Topic: NSAIDs

Course Code: BP503T

Course leader: Mrs. Akshata
 Lecture 7
Non Steroidal Anti-inflammatory Drugs

At the end of this lecture, student will be able to

• Classify NSAIDS
• Explain the general pharmacology of NSAIDS
• Describe the Pharmacology of Aspirin

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Content

Non steroidal antiinflammatory drugs

Introduction
Pharmacological action

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NSAIDs

• All drugs grouped in this class have analgesic, antipyretic and anti-
inflammatory actions in different measures

• In contrast to morphine they do not depress CNS, do not produce

physical dependence, have no abuse liability and are weaker analgesics

• They are also called non-narcotic, non-opioid or aspirin like analgesics

• They act primarily on peripheral pain mechanisms, but also in the CNS
to raise pain threshold

• They are most commonly employed and many are over the counter
drugs 4
CLASSIFICATION

A. Non selective COX inhibitors

1. Salicylates: Aspirin

2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen

3. Anthranilic acid derivative: Mephenamic acid

4. Aryl-acetyl acid derivatives: Diclofenac, Aceclofenac

5. Oxicam derivatives: Piroxicam, Tenoxicam

6. Pyrrolo-pyrrole derivative: Ketorolac

7. Indole derivative: Indomethacin

8. Pyrazolone derivatives: Phenylbutazon, Oxyphenbutazone

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CLASSIFICATION

B. Preferential COX-1 inhibitors: Nimesulide, Meloxicam

C. Selective COX-2 Inhibitors: Celecoxib, Etoricoxib, Parecoxib

D. Analgesic-antipyretics with poor anti-inflammatory action

1. Para amino phenil derivatives: paracetamol (Acetaminophen)

2. Pyrazolone derivatives: Metamizolone, Propiphenazone

3. Benzoxazocine derivatives: Nefopam

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Mechanism of action of
NSAIDs
NSAIDs

COX Enzyme

PGs- Inflammation
Pain
Fever

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Mechanism of Action

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General process of Inflammation

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 Initiation of inflammation reaction- Vasocostriction

Release of inflammatory mediators –Histamine, PGs,

Vasodilation

Fluid leakage
swelling, pain

Emigration

Extravasation of leukocytes-movement from vessel lumen to interstitial space

phagocytosis

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 Kinetics

• Taken orally or parentally

• Well absorbed from stomach and intestinal mucosa

• protein-bound in plasma ( albumin)

• metabolised in the liver

• Excreted in urine

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 Pharmacological action

• Analgesia:

Decrease the prostaglandin synthesis

inflammatory mediators- Pain

prevention of pain nerve ending sensitization

• Antipyresis: reset the hypothalamic thermostate mechanism by PGE2

Reduce body temperature

• Antiinflammatory: by inhibition of PG synthesis

• Dysmenorrhoea: Involvement of PGs in dysmenorrhoea- (painful periods) has been

clearly demonstrated: level of PGs in menstrual flow, endometrial biopsy and that
of PGF2a metabolite in circulation are raised in dysmenorrhoeic women 1
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Pharmacological action

• Antiplatelet activity: NSAIDs inhibit platelets aggregation

• Parturition: NSAIDs have potential to delay and retard labour

• Gastric mucosal damage: Gastric pain, mucosa erosion/ulceration and blood loss
are produced by all NSAIDs

• Renal effect: NSAIDs produce renal effect by 3 mechanism

COX-1 dependent impairment of renal blood flow and reduction of GFR can
worsen renal insufficiency

Juxtaglomerular COX-2 (probably COX-1 also) dependent Na+ and water retention

ability to cause papillary necrosis- kidney damage characterized by coagulative

necrosis of the renal medullary pyramids.
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ADR

• Gastrointestinal: Gastric irritation, erosions, peptic ulceration, gastric bleeding/

perforation, esophagitis

• Renal: Na+ and water retention, chronic renal failure, interstitial nephritis, papillary
necrosis (rare)- renal medullary pyramids and papillae

• Hepatic: Raised transaminases, hepatic failure (rare)

• CNS: mental confusion, behavioural disturbances, seizure precipitation

• Haematological: Bleeding, thrombocytopenia(low platelet count) , haemolytic

anaemia.

• Others Asthma, skin rashes, pruritus, angioedema- the swelling of the deeper layers
of the skin, caused by a build-up of fluid.
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Drug Interaction

• If COX-2 inhibitor taken, should not use a traditional NSAID

concomitantly

• With daily aspirin therapy, should use other NSAID carefully,

they may block the cardioprotective effect of aspirin

• Potentiates the gastric irritant effect of alcohol

• Potentiates the hypoglycemic effects of oral hypoglycaemic

drugs

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 Contra indication

• Not recommended during pregnancy, particular 3rd

trimester Cause early closure of fetal ductus arteriosus-
serves as a shunt between the pulmonary artery and the
aorta and fetal renal toxicity, premature birth

• Hypersensitivity reactions

• Viral infections mainly in children

• Peptic ulcers
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 Uses

• RA • Dysmenohhoea
• OA • Headache, migrain
• Infalmmatory arthritis, AS, • Postoperative pain
psoriatic arthritis, Reter’s
• Pyrexia ( fever)
syndrome
• Ileus
• Acute gout

• Metastatic bone pain • Renal colic

Aspirin (also an NSAID) : inhibit the clotting of blood( platelet
aggregation ) ,prevent strokes and cardiovascular attacks
 Aspirin

• SALICYLATES derivatives

• Aspirin is a prototype - is acetylsalicylic acid

• 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

• One of the oldest analgesic-antiinflammatory drugs and is still widely used

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Pharmacological action of
Aspirin
• Analgesia- decrease PG synthesis-Decreased
sensitization of pain receptor.
• Antipyretic- inhibits the prostaglandin level.
• Anti-inflammation- inflammation
• Respiration- consumption of oxygen by skeletal
muscle- CO2 production - respiration.
• GIT Effect- aspirin is gastric irritant-gastrititis, ulcer,
bleeding, mucosal congestion.
• Blood- platelet aggregation

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 Pharmacological action of Aspirin

• Metabolic effects: Cellular metabolism is increased, especially in skeletal muscles,

due to uncoupling of oxidative phosphorylation � increased heat production

• Increased utilization of glucose and blood sugar may decrease (especially in

diabetics) and liver glycogen is depleted.

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 Pharmacological action of Aspirin

• CVS: Larger doses increase cardiac out put to meet increased peripheral 02
demand and cause direct vasodilatation

• BP may fall

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Pharmacological action of Aspirin

• Long term intake of large dose decreases synthesis of clotting factors in liver

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 Kinetics of Aspirin

• Absorbed from the stomach and small Intestine

• 80% bound to plasma proteins

• Freely crosses placenta

• Metabolised in liver

• The metabolites excreted by glomerular filtration in

urine

• Plasma half life 15-20 min 2

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 ADR

• Nausea, vomiting, epigastric distress- Pain or discomfort below your ribs in this
area of the upper abdomen, increased blood loss in stools

• Peptic ulceration

• Hypersensitivity and idiosyncrasy: Rashes, urticaria, rhinorrhoea, angioedema,

asthma.

• Dizziness, tinnitus, vertigo, reversible impairment of hearing and vision,

excitement and mental confusion, hyperventilation and electrolyte imbalance

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 ADR

• Acute salicylate poisoning: It is more common in children. Fatal dose in adults is

estimated to be 15-30 g, Serious toxicity is seen at serum salicylate levels > 50
mg/ dl. Manifestations are: Vomiting, dehydration, electrolyte imbalance, acidotic
breathing, hyper /hypoglycaemia, petechial haemorrhages- brown-purple spots ,
restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death
due to respiratory failure + cardiovascular collapse

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 Precautions and contraindications

• Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer,

bleeding tendencies, in children suffering from chicken pox or influenza

• In chronic liver disease

• It should be avoided in diabetics, in those with low cardiac reserve or CHF and
in juvenile rheumatoid arthritis

• Aspirin should be stopped 1 week before elective surgery

• Given during pregnancy it may be responsible for low birth weight babies

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Precautions and contraindications

• It should be avoided by breastfeeding mothers

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 Drug Interaction

• Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin and

methotrexate from binding sites on plasma proteins

• Its anti platelet action increase the risk of bleeding in patients on oral
anticoagulants

• Aspirin blunts diuretic action of furosemide and thiazides

• Aspirin reduces protein bound iodine level by displacement of thyroxine

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USES

• As analgesic, for headache (including migraine), backache, myalgia, joint

pain etc

• Antipyretics

• Acute rheumatic fever

• Rheumatoid Arthritis

• Osteoarthritis

• Post myocardial infraction and Post stroke patients

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Para amino phenol derivatives

Paracetamol-
Good antipyretic but weak ant-inflammatory
Inflammatory site is rich in peroxides-generated by
leukocytes
In presence of peroxides paracetamol is weak cox
inhibitor
No action on respiration, acid base balance, CVS, GIT
Metabolized by microsomal enzyme

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Mechanism of- toxicity

Paracetamol
M
N-Acetyl P-benzoquinone-imine
Conjugate glutathione
Detoxified

Paracetamol

Hepatic glutathione deplated

M Toxic
Binds to Sulphydryi group

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ADR

• Large dose- toxicity

• Hepatotoxic

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Preferential COX 2 Inhibitors

Diclofenac
Analgesic, antipyretic & anti inflammatory
Well absorbed quickly attend therapeutic level-BA 50%
Post operative pain, rectal suppository
Aceclofenac
More cox 2 selective
Long acting drug
Use- chronic inflammation- rheumatoid & osteo arthritis
Acute musculo skeletal pain, painful dental visions
To reduse intraocular inflammation
Nimesulide
Sulfonamide compound – higher affinity for COX 2 than Cox 1
Its has antihistaminic & anti allergic activity
ADR- Epigastric pain , rashes, nephrotoxicity, hepatotoxicity.

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Selective Cox 2 Inhibitors

Celecoxib
Highly selective Cox 2 inhibitors
Analgesic, antipyretic & anti inflammatory
Better tolerated- mild gastric irritation
Adr- hypertension, edema in CVS
Use- post operative pain , dysmenorrhoea, dental pain, osteoarthritis.

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• Aspirin-antiplatelet, analgesic
• Paracetamol- analgesic, antipyretic
• Diclofenac- anti-inflammatory- good at synovial
fluid
• Celecoxib- highly selective cox 2 inhibitor-does not
inhibit the platelet.

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 Summary

• NSAIDs are also called non-narcotic, non-opioid or aspirin like analgesics

• Gastrointestinal: Gastric irritation, erosions, peptic ulceration, gastric bleeding/

perforation, esophagitis most common adverse effect

• Acetaminophen is more safe during pregnancy

• Aspirin (also an NSAID): Inhibit the clotting of blood (platelet aggregation),

prevent strokes and cardiovascular attacks

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