Antipyretic Analgesics and Antiinflammatory Drugs

Antipyretic Analgesics
Acetaminophen, the amphiphilic acids
acetylsalicylic acid (ASA), ibuprofen,
and others, as well as some pyrazolone
derivatives, such as aminopyrine and
dipyrone, are grouped under the label
antipyretic analgesics to distinguish
them from opioid analgesics, because
they share the ability to reduce fever.
Acetaminophen (paracetamol) has
good analgesic efficacy in toothaches
and headaches, but is of little use in inflammatory
and visceral pain. Its mechanism
of action remains unclear. It can
be administered orally or in the form of
rectal suppositories (single dose,
0.5–1.0 g). The effect develops after
about 30 min and lasts for approx. 3 h.
Acetaminophen undergoes conjugation
to glucuronic acid or sulfate at the phenolic
hydroxyl group, with subsequent
renal elimination of the conjugate. At
therapeutic dosage, a small fraction is
oxidized to the highly reactive N-acetylp-
benzoquinonimine, which is detoxified
by coupling to glutathione. After ingestion
of high doses (approx. 10 g), the
glutathione reserves of the liver are depleted
and the quinonimine reacts with
constituents of liver cells. As a result,
the cells are destroyed: liver necrosis.
Liver damage can be avoided if the thiol
group donor, N-acetylcysteine, is given
intravenously within 6–8 h after ingestion
of an excessive dose of acetaminophen.
Whether chronic regular intake of
acetaminophen leads to impaired renal
function remains a matter of debate.
Acetylsalicylic acid (ASA) exerts an
antiinflammatory effect, in addition to
its analgesic and antipyretic actions.
These can be attributed to inhibition of
cyclooxygenase. ASA can be given
in tablet form, as effervescent powder,
or injected systemically as lysinate
(analgesic or antipyretic single dose,
O.5–1.0 g). ASA undergoes rapid ester
hydrolysis, first in the gut and subsequently
in the blood. The effect outlasts
the presence of ASA in plasma (t1/2 ~
20 min), because cyclooxygenases are
irreversibly inhibited due to covalent
binding of the acetyl residue. Hence, the
duration of the effect depends on the
rate of enzyme resynthesis. Furthermore,
salicylate may contribute to the
effect. ASA irritates the gastric mucosa
(direct acid effect and inhibition of cytoprotective
PG synthesis) and
can precipitate bronchoconstriction
(“aspirin asthma,” pseudoallergy) due
to inhibition of PGE2 synthesis and overproduction
of leukotrienes. Because ASA
inhibits platelet aggregation and prolongs
bleeding time, it should
not be used in patients with impaired
blood coagulability. Caution is also
needed in children and juveniles because
of Reye’s syndrome. The latter has
been observed in association with febrile
viral infections and ingestion of
ASA; its prognosis is poor (liver and
brain damage). Administration of ASA at
the end of pregnancy may result in prolonged
labor, bleeding tendency in
mother and infant, and premature closure
of the ductus arteriosus. Acidic
nonsteroidal antiinflammatory drugs
(NSAIDS) are derived from ASA.
Among antipyretic analgesics, dipyrone
(metamizole) displays the highest
efficacy. It is also effective in visceral
pain. Its mode of action is unclear, but
probably differs from that of acetaminophen
and ASA. It is rapidly absorbed
when given via the oral or rectal route.
Because of its water solubility, it is also
available for injection. Its active metabolite,
4-aminophenazone, is eliminated
from plasma with a t1/2 of approx. 5 h.
Dipyrone is associated with a low incidence
of fatal agranulocytosis. In sensitized
subjects, cardiovascular collapse
can occur, especially after intravenous
injection. Therefore, the drug should be
restricted to the management of pain
refractory to other analgesics. Propyphenazone
presumably acts like metamizole
both pharmacologically and toxicologically.