NSAIDS
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Nonsteroidal anti-inflammatory drugs
Inflammation is a normal, protective response to tissue injury caused by physical
trauma, noxious chemicals, or microbiologic agents
.
Inflammation is triggered by the
release of chemical mediators from injured tissues and migrating cells.
The specific mediators vary with the type of inflammation. They include:
1. Amines (Histamine, 5HT)
2. Lipids (PGs)
3. Small peptides (bradykinin).
4. Large peptides (IL-1)
The NSAIDs are a group of chemically dissimilar agents that have antipyretic,
analgesic, and anti-inflammatory activities. They act primarily by inhibiting the
cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This
leads to decreased prostaglandin synthesis with both beneficial and unwanted
effects.
PGs and related eicosanoids are released in minute amounts by all tissues except
RBCs, they are synthesized and inactivated in and same place so the circulating level
is very small (i.e. PGs don't circulate in blood in significant level).
Cyclooxygenase pathway: All eicosanoids with ring structures (that is, the
prostaglandins, thromboxanes, and prostacyclins) are synthesized via the
cyclooxygenase pathway.
Two related isoforms of the cyclooxygenase enzymes have been described,
cyclooxygenase-1 (COX-1) is responsible for the physiologic production of
prostanoids, whereas cyclooxygenase-2 (COX-2) causes the elevated production of
prostanoids that occurs in sites of chronic disease and inflammation.
Aspirin and Salicylates
The prototype of this group is Aspirin, the most commonly used and the drug to
which all other anti-inflammatory agents are compared. 15% of patient show
intolerance to aspirin, they may benefit from other NSAIDs.
Some of the newer NSAIDs are better than Aspirin in certain patients either because
of less gastric irritation of standard anti-inflammatory action or can be taken less
frequently, but they are still more expensive than Aspirin and some are more toxic.
Pharmacokinetics:
Administered orally or intravenously.
Salicylates are rapidly absorbed from the stomach and upper part of the
small intestine yielding a peak plasma conc. within 1-2 hrs.
The acidic medium in the stomach (PH= 1.5) keeps large fraction of salicylates
in non-ionized from (lipid soluble) so it diffuses easily and absorption is
promoted.
Ingested salicylates and that generated by hydrolysis of aspirin may be
excreted unchanged, but most is converted to water soluble conjugates that
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are rapidly cleared by the kidney. When this pathway becomes saturated, a
small increase in aspirin dose will result in large increase in plasma level.
Urine alkalinization will prevent reabsorption of salicylates.
Mechanism of action: Aspirin is a weak organic acid irreversibly acetylate
(inactivate) Cox pathway, while other NSAIDs, including other salicylates are
reversible inhibitors for COX enzyme.
Actions
The NSAIDs, including aspirin, have three major therapeutic actions: they reduce
inflammation (anti-inflammation), pain (analgesia), and fever. However, not all
NSAIDs are equally effective in each of these actions.
Anti-inflammatory actions: Cyclooxygenase inhibition diminishes the formation of
prostaglandins and, thus, modulates aspects of inflammation in which
prostaglandins act as mediators.
NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of
the disease nor induce remission.
Analgesic action:
The salicylates are used mainly for the management of pain of low to moderate
intensity arising from musculoskeletal disorders rather than that arising from the
viscera. Combinations of opioids and NSAIDs are effective in treating pain caused by
malignancy.
Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic
thermoregulatory center is elevated.
This can be caused by PGE2 synthesis, which is stimulated when endogenous fever-
producing agents (pyrogens), such as cytokines, are released from WBCs that are
activated by infection, hypersensitivity, malignancy, or inflammation. The salicylates
lower body temperature in patients with fever by impeding PGE2 synthesis and
release. Aspirin and other NSAIDs reset the “thermostat” toward normal. Aspirin has
no effect on normal body temperature.
Respiratory actions: At therapeutic doses, aspirin increases alveolar ventilation.
Higher doses work directly on the respiratory center in the medulla, resulting in
hyperventilation and respiratory alkalosis that usually is adequately compensated for
by the kidney. At toxic levels, central respiratory paralysis occurs.
Gastrointestinal effects: Normally, PGE2 and PGF2α stimulate synthesis of
protective mucus in both the stomach and small intestine. In the presence of aspirin,
these prostanoids are not formed, resulting in increased gastric acid secretion and
diminished mucus protection.
This may cause epigastric distress, ulceration, hemorrhage, and iron-deficiency
anemia.
Buffered and enteric-coated preparations are only marginally helpful in dealing with
this problem.
Agents used for the prevention of gastric and/ or duodenal ulcers include the PGE1-
derivative (e.g. misoprostol) and the proton-pump inhibitors (PPIs) e.g. Omeprazole.
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Effect on platelets: TXA2 enhances platelet aggregation, whereas PGI2 decreases it.
Low doses (81 to 325 mg daily) of aspirin can irreversibly inhibit thromboxane
production in platelets. Because platelets lack nuclei, they cannot synthesize new
enzyme, and the lack of thromboxane persists for the lifetime of the platelet (3–7
days). As a result of the decrease in TXA2 production, platelet aggregation (the first
step in thrombus formation) is reduced, producing an antiplatelet effect with a
prolonged bleeding time.
Actions on the kidney:
Decreased synthesis of prostaglandins can result in retention of sodium and water
and may cause edema and hyperkalemia in some patients. Interstitial nephritis can
also occur with all NSAIDs.
Therapeutic uses:
1- Analgesic effect:
Aspirin most frequently is used to reduce mild to moderate pain.
Aspirin may be combined with other analgesics (as opioids) and called as
OTC drugs (out of the counter drugs that are solid without prescriptions).
Aspirin is not effective in the treatment of visceral pain such as (acute
abdomen, MI, or renal colic).
2- Anti-inflammatory action of salicylates in high dose is responsible for their
recommendations as initial major therapy in rheumatoid arthritis, acute rheumatic
fever and other inflammatory conditions.
3- Antipyretic: aspirin is the best available drug for ↓ fever.
4- Inhibition of platelet aggregation: aspirin used in 1)transient ischemic attacks,
stroke (TIAs) 2)ischemic heart diseases 3)certain revascularization procedures .
5- External application: salicylic acid is used topically for treatment of acne, warts,
corns and calluses.
Adverse reactions to salicylates
The most common adverse reactions to salicylates include
Gastric distress, nausea, vomiting,
Bleeding tendencies.
Hypersensitivity – 15%-
Other adverse reactions include:
Hearing loss (when taken for prolonged periods)
Diarrhea, thirst, sweating, tinnitus, confusion, dizziness, impaired vision, and
hyperventilation (rapid breathing)
Reye’s syndrome (when given to children with chickenpox or flulike
symptoms).
In pregnancy: Aspirin is classified as FDA pregnancy category C risk during the first
and second trimesters and category D during the third trimester. Because salicylates
are excreted in breast milk, aspirin should be avoided during pregnancy and while
breastfeeding.