ANTIDIABETIC AND HYPOGLYCEMIC DRUGS - PowerPoint Presentation

Slide1

ANTIDIABETIC

AND

HYPOGLYCEMIC DRUGS

Slide2

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.

Slide3

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.

 

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

Slide5

Medications used for treatment of

DM include:

Insulin

oral agents

:

Sulfonylureas

biguanides

α-

glucosidase

inhibitors

Thiazolidinediones

Meglitinides

Slide6

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

BiguanidesThiazolidinedionesSulfonylureasMeglitinidesAlpha-glucosidase inhibitors

Slide7

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.

Slide8

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

Slide9

Metformin

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.

Slide10

Acarbose

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.

Slide11

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.

Slide12

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.

Slide13

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.

Slide14

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.

Slide15

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.

Slide16

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 α-glucosidase. The most common adverse effects associated with therapeutic use of them are gastrointestinal, including nausea, bloating, abdominal pain, flatulence, and diarrhea.

Slide17

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.

Slide18

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.

Slide19

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.

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.

Slide21

MANAGEMENT

Treatment centers on the correction of hypoglycemia. Symptomatic patients with hypoglycemia require immediate treatment with 0.5–1 g/kg concentrated intravenous dextrose.

Slide22

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.

Slide23

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.

Slide24

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.

Slide25

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.

Slide26

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.

Slide27

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.

Slide28

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.

Slide29

Aggressive airway management and

vasopressor

therapy may be required.

Intravenous sodium bicarbonate in critically ill patients with metabolic acidosis with

hyperlactatemia

also used.