Pharmacology Chapter 3

7/27/2019 Pharmacology Chapter 3

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Chapter 3Anti-inflammatoryMedications


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NSAIDs The use of NSAIDs for the treatment of

sports-related injuries, as well as other

maladies, (namely osteoarthritis)continues to rise.

In 2001, sales of NSAID prescriptions

accounted for $10.9 billion in the UnitedStates.


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The InflammatoryResponse The acute inflammatory cascade is set

into motion by the initial tissue insult.

Grossly, acute inflammation isrecognized by the classic and familiarsigns of pain (dolor), heat (calor),

erythema (rubor), swelling (tumor), andloss of function (functio laesa).


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Figure 3-1: TheInflammatory Response


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Inflammatory Response(cont.) Following a short period of

vasoconstriction - cellular injury signals

the release of chemical mediators, suchas histamine, serotonin, anaphylatoxins,bradykinin, thromboxane, leukotrienes,and prostaglandins.


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Box 3-2 page 36 Major actions of the Eicosanoids

Prostaglandins

Thromboxane

Leukotrienes


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Anti-inflammatoryMedications Aspirin (acetylsalicylic acid) - a derivative

of salicylic acid.

Salicylic acid, in turn, was created fromsalicin, which is found in the bark of willowtrees.

Aspirin was first synthesized by a BayerCompany chemist in the late 19th century.

It proved to be far less of a gastric irritantthan salicylic acid and was introduced to the

marketplace in the spring of 1899.


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In 1971, Sir John Vane discovered that the

aspirin molecule transfers a functionalgroup onto the cyclooxygenase enzyme.Until this time the actual mechanism ofaction for aspirin was unknown.


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Cyclooxygenase Enzyme(COX)

This enzyme is irreversibly inhibited andunable to bind arachidonic acid, therefore,the enzyme can no longer convertarachidonic acid to prostaglandins andthromboxane.

The Leukotriene pathway, however, isunaffected


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Effects of Aspirin Analgesic

Antipyretic

Anticoagulant

Anti-inflammatory


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Effects of Aspirin 3000 6000 mg per day for anti-

inflammatory action; a series of chemical

events results from the blockage ofcyclooxygenase

325 mg aspirin = 12 to 18 aspirin per dayto reach an anti-inflammatory effect


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Effects of Aspirin The decrease in prostaglandin production

leads to a corresponding reduction in

inflammation and edema.


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Effects of Aspirin Blocks prostaglandin production, even

the cytoprotection.

In the GI tract, aspirin can cause gastricupset, bleeding, and even ulcers.

Various studies have shown GI disturbance

incidence of anywhere from 2 percent to 40percent.


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Effects of Aspirin The mechanism of gastric irritation

appears related to the direct effect of

aspirin upon the lining of the stomach.

Mild gastrointestinal upset can often be

avoided if aspirin is taken with a meal,due to the "buffering" action of the food.


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Effects of Aspirin Aspirin use may also result in

complications, such as prolonged

bleeding and tinnitus. Decreased platelet function lasts from 4 to 6

days (used for blood thinning in heartpatients).

Tinnitus may be an indication of aspirintoxicity.


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Reyes Syndrome Reyes syndrome is a rare and potentially

devastating, acute illness that usually

strikes children following a viral infectionwhen they are given aspirin to lowerfever.

This syndrome is now suspected in teensand young adults with viral infections whotake aspirin.


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Table 3-1: The FiveClinical Stages of ReyesSyndrome


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Aspirin Sensitive Asthma Upon exposure to even small quantities

of aspirin, those affected may developnasal congestion and acute, often severe

bronchospasm. There is an almost universal cross-

reactivity with other NSAIDs.

Patients can be desensitized over timewith daily administration of aspirin andcross-tolerance to other NSAIDs usuallyoccurs.


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Acetaminophen Acetaminophen (Tylenol) is not an anti-

inflammatory agent, it has antipyretic and

analgesic properties. Will be discussed with the analgesics

(Chapter 10).


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NSAIDs COX-2 Inhibitors

Primarily induced at sites of inflammation

COX-2 inhibitor could block the production ofproinflammatory prostaglandins withoutinterfering with gastric protection or plateletactivity

Research is controversial and the drugs areexpensive


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Overview of SelectedNSAIDs Box 3-4 Page 42 Factors to Consider in

Choosing an NSAID

Age of Patient Duration of Treatment

Time of Onset

Compliance

Other Medications General Health of Patient

Cost of Treatment


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Ibuprofen Advil, Motrin, Nuprin

Most frequently used NSAID

Introduced to the OTC market in 1985, itis available in 200 to 800 mg tablets byprescription, and 200 mg tablets OTC

Frequently used as an antipyretic inadults and children, as its longer durationof action makes it a popular alternative toacetaminophen


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Ibuprofen Peak plasma levels are achieved within

15 to 30 minutes of ingestion

Rapid onset of action can be quitebeneficial for quick relief of pain

Half-life of about 2 hours, it must be

taken every 6 to 8 hours to maintaineffect

An anti-inflammatory regimen requires

2400 3200 mg daily


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Ibuprofen Taken in three separate doses, allowing

it to be taken at meal times, lessening the

likelihood of gastric irritation. Sufficient analgesia should be achieved

by daily dosages of less than 2400 mgper day.

Approximately 10 percent to 15 percentof individuals must discontinue usesecondary to gastrointestinal symptoms.


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Naproxen Naprosyn, Aleve.

Chemically similar to ibuprofen.

Naproxen is available as the OTC preparationAleve, and asAnaproxby prescription.

Due to naproxen's long half-life (approximately12 hours), the daily recommended dosage of

750 1000 mg can be taken on a twice dailyschedule, reducing gastric upset due to onlytwo exposures and improving compliance.


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Naproxen Peak plasma levels are achieved within 2

to 4 hours

Incidence of upper gastrointestinalbleeding in OTC use is double that ofOTC ibuprofen


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Indomethacin Indocin.

Although particularly effective in maladiessuch as rheumatoid arthritis, ankylosing

spondylitis, and gout, indomethacin istypically not recommended for use as asimple analgesic or antipyretic due topotentially severe side-effects.

Up to half of those using indomethacinmay experience some side-effects andalmost one-third will discontinue use.


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Indomethacin Common side-effects include

gastrointestinal symptoms (ulceration,nausea, abdominal pain) and headaches(15 percent to 25 percent of patients).

Peak concentrations can be achieved in 1to 2 hours (in fasting subjects, onset isdelayed by food intake).


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Indomethacin A half-life of about 2.5 hours. Daily dosage ranges from 75 mg 100

mg taken in two to three doses. Indomethacins use has declined as newer

agents with a lower side-effect profile haveemerged.


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Nabumetone (Relafen) Only nonacid NSAID currently available

Once-a-day treatment; half-life is 24

hours


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Rofecoxib Vioxx

One of only three potent and highly

selective COX-2 inhibitors available. It does not inhibit COX-1 and has no

effect on platelet function.

It is FDA approved for the treatment ofosteoarthritis, dysmenorrhea, and acutepain.


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Rofecoxib Dosages range from 12.5 mg 50 mg. It

is administered once daily given its

nearly 17-hour half-life. Long-term toxic effects, including

gastrointestinal and renal effects, are not

yet known given the drugs relativelyrecent introduction.


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Celecoxib Celebrex

COX-2 inhibitor

200 mg tablets Peak Plasma levels = 3 hours

Half-life (approximate-effective) = 11 hours

Problems include: Liver and kidneys

Heart ?


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Ketorolac Toradol.

Not typically employed for its anti-

inflammatory properties. It is the only NSAID available for

intramuscular or intravenous injection as

well as oral administration.


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Ketorolac Although it also has anti-inflammatory

and antipyretic properties, it is mostcommonly marketed and used as an

analgesic, particularly in postoperativepatients.

As an analgesic, ketorolac offers great

promise as it avoids the most commonshortcomings of opioids, i.e., tolerance,withdrawal effects, and respiratory

depression.


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Ketorolac Interestingly, Tokish et al (1992) recently

reported that 28 of 30 National Football

League team medical staffs commonlyuse ketorolac intramuscular injections ongame days for pain relief.

Due to high risk of renal effects, durationof ketorolac treatment is typically held toless than 5 days.


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NSAID Indications


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NSAID Adverse Effects


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NSAID Use


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Drug-Drug Interactions


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Glucocorticosteroids Animal studies demonstrate:

Potent anti-inflammatory actions ofglucocorticosteroids and their subsequenteffects upon healing

Glucocorticosteroids induced an early,transient recovery of the force-generatingcapacity of the effected muscle

Long-term findings revealed irreversibledamage to the healing muscle, includingatrophy and diminished force-generatingcapacity


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Actions of Corticosteroids


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Corticosteroids in SportsMedicine Stanley and Weaver (1989) state that

inconsistency in the studies onglucocorticosteroid use does not lendadequate support or direction to thesports medicine clinician in their use.

Extremely powerful anti-inflammatory

medications but no good research todemonstrate their effectiveness inactivity-related injury.


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Box 3-7: Most CommonIndications for InjectableCorticosteroids


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Box 3-8: PotentialComplications ofInjectable Corticosteroids

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