Pharmacology

1. Antipyretic drugs

2. Antipyretic drug:
•Antipyretic drugs are the drugs that apparently
resets the set point or thermostats and also
increase heat loss through peripheral vasodilation
by inhibiting synthesis of prostaglandins.
•They reduce body temperature in fever but do
not cause hypothermia in normothermic
individuals.
•They do not influence body temperature when it
is elevated by factors such as exercise, or rise in
ambient temperature.

3. Some important antipyretic drugs are
1. Paracetamol (acetaminophen)
2. Aspirin
3. Sodium salicylate
4. Salicylic acid
5. Piroxicam
6. Meloxicam
7. Indomethacin
8. Naproxen
9. Ketoprophen
10.Phenylbutazone

4. Aspirin
Acetylsalicylic acid (prodrug)
• It is the salicylate ester of salicylic acid.
• It is a standard reference for non-opioid
analgesics.
• It is the most extensively used over-the-
counter drug
• It is stable in dry air but hydrolyses to salicylic
acid and acetic acid in moist air.
• It is slightly soluble in water and freely soluble
in alcohol.

5. Pharmacokinetics
• It is easily absorbed from the stomach and proximal small
intestine by passive diffusion.
• During and after absorption, most of the aspirin is hydrolysed to
salicylic acid (active metabolite) and acetic acid by the esterase
present in tissues( stomach, intestinal mucosa and liver) and
blood.
• Almost 70% becomes bound to plasma albumin. It distributes
rapidly into body fluid compartments.
• Salicylate are metabolized in the liver by conjugation with
glucuronic acid and glycine( predominant pathway).
• It has a very short half life. ( hervivores 1hr , cats 30mins)
• Excretion of salicylate and its metabolites occur mainly via
kidneys.
• Metabolism and elimination of aspirin follows first order kinetics
in low doses and zero-order kinetics in higher doses.

6. Mechanism Of Action
• Irreversibly blocks both COX-1 and COX-2
isoenzymes by acetylating serine at position 530
and 516.
• Low doses, long term aspirin use irreversibly blocks
formation of thromboxane A2 in platelets. (
anticoagulant property)
• It also uncouples oxidative phosphorylation in
cartilaginous and hepatic mitochondria. Therefore
when used in high doses, aspirin causes fever due
to the heat released from the ETC .
• At high doses, aspirin inhibits the activation of
inflammatory cells.

7. Clinical Uses
• As an ANALGESIC: it is used for the relief of mild
to moderate pain of musculo-skeletal origin e.g.
myalgia, neuralgia and minor trauma.
• As an anti-inflammatory agent : to reduce
traumatic and post-surgical oedema and to give
relief in conditions like brusitis, arthritis, laminitis
and pathogen induced inflammation.
• It is used for DIC, thromboembolic disorders and
pulmonary disease secondary to heartworm
infections in dog and cardiomyopathy in cat.

8. Pharmacological Effect
• Analgesic effect: the analgesic effect is mainly
peripheral in the form of blockade of pain
impulse generation and prevention of PGs
mediated sensitization of nerve endings.
Central analgesia is due to increase in
threshold to pain perception and inhibition of
action of PGs in causing facilitation and
perpetuation of the action of spinal
transmitters.

9. Pharmacological effect
• Anti-pyretic effect : it resets the hypothalamic
thermostat and rapidly reduces fever by increasing heat
loss. ( No effect on normal body temperature)
• Anti-inflammatory effect: at high doses it exerts this
effect.
• Metabolic effects: at high doses it uncouple OP. In larger
doses, it causes hyperglycemia and glycosuria. Chronic
use of large doses cause negative nitrogen balance. At
low doses, it decreases urate excretion.
• Endocrine effects: high doses cause epinephrine release
from adrenal medulla and very large doses may
stimulate ACTH secretion from the ant.pituitary by
action on hypothalamus.

10. Pharmacological effect
• Respiration and acid-base balance : at therapeutic
doses, aspirin stimulates alveolar ventilation , at
high doses, it increases respiratory rate and
volume by direct stimulation of respiratory centre
and by uncoupling OP→→→ respiratory alkalosis.
Toxic doses depresses medulla and results in
respiratory acidosis.
• GI tract : it results in increased gastric acid
synthesis and reduced mucous protection. Aspirin
produces dose related gastric ulceration and
hemorrhage.
• .

11. PHARMACOLOGICAL EFFECTS
• Hematological effect: even in small doses, aspirin
irreversibly inhibits the platelet cyclooxygenase
enzyme (anticoagulant effect). Large dose inhibits
synthesis of PGI2. Long term use decreases
synthesis of clotting factors.
• Renal effects: decreased synthesis of PGs can
result in retention of sodium and water, and may
cause oedema and hyperalkemia.
• Cardiovascular effect: therapeutic dose has no
direct effect. The peripheral vessels dilate after
large doses due to direct effect on vascular
smooth muscle. Toxic doses depress vasomotor
centre

12. Side effects
Therapeutic dose High dose Toxic dose
• Gastric/intestinal
irritation
• Epigastric distress
• Nausea
• Vomiting
• Anorexia
• Hyperventilation
• Gastric lesions
• Hepatitis
• Suppression of
bone marrow
erythropoiesis
• Centrally mediated
hyperpnoea
• Alkalosis
↓
• Respiratory
depression
• Acidosis
• Circulatory collapse
• Hyperpyrexia
• Convulsions
• Coma
• Death

13. Contraindications and Precautions
Use avoided in :
• Gastrointestinal ulceration and bleeding
• Last stages of pregnancy
• Before surgery
• Hypoalbuminaemia(lower dose)
• Dehydrated, hypovolaemic, hypotensive
patients
• Reye’s Syndrome( in children below 12 years)

14. Drug Interaction
• Enhances toxicity of anticoagulants
• Displaces warfarin, penicillins, sulphonamides from
binding sides on plasma proteins
• Inhibits tubular secretion of uric acid
• Decreases diuretic action of furosemide and
thiazides and blocks action of spironolactone
• Urinary acidifying drugs decreases its excretion
• Hypoglycemic action of aspirin potentiates the
action of insulin
• Phenobarbitol increases its metabolism(inducing
hepatic enzyme)

15. Clinical uses
For analgesia and
anti-pyrexia
For anti-
inflammatory and
anti-rheumatic
effects
For antithrombotic
effects
Mild to moderate
musculo-skeletal
pain
DOSE
Dogs: 10mg/kg, PO,
2 times daily
Cats: 10mg/kg, PO,
alternate day
Cattle: 50-100mg/kg,
PO, 2 times daily
To reduce traumatic
and post surgery
oedema
DOSE
Dogs: 25-20mg/kg,
PO, 3 times daily
Cats: 25mg/kg, PO,
once daily
DIC,
thromboembolic
disorders and
pulmonary artery
disease secondary
to heartworm in
dog
DOSE
Dogs: 0.5mg/kg,
PO, 2 times daily

16. Cats have reduced capacity for glucuronide conjugation so most paracetamol
are converted to reactive electrophilic metabolite.

19. PHARMACOLOGICAL EFFECTS
• Does not produce gastric irritation, erosion or
bleeding unlike salicylates
• In humans, no effects on platelets, bleeding
time or excretion of uric acid
• High dose produces anti-inflammatory effect
in animals
• Has good antipyretic and analgesic effect

20. SIDE EFFECTS
• Severe liver and kidney damage
• Cyanosis
• Heinz body anemia
• Methaemoglobinaemia
• Jaundice
• Facial oedema
TREATMENT(detoxification and supportive measures)
Acetylcysteine
1. 150mg/kg, IV or PO initially
2. Followed by 70mg/kg, PO every 4 hours for 5 to 7
treatments

21. Contraindications and
precautions
Drug interactions
• Contraindicated in cats at
any dosage
• Not recommended in hepatic
and renal toxicity, or
haematological
abnormalities for dogs
• Avoided during intermediate
post-operative phase
• Additive analgesic effect with
aspirin
• Large dose potentiates
effects of oral anticoagulants

22. Clinical uses
• Over the counter drug
• One of the best drug for human use
• It dogs used as oral analgesics
DOSE
Dogs: 10-15mg/kg, PO, 2 times daily

23. Meloxicam:
• Recently developed congener of piroxicam that
exhibits anti-inflammmatory, antipyretic and
analgesic activities
Pharmacokinetics:
•oral absorbtion is almost complete in dogs
•99.5% bound to plasma protein
•Metabolised by liver into four biologically
inactive main metabolites
•Excreted in both urine and faeces
•Halflife is about 20 hour

24. MOA:
•Greater invitro and invivo inhibitory action
against the inducible COX-2, which is
implicated in the inflammatory response than
COX-1
•In animals, COX-2:COX-1 selectivity of 11-14
times has been measured.

25. Clinical uses:
•As antipyretic in dogs and cat
•Used mainly in dogs for relieving pain and
inflammation associated with osteoarthritis
and synovitis
•Also for treatment of mastitis in cattle and
diarrhoea in calves
•Side effects:
•Gastrointestinal
toxicity(inappeance,vommiting & diarrhoea)
•Bleeding may occur after prolonged use and
in high doses

26. Contraindication and precautions:
•Should not be used for the treatments of
diarrhoe in calves less than 1 week of age and in
cats less than 2 kg body weight
Doses:
•Dogs: 0.2mg/kg, PO, SC or IV , as a single dose
for one day, then 0.1 mg/kg, once daily
•Cats: 0.2-0.3 mg/kg, SC or PO, as asingle dose
for one day, then then 0.1 mg/kg, PO, 2 times
weekly

27. Piroxicam
•Oxicam derivatives with anti-inflammatory ,
analgesics and antipyretic activities
MOA:
•Reversible inhibition of cyclooxygenase enzyme
lowers PGs concentration in synovial fluid and
inhibits platelets aggregation
•Relatively high COX-2(IC 50 ) : COX-1(IC 50)
inhibition ratio
•Anti-inflammatory function: inhibition of
superoxxide formation, inhibition of activation of
neutrophils, inhibition of collagenase in catrilages.

28. Pharmacokinetics:
•Well absorbed after oral administration.
•Highly bound to plasma protiens.
•Largely metabolised in liver by hydroxylation
&glucuoronide conjugation.
•Excreted in urine and bile,also in milk in very low
concentration(about 1%).

29. Side effects:
•Serious GI toxicity in the form of
bleeding,peptic ulceration & perforation
•Renal papillary necrosis,peritonitis,CNS
effects,tinnitus,edema,pruritus and rash &
elavation in hepatic function tests.

30. Contraindicaton & precaution:
•Should not be used in patients having pre-existing
or history of GI ulcers or bleeding disorders.
•Should be used with extreme caution in patients
having congestive heart failure.
•Drugs interactions:
•Use of piroxicam in conjuction with aspirin or
other NSAIDs may increase the potential of adverse
effects.
•Because piroxicam is highly bound to plasma
protiens,it can displace or get displaced by other
highly protein bound drugs like warfaarin and
phenyl butazone.

31. Clinical use:
•In dogs,for reducing the pain &inflammation
associated with degenerative joint
disease(eg;osteoarthritis).
•Used in some anticancer protocols to treat or
suppress certain neoplasias expressing
cycloxygenase receptor such as transitional cell
carcinoma of bladder,squamous cell carcinoma
&mammary adenocarcinoma.
•To treat oral malignant melanoma and oral
squamous cell carcinoma in dogs.

32. Dose:
For analgesic/anti-inflammatory
effects(osteoarthritis)
Dogs:0.3 mg/kg, PO,on alternate days.
As an adjunctive therapy of transitional cell
carcinoma
Dogs &cats:0.3mg/kg, PO,once daily with food.