NSAIDs and Steroids (Moniri) Flashcards Preview

Musculoskeletal Disorders and Pain Management > NSAIDs and Steroids (Moniri) > Flashcards

Flashcards in NSAIDs and Steroids (Moniri) Deck (84):
1

Prostaglandins (PG) are derivatives of ______

arachadonic acid

2

PG is a potent VASODILATOR OF______; and VASOCONSTRICTOR OF ______

vasodilator: arterioles and capillaries

vasoconstrictor: pulmonary vasculature

3

T/F PGs are known for inducing inflammatory response that causes SWELLING AND EDEMA

TRUE

4

ALL PGs contain ____ carbon atoms and a _____

20 carbon atoms; cyclopentane ring

5

Where is the COX enzyme localized?

in the smooth ER

(microsomal= the ER cyclooxygenase COX)

6

What can synthetic prostanglandins be used for? (4)

-induction of childbirth or abortion
-treatment of peptic ulcers AND gastroprotection
-treatment of glaucoma
-treatment of impotence

7

Why are PGs critical to the stomach?

they protect the stomach

8

What are the 2 steps involved in the transition from Arachidonic Acid (AA) to PGG2?

Oxygenation, then Cycliation

9

After AA bind to the active site of COX, where is molecular oxygen added?

to C11 (this step is known as oxygenation)

10

T/F PGG2 is UNSTABLE

TRUE: has a half life of about 5 minutes

11

What 2 reactions are required for AA to be held in place?

-protonation of Arginine120 to form IONIC BOND w/ -COOH of AA
-pi-pi stacking of Tyrosine385 and electron rich region of AA

12

Arginine is a ____ amine in a ______ environment inside the active site of COX, so......

basic; acidic.... it will be protonated (charged)

13

Tyrosine is a ______ acid and it will lose a ______ group

aromatic; hydroxy

14

T/F Any agent that blocks the interaction between Tyr and AA or AA and Arg will INCREASE the production of PG

FALSE; decrease

15

2 Major features of AA?

-carboxylic acid
-high electron rich area

16

What is ionization?

the amount of drug that is charged at a specific pH

17

Since Aspirin is an acid it will be ______ when it is ionized, while NE is a base and will be _____ when it is ionized

negative; positive

18

What is the pH of the stomach

1.8

19

T/F Charged drugs WILL CROSS the membrane

FALSE; will not

20

Ionized= more ____ soluble

water soluble b/c it will form hydrogen bonds with water

21

Unionized= ______ soluble

lipid soluble and it will have good absorption

22

T/F If you buffer Aspirin, then it delays the absorption in the stomach

TRUE

23

What is something that is unique about Aspirin?

Acetylation
it donates its acetic acid ester to the SER-530 near the COX active site and DECREASES PG SYNTHESIS (COVALENTLY BOND)

24

T/F Acetylation is UNIQUE to ASA

TRUE; no other NSAID does this

25

T/F One Aspirin dose can effectively inhibit COX for the life of a platelet

TRUE

26

Aspirin produces ______

Salicyclic Acid

27

T/F Salicyclic Acid (a salicylate) has affinity for COX enzyme

TRUE

28

Why do we take LOW dose ASA?

to prevent SOME platelet aggregation (prevent clotting)

29

All NSAIDs other than ASA bind to the active site _____

noncovalently

30

ASA is 100x more potent at COX____ than COX____

COX1 than COX2

31

What are the 2 insults from NSAID?

-primary- direct acid damage
-secondary- PG inhibition

32

The SE of ASA are due to what?

carboxylic acid group

(decreasing acidity maintains analgesia, but eliminates anti-INF properties)

33

ASA: Usually the acetyl group is in the -ortho position (1,2), but when you move this group to the -meta or -para......

you abolish its activity (all anti-inflammatory effects are lost)

34

T/F Salsalate is INSOLUBLE in acidic environments

TRUE

(readily soluble in small intestines)

35

What is the purpose of salicyclic acid?

to DECREASE GI distress when compared to ASA

36

What is the purpose of glucuronidation?

to make compounds more WATER soluble

37

COX 1 vs. COX 2

COX-1 activity is constant in many tissues and function in normal cellular activity

COX-2 activity is induced by cell stimulus/injury (cytokines)

38

Most NSAIDs inhibit COX- _____

1

39

Active Site Cleft in COX-1 vs COX-2

COX-1: has an ISOLEUCINE that blocks the cleft due to ethyl group

COX-2 has a VALINE that DOES NOT block the cleft

40

What is the largest class of NSAIDs?

non-selective Arylalkanic acids

41

______ is a prodrug that inhibits COX-1 ~10 fold more potently than ASA

Sulindac (not metabolized until absorbed to circulation)

lower incidence of GI problems

42

Which isomer of Sulindac is more potents as an anti-inflammatory?

Z-isomer

43

T/F Sulindac is a pro-drug that has to be metabolized in the LIVER to become active

TRUE (it can go systemically and inhibit COX-1 again)

44

What enzyme is responsible for converting SULINDAC to its active form?

sulfoxide reductase

45

COX inhibition of Indomethacin and Sulindac prefer...

non-co-planarity

46

Ketorolac is essentially a ring-fused deriative of tolmetin, what does fusion cause?

increased risk of GI bleeding and operative s sites (DO NOT use longer than 5 days)

47

What is the role of di-chloro substituents in DICLOFENAC?

-Cl is electron withdrawing and helps improve the fit into COX

48

Diclofenac inhibits ____ and _____

COX and lipoxygenase

49

Diclofenac/Misoprostol is a ____ PGE1 used to replenish PGE1 in the stomach

synthetic

50

What is the only ORALLY available prostaglandin? why?

Arthrotec (Diclofenac + Misoprostol)

the movement of hydroxyl group from C15 to C16 and the addition of methyl allows for this

51

Etodolac is a .....

preferential COX-2 inhibitor

52

T/F Nabumetone is a NON-ACIDIC prodrug that has to be activated in the liver

TRUE

53

T/F IBU in VIVO both enantiomers are active

TRUE; R is inactive, but becomes active

54

T/F IBU in VITRO S enantiomer is ACTIVE

TRUE

55

Which enantiomer is active in Naproxen?

S

56

Which enantiomer is active in Anaprox?

R (so it will not act locally in the stomach)

57

The acidity from -Oxicams (Piroxicam and Meloxicam) comes from what?

resonance delocalization

58

The enolate found in -oxicams is stabilized by?

hydrogen bonds

59

______ and _____ are preferential COX-2 inhibitors

Etodolac and Meloxicam

60

What groups gives CELECOXIB selectivity for COX-2?

para-sulfonamide

61

T/F COX-2 is highly upregulated in Colon Cancer

TRUE

62

APAP is metabolized primarily by ____

conjugation unless it becomes saturated then it uses the CYP enzyme--> which leads to a toxic intermediate

63

Glutathione is a ______ that is used to breakdown____

anti-oxidant; N-acetylmidoquinone (reactive metabolite)

64

Adrenocorticoids are synthesized in the cortex of the adrenal gland AND are similar in structure to ______

sex hormones (testosterone, progresterone, estrogen)

65

_____ are RIGID molecules with critical stereochemistry and READILY cross the membrane

steroids

66

Explain how steroids function?

Steroids come into the cell and link up with SR (steroid receptor) and then migrate to the nucleus to bind HRE--> transcription and translation happen and proteins are induced to cause anti-inflammatory effects

67

HRE=

hormone receptor element

68

Where are steroid receptors located?

inside the cell (endogenous) they ARE NOT cell surface receptors

69

What is the precursor to adrenocorticoids?

pregnenolone

70

T/F Glucocorticoids are immunosuppressants

TRUE

71

T/F Cortisone and Hydrocortisone BOTH act on GR and MR

TRUE

(aldosterone also activates MR)

72

______ was produced to get away from MR, but it increased the activity 300-800x

Fludrocortisone

73

When is Fludrocortisone used?

for Addison's Disease ONLY (severe adrenocortical insufficiency)

74

The addition of ______ in Prednisone and Prednisolone INCREASED______ and _____

C1-C2 C=C; increased selectivity for GR activity and duration of action

75

Which conformation of prednisolone and prednisone fit with better efficiency binding GR? What does this cause to happen?

flat-boat ; metabolism is decreased

76

The addition of _______ OR _____ + _____ will cause MR to be negligible in steroids

(methylprednisolone) alpha -CH3 on C6 OR

(Triamcinolone) 9-fluro + 16-hydroxy (OH)

77

What drives MR activity to be ZERO?

(this is not the only driver though)

C1-C2 C=C

78

Gout is an inflammatory disease characterized by ELEVATED _____ levels that build up due to the ______

uric acid; due to the pH of the environment

79

Uric Acid is continuously reabsorbed through

renal tubular absorption

80

GOUT
If you decrease the pH--> ______ urate solubility--> _____ crystals

decreased urate solubility--> increased crystals

81

What are the 3 drug therapy options for ACUTE gout?

-INCREASE rate of uric acid excretion
-REDUCE INFLAMMATION caused by urate deposits
-INHIBIT biosynthesis of uric acid by INHIBITING XANTHINE OXIDASE

82

Allopurinol serves as a ________ for Xanthine Oxidase with 20x greater affinity

competitive substrate

83

Allopurinol is metabolized to _______ which is a competitive inhibitor of Xanthine Oxidase

Oxypurinol (longer half life than Allopurinol and when administered chronically is responsible for effects

84

_____ is a NONPURINE SELECTIVE Xanthine Oxidase Inhibitor that leads to.........

Febuxostat; decreased synthesis of uric acid