Pharmacology Of Antipyretic Drugs 4h496e

ANTIPYRETIC Dr. Siti Syarifah, M.Biomed Dept. Pharmacology & Therapeutic Faculty of Medicine Universitas Sumatera Utara Medan, 2016

FEVER • Elevation of core temperature above the normal range • Normal range: 36,5-37,2 • A physiologic mechanism that has beneficial effects in fighting infection • Retards the growth and reproduction of • bacteria and viruses, • enhances neutrophil production and Tlymphocyte proliferation

A Physiologic Mechanism of Fever PG IL-6 TNF LTB4 LXA4 LXB4

IL-1

Thermoregulatory center in hypotalamus FEVER

FEVER REDUCTION • • • •

FEVER PHOBIA ??? Relief of patient discomfort Reduction of insensible water loss Decrease the occurrence of dehydration • Reduction in mortality • Prevention of Febrile seizure • Reduction of morbidity

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Greisman LA, Mackowiak PA. Fever: beneficial and detrimental effect of antipyretics..Current opinion in infectious disease.2002.15:241-245

DEFINITION of antipyretic ‘A drug that reduces fever by lowering the body temperature’. 8th Edition 2010, Oxford University Press, Oxford Concise Colour Medical Dictionary, Page 43

Some analgesic drugs have antipyretic activity.

The use of the bark from the Willow, utilized over centuries, for the relief of pain and inflammation was described in 1763 by Rev Edmond Stone

The evolution of NSAID chemistry for the control of pain Coxib

Salicylic Acid Class

Propionic Acid Class

Aspirin

Ibuprofen ketoprofen

1853

1970-

Oxicam Class

Acetic Acid Class

Piroxicam Meloxicam

Diclofenac Etodolac

1980-

1990-

Class Celecoxib Rofecoxib Valdecoxib Etoricoxib Parecoxib Lumiracoxib

2000-

phospholipids arachidonic acid COX-2

COX

COX-1

cyclic endoperoxides PGI2

stimulates platelet aggregation, vasoconstriction

hyperalgesia PGD2 inhibits platelet aggregation, vasodilator

5-HPETE TXA2

inhibits platelet aggregation, vasodilator,

PGE2 vasodilator,

hyperalgesia

LOX

PGF2alfa bronchoconstriction myometrial contr.

LTA4 LTB4 chemotaxis

LTC4 LTD4

hyperalgesia LTE4

brochoconstriction increase vascular permeability

ANALGETIC ANTIPYRETIC • Acetaminophen (paracetamol): toothaches and headaches • Acethylsalicilyc acid (ASA): antiinflammatory effect (+) • Ibuprofen • Pyrazolone derivates (aminopyrine and dypirone): metamizole displays the highest efficacy

ASPIRIN • Irreversible manner by acetylating the active site serine residue in both COX-1 and COX-2 • Prevents the formation of COX-1 derived prostaglandins, thromboxanes and prostacycline • Toxicities -Aspirin-induced airway hypereactivity in asthmatic -Reye’s syndrome

ASPIRIN • Action: antiplatelet, antirheumatic, antipyretic. • Dosage: 300 – 500 mg 4-6 hours. Max. 4 g daily • Aspirin-induced airway hyperreactivity in asthmatics: increased levels of leukotriene • Reye’s syndrome !! - A condition characterized by hepatic encephalopathy and liver steatosis in young children - NOT ISTERED TO CHILDREN!!

ACETAMINOPHEN CO2H O

O

H N O

CO2H

CO2H

O

HO

acetylsalicylic acid

acetaminophen

ibuprophen

ketoprophen

aspirin

Tylenol

Motrin, Nuprin

Orudis Cl

CO2H MeO

CO2 H N Cl

naproxen

diclofenac

Naprosyn, Alleve

Cataflam, Voltaren O Cl

O N

N CO2H

MeO CO2H

ketorolac

indomethacin

Toradol

Indocin

ACETAMINOPHEN • • • •

Technically not NSAID Aminophenol class Analgesic antipyretic (+) similar to aspirin Weak anti-inflammatory due to weak inhibition of COX-2 • Effective doses : 10 to 15 mg/kg per dose given every 4 to 6 hours orally

HEPATOTOXICITY!! Due to modification of acetaminophen by hepatic cytchrome P450 enzymes produces a reactive molecule

IBUPROFEN • Proprionic acid class • Non selective COX-1 and COX-2 inhibitor • Most commonly used and prescribed NSAID • Effective dose: 10 mg/kg BW every 6 hours • Major adverse reactions: -The affect on GIT, Renal and coagulation system

IBUPROFEN • -

Ibuprofen-related renal toxicities Dehydration Cardiovascular disease Pre-existing renal disease Infants younger than 6 years old Combination therapy may place infants and children at increased risk because of dosing errors and adverse outcomes

Summary of analgesic, anti-inflammatory and antipyretic activity of NSAIDs (ED50 in mg/kg) ketorolac

indomethacin

diclofenac

ketorolac

indomethacin

diclofenac

ketorolac

indomethacin

diclofenac

naproxen

ibuprofen

piroxicam

naproxen

ibuprofen

piroxicam

naproxen

ibuprofen

piroxicam

120

60

100

50

80

40

60

30

40

20

20

10

8 7 6 5 4 3 2

0

1 0

0 analgesic

antipyretic

anti-inflammatory

NSAID

Analgesic

Anti-inflammatory

Antipyretic

ketorolac

0.7

2

0.9

indomethacin

3

4

2.1

diclofenac

8

7

0.4

naproxen

13

56

0.5

ibuprofen

45

10

7

piroxicam

100

3

1.7

tenoxicam

100

5

1.7

aspirin

228

162

18