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

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 taking aspirin experience hypersensitivity reactions. 
Symptoms of true allergy include urticaria, bronchoconstriction, and angioedema. Patients 
with severe hypersensitivity to aspirin should avoid using NSAIDs.  
 
 
F) Drug interactions:  
Salicylate is roughly 80% to 90% plasma protein 
bound (albumin) and can be displaced from protein-
binding sites, resulting in increased concentration of 
free salicylate.  
 
Alternatively, aspirin can displace other highly 
protein-bound, drugs, such as warfarin, phenytoin, 
or 
valproic 
acid, 
resulting 
in 
higher 
free 
concentrations of these agents .  
 
G) Toxicity:  
Mild salicylate toxicity is called salicylism and is 
characterized 
by 
nausea, 
vomiting, 
marked 
hyperventilation, headache, mental confusion, 
dizziness, and tinnitus (ringing or roaring in the ears).  
 
 
 
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When large doses of salicylate are administered, severe 
salicylate 
intoxication 
may 
result). 
Restlessness, 
delirium, hallucinations, convulsions, coma, respiratory 
and metabolic acidosis, and death from respiratory 
failure may occur.  
 
Children are particularly prone to salicylate intoxication; 
ingestion of as little as 10 g of aspirin can be fatal.  
 
 
H) Pregnancy  
NSAIDs should be used in pregnancy only if benefits 
outweigh risks to the developing fetus. [Note: 
Acetaminophen is preferred if analgesic or antipyretic 
effects are needed during pregnancy.]  
 
In the third trimester, NSAIDs should generally be avoided due to the risk of premature 
closure of the ductus arteriosus.  
 
 
 Selective COX-2 inhibitor,  
Celecoxib  : a selective COX-2 inhibitor, is 
significantly more selective for inhibition of COX-
2 than COX-1. Unlike the inhibition of COX-1 by 
aspirin (which is irreversible), the inhibition of 
COX-2 is reversible.  
 
Therapeutic uses: Celecoxib is approved for the 
treatment of RA, osteoarthritis, and acute pain. 
Celecoxib has similar efficacy to NSAIDs in the 
treatment of pain.  
 
Pharmacokinetics  
Celecoxib 
is 
readily 
absorbed 
after 
oral 
administration. It is extensively metabolized in 
the liver by cytochrome P450 (CYP2C9), and the 
metabolites are excreted in feces and urine. The 
half-life is about 11 hours, and the drug may be 
dosed once or twice daily.  
 
 
 
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The dosage should be reduced in those with moderate hepatic impairment, and celecoxib 
should be avoided in patients with severe hepatic or renal disease.  
Adverse effects  
Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects.   
 
Celecoxib is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this 
benefit is lost when aspirin is added to celecoxib therapy. Patients who are at high risk of 
ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib.   
 
Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at 
risk for similar effects with celecoxib.   
 
Inhibitors of CYP2C9, such as fluconazole, may increase serum levels of celecoxib.  
 
Like other NSAIDs, celecoxib has a similar risk for cardiovascular events.   
 
Acetaminophen  
Acetaminophen (N-acetyl-p-aminophenol or APAP) inhibits prostaglandin synthesis in the 
CNS, leading to antipyretic and analgesic effects.   
 
Acetaminophen has less effect on cyclooxygenase in peripheral tissues (due to peripheral 
inactivation), which accounts for its weak anti-inflammatory activity. Acetaminophen does 
not affect platelet function or increase bleeding time. It is not considered an NSAID.   
 
Therapeutic uses: Acetaminophen is used for the treatment of fever and the relief of pain. It 
is useful in patients with gastric complaints/risks with NSAIDs and those who do not require 
the anti-inflammatory action of NSAIDs.  
 
 
 
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Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or 
chickenpox (due to the risk of Reye syndrome with aspirin).  
Pharmacokinetics:  
Acetaminophen is rapidly absorbed from the GI tract and undergoes significant first-pass 
metabolism.  It is conjugated in the liver to form inactive glucuronidated or sulfated 
metabolites.   
 
A portion of acetaminophen is hydroxylated to form Nacetyl-p-benzoquinoneimine, or 
NAPQI, a highly reactive metabolite that can react with sulfhydryl groups and cause liver 
damage.   
 
At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl group of glutathione 
produced by the liver, forming a nontoxic substance.   
 
Acetaminophen and its metabolites are excreted in urine.   
 
The drug is also available in intravenous and rectal formulations.  
 
 
Adverse effects:  
At normal therapeutic doses, acetaminophen has few significant adverse effects.   
With large doses of acetaminophen, the available glutathione in the liver becomes depleted, 
and NAPQI reacts with the sulfhydryl groups of hepatic proteins. Hepatic necrosis, a serious 
and potentially life-threatening condition, can result.   
 
 
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Patients with hepatic disease, viral hepatitis, or a history of alcoholism are at higher risk of 
acetaminophen-induced hepatotoxicity. [Note: N-acetylcysteine is an antidote in cases of 
overdose.] Acetaminophen should be avoided in patients with severe hepatic impairment.  
 
 Traditional Disease-Modifying Antirheumatic Drugs  
Traditional DMARDs (methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine) are 
used in the treatment of RA, slow the course of the disease, Induce remission, and prevent 
further destruction of the joints and involved tissues.  
 
Following diagnosis of RA, these agents should be started as soon as possible to delay 
progression of the disease.  
 
 
 Choice of drug  
Mono-therapy may be initiated with any of the traditional DMARDs, although Methotrexate 
is generally preferred.  
 
For patients with inadequate response to monotherapy, a combination of traditional 
DMARDs, or use of a TNF inhibitor or non-TNF biologic agent may be needed.  
 
Combination therapies are both safe and efficacious, NSAIDs or glucocorticoids can also be 
used for their anti-inflammatory actions.  
 
 
Methotrexate  
Methotrexate is a folic acid antagonist that inhibits cytokine production and purine 
nucleotide biosynthesis, leading to immunosuppressive and anti-inflammatory effects.   
 
Other traditional DMARDs, TNF inhibitors, or non-TNF biologic agents can be added to 
methotrexate if there is inadequate response to mono-therapy with this agent.   
 
Mainstay of treatment in patients with rheumatoid or psoriatic arthritis.Response to 
methotrexate occurs within 3 to 6 weeks of starting treatment. Doses of methotrexate 
required for this treatment are much lower than those needed in cancer chemotherapy and 
are given once a week, thereby minimizing adverse effects.  
 
adve

Summary :