Download NSAIDs - My UAG!

Dr. Eduardo D. Rosas Blum
Department of Pharmacology
A 5-year-old girl is brought to the emergency department
by her parents in a comatose state. Her parents refers that
she felt ill recently with high fever. Physical examination:
comatose, papilledema, hepatomegaly. A CT Scan reveals
cerebral edema.
What agent is most likely to be involved in this patient?
a) Aspirin
b) Acetaminophen
c) Codein
d) Celecoxib
e) Ibuprofen
“ Pain is an unpleasant sensory and
emotional experience associated with
actual or potential tissue damage or
described in terms of such damage”.
NSAIDs
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Relief of pain.
A major presenting symptoms in common
complaints.
Suppress the signs and symptoms of
inflammation.
Exert antipyretic and analgesic effect.
Useful in pain related to inflammation.
Pharmacokinetics
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Weak organic acids (nabumetone)
Well absorbed
Food doesn’t change their bioavailability.
Metabolized in phase I and II.
Also in CYP3A, CYP2C (part CYP450)
Renal, most important route of excretion. (biliary
excretion and absorption)
98% Bound to Albumin.
Found synovial fluid after repeating doses.
Pharmacodynamics
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Inhibition of biosynthesis of prostaglandins.
Inhibition chemotaxis, down-regulation of IL-1,
decrease production of free radicals.
Decrease sensitivity of vessels to bradykinin and
histamine.
Gastric irritants, nephrotoxity, hepatotoxicity.
Aspirin irreversibly blocks COX.
Aspirin® & Salicylates
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Acetylsalicylic Acid.
400 BC: Greek physician Hippocrates prescribes the
bark and leaves of the willow tree (rich salicin) to
relieve pain and fever.
1897: Chemist, Felix Hoffmann, at Bayer® in Germany,
synthesizes a stable form of ASA powder that relieves
his father's rheumatism.
The compound later becomes the active ingredient in
aspirin named - "a" from acetyl, "spir" from the spirea
plant (which yields salicin) and "in," a common suffix
for medications.
Pharmacokinetics
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pKa 3.5, rapidly absorbed in the stomach and upper
small bowel.
Short serum half-life (20 - 25min), peak plasma level 12hrs.
Bound to serum albumin 70%. Renal excretion.
As Aspirin dose increases the half-life increases. At low
doses its elimination follows “first order” kinetics. At
high doses, “zero-order” kinetics prevails.
Alkalinization of the urine increases the rate of
excretion.
Mechanism Actions
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Anti-inflammatory effect
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Irreversible non-selective COX inhibitor.
Inhibits platelet aggregation.
Interferes with the mediators of the kallikrein
system (bradykinins).
Inhibits chemotaxis of PMN leukocytes and
macrophages.
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Mechanism Actions
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Analgesic effect
Probably inhibits pain stimuli at a subcortical
site.
Antipyretic effect
COX inhibition in the CNS, inhibition of IL-1
(released in macrophages).
Mechanism Actions
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Antiplatelet effect
Low dose (81mg).
Irreversible non-selective COX inhibitor.
Inhibits TXA2 synthesis.
Effects last 8 – 10 days (platelet’s life).
Clinical Uses
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As analgesic to mild to moderate pain.
Combine with opiod analgesics for cancer pain.
As anti-inflammatory in rheumatoid arthritis
rheumatic, fever and inflammatory joint
conditions.
Antipyretic, when reducing the fever is desirable.
Prophylaxis of ischemic heart disease, to reduce
incidence of coronary artery disease.
Adverse Effects
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Gastrointestinal effects.
GI upset, Peptic ulcers, upper gastrointestinal
bleeding.
“Salicylism”
Nausea, vomiting, tinnitus, decrease hearing,
vertigo, hyperthermia, hyperventilation.
Adverse Effects
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Hepatotoxicity.
Elevation of liver enzymes, hepatitis.
Hypersensibility (Asthma, Rashes)
Renal toxicity (decrease function).
Changes in uric acid levels (low doses – high
serum levels)
Adverse Effects
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Reyes’s-like syndrome ( Hepatoencephalopathy)
highly lethal.
Avoid aspirin in children with influenza or
chickenpox infections (give Tylenol).
Aspirin Overdose
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Acid-base disturbance.
1st Respiratory Alkalosis (low levels).
Direct effect on the CNS respiratory centers and
as a compensatory mechanism of a metabolic
acidosis.
2nd Metabolic Acidosis (High levels)
Depletion of HCO3, accumulation of salicylic
acids derivatives, respiratory depression.
3rd Mixed Acidosis (respiratory and metabolic).
Drug Interaction
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Acetazolamine, ammonium chloride enhances
aspirin toxicity.
EtOH increases GI bleeding.
Reduces the activity of spironolactone.
Antagonizes the effect of heparin in the
platelets.
Competes with Penicillin G for renal tubular
secretion.
Drug Interactions
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Inhibits the uricosuric effect of sulfinpyrazone
and probenecid.
Displaces drugs from proteins in serum
Oral hypoglycemic agents, methotrexate, other
NSAIDs.
Nonacetylated Salicylates
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Mg Choline salicylate, sadium salicylate,
salicylsalicylate.
Chemically different for aspirin.
Reversible platelet inhibition.
Effective anti-inflammatory effect, less analgesic
effect than aspirin.
Can use in patient with asthma, bleeding
tendencies or renal dysfunction.
Nonselective COX inhibitors
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Mechanism is similar to aspirin (exceptions)
All are: inhibitors of prothrombin synthesis,
analgesic, anti-inflammatory, antipyrectic, inhibit
platelet aggregation (variations).
As a group: cause less gastric irritation
(exceptions), nephrotoxicity.
PROPIONIC ACID DERIVATIVES
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Ibuprofen, Naproxen, Fenoprofen.
Very similar in mechanism of action and effects
(compared to aspirin).
More effective as analgesics, and have less adverse
effects in the GI tract.
Ibuprofen and Fenoprofen half-life of 2 hrs.
Naproxen has a longer half-life (13 hrs).
Dysmenorrhea.
Adverse effects are similar: nephrotoxicity, jaundice,
nausea, dyspepsia, edema, rash, pruritus, tinnitus.
Interactions and contraindications: same as aspirin.
ACETIC ACIDS
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Indomethacin
Most potent inhibitor of prostaglandin synthesis
(COX-1) more effective but more toxic than
aspirin.
Orally absorbed, highly bound to plasma
proteins, half-life 2hrs.
Metabolized in liver, excreted in bile and urine.
Indomethacin
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High incidence of dose-related toxic effects:
GI, severe migraine (20-25%), dizziness,
confusion and depression, risk of fluid
retention, hyperkalemia and blood dyscrasias.
Contraindicated in pregnancy and in patients
with psychosis.
Indomethacin
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Uses
Treatment of patent ductus arteriosus in
premature babies.
Acute gouty arthritis, ankylosing spondylitis,
osteoarthritis.
Pericarditis and pleurisy.
Sulindac
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Is a pro-drug closely related to Indomethacin.
It should be converted to the active form of the
drug.
Indications and toxicity similar to Indomethacin.
May inhibit the development of breast, colon
and prostate cancer.
Suppresses familial intestinal polyposis disease.
Tolmetin
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Approved for treatment of juvenile arthritis.
Has a short half-life (60 min.).
Fewer GI and CNS side effects than
Indomethacin. Rare IgM related TTP.
Not often used. Ineffective for gout.
Diclofenac
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Gastrointestinal distress, gastrointestinal
bleeding, gastric ulceration.
Less frequent than other NSAIDs.
Combinations with misoprostol and omeprazol
reduce incidence.
High doses impairs renal function. Elevates liver
enzymes.
FENAMATES
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Meclofenamate, Mefenamic acid.
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Analgesic, anti-inflammatory properties less
effective than aspirin and clearly more toxic.
Short half-lives, and should not be used for
longer than one week and never in pregnancy
and in children.
Diarrhea and abdominal pain.
Enhances oral anticoagulants.
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PYRAZOLONE DERIVATIVES
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Phenylbutazone
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Withdrawn from the market.
Adverse effects of this drug are: agranulocytosis,
aplastic anemia, hemolytic anemia, severe gastric
irritation, nephrotic syndrome, optic neuritis,
deafness, serious allergic reactions, exfoliative
dermatitis, hepatic and renal tubular necrosis.
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PYRAZOLONE DERIVATIVES
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Oxyphenbutazone: one of the metabolites of
phenylbutazone.
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Apazone.- Similar to phenylbutazone, but less
likely to cause agranulocytosis.
OXICAM
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Piroxicam.
Half-life of 45 hrs. Once-daily dosing. Delay onset of
action.
High doses inhibits PMN migration, decrease oxygen
radical production, inhibits lymphocyte function (high
doses).
Used in osteoarthritis, ankylosing spondylitis and
rheumatoid arthritis.
Adverse effects: GI symptoms, dizziness, tinnitus,
headache, rash. Peptic ulcer (9.5 higher)
Ketorolac
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Analgesic, no anti-inflammatory effect (market).
Have typical NSAIDs properties. More analgesic
efficacy.
Can replace morphine in mild to moderate
postsurgical pain.
VO, IM, IV.
Similar toxicities. Renal toxicity common with
chronic use.
COX-2 Selective
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Celecoxib, Etoricoxib, Rofecoxib,
Valdecoxib, Meloxicam (preferential).
Inhibit prostacyclin (COX-2) in sites
of inflammation.
Do not block “housekeeping” effect
of COX-1.
Antipyretic, analgesic and antiinflammatory effect.
COX-2 Selective
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Indications
Osteoarthritis, rheumatoid arthritis,
dysmenorrhea, acute gouty attacks,
acute musculoskeletal pain.
Still under investigation.
Rofecoxib (Vioxx®)
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Withdrawn from the market.
Higher incidence of cardiovascular
thrombotic events.
Inhibits prostacyclin letting TXA2 act
freely and promote platelet
aggregation.
Acetaminophen
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Para-aminophenol.
Analgesic and antipyretic actions
equivalent aspirin.
No significant anti-inflammatory effects.
No occult bleeding or gastric irritation ,do
not inhibit platelet aggregation, or affect
prothrombin time.
No relationship with Reye’s syndrome.
Does not antagonize the effects of
uricosuric drugs.
Acetaminophen
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Hepatic toxicity is its major problem.
It is the drug of choice for analgesia
and fever reduction in patients who
cannot tolerate aspirin.
Acetaminophen is the active
metabolite of Phenacetin.
But unlike phenacetin, doesn’t
produce renal toxicity or hemolytic
anemia and methemoglobinemia
Acetaminophen
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Pharmacokinetics and Toxicity:
Acetaminophen is orally absorbed, it is
only slightly bound to plasma proteins.
In liver is metabolized to acetaminophen
glucuronide and sulfate. A minor but
highly toxic metabolite builds up when
gluthatione is depleted (overdose, hepatic
insufficiency).
Acetaminophen
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Large doses of acetaminophen (or in
patients with liver disease), may cause
severe liver damage and death.
The signs of toxicity occur in 12-24:
nausea, vomiting, diarrhea, abdominal
pain, dizziness and death being caused by
severe hepatotoxicity
Sometimes associated with acute renal
tubular necrosis.
Administration of N-acetylcysteine, is a
useful antidote.
High-Yield Slides.
Dr. Rosas Blum
NSAIDs
• Prototype aspirin.
• Ibuprofen, naproxen, indomethacin.
• Traditionally NSAIDs are non-selective and
inhibit COX-1 and COX -2.
Aspirin
• The only clinically marketed irreversible
inhibitor of COX-1.
• Inhibits platelet aggregation.
• Analgesia.
• Fever reduction.
• Anti-inflammatory effects.
Salicylates & IBD
• Salicylates derivatives are used in intra-gut
treatment of IBD.
• Oral drug dissociate in colon.
• Enema preparations.
• Mainly used in Ulcerative colitis than
Crohn’s disease.
Aspirin
• Adverse effects.
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GI Irritation (ulcers, active bleeding)
Tinnitus and vertigo (early sign intoxication)
Hypersensitivity.
Bleeding complications.
Platelet inhibition.
Acid-base disorder
• Mixed.
• Metabolic acidosis (aspirin acid).
• Respiratory alkalosis.
• Stimulatory effect on breathing centers.
Reye’s Syndrome
• Highly Lethal
• Hepatoencephalopathy.
• Aspirin and derivatives may be a trigger.
• Do not give in children with chickenpox or
influenza B infection.
Other Non-Selective NSAIDs
• Ibuprofen, Naproxen
• Analgesic, antipyretic and anti-
inflammatory effects.
• Not as effective for anti-platelet effects.
Selective COX-2 inhibitors
• Celecoxib, Rofecoxib.
• When don’t what to inhibit COX-1.
• Patients with gastric ulcers.
• Similar anti-inflammatory effects as
conventional NSAIDs.
• Vioxx produces heart attacks.
Acetaminophen
• Does not inhibit COX-1 or COX-2.
• Lacks of anti-inflammatory effects.
• Excellent analgesic and antipyretic activity.
• Mechanism of action unknown.
• Acts directly in the CNS to reduce fever.
NSAIDs vs Acethaminophen
• No antiplatelet action
• Not implicated in Reye’s syndrome.
• Not bronchospastic.
• Minimal GI effects.
Acetaminophen overdose
• Disastrous.
• Mayor cause of liver failure that require
liver transplant. (Teenagers and young
adults).
Acetaminophen Metabolism
• Metabolized by liver glucoronyl transferase to
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form an inactive compound.
Minor CYP-dependent pathway produces a Nacetyl-para-benzoquinonimine, a reactive
metabolite that is inactivated by glutathione.
In serious overdose glutathione becomes
depleted, and metabolite damages hepatocytes.
EtOH enhances liver toxicity via induction of
CYP2E1 enzyme.
Acetaminophen overdose
• Antidote N-acetylcysteine.
• Replenishes glutathione stores.
• Most effective when used in the first 12
hrs before liver damage becomes
irreversible.
A 5-year-old girl is brought to the emergency department
by her parents in a comatose state. Her parents refers that
she felt ill recently with high fever. Physical examination:
comatose, papilledema, hepatomegaly. A CT Scan reveals
cerebral edema.
What agent is most likely to be involved in this patient?
a) Aspirin
b) Acetaminophen
c) Codein
d) Celecoxib
e) Ibuprofen
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