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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) The NSAIDs are grouped in several chemical classes, as shown on the
The Immune Response lower left
Occurs when immunologically competent cells are activated in This chemical diversity yields a broad range of pharmacokinetic
response to foreign organisms or antigenic substances liberated characteristics:
during the acute or chronic inflammatory response
Chronic inflammation involves the release of multiple cytokines and
chemokines plus a very complex interplay of immunoactive cells
Therapeutic Strategies
The treatment of patients with inflammation involves two primary
goals:
1. The relief of symptoms and the maintenance of function,
which are usually the major continuing complaints of the
patient
2. The slowing or arrest of the tissue damaging process
Reduction of inflammation with NSAIDs often results in relief of pain
for significant periods
Furthermore, most of the nonopioid analgesics (aspirin, etc) have
anti-inflammatory effects, so they are appropriate for the treatment
of both acute and chronic inflammatory conditions
The glucocorticoids also have powerful anti-inflammatory effects
and when first introduced were considered to be the ultimate answer
to the treatment of inflammatory arthritis
Although there are data indicating that low-dose corticosteroids
have disease-modifying properties, particularly in the early phase
of Rheumatoid Arthritis (RA), their toxicity makes them less
favored than other medications, when it is possible to use the
others. However, the glucocorticoids continue to have a
significant role in the long-term treatment of arthritis
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
NSAIDs are all gastric irritants and can be associated with GI ulcers
and bleeds as well, although as a group the newer agents tend to
cause less GI irritation than aspirin
Nephrotoxicity, reported for all NSAIDs, is due, in part, to
interference with the autoregulation of renal blood flow, which is
modulated by prostaglandins
Hepatotoxicity also can occur with any NSAID
Although these drugs effectively inhibit inflammation, there is no
evidence that they alter the course of any arthritic disorder
This is in contrast to drugs such as methotrexate, biologics, and
other DMARDs
In July 2015 the FDA strengthened the warning that NSAIDs can Gastrointestinal: Skin:
cause heart attacks or strokes. A study found that NSAID use was o Abdominal pain o Rashes, all types
associated with increased risk of serious bleeding and o Dyspepsia o Pruritus
cardiovascular events after myocardial infarction o Nausea
The risk is higher among users of celecoxib and o Vomiting
diclofenac o Ulcers or bleeding (rarely)
The risk is lower among users of ibuprofen and
naproxen Hematologic: (all happen rarely) Renal:
o Thrombocytopenia o Renal insufficiency
o Neutropenia o Renal failure
The NSAIDs decrease the sensitivity of vessels to bradykinin and
o Aplastic anemia o Hyperkalemia
histamine, affect lymphokine production from T lymphocytes, and
o Proteinuria
reverse the vasodilation of inflammation
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
ASPIRIN
DRUG CHEMISTRY MECHANISM OF ACTION ADVERSE EFFECT T½
Main adverse effects are:
o Gastric upset (intolerance)
Irreversibly inhibits platelet o Gastric and duodenal ulcers.
Simple organic acid with a pKa COX (8-10 days) o Hepatotoxicity
Aspirin 15 min.
of 3.0 May be used in treating o Asthma
preeclampsia-eclampsia o Rashes
o GI bleeding
o Renal toxicity (rarely)
Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-
inhibiting effects
The antiplatelet action of aspirin contraindicates its use by patients with hemophilia
NON-ACETYLATED SALICYLATES
DRUG CHEMISTRY MECHANISM OF ACTION ADVERSE EFFECT T½
Preferable when COX
inhibition is undesirable
Magnesium Choline Salicylate
Non-acetylated such as in patients with
Sodium Salicylate 2-19 hrs.
salicylates asthma, those with bleeding
Salicyl Salicylate
tendencies, and renal
dysfunction
All nonacetylated salicylates are effective anti-inflammatory drugs, and they do not inhibit platelet aggregation
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
Oral or IV: effective in closing patent ductus Compared to Indomethacin ibuprofen decreases
arteriosus in preterm infants urine output less and also less fluid retention
Phenylpropionic Topical cream: absorbed in fascia and muscles Contraindicated in individuals with:
Ibuprofen o Nasal polyps 2 hours
acid derivative Liquid gel preparation: 400 mg, provides prompt o Angioedema
relief and good overall efficacy in postsurgical dental o Bronchospastic reactivity to aspirin
pain
Ibuprofen + Aspirin ibuprofen antagonizes the
irreversible platelet inhibition induced by aspirin. It
may also decrease total anti-inflammatory effect
Rare hematologic effects:
o Agranulocytosis
o Aplastic anemia
Inhibit Phosopholipase A and C
Reduce neutrophil migration Additional adverse effects:
Decrease T-cell and B-cell proliferation o Pancreatitis
Indomethacin Indole derivative Accelerate closure of patent ductus arteriosus o Headache (15-25%), dizziness, confusion, 4-5 hours
depression
Ophthalmic preparation: for conjunctival o Renal papillary necrosis
inflammation and reduce pain after traumatic corneal
abrasion
Ketoprofen + Probenecid elevates ketoprofen
Propionic acid levels and prolongs its plasma half-life
Ketoprofen Inhibits both COX (nonselectively) and Lipoxygenase 1.8 hours
derivative Effective dosage: 100-300 mg/d
Major adverse effects: GI tract & CNS
The only NON- Once a day daily dosing & does not undergo
ACID NSAID enterohepatic circulation
Nabumetone Nonselective COX inhibitor 26 hours
Renal impairment results in a doubling of its half-life
Resembles
naproxen Less damaging to the stomach
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
Other NSAIDs (that are rarely used): DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs)
Azapropazone RA is a progressive immunologic disease that causes significant
Carprofen systemic effects, shortens life, and reduces mobility and quality of life
Meclofenamate The effects of disease-modifying therapies may take 2 weeks to 6
Tenoxicam months to become clinically evident
These therapies include conventional synthetic (cs) and biologic (b)
Choice of NSAID disease-modifying antirheumatic drugs (recently designated
NSAIDs tend to be differentiated on the basis of toxicity and cost- csDMARDs and bDMARDs, respectively)
effectiveness The conventional synthetic agents include small molecule drugs such
Indomethacin and Tolmetin greatest toxicity as methotrexate, azathioprine, chloroquine and hydroxychloroquine,
Salsalate, Aspirin, and Ibuprofen least toxic cyclophosphamide, cyclosporine, leflunomide, mycophenolate
For patients with renal insufficiency DOC is nonacetylated mofetil, and sulfasalazine
salicylates Tofacitinib, though marketed as a biologic, is actually a targeted
Diclofenac and Suldinac associated with more liver function test synthetic DMARD (tsDMARD)
abnormalities than other NSAIDs Biologics are large-molecule therapeutic agents, usually proteins,
Celecoxib safest for patients at high risk for GI bleeding but may which are often produced by recombinant DNA technology
have a higher risk of cardiovascular toxicity The bDMARDs approved for RA include:
Celecoxib or nonselective NSAID + Omeprazole or Misoprostol o Abatacept T-cell modulating biologic
may be appropriate in patients at highest risk for GI bleeding o Rituximab B-cell cytotoxic agent
o Tocilizumab anti-IL-6 receptor antibody
o Anakinra, Rilonacept, Canakinumab IL-1-inhibiting
agents
o TNF-α-blocking agents (five drugs)
bDMARDs are further divided into:
o Biological original DMARDs (boDMARDs)
o Biosimilar DMARDs (bsDMARDs)
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
DMARDs
DRUG MECHANISM OF ACTION INDICATION ADVERSE EFFECTS
Risk for Upper Respiratory
Tract Infection and UTI
Used as monotherapy or in combination with other Infusion-related reactions &
DMARDs in patients with moderate to severe RA who hypersensitivity reactions:
had an inadequate response to other DMARDs o Anaphylaxis (rare)
Inhibits the activation of T cells
Abatacept Reduces the clinical signs and symptoms of RA, including o Anti-abatacept
CTLA-4 of Abatacept binds with CD80 and 86 slowing of radiographic progression antibody formation
Tested on other rheumatic diseases but most beneficial is infrequent (<5%)
effects were seen in psoriatic arthritis and has no effect on
clinical outcomes
Possible increase in lymphomas
Acts through its major metabolite, 6-thioguanine Bone marrow suppression
suppresses inosinic acid synthesis and B & T Used in RA at 2 mg/kg per day
GI disturbances
Azathiophrine cell functions, immunoglobulins production and Used to prevent kidney transplant rejection
IL-2 secretion Increase in infection risk and
Scleroderma
malignancy
Used for malaria and rheumatic arthritis Antimalarials are approved for RA, but they are not Ocular toxicity
Suppression of T lymphocyte responses to considered very effective DMARDs
Dyspepsia
mitogens There is no evidence that these compounds alter
Chloroquine & Nausea and vomiting
Inhibition of leukocyte chemotaxis bony damage in RA at their usual dosages
Hydroxychloroquine Abdominal pain
Stabilization of lysosomal enzymes It usually takes 3-6 months to obtain a response
Rashes
Inhibition of DNA and RNA synthesis Often used in the treatment of the skin manifestations,
serositis & joint pains of SLE, Sjörgen’s syndrome Nightmares
Tapping of free radicals
a csDMARD
Major active metabolite: phosphoramide
Cyclophosphamide mustard cross-links DNA to prevent cell SLE, vasculitis, Wegener’s granulomatosis
replication
It suppresses T-cell and B-cell function by 30-40%
Leukopenia, thrombocytopenia,
anemia
A peptide antibiotic but is considered a High doses: cardiotoxic,
csDMARD neurotoxic & sterility after
Regulates gene transcription by inhibiting IL-1 chronic dosing at anti-
Cyclosporine RA and retards appearance of new bony erosions
and IL-2 receptor production rheumatic doses, especially in
Inhibits macrophage -T cell interaction and T cell women
responsiveness Bladder cancer very rare but
must be looked for, even 5 years
after cessation of use
a csDMARD
Undergoes rapid conversion, both in the
intestine and in the plasma, to its active
metabolite, A77-1726 Diarrhea
A77-1726 inhibits dihydroorotate
RA adjuvant for methotrexate Elevation of liver enzymes
dehydrogenase, leading to a decrease in
ribonucleotide synthesis and the arrest of Cholestyramine can enhance leflunomide excretion and
Leflunomide Mild alopecia
stimulated cells in the G1 phase of cell growth increases total clearance by approximately 50%
It inhibits T-cell proliferation and reduces Contraindicated for pregnant women Weight gain
production of autoantibodies by B cells
Secondary effects: increases of IL-10 receptor Increased blood pressure
mRNA, decreased IL-8 receptor type A mRNA,
and decreased TNF-α–dependent nuclear factor
kappa B (NF-κB) activation
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
OTHER DRUGS:
DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION
IL-12 and IL-23 antagonist
A fully human IgG monoclonal antibody to the Indicated for treatment of adult
p40 protein subunit, which is part of both IL-12 Available as a 45- and 90-mg SC injection for PsA patients with PsA
and IL-23 and plaque psoriasis
It prevents the binding of the p40 subunit of both Bioavailability following SC injection: 57% It can be used as monotherapy or in
Ustekinumab
IL-12 and IL-23 to the IL-12 receptor b1 found on Time to peak plasma concentration: 7-13.5 days combination with methotrexate
the surface of CD4 T cells and NK cells Elimination half-life: 10-126 days
interferes with IL-12 and IL-23 signal Other indications include plaque
transduction and suppresses the formation psoriasis and Crohn’s disease
of proinflammatory TH1 and TH17 cells
Adverse effects: Upper respiratory tract infection is the most common side effect, but rare severe infection, malignancy, and reversible posterior
leukoencephalopathy syndrome have been reported
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
IL-1 INHIBITORS
DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION
Moderately to severely active RA in
Oldest drug in this family adults
Subcutaneous and reaches a maximum plasma
Now rarely used for RA DOC for CAPS, neonatal-onset
concentration after 3-7 hours
It blocks the effect of IL-1α and IL-1ß on IL-1 multisystem inflammatory disease
Anakinra T ½: 4-6 hours
receptors (NOMID)
Dose depends on body weight in the context of
Decrease the immune response in inflammatory Effective for gout, Behcet’s disease
cryopyrin-associated periodic syndrome (CAPS)
disease and adult onset JIA
Giant cell arthritis controversial
For active SJIA in children 2 yrs. or
A human IgG1/κ monoclonal antibody against IL- Subcutaneous injection
older
1β Peak serum concentration: 7 days (after single SC
Canakinumab Use to treat CAPS, particularly familial
It forms a complex with IL-1β, preventing its injection)
cold autoinflammatory syndrome and
binding to IL-1 receptors T ½: 26 days
Muckle-Wells syndrome, Gout
To treat CAPS subtypes:
Rilonacept is the ligand-binding domain of the IL-
o Familial cold
1 receptor
Subcutaneous autoinflammatory
It binds mainly to IL-1β and binds with lower
Rilonacept syndrome
affinity to IL-1α and IL-1RA
Dose for CAPS, it is age dependent o Muckle-Wells syndrome
It neutralizes IL-1β and prevents its attachment
(12 yrs. or older)
to IL-1 receptors
To treat Gout
Treatment of adult patients with
active, seropositive SLE who are
receiving standard treatment
Contraindicate: active renal or
Intravenous infusion
Antibody that specifically inhibits B-lymphocyte neurological manifestation of SLE
Belimumab Half-life of distribution: 1.75 days
stimulator (BLyS) Adverse effect: nausea, diarrhea, and
Half-life of termination: 19.4 days
respiratory tract infection
Anaphylaxis
Development of antibodies toward
belimumab
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
OTHER ANALGESICS
DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION
It does not affect uric acid levels and
lacks platelet-inhibiting effect
Mild to moderate headache, myalgia,
Administered orally
postpartum pain
Absorption: related to rate of gastric emptying
Peptic ulcer and does not antagonize
It is the active metabolite of phenacetin Peak blood concentration: 30-60 mins.
the effects of uricosuric agents
responsible for its analgesic effect Slightly protein bound
It is a weak COX-1 and COX-2 inhibitor in Partially metabolized by hepatic microsomal
Acetaminophen Ingestion of 15 gm: Fatal death
peripheral tissues and possess no significant enzyme acetaminophen SO4 & glucuronide
(Paracetamol) caused by hepatotoxicity with
anti-inflammatory effects Excretion: unchanged <5%
centrilobular necrosis & sometimes
For treatment of mild to moderate pain A minor but highly reactive metabolite (N-acetyl-
with acute renal tubular necrosis
Antipyretic effect p-benzoquinone) is important liver & kidney
Symptoms of early hepatic damage:
toxicity
N/V, diarrhea, abdominal pain
T ½: 2-3 hrs.
Antidote: N-acetylcysteine (sulfhydryl
groups)
Dosage: 325-500 mg q.i.d
Replace morphine in mild to moderate
Intramuscular, intravenous, oral surgical pain
Short term analgesia (not longer than 1 week)
Ketorolac When used with an opioid, it may decrease the
Not anti-inflammatory
opioid requirement by 25–50% Adverse effect: renal toxicity is
common with chronic use
Centrally acting synthetic analgesic, structurally
Analgesic effect:
related to opioids
Tramadol Enhancing 5-hydroxytryptamine (5-HT) release
MOA: involve opioid and non-opioid receptors
and inhibiting the reuptake of NE and 5-HT
Not have a significant anti-inflammatory effect
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
Colchicine….. Allopurinol
Dosages: Preferred and standard-of-care therapy for gout during the period in
o For prophylaxis (most common use) – 0.6 mg (1 to 3 times between acute episodes
daily) Decreases body uric acid level by inhibiting xanthine oxidase
o For termination of gouty attacks – 1.2 mg followed by a Pharmacokinetics:
single dose of 0.6 mg oral dose (was as effective as higher o An isomer of hypoxanthine
dose but associated with less adverse effect) o 80% absorbed after oral administration
o Elimination half-life: 1-2 hours
NSAIDs in Gout
o Long duration of action (alloxanthine) – given only 1 a day
Inhibit prostaglandin synthase and urate crystal phagocytosis
Pharmacodynamics:
All NSAIDs are successfully used to treat acute gouty episodes
o Inhibits xanthine oxidase decreases plasma rate level
EXCEPT Aspirin, Salicylates & Tolmetin
decreases overall rate burden
Aspirin
o More soluble xanthine and hypoxanthine are increased
o At low doses (<2.6 g/day) – renal retention of uric acid
Indications:
o At high doses (3.6 g/day) - uricosuric
o Chronic gout – first line agent in the period between
attacks and tend to prolong intercritical period
Oxaprozin
o When initiating therapy, colchicine or NSAIDs, should be
Uric acid lowering agents (effective and safe)
used until steady state uric acid level is normalized or
decreased to less than 6 mg/dL and should be continued
Indomethacin to 6 months or longer, then cautiously stopped
Commonly used in initial treatment of gout (as replacement to Adverse Effects:
Colchicine) o Precipitates gout flares (use with Colchicine and NSAIDs)
50 mg – 3 times a day for acute gout o GIT irritation (nausea, vomiting, diarrhea)
25 mg – 3x a day for 5-7 days (when response occurs after initial o Peripheral neuritis and necrotizing vasculitis, bone
treatment) marrow suppression and aplastic anemia - rare
o Hepatotoxicity and interstitial nephritis
Glucocorticoids for Gout o Pruritic maculopapular lesions
Used in the treatment of severe symptomatic gout by: (depending on o Isolated cases of exfoliative dermatitis
the degree of pain and inflammation) o Cataracts (very rare)
o Intra-articular Interactions and Precautions:
o Systemic o Azothioprine and Cyclophosphamide effects – increased
o Subcutaneous o Inhibits the metabolism of Probenecid and Oral
Most commonly used – Prednisone (oral) anticoagulants
o At 30-50 mg/day for 1-2 days, tapered over 7-10 days o Increases hepatic iron concentration
Triamcinolone acetonide – if oral route cannot be tolerated Dosages:
o For intraarticular injections o Initial dose – 50-100 mg/d, titrated upward until serum
Small joints - 10 mg uric acid level is below 6 mg/dL (commonly achieved at
Wrist, ankle and elbow – 30 mg 300-400 mg/d or as high as 800 mg/d)
Knee – 40 mg
Febuxostat
Uricosuric Agents A non-purine xanthine oxidase inhibitor
Pharmacokinetics: Pharmacokinetics:
o Organic acids o >80% absorbed following oral administration
o Probenecid - completely reabsorbed by the renal tubules o Maximum concentration achieved ~ 1 hour
and metabolized slowly (half-life 5-8 hours) o Elimination half0life – 4-18 hours
o Sulfinpyrazone (or its active hydroxylated derivative) – o Extensively metabolized in the liver
is excreted in the kidney o Once-daily dosing is effective
Pharmacodynamics: Pharmacodynamics:
o Decreases the net reabsorption of uric acid in the proximal o Potent and selective inhibitor of xanthine oxidase
tubule decreases formation of xanthine and uric acid
o Urine volume – high level, urine pH – 6.0 (alkali) o Well tolerated in patients with allopurinol intolerance
Indications: (should not be started until 2-3 weeks after an acute Pegloticase
attack) Indications refractory chronic gout
o Gouty patients with under excretion of uric acid Adverse Effects:
o When Allopurinol or Febuxostat is contraindicated o Precipitates gout flares – first 3-6 months of treatment
o When tophi are present (use with colchicine and NSAIDs)
Adverse Effects: o Immune responses
o GIT irritation (Sulfinpyrazone > Probenecid) o URTI, peripheral edema, UTI and diarrhea – less frequent
o Rash and Aplastic anemia (rare) o Infusion reaction and anaphylaxis
o Nephrotic Syndrome (Probenecid) o Nephrolithiasis, arthralgia, muscle spasm, headache,
anemia and nausea
Precaution should not be used in patients with asymptomatic
hyperuricemia
Dosage 8 mg every 2 weeks administered by IV infusion
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PHARMACOLOGY
Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36
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