Normal fasting range of blood glucose 60100 mg dL 3356 mmol L In general neurohormonal control of glucose production in healthy individuals maintains a
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Slide1
ANTIDIABETIC
AND
HYPOGLYCEMIC DRUGS
Slide2Normal 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.
Slide3Diabetes 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.
Slide4
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
Slide5Medications used for treatment of
DM include:
Insulin
oral agents
:
Sulfonylureas
biguanides
α-
glucosidase
inhibitors
Thiazolidinediones
Meglitinides
Slide6Major
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
BiguanidesThiazolidinedionesSulfonylureasMeglitinidesAlpha-glucosidase inhibitors
Slide7Insulin 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.
Slide8The
sulfonylureas
stimulate the β cells of the pancreas to release insulin; therefore, they are ineffective in type I DM resulting
from islet cell destruction
Slide9Metformin
is an oral compound approved for treatment of type II DM. Its glucose-stabilizing 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.
Slide10Acarbose
and
miglitol
inhibit
α-
glucosidase
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.
Slide11The
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.
Slide12Repaglinide
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.
Slide13To 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.
Slide14CLINICAL 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.
Slide15The 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.
Slide16Sinus 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 α-glucosidase. The most common adverse effects associated with therapeutic use of them are gastrointestinal, including nausea, bloating, abdominal pain, flatulence, and diarrhea.
Slide17Hypoglycemia 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.
Slide18DIAGNOSTIC 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.
Slide19Serum 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.
Slide20
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.
Slide21MANAGEMENT
Treatment centers on the correction of hypoglycemia. Symptomatic patients with hypoglycemia require immediate treatment with 0.5–1 g/kg concentrated intravenous dextrose.
Slide22Glucagon 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.
Slide23Single-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.
Slide24Urinary
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.
Slide25METFORMIN-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.
Slide26Phenformin
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.
Slide27Metabolic 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.
Slide28Metformin
-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.
Slide29Aggressive airway management and
vasopressor
therapy may be required.
Intravenous sodium bicarbonate in critically ill patients with metabolic acidosis with
hyperlactatemia
also used.