NSAIDs

Willem van Eeden

Department of Pharmacology
University of Pretoria
willem.vaneeden@up.ac.za
Inflammation
• Inflammation is a normal and protective response to tissue
injury that may be caused by physical trauma, noxious
chemicals or microbiological agents

• Inactivates and destroys invading organisms, removes

irritants and restores normal structure and function to

infected/damaged tissue
Inflammatory mediators
• Chemokines

• Cytokines (TNF-α, IL-1, IL-6)

• Components of the complement cascade (C3a and C5a)

• Plasma mediators (bradykinin)

• Lipid inflammatory mediators (metabolites of

arachidonic pathway)
 Inflammatory process
• Increased capillary permeability

• Allows larger molecules, normally incapable of

penetrating the endothelium to reach affected site

• Causes swelling or oedema

Inflammatory process
• Inflammatory mediators stimulate endothelial cells to
express proteins that trigger blood clotting in small
blood vessels

• Prevents spread of pathogen/microbe

Inflammatory process
• Migration of leukocytes

• Recruited to the infected site to kill any microbes

• Facilitated by newly expressed adhesion molecules on

endothelial cells
 Inflammation
• Cardinal signs of inflammation:

• Heat

• Redness

• Swelling

• Pain

• Loss of function
 Chronic inflammation
• Inflammation, tissue injury and healing process occurs
simultaneously

• Causes damage to tissue and can lead to diseases

 Prostaglandins
• Prostaglandins are chemical mediators released during
allergic and inflammatory processes

• Act locally on the tissues in which they are synthesised

and are rapidly metabolised to inactive products

Prostaglandins
• Two major pathways for synthesis : cyclooxygenase
and lipoxygenase pathways

• Arachidonic acid primary precursor of prostaglandins

• Free arachidonic acid is released from tissue

phospholipids by phospholipase A2
Synthesis of prostaglandins
Membrane proteins
Phospholipase A2

Arachidonic acid

Lipoxygenase Cyclooxygenase
pathway pathway

Leukotrienes
Synthesis of prostaglandins
Cyclooxygenase
pathway

Cyclooxygenase-1 Cyclooxygenase-2

Prostaglandins,
Prostaglandins
Thromboxanes

Gastroprotection, Inflammation, pain,

platelet aggregation fever
 Cyclooxygenase-1 (COX-1)
• Constitutive enzyme that synthesises prostaglandins
involved in normal housekeeping functions
• Present in almost all tissues and organs (blood vessels,
platelets, stomach, intestine, kidneys)
• Physiological effects
• Gastric protection
• Platelet aggregation
• Vascular homeostasis
• Maintenance of blood pressure
 Cyclooxygenase-2 (COX-2)
• COX-2 enzyme present at the site of inflammation
• Expressed by cells involved in the inflammatory processes
• Also found in other tissues and organs
• Kidneys, brain, uterus, bone and vascular endothelium
• Induced by cytokines (tumour necrosis factor alpha and
interleukin 1 & 2)
• Expressed in CNS and plays a role in central mediation of pain
and fever
Synthesis of prostaglandins
Cyclooxygenase
pathway

Cyclooxygenase-1 Cyclooxygenase-2

Prostaglandins,
Prostaglandins
Thromboxanes

Gastroprotection, Inflammation, pain,

platelet aggregation fever
NSAIDs – therapeutic effects
• Anti-inflammatory effects

• Inhibits the release of prostaglandins, histamine,

thromboxane and leukotrienes in the area of tissue
injury

• Suppress pain, swelling and increased blood flow

associated with inflammation
 NSAIDs – therapeutic effects
• Analgesia effect

• Reduction of mild to moderate pain arising from

inflammation or tissue damage

• Decrease production of prostaglandins that sensitise

nociceptors to bradykinin

• Combined with opioids for post-operative pain

 NSAIDs – therapeutic effects
• Antipyretic effect

• Normal body temperature is regulated by the

hypothalamus that controls balance between heat
loss and heat production

• Inhibit the effects of prostaglandins on the

thermoregulatory centre in the hypothalamus and
restores normal body temperature
 NSAIDs – pharmacological uses
• Symptomatic relief in chronic joint diseases (osteoarthritis,
rheumatoid arthritis)

• Acute inflammatory injuries (sport injuries, fractures, sprains,

soft tissue injuries)

• Postoperative pain i.e. dental procedures

• Menstrual pain, headaches

 NSAIDs - adverse effects
Gastrointestinal tract
• Most common adverse effect
• Inhibition of COX-1 leads to a decrease in prostaglandins
that inhibit acid secretion and protect the mucosa
• Abdominal pain, ulcerations, bleeding, anaemia, diarrhoea,
nausea and vomiting
• Proton pump inhibitors (PPIs) used for patients at high
risk for ulcers or history of peptic ulcer disease
 NSAIDs - adverse effects
Kidneys

• No adverse effects at therapeutic doses in healthy

individuals

• Renal insufficiency in susceptible patients – inhibition of

PGE2 and PGI2 responsible for maintenance of renal blood

flow

• Haematuria and renal necrosis

NSAIDs - adverse effects
Skin conditions
• Stevens Johnson syndrome – very rare, fatal
Central nervous system
• Headaches, vertigo, depression
Haematopoietic effects
• Thrombocytopenia, prolonged bleeding due to poor
clotting, leukopenia
NSAIDs classification

Non-selective More Cox-1 selective More Cox-2 selective

 Non-selective COX inhibitors
Acetates Indomethacin, diclofenac
Fenamates Mefenamic acid
Oxicams Piroxicam
Propionates Ibuprofen, ketoprofen, naproxen
Pyrazolones Phenylbutazone
Salicylates Aspirin, diflunisal
COX-1 selective inhibitors

Active ingredient Trade names

Ketorolac Toradol
Flurbiprofen Transact, Strepsils
intensive
COX-2 selective inhibitors
Active ingredient Trade names
Meloxicam -meloxicam
Celecoxib Celebrex
Etoricoxib Arcoxia
COX-2 inhibitors
• Mechanism of action

• Significantly more selective for inhibition of COX-2 than

COX-1

• Does not inhibit platelet aggregation

• Serious cardiovascular events associated with COX-2

inhibitors withdrawal of Rofecoxib, valdecoxib
 COX-2 inhibitors
Decreased risk of peptic ulceration
• COX-2 usually specific to inflamed tissue less
gastric irritation associated with COX-2 inhibitors
Indications
• Rheumatoid arthritis, osteoarthritis and pain associated with
inflammation
Adverse effects
• Dyspepsia, diarrhoea and abdominal pain
 COX-2 inhibitors
Contraindications
• Patients allergic to sulphonamides
• Chronic renal insufficiency and hepatic failure
COX-2 inhibitors
Drug-drug interactions of celecoxib

• Inhibitors of CYP2C9

• Fluconazole and fluvastatin increase levels of celecoxib

• Celecoxib is an inhibitor of CYP2D6

• Elevated levels of B-blockers, antidepressants and

antipsychotic drugs
 Aspirin
• Most commonly consumed drug worldwide

• Used for inflammatory conditions in addition to

cardiovascular disorders
Aspirin
Mechanism of action

• Irreversible acetylation of COX-1 and COX-2

• Also inhibits synthesis of thromboxane

• Inhibit platelet aggregation decreases blood

clotting
Aspirin - pharmacokinetics
• Routes of administration - oral and suppositories available

• Majority of absorption takes place in the ileum

• Absorption delayed by food intake

• Rapidly hydrolysed in plasma and tissue

• Yielding salicylate – anti-inflammatory properties

• Metabolized in liver and eliminated via kidneys

 Aspirin – therapeutic effects
Anti-inflammatory
• Inhibits cyclooxygenase activity - diminishes prostaglandin
formation
• Rheumatoid arthritis – symptomatic relief

• Reduce swelling and redness

Aspirin – therapeutic effects
Antipyretic

• Fever occurs when set point of hypothalamic

thermoregulatory center is elevated

• Reduce fever via inhibition of prostaglandin synthesis

• Peripheral vasodilation and sweating

• Rheumatic fever
 Aspirin – therapeutic effects
Analgesic
• Synthesis of prostaglandin inhibited

• PGE2 sensitises nerve endings to action of bradykinin,

histamine and other chemical mediators

• Mild to moderate pain relief
Aspirin – therapeutic effects
Antiplatelet activity

• Inhibits COX-1 enzyme and prevents formation of

thromboxane A2

• Prevent blood clotting

• Cardiovascular conditions and used to prevent strokes

 Aspirin – adverse effects
Increased risk of bleeding

• Inhibition of platelet activation causing decreased blood

clotting

• Exacerbates bleeding gastric ulcers

Aspirin – adverse effects
Gastrointestinal tract
• Inhibition of prostaglandin results in thinner mucous
layer in the stomach which can result in peptic ulcers
• Misoprostol is used to prevent ulcers (synthetic
prostaglandin analogue)

• Liver and kidney damage

 Aspirin – adverse effects
Reye’s syndrome

• Children more affected than adults (approximately

30% fatality in children)

• Results in liver and brain damage

• Symptoms: rash, vomiting, fever, convulsions and death

• Associated with viral infection and aspirin use

Aspirin – adverse effects
Teratogenic

• Contraindicated in pregnancy – can cross placenta

and enter breast milk

• Birth defects in foetus and haemorrhage at birth

 Aspirin – adverse effects
Allergic reactions

• Rash, wheezing, hives, swelling of lips and tongue,

shortness or loss breath which leads to anaphylactic
shock

• More prevalent in asthmatics

Aspirin – drug interactions
• Warfarin – potentiates effects by displacing drug
molecules from plasma proteins

• Probenecid and sulfinpyrazone – interferes with

uricosuric agents and reduces urate secretion

Aspirin – toxicity and overdose
• Chronic overdose is fatal in 25% of cases

• Nausea, vomiting, headaches, dizziness, impaired vision,

hyperthermia

• Administer activated charcoal

 Paracetamol
• Known as acetaminophen in the USA

• Weak anti-inflammatory activity, does not have gastric and

platelet effects

• Not usually classified as an NSAID but combined with

aspirin and various NSAIDs to treat pain, inflammation

and fever
Paracetamol
• Analgesic and antipyretic activity - Inhibits
prostaglandin synthesis in the CNS

• Weak anti-inflammatory activity - poor effect on

cyclooxygenase in peripheral tissues

• No effect on platelet function or blood clotting

Paracetamol
• Inhibit prostaglandin synthesis (central)
• Very weak COX-1, weak COX-2 inhibitor

• COX-3 inhibitor (found in CNS)

• Activation of descending serotonin pathway

Paracetamol - pharmacokinetics
• Given orally, rapidly absorbed from the GIT

• Peak plasma concentrations reached in 30-60 minutes

• Plasma half life of therapeutic doses is 2-4 hours

• Inactivated in the liver - conjugated with sulphate and

glucoronide

• N-acetyl-p-benzoquinone imine accumulation leads to liver

and kidney necrosis
 Paracetamol – therapeutic uses
• Used as first line of treatment for pain and where
aspirin is contraindicated

• Safe to use during pregnancy, nursing and in children

• Children with viral infections (no risk of Reye’s syndrome)

• Patients with gastric complaints or are prone to gastric

ulcers
 Paracetamol – adverse effects

• No significant adverse effects at normal therapeutic doses

• Fatal hepatotoxicity at toxic doses

• Renal tubular necrosis rare complication of prolonged, large

dose therapy

• Skin rash and minor allergic reactions occur infrequently

• Contraindicated in patients with severe hepatic impairment

 Take home questions
1. Classify the following NSAIDs according to their COX inhibitory
effects:
• Meloxicam
• Aspirin
• Ibuprofen
• Etoricoxib

2. Describe the mechanism of action of Aspirin.