PHARMACOLOGY

Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Chapter: 36

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

 Another important group of agents are characterized as disease-

modifying anti-rheumatic drugs (DMARDs) including biologics (a
subset of the DMARDs)
They decrease inflammation, improve symptoms, and slow the
bone damage associated with RA. They affect more basic
inflammatory mechanisms than do glucocorticoids or the NSAIDs.
They may also be more toxic than those alternative medications
NSAIDs
 Salicylates and other similar agents used to treat rheumatic disease
share the capacity to suppress the signs and symptoms of
inflammation including pain
 These drugs also exert antipyretic effects
Chemistry
 Although there are many differences in the kinetics of NSAIDs, they
have some general properties in common
 All but one of the NSAIDs are weak organic acids as given; the
exception, nabumetone, is a ketone prodrug that is metabolized to
the acidic active drug
Pharmacokinetics
 Most of these drugs are well absorbed, and food does not
substantially change their bioavailability
 Most of the NSAIDs are highly metabolized, some by phase I followed
by phase II mechanisms and others by direct glucuronidation (phase
II) alone
 NSAID metabolism proceeds, in large part, by way of the CYP3A or
CYP2C families of P450 enzymes in the liver
 While renal excretion is the most important route for final
elimination, nearly all undergo varying degrees of biliary excretion
and reabsorption (enterohepatic circulation)
In fact, the degree of lower gastrointestinal (GI) tract irritation
correlates with the amount of enterohepatic circulation. Most of
the NSAIDs are highly protein-bound (~ 98%), usually to albumin.
Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic
mixtures, while one, naproxen, is provided as a single enantiomer
and a few have no chiral center (eg, diclofenac)
 All NSAIDs can be found in synovial fluid after repeated dosing
 Drugs with short half-lives remain in the joints longer than would be
predicted from their half-lives, while drugs with longer half-lives
disappear from the synovial fluid at a rate proportionate to their half-
lives

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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36

 To varying degrees, all newer NSAIDs are analgesic, anti-

Pharmacodynamics inflammatory, and antipyretic, and all inhibit platelet aggregation
EXCEPT the COX-2 selective agents and the nonacetylated
salicylates

 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

 Several NSAIDs (including aspirin) reduce the incidence of colon

Figure Above: Prostanoid mediators derived from arachidonic acid and sites of
drug action. ASA, acetylsalicylic acid (aspirin); LT, leukotriene; NSAID,
nonsteroidal anti-inflammatory drug
 NSAID anti-inflammatory activity is mediated chiefly through
inhibition of prostaglandin biosynthesis
 Various NSAIDs have additional possible mechanisms of action,
including inhibition of chemotaxis, down-regulation of IL-1
production, decreased production of free radicals and superoxide,
and interference with calcium-mediated intracellular events
 Aspirin irreversibly acetylates and blocks platelet COX, while the non-
COX-selective NSAIDs are reversible inhibitors
cancer when taken chronically
Several large epidemiologic studies have shown a 50% reduction
in relative risk for this neoplasm when the drugs are taken for 5
years or longer. The mechanism for this protective effect is
unclear
 Although not all NSAIDs are approved by the FDA for the whole range
of rheumatic diseases, most are probably effective in:
o Rheumatoid arthritis
o Seronegative spondyloarthropathies (SpA, eg, psoriatic
arthritis and arthritis associated with inflammatory bowel
disease)
o Osteoarthritis
o Localized musculoskeletal syndromes (eg, sprains and
strains, low back pain)
o Gout (except tolmetin, which appears to be ineffective in
gout)

Selective COX-2 Inhibitors: Adverse Effects

 The selective COX-2 inhibitors do not affect platelet function at their
Central Nervous System: Hepatic:
usual doses
o Headaches o Abnormal liver function test
The efficacy of COX-2-selective drugs equals that of the older o Tinitus results
NSAIDs, while GI safety may be improved o Dizziness o Rare liver failure
o Aseptic meningitis (rarely)
 On the other hand, selective COX-2 inhibitors increase the incidence
of edema, hypertension, and possibly, myocardial infarction Cardiovascular System: Pulmonary:
As of August 2011, celecoxib and the less selective meloxicam o Fluid retention o Asthma
were the only COX-2 inhibitors marketed in the USA o Hypertension
o Edema
Celecoxib has a U.S Food and Drug Administration (FDA) “black Rarely:
box” warning concerning cardiovascular risks. It has been o Myocardial infarction
recommended that all NSAID product labels be revised to o Congestive heart failure
mention cardiovascular risks (CHF)

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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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

COX-2 SELECTIVE INHIBITORS

DRUG CHEMISTRY MECHANISM OF ACTION ADVERSE EFFECT T½
Celecoxib COX-2 selective inhibitor Renal Toxicity 11 hours
Preferentially inhibits COX-2
Coxib
Meloxicam Inhibits synthesis of 20 hours
Thromboxane A2
 COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation
without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets
 COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme
 In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium
o As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs
 Recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs
 Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in
their withdrawal from the market
 Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes
 It interacts occasionally with warfarin-as would be expected of a drug metabolized via CYP2C9
 Meloxicam is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective
 It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen

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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36

NON-SELECTIVE COX INHIBITORS

DRUG CHEMISTRY MECHANISM OF ACTION ADDITIONAL INFORMATION T½
Diclofenac + Misoprostol  decreases GIT ulceration
A 0.1% ophthalmic preparation is promoted for but may result to diarrhea
prevention of postoperative ophthalmic inflammation Diclofenac + Omeprazole  effective in prevention of
Phenylacetic acid A topical gel containing 3% diclofenac is effective for recurrent bleeding but renal adverse effects are
Diclofenac common among high-risk patients 1.1 hours
derivative solar keratosis
Diclofenac in rectal suppository form can be considered Diclofenac, 150 mg/d  impair renal blood flow & GFR
for preemptive analgesia and postoperative nausea Elevation of serum aminotransferases is common
with this drug
It is not metabolized to salicylic acid or salicylate
It undergoes an enterohepatic cycle with reabsorption
Salicylic acid Recommended dose for RA: 500-1000 mg daily in 2
Diflunisal of its glucuronide metabolite followed by cleavage of 13 hours
derivative divided doses
the glucuronide to again release the active moiety
Rarely used today
Recommended dosage in OA and RA:
Racemic acetic Analgesic dosage of etodolac: 200-400 mg 300 mg (2 or 3 times a day) or
Etodolac 6.5 hours
acid derivative (3-4 times daily) up to 500 mg (2 times a day) initially
Then followed by a maintenance of 600 mg/d
Its (S)(-) enantiomer inhibits COX nonselectively, TNF-α Hepatic metabolism is extensive; its (R)(+) and (S)(–)
and Nitric Oxide synthesis enantiomers are metabolized differently, and it does
not undergo chiral conversion
Topical ophthalmic formulation for inhibition of
Propionic acid intraoperative miosis Flurbiprofen is rarely associated with:
Flurbiprofen 3.8 hours
derivative o Cogwheel rigidity
Intravenously: effective for perioperative analgesia in
o Ataxia
minor ear, neck, and nose surgery
o Tremor
Lozenge form: Sore throat o Myoclonus
2400 mg daily  equivalent to 4g of aspirin in anti-
inflammatory effect
Oral ibuprofen is often prescribed in lower doses
(<1600 mg/d), at which it is analgesic but not anti-
inflammatory

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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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36

DRUG CHEMISTRY MECHANISM OF ACTION ADDITIONAL INFORMATION T½

The only NSAID presently marketed as a single
enantiomer
Naproxen’s free fraction is significantly higher in
women than in men, but half-life is similar in both
sexes
Naphthylpropionic
Naproxen Rheumatologic Relief Adverse effect: 14 hours
acid derivative
o Upper GI bleeding
o Pneumonitis
o Leukocytoclastic vasculitis Rare
o Pseudoporphyria

Its major difference from other NSAIDs is its very long

half-life 58 hours
Propionic acid
Oxaprozin (longest
derivative It does not undergo enterohepatic circulation
T ½)
It is mildly uricosuric
Inhibits polymorphonuclear leukocyte migration
Decreases oxygen free radical production Adverse effect at doses higher than 20 mg/d:
Piroxicam Oxicam Inhibits lymphocyte function o Peptic ulcer 57 hours
o Bleeding
Rheumatologic Relief

Severe adverse reaction:

Rheumatologic Relief
o Steven-Johnson epidermal necrolysis
syndrome
Suppresses familial intestinal polyposis
Sulindac Sulfoxide prodrug o Thrombocytopenia 8 hours
o Agranulocytosis
Inhibit the development of colon, breast, and prostate
o Nephrotic syndrome
cancer
o Cholestatic liver damage
Tolmetin It is ineffective in the treatment of gout 1 hour

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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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

Nausea & Mucosal ulcers

Inhibition of amino-imidazolecarboxamide
Methotrexate ribonucleotide (AICAR) transformylase and
thymidylate synthetase
A synthetic antimetabolite
(most common toxicities)
Now considered the 1st line csDMARD for treatment of
Leukopenia, anemia, stomatitis,
RA
GI ulcerations, and alopecia 
Probably the result of inhibiting
cellular proliferation

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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36

DRUG MECHANISM OF ACTION INDICATION ADVERSE EFFECTS

a csDMARD
Renal disease due to SLE Nausea
Active form: Mycophenolic acid  inhibits
inosine monophosphate dehydrogenase, leading Dyspepsia
Vasculitis
Mycophenolate to suppression of T- and B-lymphocyte
Abdominal pain
Mofetil (MMF) proliferation
Wegener’s granulomatosis Hepatotoxicity
It interferes with leukocyte adhesion to
endothelial cells through inhibition of E-selectin, RA Hematopoietic
P-selectin, and intercellular adhesion molecule 1
Chimeric monoclonal antibody biologic agent Moderately to Severe RA (in combination with Rash
that targets CD20 B lymphocytes  Depletion of methotrexate  for patients with an inadequate Decreased IgG and IgM
Rituximab these cells takes place through cell-mediated and response to one or more TNF-α antagonists)
complement-dependent cytotoxicity and Increased risk of infections
stimulation of cell apoptosis Wegener’s granulomatosis Reactivation of HBV infection
RA and reduced radiologic disease progression Common: nausea, vomiting,
A csDMARD
headache, and rash
Juvenile chronic arthritis
Active metabolite: Sulfapyridine and 5- Neutropenia,
Psoriatic arthritis
Sulfasalazine aminosalicylic acid thrombocytopenia, pulmonary
Inflammatory disease toxicity
Inhibits release of inflammatory cytokines – Ankylosing spondylitis Reversible infertility (men)
IL-1, -6, -12, and TNF-α
Spondyloarthropathy-associated uveitis It is not teratogenic
TB, fungal, viral, and other
opportunistic infections
Screening for TB should be
done prior to therapy
Most common: Upper
Binds to soluble and membrane-bound IL-6 respiratory tract infections,
receptors, and inhibits the IL-6-mediated a bDMARD indicated for adult patients with moderately headache, hypertension, and
signaling via these receptors to severely active RA who have had an inadequate elevated liver enzymes
response to one or more DMARDs Neutropenia and reduction in
Tocilizumab
IL-6 is a proinflammatory cytokine produced by platelet counts
different cell types including T cells, B cells, Patients who are older than 2 years with active SJIA or
Lipids (eg, cholesterol,
monocytes, fibroblasts, and synovial and active PJIA
triglycerides, LDL, and HDL)
endothelial cells
should be monitored
GI perforation has been
reported when using
tocilizumab in patients with
diverticulitis and in those using
corticosteroids

TUMOR NECROSIS FACTOR α (TNF-α) BLOCKING AGENTS  Exacerbate heart failure

 TNF-α affects cellular function via activation of specific membrane-  Alopecia areata, hypertrichosis, and erosive lichen planus
bound TNF receptors (TNFR1, TNFR2)  Cutaneous pseudolymphomas  mostly seen in infliximab
 Gastrointestinal ulcers and large bowel perforation including
Adverse Effects of TNF-α Blocking Agents diverticular and appendiceal perforation
 Risk of bacterial infection and specific membrane-bound dependent  Nonspecific interstitial pneumonia, psoriasis, and sarcoidosislike
infection syndrome
o Tuberculosis, fungal, and opportunistic infection  Rare cases of leukopenia, neutropenia, thrombocytopenia, and
o All patient screen for latent or active TB, screening for pancytopenia
HBV due to risk of HBV reactivation
 Risk of skin cancer – melanoma
 Newly formed dsDNA antibodies and anti-nuclear antibodies (ANA)

TNF-α BLOCKING AGENTS

DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION
Reduces the formation of new
Fully human IgG1 anti-TNF monoclonal Given subcutaneously erosions
antibody T ½: 10-20 days Indicated: RA, AS, PA, JRA, Crohn’s
This compound complexes with soluble TNF-α Dose: 40 mg once in 2 weeks disease
Adalimumab
and prevents its interaction with p55 and p75 cell With methotrexate, its action is potentiated – Adverse effect: risk of macrophage
surface receptors  this results in down- 40% reduced clearance, decreased formation of dependent infections
regulation of macrophage and T-cell function antibodies Screening for latent TB to be done
before therapy

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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Chapter: 36

DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION

Recombinant, humanized antibody Fab fragment
conjugated to a polyethylene glycol (PEG) with
specificity for human TNF-α
Certolizomab
Neutralizes membrane-bound and soluble TNF-α
in a dose-dependent manner
Recombinant fusion protein consisting of two
soluble TNF p75 receptor moieties linked to the
Fc portion of human IgG1
Etanercept
It binds TNF-α molecules and also inhibits
lymphotoxin α
Human monoclonal antibody with a high affinity
for soluble and membrane-bound TNF-α
Golimumab
Neutralizes the inflammatory effects produced
by TNF-α seen in diseases such as RA
Chimeric (25% mouse, 75% human) IgG1
monoclonal antibody that binds with high affinity
Infliximab to soluble and possibly membrane-bound TNF-α
MOA same as adalimumab
Moderate to Severe active RA
Monotherapy or in combination with
nonbiologic DMARDs
Given subcutaneously Approved to reduce sign & symptoms
T ½: 14 days and maintain clinical response in adult
Clearance is decreased with decreasing body patients with:
weight o Crohn’s disease
400 mg initially & at weeks 2 & 4, followed by 200 o Active PsA
mg every other week o Active AS
Risk of serious infections, including TB,
fungal and other opportunistic
pathogens
Treatment of RA, juvenile chronic
arthritis, psoriasis, PsA, and AS
Given subcutaneously, 25 mg twice weekly or 50 Used along with methotrexate
mg once weekly
T ½: 4.5 days Scleroderma, granulomatosis with
Drug is slowly absorbed, peak concentration 72 polyangiitis (Wegener’s
hours after administration granulomatosis), giant cell arteritis,
Behcet’s disease, uveitis, and
sarcoidosis
Indicated for the treatment of
Given subcutaneously
moderately to severely active RA
T ½: 14 daysConcomitant
Use with methotrexate increases golimumab
Indicated for the treatment of PsA and
serum levels and decreases anti-golimumab
AS and moderate to severe ulcerative
antibodies
colitis
RA, AS, PsA, Crohn’s disease,
ulcerative colitis, pediatric
inflammatory bowel disease, and
psoriasis
Given intravenous infusion with induction at 0, 2,
Granulomatosis with polyangiitis
and 6 weeks
(Wegener’s granulomatosis), giant cell
T ½: 9-12 days
arteritis, Behcet’s disease, uveitis, and
3 or 10 mg/kg every 8 weeks IV infusion
sarcoidosis
Infliximab + Methotrexate 
decreases the rate of formation of
new erosions

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

DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION

A human IgG1 monoclonal antibody that
selectively binds to the IL-17A cytokine, Available as a SC injection or lyophilized powder
Indicated for moderate to severe
inhibiting its interaction with the IL-17A receptor for injection
plaque psoriasis in patients who are
Secukinumab IL-17A is involved in normal inflammatory and Peak plasma concentration: 13.7 mcg/mL (150
candidates for systemic therapy or
immune responses mg dose) and 27.3 mcg/mL (300 mg dose)
phototherapy
Elevated concentrations of IL-17A are found in Elimination half-life: 22-31 days
psoriatic plaques and PsA
 Adverse effects: Infection is a common side effect. Nasopharyngitis occurs in about 12%. TB status should be evaluated prior to therapy
Secukinumab may exacerbate Crohn’s disease

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Chapter: 36

DRUG MECHANISM OF ACTION PHARMACOKINETICS INDICATION

To prevent solid organ allograft
Oral, targeted DMARD
Targeted synthetic small molecule (tsDMARD) rejection
T ½: 3 hours
that selectively inhibits all members of the Janus Treatment for inflammatory bowel
Tofacitinib Metabolism occur in the liver by CYP3A4 and
kinase disease, spondyloarthritis, psoriasis,
CYP2C19
Interrupts JAK-STAT pathway and dry eyes
Contraindicated in severe hepatic disease
 Adverse effect: Increased risk of infections but upper respiratory tract infection and urinary tract infection represent the most common infections

INTERLEUKIN-1 INHIBITOR Adverse Effects of IL-1 Inhibitors

 IL-1α plays a major role in the pathogenesis of several inflammatory  Most common:
and autoimmune diseases including RA o Injection site reaction (up to 40%)
 IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA) are other o Upper respiratory tract
members of the IL-1 family  Serious infections occur rarely
All three bind to IL-1 receptors in the same manner  Headache, abdominal pain, nausea, diarrhea, arthralgia, and flu-like
 However, IL-1RA does not initiate the intracellular signaling illness
pathway and thus acts as a competitive inhibitor of the  May experience transient neutropenia, which requires regular
proinflammatory IL-1α and IL-1β monitoring of neutrophil count

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

GLUCOCORTICOID DRUGS Indications of Glucocorticoid Drugs

 Most commonly used oral corticoid steroid is Prednisone  Corticosteroids have been used in 60-70% of RA patients
 Oral dose 30-50 mg/dL for 1-2 days  Their effects are prompt and dramatic, and they are capable of
 Intra-articular injection 10 mg (small joints), 30 mg (wrist, ankle, slowing the appearance of new bone erosions
elbow) 40 mg (knee) of Triamcinolone acetonide  Corticosteroids may be administered for certain serious extra-
o If oral route cannot be tolerated articular manifestations of RA such as pericarditis or eye involvement
or during periods of exacerbation
 Other rheumatic diseases in which the corticosteroids’ potent anti-
inflammatory effects may be useful include vasculitis, SLE, Wegener’s
granulomatosis, PA, giant cell arteritis, sarcoidosis, and gout

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Indications of Glucocoricoid Drugs continued…..

 Intra-articular corticosteroids are often helpful to alleviate painful
symptoms and, when successful, are preferable to increasing the
dosage of systemic medication
 Some of the symptoms of RA, especially morning stiffness and joint
pain, follow a circadian rhythm, probably due to an increase in OTHER ANALGESICS
proinflammatory cytokines in the early morning  Acetaminophen, Ketorolac, Tramdol
A recent approach uses delayed-release prednisone for the
treatment of early morning stiffness and pain in RA

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

DRUGS USED IN GOUT Colchicine…..

 Gout is a metabolic disease characterized by recurrent episodes of  Pharmacodynamics:
acute arthritis due to deposits of monosodium urate in the joints & o Relieves the pain and inflammation of gouty arthritis (12-
cartilages 24 hours)
 Usually associated with high serum uric acid level (hyperuricemia) o Does not alter metabolism & excretion of rates
 Uric acid renal calculi, tophi and interstitial nephritis may also occur o No other analgesic effect
 Treatment Goals: o Binds with intracellular protein tubulin
o To relieve acute gouty attacks Thereby preventing its polymerization into
o To prevent recurrent gouty episodes microtubules and leading to the inhibition of leukocyte
o To prevent urate lithiasis migration and phagocytosis
 Pharmacologic treatment:
o Colchicine o It also inhibits the formation of leukotriene B4 and IL-1β
o NSAIDs  Indications:
o Glucocorticoids o Gout and also used in inter-critical period – for prolonged
o Uricosuric agents prophylaxis (low doses)
o Sarcoid arthritis & hepatic cirrhosis (mild beneficial effect)
Colchicine o Treat & prevent pericarditis, pleurisy & coronary artery
 An alkaloid isolated from autumn crocus, Colchicum autumnale disease
 Pharmacokinetics:  Adverse effects (Severe form-associated with IV route)
o Readily absorbed after oral administration o GIT – diarrhea, occasional nausea, vomiting & abdominal
o Peak plasma levels: 2 hours pain
o Elimination half-life: 9 hours o Hepatic cirrhosis, acute renal failure, seizures & DIC
o Metabolites in intestinal tract and urine o Hair loss, bone marrow depression, peripheral neuritis,
myopathy and death (rare)

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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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Topic: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
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