NSAIDs (NSAIDs)

**counselor** Mon Oct 15, 2012 12:06 pm

NSAIDs (NSAIDs)

It 'a chemically heterogeneous class of drugs, which share the same mechanism of action.
In 1971 J. Vane discovered that NSAIDs inhibit the activity of cyclooxygenase, the enzyme which catalyzes the conversion of arachidonic acid in unstable endoperoxide PGG2, from which originate the prostaglandins (PG).

In support of this hypothesis:
1) NSAIDs decrease PG synthesis in humans, the dose used in therapy.
2) There is good correlation between activity antienzimatica and therapeutic potency.

ACID ARACHIDONIC and ITS METABOLITES
• Arachidonic acid is an unsaturated fatty acid to 20 carbon atoms, with 4 unsaturated bonds.
• The intracellular concentration of arachidonic acid is generally low.
• In response to various stimuli is free arachidonic acid per share especially of phospholipase A2 (PLA2), but in part also of phospholipase C.
• From the membrane phospholipids over to arachidonic acid, is also formed PAF (platelet activating factor)

From arachidonic acid are formed:
• Prostaglandins and Thromboxane through the action of the enzyme cyclooxygenase (COX)
• Leukotriene for inhibition of 5-lipoxygenase
• Acids idrossieicosatetraenoici and epossieicosatrienoici acids by the action of various CYP.
• It also reflects the endocannabinoid anandamide endogenous

The molecules derived from arachidonic acid from the cell and must come easily to act on receptors in the same cell (autocrine action) or on neighboring cells (paracrine action)
There is intracellular deposit, there is exocytosis
The lack of intracellular storage explains the marked pharmacological effects of NSAIDs that inhibit biosynthesis and release of PG.
NSAIDs do not inhibit the effects of exogenous PG.

THE cyclooxygenase
• The cyclooxygenase catalyze the oxidation of arachidonic acid to form an unstable endoperoxide (PGG2)
• This is then converted by the peroxidase activity of prostaglandin synthetase in PGH2;
• From this form then (through the work of various enzymes) several prostanoids, such as prostaglandins PGD2, PGE2, PGF2 alpha, PGI2 (prostacyclin) and TXA2 (thromboxane). PGD2 PGJ2 is formed.
(The subscript 2 denotes 2 double bonds in the molecule).

Cyclooxygenase 1 (COX1)
-E 'constitutively expressed.
-It has 3 main parts:
• Sequence homologous EGF
• Portion of anchoring to the membrane
• Region with catalytic sites
It performs the following tasks-physiological "house-keeping"):
1) Function gastroprotective
2) Adjusting vascular
3) Regulation of renal blood flow
4) Maintenance of glomerular filtration
5) Adjust the uterine activity

Cyclooxygenase 2 (COX-2)
- Its expression is mainly induced by pro-inflammatory stimuli.
- E 'induced by bacterial endotoxin (lipopolysaccharide of Escherichia Coli), cytokines (IL-1), mitogens.
- It is believed responsible for the increase of prostanoids in pathological conditions and their side effects.
- It 'very strongly expressed in skin cancers of the colon and rectum.
However, in part is also expressed constitutively. The constitutive produces PGI2 in vascular endothelium.

Has the characteristic of having a side pocket in the channel cicloossigenasico that allows to accommodate drugs much more bulky than those accepted by COX-1.

3 cyclooxygenase (COX 3)
-It 's mainly present in the CNS
-Acetaminophen has considerable affinity for COX3
-Show affinity for the COX3 also aspirin, diclofenac, ibuprofen, indomethacin
-E 'involved in the control of pain and iperpiresi

Lipoxygenase
The 5-lipoxygenase catalyzes the formation of 5-HPETE (idroperossieicosatetraenoico acid) and from this leukotriene A4 (LTA4).
LTA4 is unstable and is readily converted to LTB4 or conjugated with glutathione to form LTC4.
From LCT4 form then LTD4, LTE4, LTF4
BIOLOGICAL EFFECTS OF EICOSANOIDS
The compounds eicosanoids that are generated have a variety of biological actions, mediated by receptors specific for individual compounds.

Cardiovascular system
The PGI2 (prostacyclin), but also PGE2 and PGA2, have potent vasodilating action
The TXA2 (thromboxane) is a potent vasoconstrictor
Leukotrienes are vasoconstrictors.

Platelets
The PGI2 inhibits platelet aggregation. Is generated by the vascular endothelium constitutive COX2.
The TXA2 is a potent inducer of platelet aggregation. Is generated by COX1 in platelets.

Chemotaxis
The LTB4 is chemotactic action towards granulocytes.

Bronchi
PGE1 and PGE2 are bronchodilators.
PGF2 , TXA2 and in particular the leukotrienes are bronchoconstrictors.

Uterus
PGF2a and PGE2 low doses of harm reduction

Gastrointestinal secretions
PGE, PGA and PGI2 reduce the volume and acidity of gastric secretion and stimulate the secretion of mucus in the stomach and small intestine
Cause influx of H2O and electrolytes into the intestinal lumen.

Kidney
PGE2 and PGI2 evoke diuresis, natriuresis and kaliuresis.

Body temperature
The pyrogen fever is due to release of PGE2 into the preoptic area of the hypothalamus

Pain
Prostaglandins and especially PGE2 and PGI2 sensitizzano neurons involved in nociception:
• At the level of the peripheral terminations
• A spinal level
• At supraspinal

The stimulation of receptors for prostaglandins by especially of PGE2 and PGI2 induces activation of kinases such as PKA, through increase of cAMP.
The PKA determines activation of various ionotropic receptors, modifying the neuronal excitability.
This effect can be evoked
• On the outskirts,
• neurons in spinal-thalamic and
• in thalamocortical neurons.

In the periaqueductal gray substance arachidonic acid is involved in the control of the activity of neurons descendants antinociceptive.

The inhibition of COX moves the metabolism of arachidonic acid towards the 12-lipoxygenase. The 12-HPETE reduce the excitability of the presynaptic neuron is a neuron GABAergic inhibitory. Consequently, it has disinhibition of neurons antinociceptive descendants from the substance periaqueductal towards the spinal cord

Inflammation
In the acute phase of inflammation a fundamental role is played by arachidonic acid metabolites.

The clinical signs of inflammation include:
• erythema (rubor),
• increase in temperature (calor),
• swelling (tumor),
• pain (dolor),
• functional impairment (functio injured).

PGE2 and PGI2 contribute to these signs evoking vasodilation resulting in increased blood flow and tissue heating, and sensitizing nociceptors to pain. Histamine and bradykinin are primarily responsible for increased capillary permeability.

In chronic inflammation there is a series of events with outcomes citolesivi:
• degranulation of inflammatory cells,
• release of lysosomal enzymes,
• stimulation of neutrophils with formation of free radicals,
• development of humoral immunity.

The leukotriene LTB4 is equipped with power chemotactic toward granulocytes.
The 5-HPETE and 5-HETE release histamine from basophils. But lipoxygenases are not sensitive to NSAIDs.

The PGJ2 binds to the transcription factor peroxisome proliferator-activated receptor  (PPAR ) involved in inflammation and obesity.

The PGJ2 also binds, inhibiting it, to which phosphoric IKB kinase, then blocks the activation of the transcription factor NFkB, involved in the mediation of inflammatory processes.

Pharmacodynamics FANS
We distinguish three sub-classes of drugs:
• Class I: competitively inhibit and in an easily dissociable both COX-1 and COX-2.
• Class II: This class includes indomethacin, diclofenac, selective inhibitors of COX-2. The binding is rapid and reversible, but if it continues its occupation of the enzyme, it undergoes conformational change.
• Class III: Aspirin is the only exponent. Acts with a block irreversible COX-1 and COX-2.

Aspirin
Aspirin, or acetylsalicylic acid, turns out to be much more potent in inhibiting the COX-1, as compared to COX-2.

Pharmacodynamics

Aspirin acts acetylating Ser529 and Ser516 of COX-1 and COX-2, and therefore hindering the access of arachidonic acid in the channel cicloossigenasico

It has analgesic, antipyretic, anti-inflammatory and anti-platelet aggregation.

The duration of its effects depends on the speed with which you generate new cyclooxygenase:
• The first three actions have a duration of several hours.
• the effect on platelet aggregation lasts a few days from the time that platelets have no nucleus and do not express protein synthesis.

Antiinflammatory
Alleviates, but does not stop the progress of the pathological lesion.

Analgesic
And 'effective in mild to moderate pain, postoperative pain and inflammation, it is not very effective in visceral pain.
E 'useful in headache, myalgia, arthralgia and pain surface.
Antipyretic action
Does not modify the normal temperature, nor the increased body temperature by exercise or by high ambient temperature.

Antiplatelet action
Aspirin prolongs the bleeding time, to block platelet cyclooxygenase at doses lower than those needed to evoke the other effects.

TOXICITY '
Gastrointestinal damage
Aspirin and NSAIDs can cause:
ulceration, perforation and bleeding for:
a) inhibition of the synthesis of PGI2 and PGE2 gastric, which inhibit the secretion of HCl and stimulate the secretion of protective mucus.
b) Inhibition of platelet aggregation

Aspirin is one of the drugs that cause increased incidence of gastrointestinal damage.

Hepatotoxicity
Salicylates can cause liver damage with
• increased transaminases,
• hepatomegaly and sometimes jaundice
• anorexia
• A severe syndrome with liver disease and encephalopathy syndrome (Rye) seems to be related to the use of salicylates in viral infections in children. It is recommended not to use aspirin under 16 years of age.

Kidney damage
Aspirin causes retention of Na + and water.
In the case of heart failure or hypovolemia the salicicati can trigger acute renal failure due to reduction in renal blood flow and filtration glumerulare (PGs inhibit vasoconstriction by angiotensin II and noradrenaline).
Inhibition of COX-2 may increase the actions of angiotensin II (risk of hypertension and edema).

Pregnancy
Reduces uterine contractility and prolongs gestation.

Bronchi
In asthmatics aspirin can cause severe bronchospasm for increase of leukotrienes (aspirin deflects the metabolism of arachidonic acid towards the lipoxygenase).

Chronic intoxication
Salicylism: indicates mild chronic poisoning. It presents with headache, mental confusion, dizziness, hyperventilation, nausea and vomiting.
Poisoning more serious alteration of acid-base, convulsions, high fever, dehydration and coma. Are often observed haemorrhage.

Acute intoxication
The initial central stimulation, followed by depression to stupor and coma. Followed by cardiovascular collapse, respiratory failure, seizures. Death is usually due to respiratory failure.
The lethal dose of aspirin can be very variable (10 g or more).
The treatment of acute intoxication is symptomatic.

PHARMACOKINETICS
Good oral absorption of aspirin. The absorption occurs in the upper part of the small intestine and stomach. Oral absorption results in high concentration of salicylate in the gastric mucosa.

The half-life of 15-20 min, but on platelets 75-100 mg per day have effects throughout the life of the platelet (10 days)

Salicylates are excreted in the urine as:
a) free form of salicylate
b) salicyluric acid (conjugated with glycine) 75%.
c) salicylic phenolic glucuronide or acyl.

THERAPEUTIC USES
1) Aspirin is used for treatment and prophylaxis of diseases characterized by platelet hyperaggregability (coronary artery disease, myocardial infarction, thrombosis, post-operative).
2) As an analgesic in case of headache, arthritis, dysmenorrhea, neuralgia and myalgia. Problems for long-term use.
3) For musculoskeletal inflammatory diseases (rheumatoid arthritis, osteoarthritis, arthritis, ankylosing spondylitis) you prefer to use other NSAID or coxib less gastro.
4) How best to use antipyretic paracetamol

Coxib (inhibitor of cyclooxygenase)
The first coxib were celecoxib and rofecoxib. They then added Etoricoxib and valdecoxib

Pharmacodynamics
Selectively inhibit COX-2
Their selectivity for COX-2 depends on the fact that for their bulkiness are greeted by the "side pocket" COX-2, but not by COX-1.

The most recent acquisitions of COX-2 indicate that this is not only involved in inflammation, iperpiresi pain, but also in:
• gastrointestinal cytoprotection,
• renal electrolyte balance,
• synthesis of prostacyclin

TOXICOLOGY
The incidence of gastrointestinal perforation, gastric bleeding and peptic ulcer is reduced compared to NSAIDs, but not canceled.

Rofecoxib was withdrawn from the market after testing of chronic treatment for 18 months. Caused increase in adverse cardiovascular events (myocardial infarction, stroke, venous thrombosis, pulmonary embolism)
Probably the increase of these adverse events is observed only in case of very selective inhibition of COX-2:
• The COX-2 is responsible for the production of prostacyclin that reduces platelet aggregation and produces vasodilation.
• The COX1 generates thromboxane, platelet aggregation and vasoconstriction.
• the risk of adverse cardiovascular events increases when the coxib is highly selective for COX-2 and does not affect at all the COX1.
CLASS study found no problems for the Celecoxib Rofecoxib is less selective

THERAPEUTIC USES
1. For inflammatory diseases of the musculoskeletal (arthritis, arthrosis, arthritis, ankylosing spondylitis) you prefer to use other NSAID or coxib less gastro.
2. As analgesics in case of headache, arthritis, dysmenorrhea, neuralgia and myalgia.

Acetaminophen

Pharmacodynamics
1) It has analgesic and antipyretic activity similar to that of acetylsalicylic acid.
2) The anti-inflammatory effect is very modest. The biosynthesis of PG is inhibited at the center (COX-3) and peripheral tissues (COX-2 and COX-1).

Compared to acetylsalicylic acid has the advantage:
a) not to have effects on the cardiovascular system
b) not to alter the acid-base balance
c) not to give gastric irritation
d) to have no effect on bleeding time

PHARMACOKINETICS
Rapid gastrointestinal absorption
Paracetamol is eliminated in the urine after hepatic conjugation with glucuronic acid, sulfuric acid or cysteine.
When paracetamol is taken in high doses, undergoes an N-hydroxylation which gives rise to a highly reactive intermediate. Can combine with the sulfhydryl groups of hepatic proteins giving severe hepatic necrosis.

TOXICOLOGY
At therapeutic doses, paracetamol is well tolerated.
In case of overdose (more than 3 grams per day) gives:
a) hepatic necrosis and
b) necrosis of the renal tubules
c) there is also the possibility of hypoglycemic coma

Treatment of intoxication must be done with:
1) processes acts to block further absorption of the drug.
2) administration of N-acetylcysteine which acts as a donor of SH groups.

THERAPEUTIC USE
Paracetamol is rationally used as a fever reducer and pain reliever, particularly in patients with peptic ulcer or bleeding risk.

Arylpropionic acid derivatives and Arilacetico

Are derivatives of propionic acid:
Ibuprofen, naproxen, fenoprofen.
Diclofenac is acetic acid derivative

Pharmacodynamics
Are all a little more selective inhibitors for the COX1 that for COX2.

Ibuprofen
It 'almost equipotent with acetylsalicylic acid.
Gives gastrointestinal disorders only in 5-15% of subjects.
It 'been described as the NSAIDs with fewer gastrointestinal side effects
Usually these disorders are mild nausea, heartburn, fullness
Occult blood loss and gastric ulcers are infrequent.

Naproxen
It 'about 20 times more powerful than acetylsalicylic acid. It has an upper gastrointestinal toxicity ibuprofen. It can also cause jaundice and reduced renal function.

Fenoprofen and ketoprofen
Is approximately equivalent to acetylsalicylic acid.
Damage slight disorders of the gastrointestinal tract.

Diclofenac
Has lower affinity for COX1 that for COX2.
Has low incidence of gastrointestinal

THERAPEUTIC USES
1) Rheumatoid arthritis: good therapeutic effect (reduces swelling, pain and morning stiffness). Are better tolerated than other NSAIDs
2) Osteoarthritis
3) Ankylosing Spondylitis
4) Symptomatic treatment of pain (postpartum, following oral and ophthalmic surgery, dysmenorrhea).

Nimesulide and Meloxicam

Pharmacodynamics
These are compounds partially selective towards the COX2

TOXICITY '
Gastrointestinal disturbances have been reported with moderate frequency
For nimesulide has been described possibility of toxicity 'liver.
The mesolimbic dopaminergic neurons nimesulide active

Piroxicam and Tenoxicam
Are potent inhibitors of cyclooxygenase. Are rather non-selective between COX-1 and COX-2.
Have fewer toxic effects of acetylsalicylic acid,
They are used in rheumatoid arthritis osteoarthritis, ankylosing spondylitis, acute gout.

Indole derivatives

Indomethacin
It 'an indole derivative which happens to be one of the most potent inhibitors of cyclooxygenase. However, presents significant problems of toxicity.

Pharmacodynamics
Has poor selectivity between the COX1 and COX2. Has good affinity for the COX3
E 'with marked antipyretic activity.

PHARMACOKINETICS
Rapid gastrointestinal absorption. After meals, the absorption is very slow.
It is distributed very well in the synovial fluid.
Binds to 90% of the plasma proteins.
10-20% is excreted unchanged in the urine.

TOXICOLOGY
Disturbances in 35-50% of patients
a) Gastrointestinal: anorexia, nausea, ulcers, single or multiple. Loss of occult blood in the absence of ulceration.
b) May occur acute pancreatitis, hepatitis, jaundice.
c) Problems CNS: headache, dizziness, mental confusion, depression, hallucinations.
d) Problems Hematologic: neutropenia, thrombocytopenia and aplastic anemia sometimes.
e) There is a risk of hypersensitivity reactions.

THERAPEUTIC USE
E 'was widely used for the treatment of joint disorders, but currently prefer other NSAID or coxib.

Sulindac
It 'a similar indomethacin.
The main characteristic of Sulindac lies in the fact that it is a prodrug.

TOXICOLOGY
Gastrointestinal disorders are common

Fenamati
The mefenamic acid and meclofenamate, in addition to inhibiting cyclooxygenase, also have the ability to antagonize some effects of PG.
They are very toxic and therefore do not offer any advantage over other less toxic NSAIDs.

Derivatives of pyrazolone
These are compounds now little used because of haematological toxicity.

Phenylbutazone

PHARMACOLOGICAL ACTIONS
1) It has anti-inflammatory action that is highly effective in the treatment of rheumatoid arthritis.
2) It has good analgesic efficacy in the pain of rheumatic origin, but poor in non-rheumatic pain.
3) The antipyretic action is not well described, and in any case is not used as an antipyretic.
4) Causes marked retention of NaCl and water.

TOXICITY '
- The most frequent side effects are: nausea, vomiting, epigastric distress, fluid retention and edema, dizziness, insomnia, irritability.
- Serious side effects are: peptic ulcer, hypersensitivity reaction, hepatitis, nephritis, aplastic anemia, agranulocytosis, thrombocytopenia (even fatal).

THERAPEUTIC USE
Phenylbutazone should be used only after other medications have failed.

Oxyphenbutazone
It 'an active metabolite of phenylbutazone. Shares with phenylbutazone spectrum of pharmacological actions. It seems to have the advantage of causing less gastric irritation.

Antipyrine - Aminopyrine
In the past, have been widely used as antipyretics, analgesics.
The severe toxicity in the bone marrow (agranulocytosis) has made them virtually unused.