Medchem NSAIDs

What are the 2 pathways that arachidonic acid can go through

COX or LOX

Salicylate SAR SPECILA

Adding benzene rings increase anti inflammatory

Changing cabroxylic acid to amide decrease anti inflammatory

Prostaglandin effects

• recruit inflammatory mediators

• promote pain

• increase body temp

COX and prostaglandins in the Gastric mucosa, effects

COX-1 → PGE2 and PGI2

• lower gastric acid secretion

• increase mucous and bicarbonate

COX and prostaglandins in the Platelets, effects

COX-1 → TXA2

• causes platelet aggregation

COX and prostaglandins in the lungs, effects

COX-1 → PGE2

• Bronchodilation

COX and prostaglandins in the Kidneys, effects

COX-1 and COX-2 → PGE2, PGI2

• needed for normal renal function

COX and prostaglandins in the damaged tissues, effects

COX-2 → PGE2

• inflammation, pain

COX and prostaglandins in the brain, effects

COX-2 → PGE2

• increase temp via the hypothalamus

Which COX is inducible and where is it found

COX-2, kidney, damaged tissues, brain

What COX is in female reproductive tract and causes uterine contractions

COX-2

What medications are COX-2 selective, semi-selective and non-selective

Celecoxib - COX-2

Meloxicam - COX-2

Diclofenac - semi-COX-2 (some LOX)

Naproxen - non-selective

Ibuprofen - non-selective

Indomethacin - non-selective

Why does Aspirin have a long duration of effect if short half-life

It irreversibly blocks the COX enzymes in platelets which have no nuclei and cannot regenerate new enzymes. So new enzymes are only present when Platelets die and are remade, 8 day lifespan

Aspirin selectivity

Non-selective, but 1 at low dose

When should you avoid aspirin

Gout, Asthma

Aspirin effects of platelets at high and low dose

When is aspirin best absorbed

Stomach at low pH

Aspirin DDIS

Displaces drugs from albumin

lowers effectiveness of loop diuretics

increases effectiveness of warfarin

lower effectiveness of ACE-I

How does aspirin effect gout

It lowers excretion of urate, worsening gout

Aspirin and pregnancy

avoid in 1st trimester and also avoid due to possible uterine contracitons

Aspirin toxicity symptoms

tinnitus, hyperventilation → respiratory alkalosis

Ibuprofen and Aspirin

Ibuprofen and Aspirin compete for the same binding site in COX-1. If ibuprofen is taken prior, then Aspirin will not be able t bind and irreversibly inhibit.

ASA 2 hours before or 8 hours after

Indomethacin MOAs

• non-selectively inhibits COX

• Lowers B and T cell proliferation

• Lowers neutrophil migration

  • Inhibits PLC, and PLA

Indomethacin DDIs

Probenecid makes Indomethacin last longer

Diclofenac side effect profile

Less GI, more renal damage

How is acetaminophen metabolized

1. glucoronidated or sulfation :)

2. CYP2E1 → glutathione → :)

3. CYP2E1 → non glutathione → iminoquinone :(

What are symptoms of acetaminophen tosicity

Increased AST, ALT, bleeding

How does acetaminophen interact with Warfarin

1200mg a day for a week can lower warfarin metabolism

What are the 4 steps of inflammation response

1. initial release of chemical mediators

2. Vasodilation

3. Leukocyte migration, chemotaxis

4. Long-term can cause proliferation of connective tissue

What is the difference between autocoids and eicosanoids

autocoids are produced at the site where they are needed

eicosanoids are found in every compartment of the human body

What are the 2 components all naturally occurring PGs have

C15 - a-hydroxyl

C13=C14 trans double bond

What do the numbers 1 2 and 3 mean on PG naming

1 - only has single C13=C14 trans double bond

2 - additional C5=C6 cis double bond

3 - additional C17=C18 cis double bond

Are prostoglandins stable

Not stable, don’t last long-time as generated locally and act locally

What enzymes degrade PGs

PG - 13 reductase - makes alkane

PG - 15 dehydrogenase - makes ketone

What are the 2 rxns that COX carry out

Arachidonic Acid → PGG2 (c15 peroxide) → PGH2 (C15 Hydroxyl)

COX reaction mechanism key features

Binding pocket has 90 degree kink, uses free radicals with TYR385

PGF2 structure and effects

C9 and C11 hydroxyl

Vasoconstriction

PGD2 and PGE2 structure and effects

PGD2 Top hydroxyl, Bottom ketone

PGE2 Bottom Hydroxyl, Top ketons

both cause vasodilation

Prostacyclin structure and effect

Endoperoxide broken and reformed

• promotes vasodilation and inhibits prostacyclin inhibition

• Cardioprotective

Thromboxane structure and effect

Weird triple ring

• promotes vasoconstriction and platelet aggregation

What are the 3 domains of COX

1. catalytic domain with HEME

2. EGF domain

3. Membrane binding domain with opening to active site being in membrane to ensure only arachidonic acid substrates can enter

What are the SAR features of an NSAID

1. Acidic center

2. Aromatic Ring

3. Peroxo bridge mimic (optional)

4. 2nd center of lipophilicity

What is special about C2 in NSAIDs

The S enantiomer is active

Having a C2 methyl increase activity

Indomethacin adverse effects

lots of GI and CNS effects

Indomethacin off label use

prevent premature labor

Sulindac Structure

similar to indomethacin, has no peroxo bridge mimic and Sulfoxide tail

Which of the arylacetic acids are prodrugs

Nabumetone, Sulindac

Indomethacin class

Arylacetic acid

Sulindac class

Arylacetic acid

How does sulindac have less CNS efffects that Indomethacin

Polar Sulfur group prevents BBB crossing

Diclofenac MOAs

COX inhibition

LOX inhibition

Inhibits Arachidonic acid release

Diclofenac metabolism

CYP3A4 and CYP2C9

What is special about nabumetone

non-acidic NSAID → no GI effects

Prodrug that is activated in body

What kind of mixture are profens

Racemic, only S is active but they are interconverted in the body

Which NSAID is only S enantiomer

Naproxen

What enzyme mainly metabolizes Ibuprofen

CYP2C9

How are R enantiomers converted to S enantiomers in VIVO

Only R enantiomers cand bind Acyl-CoA to undergo racemization

Fenamic Acids SAR

need acidic group, need N bridge, steric ortho substituents help with non-coplananrity

Oxicams MOA

Inhibit COX

Inhibit release of lysosomal enzymes

inhibit collagen-induced platelet aggregation

Oxicam SAR

Has enol as acidic center

R2 heteroaryl

R1small (methyl)

Oxicam Specifcity and dosing

COX-2 once daily inhibitor

How is COX-2 pocket different than COX-1

Valine instead of Isoleucine so it is slightly bigger

Celecoxib metabolism

CYP2C9

What kind of NSAIDs inhibit sults and what the effect

Fenamic Acids and Salicylates

• potential metastatica ctiivty