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PHARM4515-16 (NSAIDs)
PHARM4515-16 (NSAIDs)
PHARM4515-16 (NSAIDs)
Books: 1. Wilson and Gisvolds Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed. Lippincott, Williams & Wilkins ed.
Structurally diverse agents with anti-inflammatory activity Activity is attributed to their ability to inhibit cyclooxygenase (COX) Cyclooxygenase involved in the biosynthesis of prostaglandins Prostaglandins are a class of eicosanoids Eicosanoids are any product derived from arachidonic acid, a twenty carbon fatty acid
Natural Eicosanoids
PGA2
O O 9 5 1 COOH CH3 20 OH O COOH CH3 O OH HO OH
PGB2
COOH CH3
PGC2
COOH CH3 OH
11
13
15 OH
HO
PGD2
PGE2
COOH CH3
HO
PGF2
COOH CH3
HO
OH
PGG2
O O OOH COOH CH3 O O
PGH2
COOH CH3 OH O
PGJ2
COOH CH3 OH
PGI2 Prostacycline
COOH O O O
TXA2 Thromboxane A2
COOH CH3 OH CH3 HO O OH
TXB2
COOH CH3 OH
OH
OH
Commercial Prostanoids
A. Ocular Hypertension & Glaucoma BIMATOPROST HO Lumigan
N H O HO OH HO OH CH3 O
LATANOPROST HO Xalatan
O CH3 CH3
HO
TRAVOPOST Travatan
O O O CH3 CH3
HO
OH
CF3
ILOPROST Ventavis
COOH COOH O
ONa
MISOPROSTOL Cytotec,(Arthortec)
OH CH3
O O CH3
CH3
Prostaglandins - Nomenclature
Prostanoic acid
9 1 COOH 20 11 15 HO OH HO OH HO OH O
PGE1
COOH
PGE2
COOH
PGE3
COOH
The different prostaglandins are divided into several main classes (A, B, C, D, E, F, G, H) depending on the type and spatial relationship of the oxygen functions on C-9 and C-11 of the cyclopentane ring (all have a hydroxyl on C-15)
The designation refers to the steroeochemistry of the OH at C-9, below and on the same side (cis) of the ring as the OH on C-11.
Prostaglandins - Function
A class of highly active endogenous mediators Depending on the individual Prostaglandin and the tissue they exert many varied actions Prostaglandins are also implicated in the inflammatory response and in sensitizing pain receptors to the action of other mediators Occurring during acute and chronic inflammatory illness, prostaglandins are produced at the site of inflammation where they mediate many of the symptoms of inflammation such as edema and pain Play critical roles in tissue homeostasis and function
Prostaglandins - Biosynthesis
Prostaglandins are biosynthesized from Arachidonic acid Archidonic acid is found esterified as a cell membrane phospholipid
Phospholipase A1 Phospholipase A2 O O O C (CH2 )nCH 3 C O O O CH 3 P N O O CH Phospholipase C CH 3 3 Phospholipase D
The concentration of free arachidonic acid is low The biosynthesis of the eicosanoids depends primarily on its release from cellular stores by acyl hydrolases or phospolipases.
Biosynthesis is enhanced by many physical, chemical and hormonal stimuli and involves activation of enzymes by an increased concentration of calcium
Membrane bound Phospholipase A2 is involved in the release of arachidonic acid.
Action of cyclooxygenase on arachidonic acid results oxygenated products containing ring structures: prostaglandins, thromboxanes, and prostacyclin
action of various lipoxygenases result the hydroxylated products: HPETEs, HETEs, lipoxins and leukotrienes
THE EICOSANOIDS
The Arachidonic Acid Cascade
Lipoxins
15HPETE
Leukotrienes
O O
COOH
LTB4
O O
COOH
LTE4
OOH
Prostaglandin G2 Peroxidase
O O COOH
Prostaglandins
OH
PGA2 PGE2
PGB2
PGC2
PGD2 PGI2
Prostaglandin H2
PGF2
O C H COOH H2C C H O OH Malondialdehyde Hydroxyhepta decatrienoic aacid HHT HO COOH HO OH OH 19Hydroxy Prostaglandin F2a HO COOH HO OH Prostaglandin F2a
COOH HO
OH COOH
Arachidonic acid
O OH Thromboxane B2
1
O O COOH OOH Prostaglandin G2 O O
COOH OH Thromboxane A2
7
HO COOH
2 3
O O OH Prostaglandin H2 O
6
O OH Prostaglandin D2
COOH
PGH2 is also converted into two unstable yet highly active thromboxanes (so named because they were first isolated from thrombocytes)
5
COOH O
4
COOH
HO O
Prostaglandin endoperoxide synthase COOH 2. Peroxidase [EC 1.14.99.1] Prostaglandin endoperoxide synthase (cylcooxyenase domain) Prostaglandin endoperoxide synthase HO OH (hydroperoxidase domain) 6Keto Prostaglandin F1a 3. Prostaglandin F2a synthase [EC 1.1.1.188] 4. Prostaglandin E2 synthase [EC 5.3.99.3] 5. Prostaglandin I2 synthase [EC 5.3.99.4] 6. Prostaglandin D2 synthase [EC 5.3.99.2] 7. Thromboxane A2 synthase [EC 5.3.99.5] 1. Cyclooxygenase
Products of 5Lipoxygenases
Leukotriene Biosynthesis
COOH Arachidonic acid
1
OOH S CH3 inhibited by O Zileuton N HO NH2 COOH 5HPETE OH
2
5HETE
COOH
1
O C5H11 Leukotriene A4 COOH
1. 2. 3. 4. 5. 6.
HO H
5Lipoxygenase + FLAP [EC 1.13.11.34] Peroxidase Leukotriene A4 epoxide hyrolase (LTA4 hydrolase) [EC 3.3.2.6] LTC4 synthetase (a glutathioneStransferase) [EC 2.5.1.37] gGlutamyl transferase [EC 2.3.2.2] Cysteinyl glycinase (an amino dipeptidase)
COOH
C5H11
5
HO H COOH HO H
COOH
HO H
COOH
Products of 15 Lipooxygenases
Lipoxin Biosynthesis
COOH
Arachidonic acid 1
COOH
2
OH
COOH
15 HPETE 3
OH COOH OOH
OOH
15 HETE
COOH
5,15 HETE
5,15 HPETE
COOH
OH
HO
OH COOH
HO
OH COOH
OH COOH
OH
OH
OH
OH
6S Lipoxin A
Lipoxin B
Lipoxin C
1. 2. 3.
The cyclooxygenase active site is buried deep within the protein, and is reachable by a tunnel that opens out in the middle of the knob. This acts like a funnel, guiding arachidonic acid out of the membrane and into the enzyme for processing
Side pocket
In COX1 residues Arg120 &Tyr355 stabilize the anionic group present in most NSAIDs. NSAID aromatic rings are accommodated in the hydrophobic channel. Ser530 is the residue acetylated by aspirin. Note the presence of the relatively bulky Ile523
In COX2 residues Arg120, Tyr355 & Ser530 are present. However, residue 6 is Val523 which allows copening of a side pocket. This pocket accommodates the sulfonamide or isoster of COX2 inhibitors. They are stabilized by hydrogen bonding with Arg513. from Nature Reviews Drug Discovery, 2, 2003
COX-1 is constitutive and its expression is regulated by hormonal signals involved in maintaining physiologic homeostasis
COX-1 is expressed in all tissues Importantly, COX-1 but not COX-2 is constitutively expressed in the stomach, where it is involved in mucosal defense and repair COX-2 expression and activity is largely responsive to adverse stimuli, such as inflammation and physiologic imbalances Control of COX-2 transcription and translation is thought to be the primary mechanism by which steroids such as hydrocortisone and dexamethasone modulate this enzyme. COX-2 has a binding site for steroids whereas COX1 does not COX-2 is constitutively expressed notably in the brain and kidney
Mechanism of Action
Inhibitors of cyclooxygenase reduce the amount of Prostaglandins and thereby reduce the inflammation process primary insult: Unionized at stomach pH that allows passage into gastric mucosal cells. The inside higher pH ionize them which can not pass through lipid barriers and is trapped inside the cell. This alters the permeability of the cell membranes and allows accumulation of hydrogen ions which cause cell damage
Mic roenvironment low pH
ARCOO
Intracellular higher pH
ARCOOH ARCOO
+ H
ARCOOH
+ H
The secondary insult is the result of the mechanism of action. The inhibition of PG synthesis prevents the cytoprotective action of the PG Most of the gastric effects of NSAIDS are attributed to their acidic character which participates in 1) decreasing surface hydrophobicity of the mucus gel layer with subsequent loss of barrier properties; 2) uncoupling of oxidative phosphorylation with subsequent increase in mucosal permeability and back diffusion of hydronium ion; 3) ion trapping into the mucosal epithelium
4.
With the exception of Aspirin, all the NSAIDS are reversible competitive inhibitors Aspirin is a nonreversible inhibitor, for it acetylates the active site which is the basis for its prophylactic use to prevent heart attacks Research suggests a role for PG in CNS transmission and raises the possibility that selective COX2 inhibitors may modulate CNS function. This is relevant for those COX2 inhibitors that lack an acidic group and thus can easily pass the BBB. COX1 provides a cytoprotective role in the stomach and kidneys. It helps maintain the integrity of the mucosal epithelium and inhibition leads to gastric damage, hemorrhage, and ulceration The cytoprotective role in the stomach and kidney is largely due to the vasodilating properties of PGs which enhance mucosal blood flow Thus COX1 produces prostaglandins that exert cytoprotective roles whereas COX2 produces prostaglandins involved in inflammation, fever and pain; and COX2 activation leads to inflammation Thus COX2 inhibition produces therapeutic effects and COX1 inhibition produces unwanted side effects. Unfortunately, most NSAIDS are more effective at inhibiting COX1 than COX 2
5.
6. 7. 8.
The Salicylates
Salicylic acid is a natural product, present in the bark of willow and poplar trees
The active ingredient, isolated by a French pharmacist in 1827, was Salicin, oxidized to Salicylic acid In 1875 a Swizz pharmacist, Lowig, distilled meadowsweet flowers and got salicylaldehyde
HO HO
OH O O OH OH
Salicin
Salicylate SARs The simplest active compound is the salicylic acid anion, The carboxylic group is necessary for activity and the hydroxyl group must be ortho to it. Introduction of electronegative groups and lipophilic groups increases antiinflammatory activity and toxicity.
ASPIRIN
O OH O H3C O
Benorylate
O C O N H O CH3
O O
Salicylic acid and Sodium salicylate were the original products used but required doses which had much gastric irritation and ulceration. Salicylic acid in the unionized form has a bad taste, thus the sodium salt is used more frequently
Salsalate and Benorylate are prodrug esters. The sodium salt is freely soluble in water and helps in its dissolution and faster absorption. Salsalate is only half as potent as an analgesic/antipyretic as Aspirin but produces less GI irritation. Salsalate is a diester of salicylic acid and benorylate is esterified with Acetaminophen Salsalate is insoluble in gastric pH but soluble in the small intestines, thus causing less gastric problems. Further, it is useful in hypersensitivity to Aspirin. Hypersensitivity to ASA is a result of acetylated plasma proteins. Since it produces Salicylic acid it can be used in Aspirin sensitive patients Sodium thiosalicylate is used in rheumatic fever and acute gout and an injectable form is available Magnesium salicylate form stable aqueous solution and show some success in overcoming the GI problems Choline salicylate is absorbed faster than Aspirin producing higher salicylate blood levels and an aqueous formulation is available
Aspirin
Searching for a less toxic better tolerated derivative of salicylic acid produced aspirin. The knowledge that acetylation of the very toxic aniline produced the less toxic acetanilide, acetylation of salicylic acid with acetic anhydride produced Aspirin The name. Aspirin was coined by adding an a for acetyl to spirin from the name of the plant from which salicylic acid was first isolated
It is slightly soluble in water, absorbed as such, but is hydrolyzed rapidly to salicylate and acetate by esterases Pharmacological actions are attributed to both the ASA and salicylic acid ASA irreversibly inhibits the enzyme acetylating a serine residue thus preventing access to the cyclooxygenase site
Salicylic acid forms a reversible ionic bond with the cationic site on cyclooxygenase
NHCOCH2NCO CH2 COOH O O O H CH3 COOH O ONHCOCH2NCO CH2 O + H+ CH3 COOH OH + O NHCOCH2NCO CH2 O CH3
DIFLUNISAL Dolobid
F O OH
OH
F OH
Salicylamide is an isostere of salicylic acid, OH replaced by NH2 to produce a non acidic amide which is stable in aqueous preparations and does not cause GI tract ulceration and is absorbed only in intestine. It has greater CNS penetration. It is reported to be as effective as Aspirin as an analgesic/antipyretic and is effective in relieving arthritis pain but does not appear to have antiinflammaatory actions. It does not satisfy SAR 1 possibly works through a different mechanism. It can be used by those allergic to Aspirin.
Diflunisal has changed absorption profile and increased duration of action. Diflunisal is absorbed only in intestine; it is not soluble in gastric fluid. Thus, gastric bleeding and GI upset is not as common. It lasts 34 times longer than aspirin. The increase in potency is attributed to an increase in binding to the receptor since it has a second aromatic ring SAR 2. The proximity of the two phenyl rings allows for the ortho hydrogen van der Walls electron radii to repel and thus keep the rings out of the same plane.
Fenemates
The Fenemates are derivatives of Anthranilic acid, an isoster of salicylic acid The most potent analogs are those disubstituted at 2 and 3. This indicates that activity resides in compounds with the substituent on the second ring that keep it out of coplanarity by the ortho substituent Mefenamic acid has only one substituent, the 2 methyl, that ensures non coplanarity Meclofenamate sodium has two such groups, the chlorine atoms, and thus more molecules of Meclofenamate assume the correct conformation and the drug is more potent
MEFENAMIC ACID Ponstel O
OH NH CH3 CH3 Cl NH Cl
CH3
Meclofenamate is 25 times more potent thus normal dose for Meclofenamate is 25 mg while the dose for Mefenamic acid is 250 mg. Since this class offers no advantage over the salicylates with respect to analgesic or anti-inflammatory actions, there is little interest in developing this class
p-Aminophenols
O H N CH3 H N O CH3 H N O CH3
Phenacetin Acetanilide
O CH3 OH
Useful for pain and fever, but not inflammation. They have an aromatic ring, but do not have an acidic group ionizable at physiologic pH. Thus they do not comply with SAR 1 possibly act by some other mechanism The first drug Acetanilide is out of market due of toxicity (both blood and liver disorders Phenacetin (1887) was used for decades, but in the 1970s it was implicated in cases of liver and nephrotoxicity and was removed from the market
Acetaminophen is also a very old drug, a metabolite of both phenacetin and acetanilide, is a safe drug, producing much better tolerance and a lower incidence of gastric bleeding compared to many of the other NSAIDs, probably because of its apparently different mechanism of action
You know the chemistry of toxicity for both phenacetin and acetaminophen
Aminopyrine
O N N N CH3 CH3
Antipyrine is the prototype and its antipyretic and analgesic activities were discovered by accident.
Aminopyrine is an analog, more potent and longer acting but both possess significant incidences of agranulocytosis leading to death and used only in otic drops
O N H3C N N O S ONa O CH3 CH3 Dipyrone
Dipyrone is a prodrug which spontaneously decomposes in aqueous solutions to aminopyrine. It is banned in the US but available in Mexico. Dichloralphenazone is a complex of Aminopyrine and Chloral hydrate It is a common agent in many OTC analgesics. It is a mild sedative used in migraine /tension headache products.
O N N Cl Cl
Cl OH
H3C Although it appears that SAR 1 does not apply, these OH CH3 drugs are able to tautomerize into enols, which in turn DICHLORALPHENAZONE ionize. Thus they have an aromatic ring with an anionic Antipyrine Chloral Hydrate charge two atoms away.
O HN NH
OH
Search for better drug produced the pyrazolidinediones which are acidic because the bdiketone tautomrizes into an acidic enol
N NH pyrazole
HN NH pyrazolidine
O
HN NH pyrazolidinedione
O N CH3 N O HO
N N O
CH3
Phenylbutazone
Oxyphenbutazone
Phenylbutazone is equipotent to antipyrine, and more potent than aspirin for treating inflammation. It has long half-life (72-84 hours). Serious toxicities, e.g., agranuylocytosis, peptic ulcers and bone marrow depression, limits its use in long term therapy. Oxyphenbutazone is its active metabolite with similar activity, equipotent but less toxic, shorter halflife (half-life 48-72 hours) and better tolerated. w-1 Hydroxyl is another metabolite with uricosuric activity but little anti inflammatory activity The keto metabolite, Kebuzone, is marketed in Europe as a uricosuric agent. Sulfinpyrazone is marketed in the US as a uricosuric. The two phenyl rings are not coplanar due to their close proximity, on adjacent nitrogens. The ortho hydrogens one each ring are effective at this close proximity
CH3 O
CH2 CO OH N C O CH3
CH3 O
CH2 CO OH N O C Cl CH3
Cl
Illustrates SAR 3. Partial double bond character of amide restrict rotation. 2-Methyl provides steric hindrance favoring the active conformer and the hydrogen atoms at 7 and 2 provide hindrance to ensure non coplanarity
Sulindac: Indomethacin has significant CNS side effects due to the indole nucleus. Thus the heterocyclic nitrogen was removed and a double bond introduced, giving the indene derivative. Z isomer is active, lacks the CNS side effects and causes less GI irritation but low water solubility. Introduction of a fluoro and a methylsulfinyl increased solubility while retaining potency. Sulindac is a prodrug. Its active form is the sulfide metabolite which has a long halflife allowing for BID administration. The phenyl is out of the plane
CH3 O CH2 CO OH CH3 C Cl H C O CH3 S H CH3 S F CH2 CO OH CH3 F
O OH CH3 H
H3 C
S O
Sulindac Clinoril
CH2 CO OH CH3 C H
Sulindac
Sulfide of Sulindac
Clinically it has only about half the potency of Indomethacin in treating inflammation and reducing fever, but is equipotent in analgesic effect. Since the drug is absorbed as the inactive sulfoxide, it causes fewer GI disturbances (no prostaglandin biosynthesis inhibition in the stomach). The thioether metabolite (shown at the right) is longer-lived than the parent (ca. 16 hours).
ONa CH3
O H3 C Cl
TOLMETIN Na Tolectin
Zomepirac Na [Zomax]
Tolmetin was designed to contain the three portions of Indomethacin deemed necessary for activity, the carboxyl, the flat indole ring and an out of plane phenyl
Compared to Indomethocin, is there anything to ensure SAR 3, that one conformer predominates and the two aromatic rings are non coplanar? Which is more potent and why? Tolmetins major metabolite is the carboxylic acid resulting from benzylic hydroxylation and subsequent oxidation. It has a halflife of 30 to 60 minutes
To increase the duration of action the methyl was replaced with a chloro which prevented metabolism at the phenyl ring. This drug was Zomepirac which was marketed but eventually removed due to reports of severe anaphylactoid reactions in patients sensitive to Aspirin.
O ONa NH Cl Cl Cl
O OK NH Cl
The SARs in Diclofenac sodium are similar to those discussed with the Fenemates. Diclofenac is probably the most popular NSAID in the world. Its mechanism of action may be a little different from the others. It is a COX inhibitor like the rest, but it also seems to inhibit lipoxygenase to some degree. This could account for its increased anti-inflammatory effectiveness and potency. The two Cl groups are necessary to force the two rings out of plane with each other. It has a profile of action similar to the others and favors anti-inflammation uses, rather than analgesic uses. Diclofenac is also available in combination with Misoprostol as Arthrotec. Why? The Sodium salt is a delayed release formulation while the Potassium salt is used in a rapid release formulation. Diclofenac sodium is available in a gel form (Solaraze) for the treatment of actinic keratosis. The mechanism is unknown.
FLURBIPROFEN Ansaid CH
3
CH3 O OH
OH F O
H3 C
CH3
Ibuprofen is the prototype, marketed as the racemate. Lacks second aromatic ring (SAR 2) but possess a secbutyl substituent that presumably renders the drug slightly less potent. Its profile is much like other NSAIDs in terms of GI distress. Flurbiprofen resulted from a study of the SARs. The 3fluoro substituent helps ensure noncoplanarity. This compound had the most favorable therapeutic profile and was first introduced as a topical product for ophthalmic use (Ocufen). Later it was introduced for systemic use (Ansaid is reputed to stand for Another NSAID). This drug is many times the potency of the other drugs (100x phenylbutazone against inflammation), and is about half as potent as methylprednisolone (an anti-inflammatory steroid).
Ketoprofen (1986): The great potential advantage of this drug is that it inhibits the leukotriene pathway as well, although its structure does not predict that. It is clinically less potent than Indomethacin, but has about the same GI disturbance profile
SUPROFEN Profenal
CH3 O OH
Suprofen (1985) is an isostere of Ketoprofen an analgesic for mild to moderate pain. It was found to cause flank pain and transient renal failure and was withdrawn in 1987. It then was reintroduced in 1989 for ophthalmic use in lens replacement surgery to prevent iris inflammation. Fenoprofen (1976) is less potent than many of the others for inflammation, with some analgesic and antipyretic activity. It does not illustrate SAR 3. No special advantage is shown by this drug. Ketorolac is related to Indomethacin and Tolmetin because it has the pyrrole ring, but is a cyclic propionic acid derivative (SAR 8), commercially available as the tromethanime salt. The tromethamine moiety enhances water solubility. The injectable formulation is incompatible with solutions of conjugate acids like meperidine hydrochloride (precipitation). It is about half as potent as Morphine when injected. After its success as a parenteral agent, an oral agent was marketed.
NAPROXEN Naprosyn
CH3 O OH
CARPROFEN Rimadyl
O
CH3 O OH
OXAPROZIN Daypro
O CH3
O CH3
ONa Cl NH
O O N OH
Naproxen does not possess a second non coplanar ring (SAR 3). The naphthyl rings are fused and aromatic thus flat and planar. It is the only drug currently marketed in the optically pure form. This is not due to resolution but is the result of the synthetic method used. Interestingly the S isomer of Naproxen is (+) as most in this class are, but the S isomer of the sodium salt is (). Carprofen is marketed as a veterinary analgesic. Does it have a second noncoplanar ring, SAR 2? Oxaprozin is an aryl propionic acid but is unique in that the propyl is not branched.
Oxicams
Pfizer developed this class to produce noncarboxylic acid NSAIDS
PIROXICAM Feldene
OH O N H CH3 N N O S O
MELOXICAM Mobic OH O
N H CH3
N S CH3
N O S O
Piroxicam is the first member of this family marketed, however it possess the three structural requirements. The enolic hydroxyl is the acidic group and the pyridyl ring is the second aromatic ring. Although it has good potency, the GI side effects limit its usefulness. A typical half-life for Piroxicam is ca. 38 hours.
Meloxicam is structurally related to Piroxicam. Although Meloxicam is frequently described in the literature as a selective COX-2 inhibitor, it is considerably less selective for the COX-2 versus COX-1 isoenzyme when compared to Celecoxib or Rofecoxib.
Miscellaneous
ETODOLAC Lodine H3C
H3C H N O O OH O CH3
NAMBUMETONE Relafen
O CH3
Etodolac can be considered a nonclassical bioisostere of the arylpropionic acids. It is ca. 50x more potent than aspirin in inflammation, 33% as potent as indomethacin. It shows a much better GI profile than aspirin or indomethacin and this can be a therapeutic advantage. It is a unique compound. How many aromatic rings does it have? Note the separation between the aromatic ring and the acid. Nabumetone is a ketone and thus nonacidic (SAR1?). It is classed as an Alkanone. It is a prodrug and must be activated by boxidation to 6Methoxy2 naphthylacetic acid. Approximately 35% of a 1000mg dose is converted to 6 MNA, which is structurally related to Naproxen, an arylacetic acid. But is only an acetic acid derivative thus weaker than Naproxen. Further, not all the dose is converted to 6MNA. The advantages of this drug is less GI tract toxicity because it is not acidic
Allopurinol is a structural analog of hypoxanthine and thus is a xanthin oxidase inhibitor used to treat hyperuricemia and its complications including chronic gout as well as prophylaxis with chemotherapeutic treatments, which can rapidly produce severe hyperuricemia.
O HN N N N H
HN
N N N H
Hypoxanthene
Allopurinol
Drugs for Inflammatory Bowel Disease (Ulcerative Colitis) Mesalamine or 5-aminosalicylic acid (5-ASA), and its prodrugs balsalazine and olsalazine are anti-inflammatory drugs/prodrugs used to treat inflammation of the digestive tract (ulcerative colitis) and mild-to-moderate Crohn's disease. Mesalazine is a bowel-specific aminosalicylate drug that acts locally in the gut and has its predominant actions there, thereby having few systemic side effects. Balsalazine and olsalazine generate mesalamine in the site of action. (How about salfasalazine??)
NaOOC
NaOOC O O ONa
N N OH COONa
H2N
OH
HO
HO
N HN
Mesalamine COOH
Olsalazine
Balsalazine
COX - 2 Inhibitors
CELECOXIB Celebrex
F 3C N N O S O NH2 O O
REFECOXIB O Vioxx
S O
CH3 O N
VALDECOXIB O Bextra
CH3 S O
NH2
DERACOXIB Deramax
F N N
O S O NH2
F OCH3
CH3
Celecoxib was the first. Structurally it differs from other NSAIDS in that is only weakly acidic. It does possess a sulfamyl group and has a warning about use in patients with a sulfonamide allergy
Valecoxib is also a sulfamyl and its package insert contains the same caution. It is this phenyl group which is inserted into the extra space in COX2
Deracoxib is also acidic but is indicated for veterinary use Rofecoxib is not acidic
Refecoxib and MI
One of the reasons given is that the endothelial cells express mainly COX2 whereas platelets express COX1. Since Refecoxib is COX 2 selective it allows for an overproduction of Thromboxane A2 (platelet). Thromboxane is released by platelets and causes vasoconstriction and platelet aggregation. Prostacycline is release by capillary endothelium and causes vasodilatation and prevents platelet aggregation. Normally these balance each other; The platelets use COX-1 and the capillaries use COX-2. Thus COX-2 selective agents unbalance the system favoring thromboxane. However this is not the only factor in play since the other COX2 selective agents have not shown the increase in MI
Study Guide
What are cyclooxygenase and peroxydase? What do you mean by prostaglandin endoperoxide H2 synthase (PGHS)? What are COX-1 and COX-2? What physiologically important prostaglandins and thromboxanes are synthesized by them blocking of which gives clinical effects of different NSAIDs? What are different chemical categories of NSAIDs? List the nonselective and COX-2 selective NSAIDs with structures. Similarities and differences between COX-1 and COX-2 with reference to physiology, active site amino acids, size and shape of active site. Diflunisal is a salicylic acid derivative yet does not cause much is gastric bleeding and GI upset. Why? Why low-dose, long term aspirin is recommended for the prevention of strokes and heart attacks? Describe the action and mechanism of action of acetaminophen. Is COX-3 important for its activity?
What is the active principle of sulfasalazine in IBS? Why it is replaced with better alternatives? Which are they?
Why coxibs are selective to COX-2 and not bound to COX-1. Why the coxibs have more CV risk than other NSAIDs?