Lecture 3

Done by : Mostafa lahalieh

Presented by : Tariq shtewi

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 Anti-inflammatory Drugs
➢Prostaglandins

➢Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

➢Acetaminophen

➢Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)

➢Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

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 Celecoxib

• Selective COX-2 inhibitor

Again selective cox2 means less gastric effects
But higher cardiac (thrombotic )problems

•Results in reversible inhibition of COX-2

Celecoxib

Therapeutic uses
• Rheumatoid arthritis potent anti-inflammatory action
• Osteoarthritis The dosage should be reduced in those with
moderate hepatic impairment, and celecoxib
should be avoided in patients with severe
• Pain analgesic action hepatic or renal disease.

(similar efficacy to non-selective NSAIDS) Inhibitors of CYP2C9, such as fluconazole,

may increase serum levels of celecoxib.
Pharmacokinetics
• Oral
• Metabolism: hepatic (CYP2C9)
• Half-life: 11 hours

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 Celecoxib

Adverse effects

❑ Headache
❑ Dyspepsia without injury or bleeding /diarrhea/abdominal pain
❑ LESS GI problems than non-selective NSAIDS
❑ Risk for cardiovascular disease Patients who are at high risk of ulcers and require aspirin for
cardiovascular prevention should avoid the use of celecoxib.

again asprine action depends on the dose

non selective cox 1 related with gastric problems
selective cox 2 related to thrombotic problems

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Anti-inflammatory Drugs
➢Prostaglandins

➢Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

➢Acetaminophen

➢Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)

➢Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs)

Acetaminophen

✔ Inhibits prostaglandin synthesis in CNS

✔ Antipyretic/analgesic
✔ Minor effect on peripheral cyclooxygenase. Which means?
Not an anti inflammatory due to peripheral inactivation

✔ Does not affect platelet function or increase bleeding time.

✔ NOT considered an NSAID.

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 Acetaminophen

Therapeutic uses
• Fever by reducing prostaglandin
• Pain
•Useful in gastric/ complaints prolongation of bleeding time is not
desirable
• Preferable for children

Acetaminophen is the analgesic/antipyretic of choice

for children with viral infections or chickenpox

Acetaminophen
Pharmacokinetics
•IV/ oral/ rectal…. 5.5 hours
•Rapidly absorbed from GI
• conjugated in the liver to form
inactive glucuronidated or sulfated metabolites
•N-acetyl-p-benzoquinoneimine, or NAPQI,
a highly reactive metabolite causes cause liver damage

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 Acetaminophen

Adverse effects
•Usually safe one of the safest drugs
•Hepatic necrosis
• Patients with hepatic disease, viral hepatitis, or a history of
alcoholism are at higher risk of acetaminophen- induced
hepatotoxicity.
•N-acetylcysteine is an antidote in cases of overdose

Acetaminophen should be avoided in patients with severe hepatic impairment.

Anti-inflammatory Drugs
➢Prostaglandins

➢Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

➢Acetaminophen

➢Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)

➢Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs)

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Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)
Advantages:
• Slow the course of the disease
‫مو بس بنقلل االلتهاب واأللم زي األدوية السابقة‬

•Induce remission
• Prevent further tissue destruction
-Usually started as soon as possible
-Monotherapy is preferred; combinational therapy for advanced or
inadequate response.

Reminder: we took it before as an anti-

Methotrexate cancer & immunosuppressive drug

•MOA: folic acid antagonist MOA: dihydrofolate reductase inhibitor

•Actions: cytokine production and

purine nucleotide biosynthesis , immunosuppression and anti-
inflammatory
•Mainstay in the treatment of RA
•Response: 3-6 weeks after initiating the therapy
•Monotherapy preferred first ,
If inadequate response? combination

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 Methotrexate
Adverse effect
REMEMBER: dose used for RA is less than anticancer dose (given once
weekly)

❑Mucosal ulceration, nausea

❑ Cytopenias +anemia

❑ Liver cirrhosis

❑ Acute pneumonia-like syndrome

Note: Supplementation with folic acid may improve tolerability of methotrexate and reduce Gl and hepatic adverse effects.

• Cancer:
inhibits dihydrofolate reductase (DHFR) and synthesis of DNA, RNA,
thymidylates, and proteins
• RA:

✔ inhibition of enzymes involved in purine metabolism - accumulation of

adenosine

✔ inhibition of T cell activation and down-regulation of B cells

✔inhibition of the binding of IL-1b

Pregnancy?
teratogenic effects: craniofacial abnormalities, limb defects, and CNS
defects
Methotrexate is contraindicated in pregnancy.

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 Hydroxychloroquine
•Used for early-mild RA
•Mechanism of action: unknown (for autoimmune diseases)
has immunosuppressive effect Hydroxychloroquine has less adverse effects on
the liver and immune system than other DMARDs.
•Response: 6 weeks to 6 months
•Adverse effects: ocular toxicity, GI upset and skin discoloration

Leflunomide
•Immunomodulatory agent used in moderate-to-severe RA
•Mechanism of action: inhibits dihydroorotate dehydrogenase
(DHODH)so reduce DNA replication(rapidly proliferating cells are affected e.g lymphocytes)
•Actions: lymphocyte cell arrest
•Used as an alternative or in combination with methotrexate

~~ Adverse effects
• weight loss, skin rash, alopecia, and hypokalemia. Hepatotoxic
• contraindicated in pregnancy.
•Monitoring parameters include signs of infection, complete blood
count, electrolytes, and liver enzymes

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 Sulfasalazine Glucocorticoids

•Mechanism of action: unclear •Anti-inflammatory drugs

Immunosuppressive action •Give time for DAMRDs to
•Response: 1-3 months work

•Adverse effect: GI • Shortest duration and lowest

disturbances, leukopenia dose.

Anti-inflammatory Drugs
➢Prostaglandins

➢Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

➢Acetaminophen

➢Traditional Disease-Modifying Antirheumatic Drugs (DMARDs)

➢Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs)

More selective than DMARDS
Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs)
• Main proinflammatory cytokines: IL-1 and TNF-α
• Both stimulate synovial cells proliferation → cartilage degradation,
bone resorption, etc
• TNF-α inhibitors vs non-TNF-α inhibitors
Signs & symptoms
• Decrease s/s of RA, progression of
disease, structural damage
• Monotherapy
vs combination in sever cases

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 Cautions
•Increased risk for infections due to its potent immunosuppressive action
(tuberculosis and sepsis) Note: TNF-a inhibitors and non-TNF biologic agents should not be used together
due to the risk of severe infections.

•Increased risk of fungal opportunistic infections

• Pancytopenia
•Live vaccinations should not be administered while on TNF-α
inhibitor therapy. Risk of viral activation & impaired immune response to vaccines
• Should be used very cautiously in those with heart failure (can
worsen heart failure).
If a patient has failed monotherapy with one TN F-a inhibitor, a traditional
DMARD may be added, or therapy with a non-TNF biologic agent or a
•Increased risk of lymphoma different TNF-a inhibitor may be tried.

Adalimumab

•Recombinant monoclonal antibody against TNF-α

•Blocks the interaction between TNF-α and its cell surface receptor
• For moderate to severe RA… SC-Weekly
•Monotherapy or in combination with methotrexate
•Other uses: psoriatic arthritis, ankylosing spondylitis, and Crohn
disease. Inflammatory bowl disease
•Adverse effects: headache, nausea, agranulocytosis, rash, reaction at
the injection site, or increased risk of infections (UTIs, URTIs) -->
urinary tract infections & upper respiratory tract infections

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 Certolizumab similar to adalimumab

• Potent neutralizer of TNF-α biological actions

• SC bi-weekly
•Adverse effects to other TNF-α inhibitors (infections etc.)

Etanercept
• Recombinant, fully human receptor fusion protein
• binds to TNF-α and blocks its interaction with
cell surface TNF-α receptors
• For moderate to severe RA… SC-Weekly
• Monotherapy or in combination with
methotrexate
[Etanercept+methotrexate > each drug alone]
• Other uses: ankylosing spondylitis and psoriasis
• Same adverse effects

Golimumab monoclonal anti body

• neutralizes the biological activity of TNF-α by binding to it and

blocking its interaction with cell surface receptors.
•Monotherapy or with methotrexate
• SC-monthly
•Can be associated with hepatitis B reactivation
Golimumab may increase hepatic enzymes.

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 murine Infliximab
Human+ mouse components
• chimeric monoclonal antibody
• binds specifically to human TNF-α and
inhibits binding with its receptors
•Approved f or patients with inadequate
response to methotrexate monotherapy
•Not used as a single agent. Why? as this leads to the development of anti-infliximab antibodies
and reduced efficacy.

•Given IV infusion bi-monthly

• Similar adverse effect profile to the other TNF-α inhibitors
Non-TNF-α inhibitors: Abatacept

• a soluble recombinant fusion protein

•Competes with CD28 for binding on CD80/CD86 protein,
thereby preventing full T-cell activation (STEP II)
• For moderate to severe RA, no response to DMARDs or TNF-
α inhibitors
•Given IV monthly
•Adverse effects: headache, upper respiratory infections,
nasopharyngitis, and nausea

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 Non-TNF-α inhibitors: Rituximab
murine/human monoclonal antibody

•B cells can perpetuate the inflammatory process in the synovium by’

1) activating T lymphocytes
2) producing autoantibodies and rheumatoid factor
3) producing proinflammatory cytokines, such as TNF-α and IL-1.
•Rituximab chimeric monoclonal against CD20 🡪 causes B-cell
depletion
•Used in combination with methotrexate for moderate to severe RA
•IV infusion 16-24 weeks, methylprednisolone before
To reduce infusion reactions, methylprednisolone, acetamino- phen, and an antihistamine are administered prior to each
infusion. Infusion reactions (urticaria, hypotension, and angioedema) are the most common complaints and typically occur
during the first infusion.

Non-TNF-α inhibitors: Tocilizumab and sarilumab

•Monoclonal antibody
•IL-6 receptor blocker
•Given IV
•Monotherapy or with methotrexate or other DMARDs
• For moderate to severe RA
High blood pressure could happen as an adverse effect

Adverse reactions include elevated liver function tests, hyperlipidemia, neutropenia, hypertension, and infusion-
related and injection site reactions.

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 Metabolism of tofaci- tinib is mediated primarily by CYP3A4

Enzymes involved in inflammatory Tofacitinib

and immune responses
•Janus kinases modulate immune cell activity
• Pro-inflammatory status - increase in Janus kinase
activity and activation of the immune system.
•Oral inhibitor of Janus Kinases
• For moderate to severe RA
•Hb must be > 9 g/dL to start tofacitinib (risk for anemia)
HB, lymphocyte and neutrophil counts should be checked prior to initiation of therapy and monitored during treatment
Anakinra
•IL-1 mediates degradation of cartilage and stimulation of bone resorption
•Anakinra is an IL-1 receptor antagonist
•Infrequently used for RA
Note: Anakinra, azathioprine, cyclosporine, gold, and minocycline are other agents used infrequently in the treatment of
RA due to their adverse effect profile or the availability of other agents with more proven efficacy.]

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