DR.

MUGIDE NURU

I. Anti-inflammatory drugs
NSAIDS
 Inflammation
 Inflammation is a complex protective response of the or-
ganism to injury caused by damaging agents.
 It is aimed at inactivation or removal of these agents and
promoting healing.
 The traditional names for signs of inflammation come from
Latin:
 Dolor (pain)
 Calor (heat)
 Rubor (redness)
 Tumor (swelling)
 Functio laesa (loss of function)
4 signs of inflammation
 • Redness ‐ due to local vessel dilatation
 • Heat ‐ due to local vessel dilatation
 • Swelling – due to influx of plasma pro-
teins and phagocytic cells into the tissue
spaces
 • Pain – due to local release of enzymes
and increased tissue pressure
 Mediators of inflammation
 Prostaglandins
 Gamma-Interferon
 Bradykinin  Tumor Necrosis Factor
 Serotonin  Transforming Growth Factor
 Histamine  Lymphotoxin
 Interleukins-2 – 6, 10,
12,13
 Platelet activating factor
 The role of some prostaglandins
in the body
 PGE2 – vasodilation, bronchodilation, inhibition of gas-
tric acid secretion, stimulation of gastric mucus secre-
tion, sensitization of pain receptors to chemical and
mechanical stimuli, promotion of anterior pituitary
hormones release;
 PGF2α - uterus contraction, bronchoconstriction, de-
crease in intraocular tension;
 TXA2 (thromboxane), produced by platelets, - induc-
tion of platelet aggregation, vasoconstriction;
 PGI 2 - inhibition of platelet aggregation, potent va-
sodilation;
 Cyclo-oxygenase (COX)
 Exists in the tissue as constitutive isoform
(COX-1).
 At site of inflammation, cytokines stim the
induction of the 2nd isoform (COX-2).
 Inhibition of COX-2 is thought to be due to
the anti-inflammatory actions of NSAIDs.
 Inhibition of COX-1 is responsible for their
GIT toxicity.
 Most currently used NSAIDs are some-
what selective for COX-1, but selective
COX-2 inhibitors are available.
NSAIDs – nonsteroidal
anti-inflammatory drugs
 1. Nonsteroidal anti-inflamma-
tory drugs (NSAIDs)
Nonselective COX inhibitors
1. Salicylates  5. Antranilic acid deriv-
 *Acetylsalicylic acid (Aspirin) atives
 * Salicylamide  *Mephenamic acid
 2. Pyrazolone derivatives  6. Aryl – acetic acid deriv-
 *Phenylbutazone atives
 *Metamizol (Analginum)  *Diclophenac sodium
 3. Indole derivatives  7. Oxicam derivatives
 *Indomethacin  *Piroxicam
 4. Propionic acid derivatives  8. Dihydropyrrolizine
carboxylic acid derivative
 *Naproxen  *Ketorolac
Clinical Classification.
 Non selective Irreversible COX inhibitors
 Non selective Reversible COX inhibitors
 Preferential COX 2 inhibitors

• 10‐20 fold COX 2 selective

• meloxicam, etodolac, nabumetone
 Selective COX 2 inhibitors

• > 50 fold COX 2 selective

• Celecoxib, Etoricoxib, Rofecoxib, Valde-
coxib
 COX 3 Inhibitor? Paracetamol
 Selective COX inhibitors
 Preferential COX-2 inhibitors
 Nimesulide
 Meloxicam
 Nabumeton
 Selective COX-2 inhibitors
 Celecoxib
 Parecoxib
 Rofecoxib
NB!!!These drugs cause little gastric
mucosa damage, they do not inhibit platelet
aggrigation!!!
 Mechanism of action of NSAIDs
(Non-Steroidal Anti-Inflammatory Drugs)

• Act by inhibiting CycloOXygenases (COX) => no PG

production
– COX-1: Constitutively expressed => house-keeping function
– COX-2: Induced by pro-inflammatory factors (TNFα, IL-1)
– COX-3: Just recently discovered
• PGs do not cause pain, but sensitize nocireceptors to stimula-
tion (e.g. by 5-HT, Bradykinine, capsaicin, …)
• IL-1 release from activated macrophages (bacteria, etc.) induces
COX-2 in the brain =>PG E produced => affects thermoregulation
=> fever=> NSAIDs have anti-pyretic effects
• Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is re-
versible, with the exception of Aspirin) => housekeeping PGs
reduced => side effects (gastrointestinal, bronchospasms,…)
• 2nd generation NSAIDs: COX-2 specific => only the inflammatory
response is inhibited => fewer side effects.
Mechanism of anti-inflammatory
drugs’ action
Pharmacological effects of NSAIDs
 Anti-inflammatory
 Analgesic
 Antipyretic
 Antiplatelet(Aspirin)
 Closure of ductus arteriosus in newborn
 Clinical uses of NSAIDs
 1. Pain: headache, toothache, myalgia, back-
pain;
 2. Fever;
 3. Arthritises: rheumatiod arthritis, osteoarthri-
tis, gout, ankylosing spondylitis;
 4. Dismenorrhoea (especially ibuprofen);
 5. Unclosure of ductus arteriosus (especially
aspirin);
 6. Prevention of MI, stroke, and reinfarction
(aspirin);
 Side effects of NSAIDs
 1. GIT disturbances: epigastric pain, nausea, gastric
peptic ulcer (especially aspirin), gastrointestinal bleed-
ing (especially indomethacin);
 2. CNS disturbances: dizziness, mental confusion,
hallucination and psychosis, depression (especially
indomethacin);
 3. Leukopenia, agranulocytosis (indomethacin,
phenylbutzone, metamizol);
 4. Water and sodium retention, edema
(phenylbutzone);
 5. Hypersensitivity reactions
 6. Reye’s syndrom, bronchospasm (aspirin)
 Contraindications
 A) Pregnancy
 B) Hemophilic patients
 C) Hypersensitivity reactions
 D) Viral infections mainly in children
 E) Peptic ulcers
 Drugs interaction

 Potentiates the gastric irritant effect of al-

cohol
 Potentiates the hypoglycaemic effects of
oral hypoglycaemic drugs
 The Salicylates - ASPIRIN
 Duration of action ~ 4 hr.
 Orally taken.
 Weak acid (pK ~ 3.5); so, non-ionized in stom-
a
ach  easily absorbed.
 Hydrolyzed by esterases in tissues and blood to
salicylate (active) and acetic acid.
 Most salicylate is converted in liver to H O-sol
2
conjugates that are rapidly excreted by kidneys.
 ASPIRIN - Therapeutic Uses
 Antipyretic, analgesic.
 Anti-inflammatory: rheumatic fever, rheumatoid
arthritis (joint dis), other rheumatological dis-
eases. High dose needed (5-8 g/day).
 But many pts cannot tolerate these doses (GIT);
so, proprionic acid derivatives, ibuprofen,
naproxen tried first.
 Prophylaxis of diseases due to platelet
aggregation.
 Pre-eclampsia and hypertension of pregnancy (ex-
cess TXA2).
 Propionic acid derivatives
IBUPROFEN:
 Pharmacokinetics
 Rapidly absorbed after oral ingestion.
 Half-life 1-2 hours
 Highly bound to plasma proteins
 Excreted through kidney as metabolites.
 IBUPROFEN
 The same mechanism & pharmacological
actions of aspirin Except that it is re-
versible inhibitor for COX enzymes
 More potent as antiinflammatory than as-
pirin!!!
 Clinical uses

 A) Analgesic
 B) Antipyretic
 C) Anti-inflammatory
 D)Acute gouty arthritis
 E) Patent ductus arteriosus
 Preparations of Ibuprofen
 Oral preparations.
 Topical cream for osteoarthritis.
 A liquid gel for rapid relief of postsurgical
dental pain.
 Intravenous route as In patent ductus arte-
riosus
 Adverse effects
 1.Gastric upset (less fre-
quent than aspirin).
 2.Fluid retention
 3.Hypersensetivity reactions
 4.Ocular disturbances
 5.Rare hematologic effects
(agranulocytosis & aplastic
anaemia).
 Contraindications

 1. Peptic ulcer
 2. Allergic patients to aspirin
 3. Kidney impairment
 4.Liver diseases
 5.Pregnancy
 6.Haemophilic patients
The concomitant administration of ibuprofen
antagonizes the irrevesible platelet inhibition
of ASPIRIN (limit cardioprotective effect of
aspirin).
 Piroxicam
 Mechanism of actions:
 A) Non-selective inhibitors to
COX1 & COX2
 B) Traps free radicals
 C) Inhibits polymorphonu-
clear leukocytes migration
 D) Inhibits lymphocyte func-
tion.
 Pharmacokinetics
 Well absorbed orally
 Half- Life 45 hours
 Given once daily
 Adverse effects
 Less frequent gastric upset (20%).
 Dizziness.
 Tinnitus.
 Headache.
 Allergy.
 Acetic acid derivatives
DICLOFENAC
 Mechanism of action
 Non-selective inhibitor to COX1 & COX2.
 More potent as anti-inflammatory than
analgesic and antipyretics.
 Clinical uses
DICLOFENAC
 A) Any inflammatory conditions
 B) Musculoskeletal pain
 C) Dysmenorrhoea
 D)Acute gouty arthritis
 E) Fever
 F) Locally to prevent or treat post opthalmic in-
flammation
 G) A topical gel for solar keratoses
 Adverse effects
DICLOFENAC
 Gastric upset
 Renal impairment
 Elevation of serum aminotransferase
 Salt & water retention
Preparations of DICLOFENAC
 Diclofenac with misoprostol decreases upper
gastrointestinal ulceration, but result in diarrhea.
 Diclofenac with omeprazole to prevent recurrent
bleeding.
 1% opthalmic preparation for postoperative
opthalmic inflammation.
 A topical gel 3% for solar keratoses.
 Rectal suppository as analgesic or for postoper-
ative nausea.
 Selective COX 2 inhibitors
 Advantages:
 1. Highly selective inhibitors to COX2
enzyme.
 2. Potent anti-inflammatory.
 3. Have analgesic & antipyretic properties.
 4. Highly bound to plasma proteins.
 Selective Cox 2 inhibitors
 5. Lower incidence of gastric upset.
 6. No effect on platelet aggregation
(COX1).
 7. Renal toxicities (they are not rec-
ommended for patients with severe
renal insufficiency).
 8. High incidence of cardiovascular
thrombotic events with some of them
as ROFECOXIB.
Selective Cox 2 inhibitors
9- They are recommended in
postoperative patients undergoing
bone repair.
10- Also, indicated in primary fa-

milial adenomatous polyposis,

dysmenorrhea, acute gouty arthri-
tis, acute musculoskeletal pain,
ankylosing spondylitis.
 SAIDs – steroidal
anti-inflammatory drugs
Steroidal anti-inflammatory drugs
 1. Short-acting glucocorti- 3. Long-acting Be-
coids (natural) tamethasone
Hydrocortisone Dexamethasone
Cortisone Paramethasone
 2. Intermediate-acting glu- 4.Topically acting glu-
cocorticoids cocorticoids
Prednisone Beclomethasone
Prednisolone dipropionate
Methylprednisolone
Triamcinolone Budesonide
Fluocinolone
acetonide
MECHANISM OF ACTION Corticosteroids
OF SAIDs
Phospholipids

Phospholipase A2
Arachidonic acids

Lipoxygenase Cycylooxygenase

Prostaglandins,
Leukotriene Thromboxane,
Prostacyclins.
 Clinical uses
of SAIDs
 Adrenal insufficiency
 Arthrities
 Collagen diseases (systemic lupus erhymatosis, scleroderma)
 Bronchial asthma
 Severe allergic reactions
 Autoimmune diseases
 Skin diseases
 Ulcerative colitis, Crohn’s disease
 Cerebral edema
 Organ transplantation and skin allograft
 Septic shock
Main side effects of SAIDs
 Susceptibility to infections
 Delayed healing of wounds
 Osteoporosis
 Growth retardation in children
 Peptic ulceration
 Cushing habitus
 Hyperglycaemia
 Muscular weakness
 Psychiatric disorders
 Withdrawal syndrom
Thank You!!!