Download ANTIDIABETICS AND HYPOGLYCEMICS

ANTIDIABETIC AND
HYPOGLYCEMIC DRUGS
• Normal fasting range of blood glucose
= 60–100 mg/dL (3.3–5.6 mmol/L)
• In general, neurohormonal control of
glucose production in healthy
individuals maintains a fasting serum
glucose conc. in this range.
• Diabetes mellitus
Is a chronic metabolic disorder
characterized by a high blood glucose
conc. (fasting plasma glucose > 7.0
mmol/l, or plasma glucose > 11.1
mmol/l 2 hours after a meal) caused
by insulin deficiency, often combined
with insulin resistance. In DM, the body
fails to maintain normal blood glucose
conc. The two glycemic complications
of DM and its therapy are
hyperglycemia and hypoglycemia.
• Types of diabetes mellitus
– Type 1: Insulin-dependent diabetes
mellitus (IDDM)
• Destruction of pancreatic beta cells
• Is the result of an autoimmune
process
– Type 2: Non-insulin dependent diabetes
mellitus (NIDDM)
• Results from a combination of insulin
resistance and altered insulin
secretion
– Gestational diabetes
• Glucose intolerance during pregnancy
• Medications used for treatment of
DM include:
Insulin
oral agents:
Sulfonylureas
 biguanides
α-glucosidase inhibitors
Thiazolidinediones
Meglitinides
Major classes of oral antidiabetic drugs
1. Drugs that sensitize the
body to insulin and/or
control hepatic glucose
production
2. Drugs that stimulate the
pancreas to make more
insulin( Insulin
secretagogues)
3. Drugs that slow the
absorption of starches
Biguanides
Thiazolidinediones
Sulfonylureas
Meglitinides
Alpha-glucosidase
inhibitors
• Insulin is synthesized in the β-islet
cells of the pancreas.
• Insulin is released from pancreatic B
cells in response to a variety of
stimuli, especially glucose.
• The sulfonylureas stimulate the β
cells of the pancreas to release
insulin; therefore, they are
ineffective in type I DM resulting
from islet cell destruction
• Metformin is an oral compound approved
for treatment of type II DM. Its glucosestabilizing effect is caused by several
mechanisms, the most important of which
appears to involve inhibition
of gluconeogenesis and subsequent
decreased hepatic glucose output.
Enhanced peripheral glucose uptake also
plays a significant role in maintaining
euglycemia. Metformin’s ability to lower
blood glucose conc. also occurs as a result
of decreased fatty acid oxidation and
increased intestinal use of glucose.
• Acarbose and miglitol inhibit αglucosidase enzymes such as sucrase,
and maltase in the brush border
of the small intestine. As a result,
postprandial elevations in blood
glucose conc. after carbohydrate
ingestion are blunted.
• Delayed gastric emptying may be
another mechanism for the
antihyperglycemic effect of these
oligosaccharides.
• The thiazolidinedione derivatives
decrease insulin resistance by
potentiating insulin sensitivity in the
liver, adipose tissue, and skeletal
muscle. Uptake of glucose into adipose
tissue and skeletal muscle is enhanced,
while hepatic glucose production is
reduced.
• Repaglinide and nateglinide are oral
agents of the meglitinide class and
differ structurally from the
sulfonylureas. However, they also
bind to K+ channels on pancreatic cells,
resulting in increased insulin secretion.
Compared to the sulfonylureas, the
hypoglycemic effects of the meglitinides
are shorter in duration.
• To varying degrees, the antidiabetics may
all produce a nearly identical clinical
condition of hypoglycemia.
• CNS symptoms predominate in
hypoglycemia because the brain depends
almost entirely on glucose as an energy
source. However, during prolonged
starvation, the brain can utilize
ketones derived from free fatty acids. In
contrast to the brain, other major organs
such as the heart, liver, and skeletal
muscle often function during
hypoglycemia because they can use
various fuel sources, particularly free fatty
acids.
CLINICAL MANIFESTATIONS
• Hypoglycemia and its secondary effects
on the CNS (neuroglycopenia) are the
most common adverse effects related
to insulin and the sulfonylureas.
• The clinical presentations of patients
with hypoglycemia are extremely
variable.
• Delirium, confusion, or manic behavior
and coma.
• The findings classically associated with
hypoglycemia, such as tremor,
sweating, tachycardia, confusion, coma,
and seizures, frequently may not occur.
The glycemic threshold is the glucose
conc. below which clinical
manifestations develop, this threshold
is host variable.
• Sinus tachycardia, atrial fibrillation, and
ventricular premature contractions are
the most common dysrhythmias
associated with hypoglycemia.
• Acarbose and miglitol are not likely to
cause hypoglycemia based on their
mechanism of action of inhibiting αglucosidase. The most common adverse
effects associated with therapeutic use
of them are gastrointestinal, including
nausea, bloating, abdominal pain,
flatulence, and diarrhea.
• Hypoglycemia may not occur until 18 hours
after lente insulin (Intermediate-acting
overdose), may persist for up to 53 hours
after insulin glargine (Long-acting)
overdose, and may persist up to 6 days after
ultralente insulin overdose.
• Death after insulin overdose cannot be
correlated directly with either the dose or
preparation type. Some patients have died
with doses estimated in the hundreds of
units, whereas others have survived in doses
of the thousands of units. Mortality and
morbidity may correlate better with delay in
recognition of the problem, duration of
symptoms, onset of therapy, and type of
complications.
DIAGNOSTIC TESTING
• Suspicion of possible hypoglycemia,
particularly neuroglycopenia, is
important in the patient with an
abnormal neurologic examination.
• The most frequent reasons for failure to
diagnose hypoglycemia and
mismanaging patients are the wrong
conclusions that the patient is not
hypoglycemic but rather is psychotic,
epileptic or intoxicated because of an
“odor of alcohol” on the breath.
• Serum glucose conc. are accurate, but
treatment cannot be delayed pending
the results of laboratory testing.
Glucose reagent strip testing can be
performed at the bedside. The
sensitivity of these tests for detecting
hypoglycemia is excellent, but these
tests are not perfect.
• Renal function test may indicate the
presence of renal impairment as a
causative factor of hypoglycemia.
This commonly occurs in diabetics
taking insulin, who often develop
renal failure after they have had the
disease for several years. Insulin
half-life increases as renal function
declines. Measures of hepatic
function may be a clue to liver
disease as a cause of hypoglycemia.
MANAGEMENT
• Treatment centers on the correction of
hypoglycemia. Symptomatic patients
with hypoglycemia require immediate
treatment with 0.5–1 g/kg
concentrated intravenous dextrose.
• Glucagon should not be considered
as an antihypoglycemic agent except
in some uncommon situation.
Glucagon has a delay onset of action.
It also stimulates insulin release
from the pancreas, which may lead to
prolonged hypoglycemia.
• Single-dose activated charcoal is
expected to be beneficial for these
overdoses.
• Multiple-dose activated charcoal and
whole-bowel irrigation may be of
benefit and should be considered
after overdose of modified-release
antidiabetics drugs.
• Urinary alkalinization to a pH of 7–8 can
reduce the half-life of chlorpropamide
from 49 hours to approximately 13
hours. Urinary alkalinization is not
useful for other oral antidiabetics,
because of their limited renal excretion.
METFORMIN-ASSOCIATED METABOLIC
ACIDOSIS WITH HYPERLACTATEMIA
• The biguanides are uniquely associated
with the occurrence of metabolic
acidosis with hyperlactatemia.
Phenformin causes lactic acid
production by several mechanisms
including interference with cellular
aerobic metabolism and subsequent
enhanced anaerobic metabolism.
• Phenformin suppresses hepatic
gluconeogenesis from pyruvate and
causes a decrease in hepatocellular
pH, resulting in decreased lactate
consumption and hepatic lactate
uptake.
• Metformin-associated metabolic
acidosis with hyperlactatemia occurs
20 times less commonly than that
occurring with phenformin.
• Metabolic acidosis with hyperlactatemia
related to metformin usually occurs in
the presence of an underlying condition,
particularly renal impairment. Other risk
factors include cardiorespiratory
insufficiency, septicemia, liver disease,
history of metabolic acidosis with
hyperlactatemia, advanced age, alcohol
abuse, and use of radiologic contrast
media.
• Metformin-associated metabolic acidosis
with hyperlactatemia is a potentially lethal
condition. Recognition and awareness of this
disorder are important. Symptoms may be
nonspecific and include abdominal pain,
nausea, vomiting, and dizziness. However,
gastrointestinal symptoms are common
adverse effects associated with therapeutic
use of metformin and do not necessarily
require discontinuation of the drug. More
severe clinical manifestations include
confusion, depression, hypothermia,
respiratory insufficiency, and hypotension.
• Aggressive airway management and
vasopressor therapy may be required.
• Intravenous sodium bicarbonate in
critically ill patients with metabolic
acidosis with hyperlactatemia also
used.