NSAIDs

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Non steroidal anti-inflammatory drugs NSAIDs
Cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins and related compounds (prostacyclin,thromoxane A2). Cyclooxygenase is found in all tissues and regulate multiple processes. at side of tissue injury ,COX catalyzes the synthesis of prostaglandin E2 (PGE2) and prostaglandin I2 which promote inflammation and sensitize receptors to painfull stimuli .

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Cyclooxygenase has 2 form : cyclooxygenase -1 (COX-1),and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 present in all tissue, and it is "housekeeping "chores such as protecting the gastric mucosa, supporting renal function, and promote platelet aggregation , in contrast COX2 is found mainly at site of tissue injury where it mediates inflammation and sensitizes receptors to painful stimuli .therefore the COX-1 has been dubbed the "the good COX"and COX-2 the "bad COX".

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Learning Objectives
In stomach : COX-1 promote synthesis of prostaglandin E2 (PGE2) and prostaglandin I2 which protect the gastric mucosa by : reduction of gastric acid secretion, increased secretion of bicarbonate and cytoprotective mucus, and maintenance of submucosal blood flow . In platelets: COX-1 promotes synthesis of thromoxane A2 ,which stimulate platelet aggregation

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In the kidney, COX-1 catalyzes the synthesis PGE2 and prostaglandin I2 which promote vasodilatation and maintain renal blood flow.In the brain , COX –1 derived prostaglandin mediate fever and contribute to pain perception .In the uterus COX –1 derived prostaglandin mediate promote contraction .

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Pain (cont’d) So inhibition of COX-1 result in harmful effect : -Gastric erosion and ulceration.,-Bleeding tendency. Acute renal failure . inhibition of COX-1 also has one beneficial effect: protection against myocardial infarction (reduced platelet aggregation). Inhibition of COX-2 results in beneficial effects : suppression of inflammation. Alleviation of pain . Reduction of fever



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Classification of cyclooxygenase inhibitors:
The NSAIDs can be divided in into 2 groups : (1) first generation NSAIDs and (2) second generation NSAIDs. The first generation inhibit COX-1and COX-2, the second generation inhibit COX-2 only. Because the first generation inhibit COX-1and COX-2, they are unable to produce their effects without posing a risk of serious side effects . in contrast , the COX-2 inhibitors can suppress pain and inflammation with minimal risk of serious adverse effects.

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First generation NSAiDs (proto type is Asperin :
Mechanism of action :Is a nonselective inhibitor of cyclooxigenase , suppress inflammation , pain , and fever –result from inhibition of COX-2. one beneficial effect –protection of myocardial infarction result from inhibition of COX-1. major adverse effects –gastric ulceration , bleeding , acute renal failure result from inhibition of COX-1.

Cont. aspirin

Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours. This in contrast with all other NSAIDs, which are reversible inhibitors , therefore duration of action depends on how quickly specific tissues can synthesize new molecule of COX-1and COX-2 . and the effect decline as soon as drug levels fall. Slide *

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Pharmacokinetics
Absorption: aspirin is absorbed rapidly and completely after oral administration in the small intestine , rectal absorption is slower and blood levels are lower than oral therapy . Metabolism : has very short half life ( 15- 20 minutes) because rapidly converted to salicylic acid , an active metabolite. At low therapeutic level salicylic acid has half life of 2 hours and at high therapeutic level the half life exceed 20 hours . Excretion : by the kidney and highly dependent on urinary pH, by raising the pH of the urine from 6 to 8 , we can increase the rate of excretion by a factor of 4.

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Therapeutic usesasperin (cont’d) 1-suppression of inflammation . Aspirin is an initial drug of choice for rheumatoid arthritis , osteoarthritis, rheumatic fever , tndinitis. The dosages employed to suppress inflammation are higher than doses used for analgesia and reduction of fever . 2-analgesia ( mild and moderate pain ). Is most effective in joint pain, muscle pain and headache, and inactively against severe pain of visceral origin, in contrast to opioid aspirin produce neither tolerance nor physical dependence . aspirin relief pain through action on the periphery . At site of injury , prostaglandin sensitize pain receptor to mechanical and chemical stimulation , by inhibition of COX-2 aspirin can relief pain . in addition aspirin has action on CNS that contribute to relief of pain.

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Therapeutic usesasperin (cont’d) 3- Reduction of fever. Aspirin is the drug of choice for reducing temperature in febrile adults , however because of Reye syndrome aspirin should never be used to treat fever in children . aspirin will not lower normal body temperature, nor will it lower temperature that it has become elevated in response to physical activity or a rise in external temperature .the mechanism also by inhibiting COX-2 and thereby inhibit pyrogen- induced synthesis of prostaglandin .


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Therapeutic usesasperin (cont’d) 4- Dysmenorrhea : benefit derive from inhibiting prostaglandin synthesis in uterine smooth muscle. 5-Suppression of platelet aggregation : synthesis of TXA2 in platelets promotes aggregation. Aspirin causes irreversible inhibition of COX-1 , the enzyme that make TXA2. since the platelets can not synthesize new COX-1 , the effect of a single dose persist for the life of platelet ( about 8 days ).

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Adverse effects
In small doses aspirin rarely cause serious side effects . toxicity is common when treating inflammatory disorders which require high doses. 1-GIT effects : gastric distress , heartburn, and nausea. Occult blood occurs which in chronic use can result in anemia .Long –term high-dose can cause ulceration , perforation and bleeding. Ulcers result from (1) increased secretion of acid pepsin , (2) decreased production of cytoprotective mucus and bicarbonate , (3) decreased sub mucosal blood flow , secondary to inhibition of COX-1.,and (4) the direct irritation of gastric mucosa.

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Adverse effects (cont’d) 2- Bleeding. by inhibiting platelet aggregation . 3- Renal impairment : by inhibiting COX-1 and thereby inhibits synthesis of prostaglandins that cause renal vasodilatation. The resultant vasoconstriction decreases renal blood flow, decrease glomerular filtration rate and promote renal ischemia.( is rare with aspirin). 4- Salicylism: is a syndrome that begins to develop when asirin level climb just slightly above therapeutic . Overt signs include tinnitus . sweating , headch and dizziness.

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Adverse effects (cont’d) 5- Reye's syndrome: is rare but serious illness of childhood that has mortality rate 20-30%, characteristic symptoms are encephalopathy and liver degeneration , related to use of aspirin in children who have influenza or chickenpox. 6- Hypersensitivity : are uncommon in children and appear in adults with predisposition factors such as asthma, hay fever, urticaria. The aspirin hypersensitivity reaction begin with profuse watery rhinorrhea , urticaria, bronchospasm , laryngeal odema, and shock.

Ibuprofen

Ibuprofen is a simple derivative of phenylpropionic acid. In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect. Oral ibuprofen is often prescribed in lower doses (<2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. the drug is used to treat fever, mild to moderate pain and arthritis , is superior to most other NSAIDs for relief of primary dysmnorrhea. This property has been attributed to effective inhibition of prostaglandin synthesis in uterine smooth muscle
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Ibuprofen is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin..In comparison with indomethacin, ibuprofen causes less fluid retention. The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect.

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Diclofenac (voltaren)
Is approved for rheumatoid arthritis , ankylosing spondylitis and primary dysmnorrhea, is well absorbed ,metabolized in the liver and excreted in the urine . The most common side effects are abdominal pain ,dyspepsia and nausea. Can cause fluid retention and this can exacerbate HT and heart failure. The risk of liver dysfunction is greater than with other NSAIDs. Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. but renal adverse effects were common in high-risk patients..


Cont. diclofenac
A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding.
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Indomethacin
is an effective antinflammatory agent , approved for arthritis, bursitis, tendonitis, and for gouty arthritis . It has been used to accelerate closure of patent ductus arteriosus.A number of interactions with other drugs have been reported ,Probenecid prolongs indomethacin’s half-life by inhibiting both renal and biliary clearance.

Adverse effects

: is sever frontal headache which occur in 15-25% of patients , mild GIT reactions,,,,, hematological reaction . it is not recommended for infants and children under the age of 14, patient with peptic ulcer, pregnant and breast feeding women .

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Mefenamic acid (ponstan): Is indicated for primary dysmnorrhea, and mild to moderate pain. The principal adverse effect is diarrhea. Piroxicam(feldene) Has antinflammatory , analgesic and antipyretic properties . is approved only for rheumatoid arthritis . has long half life (50 hrs) so therapeutic effects can be maintained with once-day dosing .

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Naproxane and Naproxane sodium
Have a prolong half life and therefore can be administered less frequently. They are approved for arthritis, bursitis, tendonitis, primary dysmnorrhea, and mild to moderate pain., Adverse effects. They are well tolerated, the most common adverse effects are GIT disturbances , and compromise renal function by decreasing renal blood flow.


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Second- generation of NSAIDs (COX-2 Inhibitors)
Because of their selectivity for COX-2 , Second- generation NSAIDs are able to suppress inflammation and pain with minimal adverse effects . Celecoxib : was the first COX-2 inhibitor , was approved on 1998. the drug can relief symptoms of arthritis with less GIT ulceration and bleeding .

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Mechanism of action Cause selective inhibition of COX-2 the enzyme that mediate inflammation and pain . Pharmacokinetics: Celecoxib is well absorbed following oral administration , metabolized in the liver and excreted by the kidney . Therapeutic uses: is indicated only for rheumatoid arthritis and osteoarthritis .

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Adverse effects :

Rofecoxib : 

Is the 2nd selective COX-2 inhibitor , it is approved for treatment rheumatoid arthritis ,osteoarthritis acute pain . benifet derived from inhibition COX-2 , the enzyme who promote inflammation and sensitize the receptor to painful stimuli . anti-inflammatory and analgesic effects are equal to those of first generation of NSAIDs, but the GI side effects are less common .
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Pharmacokinetics and Adverse effects:

Pharmacokinetics: is well absorbed following oral administration , metabolized in the liver and excreted by the kidney . Adverse effects: the most common side effects are diarrhea, dyspepsia, and abdominal pain . Treatment has also associated with headache , renal toxicity, HT, anemia , leg edema and upper respiratory tract infection . can affect fetal circulation near term , therefore contraindicated in pregnancy . Rofecoxib dose not contain sulfur group and hence is safe for Pts allergic to sulfonamide . Gastric and duodenal ulcer are less common than with traditional NSAIDs.
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