NSAIDs

NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS

Maher Khdour MSc. PhD.

Clinical Pharmacy
NSAIDs
 Large and chemically diverse group of
drugs with the following properties:
 Analgesic
 Antiinflammatory
 Antipyretic
NSAIDs: Mechanism of Action
 Activation of the arachidonic acid
pathway causes:
 Pain
 Headache

 Fever

 Inflammation
NSAIDs: Mechanism of Action
 Analgesia—treatment of headaches and
pain
 Block the undesirable effects of
prostaglandins, which cause headaches
NSAIDs: Mechanism of Action
Antipyretic: reduce fever
 Inhibit prostaglandin E2 within the area of the
brain that controls temperature
NSAIDs: Mechanism of Action
Relief of inflammation
 Inhibit the leukotriene pathway, the
prostaglandin pathway, or both
Arachidonic Acid Pathway
Gastric Mucosa

Mucosal COX-1

PGE2 and PGI2

 acid Mucosal protection

 from peptic ulcers
mucus
Thromboxane A2 in Platelets

Platelet COX-1

Tx A2

Platelet aggregation
& activation
Renal Circulation

 Renal Blood Flow

Pg E2

 Renal Blood Flow

 Two Forms of Cyclooxygenase
Cyclooxygenase-1 (COX-1) Cyclooxygenase-2 (COX-2)
• Produces prostanoids
 Produces prostanoids
that mediate that mediate
homeostatic functions inflammation, pain, and
 Constitutive fever
• Induced
 Kidney
 Platelets
 Sites of inflammation
 Vascular endothelium
 Brain
 Kidney
COX Inhibitor Actions
Arachidonic  Anti-inflammatory
acid  Analgesic
 Antipyretic
 Gastrointestinal toxicity
 Renal toxicity
 Platelet impairment
COX-1 COX-1 COX-2

Mediate
Support renal and
inflammation, pain,
platelet function Protect and fever
gastroduodenal
mucosa
 NSAID Analgesic Effect
 Central mechanisms (in the spinal cord)
 NSAIDs are effective in:
 Arthritis
 Pain of muscular and vascular origin
 Headache, toothache
 In combination with opioids: decrease in
postoperative pain
 Antiinflammatory Effect
 NSAIDs reduce mainly components of the
inflammatory and immune response in
which the products of COX-2 action play a
significant part:

 Vasodilatation
 Edema

 Pain
 Unwanted effects: GI Disturbances
 Diarrhea, nausea, vomiting

 One in five chronic users: gastric damage

(risk of serious hemorrhage and/or
perforation)

 PGs inhibit acid secretion and have protecting

action on the gastric mucosa
 Unwanted Effects
 Skin reactions (from mild rashes, urticaria to
more serious reactions)
 Renal reactions acute renal insufficiency
reversible on stopping the drug (due to
inhibition of PGE2 mediated compensatory
vasodilatation that occurs in response to NE
and ANG II)
 NSAIDs
Six structurally related groups:
 Acetic acids
 Carboxylic acids
 Propionic acids
 Enolic acids
 Fenamic acids
 Nonacidic compounds
NSAIDs: Acetic Acid
 diclofenac sodium (Voltaren)
 diclofenac potassium (Cataflam)
 etodolac (Lodine)
 indomethacin (Indocin)
NSAIDs: Carboxylic Acids
Acetylated
 Aspirin (ASA)
 choline magnesium salicylate (Trilisate)
 diflunisal (Dolobid)

Nonacetylated
 salicylamide
 salsalate (Disalcid)
 Sodium salicylate
NSAIDs: Propionic Acids
 Ibuprofen (Motrin, others)
 ketoprofen (Orudis)
 ketorolac (Toradol)
 naproxen (Naprosyn)
 oxaprozin (Daypro)
NSAIDs: Other Agents
Enolic acids
 phenylbutazone (Butazolidin)
 piroxicam (Feldene)

Fenamic acids
 meclofenamic acid (Meclomen)
 mefenamic acid (Ponstel)

Nonacidic compounds
 nabumetone (Relafen)
NSAIDs: Other Agents
COX-2 inhibitors
 celecoxib (Celebrex®)

 Rofecoxib vioox® [withdrawal 2004]

Salicylates
 Prototype

 Aspirin
 Acetylsalicylic acid
Salicylates
 Non-aspirin salicylates: magnesium salicylate;
choline salicylate; choline magnesium
salicylate; Sodium salicylate.

 Cause less bleeding.

 May not be as effective as aspirin.

 Salsalate (Disalcid).
 Dimer of salicylic acid.

 Absorbed primarily from lower intestine -

less G.I. Irritation.

Salicylates
 Mechanism of action.
 Inhibits prostaglandin synthesis by blocking

expression of cyclooxygenase.

 Therapeutic effects.
 Analgesia.

 Good for low intensity, somatic pain.

 PGE1 sensitizes pain receptors, salicylates

decrease PG synthesis.
Drug interactions
 Aspirin Pharmacokinetics

Biotransformation: aspirin is deacetylated to

salicylic acid (73% in 30 min); salicylurate (glycine
conjugate) and salicyl phenolic glucuronide are
saturable reactions; Aspirin follows dose-
dependent kinetics.
 Aspirin Pharmacokinetics
 Distribution: 50-90% bound to plasma albumin
 Plasma half life for aspirin = 15 min, for salicylate at
low dose = 3-5 hrs, for salicylate at high dose = 15
- 30 hr.
 Excretion: both filtered and secreted (active);
Excretion pH-dependent because back-diffusion is
pH dependent (pKa of salicylic acid is 3.0, aspirin is
3.5). 30% excretion in alkaline urine, 2% in acidic
urine.
 Side Effects
GI tract: gastric ulceration and bleeding.
 Mechanism: local irritation, increased back

diffusion of H+, and increased acid secretion (both

result from decreased PG synthesis).
 H blockers generally not effective in prevention or
2
treatment of gastroduodenal ulcer problems.
Proton pump inhibitors like omeprazole are
effective at treating and /or preventing mucosal
injury.
 Side Effects
Aspirin hypersensitivity.
 Resembles hypersensitivity reactions, but aspirin
intolerance is not true hypersensitivity (caused by
increased formation of leukotrienes).
 Incidence: very low (0.2 to 0.9%) in general
population, may be as high as 20-25% in patients
with asthma, nasal polyps and chronic urticaria.
 Cross sensitivity to other nonsteroidal anti-
inflammatory agents, e.g. indomethacin, is
common.
 Side Effects
Blood.
 Decreases platelet aggregation; acetylation of

platelet cyclooxygenase (COX-1) by low doses of

aspirin irreversibly prevents thromboxane
synthesis for life of platelet (8 days).

 Aspirin contraindicated in patients with severe

hepatic damage, hypoprothrombinemia, vitamin K
deficiency, or hemophilia.
 Side Effects
Reye's syndrome –.
 Sudden loss of consciousness, cerebral

edema, fatty liver and renal tubules, and brain

damage upon recovery.
 Use in Pregnancy: Caution,
Particularly During Last Trimester
 May prolong labor.
 May increase bleeding.
 Reduced birth weight if taken throughout
pregnancy.
 Drug Interactions
 Oral anticoagulants:
 decreased prothrombin, decreased platelet

aggregation
 GI effects increase bleeding;

 displaces anticoagulants from plasma protein

binding-- displaces other drugs.

 Salicylate Intoxication (20-30g Mean
Lethal Dose-adults; 250 Mg/kg -
Children.
 Tinnitis and hearing difficulty.
 Confusion and convulsions seen with toxic
doses.
 Hyperventilation because of direct effect on
medulla
 Bleeding, nausea and vomiting, dehydration,
K+ depletion, increased half-life.
 Salicylate Intoxication (20-30g Mean
Lethal Dose-adults; 250 Mg/kg -
Children.
Acid-base.
 Adults: early respiratory alkalosis (from

hyperventilation) followed by later respiratory and

metabolic acidosis.
 Infants: respiratory alkalosis usually not seen; pH

normal or acid.

Treatment.
 Symptomatic, but alkalinization of urine helps (high

pH decreases back diffusion).

 Indications:
 Antiplatelet effects:  0.1 g/day

 Analgesic effects:  0.5 g 4-6times/day

for short-term
analgesia

 Antiinflammatory  3.5 - 4 g/day

effects: for long-
term treatment
 Acetaminophen: Therapeutic Effects
Analgesia.
 Comparable with aspirin.

 Mechanism probably central PG synthesis inhibition, very

weak in peripheral PG synthesis inhibition.

Antipyretic:
 to lower temperature paracetamol is preferred

because it lacks GIT unwanted effects and unlike

aspirin, has not been associated with Reye´s
syndrome in children
 Intoxication: Hepatic Necrosis
 A major problem.

 10 g causes injury; 15 g probably fatal.

 Mechanism: acetaminophen converted to n-acetyl-

benzoquinoneimine -- Bioactivation by P450 (CYP2E1,
induced by alcohol).
 Intoxication
 Symptoms: initial are nausea and vomiting, diarrhea,
abdominal pain; Hepatic injury - elevations of liver
enzymes and prothrombin time; Renal failure due to
acute tubular necrosis may also occur.

 Half-life of drug increases with liver damage. Hepatic

necrosis will occur if half-life exceeds 4 hr; Hepatic
coma likely if half-life exceeds 12 hr (normal half-life is
2-3 hr).
 Acetaminophen / PARACETAMOL
an analgesic-antipyretic agent
given orally, metabolised in liver (t1/2 =2-4 h)

toxic doses (>5g) cause nausea and vomiting, then, after 24-48 h,
potentially fatal liver damage by saturating normal conjugating
enzymes causing the drug to be converted by mixed function
oxidases to N-acetyl-p-benzoquinone imine. It this is not inactivated

by conjugation with glutathione (in alcohol abusers), it reacts with

cell proteins and kills the cells (hepatocytes)
Agents which increase glutathion: acetylcystein i.v. or
methionin orally can prevent liver damage if given early
 Propionic Acid Derivatives
 Most famous: Ibuprofen
 Others: Naproxen, Ketoprofen, Flurbiprofen, and
oxaprozin
 Analgesic, anti-inflammatory, antipyretic
 Wide acceptance in chronic use for rheumatoid
and Osteo-arthritis.
 GI side effects less intense than aspirin
 Well absorbed, highly protein bound, hepatic
metabolism
 ADR: GI, Tinnitus, Dizziness
 Propionic Acid Derivatives:
IBUPROFEN
 Analgesic, antipyretic and antiinflammatory
action with reasonable gastric toxicity

 Used for acute pain and short-term analgesia

 For antiinflammatory effects in acute or chronic

inflammatory conditions (e.g. rheumatoid
arthritis and related connective tissue disorders)

 Given in higher doses than that for simple

analgesia and treatment may need to be
continued for long period
 Dicolfenac
 Immediate-Release Tablets,
 Delayed-Release (enteric coated) (Voltaren®)

 Extended-Release Tablets (Voltaren-XR®)

 anti-inflammatory, analgesic, and antipyretic

 Indicated for chronic therapy of osteoarthritis and

rheumatoid arthritis
 For management of pain and primary dysmenorrhea

Misoprostol (Cytotec) –.
 Prostaglandin used to decrease GI inflammation with
salicylates or NSAIDS.
 Overused and expensive, side effects include nausea and
severe diarrhea.
Diclofenac Injectable
 Not Approved in US
 Intramuscular injection
 renal colic and biliary colic;
 severe migraine attacks
 Intravenous Injections:
 Never Bolus
 IV Infusion for moderate to severe post-
operative pain
 Other NSAID’s
 Phenylbutazone: additional uricosuric effect.
ADR: agranulocytosis, aplastic anemia.
 Indomethacin: more potent anti-inflammatory,
side effects limit its use.
 Common ADR’s. CNS: halucinations, depression,
seizures; GI abdominal pain.
 Clinical use in short term treatment like gout
attacks.
 Side Effects
 GI Ulcerations and bleeding
 Renal:
 Patients with reduced renal blood flow or blood

volume, renal prostaglandins maintain renal

perfusion. NSAID results in a dose-dependent
decrease in prostaglandin synthesis thus in a
reduction of renal blood flow, which may
precipitate overt renal failure
 Hepatic: Elevation of Liver enzymes (monitor
occasionally)
 Severe, rarely fatal, anaphylactic-like reactions to
diclofenac have been reported in patients with aspirin
hypersensitivity
 Dipyrone (metamizole)
 Analgesic, antipyretic, anti-inflammatory
 Banned in US and UK
 Available in our country
 Optalgin®

 Analgin®

 Novalgin®

 Advocates: Short term use, low probability of risk

 Opponents: Efficacy similar to 400 mg Ibuprofen Why
take risk?
Chemical Class Prototype Analgesia Antipyresis Antiinflammatory

Salicylates Aspirin +++ +++ +++

Para-aminophenols Acetaminophen +++ +++ Marginal

Indoles Indomethacin +++ ++++ ++++

Pyrrol acetic acids Tolmentin, +++ +++ +++
mefenamic acid
Propionic acids Ibuprofen, ++++ +++ ++++
naproxen
Enolic acids Phenylbutazone, +++ +++ ++++
piroxicam
Alkanones Nabumetone ++ ++ +++
Sulfonamide Celecoxib ++++ +++ ++++
 Sulindac, tolmetin, Ketorolac
 Sulindac:
 is a prodrug that is oxidized to a sulfone and then to the active sulfide
 has a relatively long t1/2 (16 h) because of enterohepatic cycling.
 Tolmetin:
 has minimal effect on platelet aggregation;
 it is associated with a higher incidence of anaphylaxis than other
NSAIDs.
 Tolmetin has a relatively short t1/2 (1 h).
 Ketorolac:
 is a potent analgesic with moderate antiinflammatory activity
 can be administered:
 intravenously or

 topically in an ophthalmic solution.

Indomethacin
 Use: As anti-inflammatory
 Treatment of
 Ankylosing spondylitis

 Reiter syndrome

 Acute gouty arthritis.

 to speed the closure of patent ductus

arteriosus in premature infants (otherwise, it is
not used in children);
 it inhibits the production of prostaglandins that prevent
closure of the ductus.
Piroxicam
 Piroxicam is an oxicam derivative of enolic acid.
 Piroxicam has t1/2 of 45 hours.
 Like aspirin and indomethacin, bleeding and
ulceration are more likely with piroxicam than
with other NSAIDs.
Meclofenamate, mefenamic acid
 t1/2 of 2 hours.
 A relatively high incidence of
gastrointestinal disturbances is associated
with these agents.
 Nabumetone
 Compared with NSAIDs, nabumetone is associated
with reduced:
 inhibition of platelet function

 incidence of gastrointestinal bleeding.

 Nabumetone inhibits COX-2 more than COX-1.

Other NSAIDS include flurbiprofen, and

etodolac.
Flurbiprofen is also available for topical ophthalmic use.
 Cox-2 Selective Drugs
 Induction of COX-2 can increase 10 to 1000 folds as
a response to cytokines in inflammatory cells.
 Celecoxib (Celebrex®) & Etoricoxib (Arcoxia®).
 Anti-inflammatory efficacy with celecoxib is the same
as naproxen (500 mg b.i.d.) with gastroduodenal
ulceration of 7% (placebo was 4% and naproxin was
35%).
 Celecoxib is contraindicated to patients allergic to
sulfonamides.
 Other uses: trials for anticancer or anti-Alzheimer's
effect ongoing.
Selective COX-II
Inhibitors
 Anti-inflammatory with less adverse
effects, especially GI events.
 Potential toxicities:
 kidney and platelets?
 Increased risk of thrombotic events

reported with Rofecoxib (Vioxx®) led

to market withdrawal
VIGOR - Confirmed Thrombotic
Cardiovascular Events
Patients with Events (Rates per 100 Patient-Years)
Rofecoxib Naproxen Relative Risk
Event Category N=4047 N=4029 (95% CI)
Confirmed 45 (1.7) 19 (0.7) 0.42
CV events (0.25, 0.72)
Cardiac 28 (1.0) 10 (0.4) 0.36
events (0.17, 0.74)
Cerebrovascular 11 (0.4) 8 (0.3) 0.73
events (0.29, 1.80)
Peripheral 6 (0.2) 1 (0.04) 0.17
vascular events (0.00, 1.37)

Source: Data on file, MSD

 NSAIDs: Implications
 Before beginning therapy, assess for
conditions that may be contraindications to
therapy, especially:
 GI lesions or peptic ulcer disease.
 Bleeding disorders.
 Assess also for conditions that require
cautious use.
 Perform lab studies as indicated (cardiac,
renal, liver studies, CDC, platelet count).
 NSAIDs: Implications
 Perform a medication history to assess for
potential drug interactions.
 Several serious drug interactions exist:
 Alcohol.
 Heparin.
 phenytoin.
 Oral anticoagulants.
 Steroids.
 Sulfonamides.
NSAIDs: Implications
 Salicylates are NOT to be given to children
under age 12 because of the risk of Reye’s
syndrome.
 Because these agents generally cause GI
distress, they are often better tolerated if
taken with food, milk or an antacid to avoid
GI irritation.
 Explain to patients that therapeutic effects
may not be seen for 3 to 4 weeks.
NSAIDs: Implications
 Educate patients about the various side
effects of NSAIDs, and to notify their
physician if these effects become severe
or if bleeding or GI pain occur.
 Patients should watch closely for the
occurrence of any unusual bleeding,
such as in the stool.
 Enteric-coated tablets should not be
crushed or chewed.
NSAIDs: Implications
 Monitor for therapeutic effects, which
vary according to the condition being
treated:

Decrease in swelling, pain, stiffness,

and tenderness of a joint or muscle area