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NSAIDS
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Redness Rubor*
Swelling Tumor/Turgor*
Heat Calor*
Pain Dolor*
Loss of Functio laesa
function **
Process of
Inflammation
• Inflammation can be classified as either acute or chronic.
• The initial phase of cell injury is known as the acute
phase and is mediated by several autacoids like :
– Histamine
– 5-HT
– Bradykinin
– Prostaglandins
Membrane phospholipids
Cosrticosteroids
Phospholipase
Arachidonic acid
Prostanoids
Synthesis of Prostaglandins
Cyclo-oxygenase (COX)
pathway
Membrane Phospholipids
Phospholipase A2
Arachidonic Acid
COX
Prostaglandins
Thromboxanes
Prostacyclin
NSAID
s
• Among the most widely used all therapeutic agents
world wide
Oxyphenbutazo
ne
3. Indole derivatives Indomethacin, Sulindac
4. Propianic acid Ibuprofen, Naproxen,
derivatives Ketoprofen, Flurbiprofen
5. Anthranilic acid Mephenamic acid
8. Oxicam derivatives
derivatives Piroxicam,
Tenoxicam.
6. Aryl-acetic acid Diclofenac
derivatives
Classificati
on
Preferential COX-2 inhibitors:
Nimesulide, Meloxicam, Nabumatone
Piroxicam, Tenoxicam.
Oxicam derivatives
Mechanism of
action
• When a tissue is injured, from any cause,
prostaglandin synthesis in that tissue increases.
Membrane Phospholipids
Phospholipase A2
Arachidonic Acid
NSAIDs COX
Prostaglandins
Thromboxanes
Prostacyclin
COX
COX-
1
It is responsible for the Physiologic production of
prostanoids.
It is enzyme that regulates the normal cellular
processes (via production of PGs) such as
Gastric cytoprotection
Vascular homeostasis
Platelet aggregation
Kidney function.
Beneficial actions due to PG
synthesis
inhibition
• Analgesia
• Antipyresis
• Antiinflammatory
• Antithrombotic
• Closure of ductus
arteriosus
Shared toxicities due to PG
synthesis
inhibition
• Acetylsalicylic acid
1. Antiinflammatory action:
Potent
Exerted at high doses (3-6g/day or
100mg/kg/day)
Signs of inflammation are
suppressed
Acts mainly by inhibiting PG
synthesis
Aspirin – Pharmacological
actions
2. Analgesic action:
8. GIT:
Irritate gastric mucosa and cause epigastric
distress,
nausea and vomiting
• Also stimulates CTZ
• Heart burn, dyspepsia, erosion,
Gastric ulcers.
Aspirin – Pharmacological
actions
9. Effect on platelets/coagulation:
• TXA2 enhances platelet aggregation
• PGI2 decreases it
• Low doses(80-100mg/day) An anticoagulant effect with
a prolonged BT
Aspirin – Pharmacological
actions
10. Local irritant effect:
• Cause irritating to the skin & mucosa and destroys
epithelical cells
• Keratolytic effects
d) Salicylism
• High doses(at antiinflammatory doses) or chronic use
of aspirin may induce a syndrome characterised by
tinnitus, hearing defects, blurring of vision, dizziness,
headache and mental confusion
• Effects are reversible
Aspirin – Adverse
effects
e) Acute salicylate poisonig:
• More common in children
• Fatal dose in adults estimated to be 15-30gm, but
considerably low in children
• Serious toxicities seen at serum levels >50mg/dl
Manifestations are:
vomiting, dehydration, electrolyte imbalance, acidotic
breathing, hyper/hypoglycemia, petecheal hemorrhages,
restlessness, delirium, hallucinations, hyperpyrexia,
convulsions, coma and death due to respiratory and
cardiovascular failure
Aspirin – Adverse
effects
Treatment:
• Peptic ulcer
• Ulcerative colitis
• Gout
• Renal failure
• Hemophilias
Aspirin – Uses
1. As analgesic
2. As antipyretic
3. Antiinflammatory
i. Acute rheumatic fever
ii. Rheumatoid arthritis
iii. Osteoarthritis
4. Cardio protective
Aspirin –
Doses(oral)
• As analgesic and antipyretic:
0.3-0.6gm, 6-8 hourly
• Acute rheumatic fever:
75-100mg/kg/day in divided doses/4-6
days
50mg/kg/day/2-3wks- maintenance dose
• Rheumatoid arthritis:
3-5gm/day
• Cardio protective:
80-100mg/day
Other clinically used
Salicylates
a) Sodium salicylate:
• Aspirin alternative in rheumatic fever
• But now is obsolete
b) Methylsalicylate (Topical):
• Used topically as a counterirritant in muscle and joint
pain, in the form of liniments and ointments
• Systemic absorption can lead to toxicity
c) Salicylic acid (Topical):
• Used as keratolytic and corn remover
• Combined with benzoic acid (Whitefield ointment) for
local use in epidermophytosis
Pyrazolone
Derivatives
These are:
• Aminopyrine and antipyrine
• Phenylbutazone and oxyphenbutazone
• Analgin (dipyrone)
Phenylbutazone:
• Potent antiinflammatory drug
• Poorly tolerated by many patients
• Causes GI, hepatic, renal and fatal hematologic,
agranulocytosis toxic effects
• Gives rise to various drug interactions
• Hence now it is rarely used
Pyrazolone
Derivatives
Oxyphenbutazone:
• Metabolic degradation product of phenylbutazone
• Less gastric irritation than phenylbutazone
• It shares all toxic effects of phenylbutazone
Analgin (Dipyrone, Novalgin):
• Has potent analgesic antipyretic but no antiinflammatory
actions
• Has no advantage over aspirin
• Toxic effects are similar to phenylbutazone
Indole
Derivatives
Indomethacin:
• Potent antiinflammatory agent
• Has antipyretic, analgesic and anti-inflammatory actions
• Effective in gout, rheumatoid arthritis, ankylosing spondylitis
and osteoarthritis.
• Given orally, absorbed well
• Mainly metabolized by liver and excreted by kidneys
• Headache is the most common adverse effect, followed by
giddiness, mental confusion, blurring of vision, depression and
psychotic disturbances.
• Total daily dose is 50-150mg in divided doses (Indomethacin 25mg cap)
after food.
Indole
Derivatives
Tocolytic agent: As effective as MgSo4
It dec. preterm birth significantly by arresting
premature uterine contractions
Dose; 25mg 2-3 times a day.
Sulindac:
• Fluorinated derivative of indomethacin
• It is a prodrug and has a longer duration of action
• Given orally in the dose of 100-200mg twice a
day
Propionic acid
Derivatives
These are:
Ibuprofen, naproxen, flurbiprofen and ketoprofen
• Analgesic, antipyretic and anti-inflammatory properties
similar to Aspirin
• Better tolerated orally
• Adverse effects are lower than aspirin and
indomethacin
• Highly bound to plasma proteins (92-99%)
• ADR: cause GI disturbances such as epigastric
pain, nausea, sensation of fullness in the stomach and
heartburn
• Less frequently they may cause CNS symptoms
Anthranilic acid Derivatives
(Fenamates)
Mefenamic acid:
• Useful in chronic and dull aching pains
• No advantages over other NSAIDs
• Weaker analgesic than aspirin
• Adverse reactions include gastric upset, diarrhoea,
dizziness, headache, skin rashes, hemolytic anemia
• Dose is 500mg 2-3 times a day
• Used in Dysmenorrhoea
Arylacetic acid
Derivatives
Diclofenac:
• Probably has greater activity than other NSAIDs
• Extensively bound to plasma proteins, t1/2 is 1-2hrs
• Accumulates in the synovial fluid- probably responsible
for its longer duration of action than its t1/2
• Incidence of adverse reactions is 20%
• Adverse effects similar to propionic acid
derivatives+elevation of liver enzymes
Oxicam
Derivatives
Piroxicam:
• Structurally different from other NSAIDs
• Given orally, well absorbed, has long t1/2 (38-45hrs) –
administered OD
• Commonly causes GI and CNS disturbances
• Has been used to treat rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis and acute gout.
Pyrollo pyrollo
Derivatives
Ketorolac:
• Has less antiinflammatory activity
• IM. 20-30mg (single dose) is a moderately effective
analgesic in patients with moderate to severe
postoperative pain
• IV ketorolac has been as effective as, and have fewer
side effects than morphine in surgical and chronic cancer
pain
• Has longer duration of action (t1/2 5hrs)
• Metabolised in liver and excreted by kidneys
Para aminophenol
Derivatives
• The commonly used drug is Paracetamol
(Acetaminophen)
• Potent antipyretic and equianalgesic with aspirin in
therapeutic doses but devoid of significant
antiinflammatory effect
• Does not produce gastric irritation, acid –base
imbalance, electrolyte disturbances nor does it affect
blood clotting
• Hence is preferred to aspirin as an analgesic
antipyretic
• Absorption, fate and excretion:
• Rapidly absorbed on oral administration
• Peak plasma levels are reached within ½ an hour to
Para aminophenol
Derivatives
• Metabolised in the liver and excreted in urine as
conjugation products of glucuronic and sulfuric acids
• Poor metabolism in infants- enhanced toxicity
Adverse effects:
• At recommended therapeutic doses (500-1000mg)
in
healthy subjects is well tolerated
Hepatic and renal toxicity:
• Larger doses (7-10gm) produce extensive hepatocellular
damage and renal tubular necrosis, and may cause
death
Para aminophenol
Derivatives
Treatment:( toxicity)
• Patient is brought early (within 16hrs of ingestion)
• Vomiting should be induced or gastric lavage done
• Activated charcoal is given orally or through tube to
prevent further absorption
• Other supportive measures, as needed, should be
taken
Specific:
• N- acetylcysteine 150mg/kg should be infused i.v.
over
15min, followed by the same dose i.v. over next
Benzoxazocine
Derivatives
Nefopam:
• Different from other NSAIDs since it has atropin like
actions
• Effective in traumatic and post operative pain, and in
musculoskeletal pain not responding to other NSAIDs
• Atropine like adverse effects
• Contraindicated in epilepsy
Pref COX-2
inhibitors
These are:
Nimesulide, Meloxicam, Nabumatone
Nimesulide:
• Relative weak PGs inhibitor with COX-2 selective action
• Other mechanisms implicated are reduced superoxide
generation by neutrophils, inhibition of PAF synthesis
and free radical scavenging action
• Gastric and other adverse effects are similar to other
NSAIDs
Has been reported to cause nephrotoxicity and hepatotoxicity
Not licensed in some developed countries
And it has been withdrawn from others
Use should be avoided especially in children and old persons
Selective COX-2
Inhibitors
• Selectively block COX-2 activity more than COX-1
activity
•Less action on stomach, blood vessels and kidneys
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
• Given orally, absorption is complete
• Established analgesic- antiinflammatory NSAIDs
• They have to be shown effective in treatment of
osteoarthritis and rheumatoid arthritis
• Their major advantage is that they cause fewer
gastric
ulcers and do not inhibit platelet aggregation
• Stomach friendly
Selective COX-2
Inhibitors
Adverse effects:
• The most common adverse effects are nausea, vomiting,
dyspepsia, abdominal pain, diarrhoea and edema of the
lower extremities
• Share some of the renal adverse effects of non selective
COX inhibitors and renal toxicity
• Hence their use should be restricted to patients who do
not tolerate other NSAIDs
Selective COX-2
Inhibitors
Recently, the use of rofecoxib and valdecoxib has
been reported to be associated with increased incidence
of MI and stroke
Hence, they have been withdrawn by the original
manufacturers
Currently all the selective COX -2 inhibitors are
under
suspicion regarding their long term toxicity
They have been described as drugs with “marginal
efficacy, heighted risk and excessive cost compared with
traditional NSAIDs”
Topical
NSAIDs
• Diclofenac 1% gel
• Ibuprofen 10% gel
• Naproxen 10% gel
• Ketoprofen 2.5% gel
• Flurbiprofen 5% gel
• Nimesulide 1% gel
• Piroxicam 0.5% gel
Thank
you