145 (nsaids) – clinical effect and indication

N

Classification of NSAIDs according to chemical structure

Acid NSAIDs:Derivates of enol acids:•

pyrazolones – azapropazone, oxyphenyl- –butazone, phenylbutazone, sulfinpyrazone.oxicams –isoxicam, lornoxicam, meloxi- –cam, piroxicam, tenoxicam,

Derivates of carboxyl acids:• salicylic acid – acetylsalicyclic acid (As- –pirin®), aloxiprin, diflunisal, lysinsalicy-late, salsalate.acetoacetic acid – aceclofenac, acemeta- –cin, diclofenac, etodolac, indomethacin, sulindac, tolmetin.anthranilic acid –mefenamic acid, niflu- –mic acid.propionic acid – fenbufen, fenoprofen, –flurbiprofen, ibuprofen, ketoprofen, naproxen, pirprofen, tiaprofenic acid.

Neutral NSAIDs:alkanone – nabumetone.• coxibs – celecoxib, etoricoxib, lumiracoxib, • parecoxib.

Non-steroidal anti-inflammatory drugs (NSAIDs) – clinical effect and indica-tion They are subject to common properties and these properties are very similar among different NSAIDs. After NSAID administra-tion, relief of pain, stiffness and other symp-toms occurs. Individual variations in the ef-fectiveness of a particular NSAID can be ex-plained by the pharmacokinetics of the drug

at the cellular level. Various factors such as physical and chemical properties of the drug, pharmacokinetic parameters, the ability to inhibit a particular isoform of cyclooxyge-nase, selection of the form of application and the variability of the treated disease or symp-tom, all affect the variability of NSAID effec-tiveness (see table 6).

In clinical practice, the selection of a NSAID is subject to basic pharmacokinetic properties. Absorption of the majority of NSAIDs is rapid after oral administration (0.5 to 1.5 hours) unless it is an enteric-coat-ed or slow release form of the drug. The time of clinical effectiveness is usually determined by the plasma elimination half-life. Particular NSAID groups have different plasma elimi-nation half-life (table 7).

Table 6. Variability of NSAID effectiveness

Physical and chemical properties

Lipid solubility

Pharmacokinetics plasma half-life Pharmacodynamics selectivity of COX-2

inhibitionDose selection and application period

chronopharmacology

Variability of disease elimination organ disorders

Adverse effects, pharmacogenetic differences

idiosyncrasy

Table 7. Classification of NSAIDs based on plasma elimination half-life (Pavelka and Štolfa 2005)

Plasma elimination half-life of NSAIDs

short (to medium-long) < 6 h long > 10 h

aspirin 0.25tolmetin 1.0diclofenac 1.1flufenamic acid 1.4ketoprofen 1.8ibuprofen 2.1fenprofen 2.5etodolac 3.0tiaprofenic acid 3.0flurbiprofen 3.8indomethacin 4.6

fenbufen 10diflunisal 13naproxen 14sulindac 14azapropazone 15nabumetone 26piroxicam 57tenoxicam 60phenylbutazone 68

145 non-steroidal anti-inflammatory drugs (NSAIDs) – clinical effect and indication

non-steroidal anti-inflammatory drugs (nsaids) – common properties 146

N

NSAID groups have a broad range of indi-cations, due to their anti-inflammatory, anal-gesic, anti-aggregation and antipyretic effects.

Indications of NSAID treatment:arthritic diseases including inflammatory • rheumatic diseases, systemic connective tis-sues diseases, reactive arthritis, irritative synovitis, metabolic arthropathy (gout, chondrocalcinosis), osteoarthrosis, trau-matic synovitis, tenosynovitis, bursitis in extra-articular rheumatism, and acute lum-bosacral disease.acute and chronic nociceptive (somatic • and/or visceral) pain and malignancy as-sociated pain.prevention of ectopic calcification devel-• opment after total hip joint replacement.acute pain conditions, renal and biliary • colic, migraine, toothache (pulpitis), post-operative pain, trauma pain;dysmenorrhoea, premature labour rever-• sal;fever;• cardiovascular indications;• other: Bartter syndrome, juvenile idiopathic • arthritis, closure of patent ductus arteriosus.

Non-steroidal anti-inflammatory drugs (NSAIDs) – common properties

anti-inflammatory effect, • analgesic effect,• antipyretic effect,• acid character,*• fat soluble,• strong binding to plasma proteins,• inhibition of prostaglandin synthesis in • macrophages and fibroblasts,inhibition of thromboxane synthesis in • thrombocytes, *inhibition of prostacyclin synthesis in en-• dothelial cells, *induction of apoptosis.•

* selective COX-2 inhibitors and coxibs do not have significant effects

Non-steroidal anti-inflammatory drugs (NSAIDs) – mechanisms of action The NSAID group includes approximately 200 ac-tive substances originating from about 20 chemically different groups. Their common property is the blockade of the cyclooxyge-nase enzyme (COX) in a metabolic cascade of arachidonic acid (figure 2) through unstable

146 non-steroidal anti-inflammatory drugs (NSAIDs) – common properties

Figure 2. Metabolic pathways of arachidonic acid HPETE – hydroperoxyeicosatetraenoic acid HETE – hydroxyeicosatetraenoic acidHPETE and HETE are abbreviations in the table.