Professional Documents
Culture Documents
NSAIDs, Acetaminophen,
&Drugs Used in
Rheumatoid Arthritis
&Gout
318
Anti-inflammatory
drugs
NSAIDs
Aspirin
Other
nonselective
NSAIDs
Acetaminophen
DMARDs
COX-2
O
inhibitors
(celecoxib)
Drugs used
in gout
Acute
Chronic
Antipyretic
Cyclooxygenase (COX)
The enzyme at the head of the enzymatic pathway for prostaglandin synthesis (Figure 36-2)
Cytotoxic drug
Drugs that interfere with essential metabolic processes, especially DNA maintenance
and replication and cell division. Such drugs generally kill rapidly dividing cells and are
used for cancer chemotherapy and immunosuppression (Chapters 54 and 55)
Disease-modifying antirheumatic
drugs (DMARDs)
Diverse group of drugs that modify the inflammatory processes underlying rheumatoid
arthritis; they have a slow (weeks to months) onset of clinical effects
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Reyes syndrome
A rare syndrome of rapid liver degeneration and encephalitis in children treated with
aspirin during a viral infection
Uricosuric agent
Xanthine oxidase
Aspirin
Glucocorticoids
Colchicine
Uricosurics
(probenecid)
Xanthine oxidase
inhibitors (allopurinol)
As noted in Chapter 18, cyclooxygenase is the enzyme that converts arachidonic acid into the endoperoxide precursors of prostaglandins, important mediators of inflammation (Figure 361).
Cyclooxygenase has at least 2 isoforms: COX-1 and COX-2.
COX-1 is primarily expressed in noninflammatory cells, whereas
COX-2 is expressed in activated lymphocytes, polymorphonuclear
cells, and other inflammatory cells.
Aspirin and nonselective NSAIDs inhibit both cyclooxygenase
isoforms and thereby decrease prostaglandin and thromboxane
synthesis throughout the body. Release of prostaglandins necessary
for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation. The COX-2-selective inhibitors
317
0.25
Celecoxib
11
Diclofenac
1.1
Diflunisal
13
Etodolac
6.5
Fenoprofen
2.5
Flurbiprofen
3.8
Ibuprofen
Indomethacin
Ketoprofen
Ketorolac
B. Mechanism of Action
NSAIDs
Half-life (hours)
2
45
1.8
410
Meloxicam
20
Nabumetonea
26
Naproxen
14
Oxaprozin
58
Piroxicam
57
Sulindac
Tolmetin
(Modified and reproduced, with permission, from Katzung BG, editors: Basic & Clinical
Pharmacology, 11th ed. McGraw-Hill, 2009.)
319
Stimulus
Phospholipids
Phospholipase inhibitors
Corticosteroids
Lipoxygenase
Cyclooxygenase
NSAID, ASA
Leukotrienes
LTB4
LTC4/D4/E4
Phagocyte
attraction,
activation
Alteration of vascular
permeability, bronchial
constriction, increased
secretion
Prostaglandins
Thromboxane
Inflammation
Bronchospasm,
congestion,
mucous plugging
Leukocyte modulation
Inflammation
Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin);
LT, leukotriene; NSAID, nonsteroidal anti-inflammatory drug. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical
Pharmacology, 12thed. McGraw-Hill, 2012: Fig. 362.)
C. Effects
Arachidonic acid derivatives are important mediators of inflammation; cyclooxygenase inhibitors reduce the manifestations of
inflammation, although they have no effect on underlying tissue
damage or immunologic reactions. These inhibitors also suppress the prostaglandin synthesis in the CNS that is stimulated
by pyrogens and thereby reduces fever (antipyretic action). The
analgesic mechanism of these agents is less well understood.
Activation of peripheral pain sensors may be diminished as a
E. Toxicity
FIGURE 361
Prostacyclin
Colchicine
Receptor
antagonists
Arachidonic acid
Lipoxygenase inhibitors
Phospholipase A2
320
ACETAMINOPHEN
A. Classification and Prototype
Acetaminophen is the only over-the-counter non-anti-inflammatory
analgesic commonly available in the United States. Phenacetin, a
toxic prodrug that is metabolized to acetaminophen, is still available in some other countries.
B. Mechanism of Action
The mechanism of analgesic action of acetaminophen is unclear.
The drug is only a weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its lack of anti-inflammatory
effect. Evidence suggests that acetaminophen may inhibit a third
enzyme, COX-3, in the CNS.
C. Effects
Acetaminophen is an analgesic and antipyretic agent; it lacks antiinflammatory or antiplatelet effects.
E. Toxicity
In therapeutic dosages, acetaminophen has negligible toxicity in
most persons. However, when taken in overdose or by patients
with severe liver impairment, the drug is a dangerous hepatotoxin.
The mechanism of toxicity involves oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes. This occurs if
substrates for phase II conjugation reactions (acetate and glucuronide) are lacking (Chapter 4). Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving after an overdose.
People who regularly consume 3 or more alcoholic drinks per day
are at increased risk of acetaminophen-induced hepatotoxicity
(Chapters 4 and 23).
DISEASE-MODIFYING ANTIRHEUMATIC
DRUGS (DMARDs)
A. Classification
This heterogeneous group of agents (Table 362) has antiinflammatory actions in several connective tissue diseases. They
are called disease-modifying drugs because some evidence shows
slowing or even reversal of joint damage, an effect never seen with
321
Anakinra
Anti-IL-6 drugs
(tocilizumab)
Cyclosporine
Tissue transplantation
Hydroxychloroquine, chloroquine
D. Toxicity
All DMARDs can cause severe or fatal toxicities. Careful monitoring of patients who take these drugs is mandatory. Their major
adverse effects are listed in Table 362.
Abatacept
Gold compounds
322
Synoviocytes
Colchicine
Enzymes IL-1
Leflunomide
IL-1
Methotrexate
Anticancer
Penicillamine
Chelating agent
Rituximab
Non-Hodgkins lymphoma
Sulfasalazine
FIGURE 362
PG
C. Uricosuric Agents
PG
MNP
4. ToxicityNSAIDs can cause renal damage, and indomethacin can additionally cause bone marrow depression. Short
courses of glucocorticoids can cause behavioral changes and
impaired glucose control. Because colchicine can severely damage the liver and kidney, dosage must be carefully limited and
monitored. Overdose is often fatal.
LTB 4
PMN
PG
Urate
crystal
Indomethacin,
phenylbutazone
323
Alloxanthine,
febuxostat
O
HN 1 6 5
2
N
7
9
Xanthine
oxidase
O
N
HN
O
Xanthine
oxidase
HN
H
N
O
N
H
Hypoxanthine
N
H
N
H
Xanthine
N
H
N
H
Uric acid
FIGURE 363
The action of xanthine oxidase in uric acid synthesis and metabolism of allopurinol. (Modified and reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2012: Fig. 367.)
vasculitis, or bone marrow dysfunction, including aplastic anemia. It inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on xanthine oxidase for elimination.
Febuxostat can cause liver function abnormalities, headache,
and gastrointestinal upset.
QUESTIONS
1. Among NSAIDs, aspirin is unique because it
(A) Irreversibly inhibits its target enzyme
(B) Prevents episodes of gouty arthritis with long-term use
(C) Reduces fever
(D) Reduces the risk of colon cancer
(E) Selectively inhibits the COX-2 enzyme
2. Which of the following is an analgesic and antipyretic drug
that lacks an anti-inflammatory action?
(A) Acetaminophen
(B) Celecoxib
(C) Colchicine
(D) Indomethacin
(E) Probenecid
3. A 16-year-old girl comes to the emergency department suffering from the effects of an aspirin overdose. Which of the
following syndromes is this patient most likely to exhibit as a
result of this drug overdose?
(A) Bone marrow suppression and possibly aplastic anemia
(B) Fever, hepatic dysfunction, and encephalopathy
(C) Hyperthermia, metabolic acidosis, and coma
(D) Rapid, fulminant hepatic failure
(E) Rash, interstitial nephritis, and acute renal failure
4. Which of the following drugs is most likely to increase serum
concentrations of conventional doses of methotrexate, a weak
acid that is primarily cleared in the urine?
(A) Acetaminophen
(B) Allopurinol
(C) Colchicine
(D) Hydroxychloroquine
(E) Probenecid
324
ANSWERS
1. Aspirin differs from other NSAIDs by irreversibly inhibiting
cyclooxygenase. The answer is A.
2. Acetaminophen is the only drug that fits this description.
Indomethacin is a nonselective COX inhibitor and celecoxib is
a COX-2 inhibitor; both have analgesic, antipyretic, and antiinflammatory effects. Colchicine is a drug used for gout that
also has an anti-inflammatory action. Probenecid is a uricosuric
drug that promotes the excretion of uric acid. The answer is A.
3. Salicylate intoxication is associated with metabolic acidosis,
dehydration, and hyperthermia. If these problems are not
corrected, coma and death ensue. The answer is C.
4. Like other weak acids, methotrexate depends on active tubular excretion in the proximal tubule for efficient elimination.
Probenecid competes with methotrexate for binding to the
proximal tubule transporter and thereby decreases the rate of
clearance of methotrexate. The answer is E.
5. Ketorolac exerts typical NSAID effects. It prolongs the bleeding time and can impair renal function, especially in a patient
with preexisting renal disease. Its primary use is as a parenteral
agent for pain management, especially for treatment of postoperative patients. The answer is D.
6. In overdose, acetaminophen causes fulminant liver failure as a
result of its conversion by hepatic cytochrome P450 enzymes
to a highly reactive metabolite. The answer is C.
7. At doses needed to treat acute gout, colchicine frequently
causes significant diarrhea. Such gastrointestinal effects are
less likely with the lower doses used in chronic gout. The
answer is D.
8. Allopurinol is the only drug listed that decreases production of uric acid. Probenecid increases uric acid excretion.
Colchicine and hydroxychloroquine do not affect uric acid
metabolism. Aspirin actually slows renal secretion of uric acid
and raises uric acid blood levels. It should not be used in gout.
The answer is A.
9. Celecoxib is a COX-2-selective inhibitor. Although the
COX-2 inhibitors have the advantage over nonselective
NSAIDs of reduced gastrointestinal toxicity, clinical data
suggest that they are more likely to cause arterial thrombotic
events. A history of myocardial infarction would be a compelling reason to avoid a COX-2 inhibitor. The answer is C.
10. Etanercept is a recombinant protein that binds to tumor
necrosis factor and prevents its inflammatory effects. The
answer is B.
325
Genetic disposition
Environmental factors
Infection
trauma
Acute trigger
Synovitis
Pain
CHECKLIST
Prostaglandins
Chemotactic
factors
Inflammation
Permeability
Bone
destruction
COX-2-selective drugs.
from the market.
Phospholipases
toxicity.
gout.
Cartilage
destruction
Collagenases
Explain why several of the highly selective COX-2 inhibitors have been withdrawn
Peptidases
IL-1
Inflammation
TNF
Side effects:
Pneumonitis, nausea,
vomiting, myelosuppression
Non-steroidal
anti-inflammatory
drugs
(NSAIDs)
Glucocorticoids
Gold parenteral
Relief of symptoms
Remission
3
4
Months
6
Years
321
Reversible inhibition
of COX-1 and COX-2
results in decreased
prostaglandin synthesis
Acetylation of COX-1
and COX-2 results in
decreased prostaglandin
synthesis
Mechanism
of Action
Analgesia, antipyretic,
and anti-inflammatory
closure of patent
ductus arteriosus
Analgesia, antipyretic,
anti-inflammatory,
and antithrombotic
prevention of colon
cancer
Clinical
Applications
Duration of activity
islonger than
pharmacokinetic
half-life of drug due
to irreversible COX
inhibition
Pharmacokinetics
GI toxicity, nephrotoxicity
hypersensitivity due to increased
leukotrienes interference with aspirins
antithrombotic action
Mechanism unknown,
weak COX inhibitor
Selective, reversible
inhibition of COX-2
results in decreased
prostaglandin synthesis
Analgesia, antipyretic
Analgesia, antipyretic,
and anti-inflammatory
Cytotoxic to rapidly
dividing immune cells
due to inhibition of
dihydrofolate reductase
Anticancer, rheumatic
disorders
Inhibition of microtubule
assembly decreases macrophage migration and
phagocytosis
Active metabolite
irreversibly inhibits
xanthine oxidase and
lowers production of
uricacid
Febuxostat: reversible inhibitor of xanthine oxidase
Allopurinol
Probenecid
Uricosurics
Colchicine
Chronic
gout, adjunct
to cancer
chemotherapy
Chronic gout,
prolongation of
antimicrobial
drug action
Chronic and
acute gout,
familial
Mediterranean
fever
Diverse array of DMARDs available for clinical use. See Table 36-2
Methotrexate
Acetaminophen
Other analgesic
Celecoxib
COX-2 inhibitor
Activated by xanthine
oxidase oral drug
Oral drug
Oral drug
Renal elimination
Hepatic conjugation
Hepatic metabolism
Many nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) available for clinical use. See Table 36-1
Ibuprofen
Nonselective NSAIDs
Aspirin
Salicylates
Subclass
DRUG SUMMARY TABLE: NSAIDs, Acetaminophen, & Drugs for Rheumatoid Arthritis
& Gout
326