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Immunology & Inflammation > Exam 3-McPhail > Flashcards

Exam 3-McPhail Flashcards

1
Q

Calcineurin/mTOR inhibitors

A

Cyclosporine
FK-506
Rapamycin
Everolimus

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2
Q

Antimetabolites

A

Azathioprine

Mycophenolate

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3
Q

NSAIDs

A

COX/LOX inhibitors

Ibuprofen, naproxen

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4
Q

Mast Cell Stabilizers

A

Cromolyn

Neodocromil

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5
Q

Cyclosporine (Sandimmune, Neoral)

A

produced by fungi (natural)
Inhibits T cell signal transductions like IL2 that would express lymphocytes
Can’t translocate to the nucleus
increases TGF(B)

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6
Q

Forms a complex with cyclophilin A then binds to calcineurin to inhibit calcium stimulated phosphorylation of cytosolic NFAT

A

Cyclosporine

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7
Q

Cyclosporine indications

A

kidney, liver, heart transplants
used in combo with glucocorticoids

RA, psoriasis, Chron’s Disease, Eyes (Restasis)

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8
Q

Cyclosporine side effects

A

High BP, kidney problems, increased risk of infection and cancer because immune system is suppressed, more hair growth, gum hyperplasia, diarrhea, vomit, loss of app.

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9
Q

AVOID while on cyclosporine

A 
contact with people with infectious diseases
immunizations
sunlight--sunburn=inflammation
Grapefruit-inhibits CYP3A4
lots of potential drug interactions
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10
Q

FK-506 (Tacrolimus)

A

produced by bacterium
big macrocycle
Inhibits T cell signal transductions like IL2 that would express lymphocytes
binds to FKBP-12 and then calcineurin+calcium+calmodium

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11
Q

FK-506 side effects

A

High BP, kidney problems, increased risk of infection and cancer because immune system is suppressed, more hair growth, gum hyperplasia, diarrhea, vomit, loss of app.

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12
Q

FK-506 metabolism

A

by CYP3A5

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13
Q

How cyclosporine and FK506 inhibit Tcell activation and proliferation

A

activate other proteins by changing conformation
normally wouldn’t interact with calcineurin
prevent gene transcription

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14
Q

Rapamycin (Sirolimus)

A

polyketide macrocycle produced by bacterium
Binds to FKBP12 and inhibits kinase mTOR
inhibits Tcell activation and prolif downstream of IL2R
so cells still make IL2 but this blocks TCell Response to IL2

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15
Q

Everolimus (zortress)

A

macrocycle used in kidney and liver (not earlier than 30 days after) transplants
identical mechanism of action to rapamycin-FKBP12 and mTOR

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16
Q

Azathioprine (Imuran)

A

antimetabolite that is cleaved to 6-mercatopurine
inhibit DNA biosynthesis, and can inhibit de novo purine biosynthesis
used in kidney transplants and RA

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17
Q

Azathioprine mechanism

A

block the rate limiting enzymes IMPDH, adenylosuccinate synthase, adenylosuccinate lyase
incorporated into DNA as a nucleotide

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18
Q

Mycophenolate mofetil/sodium

A

antimetabolite ester prodrug to increase drug absorption
isolated from fermentation broths of pencillium sp.
inhibits IMPDH, and is more pronounced in lymphocytes

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19
Q

Corticosteroids

A

can bind to different areas, increase genes to fight inflammation and decrease genes that encourage inflammation
diminish production of prostaglandins and leukotrienes by inhibiting COX and PLA2 to decrease arachidonic acid metabolite productions

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20
Q

Arachidonic acid->COX1 & 2

A

->Prostaglandins->initiation of inflammation

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21
Q

Arachidonic acid->5-LO

A

->Leukotrienes->initiation of inflammation

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22
Q

Arachidonic acid->Transcellular biosynthesis

A

->Lipoxins->End inflammation

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23
Q

Arachidonic acid->COX2

A

->5LO->12-epiLipoxins->end inflammation

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24
Q

Eicosanoids

A

produced by cyclooxygenases, lipoxygenases, and cytochrome P450 epoxygenase
don’t need a lot to make a difference in the body

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25
Q

Arachidonic acid

A

AA

found in cell membranes, regulates apoptosis

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26
Q

anandamide

A

endocannabinoid that produces mind effects like those of cannabis

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27
Q

Phospholipase A2

A

PLA2
regulated by phosphorylation in the presence of Ca2+ is moved from the cytosol to the membrane of nucleus and ER
RESPONSIBLE for the release of AA from membrane phospholipids

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28
Q

COX catalyzed rate limiting steps

A

arachidonic acid -> PGG2 (peroxide) -> PGH2 (reduced to OH)

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29
Q

TXA2 - Thromboxines

A

vasoconstriction, platelet aggregation

in platelets

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30
Q

PGI2 - Prostacyclin

A

vasodilation, decreased platelet aggregation
blood vessel walls
Ex. Epoprostenol (very spread out)

31
Q

PGD2

A

erythema, edema, pain, decreased platelet aggregation

in mast cells, brain

32
Q

PGE2

A

erythema, edema, pain, fever
in most cell types
ex. Dinoprostone, Carboprost cause abortion

33
Q

PGF2

A

vasoconstriction
in uterus
ex. Latanoprost

34
Q

Protanoid Receptor Family

A

prostaglandins bind to these receptors

relaxant, contractile, inhibitory types

35
Q

COX 1 and 2

A

PGH2 synthase 1 and 2
major targets of NSAIDs
have PGG2 and PGH2 activities
membrane bound enzymes
on luminal side of ER and both sides of nucleus
have 2 active sites: COX and peroxidase active site

36
Q

What COX produce

A

small but significant amounts of 11R-HPETE, 15R-HPETE, 15S-HPETE
oxygenation of polyunsaturated fatty acids into bioactive compounds

37
Q

Actives sites of COX1

A

Arg120-interacts with carboxylate
Ser530-residue acetylated by aspirin
Tyr385-abstracts pro-S hydrogen to initiate COX rxn

38
Q

COX 1

A

always expressed, but can be induced
involved in homeostasis
active site smaller than COX2

39
Q

COX2

A

inducible but CNS, kidney have high level
endothelial cells, fibroblasts, synovial cells undetectable
induced by an inflammatory response
active site larger than COX1

40
Q

COX3

A

dogs, brain, APAP possibly

41
Q

aspirin and COX2

A

15R-HPETE is produced instead of PGG2

42
Q

NSAIDs general Mech of Action (3)

A
  1. rapid reversible binding followed by irreversible covalent modification (aspirin)
  2. rapid reversible competitive inhibition (ibuprofen)
  3. rapid, lower affinity competitive inhibition followed by time-dependent transition to high affinity poorly reversible inhibitory mode…
43
Q

Salicylic acid structure

A

phenol+carboxylic acid

44
Q

Aspirin (ASA)

modified at hydroxyl group

A

irreversibly acetylates serine 530 in COX active site
alters COX2 activity to make epi-lipoxins
many uses many side effects (GI)
50-6000 mg daily, interacts with warfarin and methotrexate

45
Q

ASA metabolism

A

ASA->salicylic acid->
salicyluric acid-inactive
gentisic acid-inactive

46
Q

Reye’s syndrome

A

salicylates may worsen existing liver or kidney problems
fatal consequenc of chicken pox/flu strains
hepatic injury and encephalopathy

47
Q

salicylism

A

mild, chronic salicylate intoxication
no antidote, can do dialysis
headache, dizzy, tinnitus, hard to hear, dim vision, confused, lazy feeling, drowsy, sweat, thirst, hyperventilate, N/V/D

48
Q

aspirin hypersensitivity (allergic)

A

uncommon, more females and middle aged
previous chem hypersens, asthma, nasal polyps
small doses
runny nose, hives, bronchospasm, hypotension
treat with epinephrine

49
Q

Salsalate

modified at carboxyl group

A

2 salicyclic acids together

less GI upset than aspirin, insoluble to stomach absorbed in SI

50
Q

Salicylamide

modified at carboxyl group

A

salicyl chloride+ammonia
not hydrolyzed to salicylic acid
less effective anti-inflammatory
may be used if sensitive to salicylates

51
Q

Flusenisal and Diflunisal

5-(p-fluorophenyl) derivatives

A

2-5 times effective as aspirin
2 times the duration
much lower GI irritation
mild-moderate pain in dentist, OA and RA

52
Q

Mesalamine

nitrogen containing salicylate

A

IBS

delayed release, doesn’t inhibit COX because not acetate group

53
Q

Sulfasalazine

nitrogen containing salicylate

A

IBS
joined mesalamine and sulfapyridine by diazo link
bacteria in bowel cleave the link
sulfapyridine inactive but causes side effects like Stevens-Johnson syndrome

54
Q

Olsalazine

nitrogen containing salicylate

A

IBS

two mesalamines by diazo link

55
Q

Indomethacin

indole-3-acetic acid derivative

A

potent antiinflam/pyretic drug
Actions directly on immune cells
cause headache, vertigo, confusion, liver probs
not popular
time dependent functionally irreversible inhibitor of COX
high affinity for COX1 because of 2-methyl group
tyrosine385 interacts with aromatic ring

56
Q

Sulindac

arylacetic and arylpropionic acid derivative

A 
no Nitrogen like indomethacin
sulfoxide increased potency and solubility
prodrug, sulfoxide->sulfide active
less severe side effects
COX1 but some COX2
57
Q

Ketorolac

arylacetic and arylpropionic acid derivative

A

more potent analgesic, modest antiinflam
high COX1 affinity, produces PGE2
use limited to 5 days because of severe side effects

58
Q

Tolmetin Sodium

arylacetic and arylpropionic acid derivative

A

comparable to ketorolac and sulindac, high COX1 affinity

less frequent side effects but can produce rare anaphylactic shock

59
Q

Diclofenac

arylacetic and arylpropionic acid derivative

A

substitured acetic acid
as selective for COX2 as celecoxib
binds to COX2 inverted with carboxylate to TYR and SER

60
Q

Etodoloc

arylacetic and arylpropionic acid derivative

A

as selective for COX2 as celecoxib

side effects less severe but do have CNS effects because of INDOLE group

61
Q

arylpropionic acid analogs

A

3 carbon acids
all have alpha methyl group, chiral center
S=active R=inactive but R->S in body
administered as racemates usually
nonselective COX inhibitors

62
Q

Ibuprofen

arylpropionic acid analog

A

racemate, pain and inflammation, GI upset take with food
RA and OA, pain, period pain
cardiovascular risk not ok for before artery bypass surgery
GI risk ulcers and bleeding

63
Q

Naproxen

arylpropionic acid analog

A

R isomer is toxic so must be only S

64
Q

Meloxicam

enolic acid

A

RA and OA

hydroxyl group of eneol interacts with TYR and SER of COX2

65
Q

Piroxicam

enolic acid

A

RA and OA

nonselective and extremely long half life (slow onset)

66
Q

Celecoxib

diaryl hehterocyclic compound

A

selective COX2 inhibitor

risk of cardiovascular events

67
Q

N-arylanthranilic acid

The Fenamates

A

mefanamic acid, less than 7 days
flufenamic acid-7 times potent as ^^
meclofenamic acid-25 time potent^^ and 150 times aspirin

68
Q

APAP

p-aminophenol derivative

A

not an NSAID, COX3
not antiinflam but yes antipyretic and analgesic
acute overdose normal pathway saturated and depletes GSH(glutathione), reversed with acetylcystine

69
Q

Zileuton

LOX inhibitor

A

inhibits 5-LOX that converts AA to 5-HPETE

asthma, 2.5 hr half life

70
Q

Zafirleukast

LOX inhibitor

A

inhibits cys-leukotriene receptor LTD4
asthma
interacts with warfarin

71
Q

Montelukast

A

inhibits cys-leukotriene receptor LTD4

asthma and allergic rhinitis, ok in kids

72
Q

Cromolyn

Mast Cell Stabilizers

A

inhibits Cl- channels which may inhibit Ca2+ availability and prevent mast cells from bursting
given by inhalation for asthma
ok for all ages

73
Q

Nedocromil

Mast Cell Stabilizers

A

more effective than cromolyn

ok for 12 yo+

74
Q

Olapatidine

A

antiallergy for eyes

prevent release of histamine and other mediator by preventing calcium influx into mast cells

Immunology & Inflammation (3 decks)

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