Abstract
Dysfunction of the complex physiologic processes of the endocrine systems can lead to significant and potentially life-threatening problems. Administration of exogenous hormones or drugs that mimic or antagonize hormonal effects to manipulate the metabolic milieu is important in many therapies. Endocrine pharmacotherapeutics range from simple supplementation of a missing hormone, such as insulin in the case of patients with type 1 diabetes mellitus (DM), to careful manipulation of physiologic processes with advanced pharmaceuticals in the case of assisted reproduction techniques. Many of these agents have implications for the practice of anesthesia, critical care, and pain medicine.
Keywords
Endocrinology, Pharmacology, Diabetes mellitus, Thyroid, Adrenal, Hormones
Chapter Outline
Drugs to Treat Disorders of the Endocrine Pancreas
Oral Hypoglycemic Agents: Sulfonylureas, Biguanides, Thiazolidinediones
Other Oral Hypoglycemic Agents
Drugs to Treat Disorders of the Hypothalamic-Pituitary-End-Organ Axis
Thioureylene Antithyroid Drugs
Drugs Used in the Treatment of Pheochromocytoma
Adrenocorticotropic Hormone and Steroid Antagonists
Posterior Pituitary Hormones, Analogs, and Antagonists
Growth Hormone, Prolactin, and Related Drugs
Drugs Related to Growth Hormone
Drugs Affecting Prolactin Physiology
Sex Hormones and Related Drugs
Parathyroid Hormone and Drugs Affecting Calcium Metabolism
Glycemic Control in the Perioperative Period and in the Critically Ill
Steroid Supplementation During Critical Illness
Dysfunction of the complex physiologic processes of the endocrine systems can lead to significant and potentially life-threatening problems. Administration of exogenous hormones or drugs that mimic or antagonize hormonal effects to manipulate the metabolic milieu is important in many therapies. Endocrine pharmacotherapeutics range from simple supplementation of a missing hormone, such as insulin in the case of patients with type 1 diabetes mellitus (DM), to careful manipulation of physiologic processes with advanced pharmaceuticals in the case of assisted reproduction techniques. Many of these agents have implications for the practice of anesthesia, critical care, and pain. Historical perspectives are highlighted with the discussion of individual drug classes.
Drugs to Treat Disorders of the Endocrine Pancreas
Insulin
The discovery of insulin by Banting and Best represents a major milestone in modern medicine. Within a few years of its discovery insulin had been purified and crystallized. Its amino acid sequence was established by Sanger in 1960. The protein was synthesized in 1963 and its three-dimensional structure elucidated in 1972. The first biosynthetic human insulin was approved by the U.S. Food and Drug Administration (FDA) in 1982.
Basic Pharmacology
Insulin is synthesized in β cells of the pancreatic islets of Langerhans. Pre-proinsulin (a single-chain, 110–amino acid precursor) is initially formed. Subsequently the N-terminal 24–amino acid peptide is cleaved to form proinsulin. Removal of four basic amino acids and a connecting (C) peptide gives rise to insulin itself. The insulin molecule contains A and B peptide chains, usually composed of 21 and 30 amino acid residues, respectively. In most species a single insulin gene gives rise to a single protein product.
When pancreatic β cells are stimulated, insulin and C-peptide are released into the circulation in equimolar amounts. Therefore functional activity of pancreatic β cells is reflected by plasma C-peptide concentrations. It is also possible to differentiate endogenous from exogenous insulin by evaluating plasma C-peptide content. Human insulin, made by recombinant DNA techniques, is used exclusively in the United States. “Purified” insulin contains less than 10 ppm of proinsulin. Refrigeration is recommended but is not crucial.
Insulin is a member of a family of peptides known as insulin-like growth factors (IGFs). IGFs are produced in many tissues and regulate cellular growth and metabolism. Specific insulin receptors in the plasma membrane are similar to IGF receptors. The insulin receptor is a large transmembrane glycoprotein that mediates its actions through intracellular tyrosine kinase activity. Insulin binding leads to autophosphorylation of intracellular insulin receptor sites, causing recruitment of numerous enzymes and mediating molecules that are activated or inactivated, leading to a myriad of intracellular events. Importantly, glucose transporters type 4 are translocated to the plasma membrane where they facilitate diffusion of glucose into cells. Other signals activate glycogen synthase, stimulate uptake of amino acids and protein synthesis, and regulate gene expression (see Chapter 30 for more information on the physiology of insulin). Insulin’s hypoglycemic actions on liver, muscle, and adipose tissue are most important ( Table 36.1 ).
| Liver | Muscle | Adipose Tissue |
|---|---|---|
| Inhibits hepatic glucose production (decreases gluconeogenesis and glycogenolysis) | Stimulates glucose uptake | Stimulates glucose uptake (amount is small compared to muscle) |
| Stimulates hepatic glucose uptake | Inhibits flow of gluconeogenic precursors to the liver (e.g., alanine, lactate, pyruvate) | Inhibits flow of gluconeogenic precursors to liver (glycerol) and reduces energy substrate for hepatic gluconeogenesis (nonesterified fatty acids) |
When injected intravenously, insulin has a plasma half-life of 5 to 6 minutes. It is degraded in liver, kidney, and muscle. When renal function is severely impaired, insulin requirements decrease because of reduced breakdown. Liver metabolism of insulin operates at near-maximal capacity and cannot compensate for loss of renal function. Although insulin is cleared relatively quickly from the circulation, its biologic effects persist for 30 to 60 minutes because it binds tightly to insulin receptors. Subcutaneous injection of insulin leads to slow release into the circulation and a sustained pharmacologic effect.
Clinical Pharmacology
Insulin is most commonly administered subcutaneously, but it can also be administered intravenously. In contrast to physiologic secretion of insulin, subcutaneous administration delivers insulin to the peripheral tissues rather than the portal system, and the pharmacokinetics do not reproduce a normal rise and fall associated with ingestion of nutrients. Nonetheless, insulin treatment is lifesaving for patients with DM.
Insulin preparations are characterized by their duration of action or their species of origin. This latter classification is less relevant now owing to the wide availability of synthetic human preparations. For historical reasons, doses and concentrations of insulin are expressed in units. In the past, preparations of the hormone were impure and were standardized by bioassay. One unit of insulin is equal to the amount of insulin required to reduce blood glucose concentration in a fasting rabbit to 45 mg/dL (2.5 mM). Insulin is supplied in solution or suspension at a concentration of 100 units/mL. Typically, a patient with type 1 DM requires between 20 and 60 units of exogenously administered insulin per day. Higher-concentration insulin preparations are available for patients who are resistant to insulin. Table 36.2 details currently available insulin preparations, and Fig. 36.1 shows typical pharmacokinetic profiles of insulin and insulin analogs following subcutaneous administration.
| Preparation | Onset (hr) | Peak (hr) | Effective Duration (hr) | |
|---|---|---|---|---|
| Short-acting | ||||
| Aspart | <0.25 | 0.5–1.5 | 3–4 | |
| Glulisine | <0.25 | 0.5–1.5 | 3–4 | |
| Lispro | <0.25 | 0.5–1.5 | 3–4 | |
| Regular | 0.5–1.0 | 2–3 | 4–6 | |
| Intermediate-acting | ||||
| NPH | 1–4 | 6–10 | 10–16 | |
| Long-acting | ||||
| Detemir | 1–4 | — a | 20–24 | |
| Glargine | 1–4 | — a | 20–24 | |
| Insulin combinations | ||||
| 75/25–75% protamine lispro, 25% lispro | <0.25 | 1.5 | Up to 10–16 | |
| 70/30–70% protamine aspart, 30% aspart | <0.25 | 1.5 | Up to 10–16 | |
| 50/50–50% protamine lispro, 50% lispro | <0.25 | 1.5 | Up to 10–16 | |
| 70/30–70% NPH, 30% regular | 0.5–1 | Dual b | 10–16 |
a Glargine and detemir have minimal peak activity.
b Dual: two peaks, one at 2 to 3 hours; the second one several hours later.
Insulin is among the drugs highlighted by the Institute for Safe Medication Practices as having an increased risk for patient harm when used in error. The administration of insulin is prone to error because of the variety of preparations used and the difficulty associated with administration of a small number of units.
Hypoglycemia is the most common adverse reaction associated with insulin administration. It can occur as the result of administration of an inappropriately large dose of insulin, when peak insulin effect does not coincide with carbohydrate intake, or because of superimposed factors such as exercise. Patients in the perioperative period are especially vulnerable to the development of hypoglycemia because of interruption of oral intake and alterations in insulin dosing regimens. The incidence of hypoglycemia increases when “tighter” glycemic control goals are adopted. Symptoms and signs of hypoglycemia include tachycardia, diaphoresis, tremor, palpitations, anxiety, and hunger. These can be absent during anesthesia. Neuroglycopenia can cause dizziness, blurred vision, and loss of consciousness, potentially progressing to coma, seizures, and even death. Lipodystrophy can occur at the sites of subcutaneous insulin injection, leading to alterations in subcutaneous fat. Lipoatrophy is probably secondary to an immune response to insulin. Enlargement of subcutaneous fat deposits (lipohypertrophy) can also occur and is thought to be due to the lipogenic action of insulin. Allergic reactions to insulin were more common before the use of recombinant human insulin or highly purified insulin preparations, although such reactions still occur. Local reactions cause erythema and induration, and are usually mediated by immunoglobulin (Ig) E. Systemic reactions are less frequent and are usually IgG antibody mediated. Prolonged use of neutral protamine Hagedorn (NPH) insulin can lead to protamine sensitization that can manifest when a large dose of protamine is administered, as in the setting of cardiopulmonary bypass. Doses of subcutaneous insulin of more than 100 units/day can indicate insulin resistance, which can be due to antiinsulin antibodies or target cell receptor dysfunction. As with allergic reactions, the incidence of insulin resistance owing to antibodies is decreasing with use of recombinant and highly purified preparations.
As detailed in Chapters 13 and 30 , several hormones antagonize the effects of insulin. These include epinephrine, which inhibits the secretion of insulin and stimulates glycogenolysis, and adrenocorticotrophic hormone (ACTH), glucagon, and estrogens, which tend to cause hyperglycemia. Certain drugs (e.g., tetracycline, salicylates) can increase the duration of action of insulin.
Individual Insulin Preparations
Regular Insulin
Regular insulin is a crystalline zinc insulin preparation, the effect of which appears within 30 minutes of subcutaneous injection. Regular insulin should be injected subcutaneously 30 to 45 minutes before meals. This causes the blood glucose to fall rapidly, reaching a nadir in 20 to 30 minutes.
Rapidly Acting Insulin Analogues
Regular insulin monomers form hexamers in currently available insulin preparations. The hexameric form delays absorption and onset of action. Insulin analogs have been developed that maintain a monomeric or dimeric configuration, increasing their speed of absorption and reducing time to onset to 5 to 15 minutes. They are identical to human insulin except for substitutions of amino acids at one or two positions. Such rapidly acting insulin preparations include insulin lispro, insulin aspart, and insulin glulisine. The use of insulin lispro rather than regular insulin can decrease the incidence of hypoglycemia and improve glycemic control. In clinical trials, insulin aspart has effects similar to insulin lispro on hypoglycemia frequency and glycemic control and causes less nocturnal hypoglycemia than regular insulin. Insulin glulisine has similar properties.
Intermediate-Acting Insulin
Intermediate-acting insulins are designed to dissolve gradually when administered subcutaneously. NPH (or isophane) insulin is a soluble crystalline zinc insulin combined with protamine zinc insulin. Lente insulin is a mixture of crystallized (ultralente) and amorphous (semilente) insulins in an acetate buffer. Their onset of action is delayed to 2 to 4 hours with a peak response at 8 to 10 hours; duration of action is less than 24 hours.
Long-Acting Insulins
Ultralente insulin (an extended insulin zinc suspension) has a slower onset of action and a prolonged peak effect. It provides a low basal concentration of insulin throughout the day and is often used in combination with other insulin preparations. The desire for insulin preparations without peak effects prompted the development of long-acting insulin analogs including insulin glargine and insulin detemir. They lack a peak effect and have durations of action of 17 to 24 hours. Insulin glargine is produced by the addition of two arginine residues to the C-terminus of the insulin B chain and replacement of a single asparagine residue with a glycine in the A chain. The resulting insulin forms a solution with a pH of 4. The low pH stabilizes the hexamer and delays absorption but also means that glargine cannot be mixed with short-acting insulin preparations that are at neutral pH. Another long-acting preparation, insulin detemir, is synthesized by the addition of a saturated fatty acid to the lysine at position B29 in human insulin. Insulin degludec is formed by deleting the last amino acid from the B chain of human insulin and adding a glutamyl linkage to a hexadecanedioic fatty acid, thus allowing the formation of slowly absorbing soluble multihexamers at the injection site. Its duration of action is more than 40 hours. Unlike glargine and detemir, insulin degludec may be mized with rapidly acting insulins.
Inhaled Insulin
Inhaled insulin is a rapidly acting preparation that can be useful for patients with needle phobias and significant lipodystrophy. The only currently available formulation, Afrezza, was approved by the FDA in 2014. Absorption is inefficient so higher doses of insulin are required, but a very rapid rise of serum insulin concentration can be achieved. Inhaled insulin should be used in combination with a long-acting insulin preparation. It is contraindicated in patients with asthma and chronic obstructive pulmonary disease because of the risk of bronchospasm.
Clinical Application
Subcutaneously administered insulin is the primary therapy for patients with type 1 DM and for many patients with type 2 DM. The American Diabetes Association recommends the following goals of therapy :
- •
Hemoglobin A1c < 7%
- •
Preprandial capillary plasma glucose 80 to 130 mg/dL (4.4–7.2 mmol/L)
- •
Peak postprandial capillary plasma glucose <180 mg/dL (10 mmol/L)
A variety of insulin dosing regimens can be used to achieve these glycemic targets depending on multiple factors, including age, compliance, frequency of significant hypoglycemia and hyperglycemia, and associated medical conditions. Fig. 36.2 illustrates three potential regimens. Although the route is not FDA approved, regular insulin is often administered intravenously during the perioperative period, during labor and delivery, for the treatment of diabetic ketoacidosis, and as an infusion in the intensive care unit (ICU). The rapidly acting insulin analogs can be injected immediately before or after a meal, allowing for smoother glycemic control because the insulin dose can be titrated to the amount of food actually consumed. In addition, the rapidly acting insulin preparations are commonly used in insulin pumps. Intermediate-acting insulins are usually given once daily (often before breakfast) or twice daily. Long-acting insulin glargine can be administered at any time during the day, has a sustained absorption profile without a peak, and provides better once-daily glycemic control with less hypoglycemia than NPH or ultralente. It is sometimes combined with oral hypoglycemic agents (OHAs; see later text) in patients with type 2 DM. Insulin detemir is administered subcutaneously once or twice daily and delivers glycemic control that is smoother and safer than NPH insulin.
Oral Hypoglycemic Agents: Sulfonylureas, Biguanides, Thiazolidinediones
In the 1940s it was discovered that some sulfonamide antibiotics cause hypoglycemia. Subsequently, more than 20 members of the related sulfonylureas have been developed and used as OHAs. Other major classes of OHAs include the biguanides, the thiazolidinediones, the α-glucosidase inhibitors, and the meglitinides. OHAs are used in patients with type 2 DM.
Basic Pharmacology
Sulfonylureas
There are two generations of sulfonylurea drugs based on an arylsulfonylurea backbone, to which substitutions at the para position on the benzene ring and at a nitrogen residue in the urea moiety are made. First-generation agents include tolbutamide, chlorpropamide, tolazamide, and acetohexamide. Second-generation sulfonylureas are more potent and include glyburide, gliclazide, glipizide, and glimepiride. They act by increasing insulin secretion by stimulating pancreatic β cells. Sulfonylureas inhibit adenosine triphosphate (ATP)-dependent potassium ion (K + [K ATP ]) channels in the β cells, causing calcium ion (Ca 2+ ) entry and release of insulin storage granules. They can also decrease hepatic clearance of insulin and have other minor extrapancreatic effects.
Biguanides
The biguanides reduce serum glucose by decreasing hepatic glucose output (presumably by decreasing gluconeogenesis) and by sensitizing peripheral tissues such as muscle and fat to the effects of insulin. They do not stimulate insulin release from the pancreas and so are very unlikely to cause hypoglycemia. As such, they are considered to be antihyperglycemic rather than hypoglycemic agents.
Thiazolidinediones
The thiazolidinediones act at extrapancreatic sites to increase insulin sensitivity. They selectively stimulate nuclear peroxisome-proliferator–activated receptor-γ, thus activating insulin-responsive genes that regulate carbohydrate and lipid metabolism. The drugs also decrease hepatic glucose production. They are especially effective in obese patients, although the thiazolidinediones can cause weight gain as edema fluid.
Clinical Pharmacology and Clinical Application
Sulfonylureas
Sulfonylurea drugs are used in patients with type 2 DM in whom diet alone is insufficient to achieve glycemic control. They are absorbed from the gastrointestinal tract where food can interfere with their absorption, so sulfonylureas with short half-lives should be taken 30 minutes before eating. They are weakly acidic and highly protein bound, especially to albumin. Because they are metabolized by the liver with urinary excretion of metabolites, they should be used cautiously in the presence of renal or hepatic dysfunction; if used in such patients, second-generation agents are typically chosen. Specific drugs have considerable variation in their duration of action and metabolism. Glyburide has significant fecal excretion. The metabolism of chlorpropamide is incomplete, with 20% excreted unchanged in the urine. Second-generation sulfonylureas are approximately 100 times more potent than the first-generation agents. Despite their relatively short half-lives of 3 to 5 hours, they have hypoglycemic effects for 12 to 24 hours, and once daily dosing is possible for some.
The sulfonylureas can cause hypoglycemia, potentially leading to coma, especially in elderly patients who have renal or hepatic dysfunction. For first-generation sulfonylureas, the risk of hypoglycemia is greatest for drugs with a longer duration of action (e.g., chlorpropamide). This is not true of the second-generation agents, however. For example, glimepiride causes hypoglycemia in 2% to 4% of patients, whereas glyburide causes hypoglycemia in 20% to 30% of patients, even though the drugs have similar durations of action. It appears that during hypoglycemia, protective mechanisms (inhibition of insulin secretion and promotion of glucagon secretion) are preserved in the presence of glimepiride but not in the presence of glyburide. Drugs that interfere with metabolism or excretion of sulfonylureas and drugs that displace them from plasma proteins can increase the risk of hypoglycemia. Sulfonylurea drugs can also cause cholestatic jaundice, aplastic and hemolytic anemias, agranulocytosis, hypersensitivity reactions, rashes, and nausea and vomiting. Chlorpropamide can cause flushing in association with alcohol ingestion. The sulfonylureas can also cause hyponatremia by potentiating the renal effects of antidiuretic hormone. They are not typically used in pregnant or lactating women.
The degree of cardiovascular risk associated with long-term use of sulfonylureas is controversial. The University Group Diabetes Program demonstrated a slightly higher incidence of cardiovascular events in patients with type 2 DM treated with tolbutamide compared with insulin or placebo. However, multiple other studies, including the large United Kingdom Prospective Diabetes Study Group, demonstrated the absence of increased cardiovascular mortality in sulfonylurea users. Indeed, glimepiride might decrease cardiovascular morbidity, in that it has beneficial effects on ischemic preconditioning. A more recent study, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial, using the newer agent gliclazide, provided reassuring data on cardiovascular risk.
Biguanides
Metformin, approved for use in the United States in 1995, is the only biguanide in common use today. It is indicated for patients with type 2 DM in whom it was shown to reduce macrovascular complications in the United Kingdom Prospective Diabetes Study Group. It is administered orally and is subsequently absorbed from the small intestine. Metformin is excreted unchanged in the urine and is relatively contraindicated in patients with renal impairment. It is not bound to plasma proteins. Its half-life in plasma is 2 to 4 hours, and it is administered two to three times daily. The drug is sometimes administered in combination with other OHAs. Metformin leads to a mild weight reduction in obese patients and has beneficial effects on lipid profiles (decreasing plasma triglycerides and cholesterol). The drug is also used in polycystic ovary syndrome.
Phenformin, a similar compound to metformin, was withdrawn from the market because of its predisposition to cause lactic acidosis. Metformin is also associated with lactic acidosis but the incidence (<1 per 10,000 patient-years) is 10 to 20 times lower than that associated with phenformin. The mechanism is thought to be related to interaction with mitochondria that leads to decreased intracellular ATP, causing glucose to be metabolized anaerobically to lactate. In addition to cautions associated with renal impairment, a history of lactic acidosis, significant liver disease, cardiac failure, chronic hypoxic lung disease, and administration of radiographic iodinated contrast agents are relative or absolute contraindications. Metformin should be stopped if the patient develops sepsis or myocardial infarction because of the risk of lactic acidosis. It should also be stopped if plasma lactate is greater than 3 mM. It has been recommended that metformin should not be given on the day of surgery because of concern for the development of lactic acidosis. Some advocate that it be held for 48 hours before surgery. However, in a study comparing a cohort of 443 patients who took metformin preoperatively and a group of 443 patients who did not, there was no difference between groups in hospital mortality, cardiac, renal, or neurologic morbidities. Metformin is also associated with nausea, taste disturbances, abdominal discomfort, diarrhea, and anorexia, although fewer than 5% of patients have side effects severe enough to warrant cessation of the drug.
Thiazolidinediones
Thiazolidinediones include pioglitazone and androsiglitazone. They are used in patients with type 2 DM, either alone or, more often, in combination with insulin or other OHAs. Maximum clinical effect does not occur for 6 to 12 weeks after initiation of therapy. They are taken orally, usually once daily, and are metabolized in the liver via the cytochrome P450 system. Drugs that interfere with cytochrome P450 enzymes alter their rate of metabolism.
Hepatic transaminase levels should be measured regularly in patients taking thiazolidinediones because these drugs can induce liver dysfunction, and hepatic disease is a contraindication to their use. In fact, another thiozolidinedione, troglitazone, was withdrawn because of associated severe hepatic dysfunction. If elevations of transaminases or other signs of hepatic dysfunction occur during therapy, treatment should be stopped. The cardiovascular effects of the thiazolidinediones have also come under scrutiny. Some patients have developed significant peripheral edema and even overt heart failure. Patients who have hypertension and/or diastolic dysfunction are especially at risk. The effects of rosiglitazone on the risk of myocardial infarction and other adverse cardiovascular events remain uncertain despite metaanalyses and data from the Rosiglitazone Evaluated for Cardic Outcomes and Regulation of Glycemia in Diabetes (RECORD) study. It appears that thiazolidinediones decrease bone density and increase fracture risk, especially in women, although the absolute risk is small.
Other Oral Hypoglycemic Agents
Both the meglitinide analog repaglinide and the D-phenylalanine derivative nateglinide inhibit K ATP channels in pancreatic β cells to stimulate insulin production. Compared with the sulfonylureas, these drugs have faster onset and shorter duration of action. Repaglinide is administered orally, peak blood levels are obtained within 1 hour, and the half-life is about 1 hour. It can be given multiple times per day before meals. It should be used with caution in patients with liver dysfunction because it is hepatically excreted, although a small portion is renally metabolized. Nateglinide is used to reduce postprandial hyperglycemia in patients with type 2 DM. It is given 1 to 10 minutes before meals. The drug is metabolized by the liver, with a smaller portion excreted unchanged in the urine. Nateglinide is less likely to cause hypoglycemia than repaglinide. Neither drug should be administered when fasting.
The α-glucosidase inhibitors (e.g., miglitol and acarbose) decrease gastrointestinal digestion of carbohydrates and absorption of disaccharides through their action at the intestinal brush border. They are usually administered in combination with insulin or other OHAs, although they can be used as single-agent therapy in patients with predominantly postprandial hyperglycemia or in older adults. They do not cause hypoglycemia unless administered in combination with other glucose-lowering agents. α-Glucosidase inhibitors should be administered at the start of a meal. The drugs can be very effective in patients with type 2 DM who are severely hyperglycemic, although they have more modest effects in those with mild to moderate hyperglycemia. Gastrointestinal side effects can be problematic, although a slow up-titration of the dose lessens these symptoms.
Incretins are gastrointestinal hormones that augment glucose-dependent insulin secretion. They include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). Both are rapidly broken down by dipeptidyl peptidase IV (DPP-4). Agonists of GIP and GLP receptors and inhibitors of DPP-4 are potentially useful in patients with type 2 DM to amplify glucose-induced insulin release. These agents improve glycemic control and do not usually cause hypoglycemia in the absence of other hypoglycemic agents. Clinically useful synthetic GLP-1 receptor agonists are resistant to the effects of DPP-4. They include exenatide, liraglutide, albiglutide, dulaglutide, taspoglutide, and lixisenatide. The GLP-1 receptor antagonists are injected and are usually combined with oral agents or insulin. They should not be used in patients with type 1 DM or in patients with a history of pancreatitis. Side effects are primarily gastrointestinal. Weight loss is often seen. DPP-4 inhibitors are administered orally, usually as second- or third-line agents, but are only moderately effective. They include sitagliptin, saxagliptin, linagliptin, and alogliptin, and the individual drugs are often combined with metformin. The relationships between DDP-4 inhibitors and heart failure and pancreatitis are subjects of ongoing investigation.
Amylin is co-secreted with insulin from pancreatic β cells. This 37–amino acid peptide decreases gastric emptying, glucagon secretion, and appetite. Pramlintide, an injectable analog of amylin, has been approved for the treatment of patients whose type 1 or type 2 DM is inadequately controlled despite insulin therapy. Drugs that interact with gastrointestinal hormones can predispose patients to increased postoperative nausea and vomiting, their effects on gastric emptying can increase the likelihood of aspiration, and their hypoglycemic effects can lead to dangerously low plasma glucose in the perioperative period. It is recommended that they be held on the day of surgery if possible. Table 36.3 compares agents used for the treatment of DM.
| Mechanism of Action | Examples | HbA1c Reduction (%) a | Agent-Specific Advantages | Agent-Specific Disadvantages | Contraindications | |
|---|---|---|---|---|---|---|
| Oral | ||||||
| Biguanides b | ↓ Hepatic glucose absorption | Metformin | 1–2 | Weight neutral Do not cause hypoglycemia Inexpensive | Diarrhea Nausea Lactic acidosis | GFR < 50 mL/min, congestive heart failure, radiographic contrast studies, seriously ill patients, acidosis |
| α-Glucosidase inhibitors b | ↓ GI glucose absorption | Acarbose, miglitol | 0.5–0.8 | Reduce postprandial glycemia | Flatulence Liver function tests | Renal/liver disease |
| Dipeptidyl peptidase-4 inhibitors b | Prolong endogenous GLP-1 action | Saxagliptin, sitagliptin, vildagliptin | 0.5–1.0 | Do not cause hypoglycemia | Reduce dose with renal disease | |
| Insulin secretagogues -sulfonylureas b | ↑ Insulin secretion | See text | 1–2 | Inexpensive | Hypoglycemia Weight gain | Renal/liver disease |
| Insulin secretagogues-nonsulfonylureas b | ↑ Insulin secretion | Repaglinide, nateglinide | 1–2 | Short onset of action Lower postprandial glucose | Hypoglycemia | Renal/liver disease |
| Thiazolidinediones b | ↓ Insulin resistance ↑ Glucose utilization | Rosiglitazone, pioglitazone | 0.5–1.4 | Lower insulin requirements | Peripheral edema CHF Weight gain Fractures Macular edema Rosiglitazone may increase risk of CV disease | CHF, liver disease |
| Bile acid sequestrants b | Bind bile acids; mechanism of glucose lowering not known | Colesevelam | 0.5 | Constipation Dyspepsia Abdominal pain Nausea ↑ Triglycerides Interfere with absorption of other drugs Intestinal obstruction | ||
| Parenteral | ||||||
| Insulin | ↑ Glucose utilization ↓ Hepatic glucose production and other anabolic actions | See text | Not limited | Known safety profile | Injection Weight gain Hypoglycemia | |
| GLP-1 agonists b | ↑ Insulin ↓ Glucose Slow gastric emptying Satiety | Exenatide, liraglutide | 0.5–1.0 | Weight loss | Injection Nausea ↑ Risk of hypoglycemia with insulin secretagogues Pancreatitis | Renal disease, agents that also slow gastrointestinal motility, pancreatitis |
| Amylin agonists b,c | Slow gastric emptying ↓ Glucagon | Pramlintide | 0.25–0.5 | Reduce postprandial glycemia Weight loss | Injection Nausea ↑ Risk of hypoglycemia with insulin | Agents that also slow gastrointestinal motility |
| Medical nutrition therapy and physical activity b | ↓ Insulin, resistance ↑ Insulin secretion | Low-calorie, low-fat diet, exercise | 1–3 | Other health benefits | Compliance difficult Long-term success low? | |
a A1c reduction (absolute) depends partly on starting A1c value.
b Used for treatment of type 2 diabetes mellitus.
c Used in conjunction with insulin for treatment of type 1 diabetes mellitus.
Glucagon
Basic Pharmacology
Glucagon is a 29–amino acid single-chain polypeptide secreted, like insulin, by the islets of Langerhans, but by the α cells rather than β cells. Glucagon is important in the regulation of glucose and ketone body metabolism. Like insulin, glucagon is synthesized as a pro-hormone. Pre-proglucagon is a 180 amino acid polypeptide that gives rise to glucagon, GLP-1 and GLP-2, and glicentin-related pancreatic peptide. Pre-proglucagon is processed differently according to the tissue in which the hormone is secreted, and a variety of glucagon analogs of varying potency can be produced. Glucagon acts on a glycoprotein receptor on target cells that mediates its action through a G-protein cyclic adenosine monophosphate (cAMP)/protein kinase A–mediated mechanism. Glucagon activates glycogen phosphorylase, the rate-limiting step in glycogenolysis, leading to increased glucose concentrations. Glycolysis is also inhibited. Glucagon is active in the liver (to regulate glucose levels), adipose tissue (where it increases lipolysis), heart (where it acts as an inotrope), and the gastrointestinal tract (where it causes relaxation). Glucagon secretion is influenced by diet and by insulin. Both glucagon and insulin release are stimulated by ingestion of amino acids, presumably to minimize hypoglycemia if a pure protein meal is taken. In normal individuals, glucagon release is stimulated by hypoglycemia, a defense mechanism to maintain serum glucose concentration homeostasis. This response is attenuated in the presence of type 1 DM.
Clinical Pharmacology and Clinical Application
Clinical preparations of glucagon are extracted from bovine and porcine pancreas because there is no structural difference between these preparations and human glucagon. The half-life of glucagon in plasma is 3 to 6 minutes, because it is broken down quickly in liver, kidney, plasma, and other sites.
Glucagon is used to treat severe hypoglycemia, especially in patients with DM when oral or intravenous (IV) administration of glucose is not possible. Intramuscular (IM), subcutaneous, or IV glucagon can be administered at a dose of 1 mg, with clinical improvement within 10 minutes. The anti-hypoglycemic effects of glucagon depend on the presence of adequate hepatic glycogen stores. The effect of glucagon is transient and steps should be taken to prevent recurrence of hypoglycemia after the initial effect has waned. Side effects include nausea and vomiting. Glucagon is also used to relax the gastrointestinal tract to improve imaging procedures and to treat biliary spasm and intussusception. It has also been used for its cardiac inotropic effects in instances of β-blocker overdose. It is contraindicated in patients with pheochromocytoma in that it can stimulate release of catecholamines from the tumor.
Somatostatin Analogs
Basic and Clinical Pharmacology
The somatostatins are actually a group of related peptides and include the original 14–amino acid peptide somatostatin, a 28–amino acid peptide, and a 12–amino acid peptide. They are released by pancreatic islets (delta cells), in the central nervous system, and in the gastrointestinal tract. The somatostatins act as inhibitors of the release of thyroid-stimulating hormone (TSH) and growth hormone (GH) from the pituitary, of insulin and glucagon from the pancreas, and of a number of vasoactive peptides from the gastrointestinal tract. Somatostatin has a half-life of less than 6 minutes, but longer-acting analogs such as octreotide and lanreotide have been developed.
Clinical Application
Somatostatin analogs are used to block hormone release in endocrine tumors. Octreotide and lanreotide are used for the treatment of carcinoid tumors, glucagonomas, VIPomas, and GH-secreting tumors. Octreotide, which has been available for longer in the United States, can be given intravenously or subcutaneously and is useful in the perioperative period. The drug is administered in 50- or 100-µg aliquots, either prophylactically or in response to hemodynamic instability, bronchospasm, or other manifestations thought to be secondary to release of vasoactive mediators. Long-term somatostatin analog use can lead to biliary abnormalities and gastrointestinal symptoms.
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