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Nonopioid (Nonnarcotic) Analgesics
• Tissue Injury & Prostaglandins
• Pain
• Classification
1. Salicylates
2. Nonsteroidal antiinflammatory drugs
3. Acetaminophen
4. Drugs used to treat gout
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When tissues damaged = release substances
such as histamine, bradykinin, prostaglandins,
serotonin = vasodilation = increase
permeability of capillary walls
 Prostaglandins are mediators of the
inflammatory response
Formed in cell membranes of most organs
Cell membrane phospholipids forms the
parent of all prostaglandins (arachidonic acid
or fatty acid)

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Slight trauma to a nerve fiber – enzyme
phospholipase stimulated & break off arachidonic
acid
 Arachidonic acid enters into 2 metabolic pathways
1. Enzyme CYCLOOXYGENASE breaks down
arachidonic acid into prostaglandin PGE2 & PGI2
(next slide)
2. Enzyme LIPOXYGENASE breaks down
arachidonic acid into leukotrienes (cover in resp
chapter)

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1. Enzyme CYCLOOXYGENASE breaks down
arachidonic acid into prostaglandin PGE2 & PGI2
 Prostaglandins capable of :
 Stimulating peripheral pain receptors
 Constricting/dilating vessels
 Elevating body temp
Bronchodilation & constriction
 Relax & contract smooth muscles of bladder,
intestines in the production of erythema, edema,
uterine contraction
Inhibit platelet clot formation
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Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Cyclooxygenase (COX)
Family of enzymes required to make prostaglandins
from arachidonic acid
3 subtypes (book outdate info on this – says there are 2)
1. COX-1: available in all cells, responsible for tissue
homeostasis, called “housekeeping” enzyme
 Protect GI tract
 Maintain normal platelet function
 Regulate renal flow
2. COX-2: produced during inflammation, found in low
amounts in tissues
3. COX-3
 Ideally drugs should inhibit COX-2 & leave COX-1 alone
 NSAIDs/Aspirin are non-selective: affect COX-1&2 – where
adverse effects of drugs come from (GI upset)
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As apprehensive dental patient comes in and states he already
took ibuprofen for the pain he anticipates from the appointment
today. As you know, tis inhibits the synthesis of prostaglandins.
All of the following statements are TRUE about prostaglandins
EXCEPT which one?
a. They have a very short half life
b. They generally act locally on or near the tissue that
produced them
c. They are synthesized only in the liver and the adrenal
cortex
d. The common precursor of prostaglandins is arachidonic
acid
e. Their synthesis can be inhibited by a number of
unrelated compounds, including aspirin and cortisol
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
As apprehensive dental patient comes in and states he already
took ibuprofen for the pain he anticipates from the appointment
today. As you know, tis inhibits the synthesis of prostaglandins.
All of the following statements are TRUE about prostaglandins
EXCEPT which one?
a. They have a very short half life
b. They generally act locally on or near the tissue that
produced them
c. They are synthesized only in the liver and the adrenal
cortex
d. The common precursor of prostaglandins is arachidonic
acid
e. Their synthesis can be inhibited by a number of
unrelated compounds, including aspirin and cortisol
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From which of the following substances are prostaglandins
formed?
a. Arachidonic acid
b. Endorphins
c. Enkephalins
d. Norepinephrine
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From which of the following substances are prostaglandins
formed?
a. Arachidonic acid
b. Endorphins
c. Enkephalins
d. Norepinephrine
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 Analgesic: selective
decrease of pain perception
 Pain originates from CNS while stimulus comes
from peripheral nervous system (PNS)
 2 components of pain:
1. Perception/Sensory (physical component)
2. Reaction (psychological component)
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

Orofacial pain
1. Nociceptive / Neuropathic pain
2. Acute / Chronic pain
Nociceptive
• Pain that arises from a stimulus out the CNS
• Ex: exposed dentin, post-surgery pain
• Nociceptors are stimulated by pain – transmit to A & C
fibers - transmit pain feeling to the brain
• Dental LA interfaces with A & C fibers
• Analgesics can block pain
 Nociceptors within the peripheral nervous system
(CH5)
 Nociceptors within the central nervous system (CH6)
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Site of action
• Nonopioid analgesics act on peripheral nerve
endings
• Opioids act primarily in the central nervous
system (CNS)
 Mechanism of action
• Nonopioid analgesics inhibit prostaglandin
synthesis
• Opioids affect the response to pain by depressing
the CNS

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Nonopioids divided into the following grps:
1. Salicylates
2. Nonsteroidal anti-inflammatory drugs (NSAIDs)
3. Acetaminophen
**Drugs used in tx of mild to moderate nociceptive dental
pain**
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Analgesics used for Dental Pain
Salicylates
aspirin(Ecotrin, Bayer)
diflunisal(Dolobid)
NSAIDs
Notations
PROTYPE
Nonacetylated salicylate
ketorolac(Toradol)
ibuprofen(Advil, Motrin)
ketoprofen(Orudis, Actron)
naproxen sodium(Anaprox, Aleve)
etodolac(Lodine)
celecoxib(Celebrex)
Selective for COX-2
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Aspirin(ASA) is the prototype salicylate
 Many references refer to aspirin as an NSAID but it
is NOT – CDC says it is a nonarcotic analgesic, not
an NSAID

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 Acetylsalicylic
acid (aspirin)
• Mechanism of action
• Pharmacokinetics
• Pharmacologic effects
• Adverse reactions
• Toxicity
• Drug interactions
 Other salicylates
• Diflunisal
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 Effects
related to the
ability to
inhibit
prostaglandin
synthesis by
blocking COX
pathway
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Administration: oral, rectal
 ABSORPTION
• Small intestine & stomach
 DISTRIBUTION: Widely distributed into most body
tissues
• Peak effect on empty stomach = 30min
• Half-life small dose aspirin (81mg): 2-3hrs
• Half-life large dose aspirin (325mg): 15-30hrs

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METABOLISM
• Liver to salicylic acid + acetic acid
• BOOK CORRECTION: salicylates are readily bound
to plasma PRO (80-90%), PLEASE CHANGE!! P.49,
2nd paragraph
 EXCRETION
• Kidney via urine

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4 As
1. Analgesic: blocks COX pathway
2. Antipyretic: increases heat loss through
sweating
3. Antiinflammatory
4. Antiplatelet (next slide)
5. Uricosuric:↑ excretion of uric acid in the urine,
thus reducing the concentration of uric acid
in blood plasma (used as a tx for GOUT)
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Antiplatelet: irreversibly binds to platelets
• Useful for MI, stroke, cardio disease
• Aspirin breaks down to salicylic acid & acetic acid
 Acetic acid irreversibly binds to COX-1 in
platelets
↓
 Prevents formation thromboxane
↓
 ↓ body ability to form clots and ↑ bleeding times
 This lasts for the life of the platelet because it is
now incapable of resynthesizing new COX
 (New platelets form every 7 days)
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Antiplatelet
• Effects dependent on DOSE taken: aspirin has a (+)
effect on 2 substances involved in blood clotting
1) Thromboxane A2
 Substance promotes clotting
 Aspirin inhibits (stops) its action = reduces
clotting
 Will occur in LOW-dose aspirin
2) Prostacyclin
 Substance inhibits (stops) clotting
 Aspirin enhances this substance = reduces
clotting
HIGH dose aspirin: no major effects on bleeding times or
thromboxane because high doses prevent formation of prostacyclin22
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



GI: most common (ulcers, bleeding)
• To reduce these effects – take with antacids, milk,
meals (NBQ)
• Avoid alcohol
Hypoglycemia
 Aspirin inhibits PGE2 which ↑ insulin
Bleeding
 Interferes with clotting mechanism by reducing
platelet adhesiveness
Reye syndrome
 Primarily kids, but can occur any age
 Using aspirin to tx viral illness (chickenpox, flu) &
given aspirin have been associated with Reye
syndrome
 Can be fatal
 US Surgeon General: no aspirin for kids <19yrs
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 Hepatic and renal effects: rare
 Asthmatics: develop bronchoconstriction
if
take aspirin
 Hypersensitivity
• Incidence of true allergy ≤1%
• Asthmatics are more likely hypersensitive
than allergic (5-15%)
 Remember from Ch3 – asthmatics have
issues with Type I hypersensitivity immunity
& IgE
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Salicylism
p.50
• Tinnitus, GI upset, decreased vision
• Hyperventilation
• Respiratory alkalosis
• Death (acidosis & electrolyte imbalance)
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Page 51
ASPIRIN INSTRUCTIONS
Take with full glass H2O
Take with food, milk, antacid (GI upset)
Do not use NSAIDs
Do not give to kids (Reye’s Syndrome)
Prolonged bleeding times possible
81mg/day for prevention MI, Stroke
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DRUG INTERACTION
ACTION
Anticoagulants
(Warfarin)
Displace Warfarin from binding sites
Increase bleeding
Probenecid
Aspirin interferes with uricosuric effect can cause an acute attack of gout
Antacids
Decrease absorption of aspirin
Methotrexate
Aspirin displace from binding site &
increase levels of drug
Antihypertensives
Aspirin reduces effects
Aspirin inhibits COX = prevent
prostaglandin formation – decrease
vasodilation
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Don’t need to know for testing:
p.50 Table 5-1
p.51 DOSES & PREPARATIONS
p.52 NONACETYLATED SALICYLATES
p.52 Table 5-2
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Aspirin inhibits prostaglandin synthesis in inflamed
tissues. Aspirin also works as a platelet inhibitor by acting
irreversibility to stop the action of cyclooxygenase, an
enzyme that is needed for platelet formation.
a. Both statements are TRUE
b. Both statements are FALSE
c. The first statement is TRUE, the second is FALSE
d. The first statement is FALSE, the second is TRUE
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Aspirin inhibits prostaglandin synthesis in inflamed
tissues. Aspirin also works as a platelet inhibitor by acting
irreversibility to stop the action of cyclooxygenase, an
enzyme that is needed for platelet formation.
a. Both statements are TRUE
b. Both statements are FALSE
c. The first statement is TRUE, the second is FALSE
d. The first statement is FALSE, the second is TRUE
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Which of the following dosages of aspirin is
recommended for men to prevent a stroke or heart attack?
a. 81mg/day
b. 325mg every 3 months
c. 650mg/day
d. 3g/day
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Which of the following dosages of aspirin is
recommended for men to prevent a stroke or heart attack?
a. 81mg/day
b. 325mg every 3 months
c. 650mg/day
d. 3g/day
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 General
 Mechanism
of action
 Pharmacokinetics
 Pharmacologic effects
 Adverse reactions
 Drug interactions
 Therapeutic uses
 Specific nonsteroidal antiinflammatory agents
• Ibuprofen
• Celebrex
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Close cousins to aspirin
• Mechanism of action, effects, adverse rxns
similar to aspirin
• If allergy to aspirin – do NOT give pt NSAIDs
 Difference between the 2 = antiplatelet activity
 NOT used as MI/stroke prevention like aspirin
 Most useful drug group for tx of dental pain (NBQ)
 Ibuprofen safest of the NSAIDs to tx a nursing
woman (not been found in breast milk like other
NSAIDs have been) (NBQ)

Don’t worry about CHEMICAL CLASS & TABLE 5-3 P.53
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
Celebrex: Relieve pain & inflammation but do NOT
cause GI upset – drug selectively interacts with COX-2
Analgesics used for Dental Pain
Notations
Salicylates
aspirin(Ecotrin, Bayer)
PROTYPE
diflunisal(Dolobid)
Nonacetylated salicylate
NSAIDs
ketorolac(Toradol)
ibuprofen(Advil, Motrin)
ketoprofen(Orudis, Actron)
naproxen sodium(Anaprox, Aleve)
etodolac(Lodine)
celecoxib(Celebrex)
Selective for COX-2
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
Like aspirin – inhibit COX enzyme
• ↓ formation prostaglandin
• Adverse rxns result from their non-selectivity
of COX inhibition (just like aspirin)
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Analgesic
 Antipyretic: inhibition COX-2 action near
hypothalamus (different than aspirin)
 Antiinflammatory actions
 Antiplatelet
• Inhibit COX1 = inhibit thromboxane = prevent
platelet aggregation
• Reversible binding to platelets (aspirin
irreversible)
• Not used to prevent MI, stroke like aspirin
• Will increase bleeding times

Can be used safely in children, unlike aspirin
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ABSORPTION: orally
• Common for these drugs to be admin with
food to ↓ GI upset
 DISTRIBUTION
• Peak 1-2 hours
• 4-6 hour duration
• Highly bound to plasma-PRO (90%)
 METABILISM: liver
 EXCRETION: kidneys

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



Many adverse rxns are likely to occur in patients on
high doses for tx of RA
GI effects: same as aspirin
No sodium mixtures for patients with HBP (naproxen
sodium)
Black Box Warnings
1) Cardiac disease patients should not take longterm
p.54
2) GI bleeds
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Which of the following adverse effects is commonly seen in
patients taking an NSAID?
a. GI bleeding
b. Hair loss
c. Sedation
d. Xerostomia
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Which of the following adverse effects is commonly seen in
patients taking an NSAID?
a. GI bleeding
b. Hair loss
c. Sedation
d. Xerostomia
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SAME AS ASPIRIN
DRUG INTERACTION
Anticoagulants
ACTION
Increase bleeding
Antacids
Decrease absorption
Methotrexate
Increase levels
Antihypertensives
Reduces effects
DIFFERENT THAN ASPIRIN
DRUG INTERACTION
ACTION
Probenecid
NSAIDs do not affect
Lithium (Bipolar – CH17)
Increase levels
Digoxin (CHF – CH14)
Increase levels
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Note the rise in lithium
levels in the body when
naproxen introduced
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Osteoarthritis
 Rheumatoid arthritis
 Gouty arthritis
 Fever
 Dysmenorrhea
 Pain
 Bursitis (pain in small fluid-filled sacs called bursae
that cushion bones, tendons, muscles near joints)
 Tendonitis

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Dental
 NSAIDs are equivalent in
analgesic efficacy to opioid
analgesics
 Unclear why use of NSAIDs in
dentistry has declined
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1.
2.
Ibuprofen
COX II-specific agents
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The oldest member of the NSAIDs
• Antacids have no effect
• The drug of choice for dental pain
 OTC 200mg
 Rx: 400, 600, 800mg

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Decrease inflammation effects of COX II & leave
COX I alone
• Fewer side effects
• NO effect on platelets (COX-1, not COX-2 effect)
 Contraindicated in patients with SULFA allergy
• Celebrex contains a sulfa chain

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Most of the COX-1/COX-2 inhibitors NSAIDs have a black box
warning of increased risk of:
a. Thrombotic cardiovascular events
b. Duodenal and gastric ulcer formation
c. Anaphylactic reactions
d. Asthmatic attacks
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Most of the COX-1/COX-2 inhibitors NSAIDs have a black box
warning of increased risk of:
a. Thrombotic cardiovascular events
b. Duodenal and gastric ulcer formation
c. Anaphylactic reactions
d. Asthmatic attacks
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Celebrex is contraindicated in patients allergic to:
a. Sulfa
b. Aspirin
c. Penicillin
d. Erythromycin
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Celebrex is contraindicated in patients allergic to:
a. Sulfa
b. Aspirin
c. Penicillin
d. Erythromycin
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NSAIDs have analgesic, antipyretic and antiinflammatory
properties. The mechanism of action for NSAIDs is that they
inhibit the cyclooxygenase step of the arachidonic acid
cascade and this inhibit the activity of prostaglandin
synthetase.
a. Both statements are TRUE
b. Both statements are FALSE
c. The first statement is TRUE, the second is FALSE
d. The first statement is FALSE, the second is TRUE
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NSAIDs have analgesic, antipyretic and antiinflammatory
properties. The mechanism of action for NSAIDs is that they
inhibit the cyclooxygenase step of the arachidonic acid
cascade and this inhibit the activity of prostaglandin
synthetase.
a. Both statements are TRUE
b. Both statements are FALSE
c. The first statement is TRUE, the second is FALSE
d. The first statement is FALSE, the second is TRUE
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Which of the following agents has anti-inflammatory
properties?
a. Ibuprofen
b. Acetaminophen
c. Hydrocodone
d. Codeine
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Which of the following agents has anti-inflammatory
properties?
a. Ibuprofen
b. Acetaminophen
c. Hydrocodone
d. Codeine
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Celebrex is a member of which category of drugs?
a. Salicylates
b. Opiates
c. COX-2 selective inhibitors
d. Non-selective inhibitors
e. Steroidal antiinflammatories
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Celebrex is a member of which category of drugs?
a. Salicylates
b. Opiates
c. COX-2 selective inhibitors
d. Non-selective inhibitors
e. Steroidal antiinflammatories
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Which of the following should NOT be
given to a person with a history of aspirin
hypersensitivity (allergy)?
a. Codeine
b. Acetaminophen
c. Ibuprofen
d. Hydrocodone
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Which of the following should NOT be
given to a person with a history of aspirin
hypersensitivity (allergy)?
a. Codeine
b. Acetaminophen
c. Ibuprofen
d. Hydrocodone
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 General
 Pharmacokinetics
 Mechanism
of action
 Pharmacologic effects
 Adverse reactions
 Drug interactions
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 Derivative
of para-amino phenol
 No Anti-inflammatory or Antiplatelet
• Poor inhibitor of COX in tissues
 Safe in pregnancy (category B)
 USES 2As
• Analgesic
• Antipyretic
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ABSORPTION
 GI tract into bloodstream
 DISTRIBUTION
 Peak blood levels: 30-60min BOOK
CORRECTION, P.56 (NOT 1-3HRS)
 NOT highly bound to plasma PRO (unlike aspirin,
NSAIDs)
 Little drug interactions
 METABOLISM: liver
 EXCRETION: kidney
 Excreted unchanged – undergoes conjugation to
glucuronic acid (Remember Phase II metabolism
from CH2)

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


Reduced elevated body temperature by direct
action on the heat regulation centers in the
hypothalamus
Effects occur through the COX-3 receptors in the
brain
BOOK CORRECTION P.56 – WE DO KNOW
MECHANISM OF ACTION OF ACETAMINOPHEN
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 OD
is the leading cause of acute liver failure
• Adults: 4g/day is max (4,000mg)
 Book discusses toxic levels – just remember 4g/day
is the max allowed
• Treated with acetylcysteine
 Narrow
margin of safety: FDA asked drug
manufacturers to limit OTC does to 325mg
 Metabolized into methemoglobin – can result in
methemoglobinemia (decrease ability RBC to
carry O2)
 Skin Rxns: 2013 FDA announced potential for
Stevens-Johnson Syndrome
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

Anti-Seizure Meds
Chronic large doses of alcohol increase toxicity of
acetaminophen (3+ drinks per day)
• Alcohol stimulates the oxidizing enzymes that
metabolize acetaminophen to its toxic metabolite
• Dose control is a MUST: instead of 4g/day for nonalcohol drinkers, alcohol-drinkers should restrict
dose to 2g/day
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Which of the following agents has little value in treating acute
inflammation?
a. Ibuprofen
b. Acetaminophen
c. Aspirin
d. Naproxen
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Which of the following agents has little value in treating acute
inflammation?
a. Ibuprofen
b. Acetaminophen
c. Aspirin
d. Naproxen
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Which of the following non-narcotic analgesics would you most
likely use in a patient taking anti-coagulant medications?
a. Ibuprofen
b. Acetaminophen
c. Aspirin
d. Naproxen
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Which of the following non-narcotic analgesics would you most
likely use in a patient taking anti-coagulant medications?
a. Ibuprofen
b. Acetaminophen
c. Aspirin
d. Naproxen
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Treatment of Gout
1.General
2.Colchicine
3.Allopurinol
4.Probenecid
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



Inherited inflammatory disease
Occurs primarily in men
Onset: 1 joint affected (big toe, knee)
Assoc with the deposition of uric acid in joint & soft
fluid
• Uric acid is formed every day from the
metabolism of nucleic acids by the liver (80%
daily uric acid), remaining comes from foods,
alcohol, etc…
• Humans cannot use uric acid = so it is excreted
by kidneys
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
Patients with gout accumulate uric acid crystals
spontaneously in their joint fluid
• Phagocytes (PMNs, WBC) enter the area & attack the
crystals – leads to ↓pH of joint fluid making it more
acidic – this causes more uric acid to accumulate in
the joint
 Vicious cycle produces edema, pain, erythema
 Chronic gout = bulging of soft tissues, deform joints
(known as tophi)
 Kidney stones common
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Drugs used to tx either relieve acute inflammatory
response or reduce the uric acid levels (chronic
gout)
 Common drugs
1. Colchicine: tx acute gout attack (use w/in 48hrs)
2. Allopurinol: prevent gout issues
3. Probenecid: prevent gout issues (next slide)
4. NSAIDs, Aspirin, Acetaminophen

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
 Uricosuric
agent
• Enhance renal excretion of uric acid w/out
altering formation of uric acid
• Blocks tubular reabsorption (meaning uric
acid not go back into the blood) of filtered
urate
 Increases the levels of NSAIDs & penicillin’s
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Gouty arthritis most commonly affects the:
a. Ankle
b. Knee
c. Wrist
d. Big toe
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Gouty arthritis most commonly affects the:
a. Ankle
b. Knee
c. Wrist
d. Big toe
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.