Nonsteroidal Anti-Inflammatory

Drugs, Disease-Modifying Antirheumatic Drugs,

Nonopioid Analgesics, & Drugs Used in Gout

By Dr. Muhammad Sajjad Haider Ghumman

Pharm-D., M.Phil., Ph.D., Pharmacology
Assistant Professor
Department of Pharmacology
Shahida Islam Medical Complex
Inflammatory pathways
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
 Prostaglandins, thromboxanes, and prostacyclins are synthesized
from arachidonic acid via the cyclooxygenase pathway.

 Cyclooxygenase-1 (COX-1), housekeeping enzyme, is responsible

for the physiologic production of prostanoids (Prostaglandins,
thromboxanes, and prostacyclins). It regulates normal cellular
processes, such as gastric cytoprotection, vascular homeostasis,
platelet aggregation, and kidney function.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
 COX-2 is constitutively expressed in tissues such as the brain, kidney,
and bone. Its expression at other sites is increased during states of
inflammation leading to enhanced production of prostanoids
(Prostaglandins, thromboxanes, and prostacyclins).

 The structural differences between COX-1 and COX-2 permitted the

development of COX-2 selective inhibitors. Cox-2 has a larger and
more flexible substrate channel than COX-1 and has a large space than
COX-1 that the site where inhibitors bind
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
 A group of chemically dissimilar agents that differ in their
antipyretic, analgesic, and anti-inflammatory activities.

 Not all NSAIDs are equally potent in each of these actions.

 Act primarily by inhibiting cyclooxygenase enzymes (COXs) that

catalyze the first step in prostanoid biosynthesis.
 Aspirin and other salicylic acid derivatives
 Aspirin is the prototype of traditional NSAIDs to which all other anti-
inflammatory agents are compared.

 Is rapidly deacetylated by esterases in the body producing salicylate,

having anti-inflammatory, antipyretic, and analgesic effects.

 Antipyretic and anti-inflammatory effects of salicylate are due

primarily to the blockade of prostaglandin synthesis at the in
hypothalamus (thermoregulatory centers) and at peripheral target
sites.
 Aspirin and other salicylic acid derivatives
 By decreasing prostaglandin synthesis (PGE2), salicylate also prevents
sensitization of pain receptors to both mechanical and chemical stimuli
(Local effects).

 Also depress pain stimuli at subcortical sites (that is, the thalamus and
hypothalamus) (Central effects).

 Salicylates are used mainly for the management of low to moderate

intensity pain arising from musculoskeletal disorders.
 It irreversibly acetylates cyclooxygenase leading to its inactivation thus
blocking inflammatory pathway in the first step.
 Aspirin and other salicylic acid derivatives
 Anti-inflammatory actions: Inhibition of prostaglandins formation is
mainly responsible for its anti-inflammatory effects (those aspects of
inflammation in which prostaglandins act as mediators).

 Inhibits inflammation in arthritis, but it neither arrests the progress of

the disease nor induces remission.
 Aspirin and other salicylic acid derivatives

 Salicylates lower body temperature in patients with fever by impeding

PGE2 synthesis and release.

 Aspirin resets the thermostat toward normal, increases heat dissipation

as a result of peripheral vasodilation and sweating leading to rapid
lowering of body temperature. Aspirin has no effect on normal body
temperature.
 Aspirin
 Due to their Anti-inflammatory, antipyretic and analgesic effects,

 Salicylic acid derivatives are used in treatment of gout, rheumatic fever,

osteoarthritis, and rheumatoid arthritis (RA) mainly to manage
inflammation and pain.

 Conditions requiring analgesia include headache, arthralgia, and myalgia.

 Salicylic acid is used topically to treat corns, calluses, and warts.

 Methyl salicylate (Wintergreen oil) is used externally as a cutaneous

counterirritant in liniments.
 Effects on other body systems
 Effects on respiratory system

 At therapeutic doses, aspirin increases alveolar ventilation.

 Higher doses act directly on respiratory center in medulla, resulting in

hyperventilation and respiratory alkalosis that usually is adequately
compensated for by kidney.

 At toxic levels, central respiratory paralysis occurs, and respiratory

acidosis ensues due to continued production of CO2.
 Effects on other body systems
 Gastrointestinal effects

 Aspirin inhibits prostacyclin (PGI2) and PGE2 resulting in increased

gastric acid secretion and diminished mucus protection. These changes
result in epigastric distress, ulceration, hemorrhage, and iron-
deficiency anemia (Aspirin doses of 1 to 4.5 g/day can produce loss of 2
to 8 mL of blood in the feces per day).
 Effects on other body systems
 Effect on platelets

 Low doses of aspirin can irreversibly inhibit thromboxane production

(TXA2) in platelets via acetylation of COX. As platelets lack nuclei, they
can't synthesize new enzyme, and lack of thromboxane persists for lifetime
of platelet (3-7 days).

 It also inhibits COX in endothelial cells, resulting in reduced PGI 2

formation; however, these cells possess nuclei able to re-synthesize new
COX. Therefore, PGI2 is available for antiplatelet action.
 Effects on other body systems
 Effect on platelets

 Low dose of aspirin are used prophylactically to reduce risk of CVS

abnormalities (Clinical use).

 Aspirin should not be taken for at least 1 week prior to surgery (Side
effect).

 When salicylates are administered, anticoagulants may have to be given

in reduced dosage, and careful monitoring and counseling of patients are
necessary.
 Effects on other body systems
 Effect on renal system

 Inhibition of PGE2 and PGI2 prostaglandins synthesis results in retention

of sodium and water and may cause edema and hyperkalemia in some
patients.

(these prostaglandins are responsible for maintaining renal blood flow,

particularly in presence of circulating vasoconstrictors).
 Pharmacokinetics
 After oral administration, un-ionized salicylates are passively absorbed
from stomach and small intestine.

 Rectal absorption of salicylates is slow and unreliable, but it is a useful

route for administration to vomiting children.

 Salicylates (except for diflunisal) cross both BBB’s and placenta and are
absorbed through intact skin (especially methyl salicylate).

 Aspirin is hydrolyzed to salicylate and acetic acid by esterases in

tissues and blood.
 Pharmacokinetics
 In liver salicylate is converted to water-soluble conjugates that are
rapidly cleared by kidney.

 Aspirin at low doses causes decreased secretion of uric acid, whereas at

high doses, uric acid secretion is increased.

 Both hepatic and renal function should be monitored periodically in those

receiving long-term, high-dose aspirin therapy.

 Aspirin should be avoided in patients with a creatinine clearance of less

than 10 mL/min.
 Adverse effects
 Metabolic processes: Large doses of salicylates uncouple oxidative
phosphorylation. The energy normally used for the production of
adenosine triphosphate is dissipated as heat, which explains the
hyperthermia caused by salicylates when taken in toxic quantities.

 Hypersensitivity: Approx. 15% of patients taking aspirin experience

hypersensitivity reactions. Symptoms of true allergy include urticaria,
bronchoconstriction, or angioedema.
 Adverse effects
 Reye's syndrome: Given during viral infections these agents increased
incidence of Reye's syndrome, which is an often fatal, fulminating
hepatitis with cerebral edema. This is especially encountered in
children.

 Acetaminophen instead of aspirin should be used when such medication

is required to reduce fever. Ibuprofen is also appropriate.
 Adverse effects
 Toxicity: Salicylate intoxication may be mild or severe. The mild form is
called salicylism and is characterized by nausea, vomiting, marked
hyperventilation, headache, mental confusion, dizziness, and tinnitus
(ringing or roaring in the ears).

 When large doses of salicylate are administered, severe salicylate

intoxication may result. The symptoms listed above are followed by
restlessness, delirium, hallucinations, convulsions, coma, respiratory
and metabolic acidosis, and death from respiratory failure.
 Adverse effects
 Aspirin is classified as FDA pregnancy category C risk during Trimesters
1 and 2 and category D during Trimester 3. Salicylates are excreted in
breast milk, aspirin should be avoided during pregnancy and while
breast-feeding.
 Propionic acid derivatives
 Ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen,
flurbiprofen, and oxaprozin.
 All these drugs possess anti-inflammatory, analgesic, and antipyretic
activity; additionally, they can alter platelet function and prolong
bleeding time.

 These drugs are reversible inhibitors of COXs and, thus, inhibit the
synthesis of prostaglandins but not of leukotrienes.

 All members are well absorbed on oral administration and are almost
totally bound to serum albumin.
 Propionic acid derivatives
 They undergo hepatic metabolism and are excreted by the kidney.

 In the chronic treatment of RA and osteoarthritis.

 GI adverse effects are generally less intense than those of aspirin.

 The most common adverse effects are GI upsets, ranging from

dyspepsia to bleeding.

 Side effects involving CNS, such as headache, tinnitus, and

dizziness, have also been reported.
 Propionic acid derivatives
 Ibuprofen is a simple derivative of phenylpropionic acid.
 In doses of about 2400 mg/d, it show anti-inflammatory effect
similar to 4 g of aspirin dose.
 Oral ibuprofen is often prescribed in lower doses (<2400 mg/d),
at which it has analgesic but not anti-inflammatory efficacy.
 A liquid gel preparation of ibuprofen, 400 mg, provides prompt
relief in postsurgical dental pain.
 Treatment with ibuprofen in patients with increased CVS risk may
limit cardioprotective effects of aspirin.
 Use of ibuprofen concomitantly with aspirin may decrease the
total anti-inflammatory effect.
 Propionic acid derivatives
 Flurbiprofen is a propionic acid derivative with a possibly more
complex MOA than other NSAIDs.

 In rat tissue to also affect tumor necrosis factor-α (TNF-α) and nitric
oxide synthesis.

 Indicated for the treatment of RA, osteoarthritis, acute gout, mild to

moderately severe pain, dysmenorrhea, soft-tissue trauma,
ankylosing spondylitis.

 IV injection is effective for perioperative analgesia in minor ear, neck,

and nose surgery and as lozenges for sore throat.
 Propionic acid derivatives
 Ketoprofen is a propionic acid derivative that inhibits both COX
(nonselectively) and lipoxygenase.

 In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen

is not superior to other NSAIDs in clinical efficacy.

 Indicated for the treatment of inflammation of joints, tendons, ligaments

and muscles and phelibitis.

 Its major adverse effects are on the GI tract and the central nervous
system.
 Propionic acid derivatives
 Naproxen is a naphthylpropionic acid derivative.

 Indicated for the relief of sign and symptoms of RA, osteoarthritis,

acute gout, tendonitis, brusitis, and dysmenorrhea.

 Oxaprozin is another propionic acid derivative NSAID.

 Major difference from the other members of this group is a very long
half-life (50–60 hours).

 Mildly uricosuric, making it potentially more useful in gout than some

other NSAIDs.
 Oxicam derivatives
 Piroxicam and meloxicam.

 They have long half-lives, which permit once-daily

administration.

 Parent drug as well as its metabolites are excreted in the urine.

 GI disturbances are encountered in approximately 20% of

patients treated with piroxicam.
Oxicam derivatives
 Piroxicam is a nonselective COX inhibitor.

 At high concentrations also inhibits polymorphonuclear

leukocyte migration, decreases oxygen radical production,
and inhibits lymphocyte function.

 Used for the usual rheumatic indications.

 When given in dosages higher than 20 mg/d, an

increased incidence of peptic ulcer and bleeding is
encountered. Risk is 9.5 times higher than with other NSAIDs.
Oxicam derivatives
 Meloxicam preferentially inhibits COX-2 over COX-1,
particularly at its lowest therapeutic dose.

 However, at high doses, meloxicam is a nonselective NSAID,

inhibiting both COX-1 and COX-2.

 It is not as selective as celecoxib and may be considered

“preferentially” selective rather than “highly” selective.

 At low to moderate doses shows less GI irritation than

piroxicam.

 Excreted in the urine and feces equally as metabolites.

Fenamates
 Mefenamic and meclofenamate.

 Have no advantages over other NSAIDs as anti-inflammatory

agents.

 Their side effects, such as diarrhea, can be severe, and they are
associated with inflammation of the bowel.

 Cases of hemolytic anemia have been reported.

 Mefenamic acid is administered orally to treat headaches,

muscle aches, dental pain, dysmenorrhea, arthritis
Fenamates
 Meclofenamic acid is given orally to treat musculoskeletal
and joint disorders including RA, OA and management of
mild to moderate pain.
Acetic acid derivatives

 Indomethacin, sulindac, and etodolac.

 All these agents have anti-inflammatory, analgesic, and

antipyretic activity.

 They act by reversibly inhibiting cyclooxygenase.

 They are generally not used to lower fever.

 Indomethacin 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.
Acetic acid derivatives

 Despite its potent anti-inflammatory action, toxicity of

indomethacin limits its use to treatment of acute gouty
arthritis, ankylosing spondylitis, and osteoarthritis of hip.

 An ophthalmic preparation is efficacious for conjunctival

inflammation and to reduce pain after traumatic corneal
abrasion.

 Indomethacin oral rinse to reduce gingival inflammation.

Acetic acid derivatives

 Epidural injections produce a degree of pain relief similar to

that achieved with methylprednisolone in post-laminectomy
syndrome.

 Sulindac is a sulfoxide prodrug. It is reversibly metabolized

to active sulfide metabolite, which is excreted in bile and then
reabsorbed from intestine. The enterohepatic cycling prolongs
the duration of action to 12–16 hours.
Acetic acid derivatives

 Sulindac is less potent than indomethacin, but it is useful in

the treatment of RA, ankylosing spondylitis, osteoarthritis,
and acute gout.

 It also suppresses familial intestinal polyposis and it may

inhibit the development of colon, breast, and prostate cancer in
humans.

 It appears to inhibit occurrence of GI cancer in rats. The latter

effect may be caused by the sulfone rather than sulfide.
Acetic acid derivatives

 Severe adverse reactions include, Stevens-Johnson/epidermal

necrolysis syndrome, thrombocytopenia, agranulocytosis, and
nephrotic syndrome have all been observed.

 Etodolac is a racemic acetic acid derivative with an

intermediate half-life.

 Etodolac has adverse effects similar to those of other NSAIDs.

GI problems are less common.
Nabumetone

 Indicated for treatment of RA and osteoarthritis.

 Associated with low incidence of adverse effects.

 Metabolized by liver to active metabolite, which displays the

anti-inflammatory, antipyretic, and analgesic activity. The
active metabolite is then hepatically metabolized to inactive
metabolites with subsequent renal elimination.

 Therefore, this agent is used with cautions in patients with

hepatic and renal impairment.
Heteroaryl acetic acids

 Diclofenac, tolmetin, and ketorolac

 Approved for long-term use in the treatment of RA,

osteoarthritis, and ankylosing spondylitis.

 Diclofenac is more potent than indomethacin or naproxen.

 Diclofenac is a phenylacetic acid derivative that is relatively

nonselective as a COX inhibitor.

 Diclofenac accumulates in synovial fluid, and the primary

route of excretion for the drug and its metabolites is the kidney.
Heteroaryl acetic acids

 A preparation combining diclofenac and misoprostol decreases

upper GI ulceration but may result in diarrhea.

A 0.1% ophthalmic preparation----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.

 Rectal suppository form can be considered for preemptive

analgesia and postoperative nausea.
Heteroaryl acetic acids

 GI ulceration may occur less frequently than with

some other NSAIDs.
Heteroaryl acetic acids

 Ketorolac is an NSAID promoted for systemic use mainly as

an analgesic, not as an anti-inflammatory drug (although it
has typical NSAID properties).

 The drug is an effective analgesic and has been used

successfully to replace morphine in some situations involving
mild to moderate postsurgical pain.

 It is mostly given by IM or IV route,

 Can also be taken orally or topically.

Heteroaryl acetic acids
 When used with an opioid, it may decrease the opioid
requirement by 25–50%.

 An ophthalmic preparation is available for ocular

inflammatory conditions.

 Toxicities are similar to those of other NSAIDs. It can cause

fatal peptic ulcers as well as GI bleeding and/or perforation of
the stomach or intestines.
Heteroaryl acetic acids

 Tolmetin is an effective anti-inflammatory, antipyretic, and

analgesic agent.

 Nonselective COX inhibitor with a short half-life

(5 / 1–2 hours) and is not often used.

 It is 99% bound to plasma proteins, and metabolites can be

found in the urine.
Heteroaryl acetic acids

 Not effective in the treatment of gout.

 In general efficacy and toxicity profiles are similar to those of

other NSAIDs.
COX-2 selective agents
 Celecoxib

 Significantly more COX-2 selective (about 10–20 times more

selective) than of COX-1.

 In fact, at concentrations achieved in vivo, celecoxib does not

block COX-1.

 Inhibition of COX-2 is time-dependent and reversible.

 Approved for treatment of RA, osteoarthritis, and pain. Unlike

aspirin, celecoxib does not inhibit platelet aggregation and
does not increase bleeding time.
Celecoxib

 Readily absorbed, reaching a peak concentration in about 3

hours.

 Extensively metabolized in the liver by cytochrome P450

(CYP2C9)

 Half-life is about 11 hours; thus, it is usually taken once a day

but can be administered as divided doses twice daily.

 Excreted in feces and urine.

 Celecoxib should be avoided in patients with severe hepatic and

renal disease
Celecoxib

 Headache, dyspepsia, diarrhea, and abdominal pain are the

most common adverse effects.

 Celecoxib should be avoided in patients with chronic renal

insufficiency, severe heart disease, volume depletion, and/or
hepatic failure.

 Higher incidence of cardiovascular thrombotic events

associated with COX-2 inhibitors such as rofecoxib and
valdecoxib, resulted in their withdrawal from the market.
 Acetaminophen

 Antipyretic and analgesic properties only.

 Inhibits prostaglandin synthesis in the CNS, has less effect on

cyclooxygenase in peripheral tissues, which accounts for its weak
anti-inflammatory activity.

 Does not affect platelet function or increase blood clotting time.

 Rapidly absorbed from GIT.

 Undergoes first-pass metabolism.

 Acetaminophen

 Conjugated in liver to form inactive glucuronidated or sulfated

metabolites.

 A portion is hydroxylated to form N-acetylbenzoiminoquinone, a

highly reactive and potentially dangerous metabolite that reacts
with sulfhydryl groups. At normal doses of acetaminophen, the N-
acetylbenzoiminoquinone reacts with the sulfhydryl group of
glutathione, forming a nontoxic substance.

 Acetaminophen and its metabolites are excreted in urine.

 Acetaminophen

 Suitable substitute for analgesic and antipyretic effects of aspirin

for those patients

a) with gastric complaints.

b) those in whom prolongation of bleeding time would be a

disadvantage.

c) or those who do not require anti-inflammatory action of aspirin.

 Acetaminophen

 Analgesic/antipyretic of choice for children with viral infections

or chickenpox (aspirin increases the risk of Reye's syndrome).

 Does not antagonize action of uricosuric agents probenecid or

sulfinpyrazone and, therefore, may be used in patients with gout
who are taking these drugs.
 Acetaminophen

 At normal doses, it is virtually free of any significant adverse effects.

 Skin rash and minor allergic reactions can occur.

 With large doses of acetaminophen, available glutathione in the

liver becomes depleted, and N-acetylbenzoiminoquinone reacts
with sulfhydryl groups of hepatic proteins, forming covalent
bonds.

 Hepatic necrosis, a very serious and potentially life-threatening

condition, can result. Renal tubular necrosis may also occur.
 Acetaminophen

 Administration of N-acetylcysteine, which contains

sulfhydryl groups to which the toxic metabolite can
bind, can be lifesaving if administered within 10 hours of
the overdose.

 This agent should be avoided in patients with severe

hepatic impairment.
Acetaminophen
Disease-Modifying Anti-rheumatic Agents
 DMARDs
 RA is a progressive immunologic disease that causes significant
systemic effects, shortens life, and reduces mobility and quality of
life.

 These agents are used in the treatment of RA and have been shown to
slow course of disease, induce remission, and prevent further
destruction of the joints and involved tissues.

 These therapies include nonbiologic disease-modifying

antirheumatics (known as DMARDs)
 DMARDs
 e.g., methotrexate, azathioprine, chloroquine and
hydroxychloroquine, cyclophosphamide, leflunomide,
mycophenolate mofetil, sulfasalazine and gold salts.

 Biologic DMARDs (designated “biologics”) include TNF-α-

blocking agents and others

 These therapies include conventional synthetic (cs) and biologic

(b) disease-modifying antirheumatic drugs (recently designated
csDMARDs and bDMARDs, respectively).
 Methotrexate
A synthetic antimetabolite, is now considered the
first-line DMARD for treatment of RA and is used in 50–
70% of patients.

 Used in low doses for RA treatment than cancer.

 Inhibits the proliferation and stimulates apoptosis of

immune-inflammatory cells.

 Also inhibit proi-nflammatory cytokines linked to

rheumatoid synovitis.
 Methotrexate

 Secondary effects on polymorphonuclear chemotaxis.

 Its MOA also relates to inhibition of aminoimidazole

carboxamide ribonucleotide (AICAR) transformylase. Net
result of which is formation of adenosine, which is a potent
inhibitor of inflammation. As a result, the inflammatory
functions of neutrophils, macrophages, dendritic cells, and
lymphocytes are suppressed.
 Methotrexate

 Rheumatoid arthritis (once weekly dosing)

 Decreases the rate of appearance of new erosions.

 Evidence supports its use in juvenile chronic arthritis,

psoriasis, psoriatic arthritis, ankylosing spondylitis,
Wegener’s granulomatosis, systemic lupus erythematosus,
and vasculitis.
 Chloroquine & Hydroxychloroquine

 Antimalarials which are approved for RA, but they are not
considered very effective DMARDs.

 Act through several mechanisms i.e., suppression of T-

lymphocyte responses to mitogens, decreased leukocyte
chemotaxis, stabilization of lysosomal enzymes, inhibition of
DNA and RNA synthesis, and trapping of free radicals.
 Chloroquine & Hydroxychloroquine

 Hydroxychloroquine is used for early, mild RA and has

relatively few side effects.

 When used alone, it does not slow joint damage, therefore, it is

often used in combination with methotrexate.
 Cyclophosphamide
 Is a synthetic DMARD.

 Major active metabolite is phosphoramide mustard, which

cross-links DNA to prevent cell replication. It suppresses T-cell
and B-cell function. T-cell suppression correlates with clinical
response in the rheumatic diseases.

 Active against RA, systemic lupus erythematosus, vasculitis,

Wegener’s granulomatosis, and other severe rheumatic diseases.
 Sulfasalazine
 Is a synthetic DMARD.

 Metabolized to sulfapyridine and 5-aminosalicylic acid. The

sulfapyridine is probably the active moiety when treating RA.

 Sulfasalazine or its metabolites inhibit the release

of inflammatory cytokines (interleukins-1, -6, and -12, and TNF-
α ) produced by monocytes or macrophages.

 Suppression of T-cell functions and inhibition of in vitro B-cell

proliferation have also been documented.
 Sulfasalazine

 Is effective in RA, also used in juvenile chronic arthritis and in

ankylosing spondylitis.

 Common adverse effects include nausea,

vomiting, headache, and rash. Neutropenia occurs in 1–5% of
patients, while thrombocytopenia is very rare.
 D-Penicillamine

 An analogue of cysteine amino acid

 Slows the progression of bone destruction and RA.

 Used as an add-on therapy to existing NSAID/glucocorticoid

therapy, but use in patients on DMARD therapy is avoided due to
serious adverse events (ranging from dermatologic problems to
nephritis and aplastic anemia).
 Gold salts
 Auranofin, a currently available gold preparation for oral
administration.

 It can only prevent further injury but cannot repair existing

damage.

 Taken up by macrophages and suppresses phagocytosis and

lysosomal enzyme activity. This leads to delayed progression of
bone and articular destruction.
 Gold salts
 Beneficial effects may be seen in 3 to 6 months.

 These compounds are being used infrequently because of serious

toxicity (myelosuppression) and the costs of monitoring.
 Azathioprine
 A synthetic DMARD that acts through its major metabolite, 6-
thioguanine. 6-Thioguanine suppresses B-cell and T-cell
function, immunoglobulin production, and interleukin-2
secretion.

 Approved for use in RA. Controlled trials show efficacy in

psoriatic arthritis, reactive arthritis.

 Adverse effects includes bone marrow suppression, GI

disturbances, and some increase in infection risk.
 Mycophenolate Mofetil (MMF)
 A semisynthetic DMARD, is converted to mycophenolic acid, the
active form of the drug.

 Inhibits inosine monophosphate dehydrogenase leading to

suppression of T- and B-lymphocyte proliferation.

 MMF is effective for treatment of renal disease due to systemic

lupus erythematosus and may be useful in vasculitis and
Wegener’s granulomatosis.

 Occasionally used at a dosage of 2 g/d to treat RA.

 Leflunomide
 Undergoes rapid conversion, both in the intestine and in the
plasma, to its active metabolite, A77-1726.

 A77-1726 inhibits dihydroorotate dehydrogenase, leading to a

decrease in pyrimidine synthesis and the arrest of stimulated
cells (lymphocytes) in G1 phase of cell growth.

 This leads to inhibition of T-cell proliferation and production

of autoantibodies by B cells.
 Leflunomide

 as effective as methotrexate in RA, including inhibition of bony

damage.

 It not only reduces pain and inflammation associated with the

disease but also appears to slow the progression of structural
damage.

 Can be used in monotherapy as an alternative to methotrexate

or as an addition to methotrexate in combination therapy.
 Leflunomide

 Well absorbed after oral administration. It is extensively bound to

albumin (> 90%) and has a half-life of 14-18 days. Rapidly converted
to active metabolite which are excreted in urine and feces.

 Diarrhea, elevation in liver enzyme, mild alopecia, weight

gain, and increased blood pressure. Leflunomide is teratogenic in
experimental animals therefore, is contraindicated in pregnancy and
in women of child-bearing potential.
 Biologic Therapies in Rheumatoid Arthritis

 Interleukin-1b and TNF-α are among the few proinflammatory

cytokines involved in the pathogenesis of RA. When secreted by synovial
macrophages, IL-1b and TNF-α stimulate synovial cells to proliferate
and synthesize collagenase, thereby degrading cartilage, stimulating
bone resorption, and inhibiting proteoglycan synthesis.
 TNF-α-Blocking Agents
1) Etanercept
 Is a genetically engineered fusion protein that binds to TNF-α, thereby
blocking its interaction with cell surface TNF receptors.

 approved for use in patients with moderate to severe RA, either alone
or in combination with methotrexate.

 combination of etanercept and methotrexate is more effective than

methotrexate or etanercept alone in retarding the disease process,
improving function, and achieving remission
 TNF-α-Blocking Agents

 Also approved for use in patients with polyarticular-course

juvenile RA, psoriatic arthritis, ankylosing spondylitis, and
psoriasis.

 Given subcutaneously twice a week (half-life is 115 hours).

 Well tolerated. No toxicities or antibodies have been reported.

Local inflammation at the site of injection is observed.
 Infliximab

 A chimeric IgG1 monoclonal antibody that binds with high

affinity to soluble and possibly membrane-bound TNF-α.

 Given as IV infusion.

 Distributes in vascular compartment.

 Half-life of 9.5 days. Its metabolism and elimination have not

been described.
 Infliximab

 Approved for use in combination with methotrexate in

patients with RA who have had inadequate response to
methotrexate monotherapy.

 Also used in plaque psoriasis, psoriatic arthritis, ulcerative

colitis, ankylosing spondylitis, and Crohn's disease.

 Adverse effects include infusion reactions, such as fever, chills,

pruritus, or urticaria. Infections leading to pneumonia,
cellulitis, and other conditions have also been reported.
 Adalimumab

 Forms complex with soluble TNF-α and prevents

its interaction with cell surface receptors. This results in down
regulation of macrophage and T-cell function.

 indicated for treatment of moderate to severe RA, either as

monotherapy or in combination with methotrexate. It is also
indicated for psoriatic arthritis, ankylosing spondylitis, and
Crohn's disease.
 Adalimumab

 Administered subcutaneously weekly or every other week.

 It may cause headache, nausea, rash, reaction at the injection

site or increased risk of infection.
 Certolizumab

 Neutralizes membrane-bound and soluble TNF-α in a dose-

dependent manner.

 Used as monotherapy or in combination with non-biologic

DMARDs.

 Indicated for the treatment of moderate to severe RA in adults.

 Golimumab

 a human monoclonal antibody with a high affinity

for soluble and membrane-bound TNF-α.

 given with methotrexate, is indicated for the treatment of

moderately to severely active RA in adult patients. It is also
indicated for the treatment of psoriatic arthritis and
ankylosing spondylitis.

 Adverse effects include increase risk of serious infections,

including TB, fungal, and other opportunistic pathogens.
 Anakinra

 an IL-1 receptor antagonist which binds to IL-1 receptor, thus

preventing actions of IL-1 (degradation of cartilage and
stimulation of bone resorption).

 treatment leads to a modest reduction in the signs and

symptoms of moderately to severely active RA in adult
patients who have failed one or more DMARDs.

 administered subcutaneously once a day (normal renal

function) and every other day (moderate to severe renal
 Anakinra

 Adverse effects include neutropenia.

 Rituximab

 a genetically engineered chimeric murine/human monoclonal

antibody directed against the CD20 antigen found on the
surface of normal and malignant B lymphocytes, resulting in
B-cell depletion.

 This leads to 1) decreased activation of T lymphocytes, 2) less

production autoantibodies such as anti-CCP (anticyclic
citrullinated peptide antibody) and rheumatoid factor, and 3)
decreased production of pro-inflammatory cytokines such as
TNF-α and IL-1.
 Rituximab

 indicated for use in combination with methotrexate to reduce

signs and symptoms of moderate to severe RA in patients who
have had an inadequate response to one or more TNF-
inhibitors.

 Rituximab has been shown to reduce joint erosion and joint

space narrowing in RA patients.

 Given by IV route. Adverse effects include infusion reactions

(urticaria, hypotension, or angioedema). Can be managed
Drugs Employed in the Treatment of Gout
 Gout
 A metabolic disorder characterized by high levels of uric acid in blood.

 Hyperuricemia can lead to deposition of urate crystals in tissues,

especially joints and kidney.

 Therapeutic strategies involve

 1) interfering with uric acid synthesis

 2) increasing uric acid excretion

 3) inhibiting leukocyte entry into the affected joint

 4) administration of NSAIDs.
 Acute gout
 Can result from a number of conditions, including excessive alcohol
consumption, diet rich in purines, or kidney disease.

 Treated with indomethacin to decrease movement of granulocytes into

the affected area; NSAIDs other than indomethacin are also effective
at decreasing pain and inflammation.

 Intra-articular administration of glucocorticoids (when only one or

two joints are affected).
Acute gout
 It can be caused by

 1) A genetic defect, such as one resulting in overproduction of

purines.

 2) Renal deficiency.

 3) Lesch-Nyhan syndrome. deficiency of the enzyme

hypoxanthine-guanine phosphoribosyltransferase (HPRT).

 4) Excessive production of uric acid associated with cancer

chemotherapy.
 Chronic gout
 Treatment strategies include,

 a) Use of uricosuric drugs that increase the excretion of uric

acid, thereby reducing its concentration in plasma

 B) Enzyme inhibitors which block the biosynthesis of uric acid.

 Colchicine
 An alkaloid isolated from Colchicum autumnale.

 It relieves pain and inflammation of gouty arthritis in 12–24 hours with

no effect on metabolism or excretion of urates.

 Produces its anti-inflammatory effects mainly by binding to

intracellular protein tubulin, thereby preventing its polymerization
into microtubules and leading to inhibition of leukocyte migration
and phagocytosis.
 Colchicine
 Blocks cell division by binding to mitotic spindles.

 Also inhibits the synthesis and release of leukotrienes.

 Well absorbed after oral administration, reaches peak plasma levels

within 2 hours.

 Serum half-life of 9 hours.

 Metabolites are excreted in the feaces and urine.

 IV use of colchicine is not recommended because of their potential

life-threatening adverse effects.
 Colchicine
 NSAIDs are sometimes used instead because of the troublesome
diarrhea (bloody diarrhea) associated with colchicine therapy.

 Currently used for prophylaxis of recurrent attacks.

 Often causes diarrhea, nausea, vomiting, and abdominal pain.

 Chronic administration may lead to myopathy, neutropenia,

aplastic anemia, and alopecia.
 Allopurinol
 A purine analogue.

 It reduces the production of uric acid by competitively inhibiting

xanthine oxidase involved in the conversion of hypoxanthine and
xanthine into uric acid (last two steps).

 Xanthine and hypoxanthine are more soluble and, therefore, are less
likely to precipitate and are easily excreted.
 Allopurinol
 Completely absorbed after oral administration.

 Its primary metabolite is alloxanthine (oxypurinol), which is also a

xanthine oxidase inhibitor with a half-life of 15-18 hours; the half-life
of allopurinol is 2 hours.

 Owing to longer half life of alloxanthine it is given once-daily.

 Drug and its active metabolite are excreted in the feces and urine.
 Allopurinol
 Effective in the treatment of primary hyperuricemia of gout and
hyperuricemia secondary to other conditions, like certain malignancies
(in which large amounts of purines are produced, particularly after
treatment with chemotherapeutic agents) or in renal disease.

 Drug of choice in those with a history of kidney stones or if the

creatinine clearance is less than 50 mL/day.

 Hypersensitivity reactions, especially skin rashes, are the most

common adverse reactions (approx. 3% of patients).
 Febuxostat
 a non-purine xanthine oxidase inhibitor.

a potent and selective inhibitor of xanthine oxidase,

thereby reducing the formation of xanthine and uric acid. Does not affect
other enzymes in purine or pyrimidine metabolic pathway.

 In clinical trials, it showed better efficacy than allopurinol. The urate-

lowering effects was comparable regardless of the pathogenic cause of
hyperuricemia—overproduction or under excretion.
 Febuxostat
 Febuxostat appears to be well tolerated in patients with a
history of allopurinol intolerance.

 The most frequent treatment-related adverse events are

liver function abnormalities, diarrhea, headache, and nausea.
 Pegloticase
 The newest urate-lowering therapy.

 Approved by the FDA for the treatment of refractory chronic gout.

a recombinant mammalian uricase that is covalently

attached to methoxy polyethylene glycol (mPEG) to prolong the
circulating half-life and diminish immunogenic response.

 Converts uric acid to allantoin which is highly water soluble

substance and can be easily eliminated by kidney.
 Pegloticase
 Has been shown to maintain low urate levels for up to 21 days at doses
of 4–12 mg, allowing for IV dosing every 2 weeks.

 The most common adverse events include infusion reactions.

Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and
nausea may occur.

 Patients show immune responses to pegloticase.

 Given by IV route.
 Uricosuric Agents
 Uricosuric drugs are weak organic acids that promote renal clearance
of uric acid by inhibiting the urate-anion exchanger in the proximal
tubule that mediates urate reabsorption.

 Probenecid and sulfinpyrazone are uricosuric drugs employed to

decrease body pool of urate in patients with tophaceous gout or in
those with increasingly frequent gouty attacks.

 Uricosuric agents should not be used in patients who excrete large

amounts of uric acid.
 Probenecid and Sulfinpyrazone

 These agents act on the active transport sites in the proximal tubule

leading to the decreased reabsorption of uric acid.

 With the ensuing increase in uric acid excretion, a predisposition to the

formation of renal stones is augmented rather than decreased; therefore,

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.
 Probenecid and Sulfinpyrazone

 Uricosuric therapy should be initiated in gouty patients with

underexcretion of uric acid when allopurinol or febuxostat is

contraindicated or when tophi are present.

 Both agents cause GI irritation, but sulfinpyrazone is more active in

this regard. A rash may appear after the use of either compound.
 Glucocorticoids
 Corticosteroids are sometimes used in the treatment of severe
symptomatic gout.

 Depending on the degree of pain and inflammation are given by intra-

articular, systemic, or subcutaneous routes.

 The most commonly agent is prednisone. Recommended dose for intra-

articular injection is 10 mg for small joints) and 30 mg for wrist, ankle,
elbow.

 40 mg (knee) of triamcinolone acetonide can be given if the patient is

unable to take oral medications.
 Interleukin-1 Inhibitors
 Drugs targeting the interleukin-1 pathway, such as anakinra,
canakinumab, and rilonacept, are being investigated for the treatment of
gout.