ANTI-INFLAMMATORY DRUGS

• Group of agents: Different in Anti-pyretic, Analgesic, Anti-inflammatory.

NSAID .
1. Aspirin Disease-modifying Antirheumatic agents
2. Propionic acid derivatives
3. Acetic acid derivatives 1. Methotrexate
4. Oxicam derivatives 2. Leflunomide
5. Fenamates 3. Hydroxychloroquine
6. Heteraryl acietic acids 4. Sulfasalazine
7. Nabumetone 5. D-Penicillamine
8. Celecoxib 6. Gold salts
7. Azathioprine
8. Cyclophosphamide
1. Acetaminophen 9. Glucocorticoids

Biological therapies in Rheumatoid Arthritis

Drugs for Gout
1. Etanercept
1.Indomethacin, aspirin =Acute 2. Infliximab
2. Allopurinol 3. Adalimumab
3.Colchicine 4. Golimumab
4.Febuxostat 5. Certolizumab pegol
5. Probenecid & Sulfinpyrazone 6. Anakindra
7. Abatacept
8. Rituximab

1. Aspirin =Acetyl Salicylic Acid = ASA

• Prototype of NSAID

A) Mechanism of Action
o It irreversibly acetylates COX. Other NSAID only reversibly do that.
o Reduces the amount of PG = Antipyretic, Analgesic, Anti-inflammatory.

B) Actions:
o Antinflammatory : Block Cox1 = Low PG=
o Analgesic = PgE2 is pain stimulant and increases the stimulation to
Bradykinin.
 -Aspirin is used mainly for the pain from musculoskeletal system
 than that from viscera. In malignancy: Opioids + NSAID
o Antipyretic: PgE2 increases the core temperature threshold in anbterior
 hypothalamus. Low PgE2 = Normal threshold.
o Respiratory actions:
Increases Alveolar ventilation due to the fact that Aspirin increases the CO2
= Increased ventilation. Also at higher doses acts upon medulla where the
 CO2 causes the patient to hyperventilate= Resp. Alkalosis. At Toxic doses=
Paralyzed medulla = Hypoventilation= Acidosis.
o -GI-effects
 Ulcerations, hemorrhages, epigastric distress, Iron-def anemia.
 1-4,5 g/day = Loss of 2-8 mL of blood in feces/day.
 PgE2 is cytoprotective of the mucosa by the production of Mucosa.
 Give along with NSAID: PPI, Misoprostol
o Platelet effects
 Thromboxane increases aggregation. PgI2 Decreases it.
 Low Thromboxane: Platetels do not have nuclei for reproduction of
thromboxane and thus by irreversible inhibition of COX = decreased production of TXA =
Antiplatelet activity.
 Low PgI2. In the endothelial cells this can be recreated even though the
aspirin irreversibly binds to COX at other site. Thus the aspirin on PgI2 is nullified as the
endothelial cells can compensate.

o Actions on the kidney

 PgE2 & PgI2 are maintaining the renal blood flow
 Low of PgE2 & PgI2 = Retention of Na and water = Edema &
hyperkalemia.

C) Therapeutic uses
 1. Antiinflammatory, analgesic, antipyretic
 To treat Gout, Rheumatic fever, Osteoarthritis, Rheumatoid arthritis
 Headache, arthralgia, myalgia
 2. External application
 Topically: Treat Acne, calluses, warts, corns

 3. Cardiovascular applications:
 Reduce risk of recurrent TIA, stroke, myocardial infarction in those who
have had that before or had Angina pectoris.

D) Pharmacokinetics
 Administration:
o Orally. Un-ionized Aspirin absorbed at stomach and intestines.
o Rectally: Not good. Slow absorption.
o Can pass the BBB & Placenta & absorbed through skin.
Ps: Avoid giving Aspirin(salicylates) to pat under 20 years who are afflicted with
Virus(varicella, influenza) to prevent Reyes syndrome(steatosis & Encephalopathy).

 Dosage
o Low doses: Analgesic effect
o High doses: Anti-inflammatory effect
o Prophylaxis of MI = 100 mg/day
Profylaxis of Stroke= 300mg/day
Rheumatoid / Osteoarthritis = 3 grams/day
 Fate
o Acetyl-salicylate is degraded by esterase = Acetyl + salicylate
o Salicylate gets conjugated in the liver and excreted via Kidney.
 o In case of high amounts of Aspirin(over 4 g/day, for rheuma) the
liver enzymes becomes saturated and 0-order kinetics is dealt with. Also Aspirin’s t½ goes from
3 hours(at 1st order kinetics) to 15 h (at 0 order kinetics).

o Aspirin competes with uric acid for elimination and thus don’t give
aspirin to Gout patient due to accumulation of urate.
o Also avoid in chronic kidney disease

E) Adverse effects
o GI: Epigastric distress, nausea, vomiting. GI bleeding
 Take aspirin with food to diminish the distress.
o Blood: Prolonged bleeding time.
 A gap of 1 week between Aspirin & surgery.
o Respiration: Respiratory depression 0 netabikuc acudisus
o Metabolic processes
 Large doses= Uncoupled oxidive phosphorylation= Hyperthermia
o Hypersensitivity: Urticaria, bronchoconstriction, angioedema.
o Reye Syndrome: Children+Virus+Aspirin= Bad combination. Lead to this syndrome
encompassing encephalitis & hepatitis. Give instead
acetaminophen to the minor.

o Drug interactions
o Aspirin is albumin bound. Drugs may dissociate it from the protein or the aspirin itself
can steal other agents places on the albumin- leading to increased conc. of other agents
o Aspirin will in this manner increase conc. of Valproic acid, phenytoin, warfarin.
o Chronic Aspirin not to be give with Probenecid or Sulfinpyrazone
 Can alter the ideal amount of urate in the blood.
o Contraindictation: Ketorolac + Aspirin = GI bleeding , aggregation inhibition.

o Pregnancy Contraindicatied: Pregnancy & Breast feeding.

G) Toxicity

Mild form= Salicylism Severe form

o Nausea, vomiting, o Restlessness, Convulsion
o Hyperventilation, o Delirium,hallucinations
o Headache, Mental fonfusion o Respiratory/metabolic acidosis
o Dizziness, Tinnitus o Death from resp. failure

2. Propionic acid derivatives

Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen Oxaprofen

o Action: Reversible inhibitors of COX.

o Bound to Albumin
o Anti-inflammatory, anti-pyretic, Analgesic
o Approved for Chronic treatment of RA, osteoarthritis = Less GI-bleeding than Aspirin.
o SE: GI-distress, headache, tinnitus, dizziness.
o Ibuprofen: Also for closing Ductus arteriosus. Better SE-profile than Indomethacin.

3 Acetic acid derivatives

Indomethacin & Sulindac
Mechanism Action: Reversible COX inhibitor
Action: Analgesic, antiinflammatory & Antipyretic
Uses: All except for lowering fever.
Indomethacin: Due to its toxicity: Limited to:PDA closure, Ankylosing spondylitis,
Osteoarthritis of hip.
Sulindac: Like indomethacin, but less potent:
Used in: Ankylosing spondylitis, RA, Acute Gout, Osteoarthritis

4. Oxicam derivatives
Piro-xicam, Melo-xicam
o Treat: RA, ankylosing spondylitis, Osteoarthritis.
o Both have long t½ = 1 tab/day.
o GI-disturbances in 20 % of the patients taking Piroxicam
o Meloxicam: Inhibitis COX1 & COX2

5. Fenamates
Me-fenamate & Meclo-fenamate
o No superiority over other NSAID. Assoiciated with inflammation of the bowel. Hemoltyic
anemia

6.Heteroaryl Acetetic Acid

Diclofenac & Tolmetin
o For long-term use in the treatment of RA, osteoarthritis, Ankylosing spondylitis.
Diclofenac= More potent than Indomethacin or Naproxen.
Tolmetin= Effective anti-inflammatory, antipyretic, analgesic agent.

Ketorolac = Potent analgesic, moderate anti-inflammatory.

Indication: Moderate-to- Severe pain up to 5 days after first IV-infusion.

Nabumetone
For what illness? RA, osteoarthritis.
Nabumetone -----Active metabolites in the liver. Active metabolites hepatically metabolized.
Hepatic failure? Be careful!

Celecoxib
COX-2 inhibitor = Time dependent and reversible.
Therapeutic uses: RA, osteoarthritis, Familial Adenomatous Polyposis(Benign gastric tumour with
thousands of polyps).
• Not prolonging bleeding time = Less GI-bleeding and dyspepsia.
Pharmacokinetics
• Readily absorbed: Peaks 3 h
• t½ = 11h.
• Metabolized by CYP-2C9 and then excreted via kidney
• Reduced to half dose in moderate hepatic/renal impairment.

Adverse effects Contraindication

Common: • If Allergic to Sulfonamides

1. Headache 1. Cardiac patients
2. Hepatic/renal failure
2. Dyspepsia, 3. Volume depletion
3. Abdominal pain
4. Diarrhea
5. Kidney toxicity

Drug interactions:
• CYP-2C9 inhibitors= Zafirlukast, fluvastatin, fluconazole= = Elevated Celebrex
• Celebrex blocks CYP-2D6 =Elevated beta-blockers, Amitryptiline Risperidone

ACETAMINOPHEN
Inhibits PG in the CNS. = Antipyretic and Analgesic
Weak anti-inflammatory, why? Low inhibition of COX in the periphery.
Not NSAID, no effect on aggregation.

A) Therapeutic Uses
1. Gastric complaint from Aspirin and want analgesia & Antipyresis? Take Acetaminophen
2. Children with viruses? Don’t give Aspirin(=Reye ). Take Acetaminophen
3. Having GI-problem/bleeding from Aspirin? Take Acetaminophen
4. You are a Gout-patient and have Uricosuric agents(urate into urin)?
Take Acetaminophen- does not antagonize these agents.
B) Pharmacokinetics
• Readily absorbed orally. First pass via intestines and liver Normally in liver metabolized to
inactive metabolites. But some of Acetominophen is hydroxylised to form
NAPQI=N-acetyl-P-BenzoQuinoNeimini which is hepatotoxic.

C) Adverse Effects
• In normal dose: Rearly any sideeffects. Maybe some rashes in minor cases
• In very high dose= Depletion of Glucuronate = Elevation of N-acetyl-p-Benzo-QuinoiNeimi
=Hepatotoxicity= Hepatic Necrosis
• Prolonged, large-dose therapy = Renal Tubular Necrosis.
Be careful in Chronic alcoholic, Viral hepatitis, hepatic disease.

Disease –Modifying Antirheumatic Agents ( DMARD )

DMARD used for RA. To impede the progression, and prevent DMARD
further injuries from the inflammation.
Ititiate treatment with DMARD within 3 months from Diagnosis of RA
(together with 10. Methotrexate
corticosterioids, NSAID, physical therapy)
We can combine and mix. 11. Leflunomide
The drug och choice: Methotrexat, Hydroxychloroquinine 12. Hydroxychloroquine
If these do not work we jump over to the newer Dmards. 13. Sulfasalazine
14. D-Penicillamine
15. Gold salts
16. Azathioprine
17. Cyclophosphamide
18. Glucocorticoids
1. Methotrexate
• Alone or combined treatment: If Alone is not efficient = Combine with other DMARDS
• Immunosuppressive – good vs Autoimmunity
• Effect after 3-6 weeks
• Dose for efficiency is much lower than that for chemotherapy = Less adverse effects

Adverse effects: Mucosal ulceration and nausea.

Cytopenias, cirrhosis of the liver, = Due to cytotoxicity!

2. Leflunomide
Action: Cytostatic drug of T-cells. How? DNA replication is in need of DHODH which is blocked by
Leflunomide.
Treatment: RA
Bonus effect: Inhibits osteoclast activity.

Pharmacokinetics
• Readily absorbed. Active metabolites from the liver bound to albumint ½= 2 weeks

Adverse effects
1. Headache Contraindication: Pregnancy, liver disease.
2. Diarrhea, nausea = Weight loss
3. Allergic reactions: Skin rash: Alopecia
4. Hypokalemia

3. Hydroxy-chloro-quine
Use: Early mild RA – often combined with Methotrexate. Alone it is useless.
Mechanism: Inhibits phospholipase A2 = low PG, Low thromboxane, antioxidant activity.
Adverse effects: Ocular toxicity (Imagine getting chlor(middle name) into the eyes)
GI upset, skin discoloration.

4. Sulfasalazine
Use: Early Mild RA. Combined with Methotrexate + Hydrochloroquine.
Mechanism: Unknown.
SE: Leukopenia.

5. D-Penicillamine
Is what?? Analogue of Cystein. = Slows the progression of bone destruction and RA.
Uses: 1. Add on therapy to NSAID/cortisole
Avoided to combine with other DMARDs= SE such as blood dyscrasias and renal impairment.
SE: Prolonged treatment: Dermatologic problems, nephritis, aplastic anemia.

6.Gold salt
Auranofin. = Only prevents further damage. Does not repair damage.
• Mechanism: Inhibits the lysosomal activities in macrophages
• Effect seen after 3-6 months
• Due to insufficient records of toxicity and very costly – infrequent use by rheumatologists.

7. Azathioprine
= Immunosuppressive
Uses: Kidney transplantation, RA, Lupus nephritis, Psoriatic arthritis
Metbolized: By the liver to: 6-mercaptopurine
Combination: Can be combined with NSAID or glucocorticoids.
Monitor: CBC, Liver status continuously
Contraindication: Pregnancy/Breast feeding

8. Cyclo-phos-phamide
= Immunosuppressive How? It is cytotoxic to B & T-cells.
Uses? RA
• 1.Increased risk for infection 2. Cytotoxic also to kidney and heart
• Common SE: GI-disturbances, Alopecia, Infertility
• Contraindication: Pregnancy/Breastfeeding

9. Glucocorticoids
Prednisone is giving together with DMARD as a bridging until the effect of DMARD appears
when treating RA:
To avoid longterm use and its SE we slowly decrease the conc. of Prednisone.

Biologic Therapies In Rheumatoid Arthritis

• IL-1 & TNF are proinflammatory produced by macrophages residing in the joints- contributing to
RA. This will stimulate the synovial cells to produce Collegenase = Destruction of the surrounding tissues,
increase the bone resorption+inhibit proteoglycans production.

What to do? Inhibit the IL-1/TNF of course.

 TNF-inhibitors =Etanercept, Adalimu-mab, Inflixi-mab, Golimu-mab, Certolizu-mab
 Action: Decrease symptoms of RA, reduce damage, improve physical activity
 Combination for RA: Methotrexate + TNF-inhibitors
 SE: Risk for infection. Therefore always make sure no latent tuberculus exist (x-ray)
Risk for lymphoma
 Cautious use in who? Cardiac patients . Because they can cause HF.

1. Etanercept
Mechanism? Protein binds to TNF –can’t act on TNF-receptors.
Treat? RA, psoriasis, Psoriatic arthritis, Ankylosing spondylitis
Route? Subcutanously- Twice / week. t½ = 115 h Max conc: = 72 h .
Combination: Methotrexate + Etan-ercept
SE:

2.Inflixi-mab
Mechanism? Antibody binding to TNF- can’t access to TNF-receptors.
Treat? RA, Psoriasis, Ankylosing Spondylitis Chron’s disease, Ulcers
Combination: Methotrexate + Inflixi-mab.
-Infliximab SHOULD NOT be used alone= Production of Anti-Infliximab ab.
 Route: IV for 2 hours.
SE: -At the site of infusion = Fever,chills, pruritus, urticaria.
-Increased infection risk = Pancytopenia

3. Adali-mumab
? Antibody binding to TNF- no access to TNF-receptors.
Mechanism Reduces amount of Collagenase, CRP
Indication RA, Psoriatic Arthritis, Ankylosing spondylitis, Chron disease
Combination: Either monotherapy or combined with Methotrexat.
Route: Subcutaneous weekly.
SE Headache, Nausea, agranulocytosis, rash, increased risk of infection.

4. Goli-mumab
? Binding to TNF and blocking the interaction with cell surface receptors.
Subcutaneously, once a month. +Methotrexate
SE Risk for malignization, infections, erythema, Pruritus, burning.
5. Certoli-zumab
? TNF - Neutralizing antibody Give together with Methotrexate.

6. AnaKinra
? IL-1 antagonist. Modest reduction in symptoms in RA.
Monotherapy or combined with other DMARDs.
Associated with Neutropenia. Subcutaneously once per day.
7. Abatacept
Activation of T-cells: 1. Antigen-presenting cells 2.CD80 on macrophage needs to connect with CD28
on T-cells. On macrophages also exist: CTLA4 which has greater affinity to CD86 than CD28.

Abatacept is similar to CTLA4 and binds to CD80 rendering inactive T-cells.

Action: Reducing symptoms, slowing progerssion of structural damage in RA.

IV-infusion.
Adverse effects: Headache, Nausea, Infection Nasopharyngitis,

8.Rituxi-mab
B-cells are required to activate T-cells via CD20.
Rituxi-mab is a monoclonal antibody directed against Cd20.
Depresses the pain from RA.
IV-infusion. To reduce injection reactions we administer Prednisone 30 min before.
Adverse effectsL Injection reactions= urticaria, hypotension, angioedema.
Use with Methotrexate.
 GOUT
Treatment: 1.Increasing the kidney excretion of urate (Probenecid or Sulfinpyrazone)
2.Decrease the production of urate(Allopurinol)
3. Decreas the leukocytic infiltrate to the joint(Colchicine)
4. Use NSAID

Acute Gout
• Causes: Excessive alcohol/Meat , Kidney disease
• Treated with: Indomethacin. Will inhibit the leukocyte migration to the joints.
Contraindication: Aspirin – which will compete with urate for urine
Intra-articular glucocorticoid injection
Prophylactic therapy: If more than 2 attacks / year

Chronic Gout
• Causes: 1.Lesh-nyhan syndrom 2.Renal disease 3.Cancer 4.Increase rate of purine production
• Treated with: Allopurinol = Inhibitor of biosynthesis of urate. For those with excessive urate
synthesis with histories of urate stones or renal insufficiency.
 Uricosuric agents= First-line agents in those with reduced urinary excretion of urate

Colchicine
What is this? Has a suppressive and prophylactic effect = Reduce frequency of attacks and
relieves pain.
What is it not? Not Uricosuric, Not Analgesic agent. Not prevent profression of gouty arthritis

Mechanism: 1. It will bind to tubulin in the leucocytes = Disruption of cell motility.

2. Will bind to mitotic spindles = No cell division.
3. Inhibit the synthesisis of Leukotriene.
Therapeutic use?
1. Specific for Gout.
2. Takes long time for effect in acute attack = Replaced with NSAID
3. Today used: Prophylactically
Pharmacokinetics?
1. Orally
2. Recycled in the bile
Adverse effects?
1.Nausea, abdominal pain, diarrhea, myopathy
2. Alopecia, neutropenia, aplastic anemia,
Contraindication: Pregnancy!
Caution: Hepatic, renal, cardiovasc. disease

Drug interactions CYP3A4 inhibitors: Itraconazole

Clarithromycin
Ketoconazol
Telithromyci
Nefazodone
n
Allopurinol
Taken orally, it will convert to AlloXanthine in the liver- being an xanthine oxidase inhibitor.
Thus, lower production of the less watersoluble Urate and increased production of hypoxanthine and
xanthine which do no precipitate.

Use: Primary hyperuricemia, secondary uricermia(cancer, renal disease etc)

Pharmacokinetics: Orally. Alloxanthine = Inhibitor. t½= 2h. 1 dose/day.
SE: Well tolerated. Hypersensitivity reactions most common.
Nausea, diarrhea are also common.
Drug interactions: Interferes with metabolism of Azathioprine & Theophylline.

Febuxo-stat
A new Xanthine oxidase inhibitor. Same indications, adverse effects, drug interactions as Allopurinol.

Uricosuric agenst = Probenecid & Sulfin-Pyrazone(deriv. from Phenylbutazone)

These will inhibit the urate-anion exchanger in the proximal tubule.

Sulfin-pyrazone= Being a derivative from Phenylbutazone(NSAID) it is contraindicated in GI distress or
bone marrow suppression.
Probenecid = 1. Blocks the proximal resorption of urate
2. Blocks the secretion of Penicillin- to elevate levels.
3. Inhibits excretion of Naproxen, ketoprofen, indomethacin.
Avoided: In creatinine clearance less than 50ml/min.