Flashcards in NSAIDs and Steroids (Moniri) Deck (84):
Prostaglandins (PG) are derivatives of ______
PG is a potent VASODILATOR OF______; and VASOCONSTRICTOR OF ______
vasodilator: arterioles and capillaries
vasoconstrictor: pulmonary vasculature
T/F PGs are known for inducing inflammatory response that causes SWELLING AND EDEMA
ALL PGs contain ____ carbon atoms and a _____
20 carbon atoms; cyclopentane ring
Where is the COX enzyme localized?
in the smooth ER
(microsomal= the ER cyclooxygenase COX)
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
Why are PGs critical to the stomach?
they protect the stomach
What are the 2 steps involved in the transition from Arachidonic Acid (AA) to PGG2?
Oxygenation, then Cycliation
After AA bind to the active site of COX, where is molecular oxygen added?
to C11 (this step is known as oxygenation)
T/F PGG2 is UNSTABLE
TRUE: has a half life of about 5 minutes
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
Arginine is a ____ amine in a ______ environment inside the active site of COX, so......
basic; acidic.... it will be protonated (charged)
Tyrosine is a ______ acid and it will lose a ______ group
T/F Any agent that blocks the interaction between Tyr and AA or AA and Arg will INCREASE the production of PG
2 Major features of AA?
-high electron rich area
What is ionization?
the amount of drug that is charged at a specific pH
Since Aspirin is an acid it will be ______ when it is ionized, while NE is a base and will be _____ when it is ionized
What is the pH of the stomach
T/F Charged drugs WILL CROSS the membrane
FALSE; will not
Ionized= more ____ soluble
water soluble b/c it will form hydrogen bonds with water
Unionized= ______ soluble
lipid soluble and it will have good absorption
T/F If you buffer Aspirin, then it delays the absorption in the stomach
What is something that is unique about Aspirin?
it donates its acetic acid ester to the SER-530 near the COX active site and DECREASES PG SYNTHESIS (COVALENTLY BOND)
T/F Acetylation is UNIQUE to ASA
TRUE; no other NSAID does this
T/F One Aspirin dose can effectively inhibit COX for the life of a platelet
Aspirin produces ______
T/F Salicyclic Acid (a salicylate) has affinity for COX enzyme
Why do we take LOW dose ASA?
to prevent SOME platelet aggregation (prevent clotting)
All NSAIDs other than ASA bind to the active site _____
ASA is 100x more potent at COX____ than COX____
COX1 than COX2
What are the 2 insults from NSAID?
-primary- direct acid damage
-secondary- PG inhibition
The SE of ASA are due to what?
carboxylic acid group
(decreasing acidity maintains analgesia, but eliminates anti-INF properties)
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)
T/F Salsalate is INSOLUBLE in acidic environments
(readily soluble in small intestines)
What is the purpose of salicyclic acid?
to DECREASE GI distress when compared to ASA
What is the purpose of glucuronidation?
to make compounds more WATER soluble
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)
Most NSAIDs inhibit COX- _____
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
What is the largest class of NSAIDs?
non-selective Arylalkanic acids
______ 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
Which isomer of Sulindac is more potents as an anti-inflammatory?
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)
What enzyme is responsible for converting SULINDAC to its active form?
COX inhibition of Indomethacin and Sulindac prefer...
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)
What is the role of di-chloro substituents in DICLOFENAC?
-Cl is electron withdrawing and helps improve the fit into COX
Diclofenac inhibits ____ and _____
COX and lipoxygenase
Diclofenac/Misoprostol is a ____ PGE1 used to replenish PGE1 in the stomach
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
Etodolac is a .....
preferential COX-2 inhibitor
T/F Nabumetone is a NON-ACIDIC prodrug that has to be activated in the liver
T/F IBU in VIVO both enantiomers are active
TRUE; R is inactive, but becomes active
T/F IBU in VITRO S enantiomer is ACTIVE
Which enantiomer is active in Naproxen?
Which enantiomer is active in Anaprox?
R (so it will not act locally in the stomach)
The acidity from -Oxicams (Piroxicam and Meloxicam) comes from what?
The enolate found in -oxicams is stabilized by?
______ and _____ are preferential COX-2 inhibitors
Etodolac and Meloxicam
What groups gives CELECOXIB selectivity for COX-2?
T/F COX-2 is highly upregulated in Colon Cancer
APAP is metabolized primarily by ____
conjugation unless it becomes saturated then it uses the CYP enzyme--> which leads to a toxic intermediate
Glutathione is a ______ that is used to breakdown____
anti-oxidant; N-acetylmidoquinone (reactive metabolite)
Adrenocorticoids are synthesized in the cortex of the adrenal gland AND are similar in structure to ______
sex hormones (testosterone, progresterone, estrogen)
_____ are RIGID molecules with critical stereochemistry and READILY cross the membrane
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
hormone receptor element
Where are steroid receptors located?
inside the cell (endogenous) they ARE NOT cell surface receptors
What is the precursor to adrenocorticoids?
T/F Glucocorticoids are immunosuppressants
T/F Cortisone and Hydrocortisone BOTH act on GR and MR
(aldosterone also activates MR)
______ was produced to get away from MR, but it increased the activity 300-800x
When is Fludrocortisone used?
for Addison's Disease ONLY (severe adrenocortical insufficiency)
The addition of ______ in Prednisone and Prednisolone INCREASED______ and _____
C1-C2 C=C; increased selectivity for GR activity and duration of action
Which conformation of prednisolone and prednisone fit with better efficiency binding GR? What does this cause to happen?
flat-boat ; metabolism is decreased
The addition of _______ OR _____ + _____ will cause MR to be negligible in steroids
(methylprednisolone) alpha -CH3 on C6 OR
(Triamcinolone) 9-fluro + 16-hydroxy (OH)
What drives MR activity to be ZERO?
(this is not the only driver though)
Gout is an inflammatory disease characterized by ELEVATED _____ levels that build up due to the ______
uric acid; due to the pH of the environment
Uric Acid is continuously reabsorbed through
renal tubular absorption
If you decrease the pH--> ______ urate solubility--> _____ crystals
decreased urate solubility--> increased crystals
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
Allopurinol serves as a ________ for Xanthine Oxidase with 20x greater affinity
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