Pharmacology PharmEd
Non-Steroidal Anti Inflammatory Drugs (NSAIDs)
Inflammation
Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious
chemicals or microbiologic agents
Inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants and set
the stage for tissue repair
When healing is complete, the inflammatory process usually subsides
Following tissue injury or irritation enzyme called Phospholipase A2 is released
This enzyme converts phospholipids in cell membrane in to arachidonic acid
Cyclo-oxygenase (cox) catalyzes the formation of prostaglandins and thromboxanes from arachidoinc
acid
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Pharmacology PharmEd
Nonsteroidal anti-inflammatory Drugs
Act primarily by inhibiting the cyclooxygenase enzymes which are used to synthesis prostaglandins
By reducing production of prostaglandins, NSAIDs help relieve the discomfort of fever and reduce
inflammation and the associated fever
Pharmacokinetics of NSAIDs
Weak acids
Well absorbed through stomach and intestinal mucosa
Highly plasma protein bound (>95%) –usually to albumin
Metabolized by liver CYP450 system
Mainly excreted by the kidneys and some drugs are partially excreted in bile
Effects of NSAIDs
Analgesia –effective against pain of mild to moderate intensity
Anti-inflammatory action
Antipyretic action – block prostaglandin synthesis in the hypothalamus
Platelet function – protection against vascular occlusion
Prolongation of gestation and labour – enhance prostaglandin synthesis by the uterus prior to
parturition
Patency of the ductus arteriosus –patency is maintained by prostaglandins
Gastric and mucosal damage – common side effect
Urticarial, rhinitis, asthma – in susceptible individuals
Renal effects
Clinical uses of NSAIDs
Indicated in the treatment of acute or chronic conditions – pain and inflammation
Used in symptomatic relief of the following conditions
Rheumatoid arthritis, osteoarthritis
Inflammatory arthropathies
Acute gout
Dysmenorrhea, headache syndromes, migraine
Metastatic bone pain, postoperative pain, ileus, renal colic
Mild to moderate pain due to inflammation and tissue injury
Pyrexia
Neonates / infants –ductus arteriosus does not close within 24 hours of birth
Doses and administration of NSAIDs
Differences in anti-inflammatory activity between NSAIDs are small but response to NSAIDs can vary
between two people
Lower doses are adequate for most people to relieve pain
Drugs can be taken on a regular basis or when the pain occurs
Higher doses are needed to treat inflammation and must be taken on a regular basis for 2 – 4 weeks
before benefit occurs
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Pharmacology PharmEd
Patients taking one NSAID should never take a 2nd NSAID at the same time for relief of pain or
inflammation
NSAIDs should always be taken after meals and never on an empty stomach
The risk of causing irritation to the stomach and bleeding from it are reduced when NSAIDs are taken
with meals
Adverse effects
Effects are dose-dependent
GI S/Es
Inhibition of Cox-1 reduces level of protective prostaglandins so acidic molecules directly irritate
the gastric mucosa
GI discomfort, , nausea, diarrhea and occasionally bleeding (less with ibuprofen and diclofenac) and
ulceration
Risk factors for NSAIDs induced ulcers
Use of toxic NSAIDs – Eg: indomethacin, ketoprofen, piroxicam
High dose of NSAIDs
Concurrent use of NSAIDs
Concurrent use of corticosteroids
History of peptic ulcer disease
NSAIDs should not be used in individuals with inflammatory bowel disease Eg: Crohn’s disease /
ulcerative colitis
Taking oral formulations with milk or food or using enteric coated formulations or changing the
route of administration may only partially reduce symptoms such as dyspepsia
Those at risk of duodenal or gastric ulceration who need to continue NSAID treatment should
receive either a selective inhibitor of Cox-2 alone or a non-selective NSAID with gastroprotective
treatment
Renal A/Es
Changes in renal haemodynamics (blood flow) normally mediated by prostaglandins, which are
affected by NSAIDs
Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli. This helps
maintain normal glomerular perfusion and GFR, an indicator of renal function. By blocking this
prostaglandin-mediated effect, NSAIDs ultimately may cause renal impairment
Salt and fluid retention (rarely precipitating congestive heart failure)
Renal impairment or failure – specially in combination with the other nephrotoxic agents and also if
the patient is concomitantly taking an ACEI and a diuretic
Cardiovascular A/Es
NSAIDs are associated with an increased risk of symptomatic heart failure (except low dose aspirin)
Cox-2 selective inhibitors are associated with an increased risk of thrombotic events (myocardial
infarction and stroke)
Non-selective NSAIDs may also be associated with a small increased risk of thrombotic events
particularly when used at high doses and long
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Pharmacology PharmEd
Hypertension
Aspirin is used in the prevention and treatment of ACS
CNS A/E
Most NSAIDs penetrate poorly into the CNS
Headache, dizziness, nervousness, drowsiness, confusion, depression, insomnia, vertigo
Somnolence
In very rare cases ibuprofen can cause aseptic meningitis
Others
Photosensitivity, rashes, Stevens-Johnson syndrome
Raised liver enzymes, hepatic injury
Hyperkalaemia
Bronchospasm
Hearing disturbances such as tinnitus
Use of NSAIDs in pregnancy and breast feeding
Not recommended during pregnancy, especially in 3rd trimester
NSAIDs are
Not direct teratogens
May cause premature closure of the fetal ductus arteriosus and renal effects in the fetus
1. Aspirin (Acetylsalicylic acid)
First discovered member of the class of drugs known as NSAIDs
MOA: cyclooxygenase (Cox) is required for prostaglandin and thromboxane synthesis
Aspirin irreversibly inactivates Cox (other NSAIDs reversibly inactivate Cox)
Aspirin is recommended in high dose (300mg) for its anti-inflammatory action
Use of low dose, long term aspirin irreversibly blocks formation of thromboxane A2 in platelets- an
inhibitory effect on platelet aggregation
Principle effects
Anti-inflammatory : rheumatoid disease, acute rheumatoid fever
Analgesic : relieves mild to moderate pain of visceral origin , headache, dysmenorrhea
Antiplatelet effect
Antipyresis
Respiratory stimulation
Metabolic effects
Pharmacokinetics
Weak acid –very little is ionized in the stomach after oral administration
Unionized drug molecules are passively absorbed from the stomach and small intestine
Aspirin absorbed more slowly during overdose and plasma concentration can continue to rise for
up to 24 hours after ingestion
50 – 80% bound to protein and protein binding is concentration dependent
Metabolized in the liver and excreted by the kidneys as salicyluric acid and free salicylic acid
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Pharmacology PharmEd
Adverse effects
GIT : heartburn, vomiting, superficial gastric erosions. Bleeding
Allergy
Salicylism (in high doses) – headache, dizziness, confusion, tinnitus, hearing difficulty
Reye’s syndrome : encephalopathy, liver injury in children recovering from acute viral infections
Should not be taken for at least 1 week prior to surgery
Overdose
Moderate overdose : nausea, vomiting, epigestric discomfort, tinnitus, deafness, headache,
pyrexia, sweating, restlessness
Severe overdose : pulmonary oedema, convulsions, coma, severe dehydration, ketosis,
metabolic changes
2. Diclofenac
Used in osteoarthritis, rheumatoid arthritis, pain, migraine, dysmenorrhea, ankylosing spondylitis
Used for dental pain
Dosage forms available : tablets(25mg, 50mg, 75mg, 100mg), suppositories, dispersible tablets,
injection solutions, modified release tablets and capsules, gastro-resistant tablets, gel, gel patch,
spray, cutaneous solution
3. Ibuprofen
Is a propionic acid derivative
Has anti-inflammatory, analgesic and antipyretic properties
Used in osteoarthritis, rheumatoid arthritis, pain, dysmenorrhea, migraine, postoperative analgesia,
fever and pain in children
Used for dental pain
Has weaker anti-inflammatory properties
Fewer side effects than other non-selective NSAIDs
Dexibuprofen is the active enantiomer of ibuprofen
Dosage forms available : Tablets and capsules (200mg, 400mg), oral suspension (100mg/5ml), syrup,
granules, gel, cream
4. Indomethacin
Non selective Cox inhibitor
Used in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain, acute gout, tendonitis,
dysmenorrhea, closure of ductus arteriousus, premature labour
Dosage forms available : capsules, suppositories
5. Mefenamic acid
Has minor anti-inflammatory properties
Used in dysmenorrhea, mild to moderate pain, RA, OA, postoperative pain
It has occasionally been associated with diarrhea and haemolytic anaemia which require
discontinuation of treatment
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Pharmacology PharmEd
Dosage forms available : Tablet (100mg, 250mg, 500mg), capsule, suspension, (suppository)
6. Meloxicam
Short term relief of pain in OA and for long term treatment of RA and ankylosing spondylitis
Dosage forms available : tablet, capsule (7.5mg, 15mg)
7. Naproxen
Dosage forms available : tablets and gastro-resistant tablets (250mg, 500mg)
8. Celecoxib
Used in osteoarthritis, rheumatoid arthritis, pain, dysmenorrhea, ankylosing spondylitis
Selective Cox-2 inhibitor
Effective as diclofenac and neproxane
Dosage forms available : capsule (100mg, 200mg)
Other NSAIDs
Ketoprofen : gel, injection
Nabumetone : tablet (500mg)
Piroxicam : tablet and capsule (20mg), gel
Sulindac : tablet (100mg, 200mg)
Tenoxicam : tablet (20mg)
Ketorolac : tablet, eye drop, injection, ophthalmic solution
Etoricoxib : tablet (60, 90, 120mg)
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