well
ex. congestive heart failure, cirrhosis of liver, etc.
if you have low BP, your body is trying to turn off urine production to help you retain water and increase your BP
in a healthy person, prostaglandins don't have anything to do with your urine production but in someone who has low BP, prostaglandins are produced in the kidneys and they dilate the blood vessels to increase blood flow through the kidney
PGE2 inhibits NaCl absorption and opposes ADH
so even though the rest of the body is trying to boost BP and constrict blood vessels, prostaglandins step in to make sure you're still producing urine!!
so if you give a patient like this NSAIDs, it'll knock out their prostaglandin production and they'll stop making urine and go into kidney failure
104
how do prostaglandins play a role in glaucoma?
there has to be a flow of fluid through the eye for it to be healthy
if there's debris in your eye covering the draining system you can cause damage to the eye and potential blindness
fluid can drain through the ciliary body which is smooth muscle so if the main draining through the trabecular mesh work is blocked, you'll start draining through the ciliary body!
**it increases uveoscleral outflow
since it's smooth muscle, prostaglandins can increase the outflow by relaxing the smooth muscle!
105
what is latanoprost used for?
PGF2α used to treat glaucoma
106
what are the side effects of latanoprost?
can increase the pigment in your iris and make them darker
can also stimulate the growth of your eyelashes and make your skin darker too
107
what is bimatoprost?
PGF2α used for eyelash hypotrichosis
it helps your eyelashes grow thicker and longer
but only on your upper lids because if you put it on your lower lids it could drip on your cheeks and cause hair growth on your cheeks
108
what are the general side effects of prostaglandins?
diarrhea
cramps
vomiting
elevation of temperature
flushing
hypotension
109
what are the general therapeutic uses of NSAIDs?
pain
fever
inflammation
antithrobotic -- aspirin only!!!
all others increase risk of thrombosis because they're all irreversible so if you're blocking COX1 and COX2 it's happening ALL over your body, not just platelets
