This 20-slide slide set created with PowerPoint describes prostanoid synthesis and their effects on the body; mechanisms of action, beneficial and adverse effects of NSAIDS; the difference between the effects of low and high dose aspirin; and the effects and toxicity of paracetamol (acetaminophen). This is an introduction to the topic of NSAIDS which would be appropriate for beginners. Contributed by Christopher Fowler, Umeå University, Sweden.

1. PROSTANOIDS AND NON-STEROIDAL
ANTI-INFLAMMATORY DRUGS
Christopher Fowler
Department of Pharmacology and Clinical
Neuroscience, Umeå University, Umeå
Sweden
November 2017

2. Synopsis
Prostanoids: synthesis and effects in the body
NSAIDs: mechanism(s) of action;
High vs. low-dose aspirin
Paracetamol (acetaminophen): effects and toxicity
(not strictly an NSAID, but usually discussed together with them)
The small print in the main body of the slides goes into more detail, but the main points are in text with
a larger font size.
Disclaimer
beneficial and adverse effects

3. Disclaimer
This presentation is designed to give the
pharmacological background to the use of
NSAIDs for the treatment of inflammation,
pain and fever. It does not give treatment
recommendations and should not be used as
such. Further, the information is accurate as
of November 2017. If you are reading this is
in 2022, things may have changed!
Christopher Fowler

4. Arachidonic acid metabolism
Arachidonic acid
other
bioactive
compounds
COX1 & 2 5-LO
other
enzymes
intermediate compounds
PLA2
Prostanoids Leukotrienes
Abbreviations: PLA2, phospholipase A2; COX, cyclooxygenase; 5-LO, lipoxygenase
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=243&familyType=ENZYME

5. Prostanoids and their targets
”Classical” prostaglandins (PGs):
e.g. PGD2, PGE2, PGF2α
Prostacyclin (PGI2)
Thromboxane A2 (TXA2)
DP1,2 EP1-4 FPreceptor families:
IP
TP
info on the receptors: http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=58 .
Note that a given prostanoid can interact with receptors for the other prostanoids, but with lower
affinity. For EP4 receptors, for example, the potency order is PGE2>PGF2α,PGI2>PGD2,TXA2.

6. Prostanoid effects in the body
Want to read more... https://www.ncbi.nlm.nih.gov/pubmed/11729303
multiple actions, dependent upon location of
synthesising enzymes and receptors
examples (by no means a complete list):
prostanoid location effect
PGD2 Th2 lymphocyte chemotaxis (G)
PGE2 sensory neurons sensisitization of pain stimuli (G)
hypothalamus regulation of body temperature (G)
stomach gastroprotection (NG)
kidney vasodilatation, natriuresis (NG)
PGF2α uterus contraction (NG)
PGI2 vascular endothelia vasodilation, ↓ platelet aggregation (NG)
TXA2 platelet
vasoconstriction, ↑ platelet aggregation
(G)
Effects are divided into ”G” (good) and ”NG” (not good) from the point of view of drug treatment

7. NSAIDs
The name NSAID says what the drug chemically isn’t and whether or not it has anti-inflammatory effect.
It says nothing about the mechanism of action. A bit like calling a fork a ”non-knife eating implement”.
Inhibit COX-1 and -2
With the exception of
aspirin, the compounds
are reversible
The coxib class of
compounds are the most
selective towards COX-2
Potency ratios for NSAIDs, The lower the number, the
more COX-1 selective the drug. Drawn from data of
Wallace et al.
(https://www.ncbi.nlm.nih.gov/pubmed/10377455)

8. A note on COX-2
Inducible1 (COX1 is constitutive)
1The degree of inducibility varies in different cells/tissues. Thus, in macrophages, the levels go from
very low to very high in response to stimuli such as cytokines, whereas in the kidney and brain, COX-2
is constitutively expressed
Wider substrate specificity than COX-1
Both isoforms can oxygenate other unsaturated long chain fatty acids, but COX-2 can also
oxygenate the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol, to
produce biologically active products. Further, in macrophages, COX-2-dependent
oxygenation of arachidonic acid can lead to production of other oxylipins (11- and 15-
eicosatetraenoic acid)
Acetylation by aspirin changes its catalytic
properties
Potentially beneficial oxylipins, such as resolvin E1 are formed by acetylated COX-2. In
contrast, acetylation of COX-1 by aspirin produces irreversible inhibition

9. NSAIDs
Wanted effects relate to blocking the
”G” effects of prostamides:
Most adverse drug reactions relate to
blocking the ”NG” effects of prostamides:
Anti-inflammatory, analgesic and
antipyretic actions
The big two:
Cardiovascular events, gastro-
intestinal disturbances
+
-

10. NSAIDs ... a bit of detail
Why analgesic ?
Prostaglandins reduce the threshold for activation of
nociceptors, resulting in an increased sensitivity. One
mechanism on the sensory neurons is PGE2 → EP1/4
receptors → ↑ cAMP → protein kinase A activation →
phosphorylation of TRPV1 and other ion channels/receptors
→ ↑ excitability. This results in an increased sensitivity of
the nociceptors to pain mediators such as heat and
bradykinin. Blocking PG production will therefore block the
reduced threshold and hence produce analgesia. PGs also
have central effects upon pain signalling, but the
sensitisation described here is the primary target for the
peripheral antinociceptive effects of NSAIDs.

11. NSAIDs ... a bit of detail
Why anti-inflammatory ?
Vasodilatory effects of prostaglandins are involved in the
inflammatory response. Prostaglandins also contribute to
the change in vascular permeability that is a core response
to inflammation. Both classical prostaglandins and PGI2
produce an increased vascular permeability by increasing
the response to mediators such as bradykinin and
histamine. Blocking PG production will thus be anti-
inflammatory.

12. NSAIDs ... a bit of detail
Why anti-pyretic ?
PGs are produced in response to pyrogens (fever-inducing agents). In
the case of fever induced by lipopolysaccharide (a membrane
component of gram-negative bacteria), the major component is due
to PGE2 produced by vascular endothelial cells in a region of the
hypothalamus (the median preoptic nucleus, to be precise) involved
in thermoregulation. PGE2 stimulates EP3 receptors located on
GABAergic nerves whose role is to modulate temperature-controlling
neuronal pathways. Activation of the EP3 receptors inhibits the
GABAergic nerves, resulting in inhibition of this modulation and hence
an increase in body temperature. In other words, PGs reset the
”hypothalamic thermostat” to a higher level. Thus, blockade of PG
production will prevent the temperature increase, but will not have
any effect upon normal temperatures.

13. High vs. low-dose aspirin
At dose 500 mg: Treatment of pain and
fever caused by infections and colds
At dose 75 mg: Prophylaxis (due to a lower
thrombotic risk) following heart attacks and
other cardiovascular disorders e.g. angina
pectoris
why the difference?

14. Normal vs. low-dose aspirin
Aspirin = acetylsalicylic acid
Route after ingestion:
mouth → intestine → portal vein → liver → circulation
75 mg
500 mg
the acetyl
group
the salicylate
group
In the portal vein, sufficient acetylsalicylic acid is present irreversibly to inhibit COX-1 and hence TXA2
production. For the low dose, however, the concentration of salicylic acid reaching the circulation is too
low to produce marked effects on PGI2 production. Such effects are seen at the 500 mg dose.

15. NSAIDs, coxibs and
cardiovascular events
An alternative hypothesis argues that a change in the balance between COX-2 (PGI2) mediated
vasodilation and COX-1 (TBX2) mediated vasoconstriction and platelet aggregation lie behind the
increased risk for cardiovascular events.
↓ PGE2 / PGI2 in kidney
due to inhibition of COX-2
will affect renal function.
Marginal in healthy people,
but even a marginal
increase in blood pressure
puts more people in the
risk bracket (see the
figure).
These data are fictitious, but show that a small
increase in blood pressure puts a larger proportion
of the population into the hypertension (≥140 mm
Hg) risk bracket → increased incidence of
cardiovascular events

16. NSAIDs, coxibs and
gastrointestinal disturbances
The data in the figure is from the study of Ray et al. (https://www.ncbi.nlm.nih.gov/pubmed/17854591)
investigating peptic ulcer hospitalisations in Tennessee Medicaid enrollees during the period 1996-2004.
IRR stands for ”incidence rate ratio” relative to NSAIDs alone. The bars are 95% confidence intervals.
↓ COX-1-derived gastric PGs
reduces gastroprotection and
therefore increases the risk for
GI-damage.
Proton pump inhibitors such as
omeprazole can help by reducing
gastric acid secretion
COX-2-derived PGs are also
involved in recovery from ulcers
Incidence of peptic ulcer hospitalisations for NSAIDs
and coxibs with or without proton pump inhibitor
(PPI) therapy. The adjusted incidence of
hospitalisations for the NSAID alone group was 5.65
per 1000 person years (~2.8-fold higher than
controls)

17. NSAIDs and pregnancy
Not to mention that NSAIDs will prolong bleeding time due to effects on platelet function, which would
be a major issue during delivery
Basically not a good idea at all.
PGs are involved in:
ovulation and inplantation
embryonic development
closure of the ductus arteriosus
uterine contractions

18. Other NSAID related issues:
This is not a complete list: skin reactions (which can be serious) and kidney disturbances in individuals
with poor kidney function are also issues, as are interactions with, for example diuretics (to reduce their
effectiveness at a given dose) and lithium (reduces its clearance),
NSAID (mainly aspirin)-induced asthma
possibly due to shunting of the arachidonic
acid along the 5-lipoxygenase pathway to
produce leukotrienes in the lung
Aspirin
Reye’s syndrome in children
salicylate displays saturation kinetics

19. Paracetamol (acetaminophen)
1 It depends on how strictly you apply the definition of an NSAID. Paracetamol’s anti-inflammatory effect is
much less than for the COX inhibitors.
Is paracetamol an NSAID?1
Mechanism of action not completely understood,
but may be
a centrally mediated effect
secondary to blockade of the COX
cycle by trapping key free radicals
Analgesic and antipyretic,
modest anti-inflammatory effect

20. Paracetamol toxicity
Safe in normal use, liver toxic upon overdosage
Paracetamol Glucuronide conjugate
liver cell death
glutathione
conjugated product
N-acetyl-p-benzoquinone imine
N-acetyl-p-benzoquinone imine, the P450 mixed function oxidase liver toxic product of paracetamol, is
abbreviated NAPQI.
safe
toxic
Important issues: dosage, liver status, CYP induction