Based on the ﬁnding that aspirin at high doses (>3 g/day) not only inhibits fever and pain but also interferes with inﬂammation, Winter developed an assay to search for drugs with a similar proﬁle of antiinﬂammatory activity (Winter et al.
1962). Amazingly, all substances that survived the test of experimental pharma- cology and clinical trials turned out to be acids with a high degree of lipophilic-
hydrophilic polarity, similar pKa values and a high degree of plasma protein binding (for review see Brune and Lanz 1986; Hinz et al. 2000c). Suggestions for indications including treatment of rheumatoid diseases are listed in Table 1.
Apart from aspirin, all of these compounds differ in their potency, i.e., the single dose necessary to achieve a certain degree of effect ranges from a few milligrams (e.g., lornoxicam) to about 1 g (e.g., salicylic acid). They also differ
in their pharmacokinetic characteristics, i.e., the speed of absorption (time to peak, tmax ; which may also depend on the galenic formulation used), the maximal plasma concentrations (cmax), the elimination half-life (t1/2), and the oral bioavailability. Interestingly, all traditional NSAIDs lack a relevant degree of COX-2 selectivity (Patrignani et al. 1997). This is surprising since they have all been selected on the basis of high antiinﬂammatory potency and low gastrotoxicity that depends on COX-1 inhibition. The key characteristics of the most important NSAIDs are compiled in Table 2 (most data are from Brune and Lanz 1985). This table also contains the data of aspirin which differs in many respects from the other NSAIDs and is therefore discussed at the end of this chapter in detail (see Sect. 2.5). Otherwise, the drugs can be categorized in four different groups that are discussed in the following sections.
NSAIDs with Low Potency and Short Elimination Half-Life
The drugs of this group are particularly useful for blocking occasional mild inﬂammatory pain. The prototype of this type of compounds is ibuprofen. De- pending on its galenic formulation, fast or slow absorption of ibuprofen may be achieved. A fast absorption of ibuprofen was observed following adminis- tration of the respective lysine salt (Geisslinger et al. 1993). The bioavailability of ibuprofen is close to 100% and the elimination is always fast even in patients suffering from mild or severe impairment of liver or kidney function (Brune and Lanz 1985). Ibuprofen is used as single doses ranging from 200 mg to 1 g. A maximum dose of 3.2 g per day (United States) or 2.4 g (Europe) for rheuma- toid arthritis is possible. At low doses ibuprofen appears particularly useful for the treatment of acute occasional inﬂammatory pain. High doses of ibupro- fen may also be administered, although with less beneﬁt, for the treatment of chronic rheumatic diseases. Remarkably, at high doses the otherwise harmless compound has been shown to result in an increased incidence of gastrointesti- nal side effects (Silverstein et al. 2000). In some countries ibuprofen is also
a Dosage range of NSAIDs and example of monosubstances (but note dosage prescribed for each agent) b Indicated only in gout attacks c Compare the sequence staged scheme of WHO for cancer pain d Blood coagulation and renal function must be normal e If other analgesics and antipyretics are contraindicated, e.g. gastro-duodenal ulcer, blood coagulation disturbances, or asthma f In particular patients
a Time to reach maximum plasma concentration after oral administration b Terminal half-life of elimination c Single dose for inhibition of thrombocyte aggregation:
50–100 mg; single analgesic dose: 0.5–1 g d Enterohepatic circulation e Monolithic acid-resistant tablet or similar galenic form
administered as the pure S-enantiomer, which comprises the active entity of the racemic mixture in terms of COX inhibition. On the other hand,a substan- tial conversion of the less potent COX inhibitor R-ibuprofen (comprises 50% of the usual racemic mixture) into the active S-enantiomer has been observed fol- lowing administration of the racemic mixture (Rudy et al. 1991). Other drugs of this group are salicylates and mefenamic acid. The latter does not appear to offer major advantages. By contrast, this and other fenamates are rather toxic at overdosage (central nervous system).