PH – 1.

16

Non Steroidal

Anti Inflammatory Drugs

Dr. Dwajani.S
Associate Professor,
Pharmacology
 Classification of NSAIDS

1. Non Selective COX inhibitors – traditional NSAIDS

Aspirin, Ibuprofen, ketoprofen, Mephenamic acid, diclofenac, aceclofenac,

piroxicam, ketorolac, indomethacin, phenylbutazon, oxyphenbutazone

2. Preferential COX 2 inhibitors – Nimesulide, meloxicam, nabumetone

3. Selective COX 2 inhibitors – celecoxib, etorocoxib, parecoxib

4. Analgesics, antipyretics with poor anti-inflammatory action – Paracetamol,

metamizol, nefopam
 Non selective Cox inhibitor - Aspirin

• Acetylsalicylic acid (ASA) - earliest drugs synthesized .

ASPIRIN
• One of the most commonly consumed drugs

Pharmacologically useful actions and uses

1. Analgesia
• Inhibits PG synthesis --- blocks the pain sensitizing

mechanism induced by bradykinin, TNFα, IL

• Not effective in visceral and ischeamic pain

• Uses headache, backache, toothache, pain of cancer metastasis of bone

• As analgesic – antipyretic 300-600mg 6-8 hrly

2. Antipyretic action
• Reduces body temperature in fever

• Acts by inhibiting COX 1 and 2 – reduced PG synthesis in

hypothalamus – resets hypothalamic thermostat
• Uses – given in dose of 75 – 100 mg/kg/day
ASPIRIN / Non selective
NSAIDS
3. Anti inflammatory action
• Acts by inhibition of PG synthesis

• Prevents from spreading

of inflammation
• Uses – higher doses 3-6 g/day

or 75-100 mg/kg/day

1. Osteoarthritis,
PGE2

2. rheumatoid arthritis,

3. Rheumatic fever Inflammation

4. Inhibition of platelet aggregation
• TXA2 enhances, while PGI2 decreases the platelet
aggregation
• Aspirin – irreversibly inhibits TXA2 production by
inhibiting COX 1 enzyme of platelets
• Dose – Low dose aspirin 75 -100mg/day

• Use – Lower the risk of reinfarction on post MI

and post stroke patients

5. Relief in dysmenorrhoea
• Levels of PGEs in menstrual flow and PGF2

in circulation in increased in dysmenorrhoea

• Aspirin decreases uterine PG levels
ASPIRIN

and provides relief

6. Closure of ductus arteriosus

Low dose aspirin can cause closure of

patent ductus arteriosus, if it fails

to occur at birth
7. Colonic and rectal cancer – regular and sustained use of
aspirin can reduce the risk of colonic and rectal cancer. But COX
2 inhibitors can be effective.

8. Preeclampsia –aspirin 100mg /day supress TXA2 production

9. Alzeimer’s diseases – regular use of aspirin in small doses,

reduces the risk and retards the onset of the disease
 Aspirin adverse effects

• Gastric mucosal damage – aspirin

inhibits COX 1 and nullifies

gastroprotective action --- dyspepsia,

diarrhea, nausea, vomiting, gastric

bleeding, ulceration.

• Increase bleeding tendency – long term

use – decreases prothrombin time

 Aspirin adverse effects

• Hypersensitivity – by inhibiting COX - more LT

production -bronchoconstriction and allergic

reactions, angioneurotic edema

• Decreases Uric acid excretion

• Anti inflammatory doses – 3-5g/day –

Salicylism/ acute salicylate poisoning

 Aspirin adverse effects
Salicylism
• Salicylate intoxication can be mild or severe

• Symptoms – headache, tinnitus, vertigo, confusion, diarrhea, sweating, electrolyte

imbalance
• Reversible on stoppage of drug

Acute salicylate poisoning

Most common in children. Vomiting, dehydration, electrolyte imbalance, restlessnss,
hyperpyrexia, confusion, coma, death due to respiratory failure and cardiovascular
collapse.
No specific antidote. Treatment is symptomatic
Aspirin adverse effects
• Hospitalization

• Gastric lavage to remove unabsorbed drug

• Hemodialysis in severe cases

• Forced alkaline diuresis

• External cooling

• IV fluids with Na+, K- and HCO3 and Glucose,

with repeated monitoring
• Blood transfusion and Vit K if bleeding occurs
 Precautions and Contraindications
• C/I in patients with peptic ulcer, bleeding tendencies, in children
suffering from chicken pox
• In chronic liver disease

• To be avoided in diabetes with cardiac abnormalities

• Precautions : Aspirin should be stopped 1 week before elective surgery

• Given during pregnancy – low weight birth; delayed or prolonged

labour, premature closure of patent DA
• To be avoided in breast feeding mother
 Drug interactions
• Aspirin displaces warfarin, naproxen, sulfonylureas,
phenytoin and ,methotrexate from binding site – toxicity of
these drugs may occur
• Inhibits tubular secretion of uric acid

• Aspirin blunts diuretic action of furosemide and thiazide and

reduces K+ conserving action in spiranolactone
 Other NSAIDS
Drug Route and dose Features
• Moderate anti-inflammatory action
Ibuprofen Oral and topical
• Better tolerated than aspirin
400-600mg • Can be used in children

Oral, im, rectal, topical • Potent anti-inflammatory

Diclofenac
gel and eye drops – • Gets concentrated in synovial fluid
50mg BD or 100mg • Increase incidence of
hepatotoxicity
• Combined with misoprostol
reduces – GI irritation
 Drug Route and dose Features
• Potent anti-inflammatory action
Indomethacin Oral, eye drops,
• Inhibits migration of neutrophils to
suppositories inflamed areas
• Effecting in Gout, psoriatic arthritis
50 mg TDs

• Potent anti-inflammatory
Piroxicam Oral, im and topical
• Long acting
20 mg OD • Increase incidence of peptic ulcer and
bleeding
• Potent analgesic
Ketorolac Oral, im, iv,
• Relieves pain without resp depression
transdermal • Used in renal colic, post operative
and metastatic cancer pain
10-20mg QID
 Drug Route and dose Features
• Has analgesic, antipyretic and weak
Mefenamic acid Oral,
anti-inflammatory
250-500mg TID • Used in dysmenorrhea, OA, RA
 Preferential COX 2 Inhibitors
Nimesulide
• relative COX-2 selectivity.

• Anti-inflammatory action may be – other mechanisms - e.g. reduced generation

of superoxide by neutrophils, inhibition of PAF synthesis and TNFα release, etc.,
• The analgesic, antipyretic and anti inflammatory activity is comparable to other
NSAIDs.
• Primary use for short-lasting painful inflammatory conditions like sports
injuries, sinusitis, ear-nose-throat disorders, dental surgery, bursitis, low
backache, dysmenorrhoea, postoperative pain, osteoarthritis and fever
 Preferential COX 2 Inhibitors
Pharamcokinetics
• Almost completely absorbed orally,
• 99% plasma protein bound,
• Extensively metabolized and excreted mainly in urine
• Plasma half life - 2-5 hours.

Adverse effects
• Gastrointestinal - epigastralgia, heart burn, nausea, loose motions
• dermatological -rash, pruritus
• central -somnolence, dizziness.

Gastric tolerability of nimesulide is better

 Preferential COX 2 Inhibitors
Meloxicam
• This newer congener of piroxicam, has a COX-2/COX-1
selectivity
• Longer acting, less toxic than piroxicam and other NSAIDs

• Dose 7.5 to 15 mg OD

• Side effects are lesser compared to piroxicam

 Preferential COX 2 Inhibitors
Nabumetone
• It is a prodrug-generates active metabolite (6-MNA), and is a
relatively potent COX-2 inhibitor than COX-1
• It posses analgesic, antipyretic and anti-inflammatory actions-

• Effective in the treatment of RA and osteoarthritis

• Has lower incidence gastric erosions, ulcers and bleeding,.

• Abdominal cramps and diarrhoea can occur

 Selective COX 2 Inhibitors
Celecoxib, Etoricoxib and Paricoxib
• Highly selective COX 2 inhibition

• They cause little gastric mucosal damage; occurrence of

peptic ulcer and ulcer bleeding is lower than with NSAIDs.
• They do not depress TXA2 production by platelets (COX-I
dependent); do not inhibit platelet aggregation or prolong
bleeding
 Selective COX 2 Inhibitors

• selective COX-2 inhibitors should be used only in patients

at high risk of peptic ulcer, perforation or bleeding.
• should be administered in the lowest dose for shortest period
of time.
• Should be avoided in patients with history of ischaemic heart
disease/ hypertension/ cardiac failure/ cerebrovascular disease
 Selective COX 2 Inhibitors
Celecoxib
• Modest - COX-2 selectivity of celecoxib.

• Has antiinflammatory, analgesic and antipyretic actions with

low ulcerogenic potential
• It is approved for use in OA and rheumatoid arthritis in a

dose of 100-200 mg BD
 Selective COX 2 Inhibitors
Etoricoxib
• This newer COX-2 inhibitor - highest COX-2 selectivity.

• It is suitable for OD – OA, RA and acute gouty arthritis,

dysmenorrhoea, acute dental surgery pain
• Doesnot affect Platelet function or damaging gastric mucosa.

• Side effects are dry mouth, taste disturbance and paresthesias.

Difference between non selective and selective COX inhibitors

Non selective COX inhibitors Selective cox 2 inhibitors

• Analgesic, antipyretic and anti- • Analgesic, antipyretic and anti-
inflammatory action inflammatory action
• Antiplatelet effect • No antiplatelet action
• GI side effects are marked • Less GI side effects
• Renal toxicity present • Renal toxicity present
Analgesics, antipyretics with poor anti-inflammatory action

Paracetamol
• Analgesic, antipyretic with weak anti inflammatory

• Peak effect in 30-60 mins and lasts for 3-5 hrs

• Glucuronide conjugation in liver

• Unwanted effects
– Few and uncommon

– Skin reactions

– Large doses, over longer periods – risk of kidney damage

 Paracetamol toxicity
• Toxic dose – x 2 or 3 times max therapeutic dose[>10gm/day or
>150mg/kg and in alcoholics >5-6g/day]
• Serious, potentially fatal hepatotoxicity

• Liver enzymes saturated --- because toxic metabolite of

Paracetamol - N-acetyl-benzoquinone is metabolized by
glutathione conjugation. On high doses glutathione is depleted --
toxic metabolite accumulates – binds to proteins in liver and
kidney --- Causes necrosis in liver and kidney tubules
 Paracetamol toxicity
• Nausea, vomiting abdominal pain

• Hepatotoxicity - Delayed manifestation: 24-48 hrs

• Treatment
– Gastric lavage –

– Activated charcoal is given orally to prevent further absorption

– Antidote - N acetyl cysteine or methionine increases glutathione

availability – 150mg/kg infused iv over 15 mins followed by same dose
for next 20 hours
– Alternatively 75mg/kg – given orally every 4-6 hrs for 2-3 days
 Analgesics, antipyretics with poor anti-
inflammatory action
Uses
• Paracetamol is one of the most commonly ' over-the-counter'
analgesic for headache, migraine, musculoskeletal pain,
dysmenorrhoea
• Ineffective when inflammation is prominent.

• Paracetamol is DOC - OA
 Mention drugs used for below conditions
1. Mild to moderate pain with inflammation : Paracetamol or low
dose ibuprofen
2. OA, musculoskeletal pain : Paracetamol or diclofenac
3. Pediatric patients – preferred drug – Paracetamol, ibuprofen,
naproxen
4. Safe in pregnancy – Paracetamol
5. GI intolerance to traditional NSAIDS – selective cox 2 inhibitor or
Paracetamol
6. Patients with history of asthma – nimesulide, cox 2 inhibitors
7. Post operative pain – ketorolac, diclofenac, nimesulide and aspirin