Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 19 GASTROINTESTINAL DRUGS
circulation and conjugated with either taurine or glycine
and excreted into bile. Only very small amounts enter
the systemic circulation and minimal amounts are
detected in urine. It undergoes enterohepatic circulation;
at each cycle some of the free and conjugated drug
is degraded by gut bacteria, oxidized or reduced to less
soluble compounds and eliminated in the feces.
Adverse effects
● Ursodeoxycholic acid appears to be well tolerated by
dogs and cats; vomiting and diarrhea are reported
rarely.
● There is some concern in human patients that taurine
depletion may be potentiated by chronic treatment
with ursodeoxycholic acid. This may be important
in cats, who are obligate taurine conjugators. This
potential for taurine depletion may be exacerbated
in some cats with hepatobiliary disease, who have
increased urinary excretion of taurine-conjugated
bile acids. Dogs are less likely to become taurine
depleted by this mechanism as they can shift to
glycine conjugation.
● Ursodeoxycholic acid should not be used in patients
with extrahepatic biliary obstruction, biliary fistulas,
cholecystitis or pancreatitis.
Known drug interactions
Aluminum-containing antacids or colestyramine resin
may bind to ursodeoxycholic acid, thus reducing its
efficacy. Ursodeoxycholic acid dissolves more rapidly in
bile and pancreatic juice; therefore, administration with
food may improve absorption and is recommended.
Colchicine
Clinical applications
Colchicine is used in the management of gout in humans,
providing acute relief of symptoms as well as prophylaxis.
It has also been used for the treatment of fibrosing
liver diseases such as primary biliary cirrhosis, alcoholic
liver disease, cryptogenic liver fibrosis and liver cirrhosis.
However, two recent meta-analyses have demonstrated
limited efficacy of this drug, but more adverse
events. Thus, this drug is likely to fall from favor in
human hepatology. In veterinary medicine it has been
used in the management of amyloidosis and chronic
hepatic fibrosis. There is anecdotal evidence from a few
case studies that colchicine may improve liver function
and slow the progression of hepatic fibrosis. However,
controlled clinical trials are lacking and, given recent
findings in human studies, it should therefore be used
cautiously or avoided altogether.
Mechanism of action
Collagen secretion from lipocytes requires microtubules,
the assembly of which is inhibited by colchicine, thereby
interfering with the transcellular movement of collagen.
The drug increases collagenase activity and may therefore
promote degradation of existing collagen, although
collagen already cross-linked cannot usually be degraded.
It has anti-inflammatory effects by inhibiting leukocyte
migration, which may suppress fibrogenesis. It may also
have a direct hepatoprotective effect by stabilizing hepatocyte
membranes. Colchicine is also reported to block
synthesis of serum amyloid A by hepatocytes, thus
preventing amyloid formation. The mechanism of its
apparent efficacy in gout is poorly understood.
Formulations and dose rates
Various colchicine preparations are available in tablet form, usually in
either 0.5 mg or 0.6 mg sizes (dependent upon manufacturer). Injectable
formulations may be available, but most experience in veterinary
species is with oral dosing. Doses in dogs have been extrapolated
from the human literature. Its use in the cat has not been reported.
Colchicine is marketed in combination with probenecid in some
countries – this combination should be avoided as probenecid can
cause nausea, vomiting and lethargy.
DOGS
• 0.025–0.03 mg/kg/d
Pharmacokinetics
No information is available on the pharmacokinetics of
colchicine in dogs and cats. Data derived from humans
and laboratory animals indicate that the drug undergoes
first-pass metabolism after absorption from the gut, the
metabolites, as well as unchanged drug, being resecreted
into the gut in bile and then reabsorbed. Colchicine is
concentrated in leukocytes. Its plasma half-life is about
20 min; leukocyte half-life is 60 h.
Colchicine is deacetylated in the liver as well as being
metabolized in other tissues. Most of the dose is excreted
in the feces, with a small amount excreted in urine,
particularly in patients with hepatic disease.
Adverse effects
● Because of the limited veterinary experience with
colchicine, little is known about its potential toxicity
in dogs and cats.
● In humans, the therapeutic window for colchicine is
quite narrow, with toxic effects occurring after only
small overdoses.
● Nausea, vomiting and diarrhea have been reported
in dogs.
● Bone marrow suppression has occurred in humans
after prolonged use.
● Myopathy and peripheral neuropathy have been
reported rarely in humans.
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