Analgesic, Antipyretic

and
Antiinflammatory
agents
 NSAIDs
 Antipyretic, analgesic, & anti-inflammatory agents
 As antipyretics
 Reduce body temperature in febrile states
 As analgesics
 Relieve mild to moderate pain such as dental pain,
dysmenorrhea, and headache. Unlike the opioid
analgesics, they do not cause neurological depression or
dependence.
 As anti-inflammatory agents
 Used to treat conditions such as musculo-skeletal
inflammatory condition
 MOA (NSAIDs)
 Anti-inflammatory
 Inhibits cycloxygenase (COX) enzyme and hence
prostaglandin synthesis
 COX-1 is a primarily constitutive in most normal cells
and tissues,
 COX-2 is induced isoform but is also constitutively
expressed in certain areas of kidney and brain.
 MOA (NSAIDs)
 NSAIDs do not inhibit the lipoxygenase pathways of AA
metabolism and hence do not suppress Leukotriene
formation.
 All NSAIDs, with the exception of Aspirin, are
competitive inhibitors of COX. Aspirin irreversibly
acetylates the enzyme
 Duration of aspirin's effects is related to the turnover rate of
cyclooxygenases in different target tissues. While that of the
non-aspirin NSAIDs relates more directly to the time course of
drug disposition.
 Analgesic
 When inflammation causes sensitization of pain
receptors to normally painless mechanical or
chemical stimuli. Pain that accompanies
inflammation and tissue injury results from local
stimulation of pain fibers and enhanced pain
sensitivity (hyperalgesia)
 Bradykinin & cytokines (such as TNF-, IL-1, and IL-8)
are important in eliciting the pain of inflammation.
Liberate PGs that promote hyperalgesia.
Neuropeptides (substance P & calcitonin gene-related
peptide), also may be involved in eliciting pain.
 Antipyretic
 Some conditions enhance formation of cytokines
such as IL-1b, IL-6, interferons, and TNF-. This
increases the synthesis of PGE2 which in turn,
increases cAMP & triggers the hypothalamus to
elevate body temperature by promoting an increase
in heat generation and a decrease in heat loss
 Therapeutic uses (NSAIDs)
 All NSAIDs are antiinflammatory, antipyretic and
analgesic, with the exception of acetaminophen, which
is largely devoid of antiinflammatory activity
 Analgesic
 Effective only in pain of low-to-moderate intensity

 Have less maximal efficacy than opiates but lack the

unwanted adverse effects of opiates
 Not useful in pain arising from the hollow viscera
 Antipyretic
 Reduce fever in most situations, but not the circadian variation in
temperature or the rise in response to exercise or increased
ambient temperature

 Anti-inflammatory
 In the treatment of musculoskeletal disorders, such as rheumatoid
arthritis and osteoarthritis.
 Generally provide only symptomatic relief from pain and
inflammation associated with the disease, do not arrest the
progression of pathological injury
 For the treatment of ankylosing spondylitis and gout.
 Adverse Effects of NSAID Therapy
 Gastrointestinal
 Anorexia, nausea, dyspepsia, abdominal pain, and
diarrhea
Related to the induction of gastric or intestinal ulcers

 Two proposed mechanisms for the GI ulceration

1.Inhibition of COX-1 in gastric epithelial cells depresses
synthesis of PGI2 and PGE2
2.Direct local irritation of gastric mucosa
 Adverse Effects of NSAID Therapy (cont’d)
 Cardiovascular
 Aspirin is associated with cardioprotection

 Use of COX-2-Selective inhibitors is associated with

increased cardiovascular hazards
They depress PGI2 formation by endothelial cells without

concomitant inhibition of platelet thromboxane

PGI2 seems to restrain the CVS effects of TXA2

 Adverse Effects of NSAID Therapy (cont’d)

 Renal & renovascular adverse events

 Loss of PG-induced inhibition of reabsorption of Cl-
and the action of ADH
Retention of salt and water

 COX-2 inhibition in kidney attributed for ed

generation of vasodilator PGs (PGE2 and PGI2)
Raise the likelihood of hypertensive complications
 Drug interactions
 Reduce effectiveness of ACE inhibitors by
blocking production of prostaglandins
 May increase GI ulceration when combined with
corticosteroids
 Augment risk of bleeding in patients on warfarin
 Pharmacokinetics & Pharmacodynamics

 Most are rapidly & completely absorbed from the GIT

 Aspirin begins to acetylate platelets within minutes of

reaching the presystemic circulation.
 Most are extensively protein-bound (95% to 99%)
 Salicylates
 Salicylic acid is irritating  only used externally

 Derivatives synthesized for systemic use

 Esters of salicylic acid (SA)

 Salicylate esters of organic acids

 Salts of salicylic acid

Salicylates
 Pharmacological Properties
 Analgesia and antipyresis

 Respiration
 Increase O2 consumption and CO2 production which

in turn increases respiration

 Cardiovascular Effects
 Low doses of aspirin (<100 mg daily) used widely for
their cardioprotective effects.
 At high therapeutic doses (>3 g daily) salt and water
retention can lead to plasma volume expansion
Cardiac output and work are increased.

CHF and pulmonary edema in patients with compromised

cardiac function
 Gastrointestinal Effects
 Epigastric distress, nausea, and vomiting, gastric
ulceration, exacerbation of peptic ulcer symptoms,
gastrointestinal haemorrhage, and erosive gastritis

 Effects on the Blood

 Prolongs the bleeding time
 Patients with hypoprothrombinemia, severe hepatic
damage, vitamin K deficiency, or hemophilia should
avoid aspirin  due to risk of haemorrhage
 Salicylates and Pregnancy.
 No evidence of teratogenicity of moderate
therapeutic doses of salicylates
 Avoid administration during the third trimester as
they may cause
Prolonged gestation and complicated deliveries

Premature closure of the ductus arteriosus

 Local Irritant Effects
 SA is irritating to skin and mucosa and destroys
epithelial cells.
 Its keratolytic action employed for the treatment of
fungal infections, and certain types of eczematous
dermatitis.
 Pharmacokinetics
 Absorption
 Is rapid on oral ingestion (from the stomach & upper small
intestine)
 Is influenced by pH
 Distribution
 Well distributed throughout most body tissues
 80% to 90% is bound to plasma proteins
 Hypoalbuminemia, as may occur in rheumatoid arthritis, is
associated higher level of free salicylate in the plasma
 Compete for plasma protein binding sites with drugs
including T4, T3, penicillin, phenytoin, sulfinpyrazone, bilirubin,
uric acid, naproxen....
 Ellimination
 Biotransformed mainly in the liver

 Excreted in the urine as free salicylic acid (10%) and

various metabolites (90%)
 Urinary excretion of free salicylates depends on the
pH of urine
More than 30% in alkaline urine and

As low as 2% in acidic urine

 Therapeutic uses
 Systemic uses
 Antipyresis
 Analgesia
 Rheumatoid arthritis
 Local use
 Inflammatory bowel syndrome
 Adverse Effects
 GI disturbance (most common)
 Occult blood loss from the GI tract, peptic ulceration, and rarely, severe GI
hemorrhage
 The nonacetylated salicylates have reduced effects on blood loss and
produce fewer adverse GI effects

 In toxic doses tinnitus, hearing impairment, blurred vision, and

light-headedness may occur
 Salicylates are contraindicated in children with febrile viral
illnesses because of a possible increased risk of Reye’s syndrome
 Para-Aminophenol Derivatives:
Acetaminophen
 AKA paracetamol; N-acetyl-p-aminophenol; TYLENOL

 It is an effective alternative to aspirin as an analgesic-

antipyretic agent; however, its antiinflammatory effects
are much weaker
 Acetaminophen is well tolerated and has a low
incidence of GI side effects.
 Pharmacological Properties
 It has analgesic & antipyretic effects similar to those
of aspirin.
 It has only weak antiinflammatory effects due to a
generally poor ability to inhibit COX
 Its antipyretic efficacy
 Disproportionately pronounced COX inhibition in the brain
 COX-3 (a COX-1 splice variant identified in canine brain)
shows some susceptibility for inhibition by acetaminophen
in vitro
 Pharmacological properties (cont’d)
 Single or repeated therapeutic doses of paracetamol
have no effect on the CV and respiratory systems, on
platelets, or on coagulation. Acid-base changes,
uricosuric effects, gastric irritation, erosion, or
bleeding do not occur in contrast to salicylates.
 Pharmacokinetics
 has excellent oral bioavailability

 Relatively uniformly distributed throughout

most body fluids
 Only 20% to 50% is protein bound at the
concentrations encountered during acute
intoxication
 Therapeutic Uses
 A suitable substitute for aspirin for analgesic or
antipyretic uses; especially when aspirin is
contraindicated (peptic ulcer, aspirin
hypersensitivity, children with a febrile illness)
 Toxicity and Common Adverse Effects
 well tolerated at therapeutic doses.

 Rash and other allergic reactions occur

occasionally.
 Neutropenia, thrombocytopenia

 Overdosage causes a potentially fatal hepatic

necrosis
 Acetic acid derivatives
 Indomethacin
 Antiinflammatory, analgesic, and antipyretic
 A more potent inhibitor of the COX than is aspirin
 Analgesic effects distinct from its antiinflammatory
properties (central and peripheral actions)
 It also inhibits the motility of polymorphonuclear
leukocytes
 Pharmacokinetics
has excellent Oral bioavailability
90% bound to plasma proteins and tissues
 Indomethacin
 Therapeutic uses
 In the treatment of acute gouty arthritis, rheumatoid arthritis,
ankylosing spondylitis, and osteoarthritis
 Not recommended for use as a simple analgesic or antipyretic
 For closure of persistent patent ductus arteriosus

 Adverse effects
 Gastrointestinal: Diarrhea, Underlying PUD is a contraindication,
 Acute pancreatitis, hepatitis
 CNS effect (frontal headache, Dizziness, vertigo, light-headedness,
Seizures, confusion, severe depression, psychosis, hallucinations, and
suicide)
 Hematopoietic (neutropenia, thrombocytopenia, and aplastic anemia)
 Sulindac
 Pharmacological Properties
Less than half as potent as indomethacin
It is a prodrug which needs to be changed to the sulfide
metabolite which is more than 500 times more potent than
sulindac as an inhibitor of cyclooxygenase
Low incidence of GI toxicity with sulindac as compared with
indomethacin
 Therapeutic Uses
Treatment of rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, and acute gout.
 Adverse effects
GI pain, nausea, diarrhea, and constipation (most frequent)
 As with indomethacin, a high incidence of CNS effects are seen
 Etodolac
 Pharmacological properties
Has some degree of COX-2 selectivity
Gastric irritation is less than with other NSAIDs
It is rapidly and well absorbed orally.
It is highly bound to plasma protein
half-life in plasma is about 7 hours.
 Therapeutic uses
Postoperative analgesia (lasts for 6 to 8 hours)
Treatment of osteoarthritis and rheumatoid arthritis
 Adverse effects
Relatively well tolerated.
Gastrointestinal effects, rashes, and CNS effects.
 The Fenamates
 They are derivatives of N-phenylanthranilic acid
 Mefenamic, meclofenamic, and flufenamic acids

 They have no clear advantages over other NSAIDs and

frequently cause GI side effects
 Used mostly in the short-term treatment of pain in soft-
tissue injuries, dysmenorrhea, and in rheumatoid and
osteoarthritis
 Not recommended in children or pregnant women
 Fenamates (cont’d)
 Pharmacological Properties
 Mefenamic acid has central and peripheral actions, and
meclofenamic acid may directly antagonize certain effects of PG
 Pharmacokinetic Properties
 Absorbed rapidly and have short durations of action.
 Common Adverse Effects and Precautions
 Gastrointestinal
 Reversible elevation of hepatic transaminases
 Diarrhea is relatively common.
 Hemolytic anemia is a potentially serious but rare side effect.
 Contraindicated in patients with a history of gastrointestinal
disease.
 Discontinue If diarrhea or rash occur
 Tolmetin, Ketorolac, and
Diclofenac
 Tolmetin and ketorolac  heteroaryl acetic
acid derivatives
 Diclofenac  phenylacetic acid derivative
 Tolmetin
 Pharmacokinetics and Metabolism
 Rapidly & completely absorbed, extensive plasma protein binding, &
short half-life
 It undergoes extensive hepatic metabolism

 Therapeutic Uses
 For the treatment of osteoarthritis, rheumatoid arthritis, and juvenile
rheumatoid arthritis, ankylosing spondylitis.
 Have similar therapeutic efficacy to aspirin

 Common Adverse Effects

 GI side effects are the most common (15%)
 CNS side effects similar to those seen with indomethacin and aspirin,
but they are less common and less severe.
 Ketorolac
 Potent analgesic, a moderately effective antiinflammatory
drug.
 Pharmacological Properties
 More analgesic than antiinflammatory.

 Inhibits platelet aggregation and promotes gastric ulceration.

 Has antiinflammatory activity when topically administered in the eye

 Pharmacokinetics and Metabolism

 Ketorolac has a rapid onset of action, extensive protein binding, and a
short duration of action
 Oral bioavailability of about 80%.
 Ketorolac (cont’d)
 Therapeutic Uses
 Short-term alternative (less than 5 days) to opioids for the treatment
of moderate to severe pain and is administered intramuscularly,
intravenously, or orally.
 In postoperative patients

 Treatment of seasonal allergic conjunctivitis and postoperative ocular

inflammation after cataract extraction.

 Common Adverse Effects

 Somnolence, dizziness, headache, gastrointestinal pain, dyspepsia,
nausea, and pain at the site of injection.
 Diclofenac
 Diclofenac is the most commonly used NSAID in Europe

 Pharmacological Properties
 Its potency against COX-2 is greater than that of several NSAIDs.

 Appears to reduce intracellular concentrations of free AA in

leukocytes
 Possible increase in CV hazard from chronic therapy

 Pharmacokinetics
 Rapid absorption, extensive protein binding, short half-life

 Substantial first-pass effect (systemic availability of about 50%)

 Diclofenac accumulates in synovial fluid

 Diclofenac (Cont’d)
 Therapeutic Uses
 Long-term symptomatic treatment of rheumatoid arthritis,
osteoarthritis, and ankylosing spondylitis.
 Short-term treatment of acute musculoskeletal pain, postoperative
pain, and dysmenorrhea.
 In combination with misoprostol (reduces the frequency of GI ulcers)
 Treatment of postoperative inflammation following cataract
extraction
 Common Adverse Effects
 GI (20%)
 Modest, usually reversible, elevation of hepatic transaminases
(Bromfenac withdrawn due its severe, irreversible liver injury)
 CNS effects, rashes, allergic reactions, fluid retention, and edema, and
rarely impairment of renal function.
 Not recommended for children, nursing mothers, or pregnant women.
 Propionic Acid Derivatives
 Used as an analgesic and antipyretic as well as in
symptomatic treatment of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, and acute gouty
arthritis.
 They are comparable in efficacy to aspirin for the
control of the signs and symptoms of rheumatoid
arthritis and osteoarthritis, perhaps with improved
tolerability
 Include Ibuprofen, naproxen, fenoprofen, ketoprofen
flurbiprofen, and oxaprozin....
 Pharmacological Properties
 All are nonselective COX inhibitors with effects and
side effects common to other NSAIDs.
 Particularly naproxen, have prominent inhibitory
effects on leukocyte function
 Drug Interactions
 May interfere with the action of antihypertensive
and diuretic agents, increase the risk of bleeding
with warfarin, and increase the risk of bone marrow
suppression with methotrexate.
 Ibuprofen
 Pharmacokinetics
Absorbed rapidly, bound avidly to protein, and
undergoes hepatic metabolism and renal excretion of
metabolites.
 Common Adverse Effects
Better tolerated than aspirin and indomethacin
GI adverse effects
Other less frequent adverse effects include
thrombocytopenia, rashes, headache, dizziness, blurred
vision, and in a few cases toxic amblyopia, fluid retention,
and edema.
Discontinue if ocular disturbances develop
 Naproxen
 Pharmacokinetics
Absorbed fully when administered orally.
The half-life of naproxen in plasma is variable (14 hours in
the young, it may increase about twofold in the elderly)
Is almost completely (99%) bound to plasma proteins

 Common Adverse Effects

GI adverse effects (approximately same frequency as with
indomethacin, but with less severity).
CNS side effects (drowsiness, headache, dizziness,
sweating, fatigue, depression, and ototoxicity)
 Enolic Acids (Oxicams)
 Nonselective COX inhibitors
 Exception: meloxicam has modest COX-2 selectivity
(approved as a selective COX-2 inhibitor in some
countries).

 Have long half-life, which permits once-a-day

dosing
 Piroxicam
 Pharmacological Properties
It can inhibit activation of neutrophils (independent of COX
inhibition)
Inhibition of proteoglycanase and collagenase in cartilage
(additional mode of antiinflammatory action)
 Pharmacokinetics and Metabolism
Absorbed completely after oral administration
Undergoes enterohepatic recirculation;
The half-life in plasma averages to about 50 hours.
It is extensively (99%) bound to plasma proteins.
Concentrations in plasma and synovial fluid are similar at steady
state
 Therapeutic Uses
Rheumatoid arthritis, osteoarthritis (approved in the USA)
less suitable for acute analgesia but has been used in acute
gout.
Caution in patients taking lithium (it reduces the renal excretion
of lithium)
 Pyrazolon Derivatives
 Include phenylbutazone, antipyrine, dipyrone,
oxyphenbutazone, and aminopyrine
 Their use has decreased because of their
propensity to cause blood dyscrasias.
 Only antipyrine, used in as otic drops is available in
the US today
 Phenylbutazone is used in Canada, and dipyrone is
used in some European countries.
 COX-2 Selective NSAIDs
 Non-selective COX inhibitors
 Cause frequent GI side effects due to significant
inhibition of cytoprotective PGs synthesized by the
COX-1 enzyme
 Selective COX-2 inhibitors
 Do not affect the house keeping activity of COX-1
 Inhibits COX-2 which is believed to be dominant in
inflammatory sites and cancers.
 Hence, drugs cause inhibition of PG synthesis in
inflammatory sites while the gastric cytoprotective
function of PG is left intact
 COX-2 Selective NSAIDs (cont’d)
 Several older drugs such as nimesulide, diclofenac,
and meloxicam exhibit relative selectivity for COX-2
inhibition
 Rofecoxib and valdecoxib have been withdrawn
from the market
 Two others, parecoxib and etoricoxib, are approved
in Europe
 Lumiracoxib is under consideration for approval in
Europe and the US.
 The relative degree of selectivity for COX-2
inhibition is lumiracoxib = etoricoxib > valdecoxib =
rofecoxib >> celecoxib
 Celecoxib
 Pharmacokinetics
 bioavailability of oral celecoxib is not known, but tmax is 2 to 4 h
 bound extensively to plasma proteins.
 Little drug is excreted unchanged; most is excreted as carboxylic acid
and glucuronide metabolites in the urine and feces.
 Pharmacological Properties and Adverse Effects
 Hypertension and edema due to inhibition of PG production in the
kidney (with the nonselective COX inhibitors and coxibs).
 Degree of COX-2 inhibtion and the selectivity with which it is attained
suggest the likelihood of hypertension due to NSAIDs
 Coxibs avoided in patients prone to CV or cerebrovascular disease.
 Therapeutic Uses
 treatment of osteoarthritis and rheumatoid arthritis (in the US)
 Use the lowest possible dose for the shortest possible time
 Evidence does not support use of coxibs as first choice
 Valdecoxib
 Pharmacokinetics.
 Absorbed rapidly (1 to 2 hours),
 It undergoes extensive hepatic metabolism
 The half-life is approximately 7 to 8 hours but can be significantly
prolonged in the elderly or those with hepatic impairment
 Pharmacological Properties, Adverse Effects, and.
 Cause fewer endoscopically demonstrable lesions than other NSAIDs.
L
 Can elevate blood pressure in predisposed individuals .
 Its use associated with a threefold increase in CV risk (should be
avoided in patients prone to heart attack and stroke).
 Also liked to Stevens-Johnson syndrome
 Has been withdrawn from the market
 Therapeutic Uses
 Osteoarthritis, adult rheumatoid arthritis, and primary dysmenorrhea.
 Moderate to severe acute pain
 Decreases postoperative opioid requirements substantially
 Use of COX-2-Selective inhibitors is associated
with increased cardiovascular hazards
They depress PGI2 formation by endothelial cells

without concomitant inhibition of platelet

thromboxane

PGI2 seems to restrain the CVS effects of TXA2

 Miscellaneous
 Apazone (Azapropazone)
 Possess antiinflammatory, analgesic, and antipyretic
 Also a potent uricosuric agent.
 Inhibit neutrophil migration, degranulation, and superoxide
production
 Therapeutic use
 Treat’t of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
and gout, but usually is restricted to cases where other NSAIDs have
failed.
 Adverse effects
 Mild GI side effects (nausea, epigastric pain, dyspepsia), rashes, less
frequent CNS effects (headache, vertigo)
 Precautions appropriate to other nonselective COX inhibitors also
apply.
 Nimesulide
 It is an antiinflammatory, analgesic, and antipyretic

 Demonstrates COX-2 selectivity similar to celecoxib

 Also activates neutrophil, decreases cytokine

production, decreases degradative enzyme
production, and possibly activates glucocorticoid
receptors.
 Associated with a low incidence of GI adverse effects
 Drugs used
in
Rheumatoid Arthritis
 Rheumatoid Arthritis
 Is the most common chronic systemic inflammatory
disease characterized by involvement of joints.
 Extra-articular involvement including rheumatoid
nodules, vasculitis, eye inflammation, neurological
dysfunction, cardiopulmonary disease,
lymphadenopathy, and spleenomegaly are
manifestations of the disease.
 Pathophysiology
 Chronic inflammation of the synovial tissue lining
the joint capsule results in the proliferation of this
tissue which invades the cartilage and eventually
the bone surface
Erosion of bone and cartilage  destruction of the joint.

 The ability of the immune system to differentiate

between self and non-self is lost and attacks
synovial and other connective tissues
 Pathophysiology (cont’d)
 End results of the chronic inflammation
Loss of cartilage results in loss of the joint space

Formation of scar tissue leads to loss of joint motion or

bony fusion (known as ankylosis)
Tendon contracture leads to chronic deformity
 Drug Therapy
 There is no curative agent available for RA
1. NSAID
 Alleviate the pain and inflammation of RA

 Do not halt the loss of bone associated with RA

2. Disease modifying antirheumatic drugs (DMARD)

 Slow the progression of joint erosion
Disease modifying
antirheumatic drugs
(DMARD)
 Methotrexate
 Basic Pharmacology
 Inhibits DHFR & other folate-dependent enzymes

 Inhibits folate-dependent enzymes in adenosine

degradation
ed adenosine  acts on cell surface receptors to inhibit
the production of TNF- and IFN-

 es the production of inflammatory prostaglandins

and proteases (does not affect COX)
 Therapeutic use
 Treatment of RA and psoriasis, psoriatic arthritis,
systemic lupus erythematosus.
 Also used as an anticancer and immunosuppressive

It is generally as efficacious as the other agents, with a

low incidence of serious side effects when
 Adverse effects
 Nausea, stomatitis, GI discomfort, rash, diarrhea, and
headaches.
 Immunosuppression

 Severe toxicities: cirrhosis, pulmonary fibrosis, and bone

marrow depression.
 Folic acid supplementation alleviates certain side effects but
contributes to resistance to methotrexate therapy
 Contraindications
 Pregnancy and breast-feeding (teratogenic)

 kidney, liver, and lung disease, moderate to high alcohol use,

immunodeficiency, blood dyscrasias

 Drug Interactions
 Its clearance decreased by NSAIDs

 Displaced from plasma protein binding sites by

phenylbutazone, phenytoin, sulfonylureas, and sulfonamides
 Additive antifolate effect with folate-inhibitory drugs
 Chlorambucil
 Mechanism of Action & Pharmacokinetics
 Probably through its metabolite phenylacetic acid
mustard, cross-links DNA, thereby preventing cell
replication.
 Indications
 RA, systemic lupus erythematosus, vasculitis, and
other autoimmune disorders

 Adverse Effects
 Bone marrow suppression, Infertility, ed risk of
neoplasia
 Cyclophosphamide
 Mechanism of Action
 Its major active metabolite, phosphoramide mustard, cross-
links DNA to prevent cell replication.
 It suppresses T cell and B cell function

 Pharmacokinetics
 The plasma half-life is 6.5 hours

 Only 10 to 15% of the circulating parent drug is protein

bound, whereas 50% of the alkylating metabolites are bound
to plasma proteins.
 Indications
 RA, systemic lupus erythematosus, vasculitis,
Wegener's granulomatosus, and other severe
rheumatic diseases.

 Adverse Effects
 Infertility in both men and women, bone marrow
suppression, alopecia
 Cyclosporine
 Mechanism of Action
 Inhibits IL-1 and IL-2 receptor production and
secondarily inhibits macrophage-T cell interaction
and T cell responsiveness
 T cell-dependent B cell function is also affected

 Pharmacokinetics
 Erratic and incomplete absorption
 Indications
 RA, systemic lupus erythematosus, Wegener's
granulomatosis, and juvenile chronic arthritis.
 Adverse Effects
 Significant nephrotoxicity (toxicity increased by drug
interactions with diltiazem, potassium-sparing
diuretics, and other drugs inhibiting CYP3A). Other
toxicities include hypertension, hyperkalemia,
hepatotoxicity, gingival hyperplasia, and hirsutism.
 Azathioprine
 Mechanism of Action
 Acts through its major metabolite, 6-thioguanine, which
suppresses inosinic acid synthesis, B cell and T cell
function, immunoglobulin production, and IL-2 secretion
 Pharmacokinetics
 Rapid metabolizers Vs slow metabolizers.
 Production of 6-thioguanine is dependent on thiopurine
methyltransferase
 Indications
 RA, psoriatic arthritis, systemic lupus erythematosus, and
Behget's disease
 Adverse Effects
 Bone marrow suppression, GI disturbances, lymphomas.
Rarely, fever, rash, and hepatotoxicity
 Chloroquine & Hydroxychloroquine
 Mechanism of Action
 Antimalarial agents
 Unclear mechanism of the anti-inflammatory action in
rheumatic diseases
 Suppression of T lymphocyte responses to mitogens, decreased
leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition
of DNA and RNA synthesis, & trapping of free radicals.
 Pharmacokinetics
 Rapidly absorbed, only 50% protein-bound in the plasma,
extensively tissue-bound, particularly in melanin-containing
tissues such as the eyes.
 Have blood elimination half-lives of up to 45 days.
 Indications
 RA, skin manifestations, and joint pains of systemic
lupus erythematosus, Sjögren's syndrome.

 Adverse Effects
 ocular toxicity, dyspepsia, nausea, vomiting,
abdominal pain, rashes, and nightmares.
 appear to be relatively safe in pregnancy
 Gold compounds
 Used infrequently due to their toxicity
 Elemental gold content:
 IM formulations (aurothiomalate & aurothioglucose)  50%
 Oral formulation (auranofin)  29%
 Mechanism of Action
 alter the morphology and functional capabilities of
macrophages
 Monocyte chemotactic factor-1, IL-8, IL-1 production, and VEGF are all
inhibited.
 IM formulations alter lysosomal enzyme activity, reduce histamine
release, & suppress the phagocytic activities of PMN leukocytes.
 Pharmacokinetics
 Have high bioavailability after IM administration
 IM gold's half-life is approximately 1 year.
 Indications
– RA, Sjögren's syndrome, juvenile rheumatoid
arthritis.
 Adverse Effects
 Pruritic skin rashes, Stomatitis, metallic taste in the
mouth
 Hematologic abnormalities (thrombocytopenia,
leukopenia, pancytopenia, Aplastic anemia)
 Proteinuria
 Sulfasalazine
 Mechanism of Action
 Metabolized to sulfapyridine and 5-aminosalicylic acid
 IgA and IgM rheumatoid factor production are
decreased
 Suppression of T cell responses to concanavalin and
inhibition of in vitro B cell proliferation
 Pharmacokinetics
 10–20% Absorbed from oral administration
 Reduced by intestinal bacteria  sulfapyridine + 5-
aminosalicylic acid.
Sulfapyridine is well absorbed while 5-aminosalicylic acid
remains unabsorbed
 Halflife is 6–17 hours
 Indications
 RA, juvenile chronic arthritis and ankylosing spondylitis and
its associated uveitis.

 Adverse Effects
 nausea, vomiting, headache, and rash

 Hemolytic anemia and methemoglobinemia, Neutropenia,

thrombocytopenia (rare)
 Reversible infertility in men, but does not affect fertility in
women
 Leflunomide
 Mechanism of Action
 Rapidly converted (in the intestine and in the
plasma), to its active metabolite, A77-1726.
Inhibits dihydroorotate dehydrogenase  ed
ribonucleotide synthesis and arrest of cell growth.
Inhibits T cell proliferation and production of
autoantibodies by B cells.
ed TNF--dependent NFB activation.
 Pharmacokinetics
– Completely absorbed with mean plasma t½ of 19
days.
– A77-1726 is subject to enterohepatic recirculation
and is efficiently reabsorbed.
 Indications
 RA

 Adverse Effects
 Diarrhea or loose bowels

 Elevation in liver enzymes

 Mild alopecia, weight gain, and increased blood

pressure. Leukopenia and thrombocytopenia (rare)
 Contraindicated in pregnancy
 TNF- Blocking Agents
 Cytokines play a central role in the immune response
and in RA
 TNF-  plays central role in RA inflammatory process.

 TNF- acts via membrane-bound TNF receptors (TNFR1,

TNFR2)
 Drugs
 Soluble TNF receptors

 Monoclonal anti-TNF antibodies

 Adalimumab
 Mechanism of Action
 It is a recombinant human anti-TNF monoclonal antibody

 It complexes with soluble TNF-  and prevents its

interaction with p55 and p75 cell surface receptors
Resulting in down-regulation of macrophage and T cell function

 Pharmacokinetics
 Administered subcutaneously

 half-life of 9–14 days.

 Indications
 RA (monotherapy and in combination with
methotrexate).
 Dose is 40 mg every other week

 Adverse Effects
 Risk of macrophage-dependent infections (including
TB and other opportunistic infections).
 Rare: leukopenias and vasculitis
 Infliximab
 Mechanism of Action
 A chimeric (25% mouse, 75% human) monoclonal
antibody that binds with high affinity to soluble and
membrane-bound TNF- 

 Pharmacokinetics
 Given as IV infusion (3 to 10 mg/kg, every 6–7 weeks
 Terminal half-life of 9–12 days
 Elicits human antichimeric antibodies (ed by concurrent
therapy with methotrexate)
 Indications
 RA, ulcerative colitis, psoriasis, psoriatic arthritis,
juvenile chronic arthritis, Wegener's granulomatosis
 Adverse Effects
 URTI, nausea, headache, sinusitis, rash, and cough
are common
 Risk of macrophage-dependent infections
(including TB and other opportunistic infections).
 Rare: leukopenia and vasculitis
 Etanercept
 Mechanism of Action
 A recombinant fusion protein consisting of two soluble TNF
p75 receptor moieties linked to the Fc portion of human IgG1
 Binds TNF- molecules and also inhibits lymphotoxin- .

 Pharmacokinetics
 Given subcutaneously (25 mg twice weekly).

 Slowly absorbed

 Mean serum elimination half-life of 4.5 days.

 Indications
 RA, juvenile chronic arthritis, psoriatic arthritis and
ankylosing spondylitis (monotherapy and in
combination with methotrexate)

 Adverse Effects
 Risk of macrophage-dependent infections (including
TB and other opportunistic infections).
Incidence may be lower with etanercept
Drugs used
in
Gout
 Gout is a familial metabolic disease
characterized by recurrent episodes of acute
arthritis due to deposits of monosodium urate in
joints and cartilage.
 Formation of uric acid calculi in the kidneys may
also occur.
 Usually associated with high serum levels of uric
acid
 Pathophysiology
 Urate crystals phagocytosed by synoviocytes 
release PGs, lysosomal enzymes, and IL-1  PMN
leukocytes migrate into the joint space and amplify
the ongoing inflammatory process.
 In the later phases of the attack, increased numbers
of macrophages appear  ingest the urate crystals,
and release more inflammatory mediators
Pathophysiologic events in a gouty
joint
 Treatment principles
 Relieving the acute gouty attack

 Preventing recurrent gouty episodes and urate

lithiasis.
 Colchicine
 Is an alkaloid isolated from the plant Colchicum
autumnale
 Pharmacokinetics
 Absorbed readily after oral administration
 Pharmacodynamics
 Relieves pain and inflammation of gouty arthritis in 12–
24 hours
without altering the metabolism or excretion of urates and
with out other analgesic effects.
 Inhibits leukocyte migration and phagocytosis by
binding to tubuline and inhibiting its polymerization to
microtubules
 It also inhibits formation of leukotriene B4.
 Indications
 Traditionally: Alleviating the inflammation of acute
gouty arthritis (largely replaced by NSAIDs [except
aspirin])
 Now : prophylaxis of recurrent episodes of gouty
arthritis.
 Adverse Effects
 Frequent diarrhea and occasional nausea, vomiting, and
abdominal pain.
 Rare: hair loss, bone marrow depression, peripheral
neuritis and myopathy.
 Dosage
 Prophylactic: 0.6 mg one to three times daily.
 Terminating an attack: initial dose of 0.6 or 1.2 mg,
followed by 0.6 mg every 2 hours until pain is relieved or
nausea and diarrhea appear.
 NSAIDs in Gout
• Inhibit urate crystal phagocytosis + the PG synthesis

• Indomethacin is commonly used as replacement for

colchicine.
• All NSAIDs except aspirin, salicylates, and tolmetin have
been successfully used to treat acute gouty episodes.
• Oxaprozin, which lowers serum uric acid, should not be
given to patients with uric acid (UA) stones because it
increases uric acid excretion in the urine
 Uricosuric Agents
 Probenecid and sulfinpyrazone
 decrease the body pool of urate
 Avoided In patient who excrete large amounts of UA
 Chemistry
 Are organic acids and act at the anionic transport
sites of the renal tubule
 Pharmacokinetics
 Probenecid is completely reabsorbed by the renal
tubules and is metabolized very slowly
 Sulfinpyrazone or its active derivative is rapidly
excreted by the kidneys.
 Pharmacodynamics
 UA is freely filtered at the glomerulus, passivelly reabsorbed
and activelly secreted in the proximal tubule.
 Uricosuric drugs—probenecid, sulfinpyrazone
 Decrease net reabsorption of UA

 Aspirin in analgesic or antipyretic doses causes net retention of UA by

inhibiting the secretory transporter

 As urinary excretion of UA ses, body urate pool es

 ed UA excretion  augment renal stone formation

 Maintain urine volume at a high level

 Urine pH should be kept above 6.0

 Indications
 Initiated if several acute attacks of gouty arthritis
have occurred, when plasma levels of uric acid in
patients with gout are so high that tissue damage is
almost inevitable.
 Therapy should not be started until 2–3 weeks after
an acute attack.
 Adverse Effects
 GI irritation

 Allergic dermatitis (more with probenecid), rash

 Nephrotic syndrome (probenecid)

 rarely cause aplastic anemia.

 Contraindications & Cautions

 Maintain large urine volume to minimize the
possibility of stone formation.
 Allopurinol
 It is an isomer of hypoxanthine
 Pharmacokinetics
  80% absorbed after oral

 Pharmacodynamics
 Purines are formed from amino acids, formate, and CO2

 Purine ribonucleotides not incorporated into nucleic acids

(NA) and those derived from the degradation of NA are
converted to xanthine or hypoxanthine and oxidized to UA
 Allopurinol, es plasma urate and the size of the urate pool
Inhibition of uric acid synthesis by
allopurinol
 Indications
 when probenecid or sulfinpyrazone cannot be used
because of adverse effects or allergic reactions, or
when they are providing less than optimal
therapeutic effect
 for recurrent renal stones

 in patients with renal functional impairment or

 when serum urate levels are grossly elevated

 Adverse Effects
 Acute attacks of gouty arthritis occur early in treatment
(coadminister colchicine or indomethacin)
 GI intolerance (nausea, vomiting, and diarrhea)
 Peripheral neuritis, bone marrow depression, aplastic anemia
 Allergic skin reactions

 Interactions & Cautions

 May increase the effect of cyclophosphamide
 Inhibits the metabolism of probenecid and oral
anticoagulants
 Safety in children and pregnancy have not been established