Non-Steroidal AntiInflammatory Drugs (NSAIDs)
Scott Kaba Matafwali
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Inflammation
• Inflammation is a complex protective response of the
organism to injury caused by damaging agents.
– noxious agents, infections, physical injuries
• It is aimed at inactivation or removal of these agents
and promoting healing.
• The traditional names for signs of inflammation come
from Latin:
• Dolor (pain)
• Calor (heat)
• Rubor (redness)
• Tumor (swelling)
• Functio laesa (loss of function)
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Inflammation
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Mediators of inflammation
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Prostaglandins
Bradykinin
Serotonin
Histamine
Interleukins 2, 6, 10, 12,13
Platelet activating factor
Gamma-Interferon
Tumor Necrosis Factor
Transforming Growth Factor
Lymphotoxin
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Pain
• Nociceptors, peripheral terminals of
primary afferent fibers that sense pain can
be activated by various stimuli
– such as heat, acids, or pressure
• Centrally active PGE2 and perhaps also
PGD2, PGI2, and PGF2α contribute to
central sensitization
– an increase in excitability of spinal dorsal horn
neurons that causes hyperalgesia and
allodynia
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Fever
• The hypothalamus regulates the set point
at which body temperature is maintained.
• This set point is elevated due
– an infection, tissue damage, inflammation,
graft rejection, malignancy.
• cytokines such as IL-1β, IL-6, TNF-α, act
as endogenous pyrogens.
• PGE2 is released which in turns acts on
the hypothalamus and causes heat
generating effects
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Role of Prostaglandins
PATHOLOGIC
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fever
asthma
ulcers
diarrhea
dysmenorrhea
inflammation
bone erosion
pain
PHYSIOLOGIC
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temperature control
bronchial tone
cytoprotection
intestinal mobility
myometrial tone
• semen viability
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PG biosynthesis
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Cox1 vs cox2
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Mechanism of NSAIDs
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NSAIDs
• Drugs provide symptomatic relief from fever,
pain and swelling.
• Used for osteo-and rheumatoid arthritis,
fractures, headaches, etc.
• NSAIDs, sometimes called “aspirin-like
drugs” or “antipyretic analgesics”,
• Are among the most widely used of all
agents.
• Effects: Analgesic, Antipyretic, Antiinflammatory
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NSAIDs –classification
Nonselective COX inhibitors
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1. Salicylates
*Acetylsalicylic acid (Aspirin)
* Salicylamide
2. Pyrazolone derivatives
*Phenylbutazone
*Metamizol (Analginum)
3. Indole derivatives
*Indomethacin
4. Propionic acid derivatives
*Naproxen
*ibuprofen
• 5. Antranilic acid
derivatives
• *Mefenamic acid
• 6. Aryl – acetic acid
derivatives
• *Diclofenac sodium
• sulindac
• 7. Oxicam derivatives
• *Piroxicam
• 8. Dihydropyrrolizine
carboxylic acid derivative
• *Ketorolac
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Selective COX inhibitors
• Preferential COX-2 inhibitors
• Nimesulide
• Meloxicam
• Nabumeton
• Selective COX-2 inhibitors
• Celecoxib
• Parecoxib
• Rofecoxib
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Classification
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Mechanism of action of NSAIDs
• Act by inhibiting CycloOXygenases
(COX) => no PG production
• Effects
– PAIN: PGs do not cause pain, but sensitize
nocireceptors to stimulation
– FEVER: IL-1 released from activated
macrophages (bacteria, etc.) induces COX-2
in the brain =>PG E produced => affects
thermoregulation => fever=> NSAIDs antipyretic effects
– INFLAMMATION: Reduce superoxides from
neutrophils – reduce inflammation (over about
3 weeks)
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Other effects
• Fetal Circulatory System
– The PGs are implicated in the maintenance of
patency of the ductus arteriosus
– indomethacin, ibuprofen, and other NSAIDs
have been used in neonates to close the
inappropriately patent ductus.
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NSAIDs and Platelets/Endothelial Cells
• Reduces platelet aggregation
• Have cardioprotective properties
• Most of these drugs will potentiate the
action of oral anticoagulants such as
wafarin, by their effects on platelet
aggregation
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NSAIDs - Gastric Irritant Effects
• PGs reduce H+ secretion and increase
mucous production
• Consequently, NSAIDs cause some
degree of gastric upset due to inhibition of
PG synthesis
• PPIs can reduce the risk of peptic ulcer
formation
• Misoprostol - a synthetic prostaglandin
analogue, can also decrease the risk of
NSAID-induced ulceration and
complications
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Clinical uses of NSAIDs
• Pain: headache, toothache, myalgia,
backpain;
• Fever;
• Arthritises: rheumatiod arthritis,
osteoarthritis, gout, ankylosing spondylitis;
• Dysmenorrhoea (especially ibuprofen);
• Unclosure of ductus arteriosus (especially
aspirin);
• Prevention of MI, stroke, (aspirin);
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Common Adverse Effects
• Platelet Dysfunction
• Gastritis and peptic ulceration with
bleeding (inhibition of PGs)
• Acute Renal Failure, nephropathy
• Sodium + water retention and edema
• Prolongation of gestation and inhibition of
labor.
• Hypersensitivity (due to PG inhibition)
• GIT bleeding and perforation
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Contraindications
• Pregnancy
• prolongs gestation,labour
• Closes the ductus in the fetus
• Haemophilic patients
• Hypersensitivity reactions
• Peptic ulcers*
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Aspirin
• History
– Salicylates were first discovered when the
observation was made that chewing willow
bark could relieve pain
– Hippocrates: Willow bark as a pain killer
during childbirth
– Stone (1700) Extract of willow bark to reduce
fever
– Piria (1838) Isolation of salicin from willow
bark
– Kolbe (1853) Synthesis of salicylate from
salicin
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Aspirin-Mechanism of Action
• ASA covalently and irreversibly
modifies both COX-1 and COX-2 by
– acetylating serine-530 in the active site
• Acetylation results in a steric block,
preventing arachidonic acid from binding
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Aspirin
• Dose-Dependent Effects:
• Low: < 300mg
- blocks platelet aggregation
• Intermediate: 300-2400mg/day
- antipyretic and analgesic effects
• High: 2400-4000mg/day
- anti-inflammatory effects
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ASPIRIN - Therapeutic Uses
• Antipyretic, analgesic.
• Anti-inflammatory: rheumatic fever, rheumatoid
arthritis (joint disease). 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. E.g M.I
• Pre-eclampsia and hypertension in pregnancy
(excess TXA2).
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Side effects of Aspirin
• Salicylism
- dose >5g/d: CNS symptoms, including mental
confusion; hyperventilation.
- remedy: I.V. NaHCO3 promote the excretion
• Hepatic damage
Overdose:
- hepatic damage
- Reye’s syndrome (kids)
- encephalopathy
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Ibuprofen
• Propionic Acid Derivative
• The same mechanism & pharmacological
actions of aspirin Except that it is
reversible inhibitor for COX enzymes
• More potent as anti-inflammatory than
aspirin
• Clinical uses: Analgesic, Antipyretic, Antiinflammatory, Acute gouty arthritis, patent
ductus arteriosus
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Preparations of Ibuprofen
• Oral preparations.
• Topical cream for osteoarthritis.
• A liquid gel for rapid relief of postsurgical
dental pain.
• Intravenous route as in patent ductus
arteriosus
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Contraindications - ibuprofen
• The concomitant administration of
ibuprofen antagonizes the irreversible
platelet inhibition of ASPIRIN (limit
cardioprotective effect of aspirin).
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Diclofenac
• Phenylacetic acid derivative
• Mechanism of action
• Non-selective inhibitor to COX1 & COX2.
• More potent as anti-inflammatory than
analgesic and antipyretics.
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Clinical uses-DICLOFENAC
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Any inflammatory conditions
Musculoskeletal pain
Dysmenorrhoea
Acute gouty arthritis
Fever
Locally to prevent or treat post ophthalmic
inflammation
• A topical gel for solar keratoses
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Preparations of DICLOFENAC
• Diclofenac with misoprostol decreases upper
gastrointestinal ulceration,
• Diclofenac with omeprazole to prevent recurrent
bleeding.
• 1% ophthalmic preparation for postoperative
ophthalmic inflammation.
• A topical gel 3% for solar keratoses.
• Rectal suppository as analgesic or for
postoperative nausea.
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Selective COX 2 inhibitors
• Advantages:
– Potent anti-inflammatory.
– Have analgesic & antipyretic properties.
– Lower incidence of gastric upset.
– No effect on platelet aggregation (COX1).
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Selective Cox 2 inhibitors
Disadvantages;
• Renal toxicities (they are not
recommended for patients with
severe renal insufficiency).
• High incidence of cardiovascular
thrombotic events with some of them
such as ROFECOXIB.
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Paracetamol
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analgesia
antipyretic
no significant anti-inflammatory effects
MOA: non-selective COX inhibitor, which acts at the
peroxide site of the enzyme.
• PK :rapidly absorbed in the GUT
– Metabolised by conjugation
– A small portion undergoes CYP-mediated N-hydroxylation to
form NAPQI
– NAPQI is detoxified by Glutathione(GSH)
– In paracetamol toxicity- the GSH is depleted and NAPQI causes
toxic effects
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Paracetamol
• The conventional oral dose is 300-1000mg
every 4–6h; total daily doses should not
exceed 4g
• Dosage forms: suppositories, tab, syrups
• Advantages over NSAIDs
– no gastric irritation
– no platelet function interference
– not contraindicated for asthma
– not associated with Reye’s Syndrome
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Toxicity management
• In adults, hepatotoxicity may occur after
ingestion of a single dose of 10–15 g (150–250
mg/kg); doses of 20–25 g or more are potentially
fatal.
– Activated charcoal, if given within 4h of ingestion,
decreases absorption by 50%–90% and should be
administered if
• the ingested dose is suspected to exceed 7.5 g.
– N-acetylcyctiene (NAC) is indicated for those at risk of
hepatic injury.
– NAC detoxifys NAPQI. It both repletes GSH stores
and may conjugate directly with NAPQI by serving as
a GSH substitute.
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– Including other supportive therapies
Thank you
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