PRINCIPLES OF ACTION/THERAPY OF COMMONLY USED

DRUGS AND CHEMICAL AGENTS

By the end of this topic the trainee should be able to define and give examples of:
i) Autacoids – -histamines and antihistamines
ii) Analgesics- NSAIDS – Salicylic acid derivatives Aniline derivatives -
pyrazolone derivatives,
(iii) Modern NSAIDS

AUTOCOIDS
 The term ‘autacoid’ is derived from Greek words – ‘autos’ meaning self and
‘akos’ meaning remedy or healing substance.
 Autacoids are locally acting hormone-like substances produced by a wide
variety of cells in the body, having intense biological activity which act
briefly at the site of synthesis and release (i.e. on adjacent cells).
OR
 Autacoids are chemical mediators that are synthesized and function in a
localized tissue or area and participate in physiologic or pathophysiologic
responses to injury.
 They are endogenous organic molecules with potent pharmacologic effects, that
are not part of traditional immune or autonomic groups.
 Autacoid modulators interfere with the synthesis, inhibit the release or the
receptors upon which they act.
 They act only locally and therefore also termed “local hormone.” Autacoids
normally do not function as the classical blood-borne hormones.
 Typically, autacoids are short-lived and rapidly degraded.
 Autacoids differ from hormones in following ways:
(I) Hormones are produced by specific cells; and
(ii) They are transported through circulation to act on distant target tissues

Physiologic function
1. Autacoids modulate blood flow in specific tissues.
 2. Some autacoids modulate secretory processes, for example, histamine on
gastric acid formation.
3. Autacoids modulate smooth muscle function.
4. Autacoids play a key role in allergy, inflammation, smooth muscle function,
pain, and certain types of drug reactions (Anaphylaxis).

Major classes of Autocoids

The autacoids to be discussed in this chapter can be divided into three categories
based on their chemical structure.
CLASSIFICATION OF AUTACOIDS:
(I) Classification based on chemical structure:
(1) Amine autacoids: Histamine, 5-Hydroxytryptamine (5-HT) or Serotonin.
(2) Lipid derived autacoids: Eicosanoids {Prostaglandins, Leukotrienes (LTs)
and Thromboxane’s (TXs)}, Platelet activating factor (PAF).
(3) Peptide autacoids: Plasma kinins (Bradykinin and Kallidin), Angiotensin,
Vasoactive Intestinal Polypeptide (VIP) and Substance P.
(II) Classification based on origin:
(1) Precursor molecules in plasma: Bradykinin, Kallidin and Angiotensin.
(2) Preformed and stored in the cell: Histamine, 5-HT, VIP and Substance P.
(3) Precursor molecules in cell membrane phospholipids: Prostaglandins, LTs
and PAF.

HISTAMINE =Tissue Amine

It is an amine present in a variety of animal tissues, venoms, bacteria
and certain plants (e.g. stinging nettle).
The amine is involved in inflammations, anaphylaxis, allergies and certain
types of drug reactions, and it regulates gastric secretion.

SYNTHESIS, STORAGE AND CATABOLISM OF HISTAMINE:

Chemically, histamine is β-imidazolyl ethylamine. It is synthesized from the
decarboxylation of amino acid histidine by a specific enzyme,
histidine decarboxylase. This enzyme is present in all cell types that contain
histamine.
Histamine is widely distributed throughout mammalian tissues. It is
generally accepted that most histamine stored within the body is synthesized
locally. Dietary histamine and histamine produced by enteric bacteria are
disposed of rapidly after absorption into the portal circulation and contribute
little or nothing to tissue storage sites.
In the animal body, histamine (basic) is found complexed with heparin
(acidic) and protein in the granules of mast cells.
Two general stores of histamine are there in mammals – one is mast cell
pool and the other is non-mast cell pool.
Mast cell pool Non-mast cell pool

(i) Made up of mast cells (i) Made up of

(connective tissue) and basophils histaminocytes localized in
(blood). GI tract, CNS, dermis and
(ii) Turnover of histamine is slow. (iii) other organs.
The mast cell pool represents (ii) Fast turnover.
the histamine that participates (iii) It is synthesized and
in inflammatory responses, released continuously
allergic phenomena, shock, some rather than being stored.
adverse drug reactions and other forms Functions:
of cellular insult. CNS – Neurotransmitter
(iv) Effect of histamine liberating GIT – Control of gastric
drug 48/80 – complete emptying secretion.
of storage granules & release (iv) Resistant to histamine
of histamine. releasing drugs such as
compound 48/80.

The catabolism of histamine includes ring methylation (to form N

methylhistamine) catalyzed by N-methyltransferase and oxidative
deamination catalyzed by diamine oxidase (histaminase) forming imidazolyl
acetic acid and its riboside. The metabolites of histamine are
pharmacologically inert and are excreted in urine.
 HISTAMINE RECEPTORS:
Histamine receptors have been classified into three types as H1, H2 and H3
receptors. The important features of the three types are presented in the
following table:
Selective H1 H2 H3
Agonist
2-methylhistamine 4-methylhistamine α-methylhistamine

Selective Chlorpheniramine Ranitidine Thioperamide

Antagonist

Histamine Receptors:
 H1 Receptors: Smooth muscle contraction, vasodilatation, increased
capillary permeability, stimulation of afferent nerve endings, ganglionic cell
stimulation, adrenal medulla catecholamine release, brain transmitter
function.
 H2 Receptors: Gastric acid secretion, blood vessel dilation, increased heart
rate and force of contraction, brain transmitter function.
 H3 Receptors: Inhibition of histamine release in the brain, reducing
histamine content in lung, spleen, skin, gastric mucosa.

Pathophysiological Functions of Endogenous Histamine

 HCl secretion in the stomach.
 Released from mast cells following Ag- Ab interactions during
hypersensitive reactions (Type-1 hypersensitivity).
 Neurotransmitter in CNS: Regulates water intake, body temperature,
release of ADH, blood pressure and pain perception.
 Regulates GI tone and motility: helps to maintain normal peristalsis.
Released in extensive tissue damage: Mediates local circulatory response
to injury and inflammatory reactions.
 Play an essential role in the process of tissue growth and repair because
these tissues contain high concentrations of histamine

Histamine Release
Various factors are responsible for release of histamine from mast cells:
1. Tissue damage by trauma, stings, venoms, proteolytic enzymes etc.
2. Antigen– antibody reactions involving IgE antibodies.
3. Some drugs like tubocurarine, morphine, atropine, polymyxin B,
vancomycin etc. release histamine without an immunological reaction.

Pharmacological Effects of Histamine

(1) Blood Vessels: Histamine causes marked dilatation of smaller blood
vessels including arterioles, capillaries and venules. However, it causes a
constrictor effect on large blood vessels. In rabbits, histamine is a “pressor
agent” as a result of pronounced constriction of blood vessels.
Histamine Shock:
The intense dilatation of capillary bed is accompanied by increase
in capillary permeability. In the presence of histamine, the capillary
endothelial cells constrict exposing the membrane (gap at the junctions),
which is freely permeable to plasma along with its proteins decreasing the
blood volume. The dilated arterioles, capillaries and venules that tag large
volumes of blood and reduce venous return to heart and thus the cardiac
output. These effects are precipitated by histamine release during allergic or
anaphylactic reactions in sensitive individuals. The condition may cause
death due to vascular shock as seen in acute surgical or hemorrhagic shock.
Triple Response:
Histamine produces a characteristic triple response in skin
following intradermal injection. It consists of the following:
A localized red spot – due to intense capillary dilatation developing within a
few seconds and attaining maximum hue within a minute.
Wheal – Localized oedema fluid forming a wheal in about 90 seconds due to
exudation of fluid from capillaries and venules; and
Flare (Diffuse redness) – i.e. redness in the surrounding area due to
arteriolar dilatation mediated by axonal reflex.

(2) Non-vascular smooth muscles: Histamine causes acute bronchial

constriction (via H1 receptors) in most of the species. However, guinea pigs
are exceptionally sensitive and even minute doses of histamine can evoke
bronchoconstriction leading to death.
Histamine causes tracheal relaxation in cat (both H1 & H2), bronchial
relaxation in sheep (H2) and uterine relaxation in rat (H2) but the uterus is
generally contracted in other species.

(3) Exocrine glands: Increased gastric acid secretion (due to H2 receptors).

 (4) Sensory nerve endings: Itching and pain due to stimulation of nerve
endings.

(5) Autonomic ganglia and adrenal medulla: Release of adrenaline and

rise of blood pressure.

(6) C.N.S.: Histamine does not penetrate the blood brain barrier.

MEDICAL USES OF HISTAMINE:

Histamine has no therapeutic application, but is used in
experimental pharmacology.
Clinical applications in human include –
(i) Use of histamine as a test agent for achlorhydria.
(ii) Used in diagnosis of pheochromocytoma, and
(iii) Used for production of triple response to evaluate integrity of
sensory innervations and circulatory competency.

ANTIHISTAMINES:
 These are drugs used to antagonize the effects of histamine liberation.
The antihistamines act as competitive antagonists of histamine at receptor sites.
 Antihistamines counteract the effect of histamine (histamine cause
bronchoconstriction and inflammatory changes)
 Antihistamines compete with histamine for receptor sites (H1 receptors
constrict smooth muscles and H2 receptors (H1 receptors mediate broncho-
constrictive effects of histamine and increase vascular permeability leading to
plasma exudation.
 H2 receptors mediate the inhibitory effect of histamine on eosinophil
degranulation. Are found in the skin, brain, endo and exocrine glands,
pulmonary system, genitourinary system and gastrointestinal muscles. Used to
treat gastric ulcers) increase gastric secretions)
 H1 blockers are used to treat pruritus, laminitis, motion sickness, anaphylactic
shock, and some upper respiratory conditions.
 Examples include diphenhydramine, dimenhydrinate, chlorpheniramine,
pyrilamine maleate, tripelennamine, terfenadine, hydroxyzine, and
meclizine.
 The antihistamines of clinical value in veterinary medicine are H1 antagonists.

H1 ANTAGONISTS:
 These are the drugs which competitively antagonize actions of histamine at H1
receptors. These are also known as Conventional Antihistamines. The
classification of H1 antagonists has been detailed as below:
Drug Trade Name

First Generation Benadryl (Parke-Davis)

(1) Ethanolamines: Histosol
Diphenhydramine HCl Jeet (Alembic), Anistamin
(2) Ethylene diamines: (Intas) Avil (Intervet)
Pyrilamine maleate Atarax (UCB Pharma)
(3) Alkylamines: Phenergan (Rhone Poulenc)
Chlorpheniramine maleate Practin (Merind)
Pheniramine maleate
(4) Piperazines:
Hydroxyzine HCL
(5) Phenothiazines:
Promethazine HCl
(6) Piperidines:
 Cyproheptadine HCl

Second Generation Cetzine (Glaxo)

(1) Piperazines: Loridin (Cadila)
Cetirizine HCl Allegra (Hoechst)
(2) Piperidines: Terin (Wockardth)
Loratadine HCl
Fexofenadine HCl
Terfenadine HCl

Out of the above classification, diphenhydramine, promethazine &

hydroxyzine are highly sedative; pheniramine and cyproheptadine are
moderately sedative and chlorpheniramine and pyrilamine are mildly
sedative while second generation antihistamines do not possess CNS
depressant property.

Cetirizine: It is a metabolite of hydroxyzine (1st generation antihistamine)

with marked affinity for peripheral H1 receptors. It penetrates the blood
brain barrier poorly, so is very less sedative. It attains high and longer lasting
concentration in skin, which may be responsible for its superior efficacy in
urticaria/ atopic dermatitis. It is indicated in upper respiratory allergies,
pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal
asthma.
Cyclizine, meclizine, promethazine, diphenhydramine (Anti- motion
sickness): These agents have prophylactic value in milder types of motion
sickness; should be taken one hour before starting the journey. Promethazine
can also be used in morning sickness, drug induced and post-operative
vomiting, radiation sickness. [H1 receptors mediate emesis in the emetic
center.]

Clinical uses of H1 blockers:

(i) In allergic and anaphylactic reactions.
(ii) In bronchial asthma, laminitis, azoturia and pulmonary emphysema in
horses.
(iii) In asthma, bloat, acetonemia, gangrenous mastitis, metritis and
retained placenta.
 (iv) In the treatment of skin affections like dermatitis, pruritus and eczema
(their mild local anesthetic action helps in pruritus).
[NB: Sodium cromoglycate: The drug is used for prevention of asthma in
men. It acts by stabilizing pulmonary mast cells sensitized to the antigen and
preventing the release of histamine. It is neither an antihistamine nor smooth
muscle relaxant. The drug inhibits activation of Ca2+ entry in sensitized mast
cells thereby preventing release of histamine. So, the drug is used
prophylactically by inhalation.]

H2 ANTAGONISTS:
These drugs block the effects of histamine that are mediated through H2
receptor stimulation, such as increase in gastric acid secretion and increase
in heart rate and automaticity of auricles and ventricles. The H2 antagonists
also act as competitive antagonists of histamine for H2 receptors. The H2
antagonists include – cimetidine, ranitidine, famotidine, roxatidine,
nizatidine etc. These drugs are of value in the treatment of peptic ulcers in
man and animals.

5-HYDROXYTRYPTAMINE (5-HT) or SEROTONIN ≅ Enteramine

or Vasotocin
Serotonin was the name given to the vasoconstrictor substance which appeared in
serum when blood clotted. Enteramine was the name given to the smooth muscle
contracting substance present in enterochromaffin cells of gut mucosa.

SOURCE:
5-HT is formed and localized in three essential pools in the body:
(i) Enterochromaffin cells of the intestine (about 90%).
(ii) Small number of neurons in CNS and mast cells of rodents (rat,
mice, hamsters) along with histamine and heparin.
(iii) Blood platelets.
In addition to the endogenous 5-HT reserve, it is also found in invertebrates and
plants (banana, pear, pineapple, tomato, stinging nettle etc.).
In the pineal gland, 5-HT is converted to melatonin after acetylation
and methylation.

ROLE OF ENDOGENOUS 5-HT:

(i) Neurotransmitter in brain in tryptaminergic nerves. Its deficiency causes
depression and excess causes excitement.
(ii) It is a precursor molecule of melatonin hormone.
(iii) It helps to regulate the tone and motility of the gastrointestinal tract.
(iv) Platelet 5-HT serves as one of the mediators of blood clot formation.

EICOSANOIDS
 The biologically active substances that are derived from 20 carbon
polyunsaturated fatty acids (mainly arachiodonic acid) which share a prefix
‘eicosa’ (means twenty) are termed eicosanoids.
 These include prostaglandins (PGs), prostacyclins (PGI2), thromboxane
(TXA2) and leucotrienes (LTs).
SYNTHESIS OF EICOSANOIDS:
Every cell in the body is capable of synthesizing eicosanoids. The first step in
their formation is release of arachiodonic acid from the phospholipids of cell
membrane and tissue triglycerides by the action of the enzyme phospholipases and
acylhydrolases. Several factors are associated with activation of these enzymes
which include physiological, pharmacological and pathological stimuli. Other
autacoids like angiotensin and kinins activate acylhydrolases and promote PG
synthesis. The sequence of formation of eicosanoids has already been shown
above.
PROSTAGLANDINS:
Two American Gynaecologists, Kurzrok and Lieb, in 1930, reported that
human semen contained a substance which was found to contract isolated uterine
and other smooth muscle strips and caused a fall in blood pressure in animals.
The active principle was termed ‘prostaglandin’, thinking that it was derived from
prostate gland.
LEUCOTRIENE:
It is synthesized in lung, platelets and white blood cells by metabolism of
arachiodonic acid via lipoxygenase pathway. Leucotrienes are thought to be
chemotactic in nature for leucocytes and participate in inflammatory responses.
FUNCTIONS OF EICOSANOIDS:
(i) Prostacyclin acts as an antagonist of prostaglandins and thromboxane A2 on
blood platelets.
(ii) Prostaglandins and prostacyclins promote vasodilatation and regulate the tone
of vasculature and control blood flow in the vital organs, possibly by
counteracting the circulatory vasoconstrictor autacoids. TXA2 is a potent
vasoconstrictor.
(iii) Prostaglandins and leucotrienes along with other autacoids are released during
allergic reactions and contribute to the bronchoconstriction and other signs.
(iv) Prostacyclin controls renal blood flow, urine formation, renin secretion and
checks the action of ADH.
(v) Presence of prostaglandins in semen may have a role in facilitating conception
following coitus. They may also help in termination of pregnancy at the term.
PGF2 elaborated by uterus (mare, cow, sow & ewe) functions like luteolytic
hormone and is used for synchronizing estrous. Aspirin inhibits uterine
contractions during parturition by interfering with prostaglandin synthesis.
(vi) Inflammation: The formation of prostaglandins and leucotrienes is enhanced
by tissue injury (mechanical, chemical, thermal or infectious) which are
responsible for reactions of inflammations (along with other autacoids), such as
increase in vascular permeability, oedema and leukocyte infiltration and potentiate
the pain inducing effect of bradykinin. Leucocytes release leucotrienes which help
in migration of leucocytes.
CLINICAL USES OF EICOSANOIDS:
(i) In veterinary practice, PGF2 analogues [like Dinoprost (Lutalyse -
Novartis), Tiaprost (Iliren - Intervet) etc.] are used for:
(a) Estrous synchronization (cow, ewe, goat, buffalo etc.)
(b) Induction of estrous in anestrous animals.
(c) Expulsion of mummified fetus; and
(d) Expulsion of pus in pyometra.
(ii) Therapeutic abortion in human females – PGE2 analogue (Dinoprostone) is
used for abortion during first trimester.
(iii) Impotency – PGE1 analogue (Alprostadil) may be used in the treatment of
impotency.
(iv) Maintenance of patent Ductus Arteriosus: PGE1 analogue (Alprostadil) is used
in the treatment of congenital malformations of the heart in neonates.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

All drugs grouped in this class have analgesic, antipyretic and anti-
inflammatory actions in different measures. Compared to morphine they
are weaker analgesics (except for inflammatory pain); do not depress
CNS, do not produce physical dependence and have no abuse liability.
They are also called non-narcotic, non-opioid or aspirin like
analgesics. They act primarily on peripheral pain mechanisms but also
in CNS to raise pain threshold.
Classification of NSAIDs based on chemical groupings:
1. Salicylates: Sodium salicylate, Acetylsalicylic acid (aspirin),
Methylsalicylate.
2. Aniline or p-aminophenol derivatives: Paracetamol (acetaminophen),
Acetanilide, Phenacetin, Aminopyrine, Antipyrine.
3. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone,
Sulphinpyrazone.
4. Indole & related drugs: Indomethacin, Sulindac.
5. Phenyl acetic acid derivatives: Diclofenac.
6. Propionic acid derivatives: Ibuprofen, Naproxen, Fenoprofen, Ketoprofen.
7. Fenamates: Mefenamic acid.
8. Oxicams: Piroxicam, Tenoxicam, Meloxicam.
9. Sulfonanilide derivatives: Nimesulide.

Classification of NSAIDs based on selectivity of COX Inhibition:

A. Non-selective COX Inhibitors (Conventional NSAIDs):
1. Salicylates: Aspirin, Diflunisal.
2. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
3. Indole derivatives: Indomethacin.
4. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen,
Flurbiprofen.
5. Anthranilic acid derivatives: Mefenamic acid.
6. Aryl acetic acid derivatives: Diclofenac.
7. Oxicam derivatives: Piroxicam, Tenoxicam.
8. Pyrrolo-pyrrole derivatives: Ketorolac.
B. Preferential COX-2 Inhibitors: Nimesulide, Meloxicam, Nabumetone.
C. Selective COX-2 Inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
D. Analgesic-antipyretic with poor anti-inflammatory action:
1. p-aminophenol derivatives: Paracetamol (Acetaminophen).
2. Pyrazolone derivatives: Metamizol.
3. Benzoxacine derivatives: Nefopam.
MECHANISM OF ACTION OF NSAIDs:
NSAIDs block the enzyme cyclo-oxygenase (COX), so block
prostaglandin (PG) synthesis and ultimately inflammation.
Beneficial actions of PG synthesis inhibition: Analgesia,
antipyresis, anti- inflammatory action and antithrombotic action
Shared toxicities due to PG synthesis inhibition:
 Gastric irritation which may range from simple discomfort to ulcer
formation,
 Limitation of renal blood flow (due to Na+ and water retention),
 A tendency to prolong bleeding (due to inhibition of platelet function),
 Delayed/ prolongation of labour,
 Asthma and anaphylactoid reactions in susceptible individuals.

Analgesia: Prostaglandins induce hyperalgesia, i.e. why NSAIDs are

effective only against pain associated with inflammation.
Antipyresis: NSAIDs reduce body temperature in fever but do not cause
hypothermia in normothermic individuals. Fever during infection is
produced through generation of pyrogen which induces PG production
in hypothalamus which raises its temperature set point.
Anti-inflammatory action: PGs cause vasodilatation & exudation
resulting in inflammation. NSAIDs inhibit PG synthesis at the site of
injury.
Dysmenorrhoea: Involvement of PGs in Dysmenorrhoea has been
clearly demonstrated. Level of PGs in menstrual outflow is increased in
dysmenorrhoeic women. NSAIDs lower uterine PG levels – affords
excellent relief in 60-70% and partial relief in the remaining.
Anti-platelet aggregatory action: Thromboxanes help in aggregation of
platelets. NSAIDs inhibit platelet aggregation by inhibiting synthesis of
thromboxanes mediated via COX. Aspirin is highly active.
Parturition: Sudden spurt of PG synthesis by uterus triggers labour and
facilitates its progression. Accordingly, NSAIDs have the potential to
delay & retard labour.
Gastric mucosal damage: Gastric pain, mucosal erosion/ ulceration and
 blood loss are produced by all NSAIDs to varying extents: relative
gastric toxicity is a major consideration in the choice of NSAIDs.
Inhibition of the synthesis of gastro-protective PGs (PgE2, PGI2 etc.) is
clearly involved; though local actions inducing back diffusion of H+ in
gastric mucosa also plays a role. Paracetamol, a very weak inhibitor of
COX is practically free of gastric toxicity. Selective COX-2 inhibitors
are safer.

ANTIPYRETIC EFFECTS OF NSAIDs:

Normal body temperature (thermostat) is maintained by the
thermoregulatory center located in the hypothalamus. Fever occurs due
to disturbance in hypothalamic thermostat, which is set at a higher
temperature. During infections and inflammatory reactions, the
pathogenic microbial endotoxins cause release of pyrogen Interleukin-
1 from neutrophils and macrophages, which stimulate the generation of
prostaglandins (E series) in the hypothalamus which set the thermostat at
a higher level, resulting in pyrexia or fever.
The antipyretics act by resetting the thermostat to normal set point and
then the body temperature regulating mechanisms (like dilatation of
superficial blood vessels, sweating and increased respiration promoting
heat loss) operate to lower the elevated body temperature to normal
level. NSAIDs also exert their antipyretic effect by irreversibly
inhibiting their cyclo-oxygenase production from arachiodonic acid in
the hypothalamus. Normal body temperature is not affected by NSAIDs
or antipyretics (at therapeutic dosage).

ANALGESIC EFFECTS OF NSAIDs:

Prostaglandins induce hyperalgesia/ hyperesthesia due to sensitization of
nociceptors to pain.
That is, why, NSAIDs are effective only against pain associated with
inflammation (like arthritis, bursitis, muscular pain, vascular pain,
toothache, dysmenorrhea and bone pain).
NSAIDs exert analgesic effect by inhibiting prostaglandin synthesis
through irreversible inhibition of cyclo-oxygenase.
ANTI-INFLAMMATORY EFFECTS OF NSAIDs:
The inflammatory reactions such as vasodilatation increased vascular
permeability, cell proliferation, pain etc. are mediated by release of
multitude of chemical mediators having varied mechanisms of action.
These mediators further induce synthesis of prostaglandins through
cyclo-oxygenase which ultimately produce inflammation. NSAIDs exert
anti-inflammatory effect by inhibition of prostaglandin synthesis through
cyclo-oxygenase -2. Aspirin in addition to the above effects also
prolongs clotting time by preventing platelet aggregation (by inhibiting
thromboxane A2 synthesis in platelets). So, also used for the treatment of
coronary blocks, myocardial infarction and angina

Table: A comparison of the spectrum of action of NSAIDs of

veterinary interest; sulphinpyrazone and glucocorticoids are
included for completeness.

NSAIDs & Central analgesic Antipyretic Anti-inflammatory Uricosuric

others
Aspirin + + + ±
Paracetamol + + 0 0
Phenylbutazone 0 ± + +
Sulphinpyrazone 0 0 0 +
Meclofenamate 0 + + NA
Naproxen 0 + + NA
Flunixin + + + NA
Glucocorticoids 0 0 + Inhibits
Relative Potency of NSAIDs:
Antipyretic Effect: Aspirin = Paracetamol > Phenacetin >
Phenylbutazone
Analgesic Effect: Aspirin > Phenacetin & Paracetamol >
Phenylbutazone
Anti-inflammatory Effect: Phenylbutazone > Aspirin

SALICYLATES
 Salicylates generally act by virtue of their content of salicylic acid which
is responsible for most of the actions.
1. Salicylic acid: Salicylic acid (orthohydroxybenzoic acid) is so
irritating that it can only be used externally; therefore, various
derivatives of this acid have been synthesized for systemic use. It
is confined to external use only as a keratolytic agent.
2. Methylsalicylate: It is a component of liniments and ointments
with rubefacient action.
3. Sodium salicylate: It is the active ingredient of oral febrifuge
prescriptions in veterinary practice. The drug is freely soluble in
water and is rapidly absorbed from GI tract.
4. Aspirin (Acetylsalicylic acid): It is rapidly converted in the body
to salicylic acid which is responsible for most of the actions of
aspirin. It is one of the oldest analgesic-anti-inflammatory drugs
and is still widely used. More potent than sodium salicylate but
less soluble.

ANILINE DERIVATIVES (p-aminophenol derivatives):

[Acetanilide, Phenacetin & Paracetamol (or Acetaminophen)]
o The members of the family are less irritant to the stomach than
salicylates and lack the anti-inflammatory potency of salicylates,
but they are equipotent as antipyretic analgesics.
o These members (acetanilide, phenacetin and paracetamol) acting
via metabolites oxidize Hb to Met Hb and Sulph Hb, shortens the
life of erythrocytes and can cause frank hemolysis. Paracetamol is
the least toxic member of the family. It is free of all the side
effects and adverse reactions of aspirin, and excreted as
conjugates in urine.
o There may be poisoning by paracetamol (in overdose) in cats.
Methionine and cysteine are glutathione precursors and have
antidotal value in paracetamol poisoning.

PYRAZOLONE DERIVATIVES:
o Previously antipyrine (phenazone) and amidopyrine
(aminopyrine) were introduced as antipyretics and analgesics.
Their use was associated with high incidence of agranulocytosis,
hypersensitivity reactions, tremors, sweating etc. That is, why,
 these drugs were banned in many countries including India.
o Phenylbutazone and its active metabolite oxyphenbutazone (less
active than phenylbutazone) have potent anti-inflammatory
actions rather than analgesic properties. These are also rarely used
now, due to residual risk of bone marrow depression and other
toxicities in human beings but used in horses and dogs. In horses
(doping agent), phenylbutazone is widely used to treat to give
symptomatic relief from muscle, bone and joint lesions in horses.
The detection of phenylbutazone or its longer-lived metabolite
oxyphenbutazone in race horse urine samples has given rise to the
so-called “8-day rule”, 8 days being suggested minimum period
between the last treatment and racing to ensure a negative urine
test.
o Other pyrazolones used safely are metamizol and
propiphenazole used as analgesic and antipyretic.
o Sulphinpyrazone – It is a uricosuric agent (unusual among
NSAIDs) with no anti-inflammatory property.

INDOMETHACIN:
o It is a more powerful anti-inflammatory drug and most potent
inhibitor of cyclo- oxygenase in vitro.
o Due to this action, it can extend the duration of pregnancy in
experimental animals.
o It also inhibits the diuretic potency of furosemide.
o Side effects – headache, diarrhea, blood dyscrasias, ulcers in GIT etc.

DICLOFENAC:
o Analgesic, antipyretic & anti-inflammatory drug.
o It is among the most extensively used NSAIDs employed in
rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis,
dysmenorrhea, post-traumatic and post-operative inflammatory
conditions – affords quick relief of pain and wound oedema.
o Side effects are generally mild.
o Now-a-days, banned for veterinary practice in India due to
mortality of vultures scavenging on carcasses of animals
containing residues of diclofenac. In poultry, diclofenac causes
gout and other pathogenic lesions which result in their mortality.
PROPIONIC ACID DERIVATIVES:
1. Ibuprofen: It is popular drug in human medicine because its use
is associated with a low incidence of GI side effects. However, GI
erosions consistently occur in dogs (hence, not recommended for
use in dogs).
2. Ketoprofen: It is a strong inhibitor of cyclo-oxygenase; hence it
has powerful anti-inflammatory, analgesic and anti-pyretic
properties (Effective in rheumatoid arthritis & post-operative pain
control). It is relatively safer.
3. Naproxen: It has analgesic, antipyretic and anti-inflammatory
effects. In horses, it can be effectively used for myositis bringing
complete relief from pain and lameness in 5 to 6 days. The drug is
toxic in dogs. In human beings, the drug produces less GI damage
than aspirin.

FENAMATES:
o It has antipyretic, analgesics and anti-inflammatory potency.
o The analgesic is secondary to anti-inflammatory effect.
o Meclofenamic acid is noted for its slow onset of action. It is an
antagonist of PGF2 and can protect against bovine experimental
anaphylaxis.

OXICAMS:
1. Piroxicam: It is a good analgesic, antipyretic and anti-
inflammatory agent. It is suited for use as short term analgesic
and long-term anti-inflammatory drug – rheumatoid and
osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal
injuries, dentistry, episiotomy, dysmenorrhea etc.
2. Meloxicam: It has 10-14 folds COX-2 selectivity than COX-1.
So, it has been labeled “preferential COX-2 Inhibitor”. Efficacy of
meloxicam in osteoarthritis & rheumatoid arthritis is comparable
to piroxicam. Gastric side effects are milder.
NIMESULIDE:
o Relative COX-2 selectivity.
o Weak inhibitor of PG synthesis.
o Analgesic, anti-pyretic and anti-inflammatory activity of
Nimesulide is comparable to other NSAIDs.

NEWER/MODERN AGENTS:
1. Celecoxib: COX-2 selectivity. Good anti-inflammatory,
analgesic, antipyretic and low ulcerogenic properties.
2. Valdecoxib: COX-2 selectivity.
3. Rofecoxib: COX-2 selectivity.

4. Carprofen: Often used for dogs, it helps manage pain and

inflammation associated with osteoarthritis.
5. Meloxicam: Used in both dogs and cats, it is effective for pain relief
and reducing inflammation.
6. Robenacoxib: A newer NSAID used for dogs and cats, known for its
rapid onset of action.
7. Firocoxib: Specifically designed for dogs, it is used to manage pain
and inflammation associated with osteoarthritis.
8. Deracoxib: Another newer NSAID for dogs, used for pain
management after surgeries.