Download Non-steroidal anti-inflammatory drugs (NSAIDs)

Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
These drugs have analgesic, antipyretic and at higher doses, anti-inflammatory actions.
They are not effective in the treatment of visceral pain ( e.g myocardial infarction , renal colic ,
acute abdominal pain) which required opioid analgesics, however , NSAIDs are effective in
certain types of severe pain (e.g bone cancer)
The NSAIDs fall under two classes, namely,
1-Inhibitors of prostaglandin (PG) synthesis as aspirin
2- Miscellaneous (locally applied ) anti-inflammatory drugs as dimethyl sulfoxide
The PG inhibitors used extensively to treatment mild to moderate pain , and is also effective in
treatment cephalgia , myalgia , arthralgia but they do not relieve visceral pain except flunixin.
Side effects of NSAIDs:
There are certain side effects which are common to NSAIDs :
1)-gastrointestinal disturbance: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis,
ulceration and GI bleeding.
Ulcerogenic effect is the major drawback of NSAIDs, which is prevented/minimized by taking:
a. NSAIDs after food.
b. proton pump inhibitors/H2-blockers/misoprostol with NSAIDs.
c. buffered aspirin (preparation of aspirin with antacid).
d. selective COX-2 inhibitors.
2)-renal distribances : prostanoids particularly PGE2 mediated acompensatory vasodilation in
response to the action of noradrenaline and angiotensine II . hence inhibition of these prostanoids
by NSAIDs lead to disturbed blood dynamics and a condition called analgesic nephropathy
comprising of chronic nephritis and renal papillary necrosis.
3)-skin reactions as it is relatively more common with aspirin .skin rashes , urticaria , rhinitis ,
bronchospasm and photosenstization.
Classes of NSAIDs :
1)- non-selective COX inhibitors :
I)-carboxylic acids derivatives :
a)-Salicylates : as aspirin
b)-Propionic acids derivatives : as Ibuprofen , Ketoprofen , carprofen , naproxen
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Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
c)-Fenamic acid derivatives : as Mefenamic acid
d)- acetic acid derivatives : as etodolac
e)-nicotinic acid derivatives : as flunixin
II)-enolic acids derivatives :
a)-Oxicam : as meloxicam
b)-pyrazolones : phenylbutazone
2)-selective COX-2 inhibitors :
Coxibs : as deracoxib , firocoxib , celecoxib
3)dual inhibitors (COX & LOX) as propanamide group : as Tepoxalin
Mechanism of action : COX is the enzyme responsible for the biosynthesis of various
prostaglandins. There are two wellrecognized isoforms of COX: COX-1 and COX-2. COX-1 is
constitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have
important role in many tissues (Fig. 7.2, p. 201). COX-2
is induced during infl ammation by cytokines and endotoxins, and is responsible for the
production of prostanoid mediators of infl ammation.
Aspirin and most of the nonsteroidal antiinfl ammatory drugs (NSAIDs) inhibit both COX-1
and COX-2 isoforms, thereby decrease prostaglandin and thromboxane synthesis. The antiinfl
amatory effect of NSAIDs is mainly due to inhibition of COX-2. Aspirin causes irreversible
inhibition of COX. Rest of the NSAIDs cause reversible inhibition of the enzyme.
Pharmacological actions of aspirin and other NSAIDs
Aspirin (acetylsalicylic acid) is the prototype drug. The other nonselective NSAIDs vary mainly
in their potency, analgesic, antiinfl ammatory effects and duration of action.
1. Analgesic effect: NSAIDs are mainly used for relieving musculoskeletal pain, dysmenorrhoea
and pain associated with infl ammation or tissue damage. Analgesic effect is mainly due to
peripheral inhibition of PG production.
They also increase pain threshold by acting at subcortical site. These drugs relieve pain without
causing sedation, tolerance or drug dependence.
2. Antipyretic effect: The thermoregulatory centre is situated in the hypothalamus. Fever occurs
when there is a disturbance in hypothalamic thermostat. NSAIDs reset the hypothalamic
thermostat and reduce the elevated body temperature during fever. They promote heat loss by
causing cutaneous vasodilatation and sweating. They do not affect normal body temperature. The
antipyretic effect is mainly due to inhibition of PGs in the hypothalamus.
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Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
3. Antiinflammatory effect: Antiinfl ammatory effect is seen at high doses (aspirin: 4–6 g/day
in divided doses). These drugs produce only symptomatic relief. They suppress signs and
symptoms of infl ammation such as pain, tenderness, swelling, vasodilatation and leukocyte infi
ltration but do not affect the progression of underlying disease.
The antiinflammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of
injury. They also affect other mediators of infl ammation (bradykinin, histamine, serotonin, etc.),
thus inhibit granulocyte adherence to the damaged vasculature. NSAIDs also cause modulation
of T-cell function, stabilization of lysosomal membrane and inhibition of chemotaxis.
4. Antiplatelet (antithrombotic) effect: Aspirin in low doses (50–325 mg/day) irreversibly
inhibits platelet TXA2 synthesis and produces antiplatelet effect, which lasts for 8–10 days, i.e.
the life-time of platelets. Aspirin in high doses (2–3 g/day) inhibits both PGI2 and TXA2
synthesis; hence beneficial effect of PGI2 is lost. Aspirin should be withdrawn 1 week prior to
elective surgery because of the
risk of bleeding.
5-Cardiovascular system (CVS): Prolonged use of aspirin and other NSAIDs causes sodium
and water retention. They may precipitate congestive cardiac failure (CCF) in patients with low
cardiac reserve. They may also decrease the effect of antihypertensive drugs.
6. Urate excretion: Salicylates, in therapeutic doses, inhibit urate (uric acid ) secretion into the
renal tubules and increase plasma urate levels. In high doses, salicylates inhibit the reabsorption
of uric acid in renal tubules and produce uricosuric effect.
Differenes between Non-selective COX & selective COX-2 inhibitors :
Non-selective COX
Analgesic effect +
Antipyretic effect +
Anti-inflammatory effect +
Antiplatelet effect +
GI side effects are marked ++
selective COX-2 inhibitors
Analgesic effect +
Antipyretic effect +
Anti-inflammatory effect +
No Antiplatelet effect
GI side effect are less ( less ulcerogenic
potential)
Renal toxicity +
Renal toxicity +
Aspirin
Aspirin and other nonsteroidal anti-inflammatory drugs are weak organic acids. They all inhibit
prostaglandin biosynthesis. They decrease the production of free radicals and of superoxide and
may interact with adenylyl cyclase to alter the cellular concentration of cAMP. Aspirin is the
drug of choice for treating the majority of articular and musculoskeletal disorders. It is also the
standard against which all anti-inflammatory agents are compared.
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Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
Pharmacokinetics: The salicylates are rapidly absorbed from the stomach and upper small
intestine. The acid medium in the stomach keeps a large fraction of the salicylate in the
nonionized form, promoting absorption. However, the drug may damage the mucosal barrier.
Aspirin is absorbed as such and is rapidly hydrolyzed to acetic acid and salicylate by esterases in
tissue and blood. Salicylate is bound to albumin. Ingested salicylate and that generated by the
hydrolysis of aspirin may be excreted unchanged, but most is converted to water-soluble
conjugates that are rapidly cleared by the kidney. Alkalinization of the urine increases the rate of
excretion of free salicylate.
Mechanism of Action: Aspirin irreversibly blocks the enzyme cyclooxygenase; the drug
decreases the formation of both the prostaglandins and thromboxane A2 but not the leukotrienes.
Ibuprofen
Ibuprofen is extensively metabolized in the liver, and little is excreted unchanged.
Gastrointestinal irritation and bleeding occur, though less frequently than with aspirin. In
addition to the gastrointestinal symptoms, rash, pruritus, tinnitus, dizziness, headache, and fluid
retention have been reported. Rare hematologic effects include agranulocytosis and aplastic
anemia. Effects on the kidney include acute renal failure, interstitial nephritis, and nephritic
syndrome, occurring very rarely.
Diclofenac
Diclofenac is a potent cyclooxygenase inhibitor with antiinflammatory, analgesic, and antipyretic
properties. The drug is rapidly absorbed following oral administration and has a half-life of 1-2
hours. It accumulates in the synovial fluid. The potency of diclofenac as a cyclooxygenase
inhibitor is greater than that of naproxen. The drug is recommended for chronic inflammatory
conditions such as rheumatoid arthritis and osteoarthritis and for the treatment of acute
musculoskeletal pain. Adverse effects include gastrointestinal distress, occult gastrointestinal
bleeding, and gastric ulceration.
Sulindac
Sulindac is a prodrug. Its active metabolite is, like diclofenac, an acetic acid derivative. The drug
is effective only after it is converted by liver enzymes to a sulfide, which is excreted in bile and
then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to
12-16 hours. The indications and adverse reactions are similar to those of other NSAIDs.
Among the more severe reactions, Stevens-Johnson epidermal necrolysis syndrome,
thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like
diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferase; it
is also sometimes associated with cholestatic liver damage.
Mefenamic Acid
Mefenamic acid, another fenamate, possesses analgesic properties but is probably less effective
than aspirin as an anti-inflammatory agent and is clearly more toxic.
Piroxicam
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Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
It is rapidly absorbed in the stomach and upper small intestine and reaches 80% of its peak
plasma concentration in 1 hour. Gastrointestinal symptoms are encountered in 20% of patients.
Other adverse reactions include dizziness, tinnitus, headache, and rash.
Nimesulide: It is a new NSAID and after oral administration it is rapidly and almost completely
absorbed. Highly bound to plasma proteins. It is a weak inhibitor of prostaglandin synthesis.The
advantage of nimesulide over other NSAIDs is that it causes minimal gastric irritation.
Rofecoxib: Rofecoxib is a highly selective and specific COX-2 inhibitor. It inhibits
prostaglandin
synthesis via inhibiting cyclooxygenase- 2. It is about 90% bound to plasma proteins. The main
adverse effects are nausea, dyspepsia, epigastric discomfort, heart burn, diarrhea, fluid
retention etc. It is mainly useful in osteoarthritis, acute pain like dental pain & primary
dysmenorrhoea.
NSAIDS FOR SPECIAL INDICATIONS
Indomethacin
Indomethacin is slightly more toxic but in certain circumstances more effective than aspirin.
Indomethacin is well absorbed after oral administration and highly bound to plasma proteins.
Metabolism occurs in the liver and unchanged drug and inactive metabolites are excreted in bile
and urine.
Clinical Uses: treatment of patent ductus arteriosus, acute gouty arthritis and ankylosing
spondylitis, pericarditis and pleurisy.
Adverse Effects: The gastrointestinal effects may include abdominal pain, diarrhea,
gastrointestinal hemorrhage, and pancreatitis. CNS effects include be associated with dizziness,
confusion, and depression. Serious hematologic reactions' including thrombocytopenia and
aplastic anemia has been reported
Paracetamol
Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely distributed all
over
the body, metabolized in liver by sulphate and glucuronide conjugation.
Uses
1. As antipyretic: To reduce body temperature during fever.
2. As analgesic: To relieve headache, toothache, myalgia, dysmenorrhoea, etc.
3. It is the preferred analgesic and antipyretic in patients with peptic ulcer, haemophilia,
bronchial
asthma and children.
Adverse effects
1. Side effects are rare, occasionally causes skin rashes and nausea.
2. Hepatotoxicity: with acute overdose or chronic use.
3. Nephrotoxicity is commonly seen on chronic use.
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Lecture 8
Non-steroidal anti-inflammatory drugs (NSAIDs)
Differences between aspirin and Paracetamol :
aspirin
paracetamol
1
It is a salicylate derivative
It is a para-aminophenol derivative
2
It has analgesic , antipyretic and potent It has potent antipyretic and analgesic effects
anti-inflammatory effects
with poor anti-inflammatory action
3
It cause GI irritation (nausea , vomiting , It usually not produce gastric irritation
peptic ulcer and bleeding
4
In large doses , it produces acid-base and it does not produces acid-base and electrolyte
electrolyte imbalance
imbalance
5
It has antiplatelet action
It has not antiplatelet action
6
It has no specific antidote
N-acetylcysteine is the antidote
7
It is contraindicated in peptic ulcer , Paracetamol
is
the
preferred
people with bleeding tendency , analgesic,antipyretic in patient having peptic
bronchial asthma and in children with ulcer , bronchial asthma and in children
viral infection
.
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