296    SECTION IV  Drugs with Important Actions on Smooth Muscle

cavity, and the endocardial tissue of the heart. These changes
occurred insidiously over months and presented as hydronephro-
sis (from obstruction of the ureters) or a cardiac murmur (from
distortion of the valves of the heart). In some cases, valve damage
required surgical replacement. As a result, this drug was with-
drawn from the US market. Similar fibrotic change has resulted
from the chronic use of non-ergot 5-HT agonists promoted in the
past for weight loss (fenfluramine, dexfenfluramine).
Other toxic effects of the ergot alkaloids include drowsi-
ness and, in the case of methysergide, occasional instances of
central stimulation and hallucinations. In fact, methysergide
was sometimes used as a substitute for LSD by members of the
so-called drug culture.
Contraindications to the use of ergot derivatives consist of the
obstructive vascular diseases, especially symptomatic coronary
artery disease, and collagen diseases.
There is no evidence that ordinary use of ergotamine for
migraine is hazardous in pregnancy. However, most clinicians
counsel restraint in the use of the ergot derivatives by preg-
nant patients. Use to deliberately cause abortion is contrain-
dicated because the high doses required often cause dangerous
vasoconstriction.

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Alkaloids
Mechanism Clinical Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Applications Interactions

H1 ANTIHISTAMINES
First generation:
  •  Diphenhydramine
Competitive Reduces or prevents histamine IgE immediate Oral and parenteral • duration 4–6 h • Toxicity:
antagonism/inverse effects on smooth muscle, allergies; especially Sedation when used in hay fever, muscarinic
agonism at H1 immune cells • also blocks hay fever, urticaria blockade symptoms, orthostatic hypotension
receptors muscarinic and α adrenoceptors • often used as a • Interactions: Additive sedation with other
• highly sedative sedative, antiemetic, sedatives, including alcohol • some inhibition of
and anti-motion CYP2D6, may prolong action of some β blockers
sickness drug

Second generation:
  •  Cetirizine Competitive Reduces or prevents histamine IgE immediate Oral • duration 12–24 h • Toxicity: Sedation and
antagonism/inverse effects on smooth muscle, allergies; especially arrhythmias in overdose • Interactions: Minimal
agonism at H1 immune cells hay fever, urticaria
receptors

  • Other first-generation H1 blockers: Chlorpheniramine is a less sedating H1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H1 blocker, is available
over-the-counter in many sleep-aid formulations and in Diclegis (in combination with pyridoxine) for use in nausea and vomiting of pregnancy
  •  Other second-generation H1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine

H2 ANTIHISTAMINES
  •  Cimetidine, others (see Chapter 62)

SEROTONIN AGONISTS
5-HT1B/1D:
  •  Sumatriptan Partial agonist at Effects not fully understood Migraine and cluster Oral, nasal, parenteral • duration 2 h • Toxicity:
5-HT1B/1D receptors • may reduce release of headache Paresthesias, dizziness, coronary
calcitonin gene-related peptide vasoconstriction • Interactions: Additive with
and perivascular edema in other vasoconstrictors
cerebral circulation

  • Other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action);
much more expensive than generic sumatriptan

5-HT2C:
  •  Lorcaserin Agonist at 5-HT2C Appears to reduce appetite Obesity Oral • duration 11 h • Toxicity: Dizziness,
receptors headache, constipation

5-HT4:
  •  Tegaserod (see Chapter 62)

(continued)
 CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    297

Mechanism Clinical Pharmacokinetics, Toxicities,

Subclass, Drug of Action Effects Applications Interactions

SEROTONIN BLOCKERS
5-HT2:
  • Ketanserin (not Competitive Prevents vasoconstriction and Hypertension Oral • duration 12–24 h • Toxicity: Hypotension
available in USA) blockade at 5-HT2 bronchospasm of carcinoid • carcinoid syndrome
receptors syndrome associated with
carcinoid tumor

5-HT3:
  •  Ondansetron, others (see Chapter 62)

ERGOT ALKALOIDS
Vasoselective:
  •  Ergotamine Mixed partial agonist Causes marked smooth muscle Migraine and cluster Oral, parenteral • duration 12–24 h • Toxicity:
effects at 5-HT2 and contraction but blocks headache Prolonged vasospasm causing angina,
α adrenoceptors α-agonist vasoconstriction gangrene; uterine spasm

Uteroselective:
  •  Ergonovine Mixed partial agonist Same as ergotamine • some Postpartum bleeding Oral, parenteral (methylergonovine) • duration
effects at 5-HT2 and selectivity for uterine smooth • migraine headache 2–4 h • Toxicity: Same as ergotamine
α adrenoceptors muscle

CNS selective:
  • Lysergic acid Central nervous Hallucinations None • widely Oral • duration several hours • Toxicity:
diethylamide system 5-HT2 and • psychotomimetic abused Prolonged psychotic state, flashbacks
dopamine agonist
• 5-HT2 antagonist in
periphery

  • Bromocriptine, pergolide: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and prolactinoma (see Chapter 37). Pergolide used in equine
Cushing’s disease

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

ANTIHISTAMINES (H 1 BLOCKERS) * Fexofenadine Generic, Allegra
Azelastine Generic, Astelin (nasal), Optivar
Hydroxyzine Generic, Vistaril
(ophthalmic)
Ketotifen Generic, Zaditor
Brompheniramine Brovex, Dimetapp, others
Levocabastine Livostin
Buclizine Bucladin-S Softabs
Levocetirizine Generic, Xyzal
Carbinoxamine Generic, Histex
Loratadine Generic, Claritin
Cetirizine Generic, Zyrtec
Chlorpheniramine Generic, Chlor-Trimeton Meclizine Generic, Antivert, Bonine

Clemastine Generic, Tavist Olopatadine Patanol, Pataday

Cyclizine Generic, Marezine Phenindamine Nolahist

Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan

Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist

Dimenhydrinate †
Generic, Dramamine H 2 BLOCKERS

Diphenhydramine Generic, Benadryl See Chapter 62.

Doxylamine Diclegis (combination with 5-HT AGONISTS

pyridoxine), Unisom Sleep Tabs Almotriptan Axert
Epinastine Generic, Elestat Eletriptan Relpax
(continued)
362    SECTION IV  Drugs with Important Actions on Smooth Muscle

SUMMARY  Drugs Used in Asthma

Subclass, Mechanism of Pharmacokinetics,
Drug Action Effects Clinical Applications Toxicities

BETA AGONISTS
  •  Albuterol Selective β2 agonist Prompt, efficacious bronchodilation Asthma, chronic obstructive Aerosol inhalation • duration several
pulmonary disease (COPD) hours • also available for nebulizer and
• drug of choice in acute parenteral use • Toxicity: Tremor,
asthmatic bronchospasm tachycardia • Overdose: arrhythmias

  •  Salmeterol Selective β2 agonist Slow onset, primarily preventive Bronchodilation, prevention of Aerosol inhalation • duration 12–24 h
action; potentiates corticosteroid asthma exacerbations • Toxicity: Tremor, tachycardia • Overdose:
effects arrhythmias

  •  Metaproterenol, terbutaline: Similar to albuterol; terbutaline available as an oral drug

  •  Formoterol, vilanterol: Similar to salmeterol

  •  Epinephrine Nonselective α and Bronchodilation plus all other Anaphylaxis, asthma, others Aerosol, nebulizer, or parenteral
β agonist sympathomimetic effects on (see Chapter 9) • rarely used for • see Chapter 9
cardiovascular and other organ asthma (β2-selective agents
systems (see Chapter 9) preferred)

  •  Isoproterenol β1 and β2 agonist Bronchodilation plus powerful Asthma, but β2-selective agents Aerosol, nebulizer, or parenteral
cardiovascular effects preferred • see Chapter 9

CORTICOSTEROIDS, INHALED
  •  Fluticasone Alters gene Reduces mediators of inflammation Asthma • adjunct in COPD Aerosol • duration hours • Toxicity:
expression • powerful prophylaxis of • hay fever (nasal) Limited by aerosol application • candidal
exacerbations infection, vocal cord changes

  •  Beclomethasone, budesonide, flunisolide, others: Similar to fluticasone

CORTICOSTEROIDS, SYSTEMIC
  •  Prednisone Like fluticasone Like fluticasone Asthma • adjunct in COPD Oral • duration 12–24 h • Toxicity:
Multiple • see Chapter 39

  •  Methylprednisolone: Parenteral agent like prednisone

STABILIZERS OF MAST AND OTHER CELLS

  • Cromolyn, Alter function of Prevention of bronchospastic Asthma (other routes used for Aerosol • duration 6–8 h • Toxicity: Cough
nedocromil delayed chloride response to allergen inhalation ocular, nasal, and • not absorbed so other toxicities are
(no longer channels • inhibit gastrointestinal allergy) minimal
available in inflammatory cell
the USA) activation

METHYLXANTHINES
  •  Theophylline Uncertain: Bronchodilation, cardiac stimulation, Asthma, COPD Oral • duration 8–12 h but extended-
• phosphodiesterase increased skeletal muscle strength release preparations often used • Toxicity:
inhibition (diaphragm) Multiple (see text)
• adenosine
receptor antagonist

  •  Roflumilast: Similar to theophylline, but with better therapeutic ratio

LEUKOTRIENE ANTAGONISTS
  • Montelukast, Block leukotriene Block airway response to exercise Prophylaxis of asthma, Oral • duration hours • Toxicity: Minimal
zafirlukast D4 receptors and antigen challenge especially in children and in
aspirin-induced asthma

  •  Zileuton: Inhibits lipoxygenase, reduces synthesis of leukotrienes

IgE ANTIBODY
  •  Omalizumab Humanized IgE Reduces frequency of asthma Severe asthma inadequately Parenteral • duration 2–4 weeks • Toxicity:
antibody reduces exacerbations controlled by above agents Injection site reactions (anaphylaxis
circulating IgE extremely rare)

(continued)
 CHAPTER 20  Drugs Used in Asthma    363

Subclass, Mechanism of Pharmacokinetics,

Drug Action Effects Clinical Applications Toxicities

ANTI-INTERLEUKIN-5 PATHWAY ANTIBODIES AND OTHER ANTIBODIES

  •  Mepolizumab Humanized anti-IL-5 Reduces frequency of asthma Severe asthma inadequately Parenteral • duration 2–4 wk • Toxicity:
antibody; reduces exacerbations controlled by above agents, Injection site reactions (anaphylaxis
circulating and with associated eosinophilia extremely rare)
tissue eosinophils

  •  Dupilumab Humanized Reduces frequency of asthma Severe asthma inadequately Parenteral injection every 2–4 wk
antibody against exacerbations; improves pulmonary controlled by ICS/LABA therapy
IL-4α receptor for function
IL-4 and IL-13

Reslizumab and benralizumab: Similar to mepolizumab

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

SHORT-ACTING BETA-AGONIST BRONCHODILATORS Budesonide Pulmicort
Albuterol Generic, Proventil, ProAir, Ventolin Ciclesonide Alvesco
Bitolterol Tornalate Mometasone Asmanex
Ephedrine Generic Flunisolide AeroBid, Aerospan
Epinephrine Generic, Adrenaline Fluticasone Flovent
Triamcinolone Azmacort
Levalbuterol Xenopex
COMBINATION INHALERS
Metaproterenol Generic, Alupent
Formoterol/budesonide Symbicort
Pirbuterol Maxair
Formoterol/mometasone Dulera
Terbutaline Breathaire, Brethine
Salmeterol/fluticasone Advair
SHORT-ACTING ANTIMUSCARINIC BRONCHODILATOR
Vilanterol/fluticasone Breo
Ipratropium Generic, Atrovent
Vilanterol/umeclidinium Anoro
COMBINATION SHORT-ACTING BRONCHODILATOR
LEUKOTRIENE INHIBITORS
Albuterol/ipratropium Combivent
Montelukast Generic, Singulair
LONG-ACTING BETA-ADRENERGIC BRONCHODILATORS
Zafirlukast Accolate
Formoterol Foradil Zileuton Zyflo
Indacaterol Arcapta PHOSPHODIESTERASE INHIBITORS, METHYLXANTHINES
Olodaterol Striverdi Dyphylline Dilor, Dylix, Lufyllin
Salmeterol Serevent Roflumilast Daliresp
LONG-ACTING ANTIMUSCARINIC BRONCHODILATORS Theophylline Generic, Elixophyllin, Slo-Phyllin,
Aclidinium Tudorza Uniphyl, Theo-Dur, Theo-24
Tiotropium Spiriva MONOCLONAL ANTIBODIES
Umeclidinium Incruse Omalizumab Xolair
Benralizumab (To be determined)
AEROSOL CORTICOSTEROIDS
Mepolizumab Nucala
See also Chapter 39
Reslizumab Cinqair
Beclomethasone QVAR, Beclovent, Vanceril
 Infliximab
NSAIDS
INTERLEUKIN-1 INHIBITORS
Acetylated Anakinra
Aspirin Canakinumab
Rilonacept
NONACETYLATED SALICYLATES
magnesium choline salicylate Other Analgesics
sodium salicylate Acetaminophen
salicyl salicylate Ketorolac
Tramadol
COX2 Selective
Celecoxib ACUTE GOUT
Meloxicam Colchicine
NSAIDS except aspirin, salicylates and tolmetin
Non-selective Probenecid
Diclofenac
Sulfinpyrazone
Diflunisal
Etodolac CHRONIC GOUT
Fluribiprofen Allopurinol
Ibuprofen Febuxostat
Indomethacin Pegloticase
Ketoprofen
Nabumetone
Naproxen
Oxaprozine
Piroxicam
Sulindac
Tolmetin

DMARDS
ABATACEPT
AZATHIOPRINE
CHLOROQUINE & HYDROXYCHLOROQUINE
CYCLOPHOSPHAMIDE
CYCLOSPORINE
LEFLUNOMIDE
METHOTREXATE
MYCOPHENOLATE MOFETIL
RITUXIMAB
SULFASALAZINE
TOCILIZUMAB

TNF-alpha-BLOCKING AGENTS
Adalimumab
Certolizumab
Etanercept
Golimumab
644    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Propionic acid derivative Pyrrolealkanoic acid derivative Phenylalkanoic acid derivative

COOH O CH3 COOH COOH

C H C N CH2
CH
H 3C
CH CH2 CH3
CH3
H3C H3C F

Ibuprofen Tolmetin Flurbiprofen

Indole derivative Pyrazolone derivative Phenylacetic acid derivative

COOH
H 3C O
CH2 CH2COOH CI

N CH3 N N
NH
O O
C O
CI
CH2 CH2 CH2 CH3
CI
Indomethacin Phenylbutazone Diclofenac

Fenamate Oxicam Naphthylacetic acid prodrug

COOH
HO O
O
N H C NH
CH2CH2CCH3
N
Cl Cl
N
S CH3 H3C O
CH3 O O

Meclofenamic acid Piroxicam Nabumetone

FIGURE 36–1  Chemical structures of some NSAIDs.

Selectivity for COX-1 versus COX-2 is variable and incomplete
for the older NSAIDs, but selective COX-2 inhibitors have been
synthesized. The selective COX-2 inhibitors do not affect platelet
function at their usual doses. The efficacy of COX-2-selective drugs
equals that of the older NSAIDs, while GI safety may be improved.
On the other hand, selective COX-2 inhibitors increase the inci-
dence of edema, hypertension, and possibly, myocardial infarction.
As of August 2011, celecoxib and the less selective meloxicam were
the only COX-2 inhibitors marketed in the USA. Celecoxib has a
U.S Food and Drug Administration (FDA) “black box” warning
concerning cardiovascular risks. It has been recommended that all
NSAID product labels be revised to mention cardiovascular risks. In
July 2015 the FDA strengthened the warning that NSAIDs can cause
heart attacks or strokes. A study found that NSAID use was associated
with increased risk of serious bleeding and cardiovascular events after
myocardial infarction. The risk is higher among users of celecoxib and
diclofenac, and lower among users of ibuprofen and naproxen.
The NSAIDs decrease the sensitivity of vessels to bradykinin
and histamine, affect lymphokine production from T lymphocytes,
and reverse the vasodilation of inflammation. To varying degrees,
all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic,
and all (except the COX-2–selective agents and the nonacetylated
salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants
and can be associated with GI ulcers and bleeds as well, although as
a group the newer agents tend to cause less GI irritation than aspirin.
Nephrotoxicity, reported for all NSAIDs, is due, in part, to interfer-
ence with the autoregulation of renal blood flow, which is modulated
by prostaglandins. Hepatotoxicity also can occur with any NSAID.
Although these drugs effectively inhibit inflammation, there is no
evidence that—in contrast to drugs such as methotrexate, biologics,
and other DMARDs—they alter the course of any arthritic disorder.
Several NSAIDs (including aspirin) reduce the incidence of
colon cancer when taken chronically. Several large epidemiologic
studies have shown a 50% reduction in relative risk for this
neoplasm when the drugs are taken for 5 years or longer. The
mechanism for this protective effect is unclear.
Although not all NSAIDs are approved by the FDA for the
whole range of rheumatic diseases, most are probably effective in
RA, seronegative spondyloarthropathies (SpA, eg, PsA and arthritis
associated with inflammatory bowel disease), OA, localized muscu-
loskeletal syndromes (eg, sprains and strains, low back pain), and
gout (except tolmetin, which appears to be ineffective in gout).
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     645

TABLE 36–1  Properties of aspirin and some other be reviewed only in terms of its antiplatelet effects (ie, doses of
nonsteroidal anti-inflammatory drugs. 81–325 mg once daily).

Urinary
1. Pharmacokinetics: Salicylic acid is a simple organic acid with a
Excretion of Recommended pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see
Half-Life Unchanged Anti-inflammatory Table 1–3). Aspirin is absorbed as such and is rapidly hydrolyzed
Drug (hours) Drug Dosage (serum half-life 15 minutes) to acetic acid and salicylate by ester-
Aspirin 0.25 <2% 1200–1500 mg tid ases in tissue and blood (Figure 36–3). Salicylate is nonlinearly
Salicylate 1
2–19 2–30% See footnote2 bound to albumin. Alkalinization of the urine increases the rate of
3 excretion of free salicylate and its water-soluble conjugates.
Celecoxib 11 27% 100–200 mg bid
2. Mechanisms of Action: Aspirin irreversibly inhibits platelet
Diclofenac 1.1 <1% 50–75 mg qid
COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life
Diflunisal 13 3–9% 500 mg bid
of the platelet). In other tissues, synthesis of new COX replaces
Etodolac 6.5 <1% 200–300 mg qid the inactivated enzyme so that ordinary doses have a duration
Fenoprofen 2.5 30% 600 mg qid of action of 6–12 hours.
Flurbiprofen 3.8 <1% 300 mg tid 3. Clinical Uses: Aspirin decreases the incidence of transient
Ibuprofen 2 <1% 600 mg qid ischemic attacks, unstable angina, coronary artery thrombosis
Indomethacin 4–5 16% 50–70 mg tid with myocardial infarction, and thrombosis after coronary
artery bypass grafting (see Chapter 34).
Ketoprofen 1.8 <1% 70 mg tid
4. Epidemiologic studies suggest that long-term use of aspirin at
Meloxicam 20 <1% 7.5–15 mg qd
low dosage is associated with a lower incidence of colon cancer,
Nabumetone4 26 1% 1000–2000 mg qd5
possibly related to its COX-inhibiting effects.
Naproxen 14 <1% 375 mg bid
5. Adverse Effects: In addition to the common side effects listed
Oxaprozin 58 1–4% 1200–1800 mg qd5 above, aspirin’s main adverse effects at antithrombotic doses are
Piroxicam 57 4–10% 20 mg qd5 gastric upset (intolerance) and gastric and duodenal ulcers.
Sulindac 8 7% 200 mg bid Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity
Tolmetin 1 7% 400 mg qid rarely if ever occur at antithrombotic doses.
1
Major anti-inflammatory metabolite of aspirin.
6. The antiplatelet action of aspirin contraindicates its use by
2
Salicylate is usually given in the form of aspirin.
patients with hemophilia. Although previously not recom-
3
Total urinary excretion including metabolites.
mended during pregnancy, aspirin may be valuable in treating
4
Nabumetone is a prodrug; the half-life and urinary excretion are for its active metabolite. preeclampsia-eclampsia.
5
A single daily dose is sufficient because of the long half-life.

Adverse effects are generally quite similar for all of the NSAIDs:
1. Central nervous system: Headaches, tinnitus, dizziness, and
rarely, aseptic meningitis.
2. Cardiovascular: Fluid retention, hypertension, edema, and rarely,
myocardial infarction and congestive heart failure (CHF).
3. Gastrointestinal: Abdominal pain, dyspepsia, nausea, vomiting,
and rarely, ulcers or bleeding.
4. Hematologic: Rare thrombocytopenia, neutropenia, or even
aplastic anemia.
5. Hepatic: Abnormal liver function test results and rare liver failure.
6. Pulmonary: Asthma.
7. Skin: Rashes, all types, pruritus.
8. Renal: Renal insufficiency, renal failure, hyperkalemia, and
proteinuria.
ASPIRIN
Aspirin’s long use and availability without prescription diminishes
its glamour compared with that of the newer NSAIDs. Aspirin
is now rarely used as an anti-inflammatory medication and will
NONACETYLATED SALICYLATES
These drugs include magnesium choline salicylate, sodium salicy-
late, and salicyl salicylate. All nonacetylated salicylates are effective
anti-inflammatory drugs, and they do not inhibit platelet aggrega-
tion. They may be preferable when COX inhibition is undesirable
such as in patients with asthma, those with bleeding tendencies,
and even (under close supervision) those with renal dysfunction.
The nonacetylated salicylates are administered in doses up to
3–4 g of salicylate a day and can be monitored using serum salicy-
late measurements.
COX-2 SELECTIVE INHIBITORS
COX-2 selective inhibitors, or coxibs, were developed in an
attempt to inhibit prostaglandin synthesis by the COX-2 isozyme
induced at sites of inflammation without affecting the action of
the constitutively active “housekeeping” COX-1 isozyme found
in the GI tract, kidneys, and platelets. COX-2 inhibitors at usual
doses have no impact on platelet aggregation, which is mediated
by thromboxane produced by the COX-1 isozyme. In contrast,
they do inhibit COX-2-mediated prostacyclin synthesis in the
vascular endothelium. As a result, COX-2 inhibitors do not offer
646    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Stimulus

Disturbance of cell membranes

Phospholipids
Phospholipase inhibitors
– Phospholipase
Corticosteroids

Fatty acid substitution (diet) Arachidonic acid

Lipoxygenase inhibitors – Lipoxygenase Cyclooxygenase – NSAID, ASA

Leukotrienes
Receptor –
antagonists

LTB4 LTC4/D4/E4 Prostaglandins Thromboxane Prostacyclin

Phagocyte Alteration of vascular

attraction, permeability, bronchial
activation constriction, increased Leukocyte modulation
secretion
Colchicine –

Inflammation Bronchospasm, Inflammation

congestion,
mucous plugging

FIGURE 36–2  Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin);
LT, leukotriene; NSAID, nonsteroidal anti-inflammatory drug.

O O

C OH C O Na
O C CH3 OH

Aspirin O Sodium salicylate

O
O
C O–
HO C CH3
OH
Acetic acid
Salicylate

Conjugation with Conjugation

glucuronic acid Oxidation
with glycine

O H O

Ester and ether C N CH2 COOH Free HO C OH

glucuronides salicylate
OH OH

Salicyluric acid Gentisic acid

(1%)

FIGURE 36–3  Structure and metabolism of the salicylates. (Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical
Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.)
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     647
the cardioprotective effects of traditional nonselective NSAIDs.
Recommended doses of COX-2 inhibitors cause renal toxicities
similar to those associated with traditional NSAIDs. Clinical
data suggested a higher incidence of cardiovascular thrombotic
events associated with COX-2 inhibitors such as rofecoxib and
valdecoxib, resulting in their withdrawal from the market.
Celecoxib
Celecoxib is a selective COX-2 inhibitor—about 10–20 times
more selective for COX-2 than for COX-1. Pharmacokinetic and
dosage considerations are given in Table 36–1.
Celecoxib is associated with fewer endoscopic ulcers than
most other NSAIDs. Probably because it is a sulfonamide, cele-
coxib may cause rashes. It does not affect platelet aggregation at
usual doses. It interacts occasionally with warfarin—as would be
expected of a drug metabolized via CYP2C9. Adverse effects are
the common toxicities listed above.
O O
S
H2N
N
N half-lives at various dosages approximating that of salicylates
CF3
H3C
Celecoxib
Meloxicam
Meloxicam is an enolcarboxamide related to piroxicam that pref-
erentially inhibits COX-2 over COX-1, particularly at its lowest
therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib
and may be considered “preferentially” selective rather than
“highly” selective. It is associated with fewer clinical GI symptoms
and complications than piroxicam, diclofenac, and naproxen.
Similarly, while meloxicam is known to inhibit synthesis of
thromboxane A2, even at supratherapeutic doses, its blockade of
thromboxane A2 does not reach levels that result in decreased in
vivo platelet function (see common adverse effects above).
NONSELECTIVE COX INHIBITORS*
Diclofenac
Diclofenac is a phenylacetic acid derivative that is relatively
nonselective as a COX inhibitor. Pharmacokinetic and dosage
characteristics are set forth in Table 36–1.
Gastrointestinal ulceration may occur less frequently than
with some other NSAIDs. A preparation combining diclofenac
and misoprostol decreases upper gastrointestinal ulceration but
may result in diarrhea. Another combination of diclofenac and
*
Listed alphabetically.
omeprazole was also effective with respect to the prevention of
recurrent bleeding, but renal adverse effects were common in
high-risk patients. Diclofenac, 150 mg/d, appears to impair renal
blood flow and glomerular filtration rate. Elevation of serum ami-
notransferases occurs more commonly with this drug than with
other NSAIDs.
A 0.1% ophthalmic preparation is promoted for prevention
of postoperative ophthalmic inflammation and can be used after
intraocular lens implantation and strabismus surgery. A topical
gel containing 3% diclofenac is effective for solar keratoses.
Diclofenac in rectal suppository form can be considered for
preemptive analgesia and postoperative nausea. In Europe,
diclofenac is also available as an oral mouthwash and for intra-
muscular administration.
Diflunisal
Although diflunisal is derived from salicylic acid, it is not metabo-
lized to salicylic acid or salicylate. It undergoes an enterohepatic
cycle with reabsorption of its glucuronide metabolite followed
by cleavage of the glucuronide to again release the active moiety.
Diflunisal is subject to capacity-limited metabolism, with serum
(Table 36–1). In RA the recommended dose is 500–1000 mg
daily in two divided doses. It is rarely used today.
Etodolac
Etodolac is a racemic acetic acid derivative with an intermediate
half-life (Table 36–1). The analgesic dosage of etodolac is 200–
400 mg three to four times daily. The recommended dose in OA
and RA is 300 mg twice or three times a day up to 500 mg twice
a day initially followed by a maintenance of 600 mg/d.
Flurbiprofen
Flurbiprofen is a propionic acid derivative with a possibly more
complex mechanism of action than other NSAIDs. Its (S)(–)
enantiomer inhibits COX nonselectively, but it has been shown
in rat tissue to also affect tumor necrosis factor α (TNF-α) and
nitric oxide synthesis. Hepatic metabolism is extensive; its (R)(+)
and (S)(–) enantiomers are metabolized differently, and it does
not undergo chiral conversion. It does demonstrate enterohepatic
circulation.
Flurbiprofen is also available in a topical ophthalmic formula-
tion for inhibition of intraoperative miosis. Flurbiprofen intrave-
nously is effective for perioperative analgesia in minor ear, neck,
and nose surgery and in lozenge form for sore throat.
Although its adverse effect profile is similar to that of other
NSAIDs in most ways, flurbiprofen is also rarely associated with
cogwheel rigidity, ataxia, tremor, and myoclonus.
Ibuprofen
Ibuprofen is a simple derivative of phenylpropionic acid
(Figure 36–1). In doses of about 2400 mg daily, ibuprofen is
equivalent to 4 g of aspirin in anti-inflammatory effect. Pharma-
cokinetic characteristics are given in Table 36–1.
648    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
Oral ibuprofen is often prescribed in lower doses (<1600 mg/d),
at which it is analgesic but not anti-inflammatory. It is available
over the counter in low-dose forms.
Ibuprofen oral and IV is effective in closing patent ductus
arteriosus in preterm infants, with much the same efficacy and
safety as indomethacin. A topical cream preparation appears to
be absorbed into fascia and muscle; ibuprofen cream was more
effective than placebo cream in the treatment of primary knee OA.
A liquid gel preparation of ibuprofen, 400 mg, provides prompt
relief and good overall efficacy in postsurgical dental pain.
In comparison with indomethacin, ibuprofen decreases urine
output less and also causes less fluid retention. The drug is
relatively contraindicated in individuals with nasal polyps, angio-
edema, and bronchospastic reactivity to aspirin. Aseptic menin-
gitis (particularly in patients with SLE), and fluid retention have
been reported. The concomitant administration of ibuprofen and
aspirin antagonizes the irreversible platelet inhibition induced by
aspirin. Thus, treatment with ibuprofen in patients with increased
cardiovascular risk may limit the cardioprotective effects of aspi-
rin. Furthermore, the use of ibuprofen concomitantly with aspirin
may decrease the total anti-inflammatory effect. Common adverse
effects are listed on page 645 rare hematologic effects include
agranulocytosis and aplastic anemia.
Indomethacin
Indomethacin, introduced in 1963, is an indole derivative
(Figure 36–1). It is a potent nonselective COX inhibitor and may
also inhibit phospholipase A and C, reduce neutrophil migration,
and decrease T-cell and B-cell proliferation.
Indomethacin differs somewhat from other NSAIDs in its
indications and toxicities. It has been used to accelerate closure of
patent ductus arteriosus. Indomethacin has been tried in numer-
ous small or uncontrolled trials for many other conditions, includ-
ing Sweet’s syndrome, juvenile RA, pleurisy, nephrotic syndrome,
diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and
prophylaxis of heterotopic ossification in arthroplasty.
An ophthalmic preparation is efficacious for conjunctival
inflammation and to reduce pain after traumatic corneal abra-
sion. Gingival inflammation is reduced after administration of
indomethacin oral rinse. Epidural injections produce a degree of
pain relief similar to that achieved with methylprednisolone in
postlaminectomy syndrome.
At usual doses, indomethacin has the common side effects
listed above. The GI effects may include pancreatitis. Headache
is experienced by 15–25% of patients and may be associated with
dizziness, confusion, and depression. Renal papillary necrosis has
also been observed. A number of interactions with other drugs
have been reported (see Chapter 66).
Ketoprofen
Ketoprofen is a propionic acid derivative that inhibits both COX
(nonselectively) and lipoxygenase. Its pharmacokinetic charac-
teristics are given in Table 36–1. Concurrent administration of
probenecid elevates ketoprofen levels and prolongs its plasma
half-life.
The effectiveness of ketoprofen at dosages of 100–300 mg/d
is equivalent to that of other NSAIDs. Its major adverse effects
are on the GI tract and the central nervous system (see common
adverse effects above).
Nabumetone
Nabumetone is the only nonacid NSAID in current use; it is
given as a ketone prodrug (Figure 36–1) and resembles naproxen
in structure. Its half-life of more than 24 hours (Table 36–1) per-
mits once-daily dosing, and the drug does not appear to undergo
enterohepatic circulation. Renal impairment results in a doubling
of its half-life and a 30% increase in the area under the curve.
Its properties are very similar to those of other NSAIDs,
though it may be less damaging to the stomach. Unfortunately,
higher dosages (eg, 1500–2000 mg/d) are often needed, and this
is a very expensive NSAID.
Naproxen
Naproxen is a naphthylpropionic acid derivative. It is the only
NSAID presently marketed as a single enantiomer. Naproxen’s free
fraction is significantly higher in women than in men, but half-life
is similar in both sexes (Table 36–1). Naproxen is effective for the
usual rheumatologic indications and is available in a slow-release
formulation, as an oral suspension, and over the counter. A topical
preparation and an ophthalmic solution are also available.
The incidence of upper GI bleeding in over-the-counter use is
low but still double that of over-the-counter ibuprofen (perhaps
due to a dose effect). Rare cases of allergic pneumonitis, leukocy-
toclastic vasculitis, and pseudoporphyria as well as the common
NSAID-associated adverse effects have been noted.
Oxaprozin
Oxaprozin is another propionic acid derivative NSAID. As noted
in Table 36–1, its major difference from the other members of
this subgroup is a very long half-life (50–60 hours), although
oxaprozin does not undergo enterohepatic circulation. It is mildly
uricosuric. Otherwise, the drug has the same benefits and risks
that are associated with other NSAIDs.
Piroxicam
Piroxicam, an oxicam (Figure 36–1), is a nonselective COX
inhibitor that at high concentrations also inhibits polymorpho-
nuclear leukocyte migration, decreases oxygen radical production,
and inhibits lymphocyte function. Its long half-life (Table 36–1)
permits once-daily dosing.
Piroxicam can be used for the usual rheumatic indications.
When piroxicam is used in dosages higher than 20 mg/d, an
increased incidence of peptic ulcer and bleeding (relative risk up
to 9.5) is encountered (see common adverse effects above).
Sulindac
Sulindac is a sulfoxide prodrug. It is reversibly metabolized to
the active sulfide metabolite and has enterohepatic cycling; this
prolongs the duration of action to 12–16 hours.
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     649
In addition to its rheumatic disease indications, sulindac sup-
presses familial intestinal polyposis and it may inhibit the develop-
ment of colon, breast, and prostate cancer in humans. Among the
more severe adverse reactions, Stevens-Johnson epidermal necroly-
sis syndrome, thrombocytopenia, agranulocytosis, and nephrotic
syndrome; all have been observed. It is sometimes associated with
cholestatic liver damage.
Tolmetin
Tolmetin is a nonselective COX inhibitor with a short half-life
(1–2 hours) and is not often used. It is ineffective (for unknown
reasons) in the treatment of gout.
Other NSAIDs
Azapropazone, carprofen, meclofenamate, and tenoxicam are
rarely used and are not reviewed here.
CHOICE OF NSAID
All NSAIDs, including aspirin, are about equally efficacious
with a few exceptions—tolmetin seems not to be effective for
gout, and aspirin is less effective than other NSAIDs (eg, indo-
methacin) for AS.
Thus, NSAIDs tend to be differentiated on the basis of toxicity
and cost-effectiveness. For example, the GI and renal side effects
of ketorolac limit its use. Some surveys suggest that indomethacin
and tolmetin are the NSAIDs associated with the greatest toxicity,
while salsalate, aspirin, and ibuprofen are least toxic. The selective
COX-2 inhibitors were not included in these analyses.
For patients with renal insufficiency, nonacetylated salicylates
may be best. Diclofenac and sulindac are associated with more
liver function test abnormalities than other NSAIDs. The rela-
tively expensive, selective COX-2 inhibitor celecoxib is probably
safest for patients at high risk for GI bleeding but may have a
higher risk of cardiovascular toxicity. Celecoxib or a nonselective
NSAID plus omeprazole or misoprostol may be appropriate in
patients at highest risk for GI bleeding; in this subpopulation
of patients, they are cost-effective despite their high acquisition
costs.
The choice of an NSAID thus requires a balance of efficacy,
cost-effectiveness, safety, and numerous personal factors (eg,
other drugs also being used, concurrent illness, compliance,
medical insurance coverage), so that there is no best NSAID for
all patients. There may, however, be one or two best NSAIDs for
a specific person.
■■ DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
RA is a progressive immunologic disease that causes signifi-
cant systemic effects, shortens life, and reduces mobility and
quality of life. Interest has centered on finding treatments that
might arrest—or at least slow—this progression by modifying
the disease itself. The effects of disease-modifying therapies may
take 2 weeks to 6 months to become clinically evident.
These therapies include conventional synthetic (cs) and
biologic (b) disease-modifying antirheumatic drugs (recently
designated csDMARDs and bDMARDs, respectively). The
conventional synthetic agents include small molecule drugs
such as methotrexate, azathioprine, chloroquine and hydroxy-
chloroquine, cyclophosphamide, cyclosporine, leflunomide,
mycophenolate mofetil, and sulfasalazine. Tofacitinib, though
marketed as a biologic, is actually a targeted synthetic DMARD
(tsDMARD). Gold salts, which were once extensively used, are
no longer recommended because of their significant toxicities
and questionable efficacy. Nevertheless, they have found lim-
ited use for RA in Canada. Biologics are large-molecule thera-
peutic agents, usually proteins, which are often produced by
recombinant DNA technology. The bDMARDs approved for
RA include a T-cell–modulating biologic (abatacept), a B-cell
cytotoxic agent (rituximab), an anti–IL-6 receptor antibody
(tocilizumab), IL-1–inhibiting agents (anakinra, rilonacept,
canakinumab), and the TNF-α–blocking agents (five drugs);
bDMARDs are further divided into biological original (or
legacy) products and biosimilar DMARDs (boDMARDs and
bsDMARDs, respectively).
The small-molecule DMARDs and biologics are discussed
alphabetically, independent of origin.
ABATACEPT
1. Mechanism of action: Abatacept is a co-stimulation modu-
lator biologic that inhibits the activation of T cells (see also
Chapter 55). After a T cell has engaged an antigen-present-
ing cell (APC), a second signal is produced by CD28 on the
T cell that interacts with CD80 or CD86 on the APC, lead-
ing to T-cell activation. Abatacept (which contains the
endogenous ligand CTLA-4) binds to CD80 and 86,
thereby inhibiting the binding to CD28 and preventing the
activation of T cells.
2. Pharmacokinetics: The recommended dose of abatacept for
the treatment of adult patients with RA is three intravenous
infusion “induction” doses (day 0, week 2, and week 4), fol-
lowed by monthly infusions. The dose is based on body weight;
patients weighing less than 60 kg receiving 500 mg, those
60–100 kg receiving 750 mg, and those more than 100 kg
receiving 1000 mg. Abatacept is also available as a subcutane-
ous formulation and is given as 125 mg subcutaneously once
weekly.
JIA can also be treated with abatacept with an induction
schedule at day 0, week 2, and week 4, followed by intravenous
infusion every 4 weeks. The recommended dose for patients
6–17 years of age and weighing less than 75 kg is 10 mg/kg,
while those weighing 75 kg or more follow the adult intrave-
nous doses to a maximum not to exceed 1000 mg. The terminal
serum half-life is 13–16 days. Co-administration with metho-
trexate, NSAIDs, and corticosteroids does not influence abata-
cept clearance.
650    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
Most patients respond to abatacept within 12–16 weeks after
the initiation of the treatment; however, some patients can
respond in as few as 2–4 weeks. A study showed equivalence
between adalimumab (see TNF-a Blocking Agents) and
abatacept.
3. Indications: Abatacept can be used as monotherapy or in com-
bination with methotrexate or other DMARDs in patients with
moderate to severe RA or severe PJIA. It has been tested in
combination with methotrexate in early rapidly progressing RA
and methotrexate-naïve patients. The combination was supe-
rior to methotrexate in achieving minimal disease activity as
early as 2 months, significantly inhibiting radiographic progres-
sion at 1 year and improving patients’ physical function and
symptoms. Such improvement is sustained or improved during
the second year. Another trial (ADJUST) tested the effective-
ness of abatacept in preventing progression to defined RA in
patients with undifferentiated inflammatory arthritis. The
results showed that numerically, RA developed in more patients
treated with placebo than in those treated with abatacept over
1 year. Abatacept has been tested in other rheumatic diseases
like SLE, primary Sjögren’s syndrome, type 1 diabetes, inflam-
matory bowel disease, and psoriasis vulgaris, but the most
beneficial effects were seen in psoriatic arthritis (PsA) patients.
4. Adverse Effects: There is a slightly increased risk of infection
(as with other biologic DMARDs), predominantly of the upper
respiratory or urinary tracts. Concomitant use with TNF-α
antagonists or other biologics is not recommended due to the
increased incidence of serious infection. All patients should be
screened for latent tuberculosis and viral hepatitis before start-
ing this medication. Live vaccines should be avoided in patients
while taking abatacept and up to 3 months after discontinua-
tion. Infusion-related reactions and hypersensitivity reactions,
including anaphylaxis, have been reported but are rare. Anti-
abatacept antibody formation is infrequent (<5%) and has no
effect on clinical outcomes. There is a possible increase in lym-
phomas but not other malignancies when using abatacept.
AZATHIOPRINE
1. Mechanism of Action: Azathioprine is a csDMARD that acts
through its major metabolite, 6-thioguanine. 6-Thioguanine
suppresses inosinic acid synthesis, B-cell and T-cell function,
immunoglobulin production, and IL-2 secretion (see Chapter 55).
2. Pharmacokinetics: Azathioprine can be given orally or paren-
terally. Its metabolism is bimodal in humans, with rapid
metabolizers clearing the drug four times faster than slow
metabolizers. Production of 6-thioguanine is dependent on
thiopurine methyltransferase (TPMT), and patients with low
or absent TPMT activity (0.3% of the population) are at par-
ticularly high risk of myelosuppression by excess concentrations
of the parent drug, if dosage is not adjusted.
3. Indications: Azathioprine is approved for use in RA at 2 mg/kg
per day. It is also used for the prevention of kidney transplant rejec-
tion in combination with other immune suppressants.
Controlled trials show efficacy in PA, reactive arthritis, polymyosi-
tis, SLE, maintenance of remission in vasculitis, and Behçet’s dis-
ease. Azathioprine is also used in scleroderma; however, in one
study, it was found to be less effective than cyclophosphamide in
controlling the progression of scleroderma lung disease. Another
registry study indicated possible usefulness in scleroderma lung
disease. Thus it is not clear what place, if any, azathioprine has for
treating scleroderma.
4. Adverse Effects: Azathioprine’s toxicity includes bone marrow
suppression, GI disturbances, and some increase in infection
risk. As noted in Chapter 55, lymphomas may be increased
with azathioprine use. Rarely, fever, rash, and hepatotoxicity
signal acute allergic reactions.
CHLOROQUINE &
HYDROXYCHLOROQUINE
1. Mechanism of Action: Chloroquine and hydroxychloroquine
are nonbiologic drugs mainly used for malaria (see Chapter 52)
and in the rheumatic diseases as csDMARDs. The following
mechanisms have been proposed: suppression of T-lymphocyte
responses to mitogens, inhibition of leukocyte chemotaxis,
stabilization of lysosomal enzymes, processing through the
Fc-receptor, inhibition of DNA and RNA synthesis, and the
trapping of free radicals.
2. Pharmacokinetics: Antimalarials are rapidly absorbed and
50% protein-bound in the plasma. They are very extensively
tissue-bound, particularly in melanin-containing tissues such as
the eyes. The drugs are deaminated in the liver and have blood
elimination half-lives of up to 45 days.
3. Indications: Antimalarials are approved for RA, but they are not
considered very effective DMARDs. Dose-loading may increase
rate of response. There is no evidence that these compounds alter
bony damage in RA at their usual dosages (up to 6.4 mg/kg per
day for hydroxychloroquine or 200 mg/d for chloroquine). It
usually takes 3–6 months to obtain a response. Antimalarials are
used very commonly in SLE because they decrease mortality and
the skin manifestations, serositis, and joint pains of this disease.
They have also been used in Sjögren’s syndrome.
4. Adverse Effects: Although ocular toxicity (see Chapter 52)
may occur at dosages greater than 250 mg/d for chloroquine
and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely
occurs at lower doses. Nevertheless, ophthalmologic monitor-
ing every 12 months is advised. Other toxicities include dyspep-
sia, nausea, vomiting, abdominal pain, rashes, and nightmares.
These drugs appear to be relatively safe in pregnancy.
CYCLOPHOSPHAMIDE
1. Mechanism of Action: Cyclophosphamide is a csDMARD. Its
major active metabolite is phosphoramide mustard, which
cross-links DNA to prevent cell replication. It suppresses T-cell
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     651
and B-cell function by 30–40%; T-cell suppression correlates
with clinical response in the rheumatic diseases. Its pharmaco-
kinetics and toxicities are discussed in Chapter 54.
2. Indications: Cyclophosphamide is used regularly at 2 mg/
kg per day to treat SLE, vasculitis, Wegener’s granulomatosis,
and other severe rheumatic diseases although mycophenolate is
now often used for SLE and rituximab is often used for some
forms of vasculitis (see below).
CYCLOSPORINE
1. Mechanism of Action: Cyclosporine is a peptide antibiotic but
is considered a csDMARD. Through regulation of gene tran-
scription, it inhibits IL-1 and IL-2 receptor production and
secondarily inhibits macrophage–T-cell interaction and T-cell
responsiveness (see Chapter 55). T-cell–dependent B-cell func-
tion is also affected.
2. Pharmacokinetics: Cyclosporine absorption is incomplete and
somewhat erratic, although a microemulsion formulation
improves its consistency and provides 20–30% bioavailability.
Grapefruit juice increases cyclosporine bioavailability by as
much as 62%. Cyclosporine is metabolized by CYP3A and
consequently is subject to a large number of drug interactions
(see Chapters 55 and 66).
3. Indications: Cyclosporine is approved for use in RA and
retards the appearance of new bony erosions. Its usual dosage is
3–5 mg/kg per day divided into two doses. Anecdotal reports
suggest that it may be useful in SLE, polymyositis and derma-
tomyositis, Wegener’s granulomatosis, juvenile chronic arthritis,
and refractory eye involvement in Behçet disease.
4. Adverse Effects: Leukopenia, thrombocytopenia, and, to a
lesser extent, anemia are predictable. High doses can be car-
diotoxic and neurotoxic, and sterility may occur after chronic
dosing at antirheumatic doses, especially in women. Bladder
cancer is very rare but must be looked for, even 5 years after
cessation of use.
LEFLUNOMIDE
1. Mechanism of Action: Leflunomide, another csDMARD,
undergoes rapid conversion, both in the intestine and in the
plasma, to its active metabolite, A77-1726. This metabolite
inhibits dihydroorotate dehydrogenase, leading to a decrease in
ribonucleotide synthesis and the arrest of stimulated cells in the
G1 phase of cell growth. Consequently, leflunomide inhibits
T-cell proliferation and reduces production of autoantibod-
ies by B cells. Secondary effects include increases of IL-10
receptor mRNA, decreased IL-8 receptor type A mRNA,
and decreased TNF-α–dependent nuclear factor kappa B
(NF-κB) activation.
2. Pharmacokinetics: Leflunomide is completely absorbed from
the gut and has a mean plasma half-life of 19 days. Its active
metabolite, A77-1726, has approximately the same half-life
and is subject to enterohepatic recirculation. Cholestyramine
can enhance leflunomide excretion and increases total clearance
by approximately 50%.
3. Indications: Leflunomide is as effective as methotrexate in RA,
including inhibition of bony damage. In one study, combined
treatment with methotrexate and leflunomide resulted in a
46.2% ACR20 response compared with 19.5% in patients
receiving methotrexate alone.
4. Adverse Effects: Diarrhea occurs in approximately 25% of
patients given leflunomide, although only about 3–5% of
patients discontinue the drug because of this side effect.
Elevation in liver enzymes can occur. Both effects can
be reduced by decreasing the dose of leflunomide. Other
adverse effects associated with leflunomide are mild alope-
cia, weight gain, and increased blood pressure. Leukopenia
and thrombocytopenia occur rarely. This drug is contrain-
dicated in pregnancy.
METHOTREXATE
Methotrexate, a synthetic nonbiologic antimetabolite, is the
first-line csDMARD for treating RA and is used in 50–70% of
patients. It is active in this condition at much lower doses than
those needed in cancer chemotherapy (see Chapter 54).
1. Mechanism of Action: Methotrexate’s principal mechanism of
action at the low doses used in the rheumatic diseases probably
relates to inhibition of amino-imidazolecarboxamide ribonu-
cleotide (AICAR) transformylase and thymidylate synthetase.
AICAR, which accumulates intracellularly, competitively
inhibits AMP deaminase, leading to an accumulation of AMP.
The AMP is released and converted extracellularly to adenos-
ine, which is a potent inhibitor of inflammation. As a result,
the inflammatory functions of neutrophils, macrophages,
dendritic cells, and lymphocytes are suppressed. Methotrexate
has secondary effects on polymorphonuclear chemotaxis.
There is some effect on dihydrofolate reductase and this affects
lymphocyte and macrophage function, but this is not its prin-
cipal mechanism of action. Methotrexate has direct inhibitory
effects on proliferation and stimulates apoptosis in immune-
inflammatory cells. Additionally, it inhibits proinflammatory
cytokines linked to rheumatoid synovitis.
2. Pharmacokinetics: Methotrexate can be administered either
orally or parentally (SC or IM). The drug is approximately
70% absorbed after oral administration (see Chapter 54).
Although variable, bioavailability decreased further in one
study when more than 25 mg weekly MTX was used. MTX
is metabolized to a less active hydroxylated product. Both
the parent compound and the metabolite are polygluta-
mated within cells where they stay for prolonged periods.
Methotrexate’s serum half-life is usually only 6–9 hours.
Hydroxychloroquine can reduce the clearance or increase
the tubular reabsorption of methotrexate. Methotrexate is
excreted principally in the urine, but up to 30% may be
excreted in bile.
652    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
3. Dosage and Indications: It is recommended to start treatment
with 7.5 mg weekly. According to patient response, methotrex-
ate is increased to the most common dosing regimen for the
treatment of RA, which is 15–25 mg weekly. Notably there is
an increased effect up to 30–35 mg weekly, although with
increased toxicity. The drug decreases the rate of appearance of
new erosions. Evidence supports its use in juvenile chronic
arthritis, and it has been used in psoriasis, PA, AS, polymyosi-
tis, dermatomyositis, Wegener’s granulomatosis, giant cell
arteritis, SLE, and vasculitis.
4. Adverse Effects: Nausea and mucosal ulcers are the most com-
mon toxicities. Additionally, many other side effects such as
leukopenia, anemia, stomatitis, GI ulcerations, and alopecia
are probably the result of inhibiting cellular proliferation.
Progressive dose-related hepatotoxicity in the form of enzyme
elevation occurs frequently, but cirrhosis is rare (<1%). Liver
toxicity is not related to serum methotrexate concentrations. A
rare hypersensitivity-like lung reaction with acute shortness of
breath has been documented, as have pseudo-lymphomatous
reactions. The incidence of GI and liver function test abnor-
malities can be reduced by the use of leucovorin 24 hours after
each weekly dose or by the use of folic acid, although this may
decrease the efficacy of the methotrexate by about 10%. This
drug is contraindicated in pregnancy.
MYCOPHENOLATE MOFETIL
1. Mechanism of Action: Mycophenolate mofetil (MMF), a csD-
MARD, is converted to mycophenolic acid, the active form of
the drug. The active product inhibits inosine monophosphate
dehydrogenase, leading to suppression of T- and B-lymphocyte
proliferation. Downstream, it interferes with leukocyte adhesion
to endothelial cells through inhibition of E-selectin, P-selectin,
and intercellular adhesion molecule 1. MMF’s pharmacokinetics
and toxicities are discussed in Chapter 55.
2. Indications: MMF is effective for the treatment of renal dis-
ease due to SLE and may be useful in vasculitis and Wegener’s
granulomatosis. Although MMF is occasionally used at a dos-
age of 2 g/d to treat RA, there are no well-controlled data
regarding its efficacy in this disease.
3. Adverse Effects: MMF is associated with nausea, dyspepsia,
and abdominal pain. Like azathioprine, it can cause hepato-
toxicity. MMF can also cause leukopenia, thrombocytopenia,
and anemia. MMF is associated with an increased incidence of
infections. It is only rarely associated with malignancy.
RITUXIMAB
1. Mechanism of Action: Rituximab is a chimeric monoclonal
antibody biologic agent that targets CD20 B lymphocytes (see
Chapter 55). Depletion of these cells takes place through cell-
mediated and complement-dependent cytotoxicity and stimu-
lation of cell apoptosis. Depletion of B lymphocytes reduces
inflammation by decreasing the presentation of antigens to T
lymphocytes and inhibiting the secretion of proinflammatory
cytokines. Rituximab rapidly depletes peripheral B cells,
although this depletion correlates neither with efficacy nor with
toxicity.
2. Pharmacokinetics: Rituximab is given as two intravenous
infusions of 1000 mg, separated by 2 weeks. It may be repeated
every 6–9 months, as needed. Repeated courses remain effec-
tive. Pretreatment with acetaminophen, an antihistamine, and
intravenous glucocorticoids (usually 100 mg of methylpred-
nisolone) given 30 minutes prior to infusion decreases the
incidence and severity of infusion reactions.
3. Indications: Rituximab is indicated for the treatment of mod-
erately to severely active RA in combination with methotrexate
in patients with an inadequate response to one or more TNF-α
antagonists. Rituximab in combination with glucocorticoids is
also approved for the treatment of adult patients with granulo-
matosis with polyangiitis (previously known as Wegener’s
granulomatosis) and microscopic polyangiitis and is used in
other forms of vasculitis as well (see Chapter 54 for its use in
lymphomas and leukemias).
4. Adverse Effects: About 30% of patients develop rash with the
first 1000-mg treatment; this incidence decreases to about 10%
with the second infusion and progressively decreases with each
course of therapy thereafter. These rashes do not usually require
discontinuation of therapy, although an urticarial or anaphy-
lactoid reaction precludes further therapy. Immunoglobulins
(particularly IgG and IgM) may decrease with repeated courses
of therapy and infections can occur, although they do not seem
directly associated with the decreases in immunoglobulins.
Serious, and sometimes fatal, bacterial, fungal, and viral infec-
tions are reported for up to 1 year of the last dose of ritux-
imab, and patients with severe and active infections should not
receive rituximab. Rituximab is associated with reactivation of
hepatitis B virus (HBV) infection, which requires monitoring
before and several months after the initiation of the treatment.
Rituximab has not been associated with either activation of
tuberculosis or the occurrence of lymphomas or other tumors
(see Chapter 55). Fatal mucocutaneous reactions have been
reported in patients receiving rituximab. Different cytopenias
can occur, which require complete blood cell monitoring every
2–4 months in RA patients. Other adverse effects, such as
cardiovascular events, are rare.
SULFASALAZINE
1. Mechanism of Action: Sulfasalazine, a csDMARD, is metabo-
lized to sulfapyridine and 5-aminosalicylic acid. The sulfapyri-
dine is probably the active moiety when treating RA (unlike
inflammatory bowel disease; see Chapter 62). Some authorities
believe that the parent compound, sulfasalazine, also has an
effect. Suppression of T-cell responses to concanavalin and
inhibition of in vitro B-cell proliferation are documented. In
vitro, sulfasalazine or its metabolites inhibit the release of
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     653
inflammatory cytokines produced by monocytes or
macrophages—eg, IL-1, -6, and -12, and TNF-α.
2. Pharmacokinetics: Only 10–20% of orally administered
sulfasalazine is absorbed, although a fraction undergoes
enterohepatic recirculation into the bowel where it is reduced by
intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic
acid (see Figure 62–8). Sulfapyridine is well absorbed while
5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is
excreted unchanged in the urine whereas sulfapyridine is excreted
after hepatic acetylation and hydroxylation. Sulfasalazine’s half-
life is 6–17 hours.
3. Indications: Sulfasalazine is effective in RA and reduces radio-
logic disease progression. It has also been used in juvenile chronic
arthritis, PsA, inflammatory bowel disease, AS, and spondyloar-
thropathy-associated uveitis. The usual regimen is 2–3 g/d.
4. Adverse Effects: Approximately 30% of patients using
sulfasalazine discontinue the drug because of toxicity.
Common adverse effects include nausea, vomiting, headache,
and rash. Hemolytic anemia and methemoglobinemia also
occur, but rarely. Neutropenia occurs in 1–5% of patients,
while thrombocytopenia is very rare. Pulmonary toxicity and
positive double-stranded DNA (dsDNA) are occasionally seen,
but drug-induced lupus is rare. Reversible infertility occurs in
men, but sulfasalazine does not affect fertility in women. The
drug does not appear to be teratogenic.
TOCILIZUMAB
1. Mechanism of Action: Tocilizumab, a newer biologic human-
ized antibody, binds to soluble and membrane-bound IL-6
receptors, and inhibits the IL-6-mediated signaling via these
receptors. IL-6 is a proinflammatory cytokine produced by dif-
ferent cell types including T cells, B cells, monocytes, fibro-
blasts, and synovial and endothelial cells. IL-6 is involved in a
variety of physiologic processes such as T-cell activation,
hepatic acute-phase protein synthesis, and stimulation of the
inflammatory processes involved in diseases such as RA and
systemic sclerosis (SSc). In a phase 4 superiority study, tocili-
zumab monotherapy was superior to adalimumab monother-
apy for reduction of signs and symptoms of rheumatoid
arthritis in patients with incomplete response to MTX.
2. Pharmacokinetics: The half-life of tocilizumab is dose-
dependent, approximately 11 days for the 4-mg/kg dose and
13 days for the 8-mg/kg dose. IL-6 can suppress several
CYP450 isoenzymes; thus, inhibiting IL-6 may restore CYP450
activities to higher levels. This may be clinically relevant for
drugs that are CYP450 substrates and have a narrow therapeu-
tic window (eg, cyclosporine or warfarin), and dosage adjust-
ment of these medications may be needed.
Tocilizumab can be used in combination with nonbio-
logic DMARDs or as monotherapy. In the United States the
recommended starting dose for RA is 4 mg/kg intravenously
every 4 weeks followed by an increase to 8 mg/kg (not
exceeding 800 mg/infusion) dependent on clinical response.
In Europe, the starting dose of tocilizumab is 8 mg/kg up to
800 mg. Tocilizumab dosage in SJIA or PJIA follows an
algorithm that accounts for body weight. Additionally, dos-
age modifications are recommended on the basis of certain
laboratory changes such as elevated liver enzymes, neutropenia,
and thrombocytopenia.
3. Indications: Tocilizumab is a bDMARD indicated for adult
patients with moderately to severely active RA who have had an
inadequate response to one or more DMARDs. It is also indi-
cated in patients who are older than 2 years with active SJIA or
active PJIA. A recent study showed that it is slightly more effec-
tive than adalimumab. There is an ongoing phase 3 study to
test its use in SSc.
4. Adverse Effects: Serious infections including tuberculosis,
fungal, viral, and other opportunistic infections have occurred.
Screening for tuberculosis should be done prior to beginning
tocilizumab. The most common adverse reactions are upper
respiratory tract infections, headache, hypertension, and
elevated liver enzymes.
Neutropenia and reduction in platelet counts occur occa-
sionally, and lipids (eg, cholesterol, triglycerides, LDL, and
HDL) should be monitored. GI perforation has been reported
when using tocilizumab in patients with diverticulitis and in
those using corticosteroids, although it is not clear that this
adverse effect is more common than with TNF-α–blocking
agents. Demyelinating disorders including multiple sclerosis are
rarely associated with tocilizumab use. Fewer than 1% of the
patients taking tocilizumab develop anaphylactic reaction.
Anti-tocilizumab antibodies develop in 2% of the patients, and
these can be associated with hypersensitivity reactions requiring
discontinuation.
TNF-`-BLOCKING AGENTS
Cytokines play a central role in the immune response (see Chapter 55)
and in RA. Although a wide range of cytokines are expressed in the
joints of RA patients, TNF-α appears to be particularly important in
the inflammatory process.
TNF-α affects cellular function via activation of specific mem-
brane-bound TNF receptors (TNFR1, TNFR2). Five “legacy”
bDMARDs interfering with TNF-α have been approved for the
treatment of RA and other rheumatic diseases (Figure 36–4).
Biosimilar biologics (bsDMARDs) with lower costs are available
in some countries and are being tested in other countries. Thus
far, the efficacy, toxicity, and immunogenicity of the biosimilars
are equivalent to the legacy compounds. These drugs have many
adverse effects in common (see below).
Adalimumab
1. Mechanism of Action: Adalimumab is a fully human IgG1
anti-TNF monoclonal antibody. This compound complexes
with soluble TNF-α and prevents its interaction with p55 and
p75 cell surface receptors. This results in down-regulation of
macrophage and T-cell function.
654    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Adalimumab Infliximab Etanercept

VH VH Extracellular domain
VL VL of human p75 receptor

CH1 CH1
CL CL

CH2 CH2 CH2

FC region of FC region of
human IgG1 human IgG1
CH3 CH3 CH3

Golimumab Certolizumab

VH
VL

CH1 Humanized Fab

CL fragment

CH2 Polyethylene
glycol (PEG)
FC region of
human IgG1
CH3

FIGURE 36–4  Structures of TNF-α antagonists used in rheumatoid arthritis. CH, constant heavy chain; CL, constant light chain; Fc, complex
immunoglobulin region; VH, variable heavy chain; VL, variable light chain. Red regions, human derived; blue regions, mouse derived; green
regions, polyethylene glycol (PEG).

2. Pharmacokinetics: Adalimumab is given subcutaneously and
has a half-life of 10–20 days. Its clearance is decreased by more
than 40% in the presence of methotrexate, and the formation
of human anti-monoclonal antibody is decreased when metho-
trexate is given at the same time. The usual dose in RA is 40 mg
every other week, but dosing is frequently increased to 40 mg
weekly. In psoriasis, 80 mg is given at week 0, 40 mg at week
1, and then 40 mg every other week thereafter. The initial dose
in inflammatory bowel disease is higher; patients receive
160 mg at week 0, and 80 mg 2 weeks later, followed by a
40-mg maintenance dose every other week. Patients with ulcer-
ative colitis should continue maintenance treatment beyond
8 weeks if they show evidence of remission by that time. Adali-
mumab dose depends on the body weight in patients with JIA:
20 mg every other week for patients weighing 15–30 kg, and
40 mg every other week in patients weighing 30 kg or more.
3. Indications: The compound is approved for RA, AS, PsA,
JIA, plaque psoriasis, Crohn’s disease, and ulcerative colitis. It
decreases the rate of formation of new erosions. It is effective
both as monotherapy and in combination with methotrexate
and other nonbiologic csDMARDs. Based only on case reports
and case series, adalimumab has also been found to be effective
in the treatment of Behçet’s disease, sarcoidosis, and notably,
noninfectious uveitis.
Certolizumab
1. Mechanism of Action: Certolizumab is a recombinant,
humanized antibody Fab fragment conjugated to a polyethyl-
ene glycol (PEG) with specificity for human TNF-α. Certoli-
zumab neutralizes membrane-bound and soluble TNF-α in a
dose-dependent manner. Additionally, certolizumab does not
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     655
contain an Fc region, found on a complete antibody, and does
not fix complement or cause antibody-dependent cell-mediated
cytotoxicity in vitro.
2. Pharmacokinetics: Certolizumab is given subcutaneously and
has a half-life of 14 days. Methotrexate decreases the appear-
ance of anti-certolizumab antibodies. The usual dose for RA is
400 mg initially and at weeks 2 and 4, followed by 200 mg
every other week, or 400 mg every 4 weeks.
3. Indications: Certolizumab is indicated for the treatment of
adults with moderately to severely active RA. It can be used as
monotherapy or in combination with nonbiologic DMARDs.
Additionally, certolizumab is approved in adult patients with
Crohn’s disease, active PsA, and active AS. The certolizumab
head-to-head TNFi trial, Exxelerate (NCT01500278), was
a multicenter, single-blind, 24-month, randomized, parallel-
group trial in moderate to severe MTX-incomplete-responder
RA patients, comparing adalimumab + MTX to certolizumab
+ MTX. ACR20 responses at 3 months and achievement of
low disease activity at 2 years were numerically comparable for
both protocols. Although putatively a 24-month trial, patients
could switch from one regimen to the other at 3 months, con-
founding comparability beyond that time frame. Not surpris-
ingly, given this confounding, the primary goal of certolizumab
+ MTX superiority was not met. Patients were switched without
washout so blood levels of TNFis as a group could be expected
to be very high during the switchover. Interestingly, no serious
infectious events occurred during the switch-over period.
Etanercept
1. Mechanism of Action: Etanercept is a recombinant fusion
protein consisting of two soluble TNF p75 receptor moieties
linked to the Fc portion of human IgG1 (Figure 36–4); it binds
TNF-α molecules and also inhibits lymphotoxin α.
2. Pharmacokinetics: Etanercept is given subcutaneously as
25 mg twice weekly or 50 mg weekly. In psoriasis, 50 mg is
given twice weekly for 12 weeks and then is followed by 50 mg
weekly. The drug is slowly absorbed, with peak concentration
72 hours after drug administration. Etanercept has a mean
serum elimination half-life of 4.5 days. A recent study demon-
strated a reduction of radiographic progression with the use of
50 mg of etanercept weekly.
3. Indications: Etanercept is approved for the treatment of RA,
juvenile chronic arthritis, psoriasis, PsA, and AS. It can be
used as monotherapy, although over 70% of patients taking
etanercept are also using methotrexate. Etanercept decreases
the rate of formation of new erosions relative to methotrex-
ate alone. It is also being used in other rheumatic syndromes
such as scleroderma, granulomatosis with polyangiitis (Wegener’s
granulomatosis), giant cell arteritis, Behçet’s disease, uveitis,
and sarcoidosis. However, a comparative study of ustekinumab
(an IL-12 and IL-23 blocker) and etanercept concluded that
ustekinumab at a dose of 45 or 90 mg was superior to high-
dose etanercept (50 mg twice weekly) over a 12-week period in
patients with psoriasis.
Golimumab
1. Mechanism of Action: Golimumab is a human monoclonal
antibody with a high affinity for soluble and membrane-bound
TNF-α. Golimumab effectively neutralizes the inflammatory
effects produced by TNF-α seen in diseases such as RA.
2. Pharmacokinetics: Golimumab is administered subcutane-
ously and has a half-life of approximately 14 days. Concomi-
tant use with methotrexate increases golimumab serum levels
and decreases anti-golimumab antibodies. The recommended
dose for the treatment of RA, PsA, and AS is 50 mg given every
4 weeks. A higher dose of golimumab is used for the treatment
of ulcerative colitis as follows: 200 mg initially at week
0 followed by 100 mg at week 2 and every 4 weeks thereafter.
3. Indications: Golimumab with methotrexate is indicated for
the treatment of moderately to severely active RA in adult
patients. It is also indicated for the treatment of PsA and AS
and moderate to severe ulcerative colitis.
Infliximab
1. Mechanism of Action: Infliximab (Figure 36–4) is a chimeric
(25% mouse, 75% human) IgG1 monoclonal antibody that
binds with high affinity to soluble and possibly membrane-
bound TNF-α. Its mechanism of action probably is the same
as that of adalimumab.
2. Pharmacokinetics: Infliximab is given as an intravenous infu-
sion with “induction” at 0, 2, and 6 weeks and maintenance
every 8 weeks thereafter. Dosing is 3–10 mg/kg, and the usual
dose is 3–5 mg/kg every 8 weeks. There is a relationship
between serum concentration and effect, although individual
clearances vary markedly. The terminal half-life is 9–12 days
without accumulation after repeated dosing at the recom-
mended interval of 8 weeks. After intermittent therapy, inflix-
imab elicits human antichimeric antibodies in up to 62% of
patients. Concurrent therapy with methotrexate markedly
decreases the prevalence of human antichimeric antibodies.
3. Indications: Infliximab is approved for use in RA, AS, PsA,
Crohn’s disease, ulcerative colitis, pediatric inflammatory
bowel disease, and psoriasis. It is being used off-label in other
diseases, including granulomatosis with polyangiitis (Wegener’s
granulomatosis), giant cell arteritis, Behçet’s disease, uveitis,
and sarcoidosis. In RA, infliximab plus methotrexate decreases
the rate of formation of new erosions. Although it is recom-
mended that methotrexate be used in conjunction with inflix-
imab, a number of other nonbiologic csDMARDs, including
antimalarials, azathioprine, leflunomide, and cyclosporine, can
be used as background therapy for this drug. Infliximab is also
used as monotherapy.
Adverse Effects of TNF-`-Blocking Agents
TNF-α–blocking agents have multiple adverse effects in common.
The risk of bacterial infections and macrophage-dependent infec-
tion (including tuberculosis, fungal, and other opportunistic
656    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
infections) is increased, although it remains very low. Activation
of latent tuberculosis is lower with etanercept than with other
TNF-α–blocking agents. Nevertheless, all patients should be
screened for latent or active tuberculosis before starting TNF-α–
blocking agents. The use of TNF-α–blocking agents is also associ-
ated with increased risk of HBV reactivation; screening for HBV
is important before starting the treatment.
TNF-α–blocking agents increase the risk of skin cancers—
including melanoma—which necessitates periodic skin examina-
tion, especially in high-risk patients. On the other hand, there is no
clear evidence of increased risk of solid malignancies or lymphomas
with TNF-α–blocking agents, and their incidence may not be
different compared with other bDMARDs or active RA itself.
A low incidence of newly formed dsDNA antibodies and
antinuclear antibodies (ANAs) has been documented when using
TNF-α–blocking agents, but clinical lupus is extremely rare and
the presence of ANA and dsDNA antibodies per se does not
contraindicate the use of TNF-α–blocking agents. In patients
with borderline or overt heart failure (HF), TNF-α–blocking
agents can exacerbate HF. TNF-α–blocking agents can induce the
immune system to develop antidrug antibodies in about 17% of
cases. These antibodies may interfere with drug efficacy and cor-
relate with infusion site reactions. Injection site reactions occur in
20–40% of patients, although they rarely result in discontinuation
of therapy. Cases of alopecia areata, hypertrichosis, and erosive
lichen planus have been reported. Cutaneous pseudo-lymphomas
are reported rarely with TNF-α–blocking agents, especially inflix-
imab. TNF-α–blocking agents may increase the risk of gastroin-
testinal ulcers and large bowel perforation including diverticular
and appendiceal perforation.
Nonspecific interstitial pneumonia, psoriasis, and sarcoidosis-
like syndrome are among the rare reported toxicities associated
with TNF-α blockers. Rare cases of leukopenia, neutropenia,
thrombocytopenia, and pancytopenia have also been reported.
The precipitating drug should be discontinued in such cases.
USTEKINUMAB
1. Mechanism of Action: Ustekinumab is an IL-12 and IL-23
antagonist. It is a fully human IgG monoclonal antibody to the
p40 protein subunit, which is part of both IL-12 and IL-23.
These two cytokines are important contributors to the chronic
inflammation in psoriasis plaques, PsA, and Crohn’s disease.
Ustekinumab prevents the binding of the p40 subunit of both
IL-12 and IL-23 to the IL-12 receptor b1 found on the surface
of CD4 T cells and NK cells. This interruption interferes with
IL-12 and IL-23 signal transduction and suppresses the forma-
tion of proinflammatory TH1 and TH17 cells.
2. Pharmacokinetics: Ustekinumab is available as a 45- and
90-mg SC injection for PsA and plaque psoriasis. Its bioavail-
ability is 57% following SC injection; time to peak plasma
concentration is 7–13.5 days and elimination half-life is
10–126 days. For adults with PsA, a loading dose at 0 and
4 weeks is followed by maintenance doses once every 12 weeks.
IV infusion as a 130 mg dose is available for Crohn’s disease.
3. Indications: Ustekinumab is indicated for treatment of adult
patients with PsA. It can be used as monotherapy or in combi-
nation with methotrexate. Other indications include plaque
psoriasis and Crohn’s disease.
4. Adverse Effects: Upper respiratory tract infection is the most
common side effect, but rare severe infection, malignancy,
and reversible posterior leukoencephalopathy syndrome have
been reported. Ustekinumab should be discontinued at least
15 weeks before live vaccines are administered and can be
resumed at least 2 weeks after.
SECUKINUMAB
1. Mechanism of Action: Secukinumab is a human IgG1 mono-
clonal antibody that selectively binds to the IL-17A cytokine,
inhibiting its interaction with the IL-17A receptor. IL-17A is
involved in normal inflammatory and immune responses.
Elevated concentrations of IL-17A are found in psoriatic
plaques and PsA.
2. Pharmakokinetics: Secukinumab is available as a SC injection
or lyophilized powder for injection. Its peak plasma concentra-
tion is 13.7 mcg/mL (150 mg dose) and 27.3 mcg/mL (300 mg
dose); elimination half-life is 22–31 days.
3. Indications and Dosage: Secukinumab is indicated for moder-
ate to severe plaque psoriasis in patients who are candidates for
systemic therapy or phototherapy. Initial loading dose is 300
mg SC at weeks 0, 1, 2, 3, and 4, followed by monthly main-
tenance (300 mg SC or 150 mg SC monthly). For adults with
active PsA and moderate to severe plaque psoriasis, the same
recommendations are followed. For patients with psoriatic
arthritis as well as AS, administer with or without a loading
dosage by SC injection; 150 mg SC every 4 weeks with or
without MTX is recommended.
4. Adverse Effects: As for any of these biologics, infection is
a common side effect (28.7%). Nasopharyngitis occurs in
about 12%. TB status should be evaluated prior to therapy.
Secukinumab may exacerbate Crohn’s disease.
TOFACITINIB
1. Mechanism of Action: Tofacitinib is a targeted synthetic small
molecule (tsDMARD) that selectively inhibits all members of
the Janus kinase (JAK; see Chapter 2) family to varying
degrees. At therapeutic doses, tofacitinib exerts its effect mainly
by inhibiting JAK3, and to a lesser extent JAK1, hence inter-
rupting the JAK-STAT signaling pathway. This pathway plays
a major role in the pathogenesis of autoimmune diseases
including RA. The JAK3/JAK1 complex is responsible for
signal transduction from the common γ-chain receptor (IL-
2RG) for IL-2, -4, -7, -9, -15, and -21, which subsequently
influences transcription of several genes that are crucial for the
differentiation, proliferation, and function of NK cells and T
and B lymphocytes. In addition, JAK1 (in combination with
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     657
other JAKs) controls signal transduction from IL-6 and inter-
feron receptors. RA patients receiving tofacitinib rapidly reduce
C-reactive protein.
2. Pharmacokinetics: The recommended dose of tofacitinib in
the treatment of RA is 5 mg twice daily; there is a clear trend
to increased response (and increased toxicity) at double this
dose. In 2016, the FDA approved extended-release (XR)
tofacitinib citrate 11 mg tablets for once-daily treatment.
Tofacitinib has an absolute oral bioavailability of 74%, high-
fat meals do not affect the AUC, and the elimination half-life
is about 3 hours. Metabolism (of 70%) occurs in the liver,
mainly by CYP3A4 and to a lesser extent by CYP2C19. The
remaining 30% is excreted unchanged by the kidneys.
Patients taking CYP enzyme inhibitors and those with mod-
erate hepatic or renal impairment require dose reduction to
5 mg once daily. It should not be given to patients with severe
hepatic disease.
3. Indications: Tofacitinib was originally developed to prevent
solid organ allograft rejection. It has also been tested for the
treatment of inflammatory bowel disease, spondyloarthritis,
psoriasis, and dry eyes. To date, tofacitinib is approved in the
United States for the treatment of adult patients with moder-
ately to severely active RA who have failed or are intolerant to
methotrexate. It is not approved in Europe for this indication.
It can be used as a monotherapy or in combination with other
csDMARDs, including methotrexate. Ongoing studies are
evaluating its role in other rheumatic diseases such as PsA,
psoriasis, and JIA.
4. Adverse Effects: Tofacitinib slightly increases the risk of
infection, and it has thus far not been used with potent
immunosuppressants (eg, azathioprine, cyclosporine) or
biologic bDMARDs because additive immunosuppression
is feared, although it has not been tested in combinations.
Upper respiratory tract infection and urinary tract infec-
tion represent the most common infections. More serious
infections are also reported, including pneumonia, celluli-
tis, esophageal candidiasis, and other opportunistic infec-
tions. All patients should be screened for latent or active
tuberculosis before the initiation of treatment. Lymphoma
and other malignancies such as lung and breast cancer have
been reported in patients taking tofacitinib, although some
studies discuss the potential use of JAK inhibitors to treat
certain lymphomas. Dose-dependent increases in the levels
of low-density lipoprotein (LDL), high-density lipoprotein
(HDL), and total cholesterol have been found in patients
receiving tofacitinib, often beginning about 6 weeks after
starting treatment; therefore, lipid levels should be moni-
tored. Although tofacitinib causes a dose-dependent
increase in CD19 B cells and CD4 T cells plus a reduc-
tion in CD16/CD56 NK cells, the clinical significance of
these changes remains unclear. Drug-related neutropenia
and anemia occur, requiring drug discontinuation. Head-
ache, diarrhea, elevation of liver enzymes, and gastrointes-
tinal perforation are among the other reported effects of
tofacitinib.
INTERLEUKIN-1 INHIBITORS
IL-1α plays a major role in the pathogenesis of several inflammatory
and autoimmune diseases including RA. IL-1α, IL-1β, and IL-1
receptor antagonist (IL-1RA) are other members of the IL-1 family.
All three bind to IL-1 receptors in the same manner. However, IL-
1RA does not initiate the intracellular signaling pathway and thus acts
as a competitive inhibitor of the proinflammatory IL-1α and IL-1β.
Anakinra
1. Mechanism of Action: Anakinra is the oldest drug in this family
but is now rarely used for RA.
2. Pharmacokinetics: Anakinra is administered subcutaneously
and reaches a maximum plasma concentration after 3–7 hours.
The absolute bioavailability of anakinra is 95%, and it has a
4- to 6-hour terminal half-life. The recommended dose in the
treatment of RA is 100 mg daily. The dose of anakinra depends
on the body weight in the treatment of cryopyrin-associated
periodic syndrome (CAPS), starting with 1–2 mg/kg per day to
a maximum of 8 mg/kg per day. Reduction in the frequency of
administering anakinra to every other day is recommended in
patients with renal insufficiency.
3. Indications: Anakinra is approved for the treatment of moder-
ately to severely active RA in adult patients, but it is rarely used for
this indication. However, anakinra is the drug of choice for CAPS,
particularly the neonatal-onset multisystem inflammatory disease
(NOMID) subtype. Anakinra is effective in gout (see below) and
is used for other diseases including Behçet’s disease and adult
onset JIA. Its use for giant cell arteritis is controversial.
Canakinumab
1. Mechanism of Action: Canakinumab is a human IgG1/κ
monoclonal antibody against IL-1β. It forms a complex with
IL-1β, preventing its binding to IL-1 receptors.
2. Pharmacokinetics: Canakinumab is given by subcutaneous
injection. It reaches peak serum concentrations 7 days after a
single subcutaneous injection. Canakinumab has an absolute
bioavailability of 66% and a 26-day mean terminal half-life.
The recommended dose for patients with SJIA who weigh
more than 7.5 kg is 4 mg/kg every 4 weeks. There is a weight-
adjusted algorithm for treating CAPS.
3. Indications: Canakinumab is indicated for active SJIA in chil-
dren 2 years or older. As noted, it is also used to treat CAPS,
particularly the familial cold autoinflammatory syndrome and
Muckle-Wells syndrome subtypes for adults and children 4 years
or older. Canakinumab is also used to treat gout (see below).
Rilonacept
1. Mechanism of Action: Rilonacept is the ligand-binding domain
of the IL-1 receptor. It binds mainly to IL-1β and binds with
lower affinity to IL-1α and IL-1RA. Rilonacept neutralizes
IL-1β and prevents its attachment to IL-1 receptors.
658    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
2. Pharmacokinetics: The subcutaneous dose of rilonacept for
CAPS is age-dependent. In patients 12–17 years of age,
4.4 mg/kg (maximum of 320 mg) is the loading dose, with a
maintenance dose of 2.2 mg/kg (maximum of 160 mg) weekly.
Those 18 years and older receive 320 mg as a loading dose and
160 mg weekly thereafter. The steady-state plasma concentra-
tion is reached after 6 weeks.
3. Indications: Rilonacept is approved to treat CAPS subtypes:
familial cold autoinflammatory syndrome and Muckle-Wells
syndrome in patients 12 years or older. Rilonacept is also used
to treat gout (see below).
Adverse Effects of Interleukin-1 Inhibitors
The most common adverse effects are injection site reactions (up
to 40%) and upper respiratory tract infections. Serious infections
occur rarely in patients given IL-1 inhibitors. Headache, abdomi-
nal pain, nausea, diarrhea, arthralgia, and flu-like illness all have
been reported, as have hypersensitivity reactions. Patients taking
IL-1 inhibitors may experience transient neutropenia, which
requires regular monitoring of neutrophil counts.
BELIMUMAB
Belimumab is an antibody that specifically inhibits B-lymphocyte
stimulator (BLyS). It is administered as an intravenous infusion.
The recommended dose is 10 mg/kg at weeks 0, 2, and 4, and
every 4 weeks thereafter. Belimumab has a distribution half-life of
1.75 days and a terminal half-life of 19.4 days.
Belimumab is approved only for the treatment of adult patients
with active, seropositive SLE who are receiving standard treatment.
The drug was approved after a protracted series of clinical trials,
and its place in the SLE armamentarium is not clear. Belimumab
should not be used in patients with active renal or neurological
manifestations of SLE, as there are no data for these conditions. In
addition, the efficacy of belimumab has not been tested in combi-
nation with other bDMARDs or cyclophosphamide.
The most common adverse effects of belimumab are nausea,
diarrhea, and respiratory tract infection. As with other bDMARDs,
there is a slight increase in the risk of infection including serious
infections. Cases of depression and suicide have been reported in
patients receiving belimumab, although these patients may have had
neurologic SLE, thus confounding the causal relationship. Infusion
reactions including anaphylaxis are among the other adverse effects.
A very small percentage of patients develop antibodies toward
belimumab; their clinical significance is not clear.
COMBINATION THERAPY WITH
DMARDs
In a 1998 survey, approximately half of North American rheuma-
tologists treated moderately aggressive RA with combination ther-
apy, and the use of drug combinations is probably much higher
now. Combinations of DMARDs can be designed rationally on
the basis of complementary mechanisms of action, nonoverlap-
ping pharmacokinetics, and nonoverlapping toxicities.
When added to methotrexate background therapy, cyclospo-
rine, chloroquine, hydroxychloroquine, leflunomide, infliximab,
adalimumab, rituximab, and etanercept have all shown improved
efficacy. Triple therapy with methotrexate, sulfasalazine, and
hydroxychloroquine appears to be as effective as etanercept and
methotrexate. In contrast, azathioprine or sulfasalazine plus
methotrexate results in no additional therapeutic benefit. Other
combinations have occasionally been used.
While it might be anticipated that combination therapy could
result in more toxicity, this is often not the case. Combination
therapy for patients not responding adequately to monotherapy is
now the rule in the treatment of RA.
GLUCOCORTICOID DRUGS
The general pharmacology of corticosteroids, including mechanism
of action, pharmacokinetics, and other applications, is discussed in
Chapter 39.
Indications
Corticosteroids have been used in 60–70% of RA patients. Their
effects are prompt and dramatic, and they are capable of slowing
the appearance of new bone erosions. Corticosteroids may be
administered for certain serious extra-articular manifestations of
RA such as pericarditis or eye involvement or during periods of
exacerbation. When prednisone is required for long-term therapy,
the dosage should not exceed 7.5 mg daily, and gradual reduction
of the dose should be encouraged. Alternate-day corticosteroid
therapy is usually unsuccessful in RA.
Other rheumatic diseases in which the corticosteroids’ potent
anti-inflammatory effects may be useful include vasculitis, SLE,
Wegener’s granulomatosis, PA, giant cell arteritis, sarcoidosis, and
gout. Intra-articular corticosteroids are often helpful to alleviate
painful symptoms and, when successful, are preferable to increas-
ing the dosage of systemic medication.
Some of the symptoms of RA, especially morning stiffness and
joint pain, follow a circadian rhythm, probably due to an increase
in proinflammatory cytokines in the early morning. A recent
approach uses delayed-release prednisone for the treatment of
early morning stiffness and pain in RA. The tablet contains an
inactive outer layer and a core of the active drug. The outer layer
dissolves over 4–6 hours, releasing the prednisone. Taking the
drug at 9–10 pm results in a small pulse of prednisone at 2–4 am,
decreasing the circadian inflammatory cytokines. At low doses of
3–5 mg prednisone, the adrenal-pituitary axis does not seem to
be impacted.
Adverse Effects
Prolonged use of corticosteroids leads to serious and disabling
toxic effects as described in Chapter 39. Many of these adverse
effects occur at doses below 7.5 mg prednisone equivalent daily
and many experts believe that even 3–5 mg/d can cause adverse
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     659
effects in susceptible individuals when this class of drugs is used
over prolonged periods.
■■ OTHER ANALGESICS
Acetaminophen is one of the most important drugs used in the
treatment of mild to moderate pain when an anti-inflammatory
effect is not necessary. Phenacetin, a prodrug that is metabolized
to acetaminophen, is more toxic and should not be used.
ACETAMINOPHEN
Acetaminophen is the active metabolite of phenacetin and is
responsible for its analgesic effect. It is a weak COX-1 and COX-2
inhibitor in peripheral tissues and possesses no significant anti-
inflammatory effects.
H O
HO N C CH3
1. Pharmacokinetics: Acetaminophen is administered orally.
Peak blood concentrations are usually reached in 30–60 minutes.
Acetaminophen is poorly bound to plasma proteins and is
partially metabolized by hepatic microsomal enzymes to the
inactive sulfate and glucuronide (see Figure 4–5). Less than 5%
is excreted unchanged. In large doses, a minor but highly reac-
tive metabolite (N-acetyl-p-benzoquinone) is important
because it is toxic to both liver and kidney (see Chapter 4). The
half-life of acetaminophen is 2–3 hours and is relatively unaf-
fected by renal function. With toxic doses or liver disease, the
half-life may be increased twofold or more.
2. Indications: Although said to be equivalent to aspirin as an
analgesic and antipyretic agent, acetaminophen lacks anti-
inflammatory properties. It does not affect uric acid levels and
lacks platelet-inhibiting effects. The drug is useful in mild to
moderate pain such as headache, myalgia, postpartum pain,
and other circumstances in which aspirin is an effective analge-
sic. Acetaminophen alone is inadequate therapy for inflamma-
tory conditions such as RA. For mild analgesia, acetaminophen
is the preferred drug in patients allergic to aspirin, when salicy-
lates are poorly tolerated. It is preferable to aspirin in patients
with hemophilia, in those with a history of peptic ulcer, and in
those in whom bronchospasm is precipitated by aspirin. Unlike
aspirin, acetaminophen does not antagonize the effects of
uricosuric agents.
3. Adverse Effects: In therapeutic doses, a mild reversible increase in
hepatic enzymes may occasionally occur. With larger doses, dizzi-
ness, excitement, and disorientation may occur. Ingestion of 15 g
of acetaminophen may be fatal, death being caused by severe hepa-
totoxicity with centrilobular necrosis, sometimes associated with
acute renal tubular necrosis (see Chapters 4 and 58).
4. Present data indicate that even 4 g acetaminophen is associated
with increased liver function test abnormalities. Doses greater than
4 g/d are not usually recommended, and a history of alcoholism
contraindicates even this dose. Early symptoms of hepatic dam-
age include nausea, vomiting, diarrhea, and abdominal pain.
Cases of renal damage without hepatic damage have occurred,
even after usual doses of acetaminophen. Therapy for overdose is
much less satisfactory than that for aspirin overdose. In addition
to supportive therapy, one should provide sulfhydryl groups in
the form of acetylcysteine to neutralize the toxic metabolites (see
Chapter 58).
5. Hemolytic anemia and methemoglobinemia are very rare
adverse events. Interstitial nephritis and papillary necrosis—
serious complications of phenacetin—have not occurred, and
GI bleeding also has not occurred. Caution is necessary in
patients with any type of liver disease.
6. Dosage: Acute pain and fever may be effectively treated with
325–500 mg four times daily and proportionately less for chil-
dren. Dosing in adults is now recommended not to exceed
4 g/d, in most cases.
KETOROLAC
Ketorolac is an NSAID promoted for systemic use mainly as a
short-term analgesic (not longer than 1 week), not as an anti-
inflammatory drug (although it has typical NSAID properties).
Pharmacokinetics are presented in Table 36–1. The drug is an
effective analgesic and has been used successfully to replace mor-
phine in some situations involving mild to moderate postsurgical
pain. It is most often given intramuscularly or intravenously, but
an oral formulation is available. When used with an opioid, it may
decrease the opioid requirement by 25–50%. Toxicities are similar
to those of other NSAIDs (see page 645), although renal toxicity
is more common with chronic use.
TRAMADOL
Tramadol is a centrally acting synthetic analgesic, structurally
related to opioids. Since naloxone, an opioid receptor blocker,
inhibits only 30% of the analgesic effect of tramadol, the mecha-
nism of action of this drug must involve both nonopioid and opioid
receptors. Tramadol does not have significant anti-inflammatory
effects. The drug may exert part of its analgesic effect by enhancing
5-hydroxytryptamine (5-HT) release and inhibiting the reuptake of
norepinephrine and 5-HT (see Chapter 31).
■■ DRUGS USED IN GOUT
Gout is a metabolic disease characterized by recurrent episodes of
acute arthritis due to deposits of monosodium urate in joints and
cartilage. Uric acid renal calculi, tophi, and interstitial nephritis
may also occur. Adverse cardiovascular outcomes are becoming
more clear as well. Gout is usually associated with a high serum
uric acid level (hyperuricemia), a poorly soluble substance that is
the major end product of purine metabolism. In most mammals,
660    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

uricase converts uric acid to the more soluble allantoin; this
enzyme is absent in humans. While clinical gouty episodes are
associated with hyperuricemia, most individuals with hyper-
uricemia may never develop a clinical event from urate crystal
deposition.
The treatment of gout aims to relieve acute gouty attacks
and prevent recurrent gouty episodes and urate lithiasis.
Therapies for acute gout are based on our current understand-
ing of the pathophysiologic events that occur in this disease
(Figure 36–5). Clinical gout is dependent on a macromolecular
complex of proteins, called NLRP3, which regulates the activa-
tion of IL-1. Urate crystals activate NLRP3, resulting in release
of prostaglandins and lysosomal enzymes by synoviocytes.
Attracted by these chemotactic mediators, polymorphonuclear
leukocytes migrate into the joint space and amplify the ongo-
ing inflammatory process. In the later phases of the attack,
increased numbers of mononuclear phagocytes (macrophages)
appear, ingest the urate crystals, and release more inflammatory
mediators.
Before starting chronic urate-lowering therapy for gout,
patients in whom hyperuricemia is associated with gout and
urate lithiasis must be clearly distinguished from individuals with
only hyperuricemia. The efficacy of long-term drug treatment in
an asymptomatic hyperuricemic person is unproved. Although
there are data suggesting a clear relationship between the degree
of uric acid elevation and the likelihood of clinical gout, in some
individuals, uric acid levels may be elevated up to 2 standard
deviations above the mean for a lifetime without adverse conse-
quences. Many different agents have been used for the treatment
of acute and chronic gout. However, non-adherence to these
drugs is exceedingly common; adherence has been documented
to be 18–26% in younger patients. Providers should be aware of
compliance as an important issue.
COLCHICINE
Although NSAIDs, corticosteroids, or colchicine are now first-line
drugs for acute gout, colchicine was the primary treatment for many
years. Colchicine is an alkaloid isolated from the autumn crocus,
Colchicum autumnale. Its structure is shown in Figure 36–6.
1. Pharmacokinetics: Colchicine is absorbed readily after oral
administration, reaches peak plasma levels within 2 hours, and
is eliminated with a serum half-life of 9 hours. Metabolites are
excreted in the intestinal tract and urine.
2. Pharmacodynamics: Colchicine relieves the pain and inflam-
mation of gouty arthritis in 12–24 hours without altering the
metabolism or excretion of urates and without other analgesic
effects. Colchicine produces its anti-inflammatory effects by
binding to the intracellular protein tubulin, thereby preventing
its polymerization into microtubules and leading to the inhibi-
tion of leukocyte migration and phagocytosis. It also inhibits
the formation of leukotriene B4 and IL-1β. Several of colchi-
cine’s adverse effects are produced by its inhibition of tubulin
polymerization and cell mitosis.
3. Indications: Colchicine is indicated for gout and is also
used between attacks (the “intercritical period”) for prolonged
H O
H3C O
N C CH3
H3C O
O
CH3
O
O

CH3
Colchicine
Synoviocytes
Colchicine
– H3C CH2 CH2 O O
Urate LTB4
crystal
N S C OH
PMN
H3C CH2 CH2 O
PG
PG
Enzymes IL-1 PG Probenecid

MNP –
–
IL-1 Indomethacin,
phenylbutazone
N
O
N
FIGURE 36–5  Pathophysiologic events in a gouty joint. Syn- O

oviocytes phagocytose urate crystals and then secrete inflammatory S CH2 CH2 O
mediators, which attract and activate polymorphonuclear leukocytes
(PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs
Sulfinpyrazone
active in gout inhibit crystal phagocytosis and polymorphonuclear
leukocyte and macrophage release of inflammatory mediators. PG,
prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4. FIGURE 36–6  Colchicine and uricosuric drugs.
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     661
prophylaxis (at low doses). It prevents attacks of acute Mediterra-
nean fever and may have a mild beneficial effect in sarcoid arthritis
and in hepatic cirrhosis. Colchicine is also used to treat and pre-
vent pericarditis, pleurisy, and coronary artery disease, probably
due to its anti-inflammatory effect. Although it has been given
intravenously, this route is no longer approved by the FDA (2009).
4. Adverse Effects: Colchicine often causes diarrhea and may
occasionally cause nausea, vomiting, and abdominal pain.
Hepatic necrosis, acute renal failure, disseminated intravascular
coagulation, and seizures have also been observed. Colchicine
may rarely cause hair loss and bone marrow depression, as well
as peripheral neuritis, myopathy, and, in some cases, death. The
more severe adverse events have been associated with the intra-
venous administration of colchicine.
5. Dosage: In prophylaxis (the most common use), the dosage
of colchicine is 0.6 mg one to three times daily. For terminat-
ing a gouty attack, a regimen of 1.2 mg followed by a single
0.6-mg oral dose was as effective as higher dose regimens, and
adverse events were less frequent. In 2008, the FDA requested
that intravenous preparations containing colchicine be dis-
continued in the United States because of their potential life-
threatening adverse effects. Therefore, intravenous colchicine is
no longer available.
In 2009, the FDA approved a new oral formulation of col-
chicine for the treatment of gout, allowing Colcrys (a branded
colchicine) marketing exclusivity in the United States. Generic
colchicine rather than Colcrys is available throughout the rest
of the world.
NSAIDS IN GOUT
In addition to inhibiting prostaglandin synthase, NSAIDs inhibit
urate crystal phagocytosis. Aspirin is not used because it causes renal
retention of uric acid at low doses (≤2.6 g/d). It is uricosuric at doses
greater than 3.6 g/d. Indomethacin is commonly used in the initial
treatment of gout as a replacement for colchicine. For acute gout,
50 mg is given three times daily; when a response occurs, the dosage
is reduced to 25 mg three times daily for 5–7 days.
All other NSAIDs except aspirin, salicylates, and tolmetin have
been successfully used to treat acute gouty episodes. Oxaprozin,
which lowers serum uric acid, is theoretically a good choice. These
agents appear to be as effective and safe as the older drugs.
URICOSURIC AGENTS
Probenecid and sulfinpyrazone are uricosuric drugs employed to
decrease the body pool of urate in patients with tophaceous gout
or in those with increasingly frequent gouty attacks. In a patient
who excretes large amounts of uric acid, the uricosuric agents
should not be used. Lesinurad (RDEA594) is a promising new
uricosuric agent that is currently in phase 3 trials.
1. Chemistry and Pharmacokinetics: Uricosuric drugs are
organic acids (Figure 36–6) and, as such, act at the anion
transport sites of the renal tubule (see Chapter 15). Probenecid
is completely reabsorbed by the renal tubules and is metabo-
lized slowly with a terminal serum half-life of 5–8 hours.
Sulfinpyrazone or its active hydroxylated derivative is excreted
by the kidneys. Even so, the duration of its effect after oral
administration is almost as long as that of probenecid, which is
given once or twice daily.
2. Pharmacodynamics: Uricosuric drugs—probenecid, sulfin-
pyrazone, as well as fenofibrate, and losartan—inhibit active
transport sites for reabsorption and secretion in the proximal
renal tubule so that net reabsorption of uric acid in the proxi-
mal tubule is decreased. Because aspirin in doses of less than
2.6 g daily causes net retention of uric acid by inhibiting the
secretory transporter, it should not be used for analgesia in
patients with gout. The secretion of other weak acids (eg,
penicillin) is also reduced by uricosuric agents.
3. As the urinary excretion of uric acid increases, the size of the
urate pool decreases, although the plasma concentration may
not be greatly reduced. In patients who respond favorably,
tophaceous deposits of urate are reabsorbed, with relief of
arthritis and remineralization of bone. With the ensuing
increase in uric acid excretion, a predisposition to the forma-
tion of renal stones is augmented rather than decreased; there-
fore, the urine volume should be maintained at a high level,
and at least early in treatment, the urine pH should be kept
above 6.0 by the administration of alkali.
4. Indications: Uricosuric therapy should be initiated in gouty
patients with underexcretion of uric acid when allopurinol or
febuxostat is contraindicated or when tophi are present.
Therapy should not be started until 2–3 weeks after an acute
attack.
5. Adverse Effects: Both of these organic acids cause equivalent
GI irritation, but sulfinpyrazone is more active in this regard.
A rash may appear after the use of either compound. Nephrotic
syndrome has occurred after the use of probenecid. Both sulfin-
pyrazone and probenecid may rarely cause aplastic anemia.
6. Contraindications and Cautions: It is essential to maintain a
large urine volume to minimize the possibility of stone
formation.
7. Dosage: Probenecid is usually started at a dosage of 0.5 g
orally daily in divided doses, progressing to 1 g daily after
1 week. Sulfinpyrazone is started at a dosage of 200 mg orally
daily, progressing to 400–800 mg daily. It should be given in
divided doses with food to reduce adverse GI effects.
ALLOPURINOL
The preferred and standard-of-care therapy for gout during the
period between acute episodes is allopurinol, which reduces total
uric acid body burden by inhibiting xanthine oxidase.
1. Chemistry and Pharmacokinetics: The structure of allopuri-
nol, an isomer of hypoxanthine, is shown in Figure 36–7.
Allopurinol is approximately 80% absorbed after oral adminis-
tration and has a terminal serum half-life of 1–2 hours.
662    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

O O
Xanthine
HN oxidase HN
N N

N O N
N H N H
H
Allopurinol Alloxanthine

O O O
Xanthine Xanthine
N N N
HN 6 oxidase HN oxidase HN
1 5 7
8 OH
2 4 9
3
N O N O N
N H N H N H
H H
Hypoxanthine Xanthine Uric acid

FIGURE 36–7  Inhibition of uric acid synthesis by allopurinol occurs because allopurinol and alloxanthine inhibit xanthine oxidase.
(Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.)

Like uric acid, allopurinol is metabolized by xanthine oxidase,
but the resulting compound, alloxanthine, retains the capacity
to inhibit xanthine oxidase and has a long enough duration of
action so that allopurinol is given only once a day.
2. Pharmacodynamics: Dietary purines are not an important
source of uric acid. Quantitatively important amounts of
purine are formed from amino acids, formate, and carbon diox-
ide in the body. Those purine ribonucleotides not incorporated
into nucleic acids and derived from nucleic acid degradation
are converted to xanthine or hypoxanthine and oxidized to uric
acid (Figure 36–7). Allopurinol inhibits this last step, resulting
in a fall in the plasma urate level and a decrease in the overall
urate burden. The more soluble xanthine and hypoxanthine are
increased.
3. Indications: Allopurinol is often the first-line agent for the
treatment of chronic gout in the period between attacks and it
tends to prolong the intercritical period. As with uricosuric
agents, the therapy is begun with the expectation that it will be
continued for years if not for life. When initiating allopurinol,
colchicine or NSAID should be used until steady-state serum
uric acid is normalized or decreased to less than 6 mg/dL and
they should be continued for 6 months or longer. Thereafter,
colchicine or the NSAID can be cautiously stopped while
continuing allopurinol therapy.
4. Adverse Effects: In addition to precipitating gout (the reason
to use concomitant colchicine or NSAID), GI intolerance
(including nausea, vomiting, and diarrhea), peripheral neuritis
and necrotizing vasculitis, bone marrow suppression, and aplas-
tic anemia may rarely occur. Hepatic toxicity and interstitial
nephritis have been reported. An allergic skin reaction charac-
terized by pruritic maculopapular lesions occurs in 3% of
patients. Isolated cases of exfoliative dermatitis have been
reported. In very rare cases, allopurinol has become bound to
the lens, resulting in cataracts.
5. Interactions and Cautions: When chemotherapeutic purines
(eg, azathioprine) are given concomitantly with allopurinol,
their dosage must be reduced by about 75%. Allopurinol may
also increase the effect of cyclophosphamide. Allopurinol
inhibits the metabolism of probenecid and oral anticoagulants
and may increase hepatic iron concentration. Safety in children
and during pregnancy has not been established.
6. Dosage: The initial dosage of allopurinol is 50–100 mg/d. It
should be titrated upward until serum uric acid is below 6 mg/
dL; this level is commonly achieved at 300–400 mg/d but is
not restricted to this dose; doses as high as 800 mg/d may be
needed.
As noted above, colchicine or an NSAID should be given dur-
ing the first months of allopurinol therapy to prevent the gouty
arthritis episodes that sometimes occur.
FEBUXOSTAT
Febuxostat is a non-purine xanthine oxidase inhibitor that was
approved by the FDA in 2009.
1. Pharmacokinetics: Febuxostat is more than 80% absorbed
following oral administration. With maximum concentration
achieved in approximately 1 hour and a half-life of 4–18 hours,
once-daily dosing is effective. Febuxostat is extensively metabo-
lized in the liver. All of the drug and its inactive metabolites
appear in the urine, although less than 5% appears as
unchanged drug.
2. Pharmacodynamics: Febuxostat is a potent and selective
inhibitor of xanthine oxidase, thereby reducing the formation
of xanthine and uric acid without affecting other enzymes in
the purine or pyrimidine metabolic pathway. In clinical trials,
Febuxostat at daily dosing of 80 mg or 120 mg was more
 CHAPTER 36  NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout     663
effective in lowering serum urate levels than was allopurinol at
a standard 300-mg daily dose. The urate-lowering effect was
comparable regardless of the pathogenic cause of hyperuricemia—
overproduction or underexcretion.
3. Indications: Febuxostat is approved at doses of 40 or 80 mg for
the treatment of chronic hyperuricemia in gout patients.
Although it appeared to be more effective then allopurinol as
urate-lowering therapy, the allopurinol dosing was limited to
300 mg/d, thus not reflecting the actual dosing regimens used
in clinical practice. At this time, the dose equivalence of
allopurinol and febuxostat is unknown.
4. Adverse Effects: As with allopurinol, prophylactic treatment
with colchicine or NSAIDs should be started at the beginning
of therapy to avoid gout flares. The most frequent treatment-
related adverse events are liver function abnormalities, diarrhea,
headache, and nausea. Febuxostat is well tolerated in patients
with a history of allopurinol intolerance. There does not appear
to be an increased risk of cardiovascular events.
5. Dosage: The recommended starting dose of febuxostat is
40 mg daily. Because there was concern for cardiovascular
events in the original phase 3 trials, the FDA approved only
40-mg and 80-mg dosing. No dose adjustment is necessary for
patients with renal impairment since it is highly metabolized
into an inactive metabolite by the liver.
PEGLOTICASE
Pegloticase is the newest urate-lowering therapy to be approved for
the treatment of refractory chronic gout.
1. Chemistry: Pegloticase is a recombinant mammalian uricase
that is covalently attached to methoxy polyethylene glycol
(mPEG) to prolong the circulating half-life and diminish
immunogenic response.
2. Pharmacokinetics and Dosage: The recommended dose for
pegloticase is 8 mg every 2 weeks administered as an intrave-
nous infusion. It is a rapidly acting drug, achieving a peak
decline in uric acid level within 24–72 hours. The serum half-
life ranges from 6 to 14 days. Several studies have shown earlier
clearance of PEG-uricase (mean of 11 days) due to antibody
response when compared to PEG-uricase antibody-negative
subjects (mean of 16.1 days).
3. Pharmacodynamics: Urate oxidase enzyme, absent in humans
and some higher primates, converts uric acid to allantoin. This
product is highly soluble and can be easily eliminated by the
kidney. Pegloticase has been shown to maintain low urate levels
for up to 21 days after a single dose at doses of 4–12 mg,
allowing for IV dosing every 2 weeks. Pegloticase should not be
used for asymptomatic hyperuricemia.
4. Adverse Effects: Gout flare can occur during treatment with
pegloticase, especially during the first 3–6 months of treat-
ment, requiring prophylaxis with NSAIDs or colchicine. Large
numbers of patients show immune responses to pegloticase.
The presence of antipegloticase antibodies is associated with
shortened circulating half-life, loss of response leading to a rise
in plasma urate levels, and a higher rate of infusion reactions
and anaphylaxis. Anaphylaxis occurs in more than 6–15% of
patients receiving pegloticase. Monitoring of plasma uric acid
level, with rising level as an indicator of antibody production,
allows for safer administration and monitoring of efficacy. In
addition, other oral urate-lowering agents should be avoided
in order not to mask the loss of pegloticase efficacy. Nephroli-
thiasis, arthralgia, muscle spasm, headache, anemia, and nausea
may occur. Other less frequent side effects noted include upper
respiratory tract infection, peripheral edema, urinary tract infec-
tion, and diarrhea. There is some concern for hemolytic anemia
in patients with glucose-6-phosphate dehydrogenase deficiency
because of the formation of hydrogen peroxide by uricase; there-
fore, pegloticase should be avoided in these patients.
GLUCOCORTICOIDS
Corticosteroids are sometimes used in the treatment of severe
symptomatic gout, by intra-articular, systemic, or subcutaneous
routes, depending on the degree of pain and inflammation.
The most commonly used oral corticosteroid is prednisone.
The recommended oral dose is 30–50 mg/d for 1–2 days, tapered
over 7–10 days. Intra-articular injection of 10 mg (small joints),
30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcino-
lone acetonide can be given if the patient is unable to take oral
medications.
INTERLEUKIN 1 INHIBITORS
Drugs targeting the IL-1 pathway, such as anakinra, canakinumab,
and rilonacept, are used for the treatment of gout. Although the
data are limited, these agents may provide a promising treatment
option for acute gout in patients with contraindications to, or who
are refractory to, traditional therapies like NSAIDs or colchicine.
A recent study suggests that canakinumab, a fully human anti-
IL-1β monoclonal antibody, can provide rapid and sustained pain
relief at a dose of 150 mg subcutaneously. These medications are
also being evaluated as therapies for prevention of gout flares while
initiating urate-lowering therapy.