588
P A R T 6
Drugs acting on the endocrine system
insulin binding to insulin receptors and may actually
increase the number of insulin receptors. They are indic
ated as an adjunct to diet and exercise to lower blood
glucose levels in type 2 diabetes mellitus. They have the
off-label use of being an adjunct to insulin to improve
glucose control in type 2 diabetics.
Pharmacokinetics
These drugs are rapidly absorbed from the GI tract and
undergo hepatic metabolism. They are excreted in the
urine. The peak effects and duration of effects differ
because of the activity of various metabolites of the dif-
ferent drugs.
Contraindications and cautions
Sulfonylureas are contraindicated in the presence of
known allergy to any sulfonylureas
to avoid hypersensitiv-
ity reactions
and in diabetes complicated by fever, severe
infection, severe trauma, major surgery, ketoacidosis,
severe renal or hepatic disease, pregnancy or breastfeed-
ing,
which require tighter control of glucose levels using
insulin.
These drugs are also contraindicated for use in
type 1 diabetes mellitus,
who do not have functioning
beta cells and would have no benefit from the drug
.
These drugs are not for use during pregnancy.
Insulin should be used if a hypoglycaemic agent is
needed during pregnancy. Some of these drugs cross into
breast milk, and adequate studies are not available on
others.
Because of the risk of hypoglycaemic effects in
the baby
, these drugs should not be used during breast-
feeding. Another method of feeding the baby should be
used. The safety and efficacy of these drugs for use in
children have not been established.
Adverse effects
The most common adverse effects related to the sulfo-
nylureas are hypoglycaemia (caused by an imbalance
in levels of glucose and insulin) and GI distress, includ-
ing nausea, vomiting, epigastric discomfort, heartburn
and anorexia. (Anorexia should be monitored because
affected individuals may not eat after taking the sulfony-
lurea, which could lead to hypoglycaemia.) Allergic skin
reactions have been reported with some of these drugs
and, as mentioned earlier, there may be an increased
risk of cardiovascular mortality, particularly with the
first-generation agents.
Clinically important drug–drug interactions
Care should be taken with any drug that acidifies the
urine because excretion of the sulfonylurea may be
decreased. Caution should also be used with beta-
blockers, which may mask the signs of hypoglycaemia,
and with alcohol, which can lead to altered glucose
levels when combined with sulfonylureas. Caution must
also be used with many herbal therapies that could alter
blood glucose levels.
Prototype summary: Glibenclamide
Indications:
Adjunct to diet and exercise in the
management of type 2 diabetes; with metformin or
insulin for stabilisation of diabetic people.
Actions:
Stimulates insulin release from functioning
beta cells in the pancreas; may improve insulin
binding to insulin receptor sites or increase the
number of insulin receptor sites.
Pharmacokinetics:
Route
Onset
Duration
Oral
1 hour
24 hours
T
1/2
:
4 hours; metabolised in the liver and excreted
in bile and urine.
Adverse effects:
GI discomfort, anorexia, nausea,
vomiting, heartburn, diarrhoea, allergic skin
reactions, hypoglycaemia.
O
ther oral hypoglycaemic agents
Several other oral hypoglycaemic agents are available.
Although these drugs are structurally unrelated to the
sulfonylureas, they are frequently effective when used
in combination with sulfonylureas or insulin. These
drugs include the alpha-glucosidase inhibitor acarbose
(
Glucobay
); the biguanide metformin (
Diaformin
,
Glucophage
); the DPP-4 inhibitors alogliptin (
Nesina
),
linagliptin (
Trajenta
), saxagliptin (
Onglyza
), sitaglip-
tin (
Januvia
) and vildagliptin (
Galvumet
,
Galvus
); the
glucagon-like peptide 1 liraglutide (
Victoza
) (not avail-
able in New Zealand); the incretin mimetic exenatide
(
Byetta
); the sodium-glucose co-transporters canagli-
flozin (
Invokana
) and dapagliflozin (
Forxiga
); and the
thiazolidinediones pioglitazone (
Actos
) and rosiglita-
zone (
Avandia
) (see Table 38.3).
Acarbose is an inhibitor of alpha-glucosidase (an
enzyme that breaks down glucose for absorption); it
delays the absorption of glucose. It has only a mild effect
on glucose levels and has been associated with severe
hepatic toxicity. It does not enhance insulin secretion,
so its effects are additive to those of the sulfonylureas in
controlling blood glucose. Alpha-glucosidase inhibitors
are used in combination with sulfonylureas, metformin
and insulin for individuals whose glucose levels cannot
be controlled with a single agent or diet and exercise
alone.
Metformin decreases the production and increases
the uptake of glucose. It is effective in lowering blood
glucose levels and does not cause hypoglycaemia as
the sulfonylureas do. It has been associated with the
