Nonsteroidal Anti-inflammatory Drugs
(NSAIDs)
Dr Zareen
Nonsteroidal anti-inflammatory drug
Non steroidal anti-inflammatory
drugs (NSAIDs ) are a drug class that groups
together provide
analgesic (pain-killing)
antipyretic (fever-reducing) effects
In higher doses, anti-inflammatory effects.
Medical uses
Osteoarthritis
Rheumatoid arthritis
Mild-to-moderate pain due to inflammation and
tissue injury
Inflammatory arthropathies (e.g., ankylosing
spondylitis, psoriatic arthritis, reactive arthritis)
Headache
Migraine
Acute gout
Dysmenorrhoea (menstrual pain)
Low back pain
Metastatic bone pain
Postoperative pain
Muscle stiffness and pain due to Parkinson's disease
Pyrexia (fever)
Ileus
Renal colic
They are also given to neonate infants whose ductus
arteriosus is not closed within 24 hours of birth
Macular edema
NSAID
Analgesic
Antipyretic
Anti-inflammatory (at higher doses)
Anti-Platelets
Common Pharmacological Effects
Analgesic (CNS and peripheral effect) may involve non-
PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (except acetaminophen) due mainly
to PG inhibition.
Some shown to inhibit activation, aggregation, adhesion of
neutrophils & release of lysosomal enzymes
Some are Uricosuric
Pharmacological Effects
Diverse group of chemicals, but all inhibit cyclooxygenase.
Resultant inhibition of PG synthesis is largely responsible for
their therapeutic effects.
But, inhibition of PG synthase in gastric mucosa GIT
damage (dyspepsia, gastritis).
Common Adverse Effects
Platelet Dysfunction
Gastritis and peptic ulceration with bleeding (inhibition
of PG + other effects)
Acute Renal Failure is susceptible
Sodium+ water retention and edema
Analgesic nephropathy
Prolongation of gestation and inhibition of labor.
Hypersenstivity (not immunologic but due to PG
inhibition)
GIT bleeding and perforation
NSAID
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of neutrophils
↑ Leukocyte-Endothelial
Interactions
Capillary Proteases +
Obstruction Oxygen Radicals
Ischemic Endo/Epithelial
Cell Injury Cell Injury
Mucosal Ulceration
Cyclo-oxygenase (COX)
Exists in the tissue as constitutive isoform (COX-1).
At site of inflammation, cytokines induce 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.
COX
Celecoxib, etoricoxib, valdecoxib – selective COX-2
inhibitors.
Have similar efficacies to that of the non-selective inhibitors,
but the GIT side effects are decr by ~50%.
Cardiovascular
• Platelets: Inhibition of platelet COX-1-derived TxA2 with
the net effect of increasing bleeding time (inhibition of
platelet aggregation)
• Endothelial COX-2 derived PGI2 can inhibit platelet
aggregation (inhibition augments aggregation by TxA2).
Aspirin (acetylsalicylic acid) covalently modifies and,
irreversibly inhibits platelet COX. The enzyme is inhibited
for the lifetime of the platelet (~8 -11 days). Effect achieved
at very low dose.
• Basis of therapeutic efficacy in stroke and MI (reduces mortality and
prevents recurrent events).
Additional Cardiovascular Considerations
Blood vessels/smooth muscle
COX-2 derived PGI2 can antagonize catecholamine- and
angiotensin II-induced vasoconstriction (NSAIDs can elevate bp).
• Atherosclerosis
Inhibition of COX-2 can destabilize atherosclerotic plaques (due
to its anti-inflammatory actions)
Gastrointestinal
PGs (generated via COX-1)
1) inhibit stomach acid secretion,
2) stimulate mucus and HCO3- secretion, vasodilation and
therefore,
3) are cytoprotective for the gastric mucosa.
Therefore, NSAIDs with COX-1 inhibitory activity will
produce opposite effects, leading to:
Gastric distress, gastric bleeding, sudden acute hemorrhage
(effects are dose-dependent)
Gestation
PGs (generated from COX-2) are involved in the initiation and
progression of labor and delivery. Therefore, inhibition of
their production by NSAIDs can prolong gestation.
Respiratory system
High doses (salicylates) cause partial uncoupling of oxidative
phosphorylation with increased CO2 production (COX-
independent effects). Increase in plasma CO2
hyperventilation. Even higher doses cause depression of
respiration.
Decreased risk of fatal colon carcinoma
1. The Salicylates - Aspirin
Effect on Respiration: triphasic
1. Low doses: uncoupling phosphorylation → ↑ CO2 →
stimulates respiration.
2. Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal
compensation
The Salicylates - Aspirin
Duration of action ~ 4 hr.
Orally taken.
Weak acid (pKa ~ 3.5); so, non-ionized in stomach easily
absorbed.
Hydrolyzed by esterases in tissues and blood to salicylate
(active) and acetic acid.
Most salicylate is converted in liver to H2O-sol conjugates
that are rapidly excreted by kidneys.
Generation of Lipoxins by Aspirin
Aspirin - Therapeutic Uses
Antipyretic, analgesic
Anti-inflammatory: rheumatic fever, rheumatoid arthritis
(joint dis), other rheumatological diseases. High dose
needed (5-8 g/day).
But many pts cannot tolerate these doses (GIT); so,
proprionic acid derivatives, ibuprofen, naproxen tried
first.
Prophylaxis of diseases due to platelet aggregation (
post-op DVT)
Pre-eclampsia and hypertension of pregnancy
REY’S SYNDROME
Aspirin when giving during viral infection.
Esp in children it produce Reye’s syndrome
characterized by hepatiits & cerebral edema.
In viral infection acetaminophen must be given.
Contraindications
HEMOPHILIA
PEPTIC ULCER
Aspirin Toxicity - Salicylism
Headache - timmitus - dizziness – hearing impairment –
dim vision
Confusion and drowziness
Sweating and hyperventilation
Nausea, vomiting
Marked acid-base disturbances
Hyperpyrexia
Dehydration
Cardiovascular and respiratory collapse, coma
convulsions and death
Aspirin Toxicity - Treatment
Decrease absorption - activated charcoal, emetics, gastric
lavage
Enhance excretion – ion trapping (alkalinize urine), forced
diuresis, hemodialysis
Supportive measures - fluids, decrease temperature,
bicarbonate, electrolytes, glucose, etc…
Role of Lipoxins in Anti-inflammatory effects of Aspirin
Generation of Lipoxins by Aspirin
PARACETAMOL
Paracetemol (tylenol)
– no significant anti-inflammatory effect, but used for its
mild analgesic effect.
Well-absorbed and without GIT irritation.
Serious disadvantage: at high doses, severe hepatotoxicity
results.
Mechanisms of Action
Analgesia – both centrally and peripherally.
- assoc with anti-inflammatory actions.
- results from inhibition of PG synthesis in inflamed tissues.
- [PGs little pain relief themselves, but potentiate the pain
caused by other mediators of inflammation (e.g., histamine,
bradykinin).
Mechanisms of Action
Antipyretic actions – Fever, heat stroke, incr T° are
hypothalamic problems.
- Fever release of endog pyrogens (e.g., interleukin-1)
released from leucocytes acts directly on the
thermoregulatory centers in hypothalamus incr body T°.
- This is assoc with incr in brain PGs (pyrogenic).
- Paracetamol prevents the T°-rising effects of interleukin-1 by
preventing the incr in brain PGs.
Selective COX-2 Inhibitors
Anti-inflammatory with less adverse effects,
especially GI events.
Potential toxicities: kidney and platelets -
increased risk of thrombotic events.
Assoc with MI and stroke because they do not
inhibit platelet aggregation. Thus,.. should not
be given to patients with CV disease
Role in Cancer prevention
Role in Alzheimer’s disease
Effect of NSAID’s on Platelet-Endothelial Interactions
Other NSAIDs
Phenylbutazone: additional uricosuric effect. Aplastic
anemia.
Indomethacin: Common adverse rxns: gastric bleeding,
ulceration, CNS most common: hallucinations, depression,
seizures, headaches, dizziness.
Proprionic acids: better tolerated. Differ in
pharmacokinetics; ibuprofen, fenbufen, naproxen widely
used for inflammatory joint disease and few side-effects.
Acetaminophen: differs in effects and adverse rxn from rest.
Main toxicity: hepatitis due to toxic intermediate which
depletes glutathione. Treat with N-acetylcysteine.