Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid

Analgesics, & Drugs Used in Gout

Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
Content Outline Terms
Terms Inflammation - complex response to cell
NSAIDs › Chemistry injury that primarily occurs in
› Pharmacokinetics vascularized connective tissue.
› Pharmacodynamics/MOA - involves the immune
› Adverse effects response
› Choice of NSAIDs Antipyretic - drug that reduces fever
COX-2-selective inhibitors Cyclooxygenase - enzymes responsible for
Nonselective COX-1 inhibitors (COX), prostaglandin (COX) and
DMARDS › Drugs lipoxygenase (LOX) leukotriene (LOX) synthesis
› MOA Reye’s syndrome - rare syndrome of rapid liver
› Pharmacokinetics degeneration and
› Indications encephalopathy
› Adverse effects - treated with aspirin during
TNF – alpha blockers › Drugs viral infection
› MOA Uricosuric agent - drug that increases the renal
› Pharmacokinetics excretion of uric acid
› Indications
Enterohepatic - biliary excretion and
› Adverse effects
circulation reabsorption
IL-1 inhibitors › Drugs
› MOA
› Pharmacokinetics
› Indications
› Adverse effects
Glucocorticoids › Drugs
› Indications
› Adverse effects
Others › Acetaminophen
› Ketorolac
› Tramadol
Drugs used in gout › Colchicine
› Uricosuric agents
› Allopurinol
› Febuxostat
› Pegloticase

NSAIDs Effectively controls inflammatory pain

Chemistry & - several chemical classes
Pharmaco- - only nabumetone (ketone prodrug) is a
kinetics weak organic acids
- most are well absorbed
- Bioavailability is not affected by food
- Most are highly metabolized by phase I 
phase II mechanisms
- others by direct glucuronidation (phase II)
alone.
- NSAID metabolism – in the liver by
CYP3A or CYP2C (P450)
- Renal excretion - most important route for
final elimination
- Nearly all undergo biliary excretion and
reabsorption (enterohepatic circulation)
- highly protein-bound to albumin (~ 98%)
- All NSAIDs - found in synovial fluid after
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
repeated dosing › NSAIDs - differentiated on the basis of
- Drugs with short half-lives = remain in the toxicity and cost-effectiveness
joints › Celecoxib – expensive, safest for
- Drugs with long half-lives = disappear patients at high risk of GI bleeding but
from synovial fluid may result to higher risk of
Pharmaco- › NSAID anti-inflammatory activity = cardiovascular toxicity
dynamics inhibition of prostaglandin biosynthesis › Celecoxib/nonselective NSAID +
› Additional MOA = (1) inhibition of omeprazole or misoprostol = most
chemotaxis, (2) down-regulation of IL-1 appropriate for patients at highest risk
production (3) decreased production of for GI bleeding
free radicals and superoxide (4) › Choice of an NSAID - requires a
interference with calcium-mediated balance of efficacy, cost-effectiveness,
intracellular events. safety, and numerous personal factors
› NSAIDs are reversible inhibitors (other drugs being used, concurrent
Effects/uses › All newer NSAIDs = analgesic, anti- illness, compliance, medical insurance)
inflammatory, and antipyretic, inhibit › No best NSAID for all patients
platelet aggregation (except COX-2 › 1 or 2 best NSAIDs for a specific
selective inhibitors and nonacetylated person
salicylates
› NSAIDs decrease sensitivity of vessels
to bradykinin and histamine = (1) affect
lymphokine production from T
lymphocytes, (2) reverse the
vasodilation of inflammation
› There is no evidence that it alters the
course of arthritic disorder
› Reduce the incidence of colon cancer
when taken chronically
› Most are effective in RA, seronegative
spondyloarthropathies, OA, localized
musculoskeletal syndromes, gout
Adverse › NSAIDs = gastric irritants;
effects associated with GI ulcers and bleeds
› Newer NSAIDs = less GI irritant
than aspirin
› Nephrotoxicity = associated with
prostaglandin inhibition = interference with
the autoregulation of renal blood flow
COX-2 SELECTIVE INHIBITORS (Coxibs)
(modulated by prostaglandins)
Hepatotoxicity – occurs with any NSAID
Important › Developed to inhibit prostaglandin
notes synthesis by the COX-2 isozyme
AE similar 1. Central nervous system: Headaches,
(inflammation) without affecting action
for all tinnitus, dizziness, aseptic meningitis
of COX-1 (GI tract, kidneys, and
NSAIDs 2. Cardiovascular: Fluid retention,
platelets)
hypertension, edema, myocardial infarction,
› Does not affect platelet aggregation
Rare congestive heart failure (CHF).
› inhibit COX-2-mediated prostacyclin
3. Gastrointestinal: Abdominal pain,
synthesis in the vascular endothelium
dyspepsia, nausea, vomiting, ulcers or
› no cardioprotective effects
bleeding.
› Recommended doses = cause renal
4. Hematologic: Rare thrombocytopenia,
toxicities
neutropenia, aplastic anemia.
› Incidence of cardiovascular thrombotic
5. Hepatic: Abnormal liver function test
results and rare liver failure.
DRUGS › 10–20 times more selective for COX-2
6. Pulmonary: Asthma. Celecoxib than for COX-1.
› Half-life = 11 hrs
7. Skin: Rashes, all types, pruritus.
› 27%= unchanged drug in urine
8. Renal: Renal insufficiency, renal failure,
excretion
hyperkalemia, proteinuria.
› Metabolized by CYP2C9 (liver)
Choice of › Tolmetin ineffective for gout
› Drug interaction: warfarin
NSAIDs › Aspirin – less effective for AS
› Fewer endoscopic ulcers than other
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
NSAIDs › <1% = unchanged drug in urine
› Sulfonamide = rashes excretion
Meloxicam › Enolcarboxamide related to piroxicam › Used in OA and RA (300 mg; 2-
› “Preferentially selective” not highly 3x/day or 500mg; 2x/day
selective followed with maintenance of 00
› Fewer clinical GI symptoms mg/d)
› inhibits synthesis of thromboxane A2 Flurbiprofen › Propionic acid derivative
without affecting platelet function › S)(–) enantiomer inhibits COX
› Half-life = 20 hrs nonselectively
› <1% = unchanged drug in urine › Rat tissue - affect α (TNF-α)
excretion (tumor necrosis factor) and nitric
oxide synthesis
› Extensive hepatic metabolism
› No chiral conversion
› Demonstrate enterohepatic
circulation
DOSAGE FORMS
NONSELECTIVE COX INHIBITORS
› Topical ophthalmic =
Important notes › intraoperative miosis
DRUGS › Phenylacetic acid derivative › IV = perioperative analgesia in
Diclofenac › Half-life = 1.1 hrs minor ear, neck, and nose
› <1% = unchanged drug in urine surgery
excretion › Lozenge = sore throat
› Less occurrence of GI ulceration AE: cogwheel rigidity, ataxia, tremor,
› Drug interaction: diclofenac and and myoclonus
misoprostol = decreased upper Ibuprofen › simple derivative of
gastrointestinal ulceration; phenylpropionic acid
induce diarrhea › equivalent to 4 g of aspirin in
› Diclofenac + omeprazole = anti-inflammatory effect
prevention of recurrent bleeding; › Half-life = 2 hrs
common renal AE in high risk › <1% = unchanged drug in urine
patients excretion
› Impair renal blood flow and DOSAGE FORMS
glomerular filtration rate › Oral (lower dose; OTC) =
› Common occurrence of serum analgesic but not anti-
aminotransferases elevation inflammatory
DOSAGE FORMS: › Oral and IV = closing patent
› 0.1% ophthalmic preparation - ductus
postoperative ophthalmic › arteriosus in preterm infants
inflammation, intraocular lens › Topical cream = absorbed into
implantation, strabismus surgery fascia and muscle; primary knee
› Topical gel containing 3% OA
diclofenac = solar keratosis › Liquid gel (400mg) = postsurgical
› Rectal suppository - preemptive dental pain
analgesia and postoperative › Effects: decreases urine output
nausea less and less fluid retention
› EU = oral mouthwash and IM › Contraindication: Patients with
Diflunisal › Derived from salicylic acid nasal polyps, angioedema, and
› Undergoes an enterohepatic bronchospastic reactivity to
cycle = reabsorption of its aspirin
glucuronide metabolite = › AE: Aseptic meningitis (patients
cleavage of glucuronide = with SLE), and fluid retention
release active moiety › Drug interaction: Ibuprofen and
› Half-life = 13 hrs, 2 divided aspirin = antagonizes the
doses irreversible platelet inhibition
› 3-9% = unchanged drug in urine induced by aspirin; limit
excretion cardioprotective effects of
Etodolac › Racemic acetic acid derivative aspirin; decrease total anti-
› Half-life = 6.5 hrs (immediate)
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
inflammatory effect › Half-life = 58 hrs (very long)
› AE: agranulocytosis and aplastic › 1-4% = unchanged drug in urine
anemia excretion
Indomethacin › indole derivative › No enterohepatic circulation
› inhibit phospholipase A and C › Mildly uricosuric = mildly
› reduce neutrophil migration, increases uric acid secretion
› decrease T-cell and B-cell Piroxicam › Oxicam
proliferation › High concentrations = inhibits
› accelerate closure of patent polymorphonuclear leukocyte
ductus arteriosus. migration, decreases oxygen
› Tried for: Sweet’s syndrome, radical production, and inhibits
juvenile RA, pleurisy, nephrotic lymphocyte function
syndrome, diabetes insipidus, › Half-life = 57 hrs (long = 1x/day
urticarial vasculitis, dosing)
postepisiotomy pain, and › 4-10% = unchanged drug in
prophylaxis of heterotopic urine excretion
ossification in arthroplasty › Used in usual rheumatic
› Half-life = 4-5 hrs indications
› 16% = unchanged drug in urine › Higher dose (20 mg/d) =
excretion increased incidence of peptic
DOSAGE FORMS ulcer and bleeding
› Ophthalmic preparation = Sulindac › Sulfoxide prodrug
conjunctival inflammation; › Reversibly metabolized to active
reduce pain after traumatic sulfide metabolite
corneal abrasion › Enterohepatic cycling prolongs
› Oral rinse = Gingival duration of action (12-16 hrs)
inflammation › Used for rheumatic disease and
› Epidural injections = pain relief in familial intestinal polyposis
postlaminectomy syndrome › Inhibit the development of colon,
› AE: GI = pancreatitis; headache, breast, and prostate cancer
dizziness, confusion, and › Half-life = 8 hrs
depression; renal papillary › 7% = unchanged drug in urine
necrosis excretion
Ketoprofen › propionic acid derivative › More severe AE: Stevens-
› inhibits lipoxygenase Johnson epidermal necrolysis
› Half-life = 1.8 hrs syndrome, thrombocytopenia,
› <1% = unchanged drug in urine agranulocytosis, and nephrotic
excretion syndrome
› Drug interaction: Concurrent › AE: cholestatic liver damage
administration of probenecid = Tolmetin › Not often used
elevates ketoprofen levels and › Half-life = 1 hr (short)
prolongs plasma half-life › 7% = unchanged drug in urine
› Effective dosage = 100-300 mg/d excretion
› Major adverse effects = GI tract › Ineffective in the treatment of
and the central nervous system gout.
Nabumetone › only nonacid NSAID Azapropazone, › Rarely used
› ketone prodrug carprofen,
› resembles naproxen in structure meclofenamate,
› Half-life = >24 hrs (1x/day tenoxicam
dosing)
› No enterohepatic circulation
› Renal impairment = doubled half- ASPIRIN
life and 30% increase in area Important notes › rarely used as an anti-
under the curve inflammatory medication
› Less damaging to the stomach › antiplatelet effects
› Needs higher dosages › acetylsalicylic acid
› Very expensive NSAID › Long-term use at low dosage
Oxaprozin › propionic acid derivative = lower incidence of colon
cancer
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
MOA › irreversibly inhibits platelet legacy) products and biosimilar
› COX (antiplatelet effect) DMARDs
Pharmacokinetics › pKa = 3 ABATACEPT › T-cell–modulating biologic
› Rapidly hydrolized (serum › MOA: inhibits the activation of T
half-life = 15 mins) cells
› Hydrolysis by esterases in – T cell will first interact with
tissue and blood = acetic antigen-presenting cell (which
acid and salicylate has CD80/CD86); a second
› Salicylate = nonlinearly signal by CD28 is produced
bound to albumin when T cell interaction with
CD80/CD86 that will activate
› Alkalinization of urine = T cell
↑ rate excretion of free – Abatacept (CTLA-4) binds to
salicylate and water-soluble CD80 and 86 which stops
conjugates binding with CD28 (no
Clinical Uses › Decreases incidence of: second signal produced) = no
1. Transient ischemic attacks activation
2. unstable angina › Pharmacokinetics: Adult with RA
3. coronary artery thrombosis = 3 IV infusion “induction” dose
4. with myocardial infarction (even # weeks); followed with
5. thrombosis after coronary monthly infusions
artery bypass grafting – Dose: based on body weight
› Valuable in treating: › Available: subcutaneous
preeclampsia-eclampsia formulation
› Contraindicated in patients › JIA: induction sched at week
with hemophilia 0,2,4; followed with infusion every
Adverse effects › Main AE (antithrombotic 4 weeks
dose): gastric upset › Indications: monotherapy or in
(intolerance); gastric and combination with methotrexate or
duodenal ulcers other DMARDs (severe RA/ PJIA)
› Hepatotoxicity, asthma, › Most beneficial effects: psoriatic
rashes, GI bleeding, and arthritis (PsA) patients
renal toxicity › Patients screened for latent
tuberculosis and viral hepatitis
DISEASE-MODIFYING before starting
ANTIRHEUMATIC DRUGS (DMARDs) › Live vaccines – avoided during;
Important notes › Rheumatic Arthritis - progressive months after discontinuation
immunologic disease › AE: slightly increased risk of
– causes significant systemic infection of upper respiratory or
effects, shortens life, and urinary tracts
reduces mobility and quality › Possible increased lymphomas
of life AZATHIOPRINE › csDMARD = major metabolite: 6-
› Treatment goal: stop or slow the thioguanine. 6-Thioguanine
progression by modifying the › MOA: suppresses inosinic acid
disease synthesis, B-cell and T-cell
› Disease-modifying therapies: function, immunoglobulin
1. conventional synthetic (cs) = production, and IL-2 secretion
small molecule drugs › Pharmacokinetics: oral or
2. biologic (b) disease-modifying parenteral
antirheumatic drugs = large- – Bimodal metabolism: Rapid
molecule therapeutic agents metabolizers 4x faster
(proteins). Often produced by – Metabolite production –
recombinant DNA technology dependent on TPMT =
› Gold salts – no longer patients with low/no TPMT
recommended = significant are at high risk of
toxicities and questionable myelosuppression (if dose is
efficacy not adjusted)
› bDMARDs - biological original (or › Indications: prevention of kidney
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
transplant rejection ribonucleotide synthesis and the
– efficacy in PA, reactive arrest of stimulated cells in the G1
arthritis, polymyositis, SLE, phase of cell growth
maintenance of remission in – Inhibits T-cell proliferation
vasculitis, and Behçet’s and reduces production of
disease autoantibodies by B cells
– Used in (less effective): – 2nd effect: increases of IL-10
scleroderma receptor mRNA, decreased
› AE: bone marrow suppression, GI IL-8 receptor type A mRNA,
disturbances, ↑ infection risk. and decreased TNF-α–
– Increase lymphomas dependent nuclear factor
– fever, rash, and hepatotoxicity kappa B (NF-κB) activation
signal acute allergic reactions › Pharmacokinetics: completely
CHLOROQUINE › nonbiologic drugs mainly used for absorbed from the gut
& malaria – Mean plasma half-life = 19
HYDROXYCH- › csDMARDs – rheumatic diseases days
LOROQUINE › MOA: – Active metabolite: A77-1726
1. suppression of T-lymphocyte – Undergoes enterohepatic
responses to mitogens recirculation
2. inhibition of leukocyte – Cholestyramine = enhance
chemotaxis leflunomide excretion and
3. stabilization of lysosomal increases total (50%)
enzymes › Indications: effective as
4. processing through the Fc- methotrexate in RA
receptor – inhibition of bony damage
5. inhibition of DNA and RNA – Combined with methotrexate
synthesis and leflunomide: 46.2%
6. trapping of free radicals ACR20 response
› Pharmacokinetics: rapidly › AE: Diarrhea (cause of
absorbed and 50% protein-bound discontinuation); Liver enzymes
– Tissue-bound (eyes) elevation; mild alopecia, weight
– Deaminated in liver gain, and increased blood
– Blood elimination half-life = 4 pressure
days › Leukopenia, thrombocytopenia
› Indications: Dose-loading › Contraindicated: pregnancy
increase rate of response METHOTREXA › synthetic nonbiologic
– 3-6 mos = response TE antimetabolite
– Used in SLE = decrease › first-line csDMARD for treating
mortality and skin RA
manifestations › MOA: Low doses = inhibition of
– Used in: Sjögren’s syndrome amino-imidazolecarboxamide
› AE: Ocular toxicity at high doses ribonucleotide (AICAR)
– dyspepsia, nausea, vomiting, transformylase and thymidylate
abdominal pain, rashes, and synthetase.
nightmares. – inflammatory functions of
CYCLOPHOSP › csDMARD neutrophils, macrophages,
HAMIDE › major active metabolite is dendritic cells, and
phosphoramide mustard = cross- lymphocytes are suppressed
links DNA to prevent cell – Secondary effects on
replication polymorphonuclear
› MOA: suppresses T-cell and B- chemotaxis
cell function (30-40%) – direct inhibitory effects on
› Indications: 2 mg/kg for SLE, proliferation and stimulates
vasculitis, Wegener’s apoptosis in immune
granulomatosis, other severe inflammatory cells.
rheumatic diseases – inhibits proinflammatory
LEFLUNOMIDE › MOA: inhibits dihydroorotate cytokines linked to
dehydrogenase = decrease in rheumatoid synovitis
› Pharmacokinetics: orally or
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
parentally (SC or IM) infections
– 70% absorbed after oral – Malignancy
administration RITUXIMAB › MOA: chimeric monoclonal
– Bioavailability decreased – antibody biologic agent that
more than 25mg used targets CD20 B lymphocytes
– metabolized to a less active – Reduces inflammation by
hydroxylated product decreasing the presentation
– Parent compound and of antigens to T lymphocytes
metabolite – polyglutamated – inhibiting the secretion of
within cells proinflammatory cytokines
– Serum half-life = 6-9 hrs › Pharmacokinetics: Repeated 6-
– excreted principally in the 9 mos
urine; 30% - excreted in bile – Pretreatment 30 mins prior to
› Indications: increased to the infusion (acetaminophen,
most common dosing regimen for antihistamine, intravenous
the treatment of RA glucocorticoids ) = decreases
– ↑ effect = ↑ toxicity the incidence and severity of
– Drug decreases the rate of infusion reactions
appearance of new erosions › Indications: With methotrexate:
– Used in: juvenile chronic treatment of moderately to
arthritis, psoriasis, PA, AS, severely active RA
polymyositis, dermatomyositis, – With glucocorticoids: treatment
Wegener’s granulomatosis, of adult patients with
giant cell arteritis, SLE, and granulomatosis with
vasculitis polyangiitis and microscopic
› AE: Most common toxicities: polyangiitis
Nausea and mucosal ulcers › AE: Rash (first 1000mg) –
– leukopenia, anemia, stomatitis, decreases 10% with second
GI ulcerations, and alopecia infusion
– Progressive dose-related – Decreased immunuglobulins =
hepatotoxicity in the form of occurrence of infections
enzyme elevation occurs – Serious, fatal, bacterial,
frequently fungal, and viral infections
– Cirrhosis – Reactivation of hepatitis B
– Leucovorin – reduce incidence virus, fatal mucocutaneous
of GI and liver function test reactions, cytopenias
abnormalities – Cardiovascular events
– Contraindicated in pregnancy SULFASALAZI › csDMARD metabolized to
MYCOPHENOL › csDMARD NE sulfapyridine and 5-aminosalicylic
ATE MOFETIL › converted to mycophenolic acid acid
› MOA: inhibits inosine › MOA: Sulfapyridine = active
monophosphate dehydrogenase moiety in treating RA
= suppression of T- and B- – Suppression of T-cell
lymphocyte proliferation responses to concanavalin
– interferes with leukocyte and inhibition of in vitro B-cell
adhesion to endothelial cells proliferation
through inhibition of E-selectin, › Pharmacokinetics: 10–20% of
P-selectin, and intercellular orally administered
adhesion molecule 1 – A little undergoes
› Indications: treatment of renal enterohepatic recirculation
disease due to SLE – 5-aminosalicylic acid is
– useful in vasculitis and unabsorbed
Wegener’s granulomatosis – Half-life = 6-17 hrs
› AE: nausea, dyspepsia, and › Indications: effective in RA
abdominal pain, hepatotoxicity, – reduces radiologic disease
leukopenia, thrombocytopenia, progression
and anemia – uvenile chronic
– increased incidence of – arthritis, PsA, inflammatory
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
bowel disease, AS, and
spondyloarthropathy-
associated uveitis
› AE: Discontinued = toxicity
– nausea, vomiting, headache,
rash
– Hemolytic anemia,
methemoglobinemia,
thrombocytopenia, lupus
– Reversible infertility in men
but not in women
TOCILIZUMAB › MOA: binds to soluble and
membrane-bound IL-6 receptors,
and inhibits the IL-6-mediated
signaling via these receptors.
– IL-6 responsible for T-cell
activation, hepatic acute-
phase protein synthesis, and
stimulation of
inflammatory processes
involved in diseases
› Pharmacokinetics: Dose-
dependent half-life
– inhibiting IL-6 may restore
CYP450 activities to higher
levels
– used in combination with
nonbiologic DMARDs or as
monotherapy
– Dosage in SJIA/PJIA =
accounts for body weight
– Dosage modifications:
elevated liver enzymes,
neutropenia,
thrombocytopenia
› Indications: moderately
severely active RA
› AE: Serious infections
tuberculosis, fungal, viral, and
other opportunistic infections
– Upper respiratory
infections, headache,
hypertension, elevated liver
enzymes, GI perforation
– Neutropenia and reduction in
platelet
– Anaphylactic reaction
TNF-α-BLOCKING AGENTS
Important notes › affects cellular function via
activation of specific membrane-
bound TNF receptors
› Five “legacy” bDMARDs –
treatment of RA and other
rheumatic diseases
› Biosimilar biologics (bsDMARDs)
– lower costs
Adalimumab › fully human IgG1 anti-TNF
monoclonal antibody
› MOA: complexes with soluble
TNF-α and prevents its interaction
with p55 and p75 cell surface
receptors
› Pharmacokinetics: Given
subcutaneously
› Drug interactions: Methotrexate
– clearance is decreased;
formation of human anti-
monoclonal antibody is
decreased
› Indications: approved for RA,
AS, PsA, JIA, plaque psoriasis,
Crohn’s disease, and ulcerative
colitis.
– decreases the rate of
formation of new erosions
the – effective as monotherapy and
in combination with
methotrexate
Certolizumab › recombinant, humanized antibody
Fab fragment conjugated to a
polyethylene glycol (PEG) with
specificity for human TNF-α
› MOA: neutralizes membrane-
bound and soluble TNF-α
› Pharmacokinetics: given
subcutaneously
– Half-life = 14 days
– decreases the appearance of
anti-certolizumab antibodies.
– Initial dose: 400mg; 200mg =
and every other week; 400mg
every 4 weeks
to › Indications: treatment of adults
with moderately to severely active
= RA; monotherapy or in
combination with nonbiologic
DMARDs; Crohn’s disease, active
tract PsA, and active AS
Etanercept › Recombinant fusion protein
consisting of two soluble TNF p75
receptor moieties linked to the Fc
portion of human IgG1
› MOA: binds TNF-α molecules
and also inhibits lymphotoxin α.
› Pharmacokinetics: Given
subcutaneously
– drug is slowly absorbed
– Peak concentration = 72 hrs
– Mean serum elimination half-
life = 4.5 days
› Indications: treatment of RA,
juvenile chronic arthritis,
psoriasis, PsA, and AS.
– Decreases rate of formation
of new erosions relative to
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
methotrexate alone develop antidrug antibodies =
– used in other rheumatic interfere with drug efficacy
syndromes › INCREASED risk of
– such as scleroderma, gastrointestinal ulcers and large
granulomatosis with bowel perforation including
polyangiitis (Wegener’s diverticular and appendiceal
granulomatosis), giant cell perforation.
arteritis, Behçet’s disease, › Etanercept: lower activation of
uveitis, and sarcoidosis. latent tuberculosis
Golimumab › human monoclonal antibody with › Alopecia areata, hypertrichosis,
a high affinity for soluble and and erosive lichen planus
membrane-bound TNF-α › Cutaneous pseudo-lymphomas,
› MOA: neutralizes the Nonspecific interstitial
inflammatory effects produced by pneumonia, psoriasis, and
TNF-α sarcoidosis-like syndrome,
› Pharmacokinetics: administered leukopenia, neutropenia,
subcutaneously thrombocytopenia, and
– Half-life = 14 days pancytopenia
– Used with methotrexate =
increases golimumab serum OTHER DRUGS
levels and decreases anti-
USTEKINUMAB › MOA: IL-12 and IL-23 antagonist
golimumab antibodies
– part of both IL-12 and IL-23 =
– 50 mg = treatment of RA,
contributors to the chronic
PsA, and AS
inflammation in psoriasis
– Higher dose – treatment of
plaques, PsA, and Crohn’s
ulcerative colitis
disease
› Indications: moderately to
– prevents the binding of the
severely active RA, PsA, AS and
p40 subunit of both IL-12 and
moderate to severe ulcerative
IL-23 to the IL-12 receptor b1
colitis
found on the surface of CD4
Infliximab › Chimeric IgG1 monoclonal T cells and NK cells
antibody › Pharmacokinetics: 45- and 90-
› MOA: down-regulation of mg SC injection for PsA and
macrophage and T-cell function plaque psoriasis
› Pharmacokinetics: IV infusion
– Peak plasma concentration =
with “induction” = week 0,2,6; 7-13.5 days
maintenance every 8 weeks – Elimination half-life = 10-126
– Terminal half-life = 9-12 days days
– Elicits human antichimeric › Indications: treatment of adult
antibodies = 62%
patients with PsA, plaque
› Indications: approved for use in
psoriasis and Crohn’s disease
RA, AS, PsA, Crohn’s disease, › AE: Common: Upper respiratory
ulcerative colitis, pediatric tract infection
inflammatory bowel disease, and › Rare severe infection,
psoriasis malignancy, reversible posterior
– granulomatosis with leukoencephalopathy syndrome
polyangiitis (Wegener’s
SECUKINUMAB › MOA: selectively binds to the IL-
granulomatosis), giant cell
17A cytokine, inhibiting its
arteritis, Behçet’s disease,
interaction with the IL-17A
uveitis, and sarcoidosis
receptor
Adverse Effects › INCREASED infections and › Pharmacokinetics: Available as
of TNF-α- macrophage-dependent infection SC injection or lyophilized powder
Blocking (including tuberculosis, fungal,
for injection
Agents and other opportunistic infections) – Elimination half-life = 22-31
› INCREASED risk of HBV days
reactivation › Indications: For moderate to
› INCREASED risk of skin cancers severe plaque psoriasis
› induce the immune system to – Initial loading dose: 300 mg
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
SC (0,1,2,3,4 weeks) same subcutaneously
for active PsA and moderate – Maximum plasma
to severe plaque psoriasis concentration: 3-7 hrs
› AE: Common side effect: infection – Absolute bioavailability: 95%
– Nasopharyngitis (12%) – Terminal half-life: 4-6 hrs
TOFACITINIB › MOA: selectively inhibits all › Indications: treatment of
members of the Janus kinase moderately to severely active RA
› Therapeutic dose: inhibiting – DOC for CAPS esp neonatal-
JAK3 and JAK1 (lesser extent) = onset multisystem
interrupt JAK-STAT signalling inflammatory disease
pathway (major role in (NOMID)
pathogenesis of autoimmune – Effective in gout, Behçet’s
diseases) disease, adult onset JIA
– JAK1 = controls signal Canakinumab › human IgG1/κ monoclonal
transduction from IL-6 and antibody against IL-1β.
interferon receptors. › MOA: forms a complex with IL-
› Pharmacokinetics: Treatment of 1β, preventing its binding to IL-1
RA = double dose increases receptors
response and toxicity › Pharmacokinetics: given by
– Oral bioavailability = 74% subcutaneous injection
– Elimination half-life = 3 hrs – Peak serum concentration = 7
– Metabolism – 70% in liver days after injection
(CYP3A4) – Bioavailability = 66%
– 30% excreted unchanged by – Mean terminal half-life – 26
the kidneys days
› Indications: prevent solid organ › Indications: active SJIA in
allograft rejection children 2 years or older
– treatment of inflammatory – Treat CAPS, familial cold
bowel disease, autoinflammatory syndrome
spondyloarthritis, psoriasis, and Muckle-Wells syndrome
and dry eyes Rilonacept › MOA: Neutralizes IL-1β and
› AE: increases the risk of infection prevents its attachment to IL-1
› Most common: upper respiratory receptors
tract infection and urinary tract › Pharmacokinetics:
infection Subcutaneous dose = age-
› More serious infections: dependent
pneumonia, cellulitis, esophageal › Indications: treat CAPS
candidiasis, and other subtypes: familial cold
opportunistic infections. autoinflammatory syndrome and
› Lymphoma and other Muckle-Wells syndrome in
malignancies (lung and breast patients 12 years or older
cancer) – reported Adverse Effects › Most common adverse effects -
› Other effects: Headache, of Interleukin-1 injection site reactions and upper
diarrhea, elevation of liver Inhibitors respiratory tract infections
enzymes, and gastrointestinal › Hypersensitivity reactions:
perforation Headache, abdominal pain,
nausea, diarrhea, arthralgia, and
INTERLEUKIN-1 INHIBITORS flu-like illness
Important notes › IL-1α plays a major role in the
pathogenesis of several GLUCOCORTICOID DRUGS
inflammatory and autoimmune Indication › 60–70% of RA patients = effects
diseases including RA are prompt and dramatic, capable
› IL-1α, IL-1β, and IL-1 receptor of slowing the appearance of new
antagonist bone erosions
› competitive inhibitor of the › Corticosteroids - serious extra-
proinflammatory IL-1α and IL-1β articular manifestations of RA
Anakinra › oldest drug; rarely used for RA (pericarditis or eye involvement or
› Pharmacokinetics: Given during periods of exacerbation)
Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid
Analgesics, & Drugs Used in Gout
Chapter 36 • Katzung, B. Basic and Clinical Pharmacology
– Other rheumatic diseases in excitement, and disorientation
which corticosteroids’ anti- – 15g of acetaminophen = fatal
inflammatory effects are – Death = severe hepatotoxicity
used: vasculitis, SLE, with centrilobular necrosis
Wegener’s granulomatosis, (sometimes = acute renal
PA, giant cell arteritis, tubular necrosis)
sarcoidosis, and gout › >4 g/d = not usually
– Increase in proinflammatory recommended; alcoholism
cytokines in the early morning contraindicates
= induces morning stiffness › Early symptoms of hepatic
and joint paint (circadian damage = nausea, vomiting,
rhythm) diarrhea, and abdominal pain
Adverse effects › Prolonged use of corticosteroids – › Adverse: Hemolytic anemia and
serious and disabling toxic effects methemoglobinemia
› Many of adverse effects occur at › Dosage: 325–500 mg four times
doses below 7.5 mg daily for acute pain and fever
KETOROLAC › Promoted for systemic use =
short-term analgesic
OTHER
› Effective analgesic
Acetaminophen › active metabolite of phenacetin = › Replace morphine involving mild
responsible for its analgesic effect to moderate postsurgical pain
› weak COX-1 and COX-2 inhibitor › Most often given intramuscularly
in peripheral tissues or intravenously, oral formulation
› no significant anti-inflammatory is available
effects › Used with opioid – decrease
› Pharmacokinetics: administered opioid requirement (25-50%)
orally. › Chronic use = renal toxicity
– Peak blood concentrations =
TRAMADOL › centrally acting synthetic
30–60 minutes
analgesic
– Poorly bound to plasma
› involve both nonopioid and opioid
proteins
receptors
– Partially metabolized by
› No significant anti-inflammatory
hepatic microsomal enzymes
effects
to the inactive sulfate and
› Analgesic effect: enhance 5-
glucuronide
hydroxytryptamine (5-HT) release
– <5% = excreted unchanged
› Analgesic effect: inhibiting the
– N-acetyl-p-benzoquinone
reuptake of norepinephrine and 5-
(highly reactive metabolite) =
HT
toxic to both liver and kidney
– Half-life = 2- hrs
– Unaffected by renal function
› Indications: acetaminophen
lacks anti-inflammatory properties
– does not affect uric acid
levels and lacks platelet-
inhibiting effects
– useful in mild to moderate
pain such as headache,
myalgia, postpartum pain
– Used alone is nadequate
therapy for inflammatory
conditions such as RA
– Preferred for patients allergic
to aspirin and in patients with
haemophilia, peptic ulcer, and
bronchospasm
› Adverse effects: Mild reversible
increase in hepatic enzymes
– Larger doses: dizziness,