1. Anti-inflammatory Drugs

2. INFLAMMATION
• Inflammation is a defense reaction caused by tissue damage
or injury
• Can be elicited by numerous stimuli including:
• infectious agents
• antigen-antibody interaction
• ischemia
• thermal and physical injury
• Noxious chemicals

3. Inflammatory responses occur in three distinct phases:
1. An acute transient phase, characterized by:
– local vasodilation and its resulting increased blood
flow causes the redness (rubor) and increased heat
(calor)
– Increased permeability of the blood vessels results in
an exudation (leakage) of plasma proteins and fluid
into the tissue (edema), which manifests itself as
swelling (tumor).
2. A delayed phase, most prominently characterized by:
– infiltration of leukocytes and phagocytic cells to
the injured /inflammed tissue
3. A chronic proliferative phase, in which:
– tissue degeneration and fibrosis occur

4. 4 signs of inflammation
• Redness –
due to vasodilation of capillaries to increase blood flow.
• Heat - due to local vessel dilatation.
• Swelling –
due to Increased vascular permeability and influx of
plasma proteins and phagocytic cells into the tissue
spaces
• Pain – due to
-Hyperalgesia, sensitization of nociceptors
-local release of enzymes and
-increased tissue pressure

6. i)Complement system- The complement system is a biochemical cascade that
helps, or “complements”, the ability of antibodies to clear pathogens from an
organism. It is part of the immune system called the innate immune system that is not
adaptable and does not change over the course of an individual's lifetime.
ii)histamine – Secreted from mast cell.
increases gap junction space
causes tissue congestion & swelling
causes bronchoconstriction
causes sneezing, watery eyes, itching
causes pressure & pain
iii) serotonin
iv)bradykinin - major contributors to symptoms of inflammation. A vasoactive
protein which is able to induce vasodilation, increase vascular permeability, cause
smooth muscle contraction, and induce pain
Mediators of the inflammatory response

7. v)leukotrienes
- increase vascular permeability and leakiness
- increase mobilization of endogenous mediators of inflammation
vi)Prostaglandins
PGE2 - promote Vasodilation, Bronchodilation leukocyte infiltration,
Directly Cause Pain and Induces Fever
PGI2 - increase vascular permeability, enhance pain producing
properties of bradykinin
vii) Thromboxane A2 (TXA2)- Thromboxane is a member of the family of
lipids known as eicosanoids. The two major thromboxanes are thromboxane
A2 and thromboxane B2.
cause platelets to aggregate
causes vasoconstriction
causes smooth muscle contraction
enhances function of inflammatory cells

8. Prostaglandins
• Prostaglandins are unsaturated fatty acid
derivatives containing 20 carbons that include
a cyclic ring structure.
• Note: These compounds are sometimes
referred to as eicosanoids; whichrefers to the
20 carbon atoms.

9. Synthesis of prostaglandins
• Arachidonic acid, a 20-carbon fatty acid, is the primary
precursor of the prostaglandins and related
compounds.
• Arachidonic acid is present as a component of the
phospholipids of cell membranes ,primarily
phosphatidylinositol and other complex lipids.
• Free arachidonic acid is released from tissue
phospholipids by the action of phospholipase A2 and
other acyl hydrolases via a process controlled by
hormones and other stimuli.
• There are two major pathways in the synthesis of the
eicosanoids from arachidonic acid.

10. • Cyclooxygenase pathway:
• All eicosanoids with ring structures that is, the
prostaglandins, thromboxanes, and prostacyclins are
synthesized via the cyclooxygenase pathway.
• Two related isoforms of the cyclooxygenase enzymes have
been described. Cyclooxygenase-1 (COX-1) is responsible
for the physiologic production of prostanoids, whereas
cyclooxygenase-2 (COX-2) causes the elevated production
of prostanoids that occurs in sites of disease and
inflammation.
• 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 is constitutively expressed in tissues such as the
brain, kidney, and bone.

11. • 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.

14. Two main forms of Cyclooxygenases (COX)
• Cyclooxygenase-1 (COX-1)
• Produces prostaglandins that
mediate homeostatic functions
• Constitutively expressed
• Homeostatic
Protection of gastric
mucosa
Platelet activation
Renal functions
Macrophage
differentiation
• Cyclooxygenase-2 (COX-2)
• Produces prostaglandins that
mediate inflammation, pain, and
fever.
• Induced mainly in sites of
inflammation by cytokines
• Pathologic
Inflammation
Pain
Fever
Dysregulated
proliferation

15. NON STEROIDAL ANTI
INFLAMMATORY DRUGS(NSAID)

16. NSAID
• The 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 with both
beneficial and unwanted effects.

19. Mechanism of action of NSAIDs
1. Antiinflammatory effect
– due to the inhibition of the enzymes cyclooxygenase, or
COX, which converts arachidonic acid to
prostaglandins, and to TXA2 and prostacyclin.
– Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
– This distinguishes it from other NSAIDs, which reversibly
inhibit COX-1 and COX-2.

20. 2. Analgesic effect
A. The analgesic effect of NSAIDs is thought to be related
to:
– the peripheral inhibition of prostaglandin
production
– may also be due to the inhibition of pain stimuli at
a subcortical site.
B. NSAIDs inhibits bradykinin from stimulating pain
receptors

21. 3. Antipyretic effect
– The antipyretic effect of NSAIDs is believed to be related
to:
• inhibition of production of prostaglandins induced by
cytokines such as interleukin-1 (IL-1) and interleukin-
6 (IL-6) in the hypothalamus
• the “resetting” of the thermoregulatory
system, leading to vasodilatation and increased heat
loss.

22. Aspirin and other salicylic acid
derivatives
• Pharmacologic properties:
– Salicylates are weak organic acids;
– aspirin has a pKa of 3.5.
– These agents are rapidly absorbed from the intestine as
well as from the stomach, where the low pH favors
absorption.

23. • Mechanism of action:
• Aspirin is a weak organic acid that is unique
among the NSAIDs in that it irreversibly
acetylates (and, thus, inactivates) cyclooxygenase
(Figure). The other NSAIDs, including
salicylate, 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.

24. – Salicylates are hydrolyzed rapidly by plasma and
tissue esterases to acetic acid and the active
metabolite salicylic acid.
esterases

26. – Metabolism

27. – Salicylates have a t1/2 of 3—6 hours after short-
term administration.
– Long-term administration of
• high doses (to treat arthritis) or
• toxic overdose
– increases the t1/2 to 15—30 hours because the
enzymes for glycine and glucuronide conjugation
become saturated.

29. – Unmetabolized salicylates are excreted by the
kidney.
– If the urine pH is raised above 8, clearance is
increased approximately fourfold as a result of
decreased reabsorption of the ionized salicylate
from the tubules.

30. Pharmacological Effects
1. Inflammation
Because aspirin inhibits cyclooxygenase
activity, it diminishes the formation of
prostaglandins and, thus, modulates those
aspects of inflammation in which
prostaglandins act as mediators. Aspirin
inhibits inflammation in arthritis, but it
neither arrests the progress of the disease nor
induces remission.

31. 2. Analgesia
• NSAIDs alleviate mild-to-moderate pain by:
– decreasing PGE- and PGF-mediated increases in pain
receptor sensitivity.
• They are more effective against pain associated with
integumental structures (pain of muscular and vascular
origin, arthritis, and bursitis) than with pain associated
with the viscera.

32. 3. Antipyresis
• NSAIDs reduce elevated body temperature
with little effect on normal body
temperature.

33. 3.Respiratory actions: At therapeutic doses, aspirin
increases alveolar ventilation.
• [Note: Salicylates uncouple oxidative
phosphorylation, which leads to elevated CO2 and
increased respiration.]
• Higher doses work directly on the respiratory center in
the medulla, resulting in hyperventilation and
respiratory alkalosis that usually is adequately
compensated for by the kidney.
• At toxic levels, central respiratory paralysis occurs, and
respiratory acidosis ensues due to continued
production of CO2

34. 4. Gastrointestinal effects:
• Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and
PGF2α stimulate synthesis of protective mucus in both the stomach and small
intestine.
• In the presence of aspirin, these prostanoids are not formed, resulting in increased
gastric acid secretion and diminished mucus protection.
• This may cause 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. Buffered and enteric-coated preparations are only marginally helpful in
dealing with this problem.
• Agents used for the prevention of gastric and/or duodenal ulcers include the PGE1-
derivative misoprostol and the proton-pump inhibitors (PPIs);
esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole);
• PPIs can also be used for the treatment of an NSAID-induced ulcer and are
especially appropriate if the patient will need to continue NSAID treatment.
• H2-antihistamines (cimetidine, famotidine, nizatidine, and ranitidine) relieve
dyspepsia due to NSAIDS, but they may mask serious GI complaints and may not
be as effective as PPIs for healing and preventing ulcer formation.

35. 5.Effect on platelets:
• TXA2 enhances platelet aggregation, whereas PGI2 decreases it.
• Low doses (60 to 81 mg daily) of aspirin can irreversibly inhibit
thromboxane production in platelets via acetylation of
cyclooxygenase. Because platelets lack nuclei, they cannot
synthesize new enzyme, and the lack of thromboxane persists for
the lifetime of the platelet (7 days).
• As a result of the decrease in TXA2, platelet aggregation (the first
step in thrombus formation) is reduced, producing an anticoagulant
effect with a prolonged bleeding time.
• Finally, aspirin also inhibits cyclooxygenase in endothelial
cells, resulting in reduced PGI2 formation; however, endothelial cells
possess nuclei able to re-synthesize new cyclooxygenase.
Therefore, PGI2 is available for antiplatelet action.

36. 6. Actions on the kidney:
Cyclooxygenase inhibitors prevent the synthesis of
PGE2 and PGI2 prostaglandins that are responsible
for maintaining renal blood flow, particularly in
the 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. Therapeutic Use
– NSAIDs are first-line drugs used to arrest inflammation
and the accompanying pain of rheumatic and
nonrheumatic diseases, including rheumatoid
arthritis, juvenile arthritis, osteoarthritis, psoriatic
arthritis, ankylosing spondylitis, Reiter syndrome, and
dysmenorrhea.
– Pain and inflammation of bursitis and tendonitis also
respond to NSAIDs.

38. – NSAIDs:
• do not significantly reverse the progress of rheumatic
disease
• they slow destruction of cartilage and bone
• allow patients increased mobility and use of their
joints.

39. – Treatment of chronic inflammation requires use of these
agents at doses well above those used for analgesia and
antipyresis
– the incidence of adverse drug effects is increased.

40. – Drug selection is generally dictated by the
patient's ability to tolerate the adverse
effects, and the cost of the drugs.
– Antiinflammatory effects may develop only after
several weeks of treatment.

41. Adverse effects
i)Gastrointestinal: The most common GI effects of the
salicylates are epigastric distress, nausea, and vomiting.
Microscopic GI bleeding is almost universal in patients
treated with salicylates.
• [Note: 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 dyspepsia.
Additionally, misoprostol or a PPI may be taken
concurrently.]

42. ii) Blood: The irreversible acetylation of platelet
cyclooxygenase 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 1
week prior to surgery. When salicylates are
administered, anticoagulants may have to be given in
reduced dosage, and careful monitoring and counseling of
patients are necessary.
iii) Respiration: In toxic doses, salicylates cause respiratory
depression and a combination of uncompensated
respiratory and metabolic acidosis.
iv) Metabolic processes: Large doses of salicylates uncouple
oxidative phosphorylation.4 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.

43. v) Reye's syndrome:
– Aspirin and other salicylates given during viral infections has been
associated with an increased incidence of Reye's syndrome, which is a
potentially fatal disease that causes numerous detrimental effects to
many organs, especially the brain and liver, as well as causing a lower
than usual level of blood sugar (hypoglycemia).
– The classic features are a rash, vomiting, and liver damage.
– The exact cause is unknown and, while it has been associated
with aspirin consumption by children with viral illness, it also occurs in
the absence of aspirin use.
-The disease causes fatty liver with minimal inflammation and
severe encephalopathy (with swelling of the brain).
-The liver may become slightly enlarged and firm, and there is a change in
the appearance of the kidneys. Jaundice is not usually present
-This is especially encountered in children, who therefore should be given
acetaminophen instead of aspirin when such medication is required to
reduce fever. Ibuprofen is also appropriate.

44. vi) Drug interactions:
Concomitant administration of salicylates with many classes of drugs may produce
undesirable side effects. Because aspirin is found in many over-the-counter
agents, patients should be counseled to read labels to verify aspirin content to avoid
overdose.
Salicylate is 90 to 95 percent protein bound and can be displaced from its protein-binding
sites, resulting in increased concentration of free salicylate; alternatively, aspirin could
displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic
acid, resulting in higher free concentrations of the other agent .
Chronic aspirin use should be avoided in patients receiving probenecid or
sulfinpyrazone, because these agents cause increased renal excretion of uric acid
whereas aspirin (<2 g/day) cause reduced clearance of uric acid.
Concomitant use of ketorolac and aspirin is contraindicated because of increased risk of GI
bleeding and platelet aggregation inhibition. Children who have received live varicella
virus vaccine should avoid aspirin for at least 6 weeks after vaccination to prevent Reye's
syndrome.
vii) In pregnancy:
Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category
D during Trimester 3. Because salicylates are excreted in breast milk, aspirin should be
avoided during pregnancy and while breast-feeding.

45. • B. Propionic acid derivatives
• Ibuprofen [eye-byoo-PROE-fen] was the first in this class of agents to
become available in the United States.
• It has been joined by naproxen [nah-PROX-en], fenoprofen [fen-oh-PROE-
fen], ketoprofen [key-toe-PROE-fen], flurbiprofen [flur-bye-PROE-fen], and
oxaprozin [ox-ah-PROE-zin].
• All these drugs possess anti-inflammatory, analgesic, and antipyretic
activity;
• additionally, they can alter platelet function and prolong bleeding time.
• They have gained wide acceptance in the chronic treatment of RA and
osteoarthritis, because their GI effects are generally less intense than
those of aspirin.
• These drugs are reversible inhibitors of the cyclooxygenases
and, thus, like aspirin, inhibit the synthesis of prostaglandins but not of
leukotrienes. All are well absorbed on oral administration and are almost
totally bound to serum albumin.
• [Note: Oxaprozin has the longest half-life and is administered once daily.]
They undergo hepatic metabolism and are excreted by the kidney. The
most common adverse effects are GI, ranging from dyspepsia to bleeding.
Side effects involving the central nervous system (CNS), such as
headache, tinnitus, and dizziness, have also been reported.

46. • Acetic acid derivatives
• This group of drugs includes indomethacin [in-
doe-METH-a-sin], sulindac [sul-IN-dak], and
etodolac [eh-TOE-doh-lak].
• All have anti-inflammatory, analgesic, and
antipyretic activity.
• They act by reversibly inhibiting
cyclooxygenase.
• They are generally not used to lower fever.

47. Indomethacin
Use: As anti-inflammatory
Treatment of
• Ankylosing spondylitis
• Reiter syndrome
• Acute gouty arthritis.
to speed the closure of patent ductus arteriosus in
premature infants (otherwise, it is not used in children);
• it inhibits the production of prostaglandins that prevent closure of
the ductus.

48. – Indomethacin is not recommended as a simple analgesic
or antipyretic because of the potential for severe adverse
effects.
– Bleeding, ulceration
– Headache
– Occasional:Tinnitus, dizziness, or confusion

49. • 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
RA, 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 are less common.

50. Oxicam derivatives
• Piroxicam [peer-OX-i-kam] and meloxicam [mel-OX-i-kam] are used to
treat RA, ankylosing spondylitis, and osteoarthritis.
• They have long half-lives, which permit once-daily
administration, Piroxicam has t1/2 of 45 hours.
• The parent drug as well as its metabolites are renally excreted in the urine.
•
• GI disturbances are encountered in approximately 20 percent of patients
treated with piroxicam.
• Meloxicam inhibits both COX-1 and COX-2, with preferential binding for
COX-2, and at low to moderate doses shows less GI irritation than
piroxicam.
• However, at high doses, meloxicam is a nonselective NSAID, inhibiting
both COX-1 and COX-2. Meloxicam excretion is predominantly in the form
of metabolites and occurs equally in the urine and feces.

51. Meclofenamate, mefenamic acid
– They have no advantages over other NSAIDs as
anti-inflammatory agent.
– t1/2 of 2 hours.
– A relatively high incidence of gastrointestinal
disturbances is associated with these agents, such
as diarrhea, can be severe, and they are
associated with inflammation of the bowel

52. Nabumetone
– Compared with NSAIDs, nabumetone is associated with
reduced:
• inhibition of platelet function
• incidence of gastrointestinal bleeding.
– Nabumetone inhibits COX-2 more than COX-1.
Other NSAIDS include
flurbiprofen, diclofenac, and etodolac.
Flurbiprofen is also available for topical ophthalmic use.

53. COX-2 Selective agents
– Celecoxib [Celebrex]
– Rofecoxib [Vioxx]
– Valdecoxib [Bextra]
– that inhibit COX-2 more than COX-1 have been developed
and approved for use.
– The rationale behind development of these drugs was
that:
A. inhibition of COX-2 would reduce the inflammatory response
and pain
B. not inhibit the cytoprotective action of prostaglandins in the
stomach, which is largely mediated by COX-1.

54. – Rofecoxib and valdecoxib have been removed from the
market due to a doubling in the incidence of heart attack
and stroke
– Celecoxib remains on the market and is approved for:
– Osteoarthritis and rheumatoid arthritis
– Pain including bone pain, dental pain, and headache
– Ankylosing spondylitis.

55. • Celecoxib
• Celecoxib [sel-eh-COCKS-ib] is significantly more selective for inhibition of COX-2
than of COX-1 (Figure 41.10).
• In fact, at concentrations achieved in vivo, celecoxib does not block COX-1.
• Unlike the inhibition of COX-1 by aspirin (which is rapid and irreversible), the
inhibition of COX-2 is time dependent and reversible.
• Celecoxib is approved for treatment of RA, osteoarthritis, and pain.
• Unlike aspirin, celecoxib does not inhibit platelet aggregation and does not
increase bleeding time.
• Celecoxib has similar efficacy to NSAIDs in the treatment of pain and the risk for
cardiovascular events.
• Celecoxib, when used without concomitant aspirin therapy, has been shown to be
associated with less GI bleeding and dyspepsia;
• however, this benefit is lost when aspirin is added to celecoxib therapy. In patients
at high risk for ulcers (that is, history of peptic ulcer disease), use of PPIs with
celecoxib and aspirin may be necessary to avoid gastric ulcers.

56. • Pharmacokinetics:
• Celecoxib is readily absorbed, reaching a peak concentration in about 3
hours.
• It is extensively metabolized in the liver by cytochrome P450 (CYP2C9)
and is excreted in the feces and urine.
• Its half-life is about 11 hours; thus, the drug is usually taken once a
day but can be administered as divided doses twice daily.
• The daily recommended dose should be reduced by 50 percent in
those with moderate hepatic impairment, and celecoxib should be
avoided in patients with severe hepatic and renal disease.
•

57. `
• Adverse effects: Headache, dyspepsia, diarrhea, and abdominal
pain are the most common adverse effects.
• Celecoxib is contraindicated in patients who are allergic to
sulfonamides.
• [Note: If there is a history of sulfonamide drug allergy, then use of a
nonselective NSAID along with a PPI is recommended.]
• As with other NSAIDs, kidney toxicity may occur.
• Celecoxib should be avoided in patients with chronic renal
insufficiency, severe heart disease, volume depletion, and/or
hepatic failure.
• Patients who have had anaphylactoid reactions to aspirin or
nonselective NSAIDs may be at risk for similar effects when
challenged with celecoxib.
• 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 antidepressants, and antipsychotic drugs.

58. Acetaminophen (Paracetamol):
– does not displace other drugs from plasma proteins
– Acetaminophen [a-SEAT-a-MIN-oh-fen] 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.
– it causes minimal gastric irritation
– has little effect on platelet adhesion and aggregation
– Acetaminophen has no significant antiinflammatory activity.

59. – Acetaminophen is administered orally and is rapidly
absorbed.
– It is metabolized by hepatic microsomal enzymes to sulfate
and glucuronide.
– Acetaminophen is a substitute for aspirin to treat mild-to-
moderate pain for selected patients who are:
• intolerant to aspirin
• have a history of peptic ulcer or hemophilia
• are using anticoagulants or a uricosuric drug to manage
gout
• are at risk for Reye's syndrome.

60. • 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.

61. • Adverse effects
• With normal therapeutic doses, acetaminophen is virtually free of any
significant adverse effects.
• Skin rash and minor allergic reactions occur infrequently.
• There may be minor alterations in the leukocyte count, but these are
generally transient.
• 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 (see Figure
41.12).
• Hepatic necrosis, a very serious and potentially life-threatening
condition, can result.
• Renal tubular necrosis may also occur.
• [Note: 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.
Periodic monitoring of liver enzymes tests is recommended for those on
high-dose acetaminophen.

62. Figure : Metabolism of acetaminophen.

63. Overdose with acetaminophen:
accumulation of a minor metabolite, N-acetyl-p-benzoquinone,
which is responsible for hepatotoxicity.

64. • Overdose is treated by:
– emesis or gastric lavage
– oral administration of N-acetyl cystine within 1 day to
neutralize the metabolite.
• Long-term use of acetaminophen has been
associated with:
– a 3-fold increase in kidney disease
– women taking more than 500 mg/day had a doubling in
the incidence of hypertension.

65. Disease-Modifying Antirheumatic
Agents
• Disease-modifying antirheumatic drugs (DMARDs) are used in
the treatment of RA .
• They have been shown-
- to slow the course of the disease by preventing further
destruction of the joints and involved tissues.
-induce remission,
When a patient is diagnosed with RA, the American College of
Rheumatology recommends initiation of therapy with
DMARDs within 3 months of diagnosis (in addition to
NSAIDs, low-dose corticosteroids, physical therapy).
Therapy with DMARDs is initiated rapidly to help stop the
progression of the disease at the earlier stages.

66. • Choice of drug
• No one DMARD is efficacious and safe in every patient, and trials of
several different drugs may be necessary.
• Most experts begin DMARD therapy with one of the traditional
drugs, such as methotrexate or hydroxychloroquine.
• These agents are efficacious and are generally well tolerated, with
well-known side-effect profiles.
• Inadequate response to the traditional agents may be followed by
use of newer DMARDs, such as leflunomide, anakinra, and TNF-
inhibitors (adalimumab, etanercept, and infliximab).
• Combination therapies are both safe and efficacious.
• In most cases, methotrexate is combined with one of the other
DMARDs.
• In patients who do not respond to combination therapy with
methotrexate plus TNF inhibitors, or other combinations, treatment
with rituximab or abatacept may be tried.
• Most of these agents are contraindicated for use in pregnant
women.

67. • Methotrexate
• Methotrexate [meth-oh-TREX-ate], used alone or in combination therapy, has
become the mainstay of treatment in patients with rheumatoid or psoriatic
arthritis.
• Methotrexate slows the appearance of new erosions within involved joints.
• Response to methotrexate occurs within 3 to 6 weeks of starting treatment.
• It is an immunosuppressant, and this may account for its effectiveness in an
autoimmune disease.
• 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 this treatment are much lower than those
needed in cancer chemotherapy and are given once a week; therefore, the
adverse effects are minimized.
• 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 on chronic administration.
• [Note: Taking leucovorin once daily after methotrexate reduces the severity of the
adverse effects.]

68. • Leflunomide
• The mechanism of action by which leflunomide works is by blocking the body's
ability to make certain nucleotide, which is a building block of DNA
synthesis, by blocking the enzyme dihydroorotate dehydrogenase.
• People who have rheumatoid arthritis have a type of immune cell (called a T
cell) that is overactive.
• T cells produce chemicals that cause inflammation and damage joint tissue.
• T cells need DNA to divide, or reproduce.
• By stopping the production of DNA, leflunomide prevents T cells from
reproducing, thereby reducing inflammation and preventing joint damage.
• Leflunomide has been approved for the treatment of RA.
• It not only reduces pain and inflammation associated with the disease but also
appears to slow the progression of structural damage.

69. Figure :Site of action of leflunomide

70. • Hydroxychloroquine
• This agent is also used in the treatment of malaria.
• It 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.
• Its mechanism of action may include inhibition of phospholipase A2 and
platelet aggregation, membrane stabilization, effects on the immune
system, and antioxidant activity.
• It may cause renal toxicity
• Sulfasalazine
• Sulfasalazine [sull-fa-SAH-la-zeen] is also used for early, mild RA in
combination with hydroxycholoroquine and methotrexate.
• Onset of activity is 1 to 3 months, and it is associated with leukopenia.
• D-Penicillamine
• D-Penicillamine [pen-ih-SILL-a-meen], an analog of the amino acid
cysteine, slows the progression of bone destruction and RA.
• This agent is used as add-on therapy to existing NSAID/glucocorticoid
therapy.

71. • Gold salts
• Gold compounds, like the other drugs in this
group, cannot repair existing damage.
• They can only prevent further injury.
• The currently available gold preparation is auranofin
for oral administration.
• This agent will suppress phagocytosis and lysosomal
enzyme activity.
• This mechanism retards the progression of bone and
articular destruction, and beneficial effects may be
seen in 3 to 6 months.
• The gold compounds are being used infrequently by
rheumatologists because of the need for meticulous
monitoring for serious toxicity (for
example, myelosuppression) and the costs of
monitoring.

72. • Other Therapies in Rheumatoid Arthritis
• Interleukin-1b and TNF- α are 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.
• The TNF inhibitors (etanercept, adalimumab, and infliximab) have been shown to decrease
signs and symptoms of RA, reduce progression of structural damage, and improve physical
function; clinical response can be seen within 2 weeks of therapy.
• If a patient has failed therapy with one TNF inhibitor, a trial with a different TNF inhibitor is
appropriate.
• Many experts propose that a TNF inhibitor plus methotrexate be considered as standard
therapy for patients with rheumatoid and psoriatic arthritis.
• Indeed, TNF inhibitors can be administered with any of the other DMARDs, except for
anakinra, an IL-1 receptor antagonist.
• Patients receiving TNF inhibitors are at increased risk for infections (tuberculosis, and
sepsis), fungal infections, and pancytopenia.
• These agents should be used very cautiously in those with heart failure, because these agents

73. Immunotherapeutic Treatment of
Rheumatoid Arthritis
Use
Molecular
TargetCharacteristicDrug
Rheumatoid arthritisPlasma & tissue
TNF-α
Anti-TNF-α antibodyAdalimumab
Rheumatoid arthritis, Crohn's
disease, uveitis, psoriasis
Plasma & tissue
TNF-α
Anti-TNF-α antibodyInfliximab
Rheumatoid arthritis, psoriasisPlasma & tissue
TNF-α
TNF-receptor
fusion protein
Etanercept
Rheumatoid arthritisInterleukin-1Recombinant IL-1Anakinra

74. • Gout
• Gout is a metabolic disorder characterized by high levels
of uric acid (end product of purine metabolism) in the
blood.
• Hyperuricemia can lead to deposition of sodium urate
crystals in tissues, especially the joints and kidney.
• The cause of hyperuricemia is an overproduction of uric
acid relative to the patient's ability to excrete it.
• The deposition of urate crystals initiates an
inflammatory process involving the infiltration of
granulocytes that phagocytize the urate crystals
(Figure).
• This process generates oxygen metabolites, which
damage tissues, resulting in the release of lysosomal
enzymes that evoke an inflammatory response.
• In addition, there is increased production of lactate in
the synovial tissues.
• The resulting local decrease in pH fosters further
deposition of urate crystals.

75. Figure: Role of uric acid in the inflammation of gout.

76. • Most therapeutic strategies for gout involve lowering the uric
acid level below the saturation point (<6 mg/dL), 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.

77. • Treating acute gout
• Acute gouty attacks can result from a number of
conditions, including excessive alcohol
consumption, a diet rich in purines, or kidney
disease.
• Acute attacks are treated with indomethacin to
decrease movement of granulocytes into the
affected area;
• NSAIDs other than indomethacin
are also effective at decreasing pain and
inflammation.
• [Note: Aspirin is contraindicated, because it
competes with uric acid for the organic acid
secretion mechanism in the proximal tubule of
the kidney.]

78. • Treating chronic gout
• Chronic gout can be caused by 1) a genetic defect, such as one
resulting in an increase in the rate of purine synthesis; 2) renal
deficiency; 3) Lesch-Nyhan syndrome; or 4) excessive production of
uric acid associated with cancer chemotherapy.
• Treatment strategies for chronic gout include
-the use of uricosuric drugs : That increase the excretion of uric
acid, thereby reducing its concentration in plasma.
Uricosuric agents are first-line agents for patients with gout
associated with reduced urinary excretion of uric acid.
- inhibits uric acid production : 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
synthesis, with previous histories of uric acid stones, or with renal
insufficiency.

79. • Colchicine
– Colchicine is an alkaloid
– It is used for relief of inflammation and pain in acute gouty
arthritis.
– Reduction of inflammation and relief from pain occur 12—
24 hours after oral administration.
– The mechanism of action in acute gout is unclear.
– Colchicine:
• Colchicine binds to tubulin, a microtubular
protein, causing its depolymerization. This disrupts
cellular functions, such as the mobility of
granulocytes, thus decreasing their migration into the
affected area.
• Furthermore, colchicine blocks cell division by binding
to mitotic spindles.
• Colchicine also inhibits the synthesis and release of the
leukotrienes

80. – The adverse effects after oral administration, which occur
in 80% of patients at a dose near that necessary to relieve
gout, include nausea, vomiting, abdominal pain, and
particularly diarrhea.
– IV administration reduces the risk of gastrointestinal
disturbances and provides faster relief (6—12 h) but
increases the risk of sloughing skin and subcutaneous
tissue.
– Higher doses may (rarely) result in liver damage.

81. • Probenecid and sulfinpyrazone
• are organic acids
• reduce urate levels by preventing reabsorption of uric acid in
the renal tubule .
• These agents are used for chronic gout, often in combination
with colchicine.
• Probenecid and sulfinpyrazone undergo rapid oral absorption.

82. • These agents inhibit the excretion of other drugs that are actively
secreted by renal tubules, including penicillin, NSAIDs,
cephalosporins, and methotrexate.
• Increased urinary concentration of uric acid may result in the
formation of urate stones (urolithiasis).
• This risk is decreased with:
1. the ingestion of large volumes of fluid or
2. alkalinization of urine with potassium citrate.
• Common adverse effects include gastrointestinal disturbances
and dermatitis; rarely, these agents cause blood dyscrasias

83. • Allopurinol
• Allopurinol inhibits the synthesis of uric acid by inhibiting
xanthine oxidase, an enzyme that converts hypoxanthine to
xanthine and xanthine to uric acid.
• Allopurinol is metabolized by xanthine oxidase to
alloxanthine, which also inhibits xanthine oxidase. Allopurinol also
inhibits de novo purine synthesis.
• Allopurinol commonly produces gastrointestinal disturbances and
dermatitis. This agent more rarely causes hypersensitivity, including
fever, hepatic dysfunction, and blood dyscrasias.
• Allopurinol should be used with caution in patients with liver
disease or bone marrow depression.

84. Mechanism of action:
Allopurinol inhibits xanthine oxidase enzyme
which is required for the synthesis of Uric acid.
This enzyme is required when purine is oxidized
to Uric acid.

85. THANKS

97. 1. Anti-TNF- drugs
A. Infliximab:
• is a recombinant antibody with human constant and murine
variable regions that specifically binds TNF-α, thereby
blocking its action.
– Approved for use for rheumatoid arthritis, Crohn's
disease, psoriasis, and other autoimmune diseases
– Administered by IV infusion at 2-week intervals initially
and repeated at 6 and 8 weeks

98. B. Adalimumab
• is approved for the treatment of rheumatoid arthritis.
• It is a humanized (no murine components) anti-TNF-α antibody
administered subcutaneously every other week.
C. Etanercept
• is a fusion protein composed of the ligand-binding pocket of a TNF-α
receptor fused to an IgG1 Fc fragment.
• The fusion protein has two TNF-binding sites per IgG molecule and is
administered subcutaneously weekly.
• The most serious adverse effect is infection including
tuberculosis, immunogenicity, and lymphoma.
• Injection site infections are common.

99. 2. Anti-IL1 drugs
– Anakinra is a recombinant protein essentially identical to
IL-1 , a soluble antagonist of IL-1 that binds to the IL-1
receptor but does not trigger a biologic response.
– Anakinra is a competitive antagonist of the IL-1 receptor.
– It is approved for use for the treatment of rheumatoid
arthritis.
– It has a relatively short half-life and must be
administered subcutaneously daily.

100. Characterized by:
1. Redness (rubor): vasodilation of capillaries to increase
blood flow
2. Heat (calor): vasodilation
3. Pain (dolor): Hyperalgesia, sensitization of nociceptors
4. Swelling (tumor): Increased vascular permeability
(microvascular structural changes and escape of
plasma proteins from the bloodstream)
5. Loss of function (functio laesa)
• Inflammatory cell transmigration through endothelium
and accumulation at the site of injury

104. Other antiinflammatory drugs are used in the more advanced
stages of some rheumatoid diseases.
• Gold compounds:
– Aurothioglucose
– Gold sodium thiomalate
– Auranofin
– may retard the destruction of bone and joints by an
unknown mechanism.
– These agents have long latency.
– Aurothioglucose and gold sodium thiomalate are
administered intramuscularly.
– Auranofin is administered orally and is 95% bound to
plasma proteins.

105.  Side effects: Gold compounds
 Serious:
• gastrointestinal disturbances, dermatitis, and mucous membrane
lesions.
 Less common effects:
• aplastic anemia
• proteinuria
 Occasional:
• nephrotic syndrome.

106. Penicillamine
– Penicillamine is a chelating drug (will chelate gold) that is a
metabolite of penicillin.
– Penicillamine has immunosuppressant activity, but its
mechanism of action is unknown.
– This agent has long latency.
– The incidence of severe adverse effects is high; these
effects are similar to those of the gold compounds.

107. • Methotrexate
– Methotrexate is an antineoplastic drug used for
rheumatoid arthritis that does not respond well to NSAIDs
or glucocorticoids.
– Methotrexate commonly produces hepatotoxicity.
• Chloroquine and hydrochloroquine
– Chloroquine and hydrochloroquine are antimalarial drugs.
– These agents have immunosuppressant activity, but their
mechanism of action is unknown.
– Used to treat joint pain associated with lupus and arthritis
• Adrenocorticosteroids