Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Uses and Side Effects 

Non-Steroidal Anti-Inflammatory Drugs/Antipyretic-Analgesics

Preferential COX-2 inhibitors

• Nimesulide
• Diclofenac
• Aceclofenac
• Meloxicam
• Etodolac

Selective COX-2 inhibitors

• Celecoxib
• Etoricoxib
• Parecoxib

Nonselective COX inhibitors

• Salicylates: Aspirin
• Propionic acid derivatives: Ibuprofen
  • Naproxen
  • Ketoprofen
  • Flurbiprofen
• Fenamate: Mephenamic acid
• Enolic acid derivatives: Piroxicam
  • Tenoxicam
• Acetic acid derivatives: Ketorolac
  • Indomethacin
  • Nabumetone
• Pyrazolone derivatives: Phenylbutazone
  • Oxyphenbutazone
  • Propyphenazone

Analgesic-antipyretics with poor anti-inflammatory action

• Para aminophenol derivative: Paracetamol (Acetaminophen)
• Benzoxazocine derivative: Nefopam

Mechanism of Action

Inhibits COX enzyme. Cyclooxygenase enzyme converts arachidonic acid into PG, TXA2. Decreases the production of PG, TXA2

NSAID Drugs

• Irreversible COX inhibitor
  • Inhibits both COX-1 and COX-2
    • Aspirin
• Non selective COX inhibitor
  • Inhibits both COX-1 and COX-2
• Preferential COX-2 inhibitor
  • Inhibits COX-2 > COX-1
• Selective COX-2 inhibitor
  • Inhibits only COX-2
• Miscellaneous drugs
  • Analgesic + Antipyretic - Poor anti inflammatory
  • Don't act on COX-1 and COX-2

Common Uses of NSAIDs

• Analgesics
  • Given in all types of pain
    • Not in neuropathic pain
  • In neuropathic pain: anti epileptics, local anaesthetics, TCAs
• Antipyretic
• Anti-inflammatory
  • Except paracetamol
• Anti platelet
  • For MI, stroke: Aspirin
• Closure of PDA: Indomethacin, Ibuprofen (DOC)
• Open ductus arteriosus: PGE (Alprostadil) 1
• Tocolytic effect (relax uterus): Delay labour
• NSAIDs in pregnancy: Avoided
  • Causes premature closure of ductus arteriosus
  • Delay labour
• Safest in Pregnancy: Paracetamol
  • Has least effect
• NSAIDs are avoided in IBD
  • Ulcerative colitis and Crohn's disease
  • Safest Drug: Paracetamol

Common Side effects of NSAIDs

• Nausea, Vomiting: M/c
• Allergic reactions
  • Rashes, urticaria, pruritus (drug eruption)
  • Steven Johnson syndrome, anaphylaxis
• Peptic ulcer

In stomach, COX-1 enzyme is present

↓ 

Produces PGE : protective.

Decreases HCL production, increases mucus and HCO3 - production

↓ 

NSAIDs inhibit COX-1 enzyme and decrease prostaglandin production

↓ 

Leads to increased HCl production and decreased mucus and HCO3 - production

↓ 

Damage stomach cells

• Aspirin causes gastric bleeding, gastritis
  • Maximum risk of peptic ulcer
• Less risk: selective COX-2 inhibitors (COXIBs)
  • Celecoxib
  • Paracetamol (COX-3)
• DOC for peptic ulcer: PPI (prazole)
  • Omeprazole, Pantoprazole
  • Misoprostol(PGE ) 1
• NSAIDs are Nephrotoxic
• PGs cause vasodilation
  • Increases blood supply to kidney
• NSAIDs reduce renal blood flow, GFR
  • Causes acute tubular necrosis.
  • Causes oliguria
    • Antidiuretic effect-  Increased plasma volume
• Increased plasma volume causes increased Na+/ K+ levels
  • Leads to HTN, edema
  • Hyperkalemia
• Precipitates heart failure
  • Causes Papillary necrosis
• NSADs reduce the effect of diuretics(loop)
  • All together known as Analgesic Nephropathy
    • Banned: Phenacetin

Aspirin

• Acetyl salicylic acid
• Irreversible COX Inhibitor
  • Hit & Run drug
  • Suicide inhibitor
• It acetylates COX enzyme by forming covalent bonds

Uses

• Low dose(40-325mg): Anti platelet drug
  • Inhibits COX-1 enzyme
  • Decrease the production of TXA2
  • Used in MI/ stroke
• Medium dose(700-800 mg)
  • Analgesic, Antipyretic
    • Avoid the use of aspirin
    • Increase the risk of “Reye's syndrome”.
• High dose(3-5g)
  • Anti Inflammatory
  • DOC of Kawasaki disease, Osteoarthritis
  • Reduce the risk of colorectal cancer (familial adenomatous polyposis)
• Miscellaneous uses Aspirin
  • Niacin induced flushing
  • ACE inhibitor induced dry cough
  • Alzheimer's disease
    • Not approved

Precautions to Aspirin

• Avoided in Gout
  • Normal dose: <2g
    • Increases uric acid levels
    • Bad for gout
  • 2-5g: has variable effect
  • >5g: decreases uric acid
    • Good for gout
    • Dosage is toxic/ never used
• Avoided in Viral fever
  • Aspirin in viral infection leads to fulminant hepatic failure
    • Known as Reye's syndrome
  • Safest Drug: Paracetamol
• Aspirin causing Asthma and Nasal polyp (Ethmoidal polyp)
  • Allergic symptoms
  • Known as Samtar's triad.
  • SAM- SAN (trick to remember)
    • AS: Aspirin
    • AS: Asthma
    • NAS: Nasal polyp

Aspirin Toxicity

• Commonly available in household
  • Available as small pink tablets
• More risk in children
• Brain: Hallucinations/ Psychosis
• Hyperthermia
  • Uncoupling of oxidative phosphorylation
• Leads to excessive bleeding
  • Due to anti platelet effect
  • Vitamin K Deficiency
• Causes hyperglycemia in normal dose
  • Hypoglycemia in toxic dose
• Ototoxic
  • Tinnitus, Vertigo
    • Known as Salicylism
• Respiratory alkalosis followed by high anion gap metabolic acidosis

Treatment

• Antidote for Aspirin: Sodium Bicarbonate
  • Forced alkaline diuresis
• Severe poisoning: Hemodialysis
• VitK supplements are given
• All NSAIDs poisonings are treated the same way

Non-Selective COX inhibitors

• Reversible inhibitors of COX-1 & COX-2
• Indomethacin: DOC for Arthritis
  • OA, RA, Reactive Arthritis
  • Given in closure of PDA
• S/E: Sedation, seizures, pancreatitis, paradoxical headache
• Sulindac: Prodrug
• Ibuprofen: DOC for closure of PDA
  • Safe NSAID in children
  • Given for dental pain
  • S/E: Aseptic meningitis
• Ketoprofen, Flurbiprofen
  • Topical eye/ nasal drops
  • To treat conjunctivitis, Rhinitis
• Mefenemic acid
  • Blocks PG receptors
  • DOC for menstrual pain/ dysmenorrhea
  • S/E: Autoimmune hemolytic Anemia
• Phenylbutazone(sulfa): Banned
  • Most effective NSAID
  • Causes aplastic anemia/ agranulocytosis
  • Leads to bone marrow suppression
• Piroxicam/ Tenoxicam
  • Longest acting NSAID
  • Excreted in bile
    • Reabsorbed in enterohepatic route
• Naproxen
  • 2nd most cardio safe
  • Safest: Aspirin
• Ketorolac
  • Given in IV/oral
  • Used in post operative analgesia
    • DOC: Opioids

Preferential COX-2 inhibitor

• Inhibits COX-2 > COX-1
• Mnemonic: NMADE
  • Nimesulide: Banned
    • Highly hepatotoxic
    • Causes Steven Johnson syndrome
  • Aceclofenac
  • Diclofenac (voveron, volini)
    • Topical cream/ spray, Oral/IV
    • Has good skin/ tissue penetration
    • Accumulated in synovial joints
    • Used in arthritis pain, sprain
    • More hepatotoxic
  • Etodolac

Selective COX-2 inhibitor 

• Only inhibit COX-2 enzyme
• End with coxib
  • Rofecoxib
  • Valdecoxib
• Low risk of gastric/ peptic ulcer
• Increase the risk of MI/ stroke
  • By platelet aggregation
    • Thromboembolism
  • So, these drugs got banned
• Approved drugs: Etoricoxib, Parecoxib, Celecoxib
  • Used in arthritis

Miscellaneous Drugs 

• Only Analgesic and Anti pyretic
• Poor anti-inflammatory effect
  • Don't act on COX-2
• Drugs: Paracetamol
  • Known as Acetaminophen
• Metamizole: Prodrug of paracetamol
• Nefopam: doesn't act on COX enzyme
  • SNDRI: seretonin norepinephrine dopamine reuptake inhibitor
  • Used to treat migraine, post anesthetic shivering
  • DOC: Pethidine

Paracetamol

• Causes COX-3 inhibition
• Increase the level of endogenous cannabinoids
  • Stimulate TRP-V1 receptor.
• Safest in:
  • Children - No risk of Reye's syndrome
  • Renal failure

Paracetamol Toxicity

• NAPQI:
  • Toxic form of paracetamol in the liver
  • Gets excreted in urine with the help of Glutathione enzyme
• Pattern of liver damage due paracetamol- Zonal necrosis/ centrilobular necrosis with periportal sparing
• High risk of paracetamol hepatotoxicity in
  • Alcoholics
  • Smokers
  • Isoniazid
    • By inducing CYP2E1 enzyme
• Antidote: N acetyl cysteine- DOC
  • Replenish glutathione stores in liver
• Methionine is also used for treatment

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