Inflammation is the body's natural response to injury or infection and involves increased blood flow, immune cell activity, and pain. Nonsteroidal anti-inflammatory drugs (NSAsIDs) like aspirin work by inhibiting the cyclooxygenase enzymes, decreasing the production of prostaglandins which mediate inflammation. Aspirin is unique in that it irreversibly inhibits cyclooxygenase. At normal doses, aspirin is hydrolyzed to salicylate which has analgesic, antipyretic, and anti-inflammatory effects. However, NSAIDs can cause adverse gastrointestinal, platelet, renal, and respiratory effects that require consideration of risks and benefits of long-term use.

2. I. OVERVIEW
• Inflammation is a normal protective response to tissue injury caused
by physical trauma, noxious chemicals, or microbiologic agents.
• Inflammation is the body's effort to inactivate or destroy invading
organisms, remove irritants. When healing is complete, the
inflammatory process usually subsides.
• However, inflammation is sometimes inappropriately triggered by an
innocuous agent, such as pollen, or by an autoimmune response, such
as in asthma or rheumatoid arthritis. In such cases (asthma or
rheumatoid arthritis), the defense reactions themselves may cause
progressive tissue injury, and anti-inflammatory or immuno-
suppressive drugs may be required to modulate the inflammatory
process.

3. II. Prostaglandins
• All NSAIDs act by inhibiting the synthesis of
prostaglandins.
• A. Role of prostaglandins as local mediators
• Prostaglandins and related compounds are produced in
minute quantities by virtually all tissues. They generally
act locally on the tissues in which they are synthesized,
and they are rapidly metabolized to inactive products at
their sites of action. Therefore, the prostaglandins do not
circulate in the blood in significant concentrations.

4. B. Synthesis of prostaglandins
• Arachidonic acid is present as a component of the
phospholipids of cell membranes-primarily phosphatidyl
inositol and other complex lipids.
• Free arachidonic acid is released from tissue phospholipids
by the action of phospholipase A2.
• There are two major pathways in the synthesis of the
eicosanoids from arachidonic acid.

6. Cyclooxygenase pathway
• Two related isoforms of the cyclooxygenase
enzymes have been described.
• Cyclooxygenase-1 (COX-1)
• Cyclooxygenase-2 (COX-2)

8. LTD4LTC4LTB4TXA2PGI2PGF2PGE2Effects
‫أو‬‫أو‬‫؟‬
Vascular tone
‫؟‬Bronchial tone
‫؟‬‫؟‬‫؟‬
(uterus tone)
‫؟‬‫؟‬‫؟‬‫؟‬‫أو‬
Platelet
agglutination
‫؟‬‫؟‬‫؟‬‫؟‬‫؟‬‫؟‬
Chemotaxis
?= Unknown effects

9. 1. Cyclooxygenase pathway
• All prostaglandins, thromboxanes, and prostacyclins, are
synthesized via the cyclooxygenase (COX) pathway.
• Two related isoforms of the COX enzymes have been
described:
• COX-1 is responsible for the physiologic production of
prostanoids. COX-1 is described as a "housekeeping
enzyme" that regulates normal cellular processes, such as
gastric cytoprotection, vascular homeostasis, platelet
aggregation, and kidney function.
• COX-2 causes the elevated production of prostanoids that
occurs in sites of disease and inflammation. COX-2 is
constitutively expressed in some tissues, such as the brain,
kidney, and bone.

10. COX-1
physiologic production
of prostanoids
housekeeping enzyme
regulates normal cellular
processes
(gastric cytoprotection,
vascular homeostasis,
platelet aggregation, and
kidney function)
COX-2
increases production of
prostanoids in sites of
disease and inflammation.
Structural differences
between COX-1 and COX2
permitted development of
COX-2-selective inhibitors.
COX-2 inhibited by
glucocorticoids
significant anti-
inflammatory effects
of these drugs.
Cyclooxygenase pathway

11. 2. Lipoxygenase pathway
• Alternatively, several lipoxygenases can act on arachidonic
acid to form 5-HPETE, 12-HPETE, and 15-HPETE, which
are unstable peroxidated derivatives that are converted to
the corresponding hydroxylated derivatives (the HETES) or
to leukotrienes or lipoxins, depending on the tissue.
• Antileukotriene drugs, such as zileuton, zafirlukast, and
montelukast, are useful for the treatment of moderate to
severe allergic asthma.

13. C. Actions of prostaglandins
• Actions of prostaglandins are mediated by their binding
to cell membrane receptors that operate via G proteins,
which subsequently activate or inhibit adenylyl cyclase or
stimulate phospholipase C.
• This causes an enhanced formation of diacylglycerol and
inositol 1,4,5-trisphosphate (IP3).
• Prostaglandin F2α (PGF2α), the leukotrienes, and
thromboxane A2 (TXA2) mediate certain actions by
activating phosphatidylinositol metabolism and causing an
increase of intracellular Ca2+.

14. • D. Functions of prostaglandins in the body
• Prostaglandins functions vary widely depending on the
tissue.
• Release of TXA2 from platelets triggers recruitment of
new platelets for aggregation (first step in clot
formation).
• Elevated levels of TXA2 in certain smooth muscle, this
compound induces contraction.
• Prostaglandins are released in allergic and inflammatory
processes.

15. Summary of anti-inflammatory drugs
• COX-2 INHIBITORS
• Celecoxib
• OTHER ANALGESICS
• Acetaminophen
• DRUGS FOR ARTHRITIS
• Adalimumab Anakinra
Chloroquine Etanercept Gold
salts Infliximab Leflunomide
Methotrexate D-Penicillamine
• DRUGS FOR GOUT
• Allopurinol Colchicine
Probenecid Sulfinpyrazone
• ANTI-INFLAMMATORY
DRUGS
• NSAIDs
• Aspirin Diflunisal
• Diclofenac Etodolac
• Fenamates Fenoprofen
Flurbiprofen Ibuprofen
Indomethacin Ketoprofen
Meloxicam Methylsalicylate
Nabumetone Naproxin
Nimesulide Oxaprazin
Piroxicam Sulindac Tolmetin

16. III. Nonsteroidal Anti-inflammatory Drugs
• NSAIDs are a group of chemically dissimilar agents
that differ in their antipyretic, analgesic, and anti-
inflammatory activities.
• They act primarily by inhibiting the cyclooxygenase
enzymes that catalyze the first step in prostanoid
biosynthesis. This leads to decreased prostaglandin
synthesis.

17. • Long-term treatment with COX-2 inhibitors have been
shown to increase risks of myocardial infarctions and
strokes, and several of these drugs have been withdrawn.
• Many experts believe that long-term therapy with older,
nonspecific NSAIDs (not including aspirin) may also
cause similar problems.
• Patients are now advised to take the lowest dose that is
effective for as short a period as possible.

18. • A. Aspirin and other salicylates
• B. Propionic acid derivatives (Ibuprofen, naproxen,
fenoprofen, ketoprofen , fIurbiprofen, oxaprozin).
• C. Acetic acid derivatives (indomethacin , sulindac,
etodolac)
• D. Oxicam derivatives (Piroxicam and meloxicam)
• E. Fenamates (Mefenamic acid, meclofenamate)
• F. Other agents (diclofenac, ketorolac, tolmetin and
nabumetone, diflunisal).
NSAID (Nonsteroidal antiinflammatory drugs)

19. A. Aspirin and other salicylates
• Aspirin is prototype of traditional NSAIDs. It is
commonly used and is the drug to which all other
anti-inflammatory agents are compared.
• However, about 15% of patients show an
intolerance to aspirin. Therefore, these individuals
may benefit from other NSAIDs.

20. • Advantages of newer NSAIDs compared with aspirin
• greater anti-inflammatory activity
• less gastric irritation
• taken less frequently
• Disdvantages of newer NSAIDs compared with aspirin
• More expensive
• More toxic in other ways.

21. 1. Mechanism of action
• Aspirin is a weak organic acid that is unique among
the NSAIDs in that it irreversibly acetylates (and thus
inactivates) cyclooxygenase.
• The other NSAIDs are all reversible inhibitors of
cyclooxygenase.
• Aspirin is rapidly deacetylated by esterases in the
body, producing salicylate, which has anti-
inflammatory, antipyretic, and analgesic effects.

22. • The antipyretic and anti-inflammatory effects of
the salicylates are due primarily to blockade of
prostaglandin synthesis at the thermoregulatory
centers in the hypothalamus and at peripheral target
sites.
• Furthermore, by decreasing prostaglandin synthesis,
the salicylates also prevent sensitization of pain
receptors to both mechanical and chemical stimuli.
• Aspirin may also depress pain stimuli at subcortical
sites (that is, the thalamus and hypothalamus).

23. 2. Actions
• The NSAIDs, including aspirin, have three major
therapeutic actions.
• They reduce inflammation (anti-inflammation),
pain (analgesia), and fever (antipyrexia).
• However not all NSAIDs are equally potent in each
of these actions.

25. 2. Actions
• a. Anti-inflammatory actions
• b. Analgesic action
• c. Antipyretic action
• d. Respiratory actions
• e. Gastrointestinal effects
• f. Effect on platelets
• g. Actions on the kidney

26. • a. Anti-inflammatory actions:
Because aspirin inhibits COX
activity, it diminishes formation of
PGs .
• Aspirin inhibits inflammation in
arthritis, but it neither arrests the
progress of the disease nor induces
remission.
• Acetaminophen has weak anti-
inflammatory activity, and is not
useful in treatment of inflammation,
such as that seen with rheumatoid
arthritis.

27. • b. Analgesic action: PGE2 is thought to sensitize nerve
endings to chemical mediators (e.g., bradykinin,
histamine), which are released locally by the inflammatory
process.
• By decreasing PGE2 synthesis, aspirin and other NSAIDs
block the sensation of pain. Salicylates are used for
management of pain of low to moderate intensity arising
from integumental (cutaneous) structures rather than that
arising from the viscera.
• NSAIDs are superior to opioids for management of pain in
which inflammation is involved. However, combinations
of opioids and NSAIDs are effective in treating pain
caused by a malignancy.

28. c. Antipyretic action:
• Fever occurs when the set-point of the anterior
hypothalamic thermoregulatory center is elevated.
• Fever can be caused by PGE2 synthesis, stimulated
when an endogenous fever-producing agent
(pyrogen), such as a cytokine, is released from
white cells that are activated by infection,
hypersensitivity, malignancy, or inflammation.

29. • The salicylates lower body temperature in
patients with fever by impeding PGE2 synthesis
and release.
• Aspirin resets the "thermostat" toward normal,
and it rapidly lowers the body temperature of
febrile patients by increasing heat dissipation as a
result of peripheral vasodilation and sweating.
• Aspirin has no effect on normal body
temperature.

30. • d. Respiratory actions:
• Therapeutic doses of aspirin increases alveolar
ventilation. Salicylates uncouple oxidative phosphorylation, which
leads to elevated CO2 and increased respiration.
• Higher doses work directly on respiratory center in the
medulla, resulting in hyperventilation and respiratory
alkalosis.
• At toxic levels, central respiratory paralysis occurs, and
respiratory acidosis due to continued production of CO2.

31. e. Gastrointestinal effects:
• Prostacyclin (PGI2) inhibits gastric acid secretion,
whereas PGE2 and PGF2α stimulate synthesis of
protective mucus in both stomach and small
intestine.
• Aspirin, these prostanoids are not formed,
resulting in increased gastric acid secretion and
diminished mucus protection. This may cause
epigastric distress, ulceration, and/or hemorrhage.
• At ordinary aspirin doses, as much as 3 to 8 ml of
blood may be lost in the feces per day.

32. • Buffered and enteric-coated preparations are only
marginally helpful in dealing with this problem.
• The PGE1 derivative misoprostol, the proton pump
inhibitor omeprazol, and H2-antihistamines also
reduce the risk of gastric ulcer, and are used in the
treatment of gastric damage induced by NSAIDs.

33. f. Effect on platelets:
• TXA2 enhances platelet aggregation, whereas
PGI2 decreases it.
• Low doses (60-80 mg daily) of aspirin can
irreversibly inhibit thromboxane production in
platelets without markedly affecting TXA2
production in the endothelial cells of the blood
vessel.

34. f. Effect on platelets:
• The acetylation of COX is irreversible.
• Because platelets lack nuclei, they cannot
synthesize new enzyme, and the lack of
thromboxane persists for the lifetime of the platelet
(3- 7days).
• This contrasts with the endothelial cells, which have nuclei and, therefore, can
produce new COX.
• As a result of the decrease in TXA2, platelet
aggregation is reduced, producing an anticoagulant
effect with a prolonged bleeding time.

35. • g. Actions on the kidney:
• COX inhibitors prevent synthesis of PGE2 and PGl2-
prostaglandins (responsible for maintaining renal blood
flow) particulary in presence of circulating vasoconstrictors.
• Decreased synthesis of prostaglandins can result in retention
of sodium and water and may cause edema and
hyperkalemia in some patients.
• Interstitial nephritis can also occur with all NSAIDs except
aspirin.

37. 3. Therapeutic uses
a. Antipyretics and analgesics
b. External applications: used topically to treat corns, calluses, and
epidermophytosis
c. Cardiovascular applications: Salicylates are used to inhibit
platelet aggregation. Low doses of aspirin are used
prophylactically to decrease the incidence of transient ischemic
attack and unstable angina in men as well as that of coronary artery
thrombosis.
d. Colon cancer: There is evidence that chronic use of aspirin
reduces the incidence of colorectal cancer.

38. Aspirin: Doses and Uses
• Low dose (160 to 325 mg/day) reduces the incidence of recurrent
myocardial infarction, and to reduce the mortality in post-myocardial
infarction patients.
• 650 mg aspirin tablets administered four times a day produce
analgesia.
• Higher doses (> 4 grams/day) produce both analgesic and anti-
inflammatory activity.
• At normal low dosages, aspirin is hydrolyzed to salicylate and acetic
acid by esterases in tissues and blood.
• Salicylate is converted by the liver to water-soluble conjugates that
are rapidly cleared by the kidney, resulting in elimination with first-
order kinetics and a serum half-life of 3.5 hours.
• At anti-inflammatory dosages (>4 g/day), the hepatic metabolic
pathway becomes saturated, and zero-order kinetics are observed,
with the drug having a halflife of 15 hours or more. Saturation of
hepatic enzymes requires treatment for several days to one week.

39. 5. Adverse effects
• a. Gastrointestinal: epigastric distress, nausea, and
vomiting and GI bleeding.
• b. Blood: prolonged bleeding time.
• c. Respiration: respiratory depression and metabolic
acidosis (in toxic doses).
• e. Hypersensitivity: urticaria, bronchoconstriction, or
angioneurotic edema. Fatal anaphylactic shock is rare.
• f. Reye syndrome: fatal, fulminating hepatitis with
cerebral edema.

40. 5. Adverse effects
• a. Gastrointestinal: The most common gastrointestinal (GI) effects
of the salicylates are epigastric distress, nausea, and vomiting.
Microscopic GI bleeding is almost universal in patients treated with
salicylates.
• Aspirin is an acid. At stomach pH, aspirin is uncharged;
consequently, it readily crosses into mucosal cells, where it ionizes
(becomes negatively charged) and becomes trapped, thus potentially
causing direct damage to the cells. Aspirin should be taken with
food and large volumes of fluids to diminish GI disturbances.
Alternatively, misoprostol may be taken concurrently.]

42. • b. Blood: The irreversible acetylation of platelet COX reduces the
level of platelet TXA2, resulting in inhibition of platelet
aggregation and a prolonged bleeding time. For this reason, aspirin
should not be taken for at least one week prior to surgery. When
salicylates are administered, anticoagulants may have to be given in
reduced dosage.
• c. Respiration: In toxic doses, salicylates cause respiratory depression and a combination of
uncompensated respiratory and metabolic acidosis.
• e. Hypersensitivity: Approximately 15% of patients taking aspirin
experience hypersensitivity reactions. Symptoms of true allergy
include urticaria, bronchoconstriction, or angioneurotic edema.
Fatal anaphylactic shock is rare.
• f. Reye syndrome: Aspirin given during viral infections has been
associated with an increased incidence of Reye syndrome, which is
an often fatal, fulminating hepatitis with cerebral edema. This is
especially encountered in children, who therefore should be given
acetaminophen instead of aspirin when such medication is required
to reduce fever.

43. • g. Drug interactions:
Concomitant
administration of
salicylates with many
classes of drugs may
produce undesirable side
effects (Figure).

44. 6. Toxicity
• Salicylate intoxication may be mild or severe.
• The mild form is called salicylism, and is characterized
by nausea, vomiting, hyperventilation, headache, mental
confusion, dizziness, and tinnitus.
• 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.
• Children are particularly prone to salicylate intoxication.

45. • Ingestion of as little as 10 g of aspirin (or 5 g of methyl
salicylate) can cause death in children. Treatment of
salicylism should include measurement of serum salicylate
concentrations and of pH to determine the best form of
therapy.
• In mild cases, symptomatic treatment is usually sufficient.
Increasing the urinary pH enhances the elimination of
salicylate.
• In serious cases, mandatory measures include the
intravenous administration of fluid, dialysis, and the
frequent assessment and correction of acid-base and
electrolyte balances. Diflunisal does not cause salicylism.

46. B. Propionic acid derivatives
• Ibuprofen, naproxen, fenoprofen, ketoprofen , fIurbiprofen.
• All these drugs possess anti-inflammatory, analgesic, and
antipyretic activity. They have gained wide acceptance in the
chronic treatment of rheumatoid arthritis and osteoarthritis, because
their gastrointestinal effects are generally less intense than that of
aspirin.
• These drugs are reversible inhibitors of the cyclooxygenases, inhibit
synthesis of prostaglandins but not of leukotrienes.
• Adverse effects: GI, ranging from dyspepsia to bleeding. Side
effects involving CNS, such as headache, tinnitus, and dizziness,
have also been reported.

47. C. Acetic acid derivatives
• indomethacin , sulindac , etodolac .
• They have anti-inflammatory, analgesic, and antipyretic activity.
• They act by reversibly inhibiting cyclooxygenase.
• They are generally not used to lower fever.
• Toxicity of indomethacin limits its use to the treatment of acute
gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip.
• Sulindac is an inactive prodrug that is closely related to
indomethacin. Although the drug is less potent than indomethacin,
it is useful in the treatment of rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis, and acute gout.
• The adverse reactions caused by sulindac are similar to, but less
severe than, those of the other NSAIDs, including indomethacin.
Etodolac has effects similar to those of the other NSAIDs. GI
problems may be less common.

48. D. Oxicam derivatives
• Piroxicam and meloxicam are used to treat rheumatoid
arthritis, ankylosing spondylitis, and osteoarthritis. They
have long half-lives, which permit administration once a
day. GI disturbances are encountered in approximately
20% percent of patients treated with piroxicam.
• Meloxicam is relatively COX-2 selective and at low to
moderate doses shows less GI irritation than piroxicam.
However, the ability of meloxicam at therapeutic dosage to
spare COX-1 is dose-related.
• At high doses, meloxicam is a nonselective NSAID,
inhibiting both COX-1 and COX-2.

49. E. Fenamates
• Mefenamic acid and meclofenamate have no advantages
over other NSAIDs as anti-inflammatory agents.
• Mefenamic acid – use for short-term relief of mild to
moderate pain including primary dysmenorrhea
• Their side effects, such as diarrhea, can be severe, and
are associated with inflammation of the bowel. Cases of
hemolytic anemia have been reported.

50. • Other NSAIDs
• Diclofenac is approved for long-term use. Diclofenac
accumulates in synovial fluid. An ophthalmic preparation
is also available.
• Ketorolac: oral route, intramuscularly in treatment of
postoperative pain.
• Diflunisal: A derivative of salicylic acid, diflunisal is not
metabolized to salicylate and, therefore, cannot cause
salicylate intoxication.
• Diflunisal is 3-4 fold more potent than aspirin as an
analgesic and an anti-inflammatory agent, but it has no
antipyretic properties. Diflunisal does not enter the CNS
and, therefore, cannot relieve fever.

51. Cox-2-Selective NSAIDs
• The structural difference between COX-1 and COX-2 has
allowed the development of COX-2-selective agents, such as
celecoxib and valdecoxib.
• Most of traditional NSAIDs inhibit both COX-1 and COX-2.
• Some traditional NSAIDs (etodolac, meloxicam, and nimesulide)
display some level of COX-2 selectivity.
• COX-2 drugs
• Have no significant effects on platelets
• May cause renal insufficiency and increase risk of
hypertension
• Chronic use of NSAIDs in high risk patients for NSAID-
related gastroduodenal toxicity, therapy with a COX-2-
selective inhibitor is a reasonable option.

52. A. Celecoxib
• Celecoxib is significantly more selective for reversible
inhibition of COX-2 than of COX-1.
• Celecoxib was approved for treatment of osteoarthritis and
rheumatoid arthritis.
• Celecoxib does not inhibit platelet aggregation and does
not increase bleeding time.
• Its half-life is about eleven hours; thus, the drug is usually
taken once a day.
• Celecoxib is contraindicated in patients who are allergic to
sulfonamides. If there is a history of sulfonamide drug
allergy, then use of a nonselective NSAID along with a
protonpump inhibitor is recommended.

53. The incidence of
gastroduodenal ulcers
in patients taking
celecoxib was less that
found in patients taking
naproxen, diclofenac,
or ibuprofen.

54. • 2. Adverse effects: Abdominal pain, diarrhea, and
dyspepsia are most common adverse effects.
• Patients who have had anaphylactoid reactions to aspirin
or nonselective NSAIDs may be at risk for similar effects
when challenged with COX-2 selective agents.
• Inhibitors of CYP2C9, such as fluconazole, fluvastatin,
and zafirlukast, may increase serum levels of celecoxib.
• Celecoxib has the ability to inhibit CYP2D6 and, thus,
could lead to elevated levels of some -blockers,
antidepressants, and antipsychotic drugs.

56. A. Acetaminophen
• Acetaminophen inhibits prostaglandin synthesis in
the CNS. This explains its antipyretic and
analgesic properties.
• Acetaminophen has less effect on cyclooxygenase
in peripheral tissues, which accounts for its weak
anti-inflammatory activity.
• Acetaminophen does not affect platelet function or
increase blood clotting time.

57. • 1. Therapeutic uses: Acetaminophen is substitute for the
analgesic and antipyretic effects of aspirin for those
patients with gastric complaints, for those for whom
prolongation of bleeding time would be a disadvantage, or
those who do not require the anti-inflammatory action of
aspirin.
• Acetaminophen is the analgesic/antipyretic of choice for
children with viral infections or chickenpox (aspirin
increases risk of Reye syndrome).
• Acetaminophen does not antagonize the uricosuric agent
probenecid and, therefore, may be used in patients with
gout who are taking that drug.

58. • 2. Pharmacokinetics: Acetaminophen is rapidly absorbed
from the GI tract. A significant first-pass metabolism occurs
in the luminal cells of the intestine and in the hepatocytes.
• Under normal circumstances, acetaminophen is conjugated
in the liver to form inactive glucuronidated or sulfated
metabolites.
• A portion of acetaminophen 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 the urine.

59. • 3. Adverse effects: With normal therapeutic doses, acetaminophen
is virtually free of any significant adverse effects. Skin rash and
minor allergic reactions occur infrequently.
• Renal tubular necrosis and hypoglycemic coma are rare
complications of prolonged, large-dose therapy.
• With large doses of acetaminophen, the available glutathione in the
liver becomes depleted, and N-acetylbenzoiminoquinone reacts
with the 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.
• N-acetylcysteine , Administration of, which contains sulfhydryl
groups to which the toxic metabolite can bind, can be lifesaving if
administered within ten hours of the overdose.

60. N-acetylcysteine
DOSAGE FORMS: Antidote, Mucolytic Agent
• Injection, solution:
• Acetadote®: 20% [200 mg/mL] (30 mL)
• Solution, inhalation/oral: 10% [100 mg/mL];
20% [200 mg/mL

61. Disease-Modifying Antirheumatic Agents
(DMARDs)
• DMARDs, or slow-acting anti-rheumatic drugs
(SAARDs) have the potential to reduce or prevent joint
damage.
• They have a long onset of action, sometimes taking 3-4
months. These drugs are used for rheumatic disorders, in
inflammatory disease does not respond to COXIs.
• The DMARDs slow course of the disease and can induce
remission, preventing further destruction of the joints and
involved tissues.

63. A. Choice of drug
• Most experts begin DMARD therapy with one of the
traditional small molecules, such as methotrexate or
hydroxychloroquine.
• Inadequate response to traditional agent may be followed
by use newer DMARDs, such as leflunomide,
adalimumab, anakinra, etanercept, and infliximab.
• Combination therapies are both safe and efficacious. In
most cases, methotrexate is combined with one of the
other DMARDs.

64. B. Methotrexate
• Treatment patients with severe rheumatoid or
psoriatic arthritis who have not responded
adequately to NSAIDs.
• Effective in arthritis, and an autoimmune disease
(immunosuppressant).
• Doses of methotrexate required for this treatment
are much lower than those needed in cancer
chemotherapy and are given once a week.
• Most common side: mucosal ulceration, nausea.
• Cytopenias (particularly depression of white-blood-cell count), cirrhosis of the liver, and an acute
pneumonia-like syndrome may occur on chronic administration.

65. C. Leflunomide
• Leflunomide is an immunomodulatory agent that
preferentially causes cell arrest of the autoimmune
lymphocytes.
• It not only reduces pain and inflammation associated with
the disease but also appears to slow the progression of
structural damage.
• Leflunomide can be used in monotherapy as an alternative
to methotrexate or as an addition to methotrexate in
combination therapy.
• Leflunomide is teratogenic in experimental animals and,
therefore, is contraindicated in pregnancy and in women of
child-bearing potential.

66. D. Chloroquine and hydroxychloroquine
• These drugs are used in the treatment of malaria.
• They are reserved for rheumatoid arthritis that has been
unresponsive to NSAIDs or are used in conjunction with an
NSAID, which allows a lower dose of chloroquine or
hydroxychloroquine to be administered.
• These drugs have been shown to slow progression of
erosive bone lesions and may induce remission. They do
cause serious adverse effects.

67. E. D-Penicillamine
• D-Penicillamine slows the progress of bone destruction and
rheumatoid arthritis.
• Prolonged treatment with penicillamine has serious side
effects, ranging from dermatologic problems to nephritis
and aplastic anemia; therefore, it is used primarily in the
treatment of rheumatoid arthritis after use of gold salts has
failed but before use of corticosteroids has been attempted.
• D-Penicillamine is used as a chelating agent in the
treatment of poisoning by heavy metals. It is also of benefit
in treating cystinuria.
• Dosage Forms: Capsule (Cuprimine®): 125, 250 mg.
Tablet (Depen®): 250 mg

68. F. Gold salts (Capsule: Ridaura®: 3 mg )
• Gold compounds, like other drugs in this group, cannot
repair existing damage. Rather, they can only prevent
further injury. The currently available gold preparations are
gold sodium thiomalate and aurothioglucose.
• Gold compounds are being used less by rheumatologists,
because of need for monitoring for serious toxicity and
costs of administration and monitoring.

69. VII. Anticytokine Therapies In Rheumatoid
Arthritis
• Interleukin-1 b (IL-1 b) and tumor necrosis factor- α (TNF-
α) are proinflammatory cytokines involved in the
pathogenesis of rheumatoid arthritis.
•
• When secreted by synovial macrophages, IL-1 band TNF-a stimulate synovial cells
to proliferate and synthesize collagenase, thereby degrading cartilage, stimulating
bone resorption, and inhibiting proteoglycan synthesis.
• Drug antagonists of these cytokines are proving to be
effective in treating rheumatoid arthritis.
•

70. • Etanercept is protein composed of two chains of
recombinant human TNF-receptor. Etanercept is given
subcutaneously twice a week.
• Adalimumab is a recombinant monoclonal antibody.
• Infliximab is a monoclonal antibody, and has been
approved for Crohn disease and for the treatment of
rheumatoid arthritis.
• Anakinra is an IL-1 receptor antagonist.
VII. Anticytokine Therapies In Rheumatoid
Arthritis

71. VIII. Drugs Used in Treatment Of Gout
• Gout is a metabolic disorder characterized by high levels
of uric acid in the blood.
• This hyperuricemia results in the deposition of sodium
urate crystals in tissues, especially the kidney and joints.
• The cause of hyperuricemia is an overproduction of uric
acid relative to the patient's ability to excrete it.

72. VIII. Drugs Used in Treatment Of Gout
• Most therapeutic strategies for gout involve lowering the
uric acid level below the saturation point, thus preventing
the deposition of urate crystals.
• This can be accomplished by
• 1) interfering with uric acid synthesis with allopurinol,
• 2) increasing uric acid excretion with probenecid or
sulfinpyrazone,
• 3) inhibiting leukocyte entry into the affected joint with
colchicine, or
• 4) administration of NSAIDs.

73. A. Treating acute gout
• Acute attacks are treated with indomethacin to
decrease movement of granulocytes into the affected
area and with NSAIDs to decrease pain and
inflammation.
• Colchicine is reserved for treatment of acute gouty
attacks.
• Aspirin is contraindicated, because it competes with
uric acid for the organic acid secretion mechanism in
the proximal tubule of the kidney.

74. B. Treating chronic gout
• Chronic gout can be caused by 1) a genetic defect (an
increase in the rate of purine synthesis; 2) renal deficiency;
3) Lesch-Nyhan syndrome; or
• 4) excessive synthesis of uric acid associated with cancer
chemotherapy.
• (a disorder of purine metabolism due to deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT); characterized by
hyperuricemia, uric acid renal stones, mental retardation, spasticity, choreoathetosis, and self-mutilation of fingers and lips by biting; X-
linked inheritance, caused by mutation in the HPRT gene).
• Treatment strategies for chronic gout include the use of
uricosuric drugs that increase the excretion of uric acid,
thereby reducing its concentration in plasma, and the use of
allopurinol, which is a selective inhibitor of the terminal
steps in the biosynthesis of uric acid. Allopurinol is
preferred in patients with excessive uric acid excretion, with
previous histories of uric acid stones.

75. C. Colchicine
• Colchicine is reserved for treatment of acute gouty attacks.
• Colchicine does reduce frequency of acute attacks and
relieves pain. It is neither a uricosuric nor an analgesic
agent. Colchicine :
1. blocks cell division by binding to mitotic spindles.
2. inhibits the synthesis and release of the leukotrienes.
• Indomethacin has largely replaced colchicine in the
treatment of acute gouty attacks.
• 4. Adverse effects: nausea, vomiting, abdominal pain, and
diarrhea, myopathy, agranulocytosis, aplastic anemia, and
alopecia. The drug should not be used in pregnancy.

76. Allopurinol reduces
production of uric acid by
competitively inhibiting last
two steps in uric acid
biosynthesis that are catalyzed
by xanthine oxidase.

77. D. Allopurinol
• Allopurinol is completely absorbed after oral
administration. The primary metabolite is
alloxanthine (oxypurinoI), which is also a xanthine
oxidase inhibitor.
• Pharmacologic effect of administered allopurinol
results from combined activity of these two
compounds. The plasma half-life of allopurinol is
short (two hours), whereas the half-life of
oxypurinol is long (fifteen hours).
• Thus, effective inhibition of xanthine oxidase can be
maintained with once-daily dosage.

78. E. 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.
• Uric acid is freely filtered at the glomerulus.
Like many other weak acids, it is also both
reabsorbed and secreted in the middle
segment (S2) of the proximal tubule.

79. E. Uricosuric agents
• Probenecid, inhibitor of tubular secretion of
organic acids, and sulfinpyrazone, a derivative of
phenylbutazone, are two most commonly used
uricosuric agents.
• At therapeutic doses, they block proximal tubular
resorption of uric acid.
• Probenecid `blocks the tubular secretion of
penicillin and is sometimes used to increase levels
of the antibiotic.