Chapter 36: Antiinflammatory, Antipyretic And Analgesic Agents Flashcards
NSAIDs
Aspirin BAYER, BUFFERIN, ECOTRIN
Celecoxib CELEBREX
Diclofenac CATAFLAM, FLECTOR, PENNSAID,
VOLTAREN
Diflunisal DOLOBID
Etodolac
Meclofenamate
Fenoprofen NALFON
Flurbiprofen ANSAID
Ibuprofen ADVIL, MOTRIN
Indomethacin INDOCIN
Ketorolac ACULAR, ACUVAIL, TORADOL
Ketoprofen
Meloxicam MOBIC
Methyl salicylate WINTERGREEN OIL
Nabumetone
Naproxen ALEVE, ANAPROX, NAPROSYN
Oxaprozin DAYPRO
Piroxicam FELDENE
Salsalate
Sulindac CLINORIL
Tolmetin TOLMETIN SODIUM
OTHER ANALGESICS
Acetaminophen (Paracetamol)
OFIRMEV, TYLENOL
DRUGS FOR RHEUMATOID ARTHRITIS
Abatacept ORENCIA
Adalimumab HUMIRA
Anakinra KINERET
Certolizumab CIMZIA
Hydroxychloroquine PLAQUENIL
Etanercept ENBREL
Golimumab SIMPONI
Infliximab REMICADE
Leflunomide ARAVA
Methotrexate RHEUMATREX, TREXALL
Rituximab RITUXAN
Tocilizumab
Tofacitinib
DRUGS FOR GOUT
Allopurinol ZYLOPRIM
Febuxostat ULORIC
Colchicine COLCRYS
Probenecid BENEMID
Pegloticase KRYSTEXXA
Alprostadil
Alprostadil [al-PROS-ta-dil] is a PGE1
that is naturally produced in tis-
sues such as seminal vesicles and cavernous tissues, in the placenta,
and in the ductus arteriosus of the fetus. Therapeutically, alprostadil
can be used to treat erectile dysfunction or to keep the ductus arte-
riosus open in neonates with congenital heart conditions until surgery
is possible. PGE1
maintains the patency of the ductus arteriosus dur-
ing pregnancy. The ductus closes soon after delivery to allow normal
blood circulation between the lungs and the heart. Infusion of the drug
maintains the ductus open as it naturally occurs during pregnancy,
allowing time until surgical correction is possible. The use of alprostadil
for erectile dysfunction is discussed in Chapter 32.
Lubiprostone
Lubiprostone [loo-bee-PROS-tone] is a PGE1
derivative indicated for
the treatment of chronic idiopathic constipation, opioid-induced con-
stipation, and irritable bowel syndrome with constipation. It stimulates
chloride channels in the luminal cells of the intestinal epithelium,
thereby increasing intestinal fluid secretion (see Chapter 31). Nausea
and diarrhea are the most common side effects of lubiprostone
(Figure 36.4). Nausea can be decreased if taken with food
Misoprostol
Misoprostol [mye-soe-PROST-ole], a PGE1
analog, is used to protect
the mucosal lining of the stomach during chronic NSAID treatment.
Misoprostol interacts with prostaglandin receptors on parietal cells within the stomach, reducing gastric acid secretion. Furthermore, misoprostol
has a GI cytoprotective effect by stimulating mucus and bicarbonate pro-
duction. This combination of effects decreases the incidence of gastric
ulcers caused by NSAIDs. [Note: There is a combination product con-
taining diclofenac and misoprostol.] Misoprostol is also used off-label in
obstetric settings for labor induction, since it increases uterine contrac-
tions by interacting with prostaglandin receptors in the uterus. Misoprostol
has the potential risk to induce abortion in pregnant women. Therefore,
the drug is contraindicated during pregnancy. Its use is limited by com-
mon side effects including diarrhea and abdominal pain.
Prostaglandin F2α analogs
Bimatoprost [bih-MAT-o-prost], latanoprost [la-TAN-oh-prost], taflu-
prost [TAF-loo-prost], and travoprost [TRA-voe-prost] are PGF2α
ana-
logs that are indicated for the treatment of open-angle glaucoma. By
binding to prostaglandin receptors, they increase uveoscleral outflow,
reducing intraocular pressure. They are administered as ophthal-
mic solutions once a day and are as effective as timolol or better in
reducing intraocular pressure. Bimatoprost increases eyelash promi-
nence, length, and darkness and is approved for the treatment of eye-
lash hypotrichosis. Ocular reactions include blurred vision, iris color
change (increased brown pigmentation), increased number and pig-
ment of eyelashes, ocular irritation, and foreign body sensation.
Prostacyclin (PGI2
) analogs
Epoprostenol [ee-poe-PROST-en-ol], the pharmaceutical form of nat-
urally occurring prostacyclin, and the synthetic analogs of prostacyclin
(iloprost [EYE-loe-prost] and treprostinil [tre-PROS-ti-nil]) are potent
pulmonary vasodilators that are used for the treatment of pulmonary
arterial hypertension. These drugs mimic the effects of prostacyclin
in endothelial cells, producing a significant reduction in pulmonary
arterial resistance with a subsequent increase in cardiac index and
oxygen delivery. These agents all have a short half-life. Epoprostenol
and treprostinil are administered as a continuous intravenous infu-
sion, and treprostinil may also be administered orally or via inhalation
or subcutaneous infusion. Inhaled iloprost requires frequent dosing
due to the short half-life (Figure 36.5). Dizziness, headache, flush-
ing, and fainting are the most common adverse effects (Figure 36.6).
Bronchospasm and cough can also occur after inhalation of ilopros
NSAIDs
Aspirin can be thought of as a traditional NSAID, but it exhibits anti-
inflammatory activity only at relatively high doses that are rarely used.
It has gained much more usage at lower doses for the prevention of
cardiovascular events such as stroke and myocardial infarction (MI).
Aspirin is often differentiated from other NSAIDs, since it is an irre-
versible inhibitor of cyclooxygenase activity.
1. Mechanism of action: Aspirin is a weak organic acid that irrevers-
ibly acetylates (and, thus, inactivates) cyclooxygenase (Figure 36.7).
The other NSAIDs are all reversible inhibitors of cyclooxygenase.
The NSAIDs, including aspirin, have three major therapeutic actions:
they reduce inflammation (anti-inflammatory), pain (analgesic effect),
and fever (antipyretic effect; Figure 36.8). However, as outlined below,
not all NSAIDs are equally effective in each of these actions.
a. Anti-inflammatory actions: Cyclooxygenase inhibition dimin-
ishes the formation of prostaglandins and, thus, modulates
aspects of inflammation in which prostaglandins act as media-
tors. NSAIDs inhibit inflammation in arthritis, but they neither
arrest the progression of the disease nor induce remission.
b. Analgesic action: PGE2
is thought to sensitize nerve end-
ings to the action of bradykinin, histamine, and other chemi-
cal mediators released locally by the inflammatory process.
Thus, by decreasing PGE2
synthesis, the sensation of pain can
be decreased. As COX-2 is expressed during times of inflam-
mation and injury, it is thought that inhibition of this enzyme
is responsible for the analgesic activity of NSAIDs. No single
NSAID has demonstrated superior efficacy over another, and
all agents are generally considered to have equivalent effi-
cacy. The NSAIDs are used mainly for the management of mild
to moderate pain arising from musculoskeletal disorders. One
exception is ketorolac, which can be used for more severe pain
but for only a short duration.
c. Antipyretic action: Fever occurs when the set-point of the ante-
rior hypothalamic thermoregulatory center is elevated. This can
be caused by PGE2
synthesis, which is stimulated when endoge-
nous fever-producing agents (pyrogens), such as cytokines, are
released from WBCs that are activated by infection, hypersen-
sitivity, malignancy, or inflammation. The NSAIDs lower body
temperature in patients with fever by impeding PGE2
synthesis
and release. These agents essentially reset the “thermostat” toward normal. This rapidly lowers the body temperature of febrile
patients by increasing heat dissipation as a result of peripheral
vasodilation and sweating. NSAIDs have no effect on normal
body temperature.
Celecoxib
Celecoxib [SEL-e-KOX-ib], a selective COX-2 inhibitor, is significantly
more selective for inhibition of COX-2 than COX-1 (Figure 36.14).
Unlike the inhibition of COX-1 by aspirin (which is rapid and irrevers-
ible), the inhibition of COX-2 is reversible.
1. Therapeutic uses: Celecoxib is approved for the treatment of
RA, osteoarthritis, and acute mild to moderate pain. Celecoxib has
similar efficacy to NSAIDs in the treatment of pain.
2. Pharmacokinetics: Celecoxib is readily absorbed after oral
administration. It is extensively metabolized in the liver by cyto-
chrome P450 (CYP2C9) and is excreted in feces and urine. The
half-life is about 11 hours, and the drug may be dosed once or
twice daily. The dosage should be reduced in those with moderate
hepatic impairment, and celecoxib should be avoided in patients
with severe hepatic or renal disease.
3. Adverse effects: Headache, dyspepsia, diarrhea, and abdomi-
nal pain are the most common adverse effects. Celecoxib, when
used without concomitant aspirin therapy, is associated with less
GI bleeding and dyspepsia than other NSAIDs. However, this ben-
efit is lost when aspirin is added to celecoxib therapy. Patients who
are at high risk of ulcers and require aspirin for cardiovascular pre-
vention should avoid the use of celecoxib. Like other NSAIDs, thdrug has a similar risk for cardiovascular events. Celecoxib should
be used with caution in patients who are allergic to sulfonamides.
Patients who have had anaphylactoid reactions to aspirin or non-
selective NSAIDs may be at risk for similar effects with celecoxib.
Inhibitors of CYP2C9, such as fluconazole and fluvastatin, may
increase serum levels of celecoxi
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS methotrexate
Methotrexate [meth-oh-TREX-ate], used alone or in combination
therapy, has become a mainstay of treatment in patients with rheu-
matoid or psoriatic arthritis. Methotrexate is a folic acid antagonist that
inhibits cytokine production and purine nucleotide biosynthesis, lead-
ing to immunosuppressive and anti-inflammatory effects. Response
to methotrexate occurs within 3 to 6 weeks of starting treatment; it
can also slow the appearance of new erosions within involved joints.
The other DMARDs can be added to methotrexate therapy if there is
partial or no response to maximum doses of methotrexate. Doses of
methotrexate required for RA treatment are much lower than those
needed in cancer chemotherapy and are given once a week, thereby
minimizing adverse effects. The most common side effects observed
after methotrexate treatment of RA are mucosal ulceration and nau-
sea. Cytopenias (particularly depression of the WBC count), cirrhosis
of the liver, and an acute pneumonia-like syndrome may occur with
chronic administration. [Note: Taking leucovorin (folinic acid) once
daily after methotrexate reduces the severity of adverse effects. Folic
acid taken on off-days is widely used.] Periodic liver enzyme tests,
complete blood counts, and monitoring for signs of infection are
recommended.
Hydroxychloroquine
Hydroxychloroquine [hye-drox-ee-KLOR-oh-kwin] is used for early,
mild RA, often combined with methotrexate. This agent is also used in
the treatment of lupus and malaria. Its mechanism of action in auto-
immune disorders is unknown, and onset of effects takes 6 weeks
to 6 months. Hydroxychloroquine has less effects on the liver and
immune system than other DMARDs; however, it may cause ocular
toxicity, including irreversible retinal damage and corneal deposits. It
may also cause CNS disturbances, GI upset, and skin discoloration
and eruptions.
Leflunomide
Leflunomide [le-FLOO-no-mide] is an immunomodulatory agent
that preferentially causes cell arrest of the autoimmune lympho-
cytes through its action on dihydroorotate dehydrogenase (DHODH).
Activated proliferating lymphocytes require constant DNA synthe-
sis to proliferate. Pyrimidines and purines are the building blocks of
DNA, and DHODH is necessary for pyrimidine synthesis. After bio-
transformation, leflunomide becomes a reversible inhibitor of DHODH
(Figure 36.17). Leflunomide is approved for the treatment of RA. It can
be used as monotherapy or in combination with methotrexate. The
most common adverse effects are headache, diarrhea, and nausea.
Other untoward effects are weight loss, allergic reactions, including
a flu-like syndrome, skin rash, alopecia, and hypokalemia. It is not
recommended in patients with liver disease, because of a risk of hep-
atotoxicity. Monitoring parameters include signs of infection, complete
blood counts, and liver enzymes.
Minocycline
Minocycline [mi-noe-SYE-kleen], a tetracycline antibiotic, is consid-
ered to be a DMARD. Although minocycline has been shown to be
effective in the treatment of early RA, it is generally not utilized as
first-line therapy. Minocycline can be used as monotherapy or in com-
bination with other DMARDs.
Sulfasalazine
Sulfasalazine [sul-fa-SAH-la-zeen] is also used for early, mild RA in
combination with methotrexate and/or hydroxychloroquine. Onset
of activity is 1 to 3 months, and it is associated with leukopenia. Its
mechanism of action in treating RA is unclear.
