This document discusses non-opioid analgesics, specifically nonsteroidal anti-inflammatory drugs (NSAIDs). It describes how NSAIDs work by inhibiting cyclooxygenase enzymes, which reduces the production of prostaglandins involved in the inflammatory process. The document outlines the different classes of NSAIDs, their mechanisms of action, therapeutic uses, and potential adverse effects, which can affect the gastrointestinal, renal, hepatic, and cardiovascular systems. It also discusses the classification of NSAIDs based on their selectivity for the COX-1 and COX-2 enzymes.

1. BRANCH OF
NON-OPIOID ANALGESICS
NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
[NSAIDS]
&
DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
2016-2017

2. NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)
 Different chemical families
 Common mechanism of action (cyclooxygenase
inhibition)
 Different selectivities to COX I and II
 Different pharmacokinetics and potency
 Common therapeutic indications
 Common adverse effects

3. NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)
Inflammation is characterized by local
 Pain (dolor):
 Swelling (tumor):(edema) escape of plasma
proteins from the bloodstream
 Redness (rubor): (erythema, vasodilation)
 Warmth (calor): vasodilation
 Loss of function (functio laesa)

4. INFLAMMATORY RESPONSES
OCCUR IN THREE DISTINCT
PHASES:
 An acute transient phase, characterized by:
Local vasodilation
Increased capillary permeability
 A delayed, subacute phase [The Immune
Response], most prominently characterized by:
Infiltration of leukocytes and phagocytic cells
 A chronic proliferative phase, in which tissue
degeneration and fibrosis occur.

5. MEDIATORS OF INFLAMMATION
Inflammation is triggered by the release of
chemical mediators from injured tissues and
migrating cells. The specific mediators vary with
the type of inflammation. They include:
 Vasoactive Amines (Histamine, Serotonin 5HT)
 Kinin system: Small peptides (bradykinin).
 Large peptides (IL-1)
 Platelet activating factor (PAF)

6. MEDIATORS OF INFLAMMATION
 Complement system
 Cytokines
 Nitric oxide
 Adhesion Molecules
 Lipids: Arachidonic acid metabolites:
Prostaglandins (PGs) (G2,H2, E2, F2ά)
mediated by cyclooxygenases (COX)
Thromboxane A2 (TXA2)
HETE (hydroxy-eicosatetraenoic acid)
Leukotrienes (LTs)

7. ANTI-INFLAMMATORY DRUGS
 Non-steroidal Anti-inflammatory Drugs
(NSAIDs) [Salicylates and Non salicylates]
 Steroidal Anti-inflammatory Drugs
 Miscellaneous Drugs

8. ANTI-INFLAMMATORY DRUGS
For Pharmacological control of inflammation:
 Preventing the release of inflammatory
mediators Lead to Inhibiting their actions and
Treating pathophysiologic responses to them.
 Their anti-inflammatory activity is similar to
aspirin in mechanism (i.e. by inhibition of PGs
synthesis).
 inflammation is reduced by ↓ release of
mediators produced by granulocytes, basophils
& mast cells.

9. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
General characteristics
 Drugs that inhibit one or more steps in the
metabolism of arachidonic acid (AA) by
inhibiting the synthesis of PGs.
 PGs and related eicosanoids are released in
minute amounts by all tissues except RBCs.
 They are synthesized and inactivated in and
same place so the circulating level is very small
(i.e. PGs don't circulate in blood in significant
level).

10. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
General characteristics
 Aspirin inhibits: BOTH COX-1 and COX-2
Irreversibly acetylates enzyme & Other NSAIDs
are reversible
 ↓Cyclo-oxygenase enzyme
 COX-I Most cells in the body
 COX-II Inflammatory and immune cells
 COX-III Hypothalamic temperature control
center

11. NSAIDS: MECHANISM OF ACTION
 NSAIDs act to block the first step of
prostaglandin synthesis, by binding to and
inhibiting cyclooxygenase:
Inhibit activity of cyclooxygenase-1 (COX-1):
Enzyme helps to maintain the stomach lining
[What do you think a possible side effect of
this could be???]
Inhibit activity of cyclooxygenase-2 (COX-2):
Enzyme triggers pain and inflammation
Stabilize cell membranes to prevent
further leakage of substances (edema)

12. NSAIDS: MECHANISM OF ACTION
 NSAIDs that act on COX-I, COX-II & COX-III →
more side effects. Selective COX-II/COX-III
NSAIDs → less side effects
 ↓Lipo-oxygenase enzyme (some of them)
additional effects:
↓Interleukin-I
↓Leukocyte migration
↓Release of lysosomal enzymes
↓Platelet aggregation

13. MECHANISM OF NSAIDS
Arachidonic acid, AA
Prostaglandin, PG
Leukotrienes, LTs
PGE2 PGF2 PGI2 TXA2
PLA2
Phospholipid
COX

14. Arachidonic acid
Phospholipase A2
Corticosteroids ⊕ Bradykinin
Angiotensin
Cyclooxygenase (COX)
PGG2
Prostacyclin(PGI2)
PGE2
PGF2α
Thromboxane A2
Dipyridamole
Hydroperoxidase
NSAIDs
Leukotrienes
5-lipoxygenase
Phospholipid
PGH2

15. COX-1 COX-2
Synthesis Intrinsic physiological: Induced physiological:
Functions  Gastrointestinal
protection
 Platelet aggregation
regulation
 Vascular resistance
regulation
 Renal blood flow
regulation
 Elevated during
pregnancy
 Pathological:
 Producing
proteinase, PG,
and other
inflammatory
mediators
CHARACTERISTICS COMPARISON
BETWEEN COX-1 AND COX-2

16. EFFECTS OF COX INHIBITION
BY MOST NSAIDS
COX-1
Gastric ulcers
Bleeding
Acute renal failure
COX-2
Reduce inflammation
Reduce pain
Reduce fever
NSAIDs: anti-platelet decreases ability of
blood to clot

17. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 All are analgesics, anti-inflammatory,
antipyretics and all inhibit platelet
aggregation.
 All are gastric irritants, but less than aspirin.
 Nephrotoxicity is observed for all of them.
 Affect lymphokin production from T-
lymphocytes and reverse vasodilation.
 They inhibit prothrombin synthesis.

18. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 Analgestic action Relieve pain [mild or
moderate pain]
 Sites of action: peripherally sites of
inflammation → subcortical sites
 Decreased prostaglandin generation means
less sensitisation of nociceptive nerve
endings to inflammatory mediators such as
bradykinin and 5-hydroxytryptamine.
 Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation.

19. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 Antipyretic action Reduce fever by inhibiting
the endogenous synthesis of PGs in
hypothalamus
Blocks pyrogen-induced prostaglandin
production in thermoregulatory center (CNS)
 Endogenous pyogen (IL-1, TNF, IFN, IL-6)→
BBB → CNS (PEG, Na+/Ca2+, cAMP,
CRH)→ fever

20. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 Anti-inflammatory action Suppress
inflammation but do not arrest the progression
of pathological injury to tissue.
Reduced synthesis: eicosanoid mediators
The decrease in vasodilator prostaglandins
(PGE2, PGI2) means less vasodilatation
and, indirectly, less oedema.

21. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 Anti-inflammatory action
Interference: kallikrein system mediators
The inhibition of activity of adhesion
molecule.
Inhibits granulocyte adherence
Stabilizes lysosomes
Inhibits leukocyte migration [Accumulation of
inflammatory cells is also reduced].

22. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacological effects
 Some nonselective NSAIDS also have anti-
thrombotic actions. [inhibit platelet
aggregation, prolong bleeding time; have
anticoagulant effects].

23. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Dose and drug dependent:
 The major therapeutic, toxic, and potency of
NSAIDs. All relate to their ability to inhibit
prostaglandin synthesis.

24. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacokinetics
 As weak acids, well absorbed after PO. Food
reduces the rate but not the extent of NSAID
absorption.
 Most NSAIDs demonstrate peak effects within
1-2 hours.
 Small volume of distribution (10%)
 Highly protein binding (98%)

25. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
(NSAIDS)
Pharmacokinetics
 Clearance: hepatic metabolism both phase I
oxidation and phase II. Conjugated metabolites
→ urine.
 Pharmacologic effects are similar to aspirin and
include analgesic, antipyretic, and anti-
inflammatory actions.

26. CLINICAL USES OF THE NSAIDS
 For analgesia in painful conditions (e.g.
headache, dysmenorrhoea, backache, bony
metastases of cancers, postoperative pain)
The drugs of choice for:
Short-term analgesia are aspirin,
paracetamol and ibuprofen.
More potent, Longer-acting drugs (diflunisal,
naproxen, piroxicam) are useful for chronic
pain.

27. CLINICAL USES OF THE NSAIDS
 For analgesia
NSAIDs are superior to opioids is the
management of pain due to inflammation.
(have max. efficacy more than that of opioids).
The requirement for narcotic analgesics can
be markedly reduced by NSAIDs. NSAIDs are
combined with opioids in some patients with
bony metastases or postoperative pain.

28. CLINICAL USES OF THE NSAIDS
 For anti-inflammatory effects in chronic or
acute inflammatory conditions (e.g. rheumatoid
arthritis and related connective tissue disorders,
gout and soft tissue diseases).

29. CLINICAL USES OF THE NSAIDS
 With many NSAIDs, the dosage required for
chronic inflammatory disorders is usually
greater than for simple analgesia and treatment
may need to be continued for long periods.
 Treatment could be initiated with an agent
known to have a low incidence of side-effects. If
this proves unsatisfactory, more potent agents
should be used.

30. CLINICAL USES OF THE NSAIDS
 To lower temperature. Paracetamol is preferred
because it lacks gastrointestinal side-effects
and, unlike aspirin, has not been associated
with Reye’s syndrome in children.
 There is substantial individual variation in
clinical response to NSAIDs and considerable
unpredictable patient preference for one drug
rather than another.

31. CLINICAL USES OF THE NSAIDS
 NSAIDs have been found to prevent the
formation and reduce the size of polyps in
patients with the genetic disease, familial
adenomatous polyposis (FAP)
 In FAP, patients develop large numbers of
polyps in their colons, and the polyps invariably
become malignant. The only cure of FAP
requires removal of the entire colon.

32. NSAIDS
Adverse Reactions: include gastrointestinal
effects, renal effects, and hypersensitivity
reactions.
 Gastrointestinal system reactions
abdominal distress or discomfort,, Nausea,
vomiting, diarrhea, constipation, epigastric
pain, indigestion [dyspepsia], intestinal
ulceration, stomatitis and rarely, ulcers or
bleeding.

33. NSAIDS
Adverse Reactions
 Renal system reactions
 In kidney, vasodilatory and tubuloactive
prostaglandins are protective, Both COX1
and COX2 mediate renal effects of
prostaglandins. Renal insufficiency, renal
failure, hyperkalemia, and proteinuria
[Analgesic nephropathy].
 Hematuria, cystitis, elevated blood urea

34. NSAIDS
Adverse Reactions
 Hematologic reactions: Neutropenia,
eosinophilia, leukopenia, pancytopenia,
thrombocytopenia, agranulocytosis, aplastic
anemia
 Hepatic: Abnormal liver function test results
and rare liver failure.

35. NSAIDS
Adverse Reactions
 Skin reactions: Rash, erythema, irritation,
skin eruptions, exfoliative dermatitis, Stevens-
Johnson syndrome, ecchymosis, Purpura.
 Hypersensitivity; there is cross-sensitivity if
allergic to one NSAID there is increased risk of
allergic reaction to others; hypersensitivity to
aspirin; during third trimester of pregnancy and

36. NSAIDS
Adverse Reactions
NSAIDs can cause central nervous
system effects including Anxiety, light-
headedness, vertigo, sedation, drowsiness,
dizziness, tinnitus confusion, depression,
headaches, and rarely, aseptic meningitis.
Sensory reactions: Blurred or diminished
vision, diplopia, swollen or irritated eyes,
photophobia, reversible loss of color vision.,

37. NSAIDS
Adverse Reactions
Cardiovascular reactions: Fluid retention,
hypertension, edema, and rarely,
myocardial infarction and congestive heart
failure (CHF).
NSAIDs reversibly inhibit platelet
aggregation. This effect only remains as
long as the drug is in the body.
Pulmonary: Asthma.

38. NSAIDS
NSAIDs: Contraindications
 Ibuprofen - hypertension, peptic ulceration, or
GI bleeding
 Celecoxib - allergic to sulfonamides, or history
of cardiac disease or stroke
Cautious use:
 Pregnancy (pregnancy category B).
 Elderly patients, patients with bleeding
disorders, renal disease, cardiovascular
disease, hepatic impairment

39. EFFECTS OF NON-STEROIDALS
ON OTHER DRUGS
 Decrease effects of
ACEI, beta blockers and diuretics
 Increase effects of
Digoxin, lithium, & methotrexate.

40. CLASSIFICATION OF
CYCLOOXYGENASE INHIBITORS
 Drugs without inflammatory properties
 Acetaminophen
 Drugs with anti-inflammatory properties
Non-steroidal anti-inflammatory drugs: 2
types
 First generation (inhibit both COX1 and
COX2)
 Non-selective COX inhibitors

41. CLASSIFICATION OF
CYCLOOXYGENASE INHIBITORS
 Second generation [non-acidic NSAIDS] (inhibit
COX2 only)
Selective COX inhibitors
 Preferential COX2 inhibitors (partial
specificity for COX2):
 Celecoxib (human drug)
 Carprofen (canine drug)
 Selective COX2 inhibitors (full specificity
for COX2)
 Rofecoxib (human drug)
 Deracoxib (canine drug)

42. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
I. Salicylic acid derivatives:
 Aspirin(acetylsalicylic acid; ASA)
 Na salicylate
 Choline Mg++ trisalicylate
 Salsalate
 Diflusinal
 Sulfasalazine

43. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
II. Non Salicylic acid derivatives [aspirin-like
drugs]
Groups of NSAIDs:
A. Aniline derivatives/Aminophenol
Derivatives:
 Para-aminophenol (Acetaminophen)

44. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
II. Non Salicylic acid derivatives [aspirin-like
drugs]
B. Selective COX-2 inhibitors:
 Celecoxib
 Rofecoxib
 Etodolac
 Nimesulide

45. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
II. Non Salicylic acid derivatives [aspirin-like
drugs]
C. Non-selective COX inhibitors:
 Para-chlorobenzoic acid derivatives or indoles
(Indomethacin, Sulindac)
 Pyrazolone derivatives (Phenylbutazone)
 Arylpropionic acid (Ibuprofen, Flurbiprofen,
Ketoprofen, Fenoprofen, Naproxen, Oxaprozin)

46. NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
C. Non-selective COX inhibitors:
 Fenamates/Anthranilic acids (Mefenamic Acid,
Meclofenamic acid)
 Enolic acids/Oxicams (Piroxicam, Meloxicam)
 Heteroaryl/Penylacetic acids (Diclofenac
Sodium, Tolmetin, ketorolac)
 Alkalones (Nabumetone)

47. NSAIDS:
CLASSIFICATIONS BASED ON
CHEMISTRY
 Salicylic acid derivatives
 Aspirin
 Para-aminophenol
derivatives
 Acetaminophen
 Indole and indene acetic
acids
 Indomethacin
 Pyranocarboxylic acids
 Etodolac
 Ketorolac
 Propionic acids
 Ibuprofen
 Naproxen
 Ketoprofen
 Carprofen
 Vedaprofen
 Fenamates
 Meclofenamic acid
 Tolfenamic acid
 Pyrazolones or enolic
acids
 Phenylbutazone
 Dipyrone
 Oxicams
 Piroxicam
 Meloxicam
 Nicotinic acid derivatives
 Flunixin meglumine
 Hydroxamic acid
derivatives
 Tepoxalin
 Coxib-class NSAIDs
 Deracoxib
 Firocoxib

48. SALICYLATES
 Drugs derived from salicyclic acid
 Prototype drug
 Developed in 1899 by Adolph Bayer
Useful in pain management due to analgesic,
antipyretic, anti-inflammatory and Anti-
thrombotic effects.

49. SALICYLATES
 Acetylsalicylic acid (Aspirin)
was first isolated in 1829 by Leroux
from willow bark(used in malaria).

50. SALICYLATES
 Non-acetylated salicylates:
Sodium salicylate
Magnesium salicylate
Choline salicylate
Sodium thiosalicylate
Sulfasalazine
Mesalamine
Salsalate

51. SALICYLATES
 Acetylsalicylic acid (aspirin) is the most
common salicylate used today.
 Aspirin is the most useful salicylate for treating
pain.

52. SALICYLATES
Mechanisms of action
 Aspirin works by inhibiting prostaglandin
synthesis. It primarily inhibits the enzyme
cyclooxygenase (COX). By Covalent bonding
and modification.
 Interferes with the chemical mediators of the
kallikrein system.
 Inhibits the migration of polymorphonuclear
leukocytes to the site of inflammation.
 Anti-oxidant activity.
 Stabilizing lysosomes

53.  The mechanism of
aspirin: acetylating COX
enzyme irreversibly.
 Aspirin is rapidly
deacetylated by Esterase
to produce salicylates
with are still active (have
anti-inflammatory,
Antipyretic and Analgesic
effects).
ASPIRIN

54. SALICYLATES
Pharmacokinetics
 Aspirin is a weak organic acid. Aspirin is rapidly
and almost completely absorbed from the stomach
and upper small intestine.
 The acidic medium in the stomach (PH= 1.5)
keeps large fraction of salicylates in non-ionized
from (lipid soluble) so it diffuses easily and
absorption is promoted.
 Most aspirin is coated because it is irritating to the
stomach when high conc. of salicylates enter the
mucosal cells, the drug may damage the mucosal
barrier and result in gastric ulcer.

55. SALICYLATES
Pharmacokinetics
 If gastric PH is raised by suitable buffer to 3.5 or
higher gastric irritation will be minimized (less
absorption → less irritation).
 It reaches its peak effects in 30 minutes when
taken on an empty stomach. Buffered tablets
reach their peak effect in 20 minutes.
 Aspirin can be administered rectally.

56. SALICYLATES
Pharmacokinetics
 After absorption of aspirin is metabolized in
liver. It is hydrolyzed by esterases into acetic
acid and salicylates.
 Salicylate binds to albumin but as serum conc.
Of salicylates increases, a greater fraction
remain unbound and available to tissue. 80-
90% protein bound.
 Cross BBB & placental barrier

57. SALICYLATES
Pharmacokinetics: Metabolism of Aspirin

58. SALICYLATES
Pharmacokinetics
 Salicylates that generated by hydrolysis of
aspirin may excreted unchanged, but most is
converted to water soluble conjugates that are
rapidly cleared by the kidney.

59. SALICYLATES
Pharmacokinetics
 Excretion: by kidneys [influenced by pH of
urine].
 85% in alkaline urine [Urine alkalinization will
prevent reabsorption of salicylates.]
 5% in acid urine

60. SALICYLATES
Pharmacokinetics
 Aspirin demonstrates first- & zero-order
kinetics.
In oral small dose，metabolized in first-order
kinetics and half life is 3-5 h.
In large dose (1g/time,>4g/day), metabolized
in zero-order kinetics because hepatic
metablic pathway becomes saturated, which
prolong t1/2 of aspirin to 15 h or more to lead

61. SALICYLATES
Pharmacokinetics
 The t1/2 also depends on the status of the
kidney and liver.
 The ↑ in t1/2 (at high aspirin doses) → occurs
about after week (till the saturation of the
hepatic enzymes) that will lead to the formation
of salicyluric conversion compounds salicyl
phenylglucuronide and salicyluric acid.

63. SALICYLATES
Pharmacologic Effects
 Anticoagulant [Antiplatelet] [at small dose
(~100 mg/d)].
Aspirin irreversibly binds to platelets COX. By
inhibition of TXA2 production, to inhibit
platelet aggregation and secondary release of
ADP from activated platelets.
Aspirin effect lasts 8-10 days till the formation
of new platelet ( life of platelets )

64. SALICYLATES
Pharmacologic Effects
Aspirin has long duration of action when
compared with other agents used to inhibit
platelet aggregation such as: clofibrate,
phenylbutazone, dipyridamole.

65. SALICYLATES
Pharmacologic Effects
Aspirin inhibits both prostacyclin and
thromboxane A2 depending on the dose used
without markedly affecting PGI2 in the
endothelial cells of the blood vessel.
This helps prevent blood from clotting,
prolongs bleeding time → decreasing risk of
myocardial infarction; reducing risk of
transient ischemic attacks.

66. COX-1 COX-1/COX-2

67. SALICYLATES
Pharmacologic Effects
 Analgesic: (At dose 300-600 mg) [Effective for
mild, moderate dull pain including muscular,
dental, post parum, arthritis and bursitis pain]
inhibits pain stimuli at a subcortical site.
Integumental pain is relieved better
It is not effective for severe visceral pain
[myocardial infarction or renal or biliary colic].

68. SALICYLATES
Pharmacologic Effects
 Antipyretic :(At dose 300-600 mg) Rapid and
moderate in potency.
 Aspirin reduces fever because of its ability to
inhibit prostaglandin synthesis in the
hypothalamus.
 ↓ Pyrogen induced PGE2 synthesis with
infection
 ↓ interleukin-I. produced during inflammation
by macrophages to activate lymphocytes
 ↓ Temp.
 By increasing heat dissipation [by inducing

69. SALICYLATES
Pharmacologic Effects
 Anti-inflammatory: [At large dose (3-6 g/d)].
 This effect is also from aspirin’s ability to block
prostaglandin synthesis and TXs (TXA2).
 ↓ Synthesis and release of inflammatory
mediators of Kallikrein synthesis; ↓ Leukocyte
migration & ↓ release of lysosomal enzymes.
 Aspirin reduces redness and swelling at the
inflamed area.
 To treat rheumatoid, rheumatic arthritis, and
ankylosing spondylitis symptomatic relief.

70. SALICYLATES
Pharmacologic Effects
 Uricosuric effects: [large doses of
aspirin(above 4g)]

71. SALICYLATES
Pharmacologic Effects
Vascular effect:
 High doses may cause peripheral vasodilation
by exerting a direct effect on smooth muscle.
 Toxic doses depress circulation directly and by
central vasomotor paralysis.
 Non-cardiogenic pulmonary edema may occur
in older patients on long-term salicylate therapy.

72. SALICYLATES
Pharmacologic Effects: Other effects
Respiratory Effect:
 Low doses: uncoupling phosphorylation → ↑
CO2 → stimulates respiration.
 Therapeutic does ↑ alveolar ventilation.

73. SALICYLATES
Respiratory Effect:
 Higher does acts directly on respiratory centre (in
medulla) causing hyperventilation and respiratory
alkalosis. Compensation rapidly occurs because
the kidney is able to increase the excretion of
bicarbonate, producing a compensated respiratory
alkalosis.
 Toxic doses or very prolonged administration can
depress the medullary resulting in an
uncompensated respiratory acidosis + metabolic

74. SALICYLATES
GIT effects:
 PGI2 inhibits gastric secretion, PGE2 stimulates
synthesis of protective mucosa in the stomach
and intestine.
 In presence of Aspirin, both PGI2 and PGE2 are
not formed and this will lead to:
 It can cause epigastric distress, nausea, and
vomiting by irritating the gastric mucosal lining
and stimulating the chemoreceptor trigger zone
in the CNS.
 Increasing gastric acid secretion and diminishing

75. SALICYLATES
GIT effects:
 With ordinary doses of Aspirin, 3-8 ml of
blood may be lost with feces every day.
 Buffered and Enteric coated Aspirin
preparations, that delay absorption of aspirin
to the upper small intestine, are only partially
helpful and more expensive.
 Misoprostol (PGE derivative) is used for
treatment of gastric damage induced by

76. SALICYLATES
Action on kidney:
 Inhibition of COX prevents the synthesis of
PGI2 and PGE2 which are responsible for
maintaining normal renal blood flow
(especially in the presence of
vasoconstrictors)
 Diminished synthesis of above PGs can
 Decreasing renal blood flow. Resulting in
retention of sodium and water. Causing

77. SALICYLATES
Pharmacologic Effects
 Other effects:
 Immune inhibition
 Effect on metabolism of connective tissue
 Effects on metabolism of glucose
[Hyperglycemia and depletion of muscle and
hepatic glycogen], fat, protein catabolism ↑]
 It can produce hyperglycemia and glycosuria in
large doses
 ACTH release ↑ [In very large doses, it can
stimulate steroid secretion by the adrenal

78. SALICYLATES
 Uses
Antiplatelet effects [Prevention of stroke or heart
attack]
Mild to moderate pain
Fever
Inflammation [Rheumatic fever, rheumatoid
arthritis, & other inflammatory joint diseases]
Keratolytic For plantar warts, Corns & Fungal
infections.
5-Amino salicylates (mesalamine, sulfasalazine)
can be used to treat Crohn's disease.

79. SALICYLATES
Adverse Reactions: Aspirin’s adverse reactions
are limited aspirin’s everyday use. These
reactions include:
 Gastrointestinal–They are a direct result of
direct gastric irritation and blockage of
prostaglandins. Gastric upset; heartburn;
nausea; vomiting; anorexia; GI bleeding.
 ↓ PGE2 & PGI2 synthesis in gastric mucosa.
 ↓ Mucin & HCO3- .

80. SALICYLATES
Adverse Reactions:
 At large doses, may cause
hypoprothrombinaemia. Bleeding time is
prolonged because of aspirin’s effects on
platelets and prostaglandins. Vit K is antidote

81. SALICYLATES
Adverse Reactions
Excessive ventilation [Hyperpnea]: respiratory
alkalosis → later acidosis supervenes (metabolic)
due to accumulation of salicylic acid derivatives &
then depression of respiratory centre.
Salicylism ： toxicity in the CNS [headache,
dizziness, nausea, vomiting, tinnitus, decreased
hearing, & vertigo] hyperthermia, sweating, thirst,
hyperventilation

82. SALICYLATES
Adverse Reactions
 Reye syndrome: Swelling of the brain and
liver (fatal hepatitis with cerebral oedema) due
to the increase of fluid pressure and massive
accumulation of fat with the symptoms of
vomiting, lethargy, irritability and confusion in
children experiencing a viral infection with VZV,
chickenpox or influenza (risk for Reyes
Syndrome).
 Often fatal combination of microvascular

83. SALICYLATES
Adverse Reactions
 Carditoxicity Toxic doses directly depress
cardiac function & dilate peripheral blood
vessels.
 Hepatotoxicity & Renal toxicity [Elevation of
liver enzymes, & decreased renal function].

84. SALICYLATES
Adverse Reactions
 Hypersensitivity: Allergy to salicylates
manifested by: Hives, Urticaria, Angioedema,
Bronchospasm, & Anaphylactoid reactions.
[Patients with asthma are at a higher risk for ,
nasal polyps & [hypersensitivity or allergic
reactions] mediated by leukotriens

85. SALICYLATES
Adverse Reactions
 Vitamin K deficiency
 Hemophilia
 Glucose intolerance
 Increases uric acid levels. Aspirin in doses of 2
mg/day or less increases serum level of uric
acid(inhibiting its secretion). Whereas by the
doubling doses exceeding 4 mg/day, it decreases
urate blood level below 2.5 mg/dl & this is known
as (paradoxic effect of aspirin) inhibiting its
reabsorption.

86. SALICYLATES TOXICITY
 Poisoning can occur with large doses. Saturate
the metabolic pathway, slow elimination and
cause drug accumulation. If overdose, measure
serum levels
 Recognize: N/V, fever, fluid and electrolyte
deficiencies, tinnitus, decreased hearing,
hyperventilation, confusion, visual
changes>>>>delirium, stupor and coma

87. PLASMA SALICYLATE LEVELS AND
EFFECTS (MG/DL)
__
__
__
__
__
__
__
0
10
20
50
100
110
160
Analgesic, anti-pyretic
Anti-platelet
80
Anti-inflammatory
T
O
X
I
C
I
T
Y
Mild
Moderate
Sever
Lethal
Effects Complications
Gastric upset, peptic ulcer
 uric acid excretion
Bleeding tendency
Hypersensitivity
Central stimulation, tinnitis
Hyperventilatin (Resp.Alkalos
 uric acid excretion
Fever, dehydration
Metabolic acidosis
Vasomotor collapse, coma
Hypoprothombenemia
Renal & Resp failure

88. ACUTE SALICYLATE POISONING
Accidental ingestion of a large dose by children or
attempted suicide may produce:
 Depression of respiratory centers
 Respiratory acidosis
 CNS depression
 Sweating
 Dehydration, electrolyte imbalance
 Hypotension & vasodilation
 Coma
 Death

89. CHRONIC SALICYLATE TOXICITY
Salicylism is a constellation of symptoms that
occur in some patients with the chronic use of
large doses of aspirin and other salicylates.
 Headache
 Nausea & Vomiting
 Vertigo
 Tinnitus (ringing in the ears)
 Delirium
 Hyperventilation (resp. alkalosis)
 Hyperglycemia

90. ASA SALICYLISM MANAGEMENT
 Gastric lavage
 Activated charcoal
 IV bicarbonate so more rapid excretion
 Hemodialysis

91. SALICYLATES:
CONTRAINDICATIONS
 Pregnancy
 Severe hepatic damage
 Bronchial Asthma.
 Renal Diseases
 Peptic ulcers
 Vitamin K deficiency, Hypoprothrombinemia,
Hemophilia, Von Willebrand disease.
 Glucose-6-Phsphate Dehydrogenase
deficiency.

92. SALICYLATES: INTERACTIONS
Aspirin can displace some drugs from the protein
binding and thus ↑their free amount → ↑ their
effects of the following drugs:
 Tolbutamide. (Oral hypoglycemic agent)
 Chlorpropamide. (Oral hypoglycemic agent)
 Methotrexate. (Cytotoxic agent, antifoliate used)
 Phenytoin (Antiepileptic) enhancing its effect.
 Valoproic acid (Antiepileptic) inc.ing its effect

93. SALICYLATES: INTERACTIONS
 Aspirin ↓ activity & competes with
spironolactone (diuretic).
 Aspirin competes with Penicillin G, for renal
tubular secretion, reducing its effect.
 It inhibits uricosuric activity of sulfinpyrazone
and probenecid (antigout).

94. SALICYLATES: INTERACTIONS
 Corticosteroids (reduce the level of salicylate).
 Anticoagulant drugs, increasing the bleeding
time.
 ACE inh.s (like captopril), reduce the
antihypertensive effect.

96. DRUG INTERACTION
Aspirin displaces oral anticoagulants, oral
antidiabetics etc.
Interfers with uric acid excretion (analgesic
dose inhibit)
Decreases the diuretic actions (thiazides and
furosemide)
Reduces the K+ sparing action of
spiranolactone.

97. NON-SALICYLATES
ANILINE DERIVATIVES
Actions
 Slow and prolonged Analgesic and antipyretic
activity: Same as salicylates
 No anti-inflammatory action
 No platelet effect
 Less stimulation to gastrointestinal tract
 Damage of liver and kidney if used for a long
time and at high dose

98. NON-SALICYLATES
ANILINE DERIVATIVES
Uses
 Used to treat mild to moderate pain; reduce
elevated body temperature; manage pain and
discomfort – arthritic disorders.
 Useful for people with aspirin allergy; bleeding
disorders; receiving anticoagulant therapy; who
had recent minor surgical procedures.
 Medications to Recognize
 Acetaminophen

99. NON-SALICYLATES
ANILINE DERIVATIVES
Adverse reactions:
 Skin eruptions; urticaria; hemolytic anemia;
pancytopenia; hypoglycemia; jaundice;
hepatotoxicity; → hepatic failure
 Overdose: Causes acute acetaminophen
poisoning or toxicity: n/v, confusion, liver
tenderness, hypotension, cardiac
arrhythmias, jaundice and acute hepatic and
renal failure.

100. NON-SALICYLATES
ANILINE DERIVATIVES
 Contraindication in patients with hypersensitivity
 Used cautiously in patients:
With severe or recurrent pain or high or
continued fever
Who are pregnant or lactating
(acetaminophen)

101. AMINOPHENOL DERIVATIVES
ACETAMINOPHEN (PARACETAMOL) &
PHENACETIN.
 Acetaminophen is not related to salicylates or
NSAIDs.
 Acetaminophen is the active metabolite of
phenacetin responsible for its analgesics effect
and is active ingredient of many over-the-
counter drugs (OTC).

102. AMINOPHENOL DERIVATIVES
ACETAMINOPHEN (PARACETAMOL) &
PHENACETIN.
 Phenacetin: It’s no longer used in medicine
because it produces:
Methemoglobinemia
Hemolytic anemia
Renal necrosis and failure

103. AMINOPHENOL DERIVATIVES
ACETAMINOPHEN (PARACETAMOL).
Mechanism of action:
 Inhibits COX3 → in the brain [CNS]
 Blocks pain impulses peripherally initiation by
inhibiting prostaglandin synthesis, but less
effect on peripheral cyclooxygenase.
 Activates the descending serotonergic pain-
inhibiting pathway.

104. ACETAMINOPHEN
 Acetaminophen has both analgesic and
antipyretic effects, no anti-inflammatory activity.
 It doesn’t interfere with platelet function.
 Therapeutic doses have no effect on the
cardiovascular and respiratory system.
 It does not have any real gastrointestinal
effects.

105. ACETAMINOPHEN
 It doesn’t interact with oral hypoglycemic
agents.
 It is useful in patients with aspirin or NSAID
hypersensitivity.
 It is useful for children because it is not known
to cause Reye syndrome

106. ACETAMINOPHEN
Pharmacokinetics
 Administered orally. It is rapidly and completely
absorbed from the gastrointestinal tract. It
achieves peak levels in 1-3 hours.
 1st pass metabolism occurs in luminal cells of
the intestine and hepatocytes.
 10% bound to plasma proteins.
 Half-life is 2-3 hrs, first order kinetics. In
overdose can be 12 hours.

107. ACETAMINOPHEN
Pharmacokinetics
 Acetaminophen is metabolized by the liver.
Partially metabolized by hepatic microsomal
enzyme → acetaminophen SO4 & glucuronide.
 If large doses are ingested, an intermediate
metabolite, N-acetyl-p-benzoquinonamine is
formed. This metabolite is toxic with sulfhydryl
group of glutathione forming non toxic
substance.
 Excretion: unchanged < 5%.

108. ACETAMINOPHEN METABOLISM
Acetaminophen Non Toxic
NAPQI
Non Toxic
Glucuronic Acid
or sulfate
Cyt P450
Cell
necrosis
80-90%
5-10%
5%
Urin
e
Liver
Heart
Renal
CNS

109. ACETAMINOPHEN:
INDICATIONS
 Suitable substitute for aspirin as antipyretic and
analgesic especially in patients with gastric
problems and prolongation of bleeding time.
 It is the drugs of choice (as analgesic &
antipyretic) in children with viral infection or
chicken pox.
 Headache, dental pain, Myalgia,
dysmenorrhoea, & postpartum pain

110. ACETAMINOPHEN:
INDICATIONS
 ASA allergy & Bronchospasm precipitated by
ASA
 History of hemophilia or PUD.
 Analgesic adjunct to anti-inflammatory therapy
 It doesn’t antagonize uricosuric agents
probenecid and may be used in gouty patients
using proberecid.

111. ACETAMINOPHEN
Adverse Effects
 Skin rash and drug fever
 Nephrotoxicity:-It has been associated with
long-term use [renal tubular necrosis and renal
failure].
 Hypoglycemic coma are rare complication with
prolonged large dose therapy

112. ACETAMINOPHEN
Adverse Effects
 Pancreatits, Jaundice-hepatitis, & Also renal
tubular necrosis may occur with large doses,
the available glutathione in the liver is depleted
and NABQI reacts with sulfhydryl (SH) groups
of cell proteins forming covalent bonds →
leading to cell necrosis and very serious life
threatening condition can result.
 Leucopenia-neutropenia-hemolytic anemia

113. ACETAMINOPHEN
Adverse Effects
 Hepatotoxicity [Acute centrilobular hepatic
necrosis in large dose] Can occur after the
ingestion of a single toxic dose (20-25 gm) or
after long term use of therapeutic doses.

114. ACETAMINOPHEN
Adverse Effects
 Hepatotoxicity: Children are at high risk for
hepatotoxicity because they are often given
doses that are not age- and weight-appropriate.
Signs and symptoms include nausea, vomiting,
abdominal pain, & anorexia.

115. ACETAMINOPHEN
Adverse Effects
 Hepatotoxicity. Chronic large doses of alcohol
can increase the risk for hepatotoxicity [Ethanol
induces drug-metabolizing enzymes in liver.
Resulting rapid metabolism of acetaminophen
produces enough toxic metabolite to exceed
glutathione. Need glutathione to inactivate toxic
metabolites]

116. ACETAMINOPHEN: ACUTE
OVERDOSE
Treatment
 Gastric lavage.
 Charcoal.
 Antidote is N-acetylcysteine. Not to exceed
4g/day [Provides cysteine, a precursor to
glutathione. Prevents the formation of
hepatotoxic metabolites].
Oral form
IV form now approved

117. ACETAMINOPHEN
Acetaminophen: Contraindications
 Drug allergy
 Severe liver disease
 Genetic disease (G6PD)
Acetaminophen: Interaction
 It interacts with alcohol, heavy smoking
increase the toxicity.

118. MAJOR DIFFERENCES BETWEEN
ASPIRIN AND ACETAMINOHEN.

119. MAJOR DIFFERENCES BETWEEN
ASPIRIN AND ACETAMINOHEN.

120. NON-STEROIDAL
ANTI-INFLAMMATORY AGENTS
 Non-acidic NSAIDs
Selective – Cyclooxygenase 2 (COX-2)
 Acidic NSAIDs
Non-selective – Cyclooxygenase 1& 2

121. NON-ACIDIC NSAIDS
 Cyclooxygenase II (COX) Specific Agents
[Selective COX-2 inhibitors]
COX II is only synthesized when inflammation
is present. Blocking COX II receptors only
should decrease the risk for adverse effects.
These drugs were thought to be less irritating
to the stomach. Not inhibit the cytoprotective
action of prostaglandins in the stomach, which
is largely mediated by COX-1.

122. NON-ACIDIC NSAIDS
 Cyclooxygenase II (COX) Specific Agents
[Selective COX-2 inhibitors]
However, these drugs can cause significant
cardiovascular and gastrointestinal toxicity.
They offer no advantage over nonselective
NSAIDs.

123. NON-ACIDIC NSAIDS
 Cyclooxygenase II (COX) Specific Agents
[Selective COX-2 inhibitors]
Nabumetone: it is a pro-drug, changed in the
body to its active metabolite. It is relatively
selective COX-2 inhibitor.
Meloxicam, rofecoxib & celecoxib are
selective COX-2 inhibitors.
Rofecoxib and celecoxib may cause cardiac
toxicity (myocarditis).

124. NABUMETONE
 The only nonacid NSAID
 Well absorbed orally; Given as a ketone
prodrug
 Metabolized in liver; Converted to the active
acetic acid derivative in the body
 t1/2: > 24 hrs; Taken once daily
 Does not undergo enterohepatic circulation
 Cause less gastric damage
 Cause pseudoporphyria & phosensitivity

125. MELOXICAM
 An enolcarboxamide; Safer than piroxicam.
 Slightly COX-2 selective [Stronger effect on
COX-2 than COX-1]
 Given orally ,rectally, I.M., I.V.
 Slowly absorbed
 t1/2: 20 hrs

126. MELOXICAM
 Excreted in urine 50% and in feces 50%.
 Cholestyramine increases the clearance of the
drug .
 Clearance: 40% decreased in elderly
 Dose: 7.5-15mg/d for RA & OA
Adverse effects
 Slightly less ulcerogenic; Skin rash; Headache

127. COXIBS
 They were developed to inhibit prostacyclin
synthesis at site of inflammation without
affecting the action of the constitutively active
"housekeeping" COX-1 isoenzyme found in GIT,
kidneys and platelets.
 COXIBs selectively bind to and block the active
site of the COX-2 enzymes much more
effectively than that of COX-1.
 Coxibs have analgesic, antipyretic and anti-
inflammatory effects (have fewer GIT side

128. COXIBS
 They have NO effect on platelets aggregation.
 Because COX-2 is constitutively active within
the kidney, COX-2 inhibitors cause renal
toxicities similar to traditional NSAIDs.
 Also, it has been found that a higher incidence
or cardiovascular thrombotic events associated
with COX-2 inhibitors (rofecoxib).

129. CELECOXIB
 Highly selective COX-2 inhibitor (10-20 times
more selective for CXO-2 than COX-1).
 Effective dose: 100-200 mg b.i.d.
 Absorption: 20-30% decreased by food
 Highly protein bound; t1/2: 11 hrs
 Metabolized by CYP2C9; Clearance affected by
hepatic impairment.
 27% of its dose excreted in urine (unchanged).
 Does not affect platelet aggregation
 DI: warfarin

130. CELECOXIB
 Inhibits only COX-2; less potential for GI
adverse reactions [dyspepsia]
 Used for: Osteoarthritis, rheumatoid arthritis,
and other musculoskeletal disorders; mild to
moderate pain; primary dysmenorrhea; fever
reduction.
Celecoxib also has been approved for
patients with familial adenomatous polyposis
(FAP) who have not had their colons

131. CELECOXIB
Side effects
 Dyspepsia & heart burn.
 Edema & renal adverse effects.
 Allergy (skin rash ) due to (salfomamide).
Drug interactions
With warfarin potentiate, through interfering with
its metabolism. actions
Contraindications: Celecoxib – allergic to
sulfonamides, or history of cardiac disease or

132. CELECOXIB

133. ROFECOXIB
 A furanose derivative
 A potent highly selective COX-2 inhibitor
 Well absorbed
 Dosage range: 12.5-50mg/d
 Slightly less protein-bound (87%)
 t1/2: 17 hrs

134. ROFECOXIB
 Given o.d., for the treatment of asteoarthritis
and rheumatoid arthritis.
 Metabolized by cytosolic liver enzymes
 it is an analgesic and antipyretic, Does not
inhibit platelet aggregation
 Have little effect on gastric mucosal PGs
 Associated with fewer gastric or duodenal
gastroscopic ulcers. At high dose, it causes
edema and hypertension (occasional).

135. VALDECOXIB
 A new, highly selective COX-2 inhibitor.
 t1/2 = 8-11 hrs and 90% eliminated unchanged
by kidney.
 GI and other toxicities are similar to other
coxibs with no effect on platelets (bleeding time)
 In treatment of dysmenorrheal, it is as effective
as non selective NSAIDs for this indication.

136. ETORICOXIB:
 A second generation COX-2 selective inhibitor
with the highest selectivity ratio of any Coxib for
inhibition of COX-2 relative to COX-1.
 It is extensively metabolized by hepatic P450
enzymes and excretion is renal (t1/2 = 22 hrs ).
 It is used for the treatment of signs and
symptoms of osteoarthritis, gouty arthritis, relief
of acute musculoskeletal pain.

137. ACIDIC NSAIDS
INDOLE DERIVATIVES
INDOMETHACIN
 Introduced in 1963
 One of the most potent inhibitors of COX
 May also inhibit phospholipase A & C
 Reduce PMN migration
 Decrease T & B cells proliferation

138. INDOMETHACIN:
PHARMACOKINETICS
 Rapidly & almost completely absorbed from GIT
 Peak concentration: 2 hrs
 High bound to plasma proteins.
 Metabolism: liver & extensive enterohepatic
circulation
 Excretion: unchanged or as inactive metabolites
in bile, urine, feces

139. ACIDIC NSAIDS
INDOLE DERIVATIVES
INDOMETHACIN
 High potency of anti-inflammatory, analgesic,
and antipyretic activity.
 Used for ankylosing spondylitis, Osteoarthritis
(OA) and gout . Rheumatic conditions, Sweet’s
syndrome, Juvenile rheumatoid arthritis,
Pleurisy, Nephrotic syndrome & Tocolytic agent.
 Effective in treating patent ductus arteriosus.

140.  35%-50% of patients report some adverse
effects and most adverse effects are dose-
related.
 High incidence of adverse effects like:
Gastrointestinal complaints (abdominal pain,
diarrhea, GI hemorrhage, pancreatitis).
 Coronary vasoconstriciton also demonstrated.
INDOLE DERIVATIVES:
INDOMETHACIN

141.  Central nervous system effects: frontal
headache, dizziness, vertigo, mental confusion,
depression etc.
 Psychosis with hallucination.
 Hematopoietic reactions: neutropenia,
thrombocytopenia, impaired platelet functions,
rare aplastic anemia.
 Allergic reactions
 Hyperkalemia due to inhibition of PGs & its
INDOLE DERIVATIVES:
INDOMETHACIN

142.  Contraindication: in pregnancy or nursing
women, patients with psychiatric disorders,
epilepsy, parkinsonism, renal diseases, peptic
ulcers, Nasal polyps, Angioedema, Asthma,
Enterocolitis, hyperbilirubinemia and machine
operators.
INDOLE DERIVATIVES:
INDOMETHACIN

143. INDOMETHACIN: DRUG
INTERACTION
 Probenecid
 Furosemide
 Thiazide
 Beta adrenergic blocking agents

144.  Sulindac and Etodolac are less toxic and used
for OA, RA, SA and acute gout.
 A sulfoxide prodrug
 An acetic acid derivative
 Reversibly metabolized to active metabolite
sulfide → more potent as cyclooxygenase
inhibitor, enterohepatic recycling prolongs DOA:
12-16 hrs, excreted in bile and then reabsorbed
from intestine.
INDOLE DERIVATIVES: SULINDAC

145. SULINDAC: PHARMACOKINETICS
 90% absorbed after oral administration
 Peak concentration: 1 hr
 t1/2: 7 hrs
 First pass kinetics

146. SULINDAC: THERAPEUTIC
INDICATIONS
 Rheumatoid arthritis
 Suppresses familial intestinal polyposis
 Ankylosing spondylitis
 Osteoarthritis
 Acute Gout
 Tocolytic agent

147. SULINDAC: ADVERSE EFFECTS
 GI side effects: abdominal pain & nausea
 CNS side effects: drowsiness, dizziness, HA,
nervousness
 Skin rash & pruritus
 Transient elevations of hepatic enzymes

148. TOLMETIN
 A nonselective COX inhibitor
 Effective anti-inflammatory with analgesic &
antipyretic effects
 Has a short half-life: 5 hrs
 Given frequently  not often used
 Ineffective in gout  unknown
 SE: allergic IgM-related thrombocytopenic
purpura, GI & CNS effects

149. DICLOFENAC
 A simple phenylacetic acid derivative
 A potent non-selective cyclooxygenase inhibitor
 Decreases arachidonic acid bioavailability
 Has the usual anti-inflammatory, antipyretic &
analgesic properties

150. DICLOFENAC:
PHARMACOKINETICS
 Rapidly absorbed following oral administration
 99% protein bound
 30-70% systemic bioavailability  first pass
hepatic metabolism; t1/2: 1-2 hrs
 Accumulates in synovial fluid  t1/2 of 2-6 hrs
 Metabolized by CYP3A4 & CYP2C9
 30% biliary clearance, urine (65%)

151. DICLOFENAC: CLINICAL USES
 Any inflammatory conditions: Approved for long
term treatment of osteoarthritis, ankylosing
spondylitis & rheumatoid arthritis. It accumulates in
synovial fluid so cause healing of arthritis.
 Musculoskeletal pain
 Dysmenorrhoea
 Acute gouty arthritis
 Fever
 Locally to prevent or treat post opthalmic
inflammation

152. DICLOFENAC: ADVERSE EFFECTS
 GI distress; Occult GI bleeding; Gastric
ulceration
 It causes rise in hepatic enzymes level,
Elevates serum aminotransferases
 Renal impairment; Salt & water retention

153. DICLOFENAC: PREPARATIONS
 Diclofenac with misoprostol decreases upper
gastrointestinal ulceration ,but result in diarrhea.
 Diclofenac with omeprazole to prevent recurrent
bleeding.
 1% opthalmic preparation for postoperative
opthalmic inflammation.
 A topical gel 3% for solar keratoses.
 Rectal suppository as analgesic or for
postoperative nausea.
 Oral mouth wash.
 Intramuscular preparations.

154. ETODOLAC
 A racemic acetic acid derivative
 Slightly more COX-2 selective, with COX-2:COX-1
activity ratio of 10
 Clinical uses: postoperative analgesia,
osteoarthritis, rheumatoid arthritis
 SE:
GI irritation & ulceration (less)
Fluid retention, abnormal kidney and liver
functions are reported.
It may increase serum level & adverse effect of
digoxin, lithium, methotrexate, and enhance
nephrotoxicity of cyclosporines.

155. ETODOLAC: PHARMACOKINETICS
 Rapidly well absorbed
 80% bioavailability
 Strongly bound to plasma proteins (99%)
 Enterohepatic circulation
 t1/2: 7 hrs
 Dosage: 400-1600mg/d
 Excreted in the urine

156. KETOROLAC
 Potent analgesic with moderate anti-
inflammatory & antipyretic effects
 Inhibits platelet aggregation
 Promotes gastric ulceration & renal impairment
 Indications: postsurgical pain, chronic pain,
inflammatory conditions of the eye, seasonal
allergic conjunctivitis  topical

157. KETOROLAC: PHARMACOKINETICS
 Rapidly absorbed after oral or IM administration
 Also given IV
 Peak concentration: 30-50 min.
 80% oral bioavailability
 Almost totally protein bound
 t1/2: 4-6 hrs
 it is metabolized by liver, Metabolized to active
& inactive forms
 Excreted in the urine (90%)

158. PROPIONIC ACID DERIVATIVES:
(IBUPROFEN,NAPROXEN, FENOPROFEN,
KETOPROFEN, FLURBIPROFEN)
 Anti-inflammatory, analgesic and antipyretic
activity
 Less gastrointestinal effects
 Change platelet function and prolong bleeding
time
 Used for the treatment of various arthritis and
dysmenorrhea.

159. ARYLPROPIONIC ACID DERIVATIVES:
(IBUPROFEN, NAPROXEN, FENOPROFEN,
KETOPROFEN, FLURBIPROFEN)
 Ibuprofen and naproxen: Block COX-2
produces pain relief; inhibit COX-1 causes
adverse reactions, including unwanted GI
reactions such as stomach irritation and ulcers.
 Ibuprofen → hypertension, peptic ulceration, or
GI bleeding

160. IBUPROFEN
 A simple derivative of phenylpropionic acid
 Dose: 2400mg daily in anti-inflammatory; in
lower doses (<2400mg/d), at which it has
analagesic
 99% protein bound
 Rapidly cleared; Extensively metabolized in
CYP2C8 & CYP2C9 in the liver; Terminal t1/2:
1-2 hrs.

161. ADVERSE EFFECTS
 Gastric upset ( less frequent than aspirin ).
 Fluid retention: effects on kidney: renal failure,
nephritis, nephrotic syndrome.
 Hypersensetivity reactions
 Ocular disturbances
 Rare hematologic effects (agranulocytosis &
aplastic anaemia).

162. IBUPROFEN
 Indications: headache -common cold-
dysmenorrhoea -acute gout -rheumatoid
arthritis –osteoarthritis -ankylosing spondylitis -
musc. and joint pain -juvenile arthritis (new) -
post-operative pain. Patent ductus arteriosus.

163. IBUPROFEN
 CI: Nasal polyps, angioedema, bronchospastic
reactivity to ASA, rash, pruritus, tinnitus,
dizziness, HA, aseptic meningitis, fluid
retention, agranulocytosis, aplastic anemia,
ARF, interstitial nephritis, nephrotic symdrome
 Interaction: Coumarin (anticoagulant)
potentiates its effect.

164. NAPROXEN
 Is a naphthylpropionic acid. A nonselective COX
inhibitor.
 Antacids delay its absorption.
 High albumin binding
 Elimination serum t1/2: 13 hrs
 Metabolism: CYP2C9, less in CYP1A2 & CYP2C8.
 Excreted in urine as inactive glucuronid
metabolites
 Prep: SR formulation, oral susp.
 Competes with aspirin for plasma protein binding
sites & it prolong prothrombin time.

165. FENOPROFEN
 A propionic acid derivative
 t1/2: 2-4 hrs
 Given q.i.d. Dose for inflammatory arthritis =
600-800 mg 4 times daily.
 Toxic effect: interstitial nephritis
 Adverse effects: nephrotoxicity, nausea,
dyspepsia, peripheral edema, rash, pruritus,
CNS & CVS effects and tinnitus

166. FLURBIPROFEN
 A propionic acid derivative
 Inhibits COX nonselectively
 Also affect TNF-a & nitric oxide synthesis
 t1/2: 0.5-4 hrs
 Extensive hepatic metabolism
 Dosages: 200-400mg/day
 Ophthalmic formulation inhibition of
intraoperative miosis
 SE: GI symptoms, cogwheel rigidity, ataxia,
tremor & myoclonus

167. KETOPROFEN
 A propionic acid derivative
 Inhibits both cyclooxygenase (nonselective) &
lipoxygenase
 Rapidly absorbed
 Elimination t1/2: 1-3 hrs
 Metabolized in the liver (glucuronide)
 DI: probenicid
 Dosage: 100-300mg/day
 Indication: RA, OA, GA, dysmenorrhea
 AE: GIT & CNS

168. OXAPROZIN
 A propionic acid derivative
 t1/2: 50-60 hrs
 Does not undergo enterohepatic circulation
 Given o.d.
 Is a mild uricosuric agent

169. AN OXICAM DERIVATIVES
PIROXICAM
Mechanism of actions
 A non-selective COX inhibitor
 Also inhibits PMN leukocyte migration.
 Inhibits lymphocyte function.
 Decreases O2 radical production [Traps free
radicals].

170. PIROXICAM: PHARMACOKINETICS
 Used for rheumatoid disease and
musculoskeletal disorders.
 Dosing: Given once daily or every other day
 Rapidly absorbed from the stomach & upper
intestine
 Peak plasma concentration: 1 hr
 99% protein bound. Mean t1/2: 50-60 hrs
 Extensively metabolized to inactive metabolites
 Elimination: renal – 5% unchanged.

171. PIROXICAM: TOXICITY
 GI symptoms, increased incidence of PUD and
bleeding.
 Dizziness.
 Tinnitus.
 Headache & Allergy rash

172. PHENYLBUTAZONE
 A pyrazolone derivative
 Powerful anti-inflammatory effects
 Weak analgesic & antipyretic activities
 Introduction in 1949 for the treatment of
rheumatic syndromes
 Promote excretion of uric acid, Used for acute
gout
 Withdrawn from the market in North American &
most European markets

173. MECLOFENAMATE, FLUFENAMIC
ACID
& MEFENAMIC ACID
 Fenamic acid derivatives
 Inhibit both COX & phospholipase A2
 Peak plasma level: 30-60 min
 t1/2: 1-3 hrs
 SE: LBM, abdominal pain (meclofenamate)
 CI: pregnancy, children
 DI: oral anticoagulants

174. MECLOFENATE
 t1/2 = 2 hrs
 It reaches peak plasma conc. in 30–60 min after
administration. Excreted in urine.
 It has similar adverse effect to other NSAIDs,
with no advantage over time.
 It enhances effects of oral anti-coagulants.
 Contraindicated in pregnancy.
 Dose for inflammatory arthritis = 200-400
mg/day divided into 4 doses (qid).

175. MEFENAMIC ACID
 It has analgesics properties .
 It is less effective than aspirin as anti-
inflammatory agent .
 It is more toxic, not to be used for longer than 1
week & never used in children below 12 years.

176. TABLE: NSAIDS
Drug* High Risk Moderate
Risk
Low Risk
Aspirin X
Celecoxib X
Diclofenac X
Etodolac X
Flurbiprofen X
Ibuprofen X X
Indomethacin X X
Ketoprofen X
Ketorolac X
Meloxicam ** X
Nabumetone X
Naproxen X
Piroxicam X
Sulindac X
** Meloxicam risk increases with doses >7.5 mg.

177. DRUGS USED TO TREAT
RHEUMATOID ARTHRITIS
ANTIRHEUMATIC
DRUGS

178. RHEUMATOID ARTHRITIS

179. RHEUMATOID ARTHRITIS

180. THE MAJOR CLASSES
OF ANTIRHEUMATIC DRUGS
 Nonsteroidal Anti-Inflammatory Drugs:
Ibuprofen; naproxen; indomethacin .
 Corticosteroids:
Prednisone and dexamethasone.

181. THE MAJOR CLASSES
OF ANTIRHEUMATIC DRUGS
 Disease Modifying Anti-Rheumatic Drugs
(DMARDs)
Antimalarials:
Chloroquine and hydroxychloroquine.
Slow-Acting Antirheumatic Drugs
(SAARDs):
Aurothioglucose (gold salt).
Sulfasalazine [Used primarily in Europe]

182. THE MAJOR CLASSES
OF ANTIRHEUMATIC DRUGS
 Disease Modifying Anti-Rheumatic Drugs
(DMARDs) []
Immunosuppresive cytotoxic drugs:
Methotrexate,mechlorethamine,
cyclophosphamid, leflunomide, cyclosporine
A, chlorambucil, and azathioprine.
 Biologic response modifiers
Monoclonal antibody:
Etanercept, infliximab anti-TNF drugs, &
Anakinra

183. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES
 Chloroquine and hydroxychloroquine
Chloroquine and hydrochloroquine are
antimalarial drugs. Used to treat joint pain
associated with lupus and arthritis
These agents have immunosuppressant activity,
but their mechanism of action is unknown.
Suppress T lymphocytes; Decrease leukocytes
action
Stabilize lysosomal activity
Inhibits DNA& RNA synthesis

184. ADVERSE EFFECTS
 Hydroxychloroquine over chloroquine because
of decreased ocular toxicity
 Nausea & vomiting
 Cinchonism ( tinnitus. vertigo )
 Irreversible retinal damage
 Ototoxicity
 Corneal deposits
 Allergic skin reaction
 Hepatitis

185. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES.
 These agents have long latency may retard the
destruction of bone and joints by an
unknown mechanism.
Gold compounds:
Aurothioglucose and gold sodium
thiomalate are administered intramuscularly.
Auranofin is administered orally and is 95%
bound to plasma proteins.

186. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES
GOLD COMPOUNDS
Side effects:
 Serious:
 Gastrointestinal disturbances, dermatitis, and
mucous membrane lesions.
 Less common effects:
 Aplastic anemia
 Proteinuria
 Occasional:
 Nephrotic syndrome.

187. SULFASALAZINE
MECHANISM OF ACTION
 Through its active metabolite sulfapyridine &the
parent drug itself.
 Suppression of T cell .
 Inhibition of B cell proliferation

188. PHARMACOKINETICS
 Only 10-20% of orally administered sulfa is
absorbed.
 Fraction undergoes enterohepatic circulation
into the bowel.
 Reduced by intestinal bacteria to liberate 5-
aminosalicylic acid

189. PHARMACOKINETICS
 And sulfapyridine which is well absorbed while
5-aminosalicylic remains unabsorbed.
 Excreted partly unchanged as sulfasalazine in
urine
 Sulfapyridine metabolized in liver by acetylation
&hydroxylation
 Half-life 6-17 hours.

190. CLINICAL USES
 Rheumatoid arthritis reduce the rate of
appearance of new joint damage.
 Juvenile chronic arthritis
 Ankylosing spondylitis.

191. ADVERSE EFFECTS
 Nausea, vomiting
 Headache
 Skin rash
 Hemolytic anemia
 Methemoglobinemia
 Reversible infertility in men
 Neutropenia & thrombocytopenia (rare)

192. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES
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.

193. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES
METHOTREXATE
Mechanism of action
 Dihydrofolate reductase inhibitor
 Immunosuppressive agent
Uses
 Methotrexate is an antineoplastic drug used for
rheumatoid arthritis that does not respond
well to NSAIDs or glucocorticoids.

194. ANTI-INFLAMMATORY DRUGS ARE
USED IN RHEUMATOID DISEASES
METHOTREXATE
Adverse effects
 Nausea
 Mucosal ulcers
 Bone marrow depression which can be
reversed by leucovorin.
 Methotrexate commonly produces
hepatotoxicity is dose related.

195. LEFLUNOMIDE
 Immunosuppressive drug used in the treatment
of Rheumatoid arthritis can be given with
methotrexate
 Undergoes rapid conversion in intestinal
mucosa & plasma to active metabolities.

196. PHARMACOKINETICS
 Orally effective
 Highly bound to plasma proteins
 Half-life 15 days
 Cholestyramine increases its clearance

197. MECHANISM OF ACTION
 Inhibits dihydroorotate dehydrogenase which
lead to inhibition of ribonucleotide synthesis &
arrest the stimulated cells in G1 phase.
 Inhibits T cell proliferation & production of
autoantibodies by β cells.
 Increase interleukin 10 receptor mRNA.
 Decrease interleukin 8 receptor type A m RNA.
 Decrease TNF-α- dependent NFkB

198. ADVERSE EFFECTS
 Diarrhea
 Elevated liver enzymes
 Mild alopecia
 Weight gain
 Increased blood pressure
 Leukopenia & thrombocytopenia
 Not recommended for patients with
Immunodeficiency
Bone marrow disorder
Severe, uncontrolled infections
 Contraindicated in pregnancy

199. AZATHIOPRINE
 6-Mercaptopurine derivative
Mimics precursor of GTP
Interferes with biosynthesis of DNA
 Effectiveness in RA not clear
Major toxicities include bone marrow
depression and increased incidence of
infection

200. CYCLOPHOSPHAMIDE
 A nitrogen mustard alkylating agent
Kills rapidly proliferating cells, e.g., a
stimulated immune system
Lymphocytes are significantly more sensitive
to cyclophosphamide than to other alkylating
agents
Somewhat effective in RA but not a first drug
of choice because of toxicity (NV &
hemorrhagic cystitis)

201. ANTI-TNF-ΑLPHA DRUGS
Tumor Necrosis Factor
TNF-α is responsible for inducing IL-1 and IL-6
and other cytokines that further the disease

202. ROLE OF TUMOR NECROSIS
FACTOR IN
RHEUMATOID ARTHRITIS
TNF
Bone resorption
Bone erosion
Joint
inflammation
Cartilage
degradation
Joint space
narrowing
Pain/joint
inflammation

203. ANTI-TNF-ΑLPHA DRUGS
INFLIXIMAB:
 Monoclonal antibody 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, Ulcerative colitis, psoriatic
arthritis, and other autoimmune diseases
[Giant cell arteritis & Sarcoidosis]

204. ANTI-TNF-ΑLPHA DRUGS
INFLIXIMAB:
 Half-life 8-12 days; Administered by IV
infusion at 2-week intervals initially and
repeated at 6 and 8 weeks
 Can be used in combination with
methotrexate reduce the prevalence of
human antichimeric antibodie
 Improvement reaches up to 60%

205. ADVERSE EFFECTS
 Upper respiratory tract infections.
 Cough.
 Nausea.
 Headache.
 Rash.
 Activate latent tuberculosis
 Infusion site reaction

206. ANTI-TNF-ΑLPHA DRUGS
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.

207. ANTI-TNF-ΑLPHA DRUGS
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.
 SC injection: Injection site infections are

208. ANTI-IL1 DRUGS
Anakinra is a recombinant protein essentially
identical to IL-1a, 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.

209. IMMUNOTHERAPEUTIC TREATMENT
OF RHEUMATOID ARTHRITIS
Use
Molecular
Target
Characteristic
Drug
Rheumatoid arthritis
Plasma &
tissue TNF-α
Anti-TNF-α
antibody
Adalimumab
Rheumatoid
arthritis, Crohn's
disease, uveitis,
psoriasis
Plasma &
tissue TNF-α
Anti-TNF-α
antibody
Infliximab
Rheumatoid
arthritis, psoriasis
Plasma &
tissue TNF-α
TNF-receptor
fusion protein
Etanercept
Rheumatoid arthritis
Interleukin-1
Recombinant
Anakinra

210. BOTTOM LINE
 Gold & Glucocorticoids
to
 NSAIDs &/or Glucocorticoids
to
 NSAIDs &/or Glucocorticoids + Methotrexate
to
 EITHER/OR
Methotrexate + TNFa/Abatacept
Methotrexate + NSAIDs &/or Glucocorticoids