*3.1.1 Prostaglandin synthesis inhibition*

These agents inhibit cyclooxygenase (COX) and, as result, the synthesis of prostaglandin, a key mediator of inflammation, in the peripheral tissues, CNS and nerves – leading to an effective raise in the threshold of nociceptors stimulation. Aspirin acetylates and irreversibly inhibits cyclo-oxygenase, while NSAIDs work by competitive inhibition, being reversible. The prostaglandins are part of the eicosanoid's family, oxygenated metabolites of arachidonic acid and other polyunsaturated fatty acids that include leukotrienes [6].

The rate of prostaglandin synthesis is usually low, being regulated by trauma and tissue stimuli, which activates phospholipases to free arachidonic acid, from which prostaglandins are produced. Prostaglandins have several physiological roles, including gastric mucosal protection, bronchodilation and maintenance of renal tubular function, renal vasodilatation, regulation of tubular electrolytes and modulation the action of renal hormones [2, 6]. The side effects on the renal system of chronic NSAIDs is well known. In certain clinical settings when there are high plasma concentration of the vasoconstrictors rennin, noradrenaline, angiotensin and vasopressin, intrarenal vasodilators including prostacyclin are produced and renal function can be affected by NSAIDs administration [2]. The concomitant use of other potential nephrotoxic drugs, such as gentamicin, can worsen the renal effect of these drugs [2]. Nevertheless, with careful patient selection and closed monitoring the incidence of NSAID-renal damage is low.

Triggering bronchospasm is a recognised phenomenon in patients with asthma, rhinitis and nasal polyps [2]. Such "aspirin induce asthma" can be severe, and goes up to 10–15% as incidence with a feature cross sensitivity with NSAIDs. A known history of aspirin induce asthma should band the administration of NSAIDs perioperatively. The mechanism is unclear, but practice shown the reaction increases with the potency of the COX inhibition [2].

Endothelial released prostacyclin induces vasodilatation and prevents platelet adhesion, and platelet thromboxane produces aggregation and vasospasm. In addition to prostaglandins, cyclooxygenase induces prostacyclin synthesis, a vasodilator that also increases GI mucosal perfusion. Also, in the gastric tissue, COX-1 increases mucus and bicarbonate production, valuable feature for stomach mucosal protection [2]. Inhibition of COX-1 is affecting this protection, predisposing to ulcerations and bleeding, which can be exacerbated by concomitant NSAID-induced platelet dysfunction [2].

#### *3.1.2 Cyclo-oxygenase isoenzymes*

Two subtypes of cyclo-oxygenase enzyme have been identified. These are constitutional COX-1 and inducible COX-2, the last one triggered by inflammation and trauma. The COX-1 is present in all cells and regulates various roles in homeostatic function. NSAIDs, like aspirin, are non-selective cyclo-oxygenase inhibitors that act on both COX-1 and COX-2, which results in multiple beneficial effects (reduction in inflammation, pain and fever) but also some important side effects.

These two COX isoenzymes have 75% aminoacid homology, with almost identical enzymes kinetics.

COX-1 is a membrane bound haemoglycoprotein found in the endoplasmic reticulum of prostaglandin-inducing cells. The COX active site is a long hydrophobic

channel. NSAIDs block COX-1 halfway down the channel by hydrogen bounding in a reversible fashion. Aspirin acetylates serine, irreversibly preventing access for arachidonic acid [6].

COX-2 has similar sites to COX-1 for the attachment of arachidonic acid, and a similar three-dimensional structure to COX-1.

Under physiological condition COX-1 activity predominates, to produce prostaglandins that regulate rapid physiological responses such as vascular homeostasis, gastric function, platelet activity and renal function. The concentration of the COX-1 isoenzyme is low, but it may increase 2 to 4-fold, triggered by grow hormones and various hormones stimulation. Low concentration of COX-2 can normally be detected in the brain, kidney and the pregnant uterus. COX-2 mRNA expression by synovial cells, fibroblasts, monocytes may be increased 10 to 80-fold when stimulated by cytokines, bacterial lipopolysaccharides or growth factors [6] These triggers increase COX-2 synthesis and tissue PGE2 concentration, resulting in inflammation and pain.

Inhibition of COX-1 induces antiplatelet activity that might be cardioprotective by inhibition of thromboxane synthesis more than prostacyclin. Inhibition of COX-2 inhibits prostacyclin synthesis more than thromboxane and may induce prothrombotic effects, leading to a higher risk of cardiovascular events [2]. In the case of nonselective COX inhibitors, both effects appear to be in balance each other out, resulting in minimal changes in cardiovascular risk [2]. But instead, the action of COX-2 inhibitors may result in result in an increased cardiovascular risk [16, 17].

Prostaglandins released by COX-1 is also a factor on keeping a good glomerular filtration rate (GFR) by renal vasodilatation that maintain renal blood flow. Inhibition of COX-1, especially in dehydrated patients can lead to affect GFR and even to an acute kidney injury [2]. Other condition that might worsen under NSAIDs treatment is congestive heart failure, due to sodium and water retention, hyperkalaemia, hypertension and acute renal failure.

The most common adverse effect of NSAIDs is GI mucosal erosion. In patients taking chronic NSAIDs (continuously for 1 year) 10 to 60% will experience abdominal pain, nausea, dyspepsia, and a 2 to 4% will end up with a symptomatic peptic ulcers [18]. Between the risk factors are known: age, concomitant use of corticosteroids and warfarin, coronary artery disease, congestive heart failure and diabetes mellitus. Several studies proved the efficiency of some protective agents as misoprostol and proton pump inhibitors [19]. The relative risk for causing GI effects under the NSAIDs treatment are shown in **Table 2** on below.

#### **3.2 Side effects**

This category of drugs is widely used, being very efficient medicines, but responsible for more serious drugs-related side effects than any other class of analgesic drugs [20]. The main side effect of NSAIDs as stated earlier is gastric erosion with the risk of GI bleeding, but also platelets dysfunction, renal failure and anaphylaxis or bronchospasm in individuals who have "aspirin – induced asthma" [2].

Single dose of NSAIDs such as diclofenac and ketorolac inhibit platelet function (prolong skin bleeding time and inhibit platelet function in vitro), but do not tend to increase bleeding in normal patients. However, when concomitant anticoagulation treatment or presence of subclinical bleeding diathesis occurs, then there is an increased risk of surgical bleeding [2].

Conversely, NSAIDs and COX-2 inhibitors have a small prothrombotic tendency. The risk is increasing by prolonged administration and by the dose taken, and for the more selective agents (COX-2) but also for diclofenac [2]. Studies shows that diclofenac 150 mg has similar risk to etoricoxib. Ibuprofen in a daily dose of 2400 mg also

**241**

**Table 3.**

*Analgesics*

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

**3.3 Contraindications of NSAIDs**

*Risk of serious gastrointestinal effects of NSAIDs [18, 19].*

**3.4 Efficiency of the NSAIDs**

disorder, vascular disease

(cardiac, vascular, etc.)

Uncontrolled hypertension Aspirin-induced asthma

*NSAIDs contraindications.*

or neurosurgery)

(**Table 3**) [23].

0.57

**Table 2.**

represents a high risk for thrombosis. But reduced doses to 1200 mg a day Ibuprofen

*Risk reduction when added to ibuprofen* Proton pump inhibitor 0.09 Misoprostol

*NSAID Relative risk of serious GI toxicity*

COX-2 inhibitor 0.6 Ibuprofen 1.0 Diclofenac 1.8 Naproxen 2.2 Indomethacin 2.4 Piroxicam 3.8 Ketoprofen 4.2 Ketorolac 24.7

There are many contraindications of this drug class presented on below

**Relative contraindications Absolute contraindication**

Impaired hepatic function, diabetes, bleeding or coagulation

Surgery where an absence of bleeding is important (eye surgery

Concurrent use of ACE inhibitors, potassium sparing diuretics, anticoagulants, methotrexate, cyclosporin, gentamicin

Pregnant and lactating women Hyperkalaemia

Age >65 years (risk of kidney impairment) Pre-existing renal impairment

Surgery with a high risk of intraoperative haemorrhage

The number needed to treat (NNT, basically the number of patients in a study to whom the drug must be given to show a benefit) for diclofenac 50 mg 2.3, ketorolac 10 mg is 2.6 and ibuprofen 400 mg 2.4. For comparison, the NNT of morphine 10 mg

History of GI bleeding or ulceration

Known allergy to NSAIDs

Sever liver dysfunction

Cardiac failure (risk of sodium, potassium and water retention)

Dehydration, hypovolemia, hypotension

and Naproxen 1 g daily are not associated with an increase risk [21, 22].


#### **Table 2.**

*Pain Management - Practices, Novel Therapies and Bioactives*

similar three-dimensional structure to COX-1.

hyperkalaemia, hypertension and acute renal failure.

under the NSAIDs treatment are shown in **Table 2** on below.

arachidonic acid [6].

inflammation and pain.

channel. NSAIDs block COX-1 halfway down the channel by hydrogen bounding in a reversible fashion. Aspirin acetylates serine, irreversibly preventing access for

Under physiological condition COX-1 activity predominates, to produce prostaglandins that regulate rapid physiological responses such as vascular homeostasis, gastric function, platelet activity and renal function. The concentration of the COX-1 isoenzyme is low, but it may increase 2 to 4-fold, triggered by grow hormones and various hormones stimulation. Low concentration of COX-2 can normally be detected in the brain, kidney and the pregnant uterus. COX-2 mRNA expression by synovial cells, fibroblasts, monocytes may be increased 10 to 80-fold when stimulated by cytokines, bacterial lipopolysaccharides or growth factors [6] These triggers increase COX-2 synthesis and tissue PGE2 concentration, resulting in

COX-2 has similar sites to COX-1 for the attachment of arachidonic acid, and a

Inhibition of COX-1 induces antiplatelet activity that might be cardioprotective by inhibition of thromboxane synthesis more than prostacyclin. Inhibition of COX-2 inhibits prostacyclin synthesis more than thromboxane and may induce prothrombotic effects, leading to a higher risk of cardiovascular events [2]. In the case of nonselective COX inhibitors, both effects appear to be in balance each other out, resulting in minimal changes in cardiovascular risk [2]. But instead, the action of COX-2 inhibitors may result in result in an increased cardiovascular risk [16, 17]. Prostaglandins released by COX-1 is also a factor on keeping a good glomerular filtration rate (GFR) by renal vasodilatation that maintain renal blood flow. Inhibition of COX-1, especially in dehydrated patients can lead to affect GFR and even to an acute kidney injury [2]. Other condition that might worsen under NSAIDs treatment is congestive heart failure, due to sodium and water retention,

The most common adverse effect of NSAIDs is GI mucosal erosion. In patients

This category of drugs is widely used, being very efficient medicines, but respon-

Single dose of NSAIDs such as diclofenac and ketorolac inhibit platelet function (prolong skin bleeding time and inhibit platelet function in vitro), but do not tend to increase bleeding in normal patients. However, when concomitant anticoagulation treatment or presence of subclinical bleeding diathesis occurs, then there is an

Conversely, NSAIDs and COX-2 inhibitors have a small prothrombotic tendency. The risk is increasing by prolonged administration and by the dose taken, and for the more selective agents (COX-2) but also for diclofenac [2]. Studies shows that diclofenac 150 mg has similar risk to etoricoxib. Ibuprofen in a daily dose of 2400 mg also

sible for more serious drugs-related side effects than any other class of analgesic drugs [20]. The main side effect of NSAIDs as stated earlier is gastric erosion with the risk of GI bleeding, but also platelets dysfunction, renal failure and anaphylaxis

or bronchospasm in individuals who have "aspirin – induced asthma" [2].

taking chronic NSAIDs (continuously for 1 year) 10 to 60% will experience abdominal pain, nausea, dyspepsia, and a 2 to 4% will end up with a symptomatic peptic ulcers [18]. Between the risk factors are known: age, concomitant use of corticosteroids and warfarin, coronary artery disease, congestive heart failure and diabetes mellitus. Several studies proved the efficiency of some protective agents as misoprostol and proton pump inhibitors [19]. The relative risk for causing GI effects

**240**

**3.2 Side effects**

increased risk of surgical bleeding [2].

*Risk of serious gastrointestinal effects of NSAIDs [18, 19].*

represents a high risk for thrombosis. But reduced doses to 1200 mg a day Ibuprofen and Naproxen 1 g daily are not associated with an increase risk [21, 22].
