Analgesics - NSAIDS and

Paracetamol
Professor Peter Carroll Presented by Dr Brent McParland,
Discipline of Pharmacology
Sydney Medical School
University of Sydney
Northern Clinical School
Royal North Shore Hospital

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 Learning Objectives
• Never, ever give up!
• If everyone disagrees with you,
it doesn’t mean you are wrong
• Understand the mechanism of http://26point3andbeyond.co
m/index.php/tag/education/

action of NSAIDs
• Discuss the pharmacological effects of
NSAIDS and their therapeutic uses
Rang and Dale’s Pharmacology, Chapters 17 and 26, 8th Ed
Basic and Clinical Pharmacology, B.G Katzung and A.J Trevor, Chapters 18 and 36, 13 th Ed
 Learning Objectives
• Describe the differences and similarities between
COX 1 and COX 2 inhibitors
• Discuss the side effects which may be produced
by NSAIDS
• Understand why NSAIDS should be used with
caution, if at all, in some patient groups
• Understand the differences in the pharmacological
and therapeutic effects of NSAIDS and
paracetamol
• Discuss paracetamol overdose and its treatment
Rang and Dale’s Pharmacology, Chapters 17 and 26, 8th Ed
Basic and Clinical Pharmacology, B.G Katzung and A.J Trevor, Chapters 18 and 36, 13 th Ed
 Pain and Inflammation
• Many mediators can induce pain and
inflammation. Examples include
- prostaglandins
- leukotrienes
- substance P
- bradykinin
• A number of medications used in the
treatment of pain and inflammation block
the effects of these mediators
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Traditional NSAIDS
- aspirin - diclofenac

- ibuprofen - naproxen

• COX 2 inhibitors
- celecoxib

- meloxicam
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• NSAIDS are used in a wide variety of conditions
including
- backache, headache, toothache
- muscular aches and pains
- osteoarthritis, rheumatoid arthritis
- dysmenorrhoea, gout, some cancer pain
- thrombotic events (low dose aspirin)
• Some NSAIDS are only available on prescription,
some only through pharmacy and some are
unscheduled and available through supermarkets
and other outlets Slide created by Prof Peter Carroll
 Nurofen Must Pay $6 Million Penalty
After Final Appeal Rejected
• The company that manufactures Nurofen must pay a
$6 million penalty it was handed for misleading
consumers with its specific pain relief range
• Each Nurofen Specific Pain product contains the
same active ingredient, ibuprofen lysine 342mg

http://www.smh.com.au/business/consumer-affairs/nurofen-must-pay-6-
million-penalty-after-final-appeal-rejected-20170405-gve15i.html
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• NSAIDS exert the following activities
- analgesic
- anti-inflammatory
- antipyretic
- anti-platelet
• Block the production of prostaglandins by
inhibiting the enzyme cyclooxygenase
Slide created by Prof Peter Carroll
 Arachidonic Acid
(liberated from phospholipids by phospholipase A2)

Cyclooxygenase 5-Lipoxygenase

Prostaglandins Leukotrienes
Slide created by Prof Peter Carroll
 Arachidonic Acid

Cyclooxygenase

PGG2 PGH2 (endoperoxides)

Isomerase, Synthase
Slide created by Prof Peter Carroll

PGD2 PGE2 PGF2alpha PGI2 TXA2

Rang and Dale’s Pharmacology, pages 214-218, 8th Ed
Prostacyclin ThromboxaneA2
 Arachidonic Acid

Cyclooxygenase NSAIDS

PGG2 PGH2 (endoperoxides)

Isomerase, Synthase Slide created by Prof Peter Carroll

PGD2 PGE2 PGF2alpha PGI2 TXA2

Prostacyclin ThromboxaneA2
 Arachidonic Acid
(liberated from phospholipids by phospholipase A2)

NSAIDS
Cyclooxygenase 5-Lipoxygenase

Prostaglandins Leukotrienes
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Cyclooxygenase exists in two forms

- cyclooxygenase 1 (COX 1)
- cyclooxygenase 2 (COX 2)
• Some evidence that other forms may also
exist e.g. COX 3, but their location and
function are not well understood
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• COX 1 is found in most cells

• It is a constitutive enzyme which

synthesises the production of
prostaglandins which are involved in
homeostasis - “housekeeping” or
“good” prostaglandins

Slide created by Prof Peter Carroll

Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• COX 2 is induced by inflammatory
stimuli and synthesises prostaglandins
which are involved in pain and
inflammation - “bad” prostaglandins
• COX 2 is also a constitutive enzyme in
some areas e.g. kidney, vascular tissue
• COX 2 is also thought to be involved in
some cancers e.g. breast, colorectal
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Prostaglandins act on prostaglandin G-protein
coupled receptors (DP, FP, IP, EP and TP)
• Prostaglandins such as PGE2 and PGI2 are
involved in pain and inflammation
- produce vasodilation
- potentiate the increased permeability of blood vessels
caused by substances such as histamine and bradykinin
- sensitise nerve terminals and potentiate the pain
producing effects of substances such as bradykinin and
5-hydroxytrypamine (they do not directly produce pain
themselves)
Rang and Dale’s Pharmacology, pages 214-218, 8th Ed
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Initial hypothesis was that
- COX 1 was a constitutive enzyme which
synthesised prostaglandins involved in
homeostasis
- COX 2 was only induced by inflammatory
stimuli and synthesised prostaglandins
involved in inflammation and pain
• In reality, however, COX 2 is also a
constitutive enzyme in some areas e.g.
kidney, vascular tissue
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Traditional NSAIDS (e.g. aspirin,
diclofenac, ibuprofen, naproxen) inhibit
both COX 1 and COX 2
• Traditional NSAIDS block the production
of all prostaglandins
• Traditional NSAIDS thus block the
production of both “bad” prostaglandins
and “good/housekeeping” prostaglandins
Slide created by Prof Peter Carroll
 Traditional NSAIDS

Slide created by Prof Peter Carroll

Grosser T et al (2006) J. Clin. Invest. 116:4-15. doi:10.1172/JCI27291

 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Blockade of the production of “bad”
prostaglandins which produce pain and
inflammation produces analgesic and
anti-inflammatory activity, which is
beneficial
• Blockade of the production of
“good/housekeeping” prostaglandins,
however, may result in adverse effects
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)

• Examples of “housekeeping”
prostaglandins include those that

- help maintain mucosal gastric

protection and reduce gastric acid
secretion e.g. PGE2 (COX 1)

Slide created by Prof Peter Carroll

 The Stomach
• The principal chemical activity
of the stomach is to begin the
digestion of proteins, primarily
through the action of pepsin www.genericlook.com

• The stomach also has gastric juice which is very

acidic (the lumen of the stomach has a pH 1-2)
• The stomach mucosa is exposed to some of the
harshest conditions in the body
• So why does the stomach not digest itself?
Slide created by Prof Peter Carroll
 Gastric Mucosal Barrier

www.en.wikibooks.org

Slide created by Prof Peter Carroll

 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• The Gastric Mucosal Barrier (bicarbonate and
mucus) protects the underlying tissue from the acid
and enzymes in the lumen of the stomach/duodenum
• Prostaglandins formed by COX 1 e.g. PGE2 help
maintain this protective barrier
- increase bicarbonate ion secretion
- increase mucus secretion
- increase mucosal blood flow
- reduce gastric acid secretion
• Traditional NSAIDS may reduce these effects leading
to possible bleeding and ulcers
Slide created by Prof Peter Carroll
Nonsteroidal Anti-inflammatory
Agents (NSAIDS)

• Examples of “housekeeping”
prostaglandins include those that

– regulate platelet function e.g.

TXA2 (COX 1) and PGI2 (COX1
and COX 2)

Slide created by Prof Peter Carroll

 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Thromboxane A2 (TXA2) and prostacyclin
(PGI2) are involved in platelet function and
blood flow
- TXA2 is formed in platelets by COX 1. It
induces platelet aggregation and produces
vasoconstriction

- PGI2 is formed in vascular tissue by COX 1

and COX 2. It inhibits platelet aggregation and
produces vasodilation
Slide created by Prof Peter Carroll
 Haemostasis

Platelets Martini, Fundamentals of Anatomy and

Slide created by Prof Peter Carroll Physiology, 4th Edition, Prentice Hall
 Platelet Aggregation
Arachidonic acid
COX 1 in COX 2 (and COX 1) in
platelets vascular tissue

Thromboxane A2 Prostacyclin
(promotes platelet aggregation (inhibits platelet aggregation
and vasoconstriction) and causes vasodilation)

Day RO and Graham GG 2004, Australian Prescriber, 27(6), 142

Salinas G et al 2007, Cardiovascular Pharmacology and Therapeutics, 12(2), 98

Slide created by Prof Peter Carroll

 Platelet Aggregation
Arachidonic acid
Low dose
aspirin
COX 2 (and COX 1) in
COX 1 in
vascular tissue
platelets

Thromboxane A2
(promotes platelet aggregation
Prostacyclin (PGI2)
and vasoconstriction) (inhibits platelet aggregation
and causes vasodilation)

Low dose aspirin inhibits platelet aggregation by

inhibiting the production of TXA2
Slide created by Rang and Dale’s Pharmacology, pages 303 and 323, 7th Edition
Day RO and Graham GG 2004, Australian Prescriber, 27(6), 142
Prof Peter Carroll Salinas G et al 2007, Cardiovascular Pharmacology and
Therapeutics, 12(2), 98
 Low Dose Aspirin
• In platelets the enzyme cyclooxygenase 1
(COX 1) converts arachidonic acid
to thromboxane A2
• Thromboxane A2 induces platelet
aggregation and vasoconstriction
• Aspirin irreversibly inhibits COX 1,
inhibits the production of thromboxane
www. health.com
A2 and reduces platelet aggregation
• Platelets cannot regenerate COX 1, vascular
tissue can regenerate COX 1 and COX 2
• Low dose aspirin (50-150mg) is used
Slide created by
clinically to inhibit platelet aggregation Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Other examples of “housekeeping”
prostaglandins include those that
- help maintain renal function e.g. PGI2, PGE2
(COX 2)
- help airway function in some patients with
asthma e.g. PGE2
- assist implantation of the fertilised ovum
- maintain patent ductus arteriosus and contract
the uterus during labour e.g. PGF2alpha
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Blockade of “good/housekeeping”
prostaglandins may result in adverse effects
such as
- gastrointestinal bleeding and ulcers
- increased tendency to bleed
- reduced renal function
- sodium and water retention
- early miscarriage and prolongation of labour
- asthma symptoms/acute asthma attack in some
patients with asthma (5-10%)
Slide created by Prof Peter Carroll
 NSAIDS and Asthma
Arachidonic Acid
(liberated from phospholipids by phospholipase A2)

NSAIDS
Cyclooxygenase 5-Lipoxygenase

Prostaglandins Leukotrienes
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Traditional NSAIDS should be used with caution, if
at all, in patients with the following conditions
- previous/active peptic ulcer
- cardiac failure
- hypertension
- renal impairment
- asthma (aspirin sensitive asthma - OK for most
patients with asthma)
- pregnancy
• Elderly patients are far more susceptible to the
adverse effects of traditional NSAIDS
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Traditional NSAIDS exert their antipyretic effect
by inhibiting the synthesis of prostaglandins
(PGE2) in the hypothalamus - they do not lower
normal temperature
• A number of important drug interactions may
occur with traditional NSAIDS. Examples
include angiotensin converting enzyme
inhibitors, angiotensin 2 receptor antagonists,
antihypertensives, diuretics, warfarin, lithium
and methotrexate Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• COX 2 inhibitors are selective for COX 2 - some
are more selective than others
• Examples of COX 2 inhibitors currently on the
market are
- celecoxib
- meloxicam
• COX 2 inhibitors produce the same analgesic and
anti-inflammatory effects as traditional NSAIDS -
they are no more effective than traditional
NSAIDS Slide created by Prof Peter Carroll
 COX 2 Inhibitors

Slide created by Prof Peter Carroll

Grosser T et al (2006) J. Clin. Invest. 116:4-15. doi:10.1172/JCI27291

 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• COX 2 inhibitors are claimed to produce
less gastrointestinal bleeding and ulcers
than traditional NSAIDS and there is some
evidence to support this - this was the
reason why they were developed
• COX 2 inhibitors do not inhibit platelet
aggregation (synthesis of thromboxane A2
is a COX 1 effect)
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• COX 2 inhibitors produce the same adverse
renal effects as traditional NSAIDS - use with
caution in patients with renal impairment,
hypertension or cardiac failure
• A number of important drug interactions may
occur with COX 2 inhibitors. Examples include
angiotensin converting enzyme inhibitors,
angiotensin 2 receptor antagonists, anti-
hypertensives, diuretics, lithium and
fluconazole Slide created by Prof Peter Carroll
 Rofecoxib (Vioxx)
• Rofecoxib was a COX 2 inhibitor marketed
under the trade name of Vioxx
• It was removed from the market because of
concerns that it increased the risk of heart
attack and stroke
• Suggestions that an increased cardiovascular
risk may be associated with the use of
rofecoxib first emerged in the VIGOR study,
and was confirmed in the APPROVe study
Slide created by Prof Peter Carroll Bombardier et al, NEJM 2000, 343(21), 1520
Bresalier et al, NEJM 2005, 352(11), 1092
 Platelet Aggregation
Arachidonic acid

COX 1 in COX 2 (and COX 1) in

platelets vascular tissue

Thromboxane A2 Prostacyclin
(promotes platelet aggregation (inhibits platelet aggregation
and vasoconstriction) and causes vasodilation)

Day RO and Graham GG 2004, Australian Prescriber, 27(6), 142

Salinas G et al 2007, Cardiovascular Pharmacology and Therapeutics, 12(2), 98

Slide created by Prof Peter Carroll

 COX 2 Inhibitors
Arachidonic acid

COX 1 in COX 2 inhibitors

platelets COX 2 (and COX 1) in
vascular tissue

Thromboxane A2 Prostacyclin
(inhibits platelet aggregation
(promotes platelet aggregation and causes vasodilation)
and vasoconstriction)

Slide created by Prof Peter Carroll

 Possible Mechanism for Adverse
Cardiovascular Events
• Selective inhibition of COX 2 in the vascular
tissues may lead to an imbalance between
thromboxane A2 (TXA2) and prostacyclin
(PGI2) production
• This imbalance between TXA2 and PGI2 may
predispose to vasoconstriction and platelet
aggregation, leading to adverse
cardiovascular effects in some individuals
• Selective inhibition of COX 2, however, is
probably not the complete explanation
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• Studies have now shown that there is an increased risk
of both heart attack and stroke with all NSAIDS
• Adverse cardiovascular effects may occur with COX 2
inhibitors such as celecoxib and meloxicam, as well as
traditional NSAIDS including ibuprofen and diclofenac
• Some evidence suggests that naproxen may exert the
least risk
• The risk may be greatest during the first month of
NSAID use, and with higher doses
Arch Intern Med 2005, 165, 978 – 984; BMJ 2011;342:c7086 doi:10.1136/bmj.c7086
BMJ 2006;332:1302-1308 doi:10.1136/bmj.332.7553.1302; MJA 2011, 195(9), 525
BMJ 2005;330:1366 doi:10.1136/bmj.330.7504.1366; RGH Pharmacy E-Bulletin, 2011, 42(1), April 25th
The Lancet, Published Online May 30, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60900-9
Bally M BMJ 2017;357:j1909 http://dx.doi.org/10.1136/bmj.j1909
Slide created by Prof Peter Carroll
 Nonsteroidal Anti-inflammatory
Agents (NSAIDS)
• In all patients, particularly the elderly and
those with cardiovascular disease, all
NSAIDS (traditional and COX 2 inhibitors)
should only be used
- when necessary
- in the lowest possible dose
- for the shortest possible time
• Consider paracetamol as an alternative
Slide created by Prof Peter Carroll
 Paracetamol
• Also known as acetaminophen
• Exerts analgesic and antipyretic activity (inhibition of
the synthesis of PGE2 in the hypothalamus)
• Does not exert anti-inflammatory activity
• Mechanism of action of the analgesic effect of
paracetamol is still not completely understood
• Does not block COX 1 or COX 2 in peripheral tissues
• Recent evidence suggests that it inhibits the reuptake
of anandamide, a neurotransmitter which is an agonist
on cannabinoid receptors involved in pain pathways
Graham GG et al (2013). The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and
recent pharmacological findings. Inflammopharmacology (2013) 21:201–232. DOI 10.1007/s10787-013-0172-x
Starowicz K et al (2013) WIREs Membr Transp Signal 2013, 2,121-132. doi: 10.1002/wmts.83 Slide created by
Clapper JR et al (2010) Nat Neurosci.13(10), 1265-1270. doi:10.1038/nn.2632
Sharma CV and Mehta V (2014) doi:10.1093/bjaceaccp/mkt049 Critical Care & Pain, 14(4) Prof Peter Carroll
Panagis G et al (214) doi: 10.3389/fpsyt.2014.00092; Guindon J and Hohmann AG (2009) CNS Neurol Disord Drug Targets 8(6) 403-421
 Paracetamol
• In therapeutic doses it is generally well
tolerated and it does not cause a number
of the side effects which may be
associated with the use of NSAIDS
• For example it does not cause
- gastrointestinal bleeding or ulcers
- increased bleeding tendencies (no effect
on platelets)
- reduced renal function
- sodium and water retention
Slide created by
- prolongation of labour Prof Peter Carroll
 Paracetamol
• May be used in some situations where NSAIDS
may be contraindicated
- previous/active peptic ulcer
- cardiac failure
- hypertension
- renal impairment
eMIMS, April 2017
- asthma (aspirin sensitive asthma)
- elderly e.g. osteoarthritis
• Has fewer drug interactions than NSAIDS but
reports of possible interaction with warfarin -
monitor INR if continual use Slide created by
Prof Peter Carroll
 Paracetamol
• Although it is well tolerated in therapeutic
doses, paracetamol may cause serious
toxicity and even death if taken in overdose
• Paracetamol normally undergoes
glucuronidation (45-55%) and sulphation
(20-30%) with a small amount being
converted to N-acetyl-p-benzoquinoneimine
(NABQI) by CYP450 2E1(and 1A2?)
• NABQI is toxic, but is normally conjugated
with glutathione and inactivated
Slide created by Prof Peter Carroll
 Paracetamol
• When taken in overdose the normal
glucuronidation/sulphation pathways may
become saturated, and more NABQI is
formed
• Glutathione stores may become depleted
• If the glutathione stores do become depleted,
NABQI is no longer inactivated and it may
combine with cellular components to cause
cell death and liver failure (hepatic necrosis)
• Renal damage may also occur
Slide created by Prof Peter Carroll
 https://www.youtube.com/watch?v=ACVNkLEG4oY
Slide created by Prof Peter Carroll
 Paracetamol
• Initial symptoms of paracetamol overdose may
be mild e.g. nausea and vomiting, and may not
reflect the potential seriousness of the situation
• Liver toxicity e.g. jaundice, metabolic
disturbances etc may not become apparent for
several days
• Antidote is acetylcysteine which restores
glutathione levels &/or inactivates NABQI
• It is most effective if administered within 10 to
12 hours of overdose Slide created by Prof Peter Carroll
 Paracetamol
• Remember that paracetamol is included
in a large number of preparations e.g.
analgesics, antipyretics, cough/cold
preparations, sinus preparations etc
• Some patients may take a number of
different products which contain
paracetamol
• Accidental overdoses have occurred
Australian Adverse Drug Reactions Bulletin, October 2005

Slide created by Prof Peter Carroll