Prostaglandins & COX Pathway

Module – I
CONTINENTAL PHARMACEUTICALS
 Prostaglandins – Introduction
• Chemical substances, made in all tissues of the body
• Derived from fatty acid (Arachidonic acid)
• Very short half life (Few minutes only)
• Not usually stored up, but synthesized “On Demand”
• Serve as signaling molecules – local hormones
• COX is the key enzyme in synthesis of Prostaglandins
• Act locally on neighboring cells (Paracrine)
• Also act on own cell (Autocrine)
– Examples: Prostaglandin (PGE2), Prostacyclin (PGI2) and
Thromboxane A2 (TXA2)
CONTINENTAL PHARMACEUTICALS
 Prostaglandins - Functions
• Blood vessels: Vasodilation and antiplatelet activity
• Platelets: adhesion and aggregation
• Uterus: Induce labor
• Cells: Control cell growth
• Bone: Bone formation and cartilage maintenance
• Kidneys: Increase glomerular filtration rate, Na/H2O
homeostasis
• Stomach: Inhibition of acid secretion, bicarbonate and
mucus secretion
• Injured cells: Cause inflammation, pain and fever
CONTINENTAL PHARMACEUTICALS
 Cyclooxygenase (COX)
• An enzyme responsible for formation of important
biological mediators called “Prostanoids”, including
Prostaglandins, Prostacyclins and Thromboxanes
• Two isoforms; COX-I and COX-II
• Initially believed that:
– COX-I: Constitutive
– COX-II: Inducible
• Now accepted that:
– COX-II: Both constitutive and inducible
 COX – 1 & COX – 2 Distribution

Thromboxane A2 PROSTACYCLIN
 Types & Role

Phospholipase A2
Expressed during
Arachidonic Acid inflammation only

COX-1 COX-2
Prostaglandins

Thromboxane A2 Prostacyclin Prostaglandins

Platelet Gastro Inflammation

Aggregation Protection & Pain
NSAIDs – Definition and Usage

Module – II
CONTINENTAL PHARMACEUTICALS
 Anti-Inflammatory Drugs
• Steroidal Anti-inflammatory Drugs (Corticosteroids)
– Prednisolone
– Dexamethasone
• Non Steroidal Anti-inflammatory Drugs (NSAIDs)
– Indomethacin
– Ibuprofen
– Diclofenac
– Celecoxib
– Nimsulide
– Aceclofenac
 NSAID’s - Prostaglandin Synthesis Inhibitors
Stimulus
Cell membrane (Phospholipid)
(Injury/Trauma etc)
Phospholipase A2

Arachidonic acid
Corticosteroids

Cyclo-oxygenases (COX-I,COX-II) Lipo-oxygenase

NSAID’s
Endoperoxides (PGG, PGH) (Leukotrines)

Prostacyclins (PGI) Prostaglandins(PGE,PGF) Thromboxane(TX-A2)

 NSAIDs - Introduction
• First choice analgesic for
– Treatment of mild or moderate pain
– Also used to potentiate effects of opioids in:
• Moderate or severe pain
• Suitable for use in- acute or chronic pain
• Lack of sedative effect makes NSAIDs of particular
value in Acute pain after day-care surgery
 NSAIDs
Carboxylic acid Sulfonanilide Enolic acids Non-acidic compounds
– Nimesulide – Bufexamac
– Proquazole
Acetic acids Salicylic acids Fenamic acids
– Aspirin – Mefenamic acid Diaryl Substitutes
– Diflunisal – Celecoxib
– Valdecoxib
Phenylacetic acids Propionic acids – Etoricoxib
– Diclofenac – Ibuprofen – Lumiracoxib
– Aceclofenac – Flurbiprofen
– Ketoprofen
Indole acetic acid – Fenbufen Pyrazolones Oxicams
– Indomethacin – Naproxen – Phenylbutazone – Piroxicam
– Sulindac – Dexibuprofen – Oxyphenbutazone – Tenoxicam
– Dipyrone – Meloxicam
– Lornoxicam
 Types of NSAID’s
Based on COX-specificity / selectivity, NSAIDs can be
classified as:
• Preferential inhibitors of COX-1
Indomethacin, Naproxen, Piroxicam
• Non-Selective inhibitors of COX-1 & COX-2
Diclofenac, Ibuprofen, Lornoxicam, Dexibuprofen
• Preferential inhibitors of COX-2
Meloxicam & Nimesulide
• Specific/Selective inhibitors of COX-2
Celecoxib, Etoricoxib, Parecoxib, Lumiracoxib
 Action of Non-Selective NSAIDs

PREFERENTIAL INHIBITORS PIROXICAM

OF COX-1
INDOMETHACIN

NAPROXEN

REDUCES PROSTACYCLIN
REDUCES THROMBOXANE-A2 NON-
SELECTIVE
NSAIDs
INHIBITORS OF COX-1 & COX-2
NON-SELECTIVE NSAIDs

DICLOFENAC

IBUPROFEN

LORNOXICAM

• G.I UPSETS • INCREASE BLEEDING TIME • OEDEMA / HYPERTENSION • CHONDRODESTRUCTION

 Action of Selective COX-2 Inhibitors

PREFERENTIAL INHIBITORS
OF COX-2 MELOXICAM

NIMESULIDE ?
NABUMETONE

THROMBOXANE-A2 REDUCES PROSTACYCLIN

SELECTIVE
COX-2
INHIBITORS
ROFECOXIB X
COX-2 INHIBITORS

VALDECOXIB X
SELECTIVE

CELECOXIB ?
ETORICOXIB
PARECOXIB
LUMIRACOXIB
• RISK OF MYOCARDIAL INFARCTION • OEDEMA / HYPERTENSION • CHONDRODESTRUCTION
Product Profile

Module – III
CONTINENTAL PHARMACEUTICALS
Product Profile

Aceclofenac 100mg Tablets

CONTINENTAL PHARMACEUTICALS
Aceclofenac - Introduction
• Aceclofenac is the new approach in development of
NSAIDs (Phenyl acetic acid derivative)
• It is similar to Diclofenac but Neutrophils,
more potent and safer
Monocytes
than Diclofenac and Synovial cells
• Aceclofenac is a pro-drug
• Selectively acts only on inflammatory cells
• Gets hydrolyzed to active metabolites by lysosomal
enzymes of inflammatory cells
• Inhibits only inducible COX-2 in inflammatory cells
• Does not alter normal physiological functions of the
body
SPIANO –– Unique
SPIANO Unique Mechanism
Mechanism
 Multifactorial Mode of Action

1. SPIANO inhibits synthesis of

inflammatory Cytokines like
interleukin IL-1 and TNF-α 4
2. SPIANO has stimulatory effect
on cartilage matrix synthesis by
inhibiting interleukin (IL)
3. SPIANO suppresses IL-1β 1
mediated promatrix 3
Metalloproteinases production
4. SPIANO has stronger effect on
proteoglycan synthesis and
hyaluronan 5
5. SPIANO decreases Nitric Oxide 2
(NO) production
Aceclofenac – Beneficial Effects
• Aceclofenac was able to increase HA synthesis
and reduce the loss of newly synthesized HA
molecules from the articular tissue
(British Journal of Pharmacology (2000) 131, 1413-1421)

• Aceclofenac decreases expression or synthesis of

mediators of inflammation, including:
• Interleukins (IL -1)
• Tumor necrosis Factor (TNF)
• Cell adhesion molecules from neutrophils
• PGE2 (Drugs, August 2001, Volume 61, Issue 9)
Aceclofenac – Beneficial Effects
• In contrast to some other NSAIDs, Aceclofenac
has shown stimulatory effects on cartilage matrix
synthesis that may be linked to the ability of the
drug to inhibit IL-1β activity
(Drugs, August 2001, Volume 61, Issue 9, pp 1351–1378)

• The inhibitory effects of Aceclofenac on synovial

levels of PGE2 have been confirmed in patients
with acute knee pain and synovial fluid effusions
(Drugs, August 2001, Volume 61, Issue 9, pp 1351–1378)
Better Inhibition of Synovial PGE2

Aceclofenac Diclofenac

PGE2 - 21%

- 41% (Drugs, 2001)

(Drugs, July 1996, Volume 52, Issue 1, pp 113–124)

 Action of SPIANO on COX

THROMBOXANE-A2 PROSTACYCLIN

SPIANO

• RELIEVES PAIN & REDUCES INFLAMMATION • PRESERVES NORMAL PHYSIOLOGICAL FUNCTIONS

Indications
• Osteoarthritis
• Rheumatoid Arthritis
• Ankylosing Spondylitis
• Low Back Pain
• Dysmenorrhea
• Generalized Musculo-skeletal Pain
• Post Surgical Pain
• Strain and Sprain
Pharmacokinetics
• Rapid & complete absorption (Oral administration)
• Bioavailability is nearly 100%
• Peak plasma concentration: within 1-3 hours (Oral
dose)
• Protein binding: 99%
• Extent of absorption is not altered in presence of
food but absorption rate may reduce (↓Tmax)
• Penetrates well into the synovial fluid
• Concentration reach approximately 60% of those in
plasma (Synovial fluid)
Metabolism & Excretion

• Major metabolite: 4’-Hydroxyaceclofenac (CYP2C9)

• Other metabolites: Diclofenac, 4’-
Hydroxydiclofenac, 5’-Hydroxydiclofenac
• Main route of Excretion:
— Renal: 70% - 80% in urine, mainly as glucuronide
Aceclofenac and its metabolites
— Biliary: 20% in feces
— Plasma Elimination Half Life: Approximately 4 hours
Dosage and Administration

• Usual adult dose is 200mg per day in two equally

divided doses (100mg B.I.D)
• No dosage adjustment required for mild renal
impairment or elderly patients
• In hepatic impairment daily dose should be
100mg per day
• Not recommended for children
 Aceclofenac – Global Presence
• Arg.: Berlofen; Bristaflam; • Hung.: Aflamin;
• Aust.: Beofenac; • India: Aceclo; Arrestin; Movon; Zerodol;
• Belg.: Air-Tal; Biofenac; • Ital.: Airtal; Gladio; Kafenac;
• Braz.: Aceflan; Cecoflan; • Mex.: Bristaflam;
Proflam; • Neth.: Biofenac;
• Chile: Airtal; Bristaflam; • Norw.: Barcan;
• Denm.: Barcan; • Philipp.: Clanza;
• Fin.: Barcan; • Port.: Airtal; Biofenac;
• Fr.: Cartrex; • Rus.: Airtal (Аэртал);
• Ger.: Beofenac; • Spain: Airtal; Airtal Difucrem; Falcol;
• Gr.: Aceclonac; Arlina; Biofenac; Gerbin; Sanein;
Sovipan; • Swed.: Barcan;
• UK: Preservex; • Switz.: Locomin;
• Venez.: Airtal†; Bristaflam. • UAE: Aceclofar; CONTINENTAL PHARMACEUTICALS
Diclofenac – Side Effects
• Major vascular events were increased by about a
third by Diclofenac, chiefly due to an increase in
major coronary events (The Lancet, Vol 382, p769–779, 31 August 2013)
• Rofecoxib and Diclofenac were associated with
increased cardiovascular mortality and morbidity
and should be used with caution in most
individuals (Circulation: Cardiovascular Quality and Outcomes, 2010;3:395-405)
• Growing evidence suggests that NSAIDs may
damage articular cartilage (Eur J Rheumatol Inflamm. 1993;13(1):7-16)
COX Isoform Selectivity Chart
Ketorolac More
Flurbiprofen COX-2
selective
Ketoprofen
Indomethacin
Tolmetin
Aspirin
Nabumetone
Fenoprofen
Meclofenamate
Sulindac
Naproxen
Piroxicam
Ibuprofen
Acetaminophen
Sodium salicylate
Diflunisal
Meloxicam
Diclofenac
Celecoxib
Valdecoxib
Etodolac
Rofecoxib
More
Etoricoxib
COX-1 Source: Goodman & Gilman’s
Lumiracoxib selective The Pharmacological Basis of Therapeutics, 12th Edition
Non-selective
 Summary

Classical inhibition
Well tolerated and
of prostaglandin
better GI safety
E2

Stimulatory effects Decrease in the

on matrix expression of
component cytokines like IL-1
synthesis and TNF-α
SPIANO
Protection of
(Aceclofenac)
chondrocytes
Faster, safer onset
against ROS and
of action
breakdown

Pain control +
More potent effect
2. Repair, and
with selectivity for
3. ↓ in disease
COX-2
progression
 SPIANO

S ite specific action

P otent analgesic, antipyretic and anti-inflammatory agent
I nhibits Pro-inflammatory cytokines
A ctively protects cartilage degeneration
N o or least G.I., Cardiac or Renal toxicity
O nly NSAID with unique, site specific mode of action
 Any Question?

Thank you for your

attention

CONTINENTAL PHARMACEUTICALS