Drugs that Alter Glucose Regulation

Without sufficient insulin, transport of glucose across certain cell membranes slows markedly to cause hyperglycemia. The formation of glucose from protein accounts for the discovery that glucose in urine may exceed oral intake. Much of the protein used for glucose formation comes from skeletal muscles; glucose loss may manifest in extreme cases as skeletal muscle wasting. Elevations in blood glucose levels and hypoinsulinemia cause diabetic myopathy via muscle proteolysis. Increased free fatty acid concentrations in the plasma of diabetic patients show inhibition of the lipase enzyme system so that mobilization of fatty acids proceeds unopposed. The insulin-deficient liver is likely to use fatty acids to produce ketones, which can serve as an energy source for skeletal muscles and cardiac muscle. Production of ketones can lead to ketoacidosis; urinary excretion of ketones contributes to the depletion of electrolytes, especially potassium. Hypokalemia, however, may not be apparent, because intracellular potassium ions are exchanged for extracellular ions to compensate for the acidosis.

Low plasma concentrations of insulin, although inadequate to prevent hyperglycemia, may block lipolysis. This differential effect of insulin explains why hyperglycemia can exist without the presence of ketone bodies. Ketosis can be reliably prevented by continuously providing all diabetic patients with glucose and insulin.³ Prevention is uniquely important in the perioperative period when nutritional intake is altered.

Hyperglycemia impairs vasodilation and induces a chronic proinflammatory, prothrombotic, and proatherogenic state leading to vascular complications.⁴ Although all tissues are affected, of greatest relevance for anesthesia are atherosclerotic vascular, renal, and nervous system effects with peripheral vascular disease, renal insufficiency, and cerebrovascular disease.

The goals of therapy for patients with diabetes mellitus include preventing the adverse consequences of hypoglycemia and hyperglycemia, avoiding weight gain, and reducing microvascular and macrovascular complications. Symptoms often resolve when blood glucose levels are less than 200 mg/dL. Long-term metabolic control of diabetes is best monitored by measurement of glycosylated hemoglobin (HbA_1c), which reflects glucose control over the previous 2 to 3 months. In general, HbA_1c values less than 6.0% to 7.0% are associated with fewer microvascular complications. Therapy choices consider compliance, age, comorbidities, and impact on organ function (heart, kidney, liver).⁵

Insulin

Because patients with type 1 diabetes mellitus do not produce insulin, they require insulin therapy to survive. Insulin is prescribed for patients with type 2 diabetes mellitus if treatment with oral glucose regulators fails. In these patients, pancreatic β cells have been destroyed or autoantibodies have developed (see Chapter 37 for insulin’s mechanism of action). Insulin therapy mirrors the normal pattern of insulin secretion (pulsatile secretion that occurs under basal conditions and in response to meals) with basal supplementation and by short-acting insulin taken before food absorption. Insulin receptors become fully saturated with low concentrations of insulin. For example, continuous infusion of insulin, 1 to 2 units per hour, has the same or even greater pharmacologic effect than a single larger intravenous (IV) dose that is cleared rapidly from the circulation. Large doses of insulin, however, will last longer and exert a greater net effect than small doses. The number of insulin receptors seems to be inversely related to the plasma concentration of insulin, which reflect the ability of insulin to regulate the population of its receptors. Obesity and type 1 diabetes mellitus appear to be associated with fewer insulin receptors.

Pharmacokinetics

The elimination half-time of IV insulin is 5 to 10 minutes in both healthy and diabetic patients. Insulin is metabolized in the kidneys and liver by a proteolytic enzyme. Approximately 50% of the insulin that reaches the liver through its portal vein is metabolized in a single passage. Nevertheless, renal dysfunction alters the disappearance rate of circulating insulin to a greater extent than does hepatic disease. Indeed, unexpected prolonged effects of insulin are found in patients with renal disease, reflecting impairment of both its metabolism and excretion by the kidneys. Peripheral tissues such as skeletal muscles and fat can bind and inactivate insulin, but this effect is of minor quantitative significance. Despite rapid clearance from plasma after IV injection of insulin, the pharmacologic effect lasts for 30 to 60 minutes because insulin is tightly bound to tissue receptors. Insulin administered subcutaneously releases slowly into the circulation to produce a sustained biologic effect.

Insulin is secreted into the portal venous system in the basal state at a rate of approximately 1 unit per hour. After food intake, the rate of insulin secretion increases to 5- to 10-fold. The total daily secretion of insulin is approximately 40 units. The sympathetic and parasympathetic nervous systems innervate the insulin-producing islet cells to influence the basal rate of hormone secretion as well as the response to stress. For example, α-adrenergic stimulation decreases and β-adrenergic or parasympathetic nervous system stimulation increases the basal secretion of insulin. The insulin response to glucose is greater after oral ingestion than after IV infusion because glucose-dependent insulinotropic polypeptide is released after oral ingestion of glucose and the pancreatic β cell response is augmented. To gain adequate glycemic control in type 1 diabetes, at least two daily subcutaneous injections of intermediate- or long-acting insulin combined with rapid-acting insulin are nearly always required.

Insulin Preparations and Delivery

Human insulin manufactured using recombinant DNA technology has replaced insulin extracted from beef and pork pancreas. Allergy or immunoresistance to animal insulins is no longer a serious problem. In rare instances of local allergy to human insulin, pure porcine insulin or lispro insulin is substituted. The basic principle of replacement is to provide a slow, long-acting, continuous supply of insulin (neutral protamine Hagedorn [NPH] insulin, insulin glargine, insulin detemir, or insulin degludec) that mimics the nocturnal and interprandial basal secretion of normal pancreatic β cells.⁶ A rapid and relatively short-acting form of insulin (insulin aspart, lispro, or glulisine) delivered before meals mimics the normal meal-stimulated (prandial) release of insulin.

A number of insulin preparations for subcutaneous administration are available (Table 38-2).⁷ The pharmacokinetics of these insulins vary from individual to individual and even within the same individual from day to day. Rates of insulin absorption from subcutaneous sites differ with the injection site (absorption from abdominal sites is least variable), depth and angle of injection, ambient temperature, and exercise of an injected extremity.

Commercially prepared insulin is bioassayed, and its physiologic activity (potency), based on the ability to decrease blood glucose concentration, is expressed in units. The potency of insulin is 22 to 26 U/mg. Insulin U-100 (100 U/mL) is the most commonly used commercial preparation. The total daily exogenous dose of insulin for treatment of type 1 diabetes mellitus is usually in the range of 0.5 to 1 U/kg/day. This insulin requirement, however, may be increased dramatically by stress associated with sepsis or trauma.

Continuous subcutaneous insulin infusion (CSII) through an external pump delivers basal insulin (0.01 to 0.015 U/kg/hour) and bolus doses before meals. With this system, nocturnal versus daytime basal requirements can be accommodated, infusions can be altered during exercise, and doses can be calculated via algorithms of previous glucose values and insulin delivery. Short-acting insulin (regular) and ultra rapid–acting insulins (lispro, aspart, and glulisine) are the only preparations used for CSII delivery pumps.

Lispro

Lispro is a short-acting insulin analogue that more closely parallels physiologic insulin secretion and needs. A feature of natural or synthetic human insulin is that six molecules associate with a zinc molecule to form hexamers. Insulin hexamers must dissociate to monomers before absorption from subcutaneous injection sites. This feature is the reason that crystalline zinc insulin (regular insulin) has a peak action 2 to 4 hours after its subcutaneous injection. It must be administered 30 to 60 minutes before eating to effectively limit postprandial hyperglycemia. By exchanging lysine and proline at positions 28 and 29 of the insulin B chain, hexamer formation is prevented and the monomer is rapidly absorbed from the injection site. Therefore, lispro insulin injected subcutaneously begins to act within 15 minutes, the peak effect is reached in 45 to 75 minutes, and the duration of action is only 2 to 4 hours. Lispro injected just before eating provides a postprandial plasma insulin concentration profile similar to that of normal insulin secretion. An important benefit of lispro is a decrease in postprandial hyperglycemia and less risk of hypoglycemia, which may follow injection of regular insulin. Loss of the late action of regular insulin, however, may result in recurrent hyperglycemia before the next meal. In patients treated with lispro, HbA_1c may not decrease unless the doses of basal insulin (NPH, detemir, or glargine) are increased.

Insulin Aspart and Glulisine

Insulin aspart and glulisine are synthetic rapid-acting analogues with a profile of action and therapeutic benefits similar to those of lispro.

Regular Insulin (Crystalline Zinc Insulin)

Regular insulin is a fast-acting preparation and is the only form of insulin that can be administered IV as well as subcutaneously. This form can be mixed in the same syringe with other insulin preparations if the pH of the solutions is similar.

Administration of regular insulin is preferred for treating the abrupt onset of hyperglycemia or the appearance of ketoacidosis. In the perioperative period, regular insulin is administered as a single IV injection (1 to 5 units) or as a continuous infusion (0.5 to 2.0 units per hour) to treat metabolic derangements associated with diabetes mellitus.

Neutral Protamine Hagedorn

NPH is an intermediate-acting preparation whose absorption from its subcutaneous injection site is delayed because the insulin is conjugated with protamine. The acronym NPH designates a neutral solution (N), protamine (P), and origin in Hagedorn’s (H) laboratory.⁸ This insulin preparation contains 0.005 mg protamine/U of insulin.

Glargine, Detemir, Degludec

Glargine, detemir, and degludec are long-acting insulin analogues for basal insulin replacement. Compared to NPH insulin, these long-acting insulins have a later onset of action and less pronounced peaks. Glargine or detemir can be administered as a single bedtime injection to provide basal insulin for 24 hours with less nocturnal hypoglycemia.⁹ Unlike glargine and detemir, degludec can be mixed with rapid-acting insulins. Degludec is not approved for use in the United States.

Side Effects

Side effects of treatment with insulin may manifest as (a) hypoglycemia, (b) allergic reactions, (c) lipodystrophy, (d) insulin resistance, or (e) drug interactions.

Hypoglycemia

The most serious side effect of insulin therapy is hypoglycemia. Patients are vulnerable to hypoglycemia if they receive exogenous insulin in the absence of carbohydrate intake, as during a perioperative period, especially before surgery. The first symptoms of hypoglycemia are the compensatory effects of increased epinephrine secretion: diaphoresis, tachycardia, and hypertension. Rebound hyperglycemia caused by sympathetic nervous system activity in response to hypoglycemia (Somogyi effect) may mask the correct diagnosis. Symptoms of hypoglycemia involving the central nervous system (CNS) include mental confusion progressing to seizures and coma. The CNS effects are intense because the brain depends on glucose as a selective substrate for oxidative metabolism. A prolonged period of hypoglycemia may result in irreversible brain damage.

The diagnosis of hypoglycemia during general anesthesia is difficult because anesthetic drugs mask the classic signs of sympathetic nervous system stimulation. The signs of sympathetic nervous system stimulation are likely to be confused with responses evoked by painful surgical stimulation in an anesthetized patient. The anesthesiologist may then decide to increase the dose of anesthetic drugs. Changes in heart rate and systemic blood pressure may be caused by hypoglycemia.¹⁰ Nonselective β-adrenergic antagonists also may mask the symptoms of hypoglycemia.

Severe hypoglycemia is treated with 50 to 100 mL of 50% glucose solution administered IV. Alternatively, glucagon, 0.5 to 1.0 mg IV or administered subcutaneously, is given. Nausea and vomiting are frequent side effects of glucagon treatment. In the absence of CNS depression, carbohydrates may be administered orally.

Allergic Reactions

Use of human insulin preparations has eliminated the problem of systemic allergic reactions that could result from administration of animal-derived insulins. Local allergic reactions to insulin are approximately 10 times more frequent than systemic allergic reactions. Local allergic reactions are characterized by an erythematous indurated area that develops at the site of insulin injection. The cause of local allergic reactions is likely to be noninsulin materials in the insulin preparation. Chronic exposure to low doses of protamine in NPH insulin may stimulate the production of antibodies against protamine. Patients remain asymptomatic until a large dose of protamine is administered IV to antagonize the anticoagulant effects of heparin. Indeed, patients with diabetes who are treated with NPH insulin have had allergic reactions to protamine.¹¹ Yet allergic reactions to protamine are not found more in patients treated with NPH insulin than in nondiabetics.¹²

Lipodystrophy

Lipodystrophy results when fat atrophies at the site of subcutaneous injection of insulin. This side effect is minimized by frequently changing the site used for injection of insulin.

Insulin Resistance

Patients requiring greater than 100 units of exogenous insulin daily are in a state of insulin resistance. Even this value is high, because insulin requirements for pancreatectomized adults are often as low as 30 units. The use of human insulins has eliminated the problem of immunoresistance that could accompany administration of animal insulins. Acute insulin resistance is associated with trauma from infection or surgery.

Drug Interactions

There are hormones administered as drugs that counter the hypoglycemic effect of insulin: adrenocorticotrophic hormone, estrogens, and glucagon. Epinephrine inhibits the secretion of insulin and stimulates glycogenolysis. Certain antibiotics (tetracycline or chloramphenicol), salicylates, and phenylbutazone increase the duration of action of insulin and may have a direct hypoglycemic effect. The hypoglycemic effect of insulin may be potentiated by monoamine oxidase inhibitors.

Oral Glucose Regulators

Oral drugs with different mechanisms of action are available for controlling plasma glucose concentrations in patients with type 2 diabetes mellitus (Table 38-3). None of these drugs will adequately control hyperglycemia indefinitely. Therefore, use of combinations of oral drugs from the onset of treatment may be indicated.¹³ Insulin itself may be administered with sulfonylureas and meglitinides. The effect on HbA_1c is similar for these drugs.