NSAIDs

Dr Usman Nawaz
Pharmacology & Therapeutics
 Learning Objectives

• Classify NSAIDS
• Name the prototype non-selective COX inhibitor
• Describe the pharmacokinetics of Aspirin
• Describe the mechanism of action of aspirin as anti-
platelet, analgesic, antipyretic and anti-inflammatory
agent
• Give the dose of Aspirin as anti-platelet,
analgesic/antipyretic and as anti-inflammatory drug
• Describe clinical uses of NSAIDs
 Learning Objectives

• Describe the adverse effects of NSAIDs

• Describe the drug treatment of Aspirin poisoning
• Describe the pharmacokinetics with emphasis on dosage,
duration of action and elimination of Diclofenac,
Ibuprofen, Indomethacin, Mefenamic acid and Piroxicam
in contrast to Aspirin
• Relate pharmacokinetics and pharmacodynamics of
NSAIDs to their clinical applications
• Differentiate between non-selective COX inhibitors and
selective COX-2 inhibitors based on mechanism of action
 NSAIDs

• NSAIDs stands for

• Non Steroidal Anti-Inflammatory Drugs

• Analgesics
• Drugs for relieving Pain
 Inflammation

• The cell damage associated with inflammation, causes

leukocytes to release lysosomal enzymes
• Arachidonic acid is then liberated from membrane
phospholipids
• Metabolism of arachidonic acid is carried out by 2
enzymes
• Cyclooxygenase (COX)
• Lipoxygenase (LOX)
 Inflammation

• Prostaglandins • Prostacyclin
• Promote edema and • Vasodilation
leukocyte infiltration
• Reduces platelet
• Increase vascular aggregation
permeability
• Sensitize nerve ending to • Thromboxane A2
the action of bradykinin, • Platelet aggregation
histamine etc.
• Vasoconstriction
 Cyclooxygenase (COX)

COX 1 COX 2
• Regulates normal cellular • Production of prostanoids at
processes the site of inflammation
• Gastric cytoprotection • Induced by inflammatory
• Vascular homeostasis –
mediators like TNF-α & IL-1
Platelet aggregation • Inhibited by glucocorticoids
• Kidneys and reproduction
 Classification of NSAIDs

• Nonselective (COX 1 + COX 2) inhibitors

• COX 2 Selective Inhibitors
• Preferential COX 2 inhibitors
 Nonselective (COX 1 + COX 2) inhibitors
Salicylates Aspirin (Dispirin)
Diflunisal
Salsalate
Propionic Acids Ibuprofen (Brufen)
Fenoprofen
Flurbiprofen (Froben)
Ketoprofen
Naproxen (Synflex))
Oxaprozin
Acetic Acids Indomethacin
Ketorolac
Etodolac
Sulindac
Toletin
Enolic Acids Piroxicam
Meloxicam
Fenamates Mefenamic Acid (Ponstan)
Meclofenamic Acid
 Classification of NSAIDs

COX 2 Selective Inhibitors Preferential COX 2 Inhibitors

• Celecoxib • Meloxicam
• Etoricoxib • Nimesulide (NIMS)
• Parecoxib • Diclofenac (Artifen)
• Acelofenac
• Nabemutone
 Non-Selective COX Inhibitor

• Prototype – Aspirin
• Weak analgesic
• Ineffective in ischemic and severe visceral pain
 Aspirin – Pharmacokinetics

• Aspirin – metabolized by esterases to acetate and

salicylate
• Cross BBB, placenta, skin
• First order kinetics of elimination - at low doses - half-life
of 3–5 h
• Zero order kinetics of elimination – at high dose – 15 hr or
more – Hepatic metabolic pathway saturated
 NSAIDs – Actions/Properties

• Anti-inflammatory
• Analgesic
• Antipyretic
• Antiplatelet
 Aspirin – Pharmacodynamics

• Irreversibly inhibits platelet COX

• Antiplatelet effect lasts 8–10 days (the life of the platelet)
(No nucleus)
• In other tissues, synthesis of new COX replaces the
inactivated enzyme so that ordinary doses have a
duration of action of 6–12 hours
 Pharmacodynamics

• Anti-Inflammatory
• Aspirin irreversibly inhibits COX by acetylation
• Other NSAIDs reversibly
• Inhibition of prostaglandin synthesis
• Other
• Inhibition of chemotaxis
• ↓ IL-1 production
• ↓ production of free radicals and superoxide
• Interference with calcium-mediated intracellular events
 Pharmacodynamics

• Analgesic
• PGE2 – sensitize nerve ending to the action of
bradykinin, histamine etc. – Hyperalgesia
• NSAIDs ↓ prostaglandin production
• Block pain sensitizing mechanism – bradykinin, TNF,
IL
• Musculoskeletal pain – mild to moderate
• Central mechanism – Raising pain threshold in brain
 Pharmacodynamics

• Antipyretic
• Temperature regulating center – Hypothalamus
• Pyrogens including ILs, TNFα, interferons produces
PGE2 in hypothalamus – raises its temperature set
point
• Inflammation, malignancy, infection, hypersensitivity
• NSAIDs inhibit COX-2 & COX-3 in brain – resetting
thermostat back to normal
 Pharmacodynamics

• Antiplatelet
• Aspirin irreversibly blocks platelet cyclooxygenase,
while other NSAIDs are reversible inhibitors
• At low doses, inhibit Thromboxane A2
• Decrease platelet aggregation
• Prolongs Bleeding time
• At high doses, inhibits prostacyclin
 Aspirin

• Aspirin has 3 therapeutic dose ranges

• <300 mg/d – Antiplatelet
• 300–2400 mg/d - Antipyretic and Analgesic
• 2400–4000 mg/d - Anti-inflammatory
 Other NSAIDs

• Diclofenac
• GIT ulceration occur less frequently
• Topical eye drops postoperative ophthalmic
inflammation
• Ibuprofen
• For closing patent ductus arteriosus in preterm
infants – Same efficacy and safety as indomethacin
 Other NSAIDs

• Indomethacin
• Used especially in gout and ankylosing spondylitis
• Accelerate closure of patent ductus arteriosus
• Piroxicam
• Higher chances of peptic ulcer and bleeding
• 9.5 times higher with piroxicam than other NSAIDs
 NSAIDs – Clinical Uses
• Analgesic – Control mild to moderate pain of musculoskeletal
origin
• Oral, Topical, Eye Drops
• Dysmenorrhea – ↑ release of PG – Endometrium
destruction
• RA, Osteoarthritis, Gout
• Migraine, Headache, Toothache
• Ketorolac – severe pain
• NSAIDs + Opioids for malignancy related pain
 NSAIDs – Clinical Uses

• Antipyretic – Fever

• Anti-inflammatory – RA, SLE etc. – High Dose

• Antiplatelet – Angina, MI, TIA, Stroke, PCA, CABG – low

dose 81mg /day (range 75-162 mg/day)
 Clinical Uses

• Patent Ductus Arteriosus Closure

• In fetus, the ductus arteriosus connects the
pulmonary artery to the aortic arch bypassing the
lungs - maintained by PGs
• Indomethacin or Ibuprofen

• Long-term use of aspirin at low dosage is associated with

a lower incidence of colon cancer, possibly related to its
COX-inhibiting effects – Familial colonic polyposis
 Clinical Uses

• Methyl Salicylate – Arthritis Cream, Sports Rub

• Ibuprofen cream, Flurbiprofen cream, Diclofenac gel
• Salicylic acid – Topical – Acne, corns, caluses, warts
• Ketorolac, Nepafenac eye drops – Allergic Conjunctivitis,
Post-op pain
 NSAIDs– Adverse Effects

• Gastric ulceration
• PGs in Stomach
• Bicarbonate production
• Mucus Secretion
• Increase blood flow – Acid washout
• COX-1 inhibition – ↓ PG production
• Promote back diffusion of acid into mucosa – erosive gastritis or
Occult blood in stools
• Give COX-2 inhibitor, paracetamol, or NSAID + Misoprostol/PPIs
 NSAIDs – Adverse Effects

• Increase risk of bleeding

• Due to antiplatelet action
• Prolonged bleeding time
• Must be stopped 1 week prior to surgery (platelet life 7-10 days)
• Cardiac Effects
• Agents with COX2 selectivity
• Promote platelet aggregation
 NSAIDs– Adverse Effects

• Renal Effects
• PGs – maintain intrarenal blood flow
• ↓ PGs – salt & water retention – edema – heart failure and
kidney patients are at risk
• Decrease effects of antihypertensives
• Ischemia
• Precipitate Asthma
• Inhibition of COX – diversion of arachidonic acid pathway to LTs
 NSAIDs – Pregnancy

• NSAIDs - pregnancy risk category C in the first two

trimesters
• Acetaminophen is preferred if analgesic or antipyretic
effects are needed during pregnancy
• In 3rd trimester, NSAIDs should be avoided due to the risk
of premature closure of the ductus arteriosus.
 Aspirin – Adverse Effects

• Reye’s Syndrome (Aspirin)

• Aspirin should be avoided in patients < 20 years old
with viral infections, such as varicella (chickenpox)or
influenza, to prevent Reye’s syndrome – Hepatitis +
Encephalitis
 Aspirin – Adverse Effects

• Respiration
• Stimulated – Initially hyperventilation (respiratory
alkalosis)
• At high doses – Respiratory depression (respiratory
acidosis)
• Death is due to respiratory failure
 Aspirin – Toxicity

• Mild salicylate toxicity – Salicylism

– Nausea, vomiting,
hyperventilation, headache,
confusion, dizziness, tinnitus
 Aspirin – Toxicity
• Aspirin Poisoning • Treatment
• Fatal dose 15 – 30 g in adults, 10 g
in children • IV fluids

• Vomiting, dehydration, • External cooling

electrolyte imbalance, acidotic • Maintain electrolyte and blood
breathing, hypoglycemia, glucose balance
petechial hemorrhages,
restlessness, delirium, • Gastric lavage
hallucinations, hyperpyrexia, • Alkaline diuresis (NaHCO3)
convulsions, respiratory
depression
• Hemodialysis

• Cause of death is respiratory

• Blood transfusions + Vit K (for
bleeding)
failure
 Drug Interactions

• Salicylate – 80% to 90% plasma protein

bound (albumin)
• Can be displaced from protein-binding
sites, resulting in ↑ concentration of
free salicylate
• Aspirin can displace other protein-
bound drugs e.g. warfarin, phenytoin,
or valproic acid, resulting in higher free
concentrations of these agents
 ?

• Differences b/w Aspirin & other NSAIDs

• Difference b/w Aspirin & Paracetamol