Antipyretic Analgesics

Eicosanoids
Origin and metabolism. The eicosanoids,
prostaglandins, thromboxane,
prostacyclin, and leukotrienes, are
formed in the organism from arachidonic
acid, a C20 fatty acid with four
double bonds (eicosatetraenoic acid).
Arachidonic acid is a regular constituent
of cell membrane phospholipids; it is
released by phospholipase A2 and forms
the substrate of cyclooxygenases and
lipoxygenases.
Synthesis of prostaglandins (PG),
prostacyclin, and thromboxane proceeds
via intermediary cyclic endoperoxides.
In the case of PG, a cyclopentane
ring forms in the acyl chain. The letters
following PG (D, E, F, G, H, or I) indicate
differences in substitution with hydroxyl
or keto groups; the number subscripts
refer to the number of double
bonds, and the Greek letter designates
the position of the hydroxyl group at C9
(the substance shown is PGF2!). PG are
primarily inactivated by the enzyme 15-
hydroxyprostaglandindehydrogenase.
Inactivation in plasma is very rapid;
during one passage through the lung,
90% of PG circulating in plasma are degraded.
PG are local mediators that attain
biologically effective concentrations
only at their site of formation.
Biological effects. The individual
PG (PGE, PGF, PGI = prostacyclin) possess
different biological effects.
Nociceptors. PG increase sensitivity
of sensory nerve fibers towards ordinary
pain stimuli (p. 194), i.e., at a given
stimulus strength there is an increased
rate of evoked action potentials.
Thermoregulation. PG raise the set
point of hypothalamic (preoptic) thermoregulatory
neurons; body temperature
increases (fever).
Vascular smooth muscle. PGE2
and PGI2 produce arteriolar vasodilation;
PGF2, venoconstriction.
Gastric secretion. PG promote the
production of gastric mucus and reduce
the formation of gastric acid .
Menstruation. PGF2! is believed to
be responsible for the ischemic necrosis

of the endometrium preceding menstruation.
The relative proportions of individual
PG are said to be altered in dysmenorrhea
and excessive menstrual
bleeding.
Uterine muscle. PG stimulate labor
contractions.
Bronchial muscle. PGE2 and PGI2
induce bronchodilation; PGF2! causes
constriction.
Renal blood flow. When renal
blood flow is lowered, vasodilating PG
are released that act to restore blood
flow.
Thromboxane A2 and prostacyclin
play a role in regulating the aggregability
of platelets and vascular diameter.

Leukotrienes increase capillary
permeability and serve as chemotactic
factors for neutrophil granulocytes. As
“slow-reacting substances of anaphylaxis,”
they are involved in allergic reactions
; together with PG, they
evoke the spectrum of characteristic inflammatory
symptoms: redness, heat,
swelling, and pain.
Therapeutic applications. PG derivatives
are used to induce labor or to
interrupt gestation; in the therapy
of peptic ulcer, and in peripheral
arterial disease.
PG are poorly tolerated if given
systemically; in that case their effects
cannot be confined to the intended site
of action.

Nonsteroidal Antiinflammatory
(Antirheumatic) Agents
At relatively high dosage (> 4 g/d), ASA
may exert antiinflammatory effects
in rheumatic diseases (e.g., rheumatoid
arthritis). In this dose range,
central nervous signs of overdosage
may occur, such as tinnitus, vertigo,
drowsiness, etc. The search for better
tolerated drugs led to the family of nonsteroidal
antiinflammatory drugs
(NSAIDs). Today, more than 30 substances
are available, all of them sharing
the organic acid nature of ASA. Structurally,
they can be grouped into carbonic
acids (e.g., diclofenac, ibuprofen, naproxene,
indomethacin) or
enolic acids (e.g., azapropazone, piroxicam,
as well as the long-known but
poorly tolerated phenylbutazone). Like
ASA, these substances have analgesic,
antipyretic, and antiinflammatory activity.
In contrast to ASA, they inhibit cyclooxygenase
in a reversible manner.
Moreover, they are not suitable as inhibitors
of platelet aggregation. Since
their desired effects are similar, the
choice between NSAIDs is dictated by
their pharmacokinetic behavior and
their adverse effects.
Salicylates additionally inhibit the
transcription factor NFKB, hence the expression
of proinflammatory proteins.
This effect is shared with glucocorticoids
and ibuprofen, but not
with some other NSAIDs.
Pharmacokinetics. NSAIDs are
well absorbed enterally. They are highly
bound to plasma proteins (A). They are
eliminated at different speeds: diclofenac
(t1/2 = 1–2 h) and piroxicam (t1/2 ~ 50
h); thus, dosing intervals and risk of accumulation
will vary. The elimination of
salicylate, the rapidly formed metabolite
of ASA, is notable for its dose dependence.
Salicylate is effectively reabsorbed
in the kidney, except at high urinary
pH. A prerequisite for rapid renal
elimination is a hepatic conjugation reaction
, mainly with glycine (salicyluric acid)
and glucuronic acid. At
high dosage, the conjugation may become
rate limiting. Elimination now increasingly
depends on unchanged salicylate,
which is excreted only slowly.
Group-specific adverse effects can
be attributed to inhibition of cyclooxygenase.
The most frequent problem,
gastric mucosal injury with risk of peptic
ulceration, results from reduced synthesis
of protective prostaglandins (PG),
apart from a direct irritant effect. Gastropathy
may be prevented by co-administration
of the PG derivative, misoprostol.
In the intestinal tract,
inhibition of PG synthesis would similarly
be expected to lead to damage of
the blood mucosa barrier and enteropathy.
In predisposed patients, asthma attacks
may occur, probably because of a
lack of bronchodilating PG and increased
production of leukotrienes. Because
this response is not immune mediated,
such “pseudoallergic” reactions
are a potential hazard with all NSAIDs.
PG also regulate renal blood flow as
functional antagonists of angiotensin II
and norepinephrine. If release of the latter
two is increased (e.g., in hypovolemia),
inhibition of PG production may
result in reduced renal blood flow and renal
impairment. Other unwanted effects
are edema and a rise in blood pressure.
Moreover, drug-specific side effects
deserve attention. These concern the
CNS (e.g., indomethacin: drowsiness,
headache, disorientation), the skin (piroxicam:
photosensitization), or the
blood (phenylbutazone: agranulocytosis).
Outlook: Cyclooxygenase (COX)
has two isozymes: COX-1, a constitutive
form present in stomach and kidney;
and COX-2, which is induced in inflammatory
cells in response to appropriate
stimuli. Presently available NSAIDs inhibit
both isozymes. The search for
COX-2-selective agents (Celecoxib, Rofecoxib)
is intensifying because, in theory,
these ought to be tolerated better.

Thermoregulation and Antipyretics
Body core temperature in the human is
about 37 °C and fluctuates within ± 1 °C
during the 24 h cycle. In the resting
state, the metabolic activity of vital organs
contributes 60% (liver 25%, brain
20%, heart 8%, kidneys 7%) to total heat
production. The absolute contribution
to heat production from these organs
changes little during physical activity,
whereas muscle work, which contributes
approx. 25% at rest, can generate
up to 90% of heat production during
strenuous exercise. The set point of the
body temperature is programmed in the
hypothalamic thermoregulatory center.
The actual value is adjusted to the set
point by means of various thermoregulatory
mechanisms. Blood vessels supplying
the skin penetrate the heat-insulating
layer of subcutaneous adipose tissue
and therefore permit controlled
heat exchange with the environment as
a function of vascular caliber and rate of
blood flow. Cutaneous blood flow can
range from ~ 0 to 30% of cardiac output,
depending on requirements. Heat conduction
via the blood from interior sites
of production to the body surface provides
a controllable mechanism for heat
loss.
Heat dissipation can also be
achieved by increased production of
sweat, because evaporation of sweat on
the skin surface consumes heat (evaporative
heat loss). Shivering is a mechanism
to generate heat. Autonomic neural
regulation of cutaneous blood flow
and sweat production permit homeostatic
control of body temperature.
The sympathetic system can either reduce
heat loss via vasoconstriction or
promote it by enhancing sweat production.
When sweating is inhibited due to
poisoning with anticholinergics (e.g.,
atropine), cutaneous blood flow increases.
If insufficient heat is dissipated
through this route, overheating occurs
(hyperthermia).
Thyroid hyperfunction poses a
particular challenge to the thermoregulatory
system, because the excessive secretion
of thyroid hormones causes
metabolic heat production to increase.
In order to maintain body temperature
at its physiological level, excess heat
must be dissipated—the patients have a
hot skin and are sweating.
The hypothalamic temperature
controller (B1) can be inactivated by
neuroleptics, without impairment
of other centers. Thus, it is possible
to lower a patient’s body temperature
without activating counter-regulatory
mechanisms (thermogenic shivering).
This can be exploited in the treatment
of severe febrile states (hyperpyrexia)
or in open-chest surgery with
cardiac by-pass, during which blood
temperature is lowered to 10 °C by
means of a heart-lung machine.
In higher doses, ethanol and barbiturates
also depress the thermoregulatory
center, thereby permitting
cooling of the body to the point of death,
given a sufficiently low ambient temperature
(freezing to death in drunkenness).
Pyrogens (e.g., bacterial matter) elevate—
probably through mediation by
prostaglandins and interleukin-
1—the set point of the hypothalamic
temperature controller. The body
responds by restricting heat loss (cutaneous
vasoconstriction ! chills) and by
elevating heat production (shivering), in
order to adjust to the new set point (fever).
Antipyretics such as acetaminophen
and ASAreturn the set
point to its normal level (B2) and thus
bring about a defervescence.