Dr.

Nasir Mehmood

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• Aspirin like or non-opioid analgesics…
• Anti-inflammatory, antipyretic, uricosuric…
Mechanism:

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Classification:
A. Non selective Cox inhibitors:
1.Salicylic acid derivatives: aspirin, sodium salicylate,
diflunasil
2.P-aminophenol derivatives: paracetamol
3.Pyrazolone derivatives: phenylbutzone, azapropazone.
4.Indole acetic acid derivatives: indomethacin,
sulindac
5.Arylacetic acid derivatives: diclofenac, ketorolac,
tolmetin
6.Propionic acid derivatives: ibuprofen, fenoprofen,
carprofen, naproxen, ketoprofen, oxaprozin
7.Antrhanilic acids: flufenamic acid, mefenemic acid.
8.Oxicams: piroxicam, tenoxicam.
9.Alkanones: nabumetone
B. Selective Cox inhibitors: 3
1.Nimesolide, celecoxib, reofecoxib, etoricoxib.
• PGE 2 – vasodilation, bronchodilation, inhibition
of gastric acid secretion, stimulation of gastric
mucus secretion, sensitization of pain receptors to
chemical and mechanical stimuli, promotion of
anterior pituitary hormones release;
• PGF2α - uterus contraction,
bronchoconstriction, decrease in intraocular
tension;
• TXA2 (thromboxane), produced by platelets, -
induction of platelet aggregation,
vasoconstriction;
• PGI 2 - inhibition of platelet aggregation, potent
vasodilation;
• Exists in the tissue as constitutive isoform (COX-
1).
• At site of inflammation, cytokines stim the
induction of the 2nd isoform (COX-2).
• Inhibition of COX-2 is thought to be due to the
anti-inflammatory actions of NSAIDs.
• Inhibition of COX-1 is responsible for their GIT
toxicity.
• Most currently used NSAIDs are somewhat
selective for COX-1, but selective COX-2 inhibitors
are available.
• Act by inhibiting CycloOXygenases (COX) => no PG production
– COX-1: Constitutively expressed => house-keeping function
– COX-2: Induced by pro-inflammatory factors (TNFα, IL-1)
– COX-3: Just recently discovered
• PGs do not cause pain, but sensitize nocireceptors to stimulation (e.g.
by 5-HT, Bradykinine, capsaicin, …)
• IL-1 release from activated macrophages (bacteria, etc.) induces COX-2 in
the brain =>PG E produced => affects thermoregulation => fever=>
NSAIDs have anti-pyretic effects
• Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is reversible,
with the exception of Aspirin) => housekeeping PGs reduced => side
effects (gastrointestinal, bronchospasms,…)
• 2nd generation NSAIDs: COX-2 specific => only the inflammatory response
is inhibited => fewer side effects.
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1. Salicylates:
salts of salicylic acid… aspirin is prototype…
Actions:
• Analgesia: good analgesic, relieves inflammatory
pain…
No euphoria & hypnosis…
• Antipyretic action: lower temperature in to
normal…inhibiting PG synthesis..

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1. Salicylates:
Actions:
• Anti-inflammatory action: higher doses…
pain, tenderness, erythema, swelling
reduced…
• Respiration: stimulate directly & indirectly…
higher doses depress resp.center.
• Acid-base/eletrolyte balance: respiratory
alkalosis…
• Higher doses… acidosis.
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1. Salicylates:
Actions:
• Metabolic effects: increased metabolism
• Blood: inhibits TXA2 synthesis by
platelets… interferes platelet aggregation
& bleeding time.
• Local effects: keratolytic, antiseptic,
fungistatic.

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1. Salicylates:
PKs:
• Not well absorbed…
• Microfine particles absorbed more easily
• Absorbed from skin
• Bound to PPs.
• Metabolized in liver, plasma
• Excreted in urine.

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1. Salicylates:
ADRs:
• Nausea, gastritis, ulcer, occult blood loss.
• Allergic reactions… angioedema, asthma..
• Hemolysis in G6PD deficiency.
• Nephrotoxicity on long term use.
• Hepatotoxicity.
• Reye’s syndrome… viral infection.
• Pregnancy & infancy… delay labour, premature
closure ductus arteriosus.. Increased post-
partum bleeding….
• Salicylism:

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1. Salicylates:
Uses:
• Analgesic…
• Fever…
• Inflammatory conditions…
• Acute rheumatic fever…
• RA…
• OA…
• Post MI & stroke… antiplatelet… inhibits
reinfarction & decreases TIA…
• To delay labour…
• Patent ductus arteriosus…

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2. P-aminophenol derivatives:
PCM:
•Analgesic, antipyretic, weak anti-
inflammatory…
•Active on COX in brain… poor in sites with
inflammation…
PKs
•Well abosrbed orally
•30% PP bound.
•Metabolized by liver by conjugation..

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2. P-aminophenol derivatives:
PCM:
ADRs
•Safer & well tolerated…
•Higher doses… acute PCM poisoning…
•Hepatotoxic.. Fulminant hepatic failure…
•Nephrotoxicity…
Uses:
•Analgesic
•Antipyretic

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3. Pyrazolon derivtives:
Phenylbutazone:
•Good antiinflammatory, weak analgesic &
antipyretic…
•Salt & water retention… edema after 12wks ..
CCF
PKs…
•Completely absorbed orally
•Local tissue damage… slow absorption on IM.
•T1/2… 60hrs

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3. Pyrazolon derivtives:
Phenylbutazone:
ADRs…
•More toxic than aspirin & poorly tolerated…
•Hypersensitivity … sr. sickness, stomatitis,
hepatitis..
•Hematological complications… bone marrow
depression, aplastic anemia…
•Inhibit thyroid iodine uptake… hypothyroidism
•CNS… insomnia, vertigo, optic nuritis, blurring…

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3. Pyrazolon derivtives:
Phenylbutazone:
Uses…
•RA
•AS
•OA
•Gout
•MSk conditions…

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4. Indole acetic acid derivatives:
Indomethacin:
•Potent anti-inflammatory, antipyretic, analgesic..
•Well absorbed… 90% PP bound…
ADRs…
•GI irritation…
•CNS … headache, ataxia…
•Hypersensitvity…asthma, leukopenia..
Drug interactions:
•Salt & water retention… blunts aciton of
furosemide, anti-HTN drugs, beta blockers, ACE
inhibitors…

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4. Indole acetic acid derivatives:
Indomethacin:
Uses…
•RA
•AS
•OA
•Gout
•Psoriatic arthritis
•Closure of ductus arteriosus…

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4. Indole acetic acid derivatives:
Diclofenac :
•Analgesic, antipyretic, anti-inflammatory…
•Good tissue penetrability… good conc. In
synovial fluid….
Uses:
•Inflammatory conditions..
•Acute MSK pain..
•Post op pain…

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4. Indole acetic acid derivatives:
Ketorolac:
•Analgesic, antipyretic, anti-inflammatory…
•Parentral
Uses:
•Inflammatory conditions..
•Acute MSK pain..
•Post op pain…

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• Ibuprofen:
analgesic, antipyretic, antiinflammatory…
slightly less efficacious than aspirin.
• ADRs:
• Gastric discomfort, hypersensitivity, fluid retention.
• Uses:
• Pain and fever.
• Soft tissue injuries.
• Gout.
Fenoprofen, ketoprofen, carprofen, naproxen….

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• Fenamates….
• analgesic, antipyretic, antiinflammatory
• Less efficacious & more toxic.
• Not used more than a week…

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• Piroxicam, meloxicam, pivoxicam,tenoxicam,
lornoxicam
• analgesic, antipyretic, good antiinflammatory
• Long acting. Better tolerated.

Uses:
• RA
• OA
• AS
• Acute muscular pain
• Post-operative pain.
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• Nabumetone:
• Anti-inflammatory…
• Efficacious in RA & OA.
• Less side effects.
• Less ulcerogenic.
• Prodrug… selectively inhibits COX-2

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Celecoxib, rofecoxib:
•Good analgesic, antipyretic, antiinflammatory
•No effect on platelet aggregation.
•Milder gastric irritation.
•Rofecoxib…. HTN & edema…

Uses:
•Pains… post-operative pain, dysmenorrhea…
•OA
•RA

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Nimesolide:
•Sulfonamide…
•Weak inhibitor of PG synthesis.
•Higher affinity for COX-2
•Inhibits leukocyte function, release of mediators
•Antihistaminic.
•Good analgesic, antipyretic, antiinflammatory
•Well absorbed orally, extensively bound to plasma
proteins, excreted by kidneys…
ARS:
•Nausea, epigastric pain, drowsiness, dizziness
•Hepatotoxicity…

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Zileuton, docebenone, piriprost:
•Some Inhibit 5-lipoxygenase… prevent snythesis of
LTs…
•Others competetively block LT receptors…

•Useful in asthma etc.

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