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FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 1 of 6
Specific Description of the Topic Being Discussed Today
I. Introduction [S1]: Inflammation, NSAIDs and Gout
II. Overview Title [S2]
a. Describe the inflammatory process
b. Discuss pharmacology of drugs used to treat inflammation
c. Non-steroidal anti-inflammatory drugs (NSAIDs)
d. Selective COX-2 inhibitors
e. Acetaminophen
f. Discuss pharmacology of drugs used to treat gout
g. NSAIDs
h. Colchicine
i. Uricosurics
III. What is Inflammation? [S3,4]
a. It has been linked to many diseases shown on this diagram. Unchecked it can be a bad thing. It can also be
very useful. Without it we wouldn’t be able to recover from injury.
b. He thinks of it as the process the body undergoes to relieve itself from some stimuli.
c. Dynamic vascular and cellular response to insult or injury.
d. It is the body trying to mobilize pro-inflammatory mediators to the site of an injury and take care of it.
e. Many things can cause inflammation.
f. Causes [S5]
i. Microorganisms and toxins- you have a cold, that is something that can set up an inflammatory process
ii. Chemical and biochemical damage- you break your arm
iii. Physical damage: heat, cold, radiation, trauma-if you break your arm
g. Immunologic hypersensitivity- allergy to certain triggering things that can set up an acute inflammatory process.
IV. Sequence of Events in Inflammation [S6]
a. Whatever the trigger, the sequence of events is almost the same. Initially there are changes in blood flow which
is a result of the release of basoactive substances from damaged cells and parts of the body. It typically
manifests itself as redness and heat. Think of sunburn which is warm to the touch.
b. He read straight from the chart.
V. Clinical Signs [S7]
a. These are the five cardinal signs of inflammation:
b. Redness
c. Swelling
d. Heat
e. Pain
f. These four were described 2000 years ago.
g. Loss of function-added about 150 years ago to the list.
VI. Nonsteroidal Anti-inflammatory Drugs (NSAIDS) [S8,9]
a. There are many mediators of inflammation. Many chemicals can aid in the process or trigger the process. One
pathway that’s very important in inflammation is the arachadonic acid pathway.
b. Phospholipids are found in membranes. They can be broken down into arachadonic acid.
c. Note the glucocorticoids or the corticosteroids. That class of medications really shut off the whole pathway at
the source. If we could, you’d treat every patient with glucocorticoids.
i. They are the Cadillac of anti-inflammatories. They are the best.
ii. However, they have a lot of nasty side effects. These side effects occur with long-term use of these
steroids. We try to minimize the use of them.
iii. Lipoxygenase causes the formation of leukotrienes.
iv. Leukotrienes have pro-inflammatory roles.
v. Cyclo-oxygenase 1 and 2 or COX 1 and 2. Those enzymes mediate Prostacyclin, Prostaglandin and
Thromboxane. They are important pro-inflammatory agents with a lot effects in the body.
d. First NSAID (salicylate) isolated in 1874 from willow bark
e. >30 NSAID compounds to date
f. They are used all the time.
g. Remember: the side effect profile will determine NSAID selection
i. Within this class of drugs, people can sometimes tolerate one but not another. Adverse affects from one
may not preclude the use of another.
ii. For mild/moderate pain they are very effective. Often times for dental treatment, you can use NSAIDs
instead of narcotics.
FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 2 of 6
h. Analgesic properties at low doses and anti-inflammatory effects at higher doses
VII. NSAIDs Mechanism of Action [S9]
a. Arachadonic acid affect for NSAIDS are at cyclo-oxygenase 1 and 2. They inhibit both COX1 and 2.
b. The NSAIDs really don’t differentiate between their inhibition of COX 1 and 2. They inhibit them both in a similar
manner. For a while that hasn’t been a great thing.
VIII. Roles of COX-1 and COX-2 [S10]
a. COX-1 is thought of as the good COX. COX2 is thought of as the bad COX.
b. COX-1
i. GI cytoprotection
ii. Platelet activity
iii. Renal function - helps stimulate renal profusion and maintain kidney health
c. COX-2
i. Inducible
ii. Inflammation - inflammatory reactions generate a lot of COX 2
iii. Pain
iv. Fever
v. Constitutive
vi. Renal function
IX. Effects of Prostanoids [S11]
a. PGE2 Vasodilation, pain sensitization, gastric cytoprotection
b. PGF2 Bronchoconstriction, uterine contraction
c. PGI2 Inhibition of platelet aggregation, gastric cytoprotection
d. TxA2 Stimulation of platelet aggregation
e. Their hand is all over the body.
X. Clinical Effects of NSAIDs [S12]
a. If you inhibit the enzyme that produces these prostanoids, there are many clinical effects.
b. Anti-inflammatory
c. Analgesic
d. Antipyretic-reduces fevers
e. Decrease platelet aggregation
XI.
Side effects of NSAIDS [S13]
a. The side effect that has been the largest problem is the GI intolerance and ulceration.
b. GI intolerance and ulceration
c. Increased bleeding
d. Hypersensitivity:
i. Urticaria (bad rash that goes all over the trunk), hypotension, bronchoconstriction (ER visit likely)
1. People will say they are allergic to NSAIDs. They mean that if they take it, their stomach doesn’t feel
well. That’s not allergic. Some people are truly allergic to them.
2. Hypersensitivity is about ½% of people.
e. CNS: dizziness, confusion-especially in older patients
f. SQ: What is urticaria? It is a bad rash that goes all over the trunk.
XII. Gastroprotective Role of PGE [S14]
a. An upset stomach from aspirin may be a chemical reaction because they get on the stomach lining and cause
irritation.
b. PGE production is inhibited by NSAIDs
c. Enhances bicarbonate secretion
d. Enhances blood flow to mucosal surfaces
e. Promotes mucus secretion
f. Promotes epithelial growth
XIII. Mortality from NSAID-induced GI complications [S15]- NSAID GI thing shouldn’t be taken likely. It can be
devastating and important.
XIV.
Renal Complications of NSAIDs [S16]
a. Some of the mediators from the COX pathway help keep the kidney profuse.
b. Sodium retention
c. Hypertension
d. Hyperkalemia-increase in serum potassium
e. Decrease in renal blood flow
FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 3 of 6
f. Interstitial nephritis (inflammation of the neprhons of the kidney) applicable to COX-2 selective as well as nonCOX selective NSAIDs
XV. Nonselective COX Inhibitors [S17]
a. SQ: Is the inhibition of COX 1 good or bad? If you inhibit COX 1 is a bad thing. It promotes renal health.
b. Both over the counter and prescription agents are available at this time.
c. Salicyclic Acid:
i. Aspirin, sodium salicylate, salsalate, sulfasalazine
d. Para-aminophenol
i. Acetaminophen
e. Indole Acetic Acids
i. Indomethacin, sulindac
f. Heteroaryl Acetic Acids
i. Tolmetin, diclofenac, ketorolac
g. Arylpropionic Acids
i. Ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin
h. Naphthalene Acetic Acids
i. Naproxen
i. Enolic Acids
i. Piroxicam, meloxicam
j. Alkanones
i. Nabumetone
XVI.
Properties of NSAIDS [S18]
a. One of the distinguishing factors between NSAIDs is their half life. That often dictates how they’re used.
b. Aspirin, ibuprofen, Indomethacin have a short half life and are used for mild/moderate pain and postoperative
pain.
c. Naproxen, Piroxicam have a much longer half life. They’re often used for osteoarthritis. The longer half life
makes it easier because it only has to be taken once a day.
XVII. Aspirin [S19,20]
a. Non-selective irreversible inhibitor of COX 1 and 2
b. It can bind covalently to COX making it out of commission so it much produces new cyclo-oxygenases. That
doesn’t happen much with the others.
c. Reduces pain of mild to moderate intensity
d. Antipyretic-reduces elevated body temperature by COX inhibition
e. Low doses (80 mg/day) produce a slightly prolonged bleeding time, affects platelet aggregation
f. Its effects on platelets are long-lived.
g. Lasts 8-10 days
h. Usage should be stopped one week prior to surgery to avoid bleeding complications
i. Higher doses may cause vomiting, tinnitus (ringing in the ears), decreased hearing and vertigo
j. Conflicting data concerning use in children and Reye’s syndrome
i. Reye’s syndrome-can happen in pediatric patients. If a child has a fever of unknown etiology, don’t use
aspirin.
XVIII. Ibuprofen [S21]
a. Main ingredient in Advil and Motrin
b. Reversible inhibition of COX
c. Low doses (<2400 mg/day) produce analgesic but not anti-inflammatory effect
d. Higher doses yield an anti-inflammatory effect
e. Gastrointestinal irritation and bleeding
f. Rash, itching, dizziness and fluid retention reported
g. Acute renal failure and interstitial nephritis-adverse drug reactions that occur less often
XIX.
Commonly prescribed NSAIDS [S22]
a. Naproxen
b. Main ingredient in Aleve
c. Non-selective COX inhibitor
d. Half life = 12 hours; CL increases at doses above 500 mg, often used in osteoarthritis
e. Like aspirin and ibuprofen it is over the counter. Be sure to ask the patient what else they are taking because it
could be potent depending on whatever NSAIDs they take.
f. Ophthalmic Preparations
g. Diclofenac-postoperative inflammation
FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 4 of 6
h. Flurbiprofen-inhibition of intraoperative miosis
XX. Risk Factors for serious NSAID GI Toxicity [S23]
a. Remember that the geriatric patients are at highest risk. If you are treating someone who is elderly, be careful
about the use of these, especially if you want to use higher doses.
b. Age
c. Higher dosing of NSAID
d. Concurrent use of corticosteroids- Concurrent usage can lead to increased cytotoxicity
e. Poor functional status- be careful with these patients
XXI.
NSAID Drug Interactions [S24]
a. Protein binding displacement [warfarin]
b. Warfarin - a drug used in a lot of elderly patients to help the blood flow better, especially patients that have a
previous history of stroke or heart attack. It is highly protein bound like many of the NSAIDs. They can pop
warfarin off and get a higher response to warfarin.
c. Inhibition of P450 metabolism-in the liver many drugs are metabolized by the P450 mechanism [Cyclosporin,
SSRIs, beta blockers]
d. Inhibition of renal clearance-many of the NSAIDs are secreted in the kidney. They are eliminated by tubular
secretion and can compete with other drugs that may be eliminated in a similar fashion [lithium, methotrexate,
aminoglycosides]
XXII. CNS Complications of NSAID use [S25]
a. Remember to be careful with non-steroidal use with elderly patients.
b. Headache [indomethacin]
c. Confusion, lethargy [elderly]
d. Tinnitus [salicylates]
e. Aseptic meningitis [ibuprofen/lupus]
XXIII. Inflammation and NSAIDs Summary [S26]
a. PG comprise one group of many biochemical mediators of inflammation
b. NSAIDs: effective inhibitors of cyclo-oxygenase and prostaglandin induced inflammation
c. NSAIDs: effective cause of adverse effects
d. gastropathy and ulcers
e. decreased GFR, renal insufficiency
f. renal sodium retention [HBP, CHF]
g. platelet inhibition
h. headache, cognitive dysfunction, tinnitus
XXIV. Selective COX-2 Inhibitors [S27]
a. The idea was that if we can inhibit the bad COX, the one important in inflammatory processes then we can leave
the good COX alone and get the best of both worlds.
b. This is an overview slide.
c. Resulted from the search for a less toxic NSAID
d. Approximately 300 times more selective for COX-2 than for COX-1
e. Slightly lower incidence of subjective GI complaints
f. Minimal effects on platelets and can be given with low dose ASA
XXV. [S28] Skipped
XXVI. Selective COX-2 Inhibitors [S29]
i. These are the three COX2-inhibitors that came on the market. Note that Vioxx and Bextra are no longer on
the market. When they came out they were targeted for patients have GI problems taking NSAIDs. They
were targeted especially for anti-arthritic patients because they take them day after day.
ii. When they came out, they were written for anything, like major aches and pains. Doctors prescribe
Celebrex for indications when the patient didn’t indicate any GI problems.
This comes from Dr. Graham:
COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk
The allure of COX-2 inhibitors was the prospect of treating pain without gastrointestinal toxicity.1 Celecoxib and rofecoxib
were the first of these new agents to gain approval and, with heavy promotion and direct-to-consumer advertising, quickly
became the most widely prescribed NSAIDs in the United States. Lurking in the background was the concern that
selective COX-2 inhibition might suppress endothelial cell synthesis of prostacyclin, leaving platelet thromboxane A2
mediated by COX-1 relatively unopposed.2-3 With loss of the antiplatelet and vasodilatory effects of prostacyclin, a relative
excess of thromboxane A2 would favor vasoconstriction, platelet aggregation, and thrombosis.
FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 5 of 6
iii. That’s basically what happens. We use this class to inhibit COX2 and there is an increase in
cardiovascular instances and MI’s. Vioxx and Bextra are no longer available for prescription use. Celebrex
is the lone COX 2 inhibitor still on the market.
iv. These can be a cautionary tale.
v. Some studies have shown that Celebrex could be better. When they first came out they weren’t marketed
like this. They marketed it for those who have problems taking the NSAIDs. They called it a therapeutic
creep. It happens with all the drugs. If something comes out and someone has been stabilized on
something else for use, why rush to use it?
b. Celecoxib (Celebrex)
i. Absorption decreased 20-30% by food
ii. Half-life of 11 hours
iii. 100-200 mg BID
c. Rofecoxib (Vioxx)**
i. 25 or 50 mg QD
ii. Significantly reduced acute pain after dental surgery compared with codeine/APAP
d. Valdecoxib (Bextra)**
i. 10 mg QD
ii. Increasing reports of rashes associated with administration **withdrawn due to thrombotic events
XXVII. Acetaminophen [S30,31]
a. Mechanism of Action
i. Weak inhibitor of cyclooxygenase in peripheral tissues
ii. Poor anti-inflammatory agent-good analgesic effects though
iii. Even if you increase the dose you won’t see great anti-inflammatory effects like ibuprofen and naproxen
iv. Tylenol is not the choice for anti-inflammatory
v. May inhibit prostaglandin synthesis in CNS accounting for analgesic/antipyretic effect
vi. Differs from ASA/NSAIDs by lack of potent anti-inflammatory and platelet inhibitory effects
b. Clinical Uses
i. Mild to moderate pain
ii. Fever
c. Pharmacokinetics
i. Metabolized by the liver—by glucuronidation or GSH
ii. Remember here that Tylenol is metabolized by the liver and high doses can cause liver dysfunction and
problems. Keep this in mind. If you prescribe Tylenol, and then you prescribe a Tylenol-containing
narcotic like Darvaset or Lortab, the patient may exceed 4 grams of Tylenol a day if they take Tylenol on
their own.
d. Adverse effects
i. Generally mild at normal doses (<4 gm/day)
ii. Hepatic toxicity most serious concern with large daily doses (>4 gm/day) or with accidental/intentional
overdose
iii. Treat with acetylcysteine
XXVIII. Gout [S32]
a. Why would a dentist prescribe Tylenol? Is pain for the pain and not for inflammation? Yes. If the procedure
causes a lot of inflammation, then Tylenol is not a good option. It has a good analgesic effect for the pain and
fever but little effect on inflammation.
b. It is a chronic inflammatory condition that is characterized by acute inflammatory episodes.
c. Basically you have a deposit of uric acid in joints and tissues from elevated levels of serum uric acid.
d. 6 times more common in men
e. Gouty arthritis is the most common form of inflammatory joint disease in men > 40 years old
XXIX. Gout [S33]
a. This was the author’s impression of gout in 1874. It was previously associated with the rich because risk factors
included large amounts of alcohol consumption and rich foods. In the 19 th century most people couldn’t afford
these things. Now, most people have access to it, so we see a greater prevalence of gout now.
XXX. Gout [S34]
a. Hyperuricemia is a risk factor
i. serum uric acid concentration above 7 mg/dL
b. Uric acid is an end product of purine metabolism
i. no physiological role, waste product
c. Humans lack uricase- animals have it but we do not.
FUN2: 10:00-11:00
Scribe: Joan-Marie Manolakis
Monday, December 8, 2008
Proof: Brittney Wise
Dr. Arnold
Inflammation, NSAIDs and Gout
Page 6 of 6
i. enzyme that breaks down uric acid into a more water-soluble product
d. Increased serum uric acid results from
i. Over-production of uric acid
ii. Underexcretion of uric acid
XXXI. [S35] Skipped
XXXII. Uric Acid Synthesis [S36]
a. This is the pathway of uric acid production. Hypoxanthine and xanthine are both water soluble. Uric acid is not
and that’s why it deposits in joints.
XXXIII. Clinical Presentation of Gout [S37]
a. Initial attack often in great toe or any joint
b. Acute attacks peak: 1-2 days; lasts 7-10 days
c. Risk factors for gout attack: alcohol consumption, obesity, hypertension
d. Tophi occur approximately 12 years after initial attack
i. Tophi are the deposition of the uric acid.
e. Nodular masses of monosodium urate cyrstals deposited in soft tissues
XXXIV. [S38]
a. Initial treatment is via NSAIDs, especially Indomethacin.
b. You can also add colchicines.
c. If NSAIDs and colchicines don’t work, then go to glucocorticoids.
d. We try to prevent an episode.
XXXV. Colchicine [S39,40]
a. Colchicine-one of the first agents used to treat an acute attack. It is an anti-mitotic. It can bind to intracellular
proteins, tubulins, and prevent polymerization. It arrests proinflammatory mediators and keeps them from
moving into the site of inflammation. It can be considered an anti-inflammatory.
b. Usually one of the first drugs put on the regimen of treatment.
c. It is only an anti-inflammatory only. It doesn’t have any analgesic effects, and that’s why we’d add
Indomethacin.
d. ASE: nausea, vomiting, abdominal pain and diarrhea
XXXVI. Uricosurics [S41]
a. Increase excretion of uric acid by increasing renal excretion-if we can get rid of uric acid that’s a treatment
method
b. Weak acid which completes with uric acid for reabsorption in proximal tubule
c. Initially increase urate-can actually compete with the tubular secretion of uric acid so Colchicine may be given
early on in case an attack comes
XXXVII. Probenecid [S42]
a. Can block the tubular secretion of other drugs
b. A gout patient on this chronically you can get elevated levels of penicillins and cephalosporins, so be careful if
you write for an antibiotic and the patient is on this.
XXXVIII.
Sulfinpyrazone [S43]
i. A non-steroidal reject.
ii. Some pronounced uricosuric properties.
XXXIX. Allopurinol [S44]
a. It Inhibits xanthine oxidase
b. Impairs the conversion of hypoxanthine to xanthine to uric acid
c. You have more water-soluble products that can be eliminated.
d. Used most often and chronically for the prevention of gout.
e. [end 49:34 min]