Non-steroidal Anti-inflammatory Drugs

1.Anti-inflammatory
 They process 2.Analgesic
3.Anti-pyretics effects
Due to inhibition of prostaglandins production by binding
to enzyme cyclooxygenase (COX)
Specific feature:-
 Weaker analgesic compare to opioids,
 No CNS depression,
 Non narcotic,
 No abuse potential,
 No dependence,
 Prominent peripheral action

Membrane phospholipids
Lyso glyceryl phosphorylcholine
Phospholipase A2
Arachidonic acid
Cyclic endoperoxides
Cyclooxygenase
(COX)
PG’s
PGI2 PGE2
TXA2 PGD2
PGF2α
PAF
Vasodilator
↑vascular permeability
Bronchoconstriction
5-Lipoxygenase
(LOX)
Leukotrienes
LTB4 LTC4
LTD4 LTE1
↑vascular permeability
Bronchoconstriction
Glucocorticoids
NSAID’s
Vasodilatation,
inhibition of
platelet
aggregation
↓IOP
GI protection
Kidney
function
Regulation of
blood flow
Platelet
aggregation Bronchoconstr
iction
vasodilatation

Effect due to inhibition of PG synthesis
Beneficial action
 Analgesia
 Antipyretics
 Anti-thrombotic
 Closure of ductus arteriosus
Non-beneficial actions
 Gastric mucosal damage
 Bleeding due to inhibition of
platelet function
 Limitation of renal blood flow
 Na+ & water retention
 Prolongation of labor
 Asthma & anaphylactic
reaction in suspected
individual

COX-1 COX-2 COX-3
Constitutive /house
keeping enzyme that
regulate normal
cellular processes
such as
 Gastric
cryoprotection
 Vascular
homeostasis
 Platelet aggregation
 Kidney function
Inducible or can be expressed
with stimuli(i.e. shear stress,
growth factor, tumor
promoters and cytokines)
• Causes the elevated
production of
Prostaglandins that occurs
in site of disease &
inflammation
• Except-in kidney COX-2
constitutive nature
Implicated in
fever & pain,
express in brain
and heart.
Not involve in
inflammation
Paracetamol acts
on COX-3

NSAID’s
Non-selective COX
inhibitors
Preferential COX-2
Inhibitors
Selective COX-2
inhibitor
Analgesic-antipyretics
with poor
Anti-inflammatory effect
Paracetamol,
nefopam.
•Aceclofenac
Salicylates:- Aspirin
Propionic acid derivative
•Ibuprofen
•Ketoprofen
•Flurbiprofen
•Naproxen
Enolic acid derivatives:-
Piroxicam,Tenoxicam
Acetic acid derivatives:-
Ketorolac
Indomethacin
Nabumetone
Pyrazolone derivatives:-
Phenylbutazone
Oxyphenbutazone
Fenamate:-
Mephenamic acid

Aspirin (Acetylsalicylic acid)
 Prototype drug
 Covalently /Irreversibly inhibit both cox-1 & 2
 Thus duration of effects of aspirin is related to the turn
over rate of cyclooxygenase(7 days)

Pharmacokinetics
 Absorption:-
• Rapid from stomach & upper small intestine
 Distribution:-
• Bound to plasma albumin (80%)-this binding is saturable
• Aspirin t½ 15–20min, Salicylic acid t½ 3-5hrs
 Metabolism:-
• Rapidly hydrolyzed in liver by esterases into acetic acid &
salicylate
 Excretion:-
 Mixed order kinetics-low dose first order kinetics
 High dose as metabolizing enzyme get saturated-switch to zero order
kinetics
• In urine-Alkalinization  excretion
(Alkaline diuresis is done in toxicity)

Pharmacodynamics
Anti-inflammatory effect:-
 This is due to irreversible inhibition of COX-2
 Effect can be seen at higher dose (3-5 gm/day)
 produce only symptomatic relief do not affect the progression of
underlying disease.
 Aspirin  prostaglandin, prostacyclin and thromboxane synthesis.
Also  chemotaxis and stabilizes lysosomes
 Inhibit granulocyte adherence to the damaged vasculature
Analgesic effect:-
• Effect can be seen at dose (1-2 gm/day)
• PGs(E2 & I2) sensitize afferent nerve ending to pain
• Most effective in reducing mild to moderate pains
• Musculoskeletal pain, dysmennorrhoea, pain with inflammation
•  inflammation peripherally & also  pain stimuli centrally

 These drugs relieve pain without causing sedation, tolerance
or drug dependence.
 Less efficacious than opioids as analgesics
Antipyretic effect:-
 Effect can be seen at dose (1-2 gm/day)
 ↓elevated temperature by resetting temp. set point of
hypothalamus without causing hypothermia in
normothermic individual.
 This is due to COX inhibition in the CNS & inhibition of
PGE2 mediated IL-1

 Antiplatelet effect:-
• Effect can be seen at low dose (75-325 mg/day)
• Inhibits platelet aggregation, so  bleeding time
• Thromboxane A2-cause aggregation of platelets
• Vascular endothelium processes PGI2-inhibit platelet
aggregation
• Aspirin-higher dose (2-3gm/day)-inhibit Thromboxane
A2+PGI2 hence beneficial effect of PGI2 is lost
• Life span of platelet-1 week(anti-platelet effect persist
for week)
• Platelet is lack of nucleus-fresh enzyme not synthesize
• Aspirin should be withdrawn 1 week prior to elective
surgery because of the risk of bleeding

 Respiratory system:-( dose dependent)
 Anti-inflammatory dose- stimulation is respiration
 Direct stimulation on RC & indirectly by ↑CO2
production-leading to respiratory acidosis
 Salicylate Poisoning-Hyperventilation -death by
respiratory depression & respiratory failure
 Acid base and electrolyte balance:-
Low dose Anti-inflammatory dose
Compensated
Respiratory alkalosis Respiratory acidosis
Renal
excretion HCO3
-

 GIT:-
&
Salicylic acid
“Ion trapping”
 Aspirin trigger CTZ and produces vomiting

 CVS:-
 Therapeutic dose-no effect
 ↑dose- ↑O2 demand - ↑COP
 Toxic doses- depress VMC -↓BP may precipitate CHF
 Aspirin- ↓↓ effect of Antihypertensive drugs
Uric Acid excretion:-
 Small doses/ therapeutic doses-↓↓UA Excretion,
(antagonize uricosuric drugs)
 Higher doses ↑UA excretion-by inhibiting reabsorption
 Not effective in Chronic gout -↑↑ doses - not tolerated

-:Clinical Uses:-
A. In mild to moderate pain-
 painful conditions:- like -toothache, headache, backache,
bodyache, muscle pain, temporomandibular and other joint
pain, neuralgias,
 Dysmenorrhoea(↓PG level in endometrial tissue), etc.as a
analgesic agent.Not effective in severe visceral pains.
B.Rheumatoid arthritis(RA):-
 only symptomatic relief due to anti-inflammatory action.do
not alter the progression of disease
 Dose-3- 5 g/day produces relief of pain, swelling and
morning stiffness but less tolerated
 Ankylosing spondylitis-↓pain & inflammation
 Osteo-arthritis(OA)-alternative to Paracetamol

C. Acute Rheumatic fever-
Aspirin -preferred drug (anti-inflammatory action).
Advantage-
 Reduces fever
 relieves swelling and joint pain
 High concn. Inhibit Antibody production
 Inhibit antigen-antibody aggregation
 Inhibit antigen induce histamine release
Corticosteroids –for chronic case
D. Post MI, post stroke- (anti-platelet action)
-low doses 75 – 150 mg /day-prevent arterial thrombosis
Prevent reinfarction
E. Pregnancy induced pre- eclampsia & hypertension

 Due to anti-platelet action (50-100mg daily)
F.Prevention of colon cancer- ↓risk upon regular
use
G. Other uses:-
 Medical closure of patent ductus arteriosus
(indomethacin is preferred)
 Delays labour by inhibition of PG
 low dose prevent progression of Alzheimer disease
 To control radiation-induced diarrhoea.
 To control pruritus and flushing associated with the use of
nicotinic acid.

Adverse Effects
 GIT:- Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis,
ulceration and GI bleeding.
 Ulcerogenic effect prevented/minimized by taking:-
a. NSAIDs after food.
b. proton pump inhibitors/H2-blockers/misoprostol with NSAIDs.
c. Selective COX-2 inhibitors
 Hypersensitivity:- common with aspirin.
 The manifestations are skin rashes,urticaria, rhinitis, bronchospasm,
angioneurotic oedema and rarely anaphylactoid reaction.
 Bronchospasm (aspirin-induced asthma) ↑production leukotrienes.
Incidence of hypersensitivity is high in patients with asthma, nasal
polyps, recurrent rhinitis or urticaria.
 Therefore, aspirin should be avoided in such patients.

 Reye’s syndrome:-
 Use – in children with viral infection (chicken
pox,influenza) may cause hepatic damage with fatty
infiltration and encephalopathy
 Hence, salicylates are contraindicated in children with viral
infection
 Salicylism:- (Anti-inflammatory doses/chronic use)
Characterized by- Tinnitus, dizziness, vertigo, loss of hearing
and vision, mental confusion ,hyperventilation, electrolytic
imbalance
Rx- ↓dose or stoppage therapy
 Prolonged use of salicylates -↓ synthesis of clotting factors
(hypoprothrombinaemia) predisposes to bleeding
Rx-administration of vitamin K

Toxicity:-Acute Salicylate Poisoning:-
 Can be suicidal or accidental as in children
 Occurs on dose-15- 30 g
 Manifestations –
 vomiting,
 dehydration,
 restlessness,
 confusion,
 coma,
 convulsions,
 cardiovascular collapse,
 pulmonary oedema,
 hyperpyrexia death

 Rx- (No specific antidote)
 Hospitalization of pt.
 Gastric lavage followed by administration of activated
charcoal (It adsorbs the toxic material—physical
antagonism)
 Maintain fluid and electrolyte balance. Correct acid–base
disturbances.
 Alkalization of urine -I.V.NaHCO3 to treat metabolic
acidosis & promote renal excretion of salicylates (since
salicylates exist in ionized form in alkaline pH).
 External cooling.
 Hemodialysis in severe cases.
 Vitamin K1 and blood transfusion, if there is bleeding

Interaction
 Aspirin × -↑toxicity
due to displace from PPB
 Aspirin × Probenecid-↓Probenecid uricosuric action
 Aspirin × ↓diuretic effect
 Aspirin × Antacids-↑ clearance of aspirin by making
urine alkaline
warfarin,
naproxen,
tolbutamides
phenytoin,
methotrexate
Frusemide,
thiazide,
spironolactone

Contraindication
 Peptic ulcer
 Infants & children suffering from viral fever-reyes
syndrome
 Bronchial asthma-induced by aspirin
 G-6-PD deficient individual-haemolysis
 Poor cardiac reserve
 Chronic liver disease
 Pregnancy-
 delay onset of labour and ↑chance of PPH.
 In the newborn-low birth weight baby.premature closure of
the ductus arteriosus.

Selective COX-2 inhibitors (Coxibs)
 Celecoxib, parecoxib, etoricoxib, lumiracoxib
Process- Anti-inflammatory, Analgesics, Anti-pyretic action
Advantage:-
 Less GI side effect
 Week acids with longer plasma half life
 No precipitation of bronchial asthma
 No bleeding –as no anti-platelet action
Disadvantages:-
 they inhibit PGI2 which is cardio-protective effect
 ↑incidence of Cardiovascular thrombotic effect
 COX-2 constitutively express in kidney-inhibition cause
renal toxicity

Celecoxib Parecoxib Etoricoxib
Analgesic, anti-
inflammatory &
antipyretic action
comparable to
naproxen/
Diclofenac
Less ulcerogenic
USES:-
Osteoarthritis & RA
Dose-100-200mg BID
Prodrug of
valdecoxib and is
administered
parenterally(iv/im)
Only parental form
coxib’s
USES:-
Short term
management of
pain-Effective
analgesics for both
pre-or post op pain
with similar
efficacy as etorolac
 Highest COX- 2
selectivity.
 Uses:-OA, RA, Acute
goute,musculoskeleta
l pain, post op pain
include dental pain &
dysmenorrhea.
SE:-
 Abdominal pain
 Dyspepsia
 Dryness of mouth
 ↑BP

Current status of Selective COX-2
Inhibitors
 Can be used – pt. who cant tolerate traditional
NSAID’s
 Otherwise should be avoided due to cardiovascular
& renal side effect

Preferential COX-2 Inhibitors
 These drug have inhibitory action less than selective COX-2
Inhibitors
Drugs includes-
Nimesulide,Diclofenac,Meloxicam,Aceclofenac, Etodolac
 Analgesic, anti-inflammatory & antipyretic
 Reduces generation of superoxide by neutrophils
 Inhibits PAF synthesis and TNFα release
 Performs Free radical scavenging
 Inhibits metalloproteinase in cartilages
SE:-hepatotoxicity, agranulocytosis-life threatening
Others- nausea, diarrhea, epigastric discomfort, rashes
Nimesulide

 Used:- for short term- Injuries, ENT disorders, Post
operative pain, Dysmenorrhoea, Fever
 Banned in India for children of age less than 12 yr.
 Valuable drug if used with all the precautions
 Meloxicam-equally effective as peroxicam in OA,RA
 Nabumetone- only non-acid NSAID T1/2>24hr.low GI
side effect but renal side effect present
 Unfortunately high dose is needed & expensive
 Etodolac-less GI side effect may undergoes entero-hepatic
circulation
 Diclofenac-
 Most effective commonly used NSAIDS by oral, parental,
topical route
 Processes-Anti-inflammatory,analgesics,anti-pyretic action

 No Anti-platelet action
 T1/2-1-2hr but duration is longer than t1/2 due to
accumulation in synovial fluid (preferred in arthritis )
 50% BA-(First pass metabolism)
USES:-
 RA,OA,Ankylosing spondylitis (dose-100-200mg)
 Short term management of acute musculoskeletal injury such as
tendonitis, bursitis
 Also used for toothache,dysmenorrhea,renal colic, PO-inflammatory
pain after cataract surgery
 SE:-abdominal discomfort, nausea, skin rashes, allergic reaction,
hepatotoxicity
 Diclofenac +misoprostol (PGE1 analogue) ↓GI irritation and peptic
ulcer
 Aceclofenac- similar properties as diclofenac

Non-selective Cox-2 inhibitors
 Ibuprofen:-It has moderate anti-inflammatory effect
 It is better-tolerated than aspirin
 It can be used in children (does not cause Reye’s syndrome)
 Mainly g.i. side effects but less than Aspirin
 Most popular OTC anti-inflammatory analgesic
 Also used for the closure of PDA
 Ketoprofen- it also inhibit LOX pathway
 Ketorolac- powerful Analgesics without anti-inflammatory
 Efficacy equal to morphine in mild-moderate pain in post
surgical pt.
 It relieves pain without causing respiratory depression, hypotension
and drug dependence

 Uses:-renal colic, PO and metastatic cancer pain
 Chronic use-renal toxicity
 Only NSAIDs used-i.v.
 Indomethacin:- Nonselective COX inhibitor with potent
anti-inflammatory effect
 It inhibits phospholipase A2 leading to ↓neutrophils
migration to inflamed area causes ↓T & B cell proliferation
 Uses-ankylosing spondylitis, acute gout and psoriatic
arthritis
 DOC-closing of PDA
 SE:- GI side effects side effects include severe headache,
confusion, hallucinations, etc.
• Contraindication-epileptics, psychiatric patients and drivers

 Potent antipyretic & analgesic effects with poor anti-
inflammatory activity
 Increases pain threshold & decreases elevated body
temperature by CNS action
 Poor inhibition of COX in periphery. Also inhibition of
COX-3 enzyme in cortex but not in human
 Advantage:-
 Doesn’t produce effect on CVS
 No respiratory stimulation
 No alteration of Acid base balance
 Doesn’t cause Gastric irritation & bleeding
 No effect on platelet action & bleeding time
 No action on uric acid excretion
Paracetamol (Acetaminophen)

Pharmacokinetics:-
 Absorption-rapid orally
 T1/2-2-3hr
 Distribution-uniformly In most of the body
 Metabolism- Acetaminophen
90%-95%
glucuronide & sulfation conjugation
Non-toxic metabolites CYP2E1
5%-10%
NAPQI-toxic metabolites
glutathione conjugation
mercapturic acid
Excretion
In Toxicity
depletion cellular glutathione
↑↑NAPQI bind to cellular macromolecule
hepatocellular injury & Death

Uses:-
1. As antipyretic: ↓body temperature during fever.
2. As analgesic: To relieve headache, toothache, myalgia,
dysmenorrhoea,OA etc.
3. It is the preferred analgesic and antipyretic in patients
with peptic ulcer, haemophilia, bronchial asthma and
children & in all age group, pregnancy & lactation
Adverse effects
1. Side effects are rare, occasionally causes skin rashes and
nausea.
2. Hepatotoxicity: with acute overdose or chronic use.
3. Nephrotoxicity is commonly seen on chronic use.

 Acute paracetamol poisoning:-
 Susceptible individual-
 Premature infants/children who have low hepatic
glucuronide conjugating ability.
 Alcoholic’s
 Toxic dose-Children dose > 150 mg/kg
Adult dose-> 10 g
 Fatality is common with > 250 mg/kg
 Symptoms-mainly hepatotoxicity
 Others- nausea, vomiting, diarrhoea, abdominal pain,
hypoglycaemia, hypotension, hypoprothrombinaemia, coma, etc.
Death is usually due to hepatic necrosis.

Rx-
 Induce vomiting
 gastric lavage
 Antidote- N-acetylcysteine or
 oral methionine(Essential amino acid) replenishes the
glutathione stores of liver and protects the liver cells.
 Activated charcoal -↓absorption of paracetamol from the
gut.
 Hemodialysis may be required in cases with acute renal
failure.
 Last resort-liver transplant

FDC
 Ibuprofen + Paracetamol
 Diclofenac + paracetamol
 Nimesulide + paracetamol
 Codeine + Aspirin/paracetamol
 Diclofenac+ Misoprostol

Rational Selection of NSAID’s
1.Type of pain-
 Mild – moderate pain (with little/without inflammation)
e.g.-Acute musculoskeletal condition, myalgia, headache,
migraine, OA-
Drug-Paracetamol/Ibuprofen
 PO-Pain- ketorolac, diclofenac, Nimesulide
2.Inflammatory condition-
 RA, Ankylosing Spondylitis,rheumatic fever-naproxen,
piroxicam, high dose aspirin
 Acute gout-indomethacin, Naproxen, piroxicam
3.Gastric intolerance/anaphylactoid reaction- Cox-2
inhibitors, paracetamol

4.Age Factor:-
Children- PCM, Ibuprofen, naproxen
Elderly- Any NSAID’s in a low dose
5.Pragnancy-PCM,Aspirin(low dose)
6.Associated disease-
Bronchial asthma-Nimesulide, COX-II inhibitors
Hypertension, heart failure,diabetes,epilepsy-rule
out clinical significant drug interactions before
prescribing

Non-steroidal Anti-inflammatory Drugs

Non-steroidal Anti-inflammatory Drugs

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