Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ORAL HYPOGLYCEMIC AGENTS
urea moiety. All the sulfonylureas currently used in
small animals are from the so-called second-generation
groups which contain a second benzene ring linked
through the para position and a 6-carbon ring attached
to the urea moiety.
Mechanism of action
The primary effect of sulfonylureas is the direct stimulation
of insulin secretion from β-cells within pancreatic
islets. This occurs through direct binding to cell membrane
receptors, resulting in an increase in intracellular
calcium and resultant increased release of presynthesized
insulin granules. Extrapancreatic effects including
increased peripheral insulin sensitivity and modification
of hepatic gluconeogenesis and glycolysis have also been
postulated, although these effects are unlikely to be
clinically significant in the absence of any direct effect
on insulin secretion. Consequently, the benefits of
therapy with sulfonylureas are only likely in animals in
which actual or potential insulin-secreting capacity is
present.
Formulations and dose rates
CATS
• The recommended dose is 2.5–7.5 mg/cat/12 h of glipizide and
glibenclamide and 0.625–2 mg/cat/24 h of glyburide. It is
generally recommended to start at a lower dose and increase
it to achieve a satisfactory effect. Doses need to be adjusted
on the basis of changes in overall diabetic control which
are generally best assessed using weekly fructosamine
estimations
DOGS
• Although the sulfonylureas are far more commonly used in cats,
one experimental study demonstrated that single doses of both
glipizide at 180 µg/kg/12 h and glibenclamide at 90 µg/kg/12 h
were effective in lowering blood glucose and increasing insulin
concentrations in normal dogs
Adverse effects
Adverse effects of the sulfonylureas are relatively uncommon
although reports of the prevalence of side effects
have varied from none observed in 10 normal cats
receiving various doses through to 16% of 50 diabetic
cats showing adverse reactions. The signs included
anorexia, vomiting, icterus and elevated liver enzymes,
all of which were reversible with either reduction of
dose or cessation of medication.
In humans nausea, vomiting, cholestatic jaundice,
agranulocytosis, aplastic and hemolytic anemias and
dermatological reactions have all been reported. Also,
in around 5% of cases hyponatremia has been reported,
possibly as a result of potentiation of antidiuretic
hormone’s effects on the renal collecting tubule.
Known drug interactions
A number of drugs may displace glipizide or be displaced
by glipizide, thereby enhancing the pharmacological
effects of both drugs. Relevent drugs include:
chloramphenicol, nonsteroidal anti-inflammatory
agents, sulfonamides and warfarin. Glipizide potentiates
the effects of phenobarbital and glipizide’s actions
are enhanced by cimetidine.
Special considerations
Therapy with the sulfonylureas should only be continued
whilst the diabetes is controlled. The sulfonylurea
should be discontinued and insulin therapy initiated
if the clinical signs deteriorate, ketoacidosis develops
or marked hyperglycemia persists after 6–8 weeks of
treatment.
Biguanides
Currently the most commonly used drug in this class
is metformin (1,1-dimethylbiguanide) which has
replaced the older, more toxic phenformin
(phenethylbiguanide).
Pharmacokinetics
Limited information is available on the pharmacokinetics
of sulfonylureas in cats although studies in normal
cats suggested significantly increased insulin secretion
within 7.5 min of glipizide administration with the
hyperinsulinism persisting for up to 60 min.
In humans the half-lives of the second-generation sulfonylureas
are short, generally 1.5–5 h, although their
effects can last as long as 24 h. All the sulfonylureas are
metabolized by the liver and the metabolites are excreted
in the urine.
Mechanism of action
The mechanism of action of the biguanides remains
incompletely understood although there is general
agreement that it does not involve stimulation of insulin
secretion. Depending on the experimental protocol used
to explore its mechanism of action, it has been variably
credited with inhibiting gluconeogenesis, stimulating
peripheral glycolysis, utilizing the nonoxidative components
of the glycolytic pathways, inhibiting intestinal
carbohydrate absorption and producing an overall
reduction in plasma fatty acids and bodyweight.
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