By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 4

ANTI-INFLAMMATORY DRUGS

Inhibition of eicosanoid synthesis

• Corticosteroids
• Also known as steroidal anti inflammatory drugs
• Inhibits arachidonic acid release and metabolism.
• Inhibits both the production of prostinoids and leukotrienes by inhibiting phospholipase A2
• More in the next lecture
• Non Steroidal Anti-inflammatory Drugs (NSAID)
• Inhibits cyclo-oxygenase (mainly COX1)
• Recall that COX1 is the constitutive enzyme which produces physiologically relevant prostaglandins. It
appears that we have inhibited the wrong COX - it would have been preferable to have inhibited COX2
which is activated under pathological conditions.
• Since only COX is inhibited, synthesis of leukotrienes by lipoxygenase is unaffected. In fact, there may be
a slight increase in leukotriene synthesis because we have more arachidonic acid present (since it is not
being used up by COX).

Uses of NSAIDS
• Anti pyretic
• Reduce fever
• Anti inflammatory
• Analgesic
• Reduce pain
• Anti aggregatory
• Reduce platelet plug and clot formation

Examples of NSAIDs

COX inhibition Anti inflammatory activity

Aspirin 1 1
Indomethacin 100 20
Meclofenamate 200 20
(Paracetamol) 0 0

• Note that paracetamol does not have any direct anti inflammatory effect (since it does not inhibit COX). It is often
used in conjunction with aspirin and acts to reduce pain.
• Note that there is a direct correlation between the ability to inhibit COX and the anti inflammatory activity.
• Aspirin is relatively weak compared to the other two examples.
• However, the more potent a drug is, the better it is able to inhibit COX but the more adverse side effects
there are.

Mediators of inflammation

Dilation Vascular permeability Chemotaxis Pain

Histamine ++ ↑↑↑ - -
Serotonin +/- ↑ - -
Bradykinin +++ ↑ - +++
Prostinoids +++ ↑ +++ +
Leukotrienes - ↑↑↑ +++ -

• As you can see, inflammation is mediated by many chemicals, not just prostanoids. However, prostanoids are the
only chemicals involved in all the processes of inflammation. That is why NSAID use which targets prostanoids are
effective at reducing inflammation
• It is possible to achieve greater levels of anti-inflammation by affecting other mediators, not just postanoids.
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 4

Uses of NSAIDs
• Mild analgesic
• PGI2 and PGE2 are hyperalgesic, which means that they increase the sensitivity of pain receptors to painful
stimuli (mainly bradykinin)
• NSAIDs are mainly useful to mild or moderate pain which is associated with inflammation.
• Fever Neutrophil Cytokines
Inflammation activation stimulate
synthesis of

PGE2

cAMP

↑ temperature

• cAMP changes the body’s thermostat to a higher temperature (it changes the body’s thermoregulatory set
point.
• NSAIDs prevent the change in set point by reducing the amount of PGE2. An increase in body temperature
as a result of increased PGE2 only occurs in inflammatory states. If body temperature is elevated due to
exertion or the environment, then NSAIDs will be of no use.
• Anti inflammation
• Used mainly to reduce the inflammation associated with arthritis in joints.

Adverse effects
• Gastrointestinal
• Local irritation because NSAIDs are acidic in nature
• They also inhibit the mucosal synthesis of PGI2 and PGE2.
• These prostanoids promote blood flow to the gastrointestinal tract which aids in the production of
mucous to protect the mucosal lining.
• Thus NSAIDs decrease the defense mechanisms of the GIT
• If a normal dose of NSAIDs are taken, it is possible to detect a small amount of blood in the faces
• If a chronic user, there is prolonged damage to the GIT with more severe bleeding and ulceration
• Bleeding time
• A decrease in TxA2 synthesis will prevent platelet aggregation. NSAIDs also inhibit the production of
PGI2 which is produced by the endothelial cells to prevent platelet sticking. However, endothelial cells can
regenerate COX (which platelets cannot) so the inhibition of platelets is more prolonged.
• In coronary artery disease, this is useful as a prophylactic treatment but it can complicate GIT bleeding,
leading to severe hemorrhage and death.
• Renal
• NSAIDs may cause renal failure only if there is an underlying condition that results in underperfusion of
the kidney.
• These conditions may be
• Hypovolemia
• Heart failure leading to decreased cardiac output
• Renal disease (renal stenosis due to atherosclerosis
• Recall that prostaglandins increase the blood flow to the kidney (via vasodilation of the afferent arteriole)
when there is a decrease in renal blood flow. This ensures that there is adequate perfusion of the kidney’s
even under marked reduction in blood pressure.
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 4

• A reduction in prostaglandins will result in a reduced perfusion to the kidney’s under conditions
of underperfusion.
• Analgesic nephropathy
• Results from taking a combination of analgesics (e.g. aspirin with other NSAIDs) over a number
of years.
• Long term use can lead to irreversible cell death in the kidney (maybe due to ischaemia
• Pulmonary
• Bronchoconstrictor effect perhaps due to the increased production of leukotrienes
• Leukotriene C4, D4 and E4 are all potent bronchoconstrictors
• Different NSAIDs will result in a different affect on bronchoconstriction. E.g. If aspirin causes
bronchoconstriction, then you can switch to another NSAID which may not cause it.

Individual groups of NSAIDs

Salicylates
• Examples of drugs in this group:
• Aspirin
• Diflunisal (no advantages over aspirin, more expensive)
• Uses:
• Analgesic
• Antipyretic
• Antithrombotic (aspirin is the drug of choice for being an antithrombotic)
• Because aspirin has a lower potency than the other NSAIDs it is less likely to be used as an anti-inflammatant.
However, because it has a lower potency, there are less adverse effects.
• Adverse effects:
• The same as for all NSAIDs, but in addition you can have:
• Reyes syndrome
• An encephaly leading to coma in children using aspirin to treat fever in certain types of
infection.
• Some of these infections are chicken pox, measles and mumps
• Therefore, aspirin must not be given to children less than 14 years with these types of
infections and fever.
• Tinnitus
• Not severe but it is the first indication of an aspirin overdose
• Uric acid retention
• Aspirin competes for uric acid excretion in the kidney tubules. Hence, aspirin will result
in the retention of uric acid and only exacerbate the effects of gout.
• Therefore, aspirin must not be used to treat gout (other NSAIDs are fine).
• How aspirin can kill:

Noirmal therapeutic dose • Uncouple oxidative phosporylation

• Raises cellular respiration. Hence, increases CO2 production which causes
respiratory stimulation. The excess energy produced is dissipated as heat,
hence there is a slight increase in body temperature.
• Central respiratory stimulation
• Causes hyperventilation and respiratory alkalosis
• Respiratory alkalosis is compensated by an increase in HCO3 excretion

• Central respiratory depression

• Results in respiratory acidosis
• The acidosis is made worse by a metabolic acidosis due to:
• High doses of an acidic drug
• Uncoupling of oxidative phosphorylation leading to lactic acid
buildup
• Decreased renal perfusion (no PG’s) leading to failure to excrete
acid so acid accumulates in the blood.
Toxic dose
• Acid accumulates to levels which cause coma and death
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 4

• Pharmacokinetics of salicylates
• Since aspirin (and all other NSAIDs) are acidic drugs, they are well absorbed in the stomach (since at an
acidic pH, the drug will be unionised)
• The distribution of aspirin is predominantly in the plasma (Vd = 0.1ml/Kg), with 80-90% being bound to
plasma proteins.
• Aspirin undergoes saturation kinetics at high doseas, having a half life greater thsn 15 hours. At low
doses, the elimination of aspirin follows first order kinetics, with a half life of 4 hours.
• Slow to enter CNS
• To reduce the irritation aspirin has on the stomach, buffered preparations can be used (e.g. Asproclear)
• Aspirin is mixed with a buffer to make it soluble in a glass of water.
• This buffered solution of aspirin enters the stomach, lowers the acidity and reduces damage to the
stomach lining.
• When the aspirin is soluble, it is in an ionised form, and hence, less absorption will occur.
However, because it is already in solution, it can more easily contact the stomach lining and be
absorbed there so absorption is not really affected.
• An alternative to a buffered solution is o have an enteric coating. This coating can only dissolve in a basic
environment, and so will reduce the irritation in the stomach.

Propionic acids
• More potent than aspirin and hence better at inhibiting COX, but comes with more side effects.
• Examples include:
• Naproxen (naprogesic)
• Used to treat menstrual pain.
• In menstruation, there is a large release of prostaglandins which may be associated with the pain.
• Ibuprofen
• These drugs are now available over the counter.
• Uses:
• Antipyretic
• Analgesic
• Antiinflammatory

Acetic acids
• Indomethacin
• Sulindac
• These drugs are very effective
• They have a high potency
• Increase in adverse effects
• 40% of people experience GI problems
• These drugs are predominantly used as anti-inflammatants and not used as anti-pyretics or analgesics because the
risks of using the drugs for those minor conditions are too great.
• Can be given rectally to reduce gastric irritation.
• Other NSAIDs
• Metenamic acid
• Piroxicam
• Diclofenac
• Phenylbutazone
• Only used in severe situations for a short term only. Never used long term

Selective COX 2 inhibitors

• Meloxicam
• Inhibits COX2 100 times more effectively than COX1
• Less adverse effects?
• Reduces the prostaglandins produced in pathological situations