Page 674 - Basic _ Clinical Pharmacology ( PDFDrive )

660 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

uricase converts uric acid to the more soluble allantoin; this COLCHICINE
enzyme is absent in humans. While clinical gouty episodes are
associated with hyperuricemia, most individuals with hyper- Although NSAIDs, corticosteroids, or colchicine are now first-line
uricemia may never develop a clinical event from urate crystal drugs for acute gout, colchicine was the primary treatment for many
deposition. years. Colchicine is an alkaloid isolated from the autumn crocus,
The treatment of gout aims to relieve acute gouty attacks Colchicum autumnale. Its structure is shown in Figure 36–6.
and prevent recurrent gouty episodes and urate lithiasis. 1. Pharmacokinetics: Colchicine is absorbed readily after oral
Therapies for acute gout are based on our current understand- administration, reaches peak plasma levels within 2 hours, and
ing of the pathophysiologic events that occur in this disease is eliminated with a serum half-life of 9 hours. Metabolites are
(Figure 36–5). Clinical gout is dependent on a macromolecular excreted in the intestinal tract and urine.
complex of proteins, called NLRP3, which regulates the activa-
tion of IL-1. Urate crystals activate NLRP3, resulting in release 2. Pharmacodynamics: Colchicine relieves the pain and inflam-
of prostaglandins and lysosomal enzymes by synoviocytes. mation of gouty arthritis in 12–24 hours without altering the
Attracted by these chemotactic mediators, polymorphonuclear metabolism or excretion of urates and without other analgesic
leukocytes migrate into the joint space and amplify the ongo- effects. Colchicine produces its anti-inflammatory effects by
ing inflammatory process. In the later phases of the attack, binding to the intracellular protein tubulin, thereby preventing
increased numbers of mononuclear phagocytes (macrophages) its polymerization into microtubules and leading to the inhibi-
appear, ingest the urate crystals, and release more inflammatory tion of leukocyte migration and phagocytosis. It also inhibits
mediators. the formation of leukotriene B and IL-1β. Several of colchi-
4
Before starting chronic urate-lowering therapy for gout, cine’s adverse effects are produced by its inhibition of tubulin
patients in whom hyperuricemia is associated with gout and polymerization and cell mitosis.
urate lithiasis must be clearly distinguished from individuals with 3. Indications: Colchicine is indicated for gout and is also
only hyperuricemia. The efficacy of long-term drug treatment in used between attacks (the “intercritical period”) for prolonged
an asymptomatic hyperuricemic person is unproved. Although
there are data suggesting a clear relationship between the degree
of uric acid elevation and the likelihood of clinical gout, in some H O
3
individuals, uric acid levels may be elevated up to 2 standard H C O
deviations above the mean for a lifetime without adverse conse- N C CH 3
quences. Many different agents have been used for the treatment H C O
3
of acute and chronic gout. However, non-adherence to these O
drugs is exceedingly common; adherence has been documented
to be 18–26% in younger patients. Providers should be aware of CH 3
compliance as an important issue. O
O
CH 3
Colchicine
Synoviocytes
Colchicine
Urate – H C CH 2 CH 2 O O
3
crystal LTB 4
N S C OH
PMN H C CH
PG 3 2 CH 2 O
PG
Enzymes IL-1 PG Probenecid
MNP –
MNP
MNP
–
IL-1 Indomethacin,
phenylbutazone
N
O
N
FIGURE 36–5 Pathophysiologic events in a gouty joint. Syn- O
oviocytes phagocytose urate crystals and then secrete inflammatory S CH 2 CH 2 O
mediators, which attract and activate polymorphonuclear leukocytes
(PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs
active in gout inhibit crystal phagocytosis and polymorphonuclear Sulfinpyrazone
leukocyte and macrophage release of inflammatory mediators. PG,
prostaglandin; IL-1, interleukin-1; LTB 4 , leukotriene B 4 . FIGURE 36–6 Colchicine and uricosuric drugs.