NSAIDs, ACETAMINOPHEN, & DRUGS USED IN GOUT

Inflammation
Common nonspecific manifestation of many diseases
2 forms:
o Acute
o Chronic

** IMMUNE RESPONSE is involved in most types of inflammation; thus, many treatment

strategies applied to the reduction of inflammation are targeted at immune process

Anti-inflammatory drugs,
acetaminophen, drugs used in gout

Anti-inflammatory
Acetaminophen Drugs used in gout
drugs

NSAIDs DMARDs Acute Chronic

Aspirin NSAIDs Colchicine

Other
nonselective Glucocorticoids Uricosurics
NSAIDs (probenicid)
COX 2
inhibitors Allopurinol
ASPIRIN & OTHER NSAIDs
A. CLASSIFICATION AND PROTOTYPES
Aspirin (acetylsalicylic acid)
Prototype of salicylates

Other older nonselective NSAIDs

Ibuprofen, indomethacin, and many others
Vary primarily in their potency, analgesic and anti-inflammatory effectiveness,
and duration of action

Ibuprofen and Naproxen

Have moderate effectiveness

Ketorolac
Has greater analgesic effectiveness

Celecoxib and rofecoxib

First members of a new NSAID subgroup, the cyclooxygenase-2 (COX-2)-
selective inhibitors

B. MECHANISM OF ACTION
Cyclooxygenase
Enzyme that converts arachidonic acid into the endoperoxide precursors of
prostaglandins
Has at least 2 isoforms: COX-1 and COX-2

COX-1
Primarily expressed in noninflammatory cells

COX-2
Expressed in activated lymphocytes, polymorphonuclear cells, and other
inflammatory cells

Aspirin and the older 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

COX-2-selective inhibitors
Have less effect on the prostaglandins involved in homeostatic function,
particularly those in the gastrointestinal tract

Aspirin
Acetylates and thereby irreversibly inhibits cyclooxygenase
Irreversible action results in a longer duration of its antiplatelet effect
Other NSAIDs
Inhibition produced is reversible

C. EFFECTS
Arachidonic acid derivatives
Important mediators of inflammation

Cyclooxygenase inhibitors
Reduce the manifestations of inflammation
Have no effect on the underlying tissue damage or immunologic reactions
Interfere with the homeostatic function of prostaglandins
Reduce prostaglandin-mediated cytoprotection in the gastrointestinal tract and
autoregulation of renal function

NSAIDs
Suppresses prostaglandin synthesis in the CNS that is stimulated by pyrogens,
resulting in reduction of fever (antipyretic action)
Analgesic mechanism is less well understood
Activation of peripheral pain sensors may be diminished as a result of reduced
production of prostaglandins in injured tissue
A central mechanism is operative

D. PHARMACOKINETICS AND CLINICAL USE

1. Aspirin
3 therapeutic dose ranges:
o Low range (< 300mg/day)
- Effective in reducing platelet aggregation
o Intermediate dose (300-2400 mg/day)
- Have antipyretic and analgesic effects
o High dose (2400-4000 mg/day)
- Used for their anti-inflammatory effect
Readily absorbed
Hydrolyzed in blood and tissues to acetate and salicylic acid

Salicylate
Reversible nonselective inhibitor of cyclooxygenase
Elimination is first order at low doses, with a half-life of 3-5 h
At high doses, half-life increases to 15 h or more
Elimination becomes zero order
Excretion is via kidney

2. Other NSAIDs
Well absorbed after oral administration

Ibuprofen
Has a half-life of about 2h
Relatively safe
Least expensive of the older, nonselective NSAIDs
Indomethacin
A potent NSAID with increased toxicity

Naproxen and piroxicam

Longer half-lives (12-24 h)
Permit less frequent dosing

Used for the treatment of mild to moderate pain, especially the pain of
inflammation such as that seen in arthritis and gout

COX-2 inhibitors
Primarily used in inflammatory disorders

Selected NSAIDs
Used to treat other conditions including dysmenorrheal, headache, and patent
ductus arteriosus in premature infants

Ketorolac
Used mainly as a systemic analgesic NOT as an anti-inflammatory
Has a typical nonselective NSAID properties
Only NSAID available in parenteral formulation

Nonselective NSAIDs and COX-2-selective drugs

Reduce polyp formation in patients with primary familial adenomatous polyposis

**LONG TERM USE of NSAIDs reduces the risk of colon cancer

E. TOXICITY

1. Aspirin
Increases the bleeding time

Gastric upset most common adverse effect from therapeutic anti-inflammatory
doses of aspirin

Chronic use can result in gastric ulcerations, upper gastrointestinal bleeding

and renal effects, including acute failure and interstitial nephritis
when prostaglandin synthesis is inhibited by:
o Small doses of aspirin
persons with aspirin sensitivity (especially associated with nasal polyps)
may experience asthma from the increased synthesis of leukotrienes
this type of hypersensitivity to aspirin precludes treatment with any
NSAID
o Higher doses of aspirin
tinnitus, vertigo, hyperventilation, and respiratory alkalosis are observed
o Very high doses of aspirin
causes metabolic acidosis, dehydration, hyperthermia, collapse, coma
 and death

**Children with viral infections at increased risk for Reyes syndrome (hepatic
fatty degeneration and encephalopathy) if given aspirin.

2. Nonselective NSAID
Associated with significant gastrointestinal disturbance, but the incidence is lower
than with aspirin
Risk of renal damage with any of the NSAIDs, especially in patients with
preexisting renal disease
Cleared by the kidney
Renal damage results in higher, more toxic serum concentrations

o Phenylbutazone
Older NSAID
SHOULD NOT BE USED chronically
Causes aplastic anemia and agranulocytosis

o Use of parenteral ketorolac

Generally restricted to 72h because of the risk of gastrointestinal and renal
damage with longer administration

o Indomethacin
Serious hematologic reactions have been noted

3. COX-2-selective inhibitors
o Celecoxib
o Rofecoxib
o Valdecoxib
Have a reduced risk of gastrointestinal effects including gastric ulders and
serious gastrointestinal bleeding
Do not have antiplatelet effects at conventional doses and are, therefore, not
cardioprotective
Not recommended in renal dysfunction because COX-2 is constitutively active in
the kidney

Celecoxib
A sulfonamide
May cause a hypersensitivity reaction in patients who are allergic to other
sulfonamides

DISEASE-MODIFYING, SLOW-ACTING ANTIRHEUMATIC DRUGS (DMARDS,

SAARDS)

A. CLASSIFICATION AND PROTOTYPES

Disease-modifying drugs
 Heterogenous groups of agents
Has anti-inflammatory actions in several connective tissue diseases
Shows slowing or even reversal of joint damage, an effect never seen in NSAIDs
Also called slow-acting because it may take 6 weeks or 6 months for their
benefits to become apparent

Corticosteroids
May be considered anti-inflammatory drugs with an intermediate rate of action
(ie, slower than NSAIDs but faster than the other DMARDs)
Too toxic for routine chronic use
Reserved for temporary control of severe exacerbations and long term use in
patients with severe disease not controlled by other agents

B. MECHANISM OF ACTION
Cytotoxic drugs (eg, methotrexate)
Act by reducing the numbers of immune cells available to maintain the
inflammatory response

Sulfsalazine
Action as an antirheumatic drug appears to differ from its action in ulverative
colitis in that the sulfapyridine moiety appears to be more important for the
antirheumatic action than the 5-aminosalicylic acid component

Hydrochloroquine
May interfere with the activity of T lymphocytes
Decrease leukocyte chemotaxis
Stabilize lysosomal membranes
Interfere with DNA and RNA synthesis
Trap free radicals

Penicillamine
Appears to have anti-inflammatory effects similar to those of hydrochloroquine

Organic gold compounds alter the activity of macrophages, cells that pla a
central role in inflammation, especially that of arthritis
suppress phagocytic activity by polymorphonuclear
leukocytes

New DMARDs:
1. Leflunomide
Prodrug that is rapidly metabolized to a compound that inhibits
dihydroorotate dehydrogenase, an enzyme required by activated
lymphocytes for the synthesis of pyrimidines that are needed for RNA
synthesis
 In lympocytes, inhibition of this enzyme results in cell cycle arrest

2. Infliximab and adalimumab

Monoclonal antibodies that bind to and prevent the action of tumor
necrosis factor- (TNF-), a cytokine that appears to play a key role in
chronic inflammation

3. Etanercept
A recombinant fusion protein comprising 2TNF receptors linked to
immunoglobulin
Acts as a decoy decreasing the cellular actions of TNF-
C. EFFECTS
DMARDs
Used in patients with rheumatoid arthritis not responsive to other agents
Also used in other rheumatic diseases such as lupus erythematosus, arthritis
associated with Sjgrens syndrome, and juvenile rheumatoid arthritis and in
other immunologic disorders

D. PHARMACOKINETICS AND CLINICAL USE

Drugs given orally:
- Sulfzalazine
- Hydroxychloroquine
- methotrexate
- cyclospoprine
- penicillamine
- leflunomide

Anti-TNF- drugs given by injection

Gold compounds gold sodium thiomalate and aurothioglucose

(available for parenteral use)
auranofin (oral administration)

E. TOXICITY
ALL disease-modifying agents can cause severe or fatal toxicities.

Careful monitoring of patients who take these drugs is MANDATORY.

Toxicity when used for

Drug Other Clinical Uses
Rheumatoid Arthritis
Rash, gastrointestinal
Inflammatory bowel
Sulfasalazine disturbance, dizziness,
disease
headache, leukopenia
Rash, gastrointestinal
disturbance, ototoxicity,
Hydroxychloroquine Antimalarial
myopathy, peripheral
neuropathy
Nausea, mucosal ulcers,
Methotrexate Anticancer
hematotoxicity, teratogenicity
Cyclosporine Tissue replantation Nephrotoxicity, hypertension,
 peripheral neuropathy
Upper respiratory infection,
Inflammatory bowel
Infliximab activation of latent
disease
tuberculosis
Etanercept Injection site reactions
Teratogen,
Leflunomide hepatotoxicity,gastrointestinal
disturbance, skin reactions
Many adverse effects,
including diarrhea, dermatitis,
Gold Compounds
hematologic abnormalities
(including aplastic anemia)
Many adverse effects
including proteinuria,
dermatitis, gastrointestinal
Penicillamine Chelating agent
disturbance, hematologic
abnormalities(including
aplastic anemia)

ACETAMINOPHEN

A. CLASSIFICATION AND PROTOTYPE

Acetaminophen
Only over-the-counter non-anti-inflammatory analgesic commonly available in the
United States

Phenacetin
Toxic prodrug
Metabolized to acetaminophen
Still available in some other countries

B. MECHANISM OF ACTION
Acetaminophen
Mechanism of analgesic action is unclear
Is a weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its
lack of anti-inflammatory effect
May inhibit a third enzyme, COX-3, in the CNS

C. EFFECTS
Acetaminophen
An analgesic and antipyretic agent lacking anti-inflammatory or antiplatelet
effects

D. PHARMACOKINETICS AND CLINICAL USE

Acetaminophen
Effective for the same indications as intermediate-dose aspirin
Useful as an aspirin substitute, especially in children with viral infections and in
individuals with any type of aspirin intolerance
 Well absorbed orally
Metabolized in the liver
Its half-life, which is 2-3h in persons with normal hepatic function, is unaffected
by renal disease

E. TOXICITY
Acetaminophen
Has negligible toxicity in most individuals, in therapeutic dosages
Is a dangerous hepatotoxin when taken in overdose or by patients with liver
impairment
The mechanism of toxicity requires oxidation to cytotoxic intermediates by phase
I cytochrome P450 enzymes. This occurs if substrates for ohase II conjugation
reactions (acetate and glucuronide) are lacking.
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
for acteminophen-induced hepatotoxicity.

DRUGS USED IN GOUT

A. CLASSIFICATION AND PROTOTYPE

Gout
Associated with increased serum concentrations of uric acid
Acute attacks involve joint inflammation initiated by precipitation of uric acid
crystals

Treatment strategies include:

1. reducing inflammation during acute attacks (with colchicines, NSAIDs, or
glucocorticoids)
2. accelerating renal excretion of uric acid with uricosuric drugs (probenecid or
sulfinpyrazone )
3. reducing (with allopurinol) the conversion of purines to uric acid by xanthine
oxidase

B. ANTI-INFLAMMATORY DURGS USED FOR GOUT

1. Mechanisms

Potent NSAIDs:
o Indomethacin
Effective in inhibiting the inflammation of acute gouty arthritis
Act through the reduction of prostaglandin formation and the inhibition
of crystal phagocytosis by macrophages
o Colchicine
A selective inhibitor of microtubule assembly
Reduces leukocyte migration and phagocytosis
 May also reduce production of leukotriene B4 and decrease free
radical formation

2. Effects
NSAIDs and glucocorticoids
Reduce the synthesis of mediators of inflammation by inflammatory cells
in the gouty joint
Because it reacts with tubulin and interferes with microtubule assembly,
colchicines is a general mitotic poison

Tubulin necessary for normal cell division and many other processes

3. Pharmacokinetics and clinical use

Indomethacin or a glucocorticoid
preferred for the treatment of acute gouty arthritis

Colchicine
doses required cause significant gastrointestinal disturbance, particularly
diarrhea
lower doses are used to prevent attack of gout in patients with a history of
multiple acute attacks
of value in the management of Mediterranean fever, a disease of unknown
cause characterized by fever, hepatitis, peritonitis, pleuritis, arthritis, and
occasionally amyloidosis

Indomethacin, some glucocorticoids and colchicines used orally

Parenteral preparations of glucocorticoids and colchicines are also available.

4. Toxicity
Indomethacin
May cause renal damage or bone marrow depression

Short courses of glucocorticoids

Can cause behavioral changes and impaired glucose control

Colchicine
Can severely damage the liver and kidney
Dosage must be carefully limited and monitored
Overdose is often fatal

C. URICOSURIC AGENTS

1. Mechanism
Uricosuric agents:
o Probenecid
 o Sulfinpyrazone
Weak acids that compete with uric acid for reabsorption by the weak acid
transport mechanism in the proximal tubules of the kidney
May also compete with uric acid for secretion by the tubule at low doses
Can elevate serum uric acid concentration occasionally

Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid)
over much of its dose range.

2. Effects
Uricosuric drugs
Act primarily in the kidney
Inhibit the secretion of a large number of other weak acids (eg, penicillin,
methrotrexate) in addition to inhibiting the reabsorption of the uric acid

3. Pharmacokinetics and clinical use

Chronic gout treated orally with a uricosuric or allopurinol

- are of no value in acute gouty arthritis

- best withheld for 1-2 weeks after an
acute episode

4. Toxicity
Uricosuric drugs
Amy precipitate an attack of acute gouty arthritis during the early phase of
their action. This can be avoided by simultaneously administering colchicines
or indomethacin
May share allergenicity with other classes of sulfonamide drugs (diuretics,
antimicrobials, oral hypoglycemic drugs)

D. ALLOPURINOL
1. Mechanism
Allopurinol
Converted to oxypurinol (alloxanthine) by xanthine oxidase, the enzyme
that converts hypoxanthine to xanthine and xanthine to uric acid

Allopurinol and oxipurinol irreversible suicide inhibitors of this enzyme

2. Effects
inhibition of xanthine oxidase increases the concentration of the more
soluble hypoxanthine and xanthine
decreases the concentration of the less
soluble uric acid

As a result, there is less likelihood of precipitation of uric acid crystals in joints and
tissues.

3. Pharmacokinetics and clinical use

Allopurinol
Given orally in the management of chronic gout
Usually withheld 1-2 weeks after an acute episode of gouty arthritis
Also used as an adjunct to cancer chemotherapy to slow the formation of uric
acid from purines released by the death of large numbers of neoplastic cells

4. Toxicity and drug interactions

Allopurinol
Can precipitate acute attacks of gout during the early phase of treatment
Causes gastrointestinal upset, rash, and rarely, peripheral neuritis, vasculitis,
or bone marrow dysfunction, including aplastic anemia
Inhibits the metabolism of mercaptopurine and azathioprine, drugs that
depend on xanthine oxidase from elimination