NAGPUR COLLEGE OF PHARMACY

PHARMACOLOGY-II
Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)

By-
SIDDHI SHRIGIRIWAR
Nagpur, Maharashtra, India
Email- sshrigiriwar9@gmail.com
[Copyright]
 Non-Steroidal Anti-Inflammatory Drugs

ANTI INFLAMMATORY

INVERSE/OPPOSITE SWELLING/PAIN

These are those drugs that have anti-inflammatory effects which means
these drugs reduce or inhibit inflammation.
i.e. Pain, fever, swelling, redness, allergy, burning, itching.

All drugs grouped in this class have analgesic, anti-pyretic & anti-inflammatory actions in
different
measures.
In contrast to morphine,
they do not depress CNS,
Do not produce physical dependence,
No abuse liability, and are weaker analgesics.
They are also called non-narcotic, non-opioid, or aspirin-like analgesics.
 INFLAMMATION
Inflammation refers:
our body's process of fighting against things that harm it, like
infections, injuries, and toxins, in an attempt to heal itself. When
something damages your cells, your body releases chemicals that
trigger a response from your immune system. (WBCs protect our
body from invading foreign particles)

Acute Chronic
Inflammation Inflammation

Allergic reaction Cardiovascular Disease

Frostbite Rheumatoid Arthritis
Chemical Irritants Autoimmune Disease
Infections Neurological Disease
Burn, Cuts Cancer
 Mechanism of Inflammation & NSAIDS

Injury Phospholipid (cell membrane)

Phospholipase A2
NSAIDS
Arachidonic Acid
cyclo-oxygenase 5- Lipo-oxygenase
enzymes COX 2 COX 1 COX 5-LOX
NSAIDS

synthesis
Prostaglandins(PGs) Leukotrienes(LTS)
Thromboxane(TAX2) Eicosanoids
Prostacyclin(PGI2) Protection/regulation of Gastrointestinal Mucosa (HCL) COX1
A key role in the generation of the inflammatory response. COX2 PGS

Maintain vascular homeostasis & platelet aggregation, vasoconstriction. COX1

INFLAMMATION Inhibits platelet aggregation by increasing cyclic AMP levels,
vasodilation. COX2 PGI2
NSAIDS INFLAMMATION
 ANTI-INFLAMMATORY

STEROIDAL/ OPIOID NON-STEROIDAL/ NON-OPIOID

Use for most severe types of Use for less severe types of pain
pain

Non-Opioid will not depress CNS

Opioids will Depress the CNS & act Peripherally

Opioids have more ADR & These drugs are commonly used
are commonly use & many are
Side effects
OTC drugs

e.g. Morphine, Codeine etc e.g. Aspirin, Ibuprofen etc

 NSAIDs
Analgesic- Antipyretic
Non-Selective Preferential Selective with poor
COX Inhibitor COX2 Inhibitors COX2 Inhibitor Anti-Inflammatory
Action

Class Example Example Example Class Example

Salicylates Aspirin Nimesulide Celecoxib Paraaminophenol Paracetomol
Propionic acid Ibuprofen, Naproxen, Meloxicam Etoricoxib derivatives (Acetaminophen)
derivatives Ketoprofen,
Flurbiprofen Nabumetone Parecoxib Pyrazolone Metamizol,
derivatives Propiphenazone
Anthranilic acid Mephenamic acid
derivatives
Benzoxazocine Nefopam
Aryl-acetic acid Diclofenac, derivative
derivatives Aceclofenac
Oxicam derivatives Piroxicam, Tenoxicam
Indole/Pyrrole Indomethacin, /
derivative Ketorolac
Pyrazolone Phenylbutazone,
derivatives Oxyphenbutazone
 Non-Selective
COX Inhibitor

Salicylates: ASPIRIN

Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible
for most of the actions. Other actions are the result of acetylation of certain macromolecules including COX. It
is one of the oldest analgesic, anti inflammatory drugs and is still widely used.

COOH COOH

OCOCH3 OH

ASPIRIN Salicylic Acid

{Acetylsalicylic Acid}
 Mechanism of action of Non-Selective COX inhibitors

Phospholipid (cell membrane)

Arachidonic Acid
Inhibit both the enzymes
COX1 & COX2 Non-Selective COX inhibitors

cyclo-oxygenase cox
Prostaglandins(PGs)
Thromboxane(TAX2)
Prostacyclin(PGI2)

INFLAMMATION
 PHARMACOLOGICAL ACTIONS OF ASPIRIN
1. Analgesic, antipyretic, anti-inflammatory Actions

Aspirin is a weaker analgesic than morphine-type drugs:

aspirin 600 mg ~ codeine60 mg. However, it effectively relieves inflammatory, tissue injury-related,
connective tissue, and integumental pain, but is relatively ineffective in severe visceral and ischaemic
pain. No sedation, subjective effects, tolerance, or physical dependence is produced. Aspirin resets the
hypothalamic thermostat and rapidly reduces fever by promoting heat loss(sweating, cutaneous
vasodilatation), but does not decrease heat production. Anti-inflammatory action is exerted at high
doses (3–6 g/day or 100 mg/kg/ day). Signs of inflammation like pain, tenderness, swelling,
vasodilation, and leucocyte infiltration are suppressed. In addition to COX inhibition, quenching of
free radicals may contribute to its anti-inflammatory action. {Block PGS Production}

2. CVS
Aspirin has no direct effect in therapeutic doses. Larger doses increase cardiac output to meet
increased peripheral O2 demand and cause direct vasodilatation. Toxic doses depress vasomotor
centre. BP may fall. Because of increased cardiac work as well as Na+ and water retention.
3.GIT
Aspirin and released salicylic acid irritate gastric mucosa → cause epigastric
distress, nausea, and vomiting. Aspirin (pKa 3.5) remains unionized and
diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it
ionizes and becomes indiffusible. This ‘ion trapping’ in the gastric mucosal cell
enhances gastric toxicity.
Soluble aspirin tablets containing calcium carbonate + citric acid and other
buffered preparations are less liable to cause gastric ulceration.

4. Blood
Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets.
Thus, it interferes with platelet aggregation and bleeding time is prolonged to
nearly twice the normal value. This effect lasts for about a week (turn over
time of platelets).
Long-term intake of large doses decreases synthesis of clotting factors in the
liver. And predisposes to bleeding; this can be prevented by prophylactic vit K
therapy.
 PHARMACOKINETICS OF ASPIRIN
ABSORPTION:
Aspirin is absorbed from the stomach and small intestines {GI Tract}.

DISTRIBUTION:
Aspirin is rapidly deacetylated in the gut wall, liver, plasma, and other tissues to release
salicylic acid which is the major circulating and active form. It is ~80% bound to plasma proteins and
has a volume of distribution of ~0.17 L/kg.

METABOLISM:
It slowly enters brain {BBB} but freely crosses placenta. Both aspirin
and salicylic acid are conjugated in liver with glycine → salicyluric acid (major pathway);and with
glucuronic acid. Few other minor metabolites are also produced.

EXCRETION:
The metabolites are excreted by glomerular filtration as well as tubular secretion.
Normally, only 1/10th is excreted as free salicylic acid, but this can be increased by alkalinization.
It is dose dependent.
 ADVERSE EFFECTS OF ASPIRIN
ADR of NSAIDS
Gastrointestinal Asthma
Gastric irritation, erosions, peptic ulceration, gastric Salicylates intolerance
bleeding/perforation, esophagitis
Renal Peptic Ulcer
Na+ and water retention, chronic renal failure, interstitial Intestinal/Gastro
nephritis, papillary necrosis (rare)
bleeding Reye's
Hepatic
Raised transaminases, hepatic failure (rare) syndrome in kids
CNS Idiosyncrasy
Headache, mental confusion, behavioural disturbances,
seizure precipitation
Noise (tinnitus at high
Haematological dose)
Bleeding, thrombocytopenia, haemolytic anaemia,
agranulocytosis
Others
Asthma exacerbation, nasal polyposis, skin rashes, pruritus,
angioedema
 Selective
COX2 Inhibitor
CELECOXIB

COX-2 selectivity of celecoxib is modest (6–20 fold).

It exerts anti-inflammatory, analgesic and antipyretic actions
with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as
effective as naproxen or diclofenac, without affecting COX-1 activity in gastroduodenal mucosa.
Platelet aggregation in response to collagen exposure remained intact in celecoxib recipients and serum
TXB2 levels were not reduced. Though tolerability of celecoxib is better than traditional NSAIDs, still
abdominal pain, dyspepsia and
mild diarrhoea are the common side effects. Rashes, edema and a small rise in BP have also been noted.

PHARMACOKINETICS
Celecoxib is slowly absorbed, 97% plasma protein bound metabolized primarily by
CYP2C9 with a t½ of ~10 hours. It is approved for use in osteo- and rheumatoid arthritis
in a dose of 100–200 mg BD.
 Mechanism of action of Selective COX2 Inhibitors

Phospholipid (cell membrane)

Arachidonic Acid

Inhibit only COX2 enzyme Selective COX2 inhibitors

cyclo-oxygenase cox2
Prostaglandins(PGs)
Prostacyclin(PGI2)

INFLAMMATION
 Analgesic- Antipyretic with poor
Anti-Inflammatory Action

Paraaminophenol derivatives: PARACETAMOL

Phenacetin introduced in 1887 was extensively used as an analgesic-antipyretic, but is now

banned because it was implicated in analgesic abuse nephropathy.

Paracetamol (acetaminophen) the deethylated active metabolite of phenacetin, was also introduced
in the last century but has come into common use only since 1950.

NHCOCH3

PARACETAMOL -O-C2H5 Phenacetin

ethyl acetate

OH
 Mechanism of action of PARA-AMINO PHENOL DERIVATIVES

Phospholipid (cell membrane

Arachidonic Acid
Poor inhibitor of PGS synthesis in
Peripherally PARA-AMINO PHENOL DERIVATIVES
More effective on CNS

PAIN FEVER DECREASES

ANTI-INFLAMMATORY cyclo-oxygenase cox
PROPERTY LESS
Prostaglandins(PGs)
Thromboxane(TAX2)
Prostacyclin(PGI2)

INFLAMMATION
 PHARMACOLOGICAL ACTIONS OF PARACETAMOL

The central analgesic action of paracetamol is like aspirin, i.e. it raises the
pain threshold but has a weak peripheral anti-inflammatory component. The
analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and
promptly acting antipyretic. Paracetamol has negligible anti inflammatory action.
It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on
COX in the brain. In contrast to aspirin, paracetamol does not stimulate
respiration or affect acid-base balance; does not increase cellular metabolism. It
does not affect CVS. Gastric irritation is insignificant mucosal erosion and
bleeding occurs rarely only in overdose. It does not affect platelet function or
clotting factors and is not uricosuric.

Paracetamol has a central analgesic effect that is mediated through the activation of
descending serotonergic pathways. Debate exists about its primary site of action, which may be
inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid
receptors.
 PHARMACOKINETICS OF PARACETAMOL

ABSORPTION:
Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma

DISTRIBUTION:
It is uniformly distributed in the body.

METABOLISM:
Metabolism occurs mainly by conjugation with glucuronic acid and sulfate

EXCRETION:
Excreted rapidly in urine. Plasma t½ is 2–3 hours. Effects after an oral dose last for 3–5
hours.
 ADVERSE EFFECTS OF PARACETAMOL
ADR of NSAIDS

Gastrointestinal Paleness
Gastric irritation, erosions, peptic ulceration, gastric
bleeding/perforation, esophagitis Anaphylactic shock
Renal Rashes
Na+ and water retention, chronic renal failure, interstitial
nephritis, papillary necrosis (rare) Anorexia
Hepatic
Raised transaminases, hepatic failure (rare)
Colour (yellow) to Eye/Skin
CNS Erythema
Headache, mental confusion, behavioural disturbances,
seizure precipitation
Tachycardia
Haematological Angioneurotic Oedema
Bleeding, thrombocytopenia, haemolytic anaemia,
agranulocytosis Muscle Ache
Others Oedema
Asthma exacerbation, nasal polyposis, skin rashes, pruritus,
angioedema Liver damage
THANKYOU
N ON
S TEROIDAL
A NTI
I NFLAMMATORY
D RUGs

-SIDDHISHRIGIRWAR