Pharmacology of Anti-inflammatory Drugs

Inflammation: (Latin, inflammare, to set on fire) is part of the complex biological response of vascular
tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The invasion of tissues by these
noxious agents triggers the release of cytokines (IL-1, IL-6 and TNF ). Moreover membrane phospholipids
are broken down to yield arachidonic acid (through the catalytic action of phopholipase A2) and then it is
converted to eicosanides (PGE2, PGI2, PGF2 and TXA2) and leukotriens by cyclo-oxygenase (COX) and
lipo-oxygenase respectively. Prostaglandins, leukotriens, thromboxanes, cytokines and histamine are called
inflammatory mediators that are responsible for the manifestation of cardinal signs of inflammation; dolor
(pain), calor (heat), rubor (redness), tumor (swelling) and functiolesa (loss of function). Although
inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the
healing process, widespread and chronic inflammation may become detrimental and interrupt normal body
functioning (can also lead to abscessation and fibrosis if left untreated) thereby requiring optimal
intervention through the use of anti-inflammatory drugs.
Origin and functions of some inflammatory mediators
Mediator(s)

PGE2
PGI2
PGF2
TXA2
Leukotriens
Histamine
Cytokines

Source

Main Actions

Membrane phospholipids, mast cells

Membrane phospholipids, platelets
Membrane phospholipids, leukocytes
Mast cells
Macrophages, lymphocytes

Inhibition of gastric acid secretion, broncho-constriction

Vasodilation, inhibition of platelet aggregation
Improves uterine motility and renal perfusion
Stimulation of platelet aggregation, vasoconstriction
Increase vascular permeability, broncho-constriction
Vasodilation and stimulation of nociceptors
Cartilage degeneration, necrosis

Anti-inflammatory drugs: These are broadly divided into two groups; Corticosteroids and Non-steroidal
anti-inflammatory drugs (NSAIDs).
1. Corticosteroids: Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex to
perform many significant physiological functions. Many synthetic steroids have been prepared that are used
to achieve various therapeutic goals. Corticosteroids can strengthen the tolerance of organism to bacterial
endotoxins, antagonize and relieve the reactions caused by bacterial endotoxins. However, they cant
neutralize bacterial endotoxins, and have no defensive effects on bacterial exotoxins. Large dose of
Corticosteroids has the effect of antishock (by reducing peripheral vascular resistance, improving the
blockage of microcirculation they increase returned blood volume) and are widely used in various kinds of
shock like toxic shock, septic shock, anaphylactic shock and hypovolumic shock.
Salient features of natural Corticosteroids (Adrenal steroids)
Portion

Adrenal
cortex

Adrenal
medulla

Functional zone

Secretion

Zona Glomerulosa
(outermost zone)

Mineralocorticoid
s (Aldosterone)

Zona Fasiculata
(middle zone)

Glucocorticoids
(Cortisol)

Zona Reticularis
(inner zone)

Sex steroids
(Androgens)

Chromaffin cells

Catecholamines
(Epinephrine and
Norepinephrine)

Functions

Regulate electrolyte and water levels, mainly by promoting

sodium retention in the kidney
Control carbohydrate, fat and protein metabolism and are
anti-inflammatory by preventing the synthesis of
inflammatory mediators
Affect the growth or function of reproductive organs, the
development of secondary sex characteristics, and sexual
behavioral of animals
Catecholamines cause general physiological changes that
prepare the body for physical activity (fight, flight or fright
response). Some typical effects are increases in heart rate,
blood pressure, blood glucose levels, and a general reaction
of the sympathetic nervous system

Classification of Corticosteroids
Mode of action

Inhibition of
phospholipase-A2
mediated
production of
inflammatory
mediators

Category

Biological half life

Short acting
corticosteroids

< 12 hours

Intermediate acting
corticosteroids

12-36 hours

Long acting
corticosteroids

> 36 hours

Examples

Cortisone
Hydrocortisone
Triamcinolone
Prednisone
Prednisolone
Paramethasone
Dexamethasone
Betamethasone
Flumethasone

Anti-inflammatory potency

0.7
1
3
4
5
10
25
25
30

Clinical uses: They are used in shock, allergic rhinitis, conjunctivitis, rheumatoid arthritis, bursitis,
synovitis, tendinitis and otitis externa (inflammation of external ear). Corticosteroids can induce labor (by
triggering the activity of desmolase, hydro-oxylase and aromatase enzymes which convert progesterone into
estrogen) in cattle and has been used (as abortificient) to terminate pregnancy in bitches.
Adverse effects and contraindications: Corticosteroids should not be used in equines as they can cause
laminitis or can worsen the already existing laminitis. These drugs suppress immune response and have
many depressant effects on immunoreaction. They cause lymphocyte destruction, reduce the number of the
lymphocyte by moving them outside the blood vessels, induce lymphocytic apoptosis and interrupt their
division and proliferation. Therefore they should not be used in immuno-compromised patients. Animals
receiving systemic corticosteroids may be more susceptible to bacterial or viral infections and the immune
response to vaccination may be reduced when corticosteroids are given at the same time. Corticosteroids
should be avoided during pregnancy and lactation unless the benefits outweigh the risks. Prolonged use of
corticosteroids can give rise to iatrogenic hyperadrenocorticism in dogs and cats.
2. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs by virtue of inhibiting cyclooxygenases,
are effective in suppressing inflammation, alleviating pain, and lowering fever. Cyclooxygenases (COX)
(localized in endoplasmic reticulum) are responsible for the formation of a group of local hormones
comprising the prostaglandins, prostacyclin, and thromboxanes (from arachidonic acid). These enzymes
possess an elongated pore into which the substrate arachidonic acid is inserted and converted to an active
product. NSAIDs penetrate into this pore and thus prevent access for arachidonic acid, leading to reversible
blockade of the enzyme. Two principal types of COX can be distinguished: COX-1 is constitutive, that is,
always present and active; it contributes to the physiological function of organs. Inhibition inevitably
produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances
of uterine function. COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize
nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular
permeability. However, in some organs, COX-2 is also expressed constitutively (kidney, vascular
endothelium, uterus, and CNS).
Non-selective COX-inhibitors: These include Acetylsalicylic acid or Aspirin (Disprin), Paracetamol or
Acetaminophen (Panadol), Ibuprofen (Brufen), Meclofenamic acid (Ponston), Diclofenac (Voren, Phlogen,
Dyclo, Dicloron, Diclostar, Fenac), Metamizole (Dipyrone, Magnapyrol, Novalgene), Phenylbutazone
(Butadin), Piroxicam (Feldene) and Naproxen (Neoprox).
Selective COX-inhibitors: Meloxicam and Nimusulide (Nims) are included in this group.
Pharmacological actions of NSAIDs:
(a) Antipyretic effect: The hypothalamus that is responsible for thermo-regulation, is affected by exogenous
pyrogens such as bacterial toxins and endogenous pyrogens (now considered to be IL -1). Pyrogens promote
the synthesis and subsequent release of prostaglandin E (PGE). PGE can raise the set-point of body
temperature, in order to increase heat production, dissipate heat production, and to raise the body
2

temperature. NSAIDs being the inhibitors of prostaglandin synthesis are helpful to restore normal
thermoregulatory control mechanism.
(b) Analgesic effect: Some inflammatory mediators like prostaglandins and bradykinins are also involved in
pain sensation. Therefore the anti-prostaglandinic action of NSAIDs can provide good analgesia in many
conditions such as neuralgia, myalgia, joint pain, muscle pain, and so on, but these agents are not effective
for the suppression of acute pain and visceral pain.
(c) Anti-inflammatory effect: Prostaglandins are key mediators in inflammatory reaction, a large number of
them exist in inflammation organizations. NSAIDs have the ability to subside inflammation by inhibiting the
synthesis of prostaglandins.
Clinical uses: NSAIDs are generally indicated for the symptomatic relief of the many conditions like
rheumatoid arthritis (auto-immune-mediated inflammatory disorder that may affect many tissues and organs,
but principally attacks synovial joints), osteoarthritis, laminitis, dysmenorrhoea (menstrual pain), metastatic
bone pain, headache and migraine, postoperative pain, pyrexia (fever), renal colic, myalgia and mild-tomoderate pain due to inflammation and tissue injury. Aspirin is used (for its inhibitory effect on platelet
aggregation) in dissiminated intravascular coagulation (DIC), thrombo-embolic disorders and heartworm
(Dirrofilaria immitis) infection in dogs.
Adverse effects: The following side effects are linked with improper administration of NSAIDs.
1. Some prostaglandins (like PGE) possess beneficial role in terms of suppression of gastric acid secretion
and regulation of renal microperfusion. Thus prostaglandin inhibitors (NSAIDs) can cause (or aggravate)
gastric hyperacidity and renal disturbances.
2. Inhibition of TXA2 synthesis by NSAIDs results in profused bleeding and delayed clotting time (via
inhibiting platelet aggregation). This property can be benefited to resolve intravascular thrombi (that can
cause embolism and ischemia) in some cardiac disorders like myocardial infarction.
3. NSAIDs that are acidic in nature (like Aspirin and Paracetamol) undergo hepatic metabolism through
glucoronide conjugation. Species that are inherently deficient in glucoronide conjugatory mechanism (such
as glucoronyl transferase deficiency) are susceptible to serious toxicosis (the half life of these drugs is
abnormally prolonged due to lack of sufficient biotransformation). Acetylcysteine (precursor of Glutathione
and potent antioxidant) should be used to suppress free radical induced cellular damage that occurs during
this idiosyncratic condition.
4. Large doses of Aspirin may cause hyperglycemia (by uncoupling phosphorylation during glycolysis)
followed by glycosuria (release of glucose in urine) and deplete liver and muscle glycogen.
5. In humans the use of Aspirin has been implicated in the causation of salicylism (a syndrome that is
characterized by dizziness, vertigo and reversible visual and auditory impairment) and Reyes syndrome
(occurs in infants suffering from viral infection and it is manifested by hepatic damage and encephalopathy).
6. Metamizole is known to cause agranulocytosis (decresed synthesis of agranulocytes; lymphocytes and
monocytes).
7. Diclofenac has been banned in many countries (in Nepal, India and Pakistan in 2006 and in Bangladesh in
2010) for use in livestock because it causes kidney necrosis in vultures, leading to reduced excretion of uric
acid and the deposition of uric acid crystals in tissues. Death usually occurs within two days. Studies
conducted in Pakistan showed that diclofenac caused acute kidney failure in vultures when they ate the
carcasses of animals that had recently been treated with it.
Contraindications: NSAIDs are contraindicated in persons suffering from gastrointestinal ulceration,
bleeding disorders and human infants (having viral infection). Aspirin therapy should be stopped one week
before surgery (to avoid excessive bleeding), and it should be used cautiously in species with improper
metabolizing potential (cats and fish).
Interactions: Aspirin enhances the action and toxicity of oral anticoagulants and Heparin by increasing risk
of bleeding. The urinary excretion of acidic NSAIDs is increased and decreased by the concomitant
administration of urinary alkalizers (like sodium bi carbonate) and urinary acidifiers (like ammonium
chloride) respectively.