Anti Pyretic Drugs

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 Paracetamol (acetaminophen) Aspirin Sodium salicylate Salicylic acid Piroxicam Meloxicam Indomethacin Naproxen Ketoprophen 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.

17. 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

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

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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

25. 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 .

26. 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%).

27. 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.

28. 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 .

29. 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.

30. 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.