At relatively high dosage (>4 g/d), ASA (p. 198) 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 non-steroidal 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, na-proxene, indomethacin [p. 320]) or enolic acids (e.g., azapropazone, piroxi-cam, 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 cy-clooxygenase 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 (p. 248) 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 (p. 38), mainly with glycine (^ salicyluric acid) and glucuronic acid. At high dosage, the conjugation may be come rate limiting. Elimination now increasingly depends on unchanged sa-licylate, which is excreted only slowly.
Group-specific adverse effects can be attributed to inhibition of cyclooxy-genase (B). 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. Gas-tropathy may be prevented by co-administration of the PG derivative, mis-oprostol (p. 168). In the intestinal tract, inhibition of PG synthesis would similarly be expected to lead to damage of the blood mucosa barrier and enteropa-thy. 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 hypovole-mia), 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 (pi-roxicam: photosensitization), or the blood (phenylbutazone: agranulocyto-sis).
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, Ro-fecoxib) is intensifying because, in theory, these ought to be tolerated better.
A. Nonsteroidal antiinflammatory drugs (NSAIDs)
A. Nonsteroidal antiinflammatory drugs (NSAIDs)
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 thermoregu-latory 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 homeo-static control of body temperature (A). 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
Thyroid hyperfunction poses a particular challenge to the thermoregu-
latory 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 (p. 236), 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 (hyperpy-rexia) 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 thermoregu-latory center (B1), 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 (p. 196) and interleukin-1—the set point of the hypothalamic temperature controller (B2). 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 ASA (p. 198) return the set point to its normal level (B2) and thus bring about a defervescence.
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