Anti rheumatic drug ( NSAIDs and DMARDs )

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Inflammation plays a major role in the pathophysiology of a wide spectrum of
diseases. It is primarily a protective response, but if excessive or
inappropriately prolonged can contribute adversely to the disease process.
Inflammatory cells: many different cells are involved in different stages of
different kinds of inflammatory response, including neutrophils (e.g. in acute
bacterial infections), eosinophils, mast cells and lymphocytes (e.g. in asthma),
monocytes, macrophages and lymphocytes (for example, in autoimmune
disease, including chronic joint diseases, such as rheumatoid arthritis).
Inflammatory mediators: include prostaglandins, complement and coagulation
cascade-derived peptides, and cytokines (for example, interleukins, especially
IL-2 and IL-6, and tumor necrosis factor (TNF)). The mediators amplify the
inflammatory cell responses.
Anti-inflammatory drugs work on different aspects of the inflammatory
cascade including the synthesis and action of mediators, and in the case of
immunesuppressants on the amplification of the response.
A non-steroidal anti-inflammatory drug (NSAID) is indicated for pain and
stiffness resulting from inflammatory rheumatic disease. Analgesics such as
paracetamol or codeine phosphate can also be used.
Drugs are also used to influence the rheumatic disease process itself. For
rheumatoid arthritis these disease modifying anti-rheumatic drugs (DMARDs)
include methotrexate, cytokine modulators, azathioprine, cyclosporine,
cyclophosphamide, leflunomide, penicillamine, gold, anti-malarials (chloro-
quine and hydroxylchloroquine sulfate), and sulfasalazine.
Corticosteroids also have a significant role in the management of rheumatoid
arthritis.
INTRODUCTION:
Anti-rheumatoid drug

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Non-steroidal anti-inflammatory
drug (NSAID)
The NSAIDs are a group of chemically dissimilar agents that differ in their
antipyretic, analgesic, and anti-inflammatory activities at relatively high
dosage (> 4 g/d) effects in rheumatic diseases (e.g., rheumatoid arthritis).
The class includes derivatives of salicylic acid (aspirin, diflunisal, salsalate,
sulfasalazine),propionic acid(ibuprofen, fenoprofen, flurbiprofen, ketoprofen
,naproxen, oxaprozin ) , acetic acid (diclofenac , indomethacin , ketorolac,
sulindac,tolmetin),enolic acid(meloxicam, piroxicam),fenamates (mefenamic
acid, meclofenamate), and the selective COX-2 inhibitor (celecoxib). They act
primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step
in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis
with both beneficial and unwanted effects.
Differences in safety and efficacy of the NSAIDs may be explained by relative
selectivity for the COX-1 or COX-2 enzyme. Inhibition of COX-2 is thought
to lead to the anti-inflammatory and analgesic actions of NSAIDs, while
inhibition of COX-1 is responsible for prevention of cardiovascular events and
most adverse events.
Non-steroidal anti-inflammatory drug

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The arachidonic acid cascade.

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1- Acetylsalicylic acid ( Aspirin ) :
Aspirin can be thought of as a traditional NSAID, but it
exhibits anti-inﬂammatory activity at relatively high
doses that are rarely used.
It has gained much more usage at lower doses for the
prevention of cardiovascular events such as stroke and
myocardial infarction (MI).
Mechanism of action:
Aspirin effects and respective mechanisms of action vary with dose:
 Low doses (typically 75 to 81 mg/day) are sufficient to irreversibly
acetylate serine 530 of cyclooxygenase (COX)-1. This effect inhibits
platelet generation of thromboxane A2, resulting in an antithrombotic
effect.
 Intermediate doses (650 mg to 4 g/day) inhibit cyclooxygenase (COX)-
1 and COX-2, blocking prostaglandin (PG) production, and have
analgesic and antipyretic effects.
 High doses (between 4 and 8 g/day) are effective as anti-inflammatory
agents in rheumatic disorders; the mechanism(s) of action at these high
doses may include both PG-dependent (particularly COX-2 dependent
PGE2) and independent effects. However, the usefulness of aspirin at
these high doses is limited by toxicity, including tinnitus, hearing loss,
and gastric intolerance.
Aspirin is often differentiated from other NSAIDs, since it is an irreversible
inhibitor of cyclooxygenase activity.

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Pharmacokinetics:
After oral administration, aspirin is rapidly deacetylated by esterases in the
body, thereby producing salicylate. Unionized salicylates are passively
absorbed mostly from the upper small intestine (dissolution of the tablets is
favored at the higher pH of the gut). Salicylates (except for diﬂunisal) cross
both the blood brain barrier and the placenta and are absorbed through intact
skin (especially methyl salicylate). Salicylate is converted by the liver to water-
soluble conjugates that are rapidly cleared by the kidney, resulting in first order
elimination and a serum half-life of 3.5 hours.
At anti-inﬂammatory dosages (more than 4 g/day), the hepatic metabolic
pathway becomes saturated, and zero-order kinetics are observed, leading to a
half-life of 15 hours or more. Being an organic acid, salicylate is secreted into
the urine and can affect uric acid excretion.
At low doses of aspirin (less than 2 g/day), uric acid secretion is decreased,
whereas at high doses, uric acid secretion may be unchanged or increased.
Therefore, aspirin is avoided in gout or in patients taking probenecid.
Adverse effects:
Group of specific adverse effects can be attributed to inhibition of cyclooxy-
genase. The most frequent problem, gastric mucosal injury with risk of peptic
ulceration, results from reduced synthesis of protective prostaglandins (PG),
apart from a direct irritant effect.Gastropathy may be prevented by co admini-
stration of the PG derivative as misoprostol.
In the intestinal tract, inhibition of PG synthesis would similarly be expected to
lead to damage of the blood mucosa barrier and enteropathy.
In predisposed patients, asthma attacks may occur, probably because of a lack
of bronchodilating PG and increased production of leukotrienes. Because this
response is not immune mediated, such “pseudoallergic” reactions are a
potential hazard with all NSAIDs.
PG also regulate renal blood flow as functional antagonists of angiotensin II
and norepinephrine. If release of the latter two is increased (e.g., in
hypovolemia), inhibition of PG production may result in reduced renal blood
flow and renal impairment. Other unwanted effects are edema and a rise in
blood pressure.

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2- Ibuprofen:
Ibuprofen, a propionic acid derivative, is a prototypical
nonsteroidal anti-inflammatory drug with analgesic and
antipyretic properties.
Ibuprofen used as symptomatic treatment of rheumatoid
arthritis, juvenile rheumatoid arthritis and osteoarthritis.
And used to treat mild to moderate pain and for the
management of dysmenorrhea gout and psoriatic
arthritis. And reduce fever. May be used IV with opiates
Ibuprofen has pharmacologic actions similar to those of other prototypical
NSAIDs, which are thought to act through inhibition of prostaglandin synthesis.
Ibuprofen is a non-selective inhibitor of cyclooxygenase (COX-1 and COX-2),
its pharmacological effects due to inhibition cylooxygenase-2 (COX-2) which
decreases the synthesis of prostaglandins involved in mediating inflammation,
pain, fever and swelling.
Antipyretic effects may be due to action on the hypothalamus, resulting in an
increased peripheral blood flow, vasodilation, and subsequent heat dissipation.
Inhibition of COX-1 is thought to cause some of the side effects of ibuprofen
including GI ulceration. Ibuprofen is administered as a racemic mixture. The
R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo.
The S-enantiomer is believed to be the more pharmacologically active
enantiomer.
to relieve moderate to severe pain. Ibuprofen lysine may be used IV to treat
patent ductus arteriosus (PDA) in premature neonates.
Dose:
Patient Ibuprofen Dose
Adult
Children
Anti-pyretic
Anti-inflammatory
Analgesic
Anti-inflammatory
200-400 mg, Every 4-6 hrs.
300 mg, Every 6-8 hrs or 400-800 mg 3-4 times daily
5-10 mg/Kg. Every 6 hrs. (max. 40 mg/Kg per day
20-40 mg/Kg/day in 3-4 divided dose

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Ibuprofen ~ 80% absorbed from GI tract
Time to reach peak plasma concentration = 47 minutes (suspension), 62
minutes (chewable tablets), 120 minutes (conventional tablets)
R-enantiomer undergoes extensive enantiomeric conversion (53-65%) to the
more active S-enantiomer in vivo. Metabolized by oxidation to 2 inactive
metabolites: (+)-2[4´-(2-hydroxy-2-methylpropyl) phenyl] propionic acid and
(+)-2-[4´-(2-carboxypropyl) phenyl] propionic acid. Very small amounts of 1-
hydroxyibuprofen and 3-hydroxyibuprofen have been recovered from urine.
Cytochrome P450 2C9 is the major catalyst in the formation of oxidative
metabolites. Oxidative metabolites may be conjugated to glucuronide prior to
excretion.
Pharmacokinetics:
Adverse effects:
As other NSAIDs, Ibuprofen may gastric mucosal injury with risk of peptic
ulceration, results from reduced synthesis of protective prostaglandins (PG)
and most common symptoms of overdose are abdominal pain, nausea,
vomiting, lethargy and vertigo.

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3- Diclofenac:
Diclofenac is a phenyl acetic acid derivative which
has analgesic, antipyretic and anti-inflammatory
actions.
It is mostly employed in the treatment of rheumatoid
arthritis and other rheumatic disorders.
Dose:
Diclofenac potassium immediate-release tablets:
50 mg orally 3 or 4 times a day
Diclofenac sodium enteric-coated and delayed-release tablets:
50 mg orally 3 to 4 times a day or 75 mg orally twice a day
Maximum dose: 225 mg daily
Diclofenac is believed to exert a wide spectrum of its effects as a consequence
of its ability to inhibit the prostaglandin synthesis noticeably.
However, its anti-inflammatory activity is very much akin to other members of
NSAIDs having a potency, on weight basis, which is nearly 2.5 times that of
indomethacin.
Likewise, on weight basis, its analgesic potency is about 8-16 times than that
of ibuprofen.
Diclofenac has pharmacologic actions similar to other prototypical NSAIDs,
which act through inhibition of prostaglandin synthesis due to inhibition of
cyclooxygenase (COX-1 and COX-2).

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4- Indomethacin:
It is a non-steroid drug possessing anti-
inflammatory, antipyretic and analgesic properties.
It is usually used for the treatment of rheumatoid
arthritis, gouty arthritis and osteoarthritis. It is not
an ordinary simple analgesic and owing to its
reasonaly serious untoward effects should be used
with great caution.
Indomethacin exerts its pharmacologic activity by inhibiting the enzyme
cyclo-oxygenase. As other prototypical NSAIDs.
Indomethacin, is invariably absorbed quite rapidly after oral administration;
peak plasma levels are accomplished in just 2 hours; and almost 97% of the
drug is protein bound. It has a half-life of 2.6 to 11.2 hours; and only 10-20%
of the drug gets excreted practically unchanged in the urine.
Pharmacokinetics:
Dose:
Indomethacin immediate-release tablets:
50–200 mg daily in divided doses
Indomethacin enteric-coated and delayed-release tablets:
75 mg 1–2 times a day
Adverse reaction:
Indomethacin is contraindicated in pregnancy unless the potential benefit
outweighs the risk. Avoid during the third trimester (risk of closure of fetal
ductus arteriosus in utero and possibly persistent pulmonary hypertension of
the newborn); onset of labour may be delayed and duration may be increased.

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5- Sulindac:
Sulindac is a fluorinated indene with a structural
resemblance to indomethacin. It has anti-inflammatory,
analgesic and antipyretic properties. It is usually
employed in the treatment of rheumatic and
musculoskeletal disorders; and also for severe and
long-term relief of signs and symptoms of acute painful
shoulder, acute gouty arthritis and osteoarthritis.
Dose:
Oral:
200 mg twice daily for maximum duration 7–10 days
The precise mechanism of action of Sulindac is still unknown. However, it is
believed that the ‘sulphide metabolite’ may perhaps inhibit the prostaglandin
synthesis. Interestingly, it exerts appreciably much less effect on the platelet
function and bleeding time in comparison to ‘aspirin’, it must be used with
great caution in such patients who could be affected quite adversely by this sort
of action.
Pharmacokinetics:
Sulindac gets absorbed invariably to the extent of 90% after the oral
administration. The peak plasma levels are usually accomplished in about 2
hour in the fasting patient and may be extended between 3-4 hours when given
with food. It has been duly observed that the mean half-life of sulindac is 7 = 8
hours; and the mean half-life of the corresponding sulphide-metabolite is 16.4
hour (almost double than the parent drug).

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6- Celecoxib:
Celecoxib is a selective COX-2 inhibitor.
Approved for the treatment of rheumatoid
arthritis, osteoarthritis, and acute mild to
moderate pain. Celecoxib has similar efficacy to
NSAIDs in the treatment of pain.
Dose:
Oral:
100 mg twice daily, then increased if necessary to 200 mg twice daily
discontinue if no improvement after 2 weeks on maximum dose.
Selective COX-2 inhibitors have less inhibitory action on COX-1, but the
degree of selectivity for COX-2 varies among the drugs in this class. Selective
COX-2 inhibitors have anti-inﬂammatory actions similar to conventional
nonselective NSAIDs, but there is some evidence that they may be less
effective analgesics. This may possibly be due to less inhibition of COX-3 in
the brain and spinal cord.
Selective COX-2 inhibitors have little direct effect on platelet TXA2
production and do not impair platelet aggregation; however, they suppress the
production of the anti-aggregator and vasodilator PGI2 by blood vessels,
which may allow TXA2 to exert unopposed aggregatory effects on platelets.
Selective COX-2 inhibitors also interact with PPARs and impair macrophage
activity and T-cell-mediated immune responses.
Selective COX-2 inhibitor

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Pharmacokinetics:
Celecoxib is readily absorbed after oral administration. It is extensively
metabolized in the liver by cytochrome P450 (CYP2C9) and is excreted in
feces and urine.
The half-life is about 11 hours, and the drug may be dosed once or twice daily.
The dosage should be reduced in those with moderate hepatic impairment, and
celecoxib should be avoided in patients with severe hepatic or renal disease.
Adverse reaction:
Headache, dyspepsia, diarrhea, and abdominal pain are the most common
adverse effects.
Celecoxib, when used without concomitant aspirin therapy, is associated with
less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is
lost when aspirin is added to celecoxib therapy. Patients who are at high risk
of ulcers and require aspirin for cardiovascular prevention should avoid the
use of celecoxib.
Like other NSAIDs, the drug has a similar risk for cardiovascular events.
Celecoxib should be used with caution in patients who are allergic to
sulfonamides.
Patients who have had anaphylactic reactions to aspirin or nonselective
NSAIDs may be at risk for similar effects with celecoxib.
Inhibitors of CYP2C9, such as ﬂuconazole and ﬂuvastatin, may increase serum
levels of celecoxib.
Celecoxib is contraindicated in pregnancy as it cause teratogenic in animal
studies and in breast feeding as it present in milk in animal studies.

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Disease modifying anti-rheumatic drugs
Disease modifying anti-rheumatic
drugs (DMARDs)
Non-steroidal anti-inflammatory drugs provide symptomatic relief but do not
alter the long-term progression of joint destruction in rheumatoid arthritis.
A diverse group of compounds can reduce the rate of progression of joint
erosion and destruction, leading to improvement both in symptoms and in the
clinical and serological markers of rheumatoid arthritis activity.
These drugs produce long-term depression of the inflammatory response even
though they have little direct anti-inflammatory effect. They all have a slow
onset of action, with many producing little improvement until about 3 months
after starting treatment. Such drugs are grouped together and known as
disease-modifying ant-rheumatic drugs (DMARDs).
No one DMARD is efficacious and safe in every patient, and trials of several
different drugs may be necessary. Monotherapy may be initiated with any of
the DMARDs (methotrexate, leflunomide, hydroxychloroquine, or sulfa-
salazine) for patients with low disease activity.
For patients with moderate to high disease activity or inadequate response to
monotherapy, combination DMARD therapy (usually methotrexate based) or
use of anti TNF drugs (adalimumab, certolizumab, etanercept, golimumab, and
infliximab) may be needed.
For patients with more established disease, use of other biologic therapies (for
example, abatacept and rituximab) can be considered. Most of these agents are
contraindicated for use in pregnant women.

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Response to methotrexate occurs within 3 to 6 weeks of starting treatment; it
can also slow the appearance of new erosions within involved joints. The other
DMARDs can be added to methotrexate therapy if there is partial or no
response to maximum doses of methotrexate. Doses of methotrexate required
for RA treatment are much lower than those needed in cancer chemotherapy
and are given once a week, thereby minimizing adverse effects.
Methotrexate is an antineoplastic antimetabolite with immunosuppressant
properties. Used alone or in combination therapy, has become a mainstay of
treatment in patients with rheumatoid or psoriatic arthritis.
Dose for Moderate to severe active rheumatoid arthritis:
7.5 mg once weekly, adjusted according to response
Maximum dose: 20 mg per week
Concomitant folic acid at a dose of least 5 mg/week (except the day of
methotrexate) is recommended to reduce hematologic, gastrointestinal, and
hepatic adverse events related to methotrexate.
1-Methotrexate:
Methotrexate is a folic acid antagonist that competitively inhibits
dihydrofolate reductase, which catalysesthe conversion of dihydrofolate to
tetrahydrofolate. Tetrahydrofolate is a co-factor in thymidine and purine
synthesis, therefore methotrexate prevents DNA and RNA synthesis.
The MOA in the treatment of rheumatoid arthritis is unknown, but may affect
immune function.

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Pharmacokinetics:
Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites mas-
querade as purine or pyrimidine - which become the building blocks of DNA.
They prevent these substances becoming incorporated in to DNA during the
"S" phase (of the cell cycle), stopping normal development and division.
Methotrexate inhibits folic acid reductase which is responsible for the
conversion of folic acid to tetrahydrofolic acid.
At two stages in the biosynthesis of purines and at one stage in the synthesis of
pyrimidine, one-carbon transfer reactions occur which require specific co-
enzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid
itself is synthesized in the cell from folic acid with the help of an enzyme, folic
acid reductase.
Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite
strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed
because the coenzymes needed for one-carbon transfer reactions are not
produced from tetrahydrofolic acid because there is no tetrahydrofolic acid.
Methotrexate selectively affects the most rapidly dividing cells (neoplastic and
psoriatic cells). Methotrexate is also indicated in the management of severe,
active, classical, or definite rheumatoid arthritis.
Adverse reaction:
The most common side effects observed after methotrexate treatment of RA
are mucosal ulceration and nausea. Cytopenias (particularly depression of the
WBC count), cirrhosis of the liver, and an acute pneumonia-like syndrome may
occur with chronic administration.
[Taking leucovorin (folinic acid) once daily after methotrexate reduces the
severity of adverse effects. Folic acid taken on off-days is widely used.]
Methotrexate is contraindicated in pregnancy as it is teratogenic and also
discontinued during breastfeeding.
Periodic liver enzyme tests, complete blood counts, and monitoring for signs
of infection are recommended.

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The exact mechanism of action in autoimmune disorders is unknown, it may
be based on ability of Chloroquine and hydroxychloroquine to increase pH
within intracellular vacuoles and alter processes such as protein degradation
by acidic hydrolases in the lysosome, assembly of macromolecules in the
endosomes, and posttranslation modification of proteins in the Golgi
apparatus.
It is proposed that the anti-rheumatic properties of these compounds results
from their interference with "antigen processing" in macrophages and other
antigen-presenting cells. Acidic cytoplasmic compartments are required for
the antigenic protein to be digested and for the peptides to assemble with the
alpha and beta chains of MHC class II proteins.
As a result, anti-malarials diminish the formation of peptide-MHC protein
complexes required to stimulate CD4+ T cells and result in down-regulation
of the immune response against autoantigenic peptides. Because this
mechanism differs from other anti-rheumatic drugs, anti-malarials are well
suited to complement these other compounds in combination drug therapy.
2-Hydroxychloroquine:
Chloroquine and hydroxychloroquine belonging to the class of 4-amino-
quinoline anti-malarials are being used in clinical practice in the cure and
treatment of early, mild rheumatoid arthritis since 1957, often combined with
methotrexate and onset of effects takes 6 weeks to 6 months.
Dose for active rheumatoid arthritis:
200–400 mg daily
Maximum dose: 6.5 mg/kg per day

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Pharmacokinetics:
Hydroxychloroquine and chloroquine are well absorbed when given orally.
Severe malnutrition (such as kwashiorkor) effects absorption but diarrhea
does not. Both Hydroxychloroquine and chloroquine have prolonged half-
lives, between 40 and 50 days, and low blood clearance (e.g. hydroxyl-
chloroquine's blood clearance is 96 ml/min). There is great variability of blood
concentrations with an eleven-fold range of drug concentrations found after
similar doses in rheumatic arthritis patients. Protein binding ranges between
30 and 40% with binding to both albumin and alpha-glycoprotein.
There is differential binding and metabolism of the (R) and (S) stereoisomers.
Both drugs bind strongly to pigmented tissues but also bind to mononuclear
cells, muscles, etc. There is stereo-selective excretion of both drugs and 40-
50% of the drug is excreted renally. Between 21 and 47% is excreted
unchanged.
There is a suggestion of concentration response and concentration toxicity
relationships with decreased morning stiffness as Hydroxy-chloroquine
concentrations increase and increased EKG abnormalities as chloroquine
concentrations become higher, but further testing is required.
Metabolism of Hydroxychloroquine

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Adverse reaction:
Gastro-intestinal disturbances, headache, pruritus, rashes and skin reactions
are more common as a side effect of administration of chloroquine. And it
may cause ocular toxicity, including irreversible retinal damage and corneal
deposits due to selective binding to photoreceptor cells in the macula and
subsequent disruption of lysosomal function. It may also cause CNS
disturbances.
Hydroxychloroquine is very toxic in overdosage; overdosage is extremely
hazardous and difficult to treat. Urgent advice from the National Poisons
Information Service is essential. Life-threatening features include arrhythmias
(which can have a very rapid onset) and convulsions (which can be
intractable).
It is not necessary to withdraw an anti-malarial drug during pregnancy if the
rheumatic disease is well controlled but it is contraindicated in breast feeding
to avoid risk of toxicity in infant.
3-Sulfasalazine:
Sulfasalazine is a prodrug composed of 5-aminosalicylic acid (5-ASA) linked
to sulfapyridine through an azo bond. It is reducing the damage to the joints,
rather than just relieve the pain so it belongs to the group of medicines called
disease modifying anti- rheumatic drugs (DMARDs).
Dose for active rheumatoid arthritis:
Initially 500 mg daily, increased in steps of 500 mg every week,
increased to 2–3 g daily in divided doses.
Morning
Evening
1st Week 2nd Week 3rd Week
4th Week and
after
1 Delayed-release
tablet
1 Delayed-release
tablet
1 Delayed-release
tablet
1 Delayed-release
tablet
2 Delayed-release
tablet
1 Delayed-release
tablet
1 Delayed-release
tablet

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The mode of action of Sulfasalazine or its metabolites, 5-aminosalicylic acid
(5-ASA) and sulfapyridine (SP), is still under investigation, but may be related
to Their anti-inflammatory and immunomodulatory effect which mediated by
inhibition of prostaglandin and leukotriene production, as well as scavenging
reactive oxygen species produced in the bowel.
Pharmacokinetics:
About 20% of sulfasalazine is absorbed in the small intestine after oral
administration. A small percentage of the absorbed sulfasalazine is excreted
in the urine and the rest via the bile into the small intestine (enterohepatic
circulation). This portion together with the unabsorbed sulfasalazine enters the
colon where it is split by bacteria into two main metabolites, sulfapyridine and
5-amino-salicylic acid (5-ASA). The peak serum concentration is reached
after 3-5 hours. The mean serum half-life after a single dose is about 6 hours;
after repeated doses it is about 8 hours. After intake of SALAZOPYRIN EN-
tabs (sulfasalazine delayed-release tablets), sulfasalazine has been detected in
serum somewhat later than after intake of plain tablets, as expected, the peak
serum concentration being observed between 3 and 12 hours. Sulfapyridine is
absorbed, partially acetylated and/or hydroxylated in the liver and/or
conjugated with glucuronic acid. In patients who are slow acetylators, the
serum concentration of free sulfapyridine is higher than that in fast acetylators.
The major part is excreted in the urine. Non-acetylated sulfapyridine is bound
to serum proteins and reaches a maximum serum concentration after 12 hours.
Sulfapyridine has a tendency to accumulate. It does not disappear completely
from the serum until 3 days after withdrawal of the drug. The total urinary
recovery of sulfasalazine and its sulfapyridine metabolites in healthy subjects
during 3 days after the administration of a single 2 g dose of sulfasalazine

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averaged 91%. The absorbed 5-aminosalicylic acid is partly excreted in the
urine, mainly as acetyl-5-aminosalicylic acid. A larger portion of 5-
aminosalicylic acid is excreted in the feces.
Adverse reaction:
Sulfasalazine is may cause GI disturbance, Headache, cough, dizziness,
Pancreatitis, Hepatitis, Blood disorders (aplastic anaemia, leucopenia,
thrombocytopenia) and Myocarditis/pericarditis.
Gastro-intestinal side effects Upper gastro-intestinal side effects common over
4 g daily. Blood disorders Haematological abnormalities occur usually in the
first 3 to 6 months of treatment and are reversible on cessation of treatment.
3-Leflunomide:
Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD
class of drugs, which are chemically and pharmacologically very
heterogeneous.
Dose:
For Moderate to severe active rheumatoid arthritis:
Adult: Initially 100 mg once daily for 3 days, then reduced to 10–20 mg
once daily.
For Active psoriatic arthritis:
Adult: Initially 100 mg once daily for 3 days, then reduced to 20 mg
once daily

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Leflunomide is an isoxazole derivative that inhibits dihydroorotate
dehydrogenase, a key mitochondrial enzyme in synthesis of the pyrimidine
ribonucleotide uridine monophosphate (UMP). Inadequate provision of UMP
increases the expression of the tumoursuppressor molecule p53 which
translocates to the cell nucleus and arrests the cell cycle in the G1 phase. This
cytostatic action reduces the expansion of the activated autoimmune T- and B-
lymphocyte, thereby suppressing immunoglobulin production and cellular
immune processes. Other dividing cells can obtain adequate pyrimidines from
a separate salvage pathway that reuses existing ribonucleotides and is not
affected by leflunomide. There are other potential mechanisms of immune-
modulation by leflunomide, such as inhibition of tyrosine kinases and
suppression of transcription factors that stimulate osteoclast formation, but
they are probably of lesser importance.
Pharmacokinetics:
Leflunomide is a prodrug. It is well absorbed from the gut and is converted
non-enzymatically, mainly in the intestinal mucosa and plasma, to its active
metabolite. The metabolite is excreted via the bile, and enterohepatic
circulation contributes to its very long plasma half-life (15 days).
Adverse reaction:
Leflunomide may cause Abdominal pain, Alopecia, diarrhea, dizziness, dry
skin, headache, increased blood pressure, nausea, vomiting, oral mucosal
disorders, paraesthesia and rash.

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Anti- tumour necrosis factor α
(Anti-TNF)
TNF inhibitors are a type of drug used to treat inflammatory conditions such
as rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis,
inflammatory bowel disease (Crohn’s and ulcerative colitis), ankylosing
spondylitis, and psoriasis. They reduce inflammation and stop disease
progression by targeting an inflammation-causing substance called Tumor
Necrosis Factor (TNF).
In healthy individuals, excess TNF in the blood is blocked naturally, but in
those who have rheumatic conditions, higher levels of TNF in the blood lead
to more inflammation and persistent symptoms. They can alter a disease’s
effect on the body by controlling inflammation in the joints, gastrointestinal
tract, and skin.
There are six different TNF inhibitors that have been approved by the U.S.
Food and Drug Administration for the treatment of rheumatic diseases. To
decrease side effects and costs, most patients with mild or moderate disease
may be treated with methotrexate before adding or switching to a TNF
inhibitor. These agents can be used by themselves or in combination with other
medications such as prednisone, methotrexate, hydroxychloroquine, lefluno-
mide, or sulfasalazine.
TNF inhibitors drugs may be given by injection under the skin or by infusion
into the vein. The medicine can be injected into the thigh or abdomen. The site
of injection should be rotated so the same site is not used multiple times.
Infliximab and golimumab infusions are administered at a doctor’s office or
an infusion center. These treatments take up to four hours.
The time that it takes for the medication to have an effect may vary by patient.
Most patients have reported a change in their symptoms after two or three
doses, but it usually takes three months to see the full benefit.

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TNFα inhibiter acts by binding to one of two cell surface receptors, type 1 and
type 2, which are found in several tissues. There are several antibody
derivatives available that block the action of TNFα.
 Adalimumab and golimumab are fully humanized monoclonal antibodies
specific for TNFα.
 Certolizumab pegol is a pegylated Fab fragment of a humanized
monoclonal antibody for TNFα.
 Etanercept is a fusion protein consisting of two recombinant soluble
extracellular portions of the human Type2 TNF receptor, fused to the
constant (Fc) domain of human immunoglobulin (IgG1). It binds to
TNFα and the cytokine lymphotoxin α (also known as TNFβ).
Infliximab
Etanercept
Golimumab
Certolizumab
Drug Dose For Rheumatoid arthritis
Initially: Given at the clinic or at an infusion center as an
intravenous infusion (IV) at a dose of 3-5 mg/kg (according to
body weight) at weeks 0, 2, and 6.
Maintenance: IV infusions every 8 weeks. Dose may be
increased to 5-10 mg/kg and frequency may be increased to
every 4 weeks.
Initially: 50 mg once a week or 25 mg twice a week as a self-
administered subcutaneous injection.
Maintenance: Same
Initially: 50 mg once per month as a self-administered
subcutaneous injection.
Maintenance: Same
Initially: 400 mg (given as 2 x 200 mg injections) self-
administered every 2 weeks at weeks 0, 2 and 4.
Maintenance: 200 mg every 2 weeks or 400 mg (2 x200 mg
injections) every 4 weeks as a self-administered injection.
Anti- tumour necrosis factor α (Anti-TNF)

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Pharmacokinetics:
Adalimumab, certolizumab pegol, etanercept and golimumab are given by
subcutaneous injection and inﬂiximab by intravenous infusion. The
mechanism of elimination of these recombinant compounds is poorly defined
but likely to be by proteolysis. They have very long half-lives between 5 and
20 days, enabling dosing at frequencies ranging from twice weekly to monthly.
Adverse reaction:
The most common side effect seen with the injectable drugs are skin reactions,
commonly referred to as “injection site reactions.” The patients usually
complain of a localized rash with burning or itching. These reactions can last
up to a week. Infliximab has been associated with a severe allergic reaction
with swelling of the lips, difficulty breathing and low blood pressure. Your
doctor will usually order a pre-medication to decrease the chances of an
infusion reaction.
The most significant side effect is an increased risk for all types of infections,
including tuberculosis (TB) and fungal infections. Some of these infections
may be severe. Patients should be tested for TB before starting therapy,
because a hepatitis B infection can worsen during treatment. The usual way of
testing is with a skin test, but a blood test is also available.
Long-term use of TNF inhibitors may increase the risk of cancers such as
lymphoma and skin cancer. There are rare neurologic complications as well.
People who have a history of multiple sclerosis should not use them. People
with significant heart failure should not use a TNF inhibitor, because their
heart disease could worsen.
Anti-TNF is contraindicated with Moderate or severe heart failure patient.
 Inﬂiximab is a chimaeric monoclonal antibody comprising the
variable region of a murine antibody, which neutralises TNFα, spliced
to the constant region of a human antibody.

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MANAGEMENT OF RHEUMATOID
ARTHRITIS
Progressive joint damage is common in rheumatoid arthritis. There is now a
substantial body of evidence that early use of DMARDs (within three months
of the onset of symptoms) leads to a better long-term outcome. DMARDs do
not have signifcant anti-inflammatory action and require 2–3 months before an
effect is established. Therefore, they are almost always used initially in
combination with a corticosteroid or an NSAID.
Methotrexate, given with folic acid supplementation, is the frst-choice
DMARD. It is usually taken orally, but parenteral use can be considered if
gastrointestinal tolerability is a problem. A combination of two DMARDs is
now recommended as standard frst-line therapy and is more effective than a
single drug. Sulfasalazine, leflunomide or hydroxychloroquine are most
frequently used in combination with methotrexate.
Intra-articular injections of corticosteroid are used for individual inflamed
joints (especially knee and shoulder). Pulsed intramuscular corticosteroid
therapy can be given for disease flares, or to ameliorate symptoms in the frst
few weeks after initiating DMARD therapy (because of the slow response). In
early rheumatoid disease a low dose of corticosteroid, given for six months in
combination with DMARDs, retards bone destruction and slows disease
progression.
Anti-TNFα drugs such as etanercept (the most frequently used biological
agents for rheumatoid arthritis) are usually reserved for those who fail to
respond to combination therapy with DMARDs, or who are intolerant of
several DMARDs. They are typically used in combination with methotrexate,
or leflunomide if methotrexate is not tolerated, which produces a better
response than the biological agent given alone. The combination produces
remission and halts disease progression in up to 60% of people who are treated.
If one anti-TNFα drug is ineffective or poorly tolerated, then a different drug
from the same class should be tried. Abatacept, tocilizumab and rituximab
have been shown to be effective for people with rheumatoid arthritis who fail
to respond to, or who cannot tolerate, TNFα blockers. Anakinra is less
effective than anti-TNFα drugs and is currently not recommended in the UK.

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NSAIDs are useful for symptomatic treatment of all types of inflammatory
arthritis since they reduce both pain and stiffness. However, they do not affect
the 30 long-term course of the disease, and DMARDs have superseded them
as the mainstay of treatment of rheumatoid arthritis. There is considerable
variation in responses to different NSAIDs, and there is no way of predicting
effectiveness in an individual. Propionic acid derivatives, such as ibuprofen,
are often used first. They have a weaker anti-inflammatory activity than other
classes of NSAID, but generally have fewer unwanted effects. More powerful
drugs such as naproxen can be used when ibuprofen fails to control symptoms,
although the increased risk of gastrointestinal irritation and cardiovascular
events limit their use, especially in the elderly. Morning stiffness is often
disabling in inflammatory arthritis. This is helped by giving a late evening dose
of an NSAID with a long half-life. Topical NSAIDs applied over the affected
joint(s) are not usually recommended. Selective cyclo-oxygenase (COX)-2
inhibitors are usually reserved for people who are intolerant of NSAIDs, or
who have a higher risk of serious gastrointestinal complications with an
NSAID
Physical aids such as splinting and bed rest can help acute flares of joint
inflammation. There is an increased risk of cardiovascular disease in people
with rheumatoid arthritis, and attention to the conventional risk factors for
prevention of atherosclerosis is important.

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1. Joint Formulary Committee. (2017). British national formulary (BNF)
73 (Vol. 73). Pharmaceutical Press.
2. Waller, D. G., & Sampson, T. (2014). Medical pharmacology and
therapeutics E-Book. Elsevier Health Sciences.
3. Kar, A. (2007). Medicinal chemistry. New Age International.
4. Mant, T. G., Lewis, L. D., Ritter, J. M., & Ferro, A. (2008). A textbook
of clinical pharmacology and therapeutics. CRC Press.
5. Lacy, C. F., Armstrong, L. L., Goldman, M. P., & Lance, L. L. (2012).
Drug information handbook with international trade names index. Lexi-
Comp Inc.
6. Harvey, R. A., Clark, M. A., Finkel, R., Rey, J. A., & Whalen, K. (2015).
Lippincott’s illustrated reviews: Pharmacology. Medicine and Science in
Sports and Exercise, 538.
7. Lüllmann, H., Mohr, K., Hein, L., & Bieger, D. (2000). Color atlas of
pharmacology. New York: Thieme.
8. www.uptodate.com
Reference:

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