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Home , Pyrazolidine, Salicylamide, Sulfinpyrazone

Nonsteroidal Anti-inflammatory (NSAIDs) Cell membrane Cell injury

Phospholipase A2

Arachidonic acid

NSAIDs Inhibitors X

PGG2, PGH2 PG endoperoxide E glutathione-S-transferase isomerase PG endoperoxide reductase TXA2, TXB2 PGG2, PGH2 PGI2 The eicosanoids are important mediators: - Pain - Inflammation - Protection of the gastric mucosa - aggregation And maintenance of normal function. *** The NSAIDs can be divided into the following groups: - 1- Salicylates 2- p-Aminophenol derivatives. 3- Anthranilates 4- Arylacetic acids 5- Arylpropionic acids 6- and derivatives 7- Aryl sulfonamides () 8- COX-2-inhibitors. 1 - Salicylates Salicylates possess , , and anti- inflammatory properties. Salicylates possess other actions such as treatment of gouty arthritis and blocking formation of the potent platelet aggregating factor A2 in an irreversible manner.

1- (Acetylsalicylic acid) O

2 -Acetyloxybenzoic acid. O C CH3 Synthesis COOH

OH (CH3CO)2O OCOCH3

COOH COOH

** Aspirin is the prototype of a nonsteroidal anti-inflammatory drugs and is used in a large number of inflammatory and pain indications including musculoskeletal, soft-tissue and joint disorders, headache, dysmenorrhoea, and fever.

** Acetylsalicylic acid shows a balanced inhibition of COX-1 and COX-2.

Assay Acid-base titration:- Depending on refluxing aspirin with 0.5 M NaOH and the excess of NaOH is back titrated with 0.5 M HCl using phenol red as indicator.

OCOCH3 OH + 2 NaOH + CH3COONa + H2O

COOH COOH 2- 2-Hydroxybenzamide CONH2

Synthesis OH

COOCH3 NH3 CONH2

OH OH Methylsalicylate ** It is characterized by lack of gastric irritation, compared with aspirin, it is used in patients who are hypersensitive to aspirin. ** Salicylamide enters the CNS more rapidly than other salicylates so it causes sedation and drowsiness when administered in large doses. ** Salicylamide shows analgesic and antipyretic efficacy, and is used in multi- combinations for the treatment of a variety of mild pain conditions including musculoskeletal, soft-tissue and joint disorders. 2- Aniline and p-aminophenol derivatives (Acetaminophen) (Tempera, Tylenol) NHCOCH3

N-Acetyl-p-aminophenol. Or 4-Hydroxyacetanilide.

Synthesis OH

OH OH OH NHCOCH3

HNO3 H2/ Rany-Ni (CH3CO)2O

H2SO4

NO2 NH2 OH ** Paracetamol has analgesic and antipyretic properties without anti-inflammatory action.

** It is used for the treatment of various mild to moderate pain conditions and to reduce fever. Mode of action Inhibition of COX-3 could represent a primary CNS mechanism by which acetaminophen and exerted their analgesic and antipyretic effects.

** Individuals who are hypersensitive to salicylates generally respond well to acetaminophen (advantage over aspirin as analgesic). ** Paracetamol is marketed in combination with aspirin and (Trigesic).

Assay Spectrophotometrically at specific l max. Toxic metabolites of paracetamol

3- Anthranilates These derivatives are nitrogen isosters of (replacement of OH of salicylic acid by NH gives products which retain analgesic activity). 1- , flufenamate COOH H N CF3

N-(3-Trifluoromethylphenyl)anthranilic acid.

Synthesis COOH COOH H Cl H2N CF3 N CF3 Cu +

K2CO3 Clinical use: ** Flufenamic acid is a non-steroidal anti-inflammatory drug used for the treatment of mild to moderate pain of musculoskeletal, joint or soft-tissue origin. Assay 1- Titrimetric analysis: Flufenamic acid can be titrated in acetone with 0.1 N aqueous KOH in the presence of phenolphthalein as indicator. 2 - Non-aqueous titration By using 0.1 N sodium methoxide as the titrant and DMF or tetramethylurea as the solvent, measuring the end point either with thymol blue indicator or potentiometrically.

3- Spectrophotometrically at specific l max.

2- (Ponstan) O OH CH3 H N CH3

N-(2,3-Dimethylphenyl)anthranilic acid.

** Mefenamic acid exhibits both analgesic and anti- inflammatory actions, through blockage of synthetase. Assay

Like flufenamic acid assay.

4- Arylacetic acids CH2COOH 1-

NH

Cl Cl

[2-(2,6-Dichlorophenylamino)phenyl] .

Diclofenac is a non-steroidal anti-inflammatory drug with balanced COX-1 and COX-2 inhibition. It is commonly used for a variety of inflammatory and pain conditions such as musculoskeletal and joint disorders and postoperative pain.

Assay 1- Acid-base titration. 2- Non-aqueous titration. 3- Determination of the Cl- content by Volhard’s method after oxygen flask method.

2- Diclofenac Potassium and Sodium CH2COONa or K

NH

Cl Cl

Sodium [o-(2,6-Dichloroanilino)phenyl]acetate. (Voltaren) Potassium [o-(2,6-Dichloroanilino)phenyl]acetate. (Cataflam)

** It is indicated for acute and chronic treatment of rheumatoid arthritis and osteoarthritis.

** Cataflam, which is faster acting, is indicated for the management of acute pain and primary dysmenorrhea. 3- Indomethacin (Indacin) H3CO CH2COOH

CH3 N 1-(p-Chlorobenzoyl)-5-methoxy-2- methylindole-3-acetic acid. O C Cl

** Indomethacin is one of the most potent NSAIDs, it possess about 10 times analgesic potency of aspirin. ** Indomethacin is a COX-1 selective inhibitor with 10- 60 fold selectivity compared to COX-2. ** Indomethacin is used in acute and chronic pain states like rheumatoid arthritis, osteoarthritis, joint and soft-tissue pain, dental pain, postoperative pain and dysmenorrhoea. ** The major side effects of indomethacin are gastric distress, peptic ulceration and central nervous system disturbance like depression, drowsiness and convulsions. Assay Spectrophotometrically at specific l max. 5- Arylpropionic acids The introduction of methyl group at a-carbon atom in acetic acid yield derivatives, which have increasing anti-inflammatory effect and decreasing hepatotoxicity.

1- (Brufen, Motrin) CH3

2-(4-Isobutylphenyl)propionic acid. H3C

Clinical use H3C COOH It is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, relief of mild to moderate pain, reduction of fever, and treatment of dysmenorrhea . Assay Acid-base titration.

2- (Ketofan, Orudis) H3C COOH

2-(3-Benzoylphenyl)propionic acid.

O

Ketoprofen is closely related to in structure and properties, it has demonstrated a low incidence of side effects.

Assay 1- Acid-base titration. 2- Colourimetric assay: Due to the presence of C=O so it can form hydrazone derivative with p-nitrophenylhydrazine, this hydrazone derivative measured colourimetrically at specific l max.

6- Arylsulfonamides (Oxicams) It is a group of nonsteroidal anti-inflammatory agents containing a 2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide moiety as common structural entity. (Feldene)

OH O

N N

N H S CH3 O O

4-Hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3- carboxamide-1,1-dioxide.

Synthesis Methyl chloro acetate OH O O OCH3 Cl 1- OCH O 3 H N N NH 2 N S 2- NaOCH3/toluene/ S CH O butanol 3 O O 3- CH3I O Saccharine

OH O

N N

N H S CH3 O O Piroxicam represents a class of acidic inhibitors of prostaglandin synthetase, this drug is very long acting with a plasma half life of 38 hr. Piroxicam shows a 600-fold selectivity for COX-1 compared to COX-2 in cultured animal cells . Assay Spectrophotometrically at specific l max. 7- COX-2 Inhibitors First generation COX-2 inhibitors

Meloxicam (Mobec)

4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzo- thiazine-3-carboxamide-1,1-dioxide.

Clinical use belongs to the first generation of COX-2 selective drugs and it shows 10 times selectivity for COX-2 compared to COX-1. Meloxicam is used for the acute and chronic treatment of mild to moderate pain such as arthritis. Second generation COX-2 inhibitor 1- (Celebrex)

4-(5-p-Tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide.

Clinical use ** Celecoxib is a selective COX-2 inhibitor, the selectivity for COX-2 compared to COX-1 is about 375- fold. ** Celecoxib has been approved for rheumatoid arthritis and osteoarthritis. It is given orally (200-400 mg/day).

2- (Vioxx) O

H3C S

O

O

O

4-[4-(Methylsulfonyl)phenyl]-3-phenylfuran-2(5H)-one.

Clinical use Rofecoxib is a second-generation COX-2 selective inhibitor. The selectivity for COX-2 compared to COX-1 is about 800- fold. Rofecoxib is used once/daily in the treatment of osteoarthritis (12.5-25 mg/day) and pain (50 mg/day). Rofecoxib shows significantly less gastrointestinal toxicity than ibuprofen in studies with osteoarthritis patients.

Antirheumatic agents The formation of from adenine and guanine is illustrated in the following figure: OH

N N

H2N N N H Guanine

NH2 OH OH OH

N N N N Adenine Xanthine N N Xanthine N N deaminase oxidase oxidase N N N N HO N N HO N N OH H H H H Adenine Hydroxanthine Xanthine Uric acid The control of has been approached from the following therapeutic strategies:

(1) Control of acute attacks by drugs to reduce inflammation caused by the deposition of urate crystals (these drugs may possess only an anti-inflammatory component such as or both anti-inflammatory and analgesic actions such as in indomethacin, and ).

(2) Increasing the rate of uric acid by the use of agents such as and .

(3) Inhibiting the biosynthesis of uric acid by inhibiting the enzyme xanthine oxidase with drugs such as .

1- Uricosuric agents

Probenecid C3H7 O

C3H7 N S COOH

O 4-(N,N-Dipropylaminosulfonyl)benzoic acid.

** Probenecid promotes the excretion of uric acid by decreasing the reabsorption of uric acid in the proximal tubules.

** The uricosuric activity increases with increasing size of the alkyl group in the series methyl, ethyl, and propyl. 2- Inhibitors of uric acid synthesis Inhibition of the biosynthesis of uric acid from xanthine, through inhibition of enzyme xanthine oxidase. Allopurinol OH

1H-Pyrazolo[3,4-d]pyrimidin-4-ol. N

N N N Assay H Spectrophotometrically at specific l max.

** Allopurinol serves as a substrate for xanthine oxidase (15-20 times greater the affinity of xanthine) and reversibly inhibits that enzyme.