Summarize the following text to main points and sub-points and make detailed explain for them:

 by impeding PGE2 synthesis and 
release, resetting the “thermostat” back toward normal.   
 
This rapidly lowers the body temperature of febrile patients by increasing heat dissipation 
through peripheral vasodilation and sweating. NSAIDs have no effect on normal body 
temperature.  
 
 
 Therapeutic uses of NSAIDs  
-Anti-inflammatory and analgesic uses: NSAIDs are used in the treatment of osteoarthritis, 
gout, RA, and common conditions requiring analgesia (for example, headache, arthralgia, 
myalgia, and dysmenorrhea).  
 
Combinations of opioids and NSAIDs may be effective in treating pain caused by malignancy. 
Furthermore, the addition of NSAIDs may lead to an opioid-sparing effect, allowing for lower 
doses of opioids to be utilized.   
 
 
 
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5 
The salicylates exhibit analgesic activity at lower doses. Only at higher doses do these drugs 
show anti-inflammatory activity. For example, two 325-mg aspirin tablets administered four 
times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and 
anti-inflammatory activity.  
 
-Antipyretic uses: Aspirin, ibuprofen, and naproxen may be used to treat fever. [Note: Aspirin 
should be avoided in patients less than 19 years old with viral infections, such as varicella 
(chickenpox) or influenza, to prevent Reye syndrome—a syndrome that can cause 
fulminating hepatitis with cerebral edema, often leading to death.  
 
• Cardiovascular applications  
Aspirin irreversibly inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-
mediated vasoconstriction and platelet aggregation and the subsequent risk of 
cardiovascular events. The antiplatelet effects persist for the life of the platelet.  
 
Low doses of aspirin (75 to 162 mg—commonly 81 mg) are used prophylactically to reduce 
the risk of recurrent cardiovascular events, transient ischemic attacks (TIAs), stroke, and 
death in patients with a history of previous MI, TIA, or stroke.  
 
Chronic use of aspirin allows for continued inhibition as new platelets are generated. Aspirin 
is also used acutely to reduce the risk of death in acute MI and in patients undergoing certain 
revascularization procedures.  
  
-External applications: Salicylic acid is used topically to treat corns, calluses, and warts. 
Methyl salicylate is used externally as a cutaneous counterirritant in liniments, such as 
arthritis creams and sports rubs. Diclofenac is available in topical formulations (gel or 
solution) for treatment of osteoarthritis in the knees or hands.   
 
In addition, ocular formulations of ketorolac are approved for management of seasonal 
allergic conjunctivitis and inflammation and pain related to ocular surgery.  
 
 
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 Pharmacokinetics  
A.Aspirin: After oral administration, aspirin is rapidly deacetylated by esterases in the body 
to produce salicylate. Unionized salicylates are passively absorbed mainly from the upper 
small intestine.  
 
Salicylates (except for diflunisal) cross both the blood–brain barrier (BBB) and the placenta 
and are absorbed through intact skin (especially methyl salicylate).  
 
Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the 
kidney, resulting in first-order elimination and a serum half-life of 3.5 hours.  
 
At anti-inflammatory dosages of aspirin (more than 4 g/day), the hepatic metabolic pathway 
becomes saturated, and zero-order kinetics are observed, leading to a half-life of 15 hours 
or more .  
 
Salicylate is secreted into the urine and can affect uric acid excretion. Therefore, aspirin 
should be avoided in gout, if possible, or in patients taking probenecid.  
 
  
 
 
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B.Other NSAIDs: Most NSAIDs are well 
absorbed 
after 
oral 
administration 
and 
circulate highly bound to plasma proteins. The 
majority are metabolized by the liver, mostly to 
inactivate metabolites.  
 
Few (for example, nabumetone and sulindac) 
have active metabolites. Excretion of active 
drug and metabolites is primarily via the urine.  
 
 
 
 
 
 
 
 
 
 Adverse effects of NSAIDs:  
Because of the adverse event profile, it is preferable to use NSAIDs at the lowest effective 
dose for the shortest duration possible.  
 
A) Gastrointestinal:  
These are the most common adverse effects of NSAIDs, ranging from dyspepsia to bleeding.  
 
Normally, production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and 
PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine.  
 
Agents that inhibit COX-1 reduce beneficial levels of these prostaglandins, resulting in 
increased gastric acid secretion, diminished mucus protection, and increased risk for GI 
bleeding and ulceration.  
 
Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events 
compared to those with a lower relative selectivity for COX-1 (that is, higher COX-2 
selectivity).  
NSAIDs should be taken with food or fluids to diminish GI upset. If NSAIDs are used in patients 
at high risk for GI events, proton pump inhibitors or misoprostol should be used 
concomitantly to prevent NSAID-induced ulcers.  
 
 
 
 
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B) Increased risk of bleeding (antiplatelet effect):   
As aspirin inhibits COX-1–mediated formation of TXA2 and reduces platelet aggregation for 
the lifetime of the platelet (3 to 7 days). Platelet aggregation is the first step in thrombus 
formation, and the antiplatelet effect of aspirin results in a prolonged bleeding time.  
 
For this reason, aspirin is often withheld for at least 1 week prior to surgery. NSAIDs other 
than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time, 
especially when combined with anticoagulants.   
 
Concomitant use of NSAIDs and aspirin can prevent aspirin from binding to cyclooxygenase. 
Patients who take aspirin for cardioprotection should avoid concomitant NSAID use if 
possible or take aspirin at least 30 minutes prior to the NSAID.  
 
 
C) Renal effects:  
NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for 
maintaining renal blood flow, that the synthesis of PGE2 and PGI2 normally antagonizes the 
intra-renal effect of vasoconstrictors.  
 
NSAIDs leave the actions of vasoconstrictors unopposed. Decreased synthesis of 
prostaglandins can result in retention of sodium and water and may cause edema.  
 
Patients with a history of heart failure or kidney disease are at particularly high risk. These 
effects can also decrease the beneficial effects of antihypertensive medications. In 
susceptible patients, NSAIDs have led to acute kidney injury.  
 
Glomeruli and arterioles synthesize not only the vasodilatory prostaglandins PGE2 and PGI2, 
but also the vasoconstrictor, thromboxane A2.  
 
The primary renal cortical actions of these prostaglandins are renal vasodilatation and 
maintenance of GFR (PGE2 and PGI2) or renal vasoconstriction and reduction of GFR 
(thromboxane A2).   
 
 
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Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances 
but play a modulatory role after ischemia or in the presence of increased concentrations of 
vasoconstrictor substances such as angiotensin II (ANG II), vasopressin or norepinephrine.   
 
Conversely, arachidonic acid reduces the glomerular contractile effect of ANG II. It is, 
therefore, concluded that renal prostaglandins play an important vasoregulatory role.  
 
  
 Lec 2 Anti-inflammatory drugs (cont.)  
D) Cardiac effects:  
Agents such as aspirin, with a very high degree of COX-1 selectivity at low doses, have a 
cardiovascular protective effect thought to be due to a reduction in the production of TXA2.  
 
Agents with higher relative COX-2 selectivity have been associated with an increased risk for 
cardiovascular events, possibly by decreasing PGI2 production mediated by COX-2.   
 
An increased risk for cardiovascular events, including MI and stroke, has been associated with 
all NSAIDs except aspirin.  
 
Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular 
disease .For patients with cardiovascular disease in whom NSAID treatment cannot be 
avoided, naproxen may be the least likely to be harmful.  
 
E) Other adverse effects:  
NSAIDs are inhibitors of cyclooxygenases and, therefore, inhibit the synthesis of 
prostaglandins but not of leukotrienes.  
 
 
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For this reason, NSAIDs should be used with caution in patients with asthma, as inhibition of 
prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk 
of asthma exacerbations.  
 
Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may 
occur.  
 
Approximately 15% of patients ta

Summary :