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 Biguanides Thiazolidinediones Sulfonylureas Meglitinides Alpha-glucosidase inhibitors 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

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 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.

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.

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 α-glucosidase. 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.