Nonsteroidal antiinflammatory
drugs and antipyretic-analgesics
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

Introduction to NSAIDs
• Chemically diverse, but most are organic acids
• Grouped together as these drugs have common analgesic
(pain reducing) and antipyretic (fever-reducing) effects and
which have, in higher doses, anti-inflammatory effects
• Do not depress CNS – no physical dependence or abuse
liability
• Weaker analgesic than Morphine – except inflammatory
pain
• Also called non-narcotic, nonopioid and aspirin-like
analgesics
• Primarily act on peripheral pain mechanism, and also in
CNS (Raise threshold)

History of NSAIDs
• Salix alba or White Willow bark
• Sodium salicylate – 1875
• Acetylsalicylic acid – 1899
– Also phenacetin and antipyrine
• Phenylbutazone – 1949
• Indomethacin - 1963

Classification
Traditional – Nonselective COX inhibitors
Traditional – Nonselective COX inhibitors
Group Drugs
Salicylic acids Aspirin
Propionic acids
Propionic acids Naproxen, Ibuprofen, Ketoprofen,
Oxaprozin and Flurbiprofen
Anthranilic acid
Anthranilic acid Mefenamic acid
Aryl-acetic acid derivative
Aryl-acetic acid derivative Diclofenac and Aceclofenac
Oxicam derivatives
Oxicam derivatives Piroxicam and Tenoxicam
Pyrrolo-pyrrole derivative
Pyrrolo-pyrrole derivative Ketorolac, Indomethacin,
Nabumetone
Indole derivatives
Indole derivatives Sulindac and Indomethacin
Pyrazolone derivative
Pyrazolone derivative Phenylbutazone, Oxyphenbutazone

Classification – contd.
Preferential COX-2 inhibitors Nimesulide, Diclofenac,
Aceclofenac, Meloxicam and
Nabumetone
Selective COX-2 inhibitors Celecoxib, Etoricoxib and
Parecoxib
Analgesic-antipyretic with
poor antiinflammatory
action:
Paraaminophenol derivative
Pyrazolone derivative
Benzoxazocine derivative
Paracetamol (acetaminophen)
Metamizole and Propiphenazone
Nefopam

NSAIDs and Prostaglandins
• All NSAIDs inhibit PG synthesis
• Prostaglandins, prostacyclines (PGI2) and Tromboxane A2
(TXA2) are produced from Arachidonic acid
• The enzyme responsible is prostaglandin synthase, also
known as cycloxygenase or COX
• COX in 2 isoforms: constitutive - COX-1 and inducible COX-2
• COX-1 serves house keeping functions
• COX-2 is generated by cytokines and others during
inflammation (constitutive in brain and JG cells) – PG
synthesis
• Most NSAIDs inhibit COX-1 and COX-2 non-selectively and
inhibit PG synthesis
• Aspirin inhibits COX irreversibly – acetylation
• Other NSAIDs are competitive reversible inhibitors

Proposed Mechanism: COX-1, COX-2, & COX-3
Arachidonic acid
COX-2
(inducible)
Body homeostasis
• Stomach
• Intestine
• Kidney
• Platelet
Inflammatory Site
• Macrophages
• Synoviocytes
• Endothelial cells
X X
Selective
COX-2 inhibitor
COX-1
(normal constituent)
X
Normal Constituent
• CNS
• Kidney
• Female U/G tract
Glucocorticoids
(block mRNA expression)
X
X
Acetaminophen
COX-3
(normal constituent)
Pain
Fever
?HTN
?GI
• CNS, Heart, Aorta
Nonselective
NSAID

NSAIDs and Prostaglandin
Mediate
Mediate
inflammation,
inflammation,
pain, and fever
pain, and fever
Mediate
Mediate
inflammation,
inflammation,
pain, and fever
pain, and fever
COX-2–
COX-2–
specific inhibitors
specific inhibitors
COX-2–
COX-2–
specific inhibitors
specific inhibitors
Protect
Protect
gastroduodenal
gastroduodenal
mucosa
mucosa
Protect
Protect
gastroduodenal
gastroduodenal
mucosa
mucosa
Supports platelet
Supports platelet
function
function
Supports platelet
Supports platelet
function
function
COX-1
COX-1
COX-1
COX-1 COX-2
COX-2
COX-2
COX-2
Nonspecific
Nonspecific
NSAIDs
NSAIDs
Nonspecific
Nonspecific
NSAIDs
NSAIDs
Prostaglandins
Thromboxane
Prostaglandins
Arachidonic Acid
Membrane
Phospholipid
Phospholipase A

Major effects of PG synthesis
inhibition
1. Analgesia: Prevention of pain nerve ending
sensitization
2. Antipyresis: Reduction of Body temperature in
hyperthermia
3. Anti-inflammatory action: reduction in signs of
inflammation (pain, tenderness, swelling and
vasodilatation)
4. Antithrombotic action: Inhibition of platelet
aggregation
5. Closure of Ductus arteriosus in Newborn

1. Analgesia
What is Pain ?
“An unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.”
International Association for the Study of Pain (IASP)
Merskey and Bogduk. Classification of Chronic Pain. 1994.

Classification of Pain
Acute
Chronic
vs
Duration
Nociceptive
Neuropathic
vs
Pathophysiology

Acute Pain vs Chronic Pain
Acute Chronic
 Usually accompanied by obvious
tissue damage
 Increased autonomic nervous
activity
 Pain resolves with healing of the
underlying injury
 Serves a protective function
 Pain that extends 3 or 6 months
beyond onset or beyond the
expected period of healing1
 Ceases to serve a protective
function2
 Degrades health and functional
capability2
 Depressed mood3
vs.
1
Turk and Okifuji. Bonica’s Management of Pain. 2001.
2
Chapman and Stillman. Pain and Touch. 1996.
3
Fields. NNBN. 1991;4:83-92.

Nociceptive Neuropathic
Classification of Pain
• Pain that arises from a stimulus
that is outside of the nervous
system – receptors stimulated
• Proportionate to the
stimulation of the receptor
• When acute serves a protective
function
• Musculoskeletal disorders are a
very common cause
of nociceptive pain
• Pain initiated or caused by a
primary lesion or dysfunction
in the nervous system
• No nociceptive stimulation
required
• Disproportionate to the
stimulation of receptor
vs

• Transduction
• Transmission
• Modulation
• Perception
• Interpretation
• Pain Behavior
Peripheral
Peripheral
Nerve
Nerve
Ascending
Ascending
Pathways
Pathways
Injury
Injury
Descending
Descending
Pathway
Pathway
Dorsal
Dorsal
Root
Root
Ganglion
Ganglion
C-Fiber
C-Fiber
A-beta Fiber
A-beta Fiber
A-delta Fiber
A-delta Fiber
Dorsal
Dorsal
Horn
Horn
Brain
Brain
Spinal Cord
Spinal Cord
NSAIDs and Analgesia

NSAIDs induced Analgesia
• Peripheral component:
– PGs (especially E2 and I2) sensitize afferent nerve endings to pain
– induces chemical and mechanical stimuli
– Induce hyperalgesia – by affecting transducing property of free
nerve endings – normal stimuli may become painful
– NSAIDs do not block direct PG application related pain and
tenderness
– But, block the pain sensitizing mechanism induced by –
Bradykinin, TNF and Interleukins (IL) and others – by inhibiting
COX-2
– More effective against pain due to inflammation
• Central Component: Antihyperalgesic (analgesic) effects
through inhibition of PGs release in spinal dorsal horn and
CNS

Peripheral & Central Sensitization
Peripherally & Centrally Induced COX-2
Trauma/inflammation
Release of arachidonic acid
COX-2
COX-2
 Prostaglandins E2
Pain
sensitization
COX-2
COX-2
 Prostaglandins
sensitization
Pain
IL-1ß
IL-6?

2. Antipyresis
• Against Pyrexia (Fever)
• Reduction in body temperature in case of hyperthermia - not
in normothermic individuals
• MOA: During infection and tissue injury
 Fever – by generation of Pyrogens - Interleukins, TNF-alpha and
Interferones – induce production of PGE2 in Hypothalamus – raise its
temperature set point
 COX-2 and COX-3 (?) isoforms
• NSAIDs block the action of PG production in hypothalumus
and reduce temperature

3. Antiinflammatory
• At the site of injury – enhanced COX-2 mediated PG
synthesis
• NSAIDs inhibit PG synthesis at the site of injury –
antiiflammatory response of different NSAIDs depend on
capacity to inhibit COX (Potency)
• Also inhibit other mechanisms: PGs are not sole mediators
of inflammation - other mediators - LTs, PAF and cytokines
etc. -
• Also, adhesion molecules – ELAM-1 & ICAM-1 – chemotaxis
• Inflammatory cell express Selectins and Integrins
• Some NSAIDS also act – inhibition of generation of
superoxide/free radicals - also GM-CSF, IL-6 etc.

4. Antiplatelet aggregator
• TXA2 is pro-aggregator (COX-1)
• PGI2 is anti-aggregator
• Most NSAIDs - effects on TXA2 predominates and
inhibits aggregation – prolonged bleeding time
• Aspirin is highly active and acetylates COX in
circulation – before hepatic 1st
pass metabolism
• Even small dose
Antithrombotic effect – Myocardial Infarction and
other cardiac conditions

5. Ductus arteriosus
• It is a shunt connecting the pulmonary artery to the
aortic arch
• Maintained by local PGE2 and PGI2
• Closes at birth
• Failure to close – small doses of NSAIDs (aspirin or
indomethacin) – closes
(No NSAIDs in late pregnancy – premature closure)

Dysmenorrhoea
• Severe pain during menstruation – may
precede menstruation or during menstruation
• Caused by increased release of PGs (PGF2α)
due to increased destruction of endometrial
cells and release of their contents
• Intermittent ischaemia of myometrium –
cramps
• NSAIDs - decrease PG release

Gastric Mucosa
• All NSAIDs produce gastric mucosal damage, ulceration and
blood loss – varying extent
• Due to inhibition of COX-1 mediated synthesis of gastro
protective PG (PGE2 and PGI2)
– Also back diffusion of H+ in gastric mucosa
• Deficiency of PGs reduces mucus and HCO3 secretion –
promote mucosal ischaemia
• Enhance aggressive factors over defensive factors - Ulcerogeic
Paracetamol – free of gastric toxicities
Selective COX-2 inhibitors
Misoprostol

Renal effects
• During hypovolemia, decreased renal perfusion
• Particularly important in conditions of
– CHF, hypovolaemia, cirrhosis and renal impairment (Na+ retention
and edema)
– Patent under antihypertensives and diuretics
• PGs cause: (Intrarenal regulator)
– Renal vasodilatation and inhibition of tubular reabsorption
– Frusemide like effect – inhibition of Cl- reabsorption
– Increased excretion of Na+, K+ and water
• NSAIDs block these renal effects by inhibition PGs
– Impairment of renal blood flow
– Na+ and water retention
– Papillary necrosis on prolonged use
•

From Last Class

Salicylates
•ASPIRIN is acetylsalicylic acid, the Prototype - converted in the
Body to Salicylic acid – Oldest analgesic
•Other important salicylates – Sulfasalazine, Diflunisal
•Natural Sources - fruits, vegetables, herbs, spices, nuts, and tea

Pharmacological – analgesic,
antipyretic and antiinflammatory
• Weaker analgesic than Morphine – 600 mg Vs Codeine 60 mg
• Aspirin irreversibly inhibits COX-1 & COX-2 activity
• Inhibits COX irreversibly by acetylation – fresh enzyme
synthesis requires for return
– Mainly effective in pains related to inflammation, tissue injury,
connective tissue and integument pain
– Not much effective in visceral and ischemic pain
• Mechanism – prevention of PG-mediated sensitization of
nerve endings
• Other mechanisms:
– Raising of pain threshold by acting centrally – morphine like – but no
sedation, subjective effects, tolerance or physical dependence
– Resetting of hypothalamic thermostat – fever reduction
• Anti-inflammatory doses are higher than analgesic doses

Pharmacological actions – contd.
• Metabolic effects: Increased cellular metabolism
• Uncoupling of oxydative phosphorylation → increased heat
production
• Increased utilization of glucose – decreased blood sugar and
glycogen depletion
• Negative Nitrogen balance (increased protein to carbohydrate)
• Toxic doses: Hyperglycaemia
• Respiration:
• Low doses: ↑ CO2 → stimulates respiration
• Increased sensitivity of Respiratory centre to CO2
• In Poisoning - Direct stimulation of respiratory center →
Hyperventilation
• Higher doses - depression of respiratory center →Death due to
Respiratory Failure

Aspirin – acid-base Balance
• Analgesic doses (0.3 – 1.0 gm /day) – no effects
• Anti-inflammatory doses (4 - 5 gm/day) – very important
changes in acid-base balance
– Initially Respiratory stimulation – due to stimulation of respiration
and hyperventilation - Increased expelling of CO2 in spite of increased
production – Respiratory alkalosis
• Increased excretion of HCO3- with Na+, K+ and water – Compensated
Respiratory Alkalosis
– Still Higher doses: Respiratory depression – retention of CO2 –
Respiratory acidosis
• Added acids – pyruvic acid, lactic acid and dissociated salicylic acid Net
result is – Uncompensated Metabolic acidosis

Aspirin – contd.
• GIT:
– Salicylic acid – irritant to mucosa causing nausea and vomiting
– Unionized in stomach and absorbed but upon absorption – ionizes and
indiffusible (Ion trapping)
– Locally – back diffusion of acid – necrosis of mucosa and arteries – ulceration,
erosive gastritis etc.
– Occult blood loss – haematemesis
– Salicylate-induced gastric bleeding is painless and may lead to an iron
deficiency anemia
• CVS:
– Therapeutic doses have no significant cardiovascular effect
– High doses- increased BP - increased CO and peripheral vasodilation by
exerting a direct effect on smooth muscle
– Toxic doses - depress circulation directly and by central vasomotor paralysis
– CCF – low cardiac reserve patients

Aspirin – contd.
• Hematologic effects:
– It inhibits the platelet aggregation by decreasing the
production of TXA2 – lasts for a week
– In doses greater than 6 gm/day, aspirin may reduce
plasma prothrombin levels
– Prolonged use – decrease in synthesis of clotting factors
• Urate Excretion:
– Dose less than 2 gm/day – urate retention
– 2-5 gm/day – variable effects
– More than 5 gm/day – increased urate excretion

Aspirin Pharmacokinetics
• Absorbed from stomach and SI
• Poorly water soluble – limitation
– Solubility can be increased by alkalizations – but ???
• Converted to salicylic acid in gut, liver and plasma
• 80-85% bound to plasma protein - can cross placenta and CSF
• Metabolized in liver by conjugation with glycine – salicyluric
acid
• Excreted as glomerular filtration and tubular secretion
• T1/2 life is 15-20 minutes
– 8 – 12 Hrs due to metabolic process saturation
– High doses have long t1/2

Aspirin - ADRs
• Gastrointestinal disturbances
– Nausea, vomiting, epigastric distress and gastric mucosal damage
• Hypersensitivity and Idiosyncrasy: FDE, rash, urticaria, asthma
(bronchospasm – aspirin sensitive asthmatics)
• Salicylism: on repeated administration (3-5 gm/day)
– headache, mental confusion, lassitude, and drowsiness
– tinnitus and difficulty in hearing
– hyperthermia, sweating, thirst, hyperventilation, vomiting, and diarrhea
• Hepatotoxicity:
– Rise in serum transaminases – hepatotoxic
– Reye`s Syndrome – rare disease of hepatic encephalopathy when given in
viral conditions of influenza and varicella
• Nephrotoxicity: Na+ and water retention, ch. Renal failure
• Prolongation of bleed time or reduce prothrombin level
• Respiratory: Asthma, rhinitis

Treatment of acute Poisoning -
Aspirin
• Fatal dose: 15 – 30 gm
• Low in case of children
• Features: Vomiting, dehydration, acidosis, petechial
haemorrhage, hyperglycaemia, hyperpyrexia, confusion
and coma etc.
• Management:
– Inducing emesis or administering gastric lavage
– Appropriate infusion measures to correct abnormal electrolyte
balance and dehydration – Na+, K+, HCO3 etc. as per need
– Alkalinization of the urine
– Dialysis as required
– Vit.K injection

Aspirin –
Therapeutic uses
1. Analgesic: Headache, migraine, backache, tothache,
dysmenorrhea etc (300 to 600 mg 8 Hrly)
2. Rheumatoid arthritis: (3-5 gm/day)
 Used to be standard first line of drug
 Poorly tolerated – newer NSAIDS
1. Acute Rheumatic Fever: (4-5 gm/day)
 First drug of choice – other drugs are added when it fails
 Dose is reduced after 1 week therapy
 Continued for 3-4 weeks
 gradual withdrawal for over 2 weeks
1. Osteoarthritis
2. Antipyrretic

Aspirin and Myocardial infarction
• Routinely prescribed for post myocardial infarction patients –
prophylaxis purpose to prevent re-infarction
• MOA - TXA2 (pro-aggregator) inhibition
• Dose is very low (60 – 100 mg/day)
• High doses inhibit PGI2 (anti-aggregator)
• Primary prophylaxis (100 to 150 mg – more useful)
• Reduces TIA and lowers incidence of stroke
Aspirin preparations: Tablets of various strength – 75 mg, 100
mg, 325 mg, 650 mg etc. Aspirin, Disprin, Loprin, Ecospirin
etc.

Aspirin – Contraindications
1. Sensitive Persons
2. Children with viral diseases
3. Peptic ulcer disease and bleeding disorders
4. Chronic liver diseases
5. Diabetes, CHF and juvenile Rh. Arthritis
6. G-6-PD deficient persons
7. Stop prior to surgery, near term pregnancy,
breast feeding mothers etc

Aspirin – Drug Interactions
• Aspirin and Probenecid:
– Antagonize Uricosuric action of probenecid
– Probenecid become ineffective in Gout
• Aspirin and oral anticoagulants (warfarin and
sulfonylureas)
– Toxicity (increased tendency of bleeding)
• Aspirin and anti-hypertensive:
– NSAIDs cause fluid retention and oedema –
antihypertensive effects are decreased
• Aspirin and Diuretics: (furosemide and thiazides)
– Blunting of Furosemide effects

Aspirin - Uses
• Analgesic : Backache, myalgia, toothache, joint pain, pulled muscle and
dysmenorrhoea
• Antipyretic : Fever of any origin – Paracetamol safer
• Acute Rheumatic fever: 75 – 100 mg/kg/day (or, 4 – 5 gm/day) – marked
symptomatic relief – all cases
– dose reduced after 4 - 7 days and maintained for 2 - 3 weeks till s/s
stops - withdrawal should be gradual
• Rheumatoid Arthritis: Reduction in pain, swelling and stiffness – large
dose
• Osteoarthritis: As and when needed – Paracetamol is the choice
• Post-myocardial infarction and post stroke: Routinely used – inhibits
platelet aggregation (TXA2) at low dose (60 – 100mg/day) – but, high dose
can reverse (PGI2 inhibition)
– New onset or sudden onset angina (risk of infarction) - 75 to 150 mg/day for
12 weeks …. Also in TIA
• Other uses: PIH, PDA, Familial colonic polyposis and Prevention of colonic
cancer

Propionic acid derivatives
• Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
• Analgesic, antipyretic and anti-inflammatory efficacy is lower
than aspirin (low potency) – all inhibits PG synthesis
(Naproxen – most potent)
– Antiplatelet activity – short with Ibuprofen but longer with naproxen
• Adverse Effects: Better tolerated than aspirin and
Indomethacin – milder – gastric discomfort, nausea, vomiting,
– gastric erosion rarely
– CNS effects - headache, dizziness, blurring of vision, tinnitus and
depression
– Rash, itching and hypersensitivity are less
– Precipitates aspirin induced asthma

Propionic acid derivatives – contd.
• Pharmacokinetics: All are well absorbed orally – 90-99% plasma protein
bound
– But lesser displacement of other drugs
– Inhibits platelet function – use with anticoagulants are avoided
– Decreases antihypertensive and diuretic actions of furosemide, thiazides and
beta-blockers
• Uses: Not given in pregnancy and Peptic ulcer patient
– Ibuprofen: Simple analgesic and antipyretic – like low dose aspirin –
dysmenorrhoea
– Also in Rh. Arthritis, OA and musculoskeletal disorders – pain prominent
conditions
– Also in STI, fractures, vasectomy, tooth extraction, postpartum and post
operative pain
– Naproxen – preferred in acute gout – stronger anti-inflammatory and
inhibition of leucocyte migration – longer half-life (12-16 hours)

Fenamates - Mephenamic acid
• Analgesic, antipyretic and weak anti-inflammatory –
inhibition of certain PG synthesis – peripheral +
central analgesic
• ADRs: Diarrhoea, epigastric distress, skin rash,
dizziness and other CNS ADRs
• Kinetics: Slow oral absorption, but complete, bound
to plasma protein – displacement reactions
• Uses: as analgesic in muscle, joint and soft tissue
pain ---- Dysmenorrhoea

Enolic acid derivatives - Piroxicam
• Multiple action NSAID, Long acting, good anti-inflammatory, good
analgesic-antipyretic action
– Reversible, non-selective COX inhibition
– Synovial fluid – lowers PG synthesis and inhibits platelet aggregation
– Decreases IgM rheumatoid factor and leucocyte chemotaxis
• ADRs: Contrast COX-1 blocking action - More GI effects than Ibuprofen -
but less than Indomethacin, lesser ulcerogenic – lesser occult blood than
aspirin - also rash, pruritus and serious skin reactions
• Kinetics: Rapid complete absorption, 99% plasma bound, t1/2 – 2 days (ss –
1 week); excreted in bile and urine – EH circulation
• Uses: Long term anti-inflammatory – rheumatoid arthritis, osteo-arthritis,
ankylosing spondylosis, acute gout etc. – Not first choice for any
conditions … Relative higher toxicity than Others

Acetic acid - Indomethacin
• Indole acetic acid derivative - Potent anti-inflammatory and prompt
antipyretic
– Relieves only inflammatory and injury related pain
– Highly potent inhibitor of PG and neutrophil motility
• Use: Reserve drug - ankylosing spondylitis, destructive arthropathies,
psoriatic arthritis, postoperative pain, malignancy associated fever,
medical closure of PDA
• Kinetics: well absorbed orally, 90% PP bound and t1/2 2 – 5 Hours
• ADRs: High incidence of gastric and CNS side effects (COX-1 related) –
gastric, irritation, nausea, anorexia, bleeding and diarrhoea
– CNS: Frontal headache, dizziness, ataxia, mental confusion, hallucination,
depression and psychosis
– Leucopenia, hypersensitivity, rash etc.
– Increased risk of bleeding – low platelet aggregation
• Contraindications: machinery operators, drivers, psychiatric & epileptic
patients kidney disease, pregnancy & children

Acetic acid derivatives - Ketorolac
• Potent analgesic – but modest anti-inflammatory – post operative pain –
equal efficacy with Morphine (but no receptor interaction)
• Inhibits PG synthesis – inhibits pain peripherally
• Uses: Given IM and orally - Post-operative, dental, musculo-skeletal pain
– also in renal colic, migraine – short term management of moderate pain
– rated superior to aspirin and paracetamol and equivalent to ibuprofen
– Concurrent use with morphine (reduce dose) – but not used with
anticoagulant – not to be used for more than 5 days
• Kinetics: Well absorbed orally and IM – highly plasma protein bound; t1/2 5
– 7 Hrs – 60% excretes unchanged in urine
• ADRs: Nausea, abdominal pain, dyspepsia, ulceration, dizziness,
nervousness, pain in injection site, rise in serum transaminase, fluid
retention etc.

Pyrazolones
• Metamizole (Analgin) is a derivative of
Amidopyrine. It is a potent and promptly
acting analgesic, antipyretic, and spasmolytic
- but poor antiinflammatory and not uricosuric
activity
– Analgin can be given orally, i.m. as well as i.v.
(very slowly)
• ADRs: Agranulocytosis
• Analgin, Novalgin, Baralgan, Ultragin etc

Preferential COX-2 inhibitors -
Nimesulide
• Weak PG synthesis inhibitor, moderate COX-2 selective
– Other Mechanisms: reduced superoxide generation by neutrophils,
inhibition of PAF, TNFα release & free radical scavenging
– Completely absorbed and 99% plasma protein bound
– Half life – 4-5 hours and excreted in urine
• Uses: sports injuries, sinusitis, dental surgeries, renal colic,
arthritis, postoperative inflammatory condition, fever, low
back pain, ENT disorders– no cross reaction of aspirin and
other NSAIDS related bronchospasm – specific usefulness
• ADRs: epigastric pain, nausea, loose motion, heart burn,
rash, pruritus, somnolence and dizziness – GIT tolerant but
Ulceration - Fulminant hepatic failure

Preferential COX-2 inhibitors –
Diclofenac
• Analgesic-antipyrretic and antiinflammatory – efficacy similar to naproxen
• Inhibits PG synthesis – somewhat COX-2 selective
– Reduced Neutrophil chemotaxis and reduced superoxide generation
– No antiplatelet action (COX-1 sparing)
• 99% plasma protein boung – 2 hours half-life
• Good tissue and synovial fluid penetration
• Uses: Most widely used drug – RA, OA, Bursitis, ankylosin spondi;it is,
bursitis, toothache, dysmenorrhoea, renal colic, post trauma and post
inflammatory conditions
• ADRs: Mild epigastric pain, nausea, headache, dizziness and rashes – less
gastric ulceration and bleeding - Risk of heart attack and stroke

Selective COX-2 inhibitors - Celecoxib,
Etoricoxib and Parecoxib
• Inhibit COX-2 without inhibiting COX-1 - benefits
– Less peptic ulcer occurrence, less ulcer bleeds
– Do not depress TXA2 production (COX-1) of platelets
– Do not inhibit platelet aggregation, & do not prolong bleeding time –
But reduce PGI2 production
• Disadvantage: Reduce PGI2 production by vascular
endothelium leading to increase prothrombotic effect &
enhance cardiovascular risks
• Uses : Patients with high risks of PU, perforation at lowest
dose and shortest period
• Contraindications: History of IHD, hypertension, CHF and
CVA

Coxibs – contd.
Other concerns of selective COX-2 inhibition:
• Efficacy: COX-1 generated PGs may play role in
inflammation – broad range action (??)
• Gostroprotectivity disturbed: Injury and H. pylori
induce COX-2 – gatsroprotective PG synthesis locally
…. Delay in ulcer healing
• Concern over COX-2 Physiological Role: Constitutive
in JG renal cells – Na+ and water retention, oedema,
precipitation of CHF and rise in BP

Para-amino phenol derivatives -
Paracetamol (acetaminophen)
• Phenacetin 1887 – banned now (Nephropathy)
• Its deethylated active metabolite of Phenacetin
• Analgesic – Like aspirin - Antipyretic , raises pain threshold but no PG
inhibition except COX inhibition in brain – no peripheral anti-inflammatory
action
– Good promptly acting antipyretic
– Additive analgesic action with Aspirin (central + peripheral)
– Negligible antiinflammatory action
– Poor inhibition of PG in peripheral tissues – but high in CNS !!
– Explanation: Inflammatory area – peroxide generation – cannot inhibit COX in
its presence at periphery – centrally its lacking – also COX-3 (??)
– No stimulation of respiration or affect acid base balance (unlike aspirin) …no
increase in cellular metabolism
– No Gastric erosion or platelet function alteration

Paracetamol – contd.
• Kinetics: orally absorbed, 1/4th
PP bound, t1/2: 3 – 5 hours; Metabolism by
conjugation with glucoronic acid and sulfate
• ADRs: Safe and well tolerated – analgesic nephropathy (after years)
• ACUTE PARACETAMOL POISONING
• Commonly occur in Children – low hepatic glucoronidation conjugation
capacity – also in adults
• Large dose - >150 mg/kg or >10 gm in adults
• Manifestations: Nausea, vomiting, abdominal pain and liver tenderness
– After 12 – 18 hours – centrilobular hepatic necrosis, renal tubular necrosis and
hypoglycaemia … and coma
– Jaundice after 2 days
– High dose poisoning – fulminating hepatic failure and DEATH

Paracetamol toxicity
• N-acetyl-p-benzoquinoneimine (NAQBI) – highly reactive
arylating minor metabolite – normally detoxified by
conjugation with glutathione
• Large dose of Paracetamol – glucoronidation capacity gets
saturated – more NAQBI formed
• Hepatic glutathione depleted – metabolites bind covalently to
proteins in liver and renal tubular cells – necrosis
– 5-6 gm in alcoholics (CYP2E1) - dangerous
• Treatment: Early cases - Induction of vomiting (activated
charcoal) and other supportive measures
– N-acetylcysteine – 150 mg/kg IV for 15 min – followed by same dose
for 20 hours … replenishes glutathione store and prevents further
binding with cellular contents

Paracetamol poisoning - Mechanism
N-
acetylparabenzoquinoneimine
Acetaminophen glutathione conjugate
Acetaminophen glucuronide
Urine
Acetaminophen
Acetaminophen sulfate
Phenosulfotransferase
UDP-
glucuronosyl-
transferase
50%
40%
<5%
5-15%
CytoP450
Glutathione (GSH)
Binds
covalently
with liver
cells and
renal
tubules

Paracetamol Uses
• Most commonly used – over the counter drug
• Headache, mild migraine, musculoskeletal pain
dysmenorrhoea etc.
• 1st
choice in osteoarthritis, not effective in Rheumatoid
arthritis
• Safest Antipyretic in children – no Reye`s syndrome
• Advantages – 1) lesser gastric irritation, ulceration and
bleeding (can be given in ulceration) 2) does not prolong
bleeding time 3) Hypersensitivity rarely 4) no metabolic
disturbances 5) can be given in all age group – pregnancy-
lactation 6) No significant drug interactions

Topical NSAIDS
• NSAIDS are also effective topically – gel/spray etc.
• Advantages:
1. Attains higher conc. Locally in muscles and joints – low blood levels
2. GI and other systemic ADRs are minimized
3. First pass metabolism avoided
• Kinetics: slow absorption – 10 times longer time to attain peak plasma
conc. to oral dosing
• Highest blood level – 15% of the same oral dose,
• Local conc. Upto 4 - 6mm high (dermis); 25 mm in muscles (low)
• Overall efficacy depends on site
• Uses: Osteoarthritis, sprains, sports injuries, spondylitis and soft tissue
rheumatism etc. – safety no issue but efficacy (!) local application,
massaging – counter irritant - menthol and methyl salicylate
• More efficacious in short lasting musculo-skeletal pain

Choices of NSAIDS ???
• H/o asthma
– Selective COX-2 inhibitors
• Hypertension or risk of heart attack
– COX-2 inhibitors
• Paediatrics
– Paracetamol, elderly – low dose of NSAIDS
• Pregnancy
– Paracetamol

Choices of NSAIDS
1. Mild to moderate pain – Paracetamol or low dose Ibuprofen
2. Post operative acute short lasting pain – Ketorolac, Propionic acid derivatives,
diclofenac or nimesulide
3. Acute musculo-skeletal, osteoarthritic or injury pain – Paracetamol or propionic
acid
4. Exacerbation of Rh. Arthritis, acute gout, ankylosing spondylosis – naproxen,
piroxicam, indomethacin
5. Gastric intolarance to NSAIDS - Selective COX-2 inhibitors
6. H/o asthma – nimesulide or selective COX-2 inhibitors
7. Hypertension or risk of heart attack – COX-2 inhibitors and PA derivatives
8. Paediatric – paracetamol, elderly – low dose of NSAIDS
9. Pregnancy – Paracetamol
10. Fast acting ones – fever, headache and other short lasting pain SR preparations
for chronic long lasting pain
11. IHD, hypertension, DM – consider drug interactions

Combinations
• Aspirin + Paracetamol – Supra-additive
• Also Paracetamol + Ibuprofen and
• Diclofenac + Paracetamol

Summary
• Everything about aspirin
• Individual drugs – Mephenemic acid,
Ketorolac, Indomethacin and Diclofenac
• Selective COX-2 inhibitors
• Everything about Paracetamol including
poisoning

Thank you