Fever; definition, pathophysiology, etiology, management with acetaminophen and it's mechanism of action, toxicity and management.

1. FEVER and
ACETAMINOPHEN
Dr Joyce Mwatonoka
MMED Pediatrics and Child Health
1st year

3. Cont…
• The temperature of the deep tissues of the
body the “core” of the body remains very
constant, within ±0.6°C, except when a person
develops a febrile illness
• The skin temperature, in contrast to the core
temperature, rises and falls with the
temperature of the surroundings
Guyton, Text Book of Medical Physiology, 11th ed

4. Heat Production
Principally by-product of metabolism
1) Basal rate of metabolism of all the cells of the
body;
2) Extra rate of metabolism caused by muscle
activity including shivering
3) Extra metabolism caused by the effect of
thyroxine (to a less extent, other hormones,
eg; GH and testosterone) on the cells

5. Cont…
4) Extra metabolism caused by the effect of
epinephrine, norepinephrine, and sympathetic
stimulation on the cells;
5) Extra metabolism caused by increased chemical
activity in the cells themselves, especially when
the cell temperature increases; and
6) Extra metabolism needed for digestion,
absorption, and storage of food (thermogenic
effect of food)

6. Hypothalamic Temperature Control
Centre
• The anterior hypothalamus; heat losing
centre
Skin vasodilation
Sympathetic cholinergic activation of sweat
glands
Lower metabolic rate

7. Cont…
• The posterior hypothalamus; heat gaining
centre
 Vasoconstriction in all skin areas
 Contraction of erector pilli muscles → entrap
layer of air for insulation
 Increase metabolic rate via SNS activation,
thyroid hormones
 Shivering

8. nerves
More heat
generated
Less water covers the
skin.
Less evaporation
Skin arteries
constrict
Less blood to the
skin.
Less radiation &
conduction of heat
Muscles of
skin arteriole
walls
constrict
Sweat
glands
decrease
secretion
Muscles
shivering
nerves
Core body
temperature
<37°C
Thermoreceptors
Hypothalamus
© 2008 Paul Billiet ODWS

10. FEVER
• Fever generally means a body temperature
above the usual range of normal
• It can be caused by abnormalities in the brain
itself or by toxic substances (pyrogens) that
affect the temperature-regulating centers
• Pyrogens are substances that can cause the
set-point of the hypothalamic thermostat to
rise

11. Cont…
• Pyrogens released from toxic bacteria or those
released from degenerating body tissues
cause fever during disease conditions
• When the set-point of the hypothalamic
temperature-regulating center becomes
higher than normal, all the mechanisms for
raising the body temperature are brought into
play, including heat conservation and
increased heat production

12. American academy of Pediatrics

16. Acetaminophen/Paracetamol
• It is a medication used to treat pain and fever
• It is typically used for mild to moderate pain
relief
• It is the drug of choice in patients that cannot
be treated with NSAIDs, such as people with
bronchial asthma, peptic ulcer disease,
hemophilia, salicylate-sensitized people,
children under 12 years of age, pregnant or
breastfeeding women

17. MOA
• It has analgesic and antipyretic properties
similarly to NSAIDs, but it does not possess
any anti-inflammatory activity
• In recommended doses, it does not induce
typical for NSAIDs GI side effects
• However, it suppresses PG production likewise
NSAIDs
Bebenista et al Paracetamol: mechanism of action, applications and safety concern. 2014 Jan-Feb;71(1):11-23

18. Cont…
• MOA generally considered to be a weak
inhibitor of PGs synthesis
• However, the in vivo effects of paracetamol
are similar to those of the selective COX-2
inhibitors
• But, unlike the selective COX-2 does not
suppress the inflammation of rheumatoid
arthritis
Acetaminophen Mechanism of Action October 5, 2018 Generic Fioricet

19. Cont…
• COX-3, a splice variant of COX-1, has been
suggested to be the site of action of paracetamol,
but genomic and kinetic analysis indicates that
this selective interaction is unlikely to be clinically
relevant
• There is considerable evidence that the analgesic
effect of paracetamol is central and is due to
activation of descending serotonergic pathways,
but its primary site of action may still be
inhibition of PG synthesis

20. Acetaminophen Toxicity
• It has an excellent safety profile when
administered in proper therapeutic doses, but
hepatotoxicity can occur after overdose or
when misused in at-risk populations
• Minimum toxic doses for a single ingestion
with significant risk of severe hepatotoxicity:
• Adults: 7.5-10 g
• Children: 150 mg/kg; 200 mg/kg in healthy
children aged 1-6 years

21. Cont…
• Initially be asymptomatic, as clinical symptoms
of end-organ toxicity do not manifest until 24-
48 hours after an acute ingestion
• Anorexia, nausea or vomiting, malaise
• 18-72 h; RUQ abdominal pain/tenderness,
tachycardia and hypotension may indicate
volume losses, oliguria

22. Cont…
• 72-96 h; continued nausea and vomiting,
abdominal pain, hepatic necrosis and
dysfunction manifesting as jaundice,
coagulopathy, hypoglycemia, and hepatic
encephalopathy, ARF, death from multiorgan
failure may occur
• Recovery 4 days to 3 wks after ingestion

23. Rumack-Matthew nomogram

24. Management of Acetaminophen
toxicity
• Activated charcoal; if the patient has a stable
mental and clinical status, patent airway, and
presents to the emergency department within
1 hour of ingestion
• If above the "possible" line on the Rumack-
Matthew nomogram treat with N-
acetylcysteine (NAC)