Endocrine Pharmacology

36 

Endocrine Pharmacology MARK T. KEEGAN

CHAPTER OUTLINE Drugs to Treat Disorders of the Endocrine Pancreas Insulin Basic Pharmacology Clinical Pharmacology Individual Insulin Preparations Regular Insulin Rapidly Acting Insulin Analogues Intermediate-Acting Insulin Long-Acting Insulins Inhaled Insulin Clinical Application Oral Hypoglycemic Agents: Sulfonylureas, Biguanides, Thiazolidinediones Basic Pharmacology Sulfonylureas Biguanides Thiazolidinediones Clinical Pharmacology and Clinical Application Sulfonylureas Biguanides Thiazolidinediones Other Oral Hypoglycemic Agents Glucagon Basic Pharmacology Clinical Pharmacology and Clinical Application Somatostatin Analogs Basic and Clinical Pharmacology Clinical Application Drugs to Treat Disorders of the Hypothalamic-Pituitary-End-Organ Axis Thyroid Hormones Basic Pharmacology Clinical Pharmacology Clinical Application Thioureylene Antithyroid Drugs Basic and Clinical Pharmacology Clinical Application Other Antithyroid Drugs Preparing a Patient With Hyperthyroidism for Surgical Intervention Drugs Used in the Treatment of Pheochromocytoma Basic and Clinical Pharmacology α Antagonists α-Methyl-para-tyrosine (Metyrosine) Clinical Application 708

Corticosteroids Basic Pharmacology Clinical Pharmacology Adverse Effects Clinical Application Adrenal Insufficiency Reactive Airways Disease Corticosteroid Therapy in Neurologic Critical Care Nausea and Vomiting Immunosuppression Treatment of Inflammatory Conditions Airway Edema Allergy Perioperative Steroid Supplementation Adrenocorticotropic Hormone and Steroid Antagonists Posterior Pituitary Hormones, Analogs, and Antagonists Basic and Clinical Pharmacology Vasopressin and Desmopressin Oxytocin Clinical Application Vasopressin and Desmopressin Oxytocin Other Agents Growth Hormone, Prolactin, and Related Drugs Growth Hormone Basic Pharmacology Clinical Pharmacology Clinical Application Drugs Related to Growth Hormone Drugs Affecting Prolactin Physiology Sex Hormones and Related Drugs Basic and Clinical Pharmacology The Gonadotropins Sex Steroids Clinical Application Gonadotropins Estrogens Hormonal Contraceptives Parathyroid Hormone and Drugs Affecting Calcium Metabolism Emerging Developments Glycemic Control in the Perioperative Period and in the Critically Ill Steroid Supplementation During Critical Illness Hormone Supplementation in Potential Organ Donors

CHAPTER 36  Endocrine Pharmacology 708.e1



Abstract

Keywords

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.

Endocrinology Pharmacology Diabetes mellitus Thyroid Adrenal Hormones

CHAPTER 36  Endocrine Pharmacology



D

ysfunction 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.1 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 1982.2

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).

709

TABLE 36.1  Hypoglycemic Actions of Insulin

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)

Modified from Table 60.2 in Brunton LL, ed. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 11th ed. New York, NY: McGraw Hill; 2006.

Insulin’s hypoglycemic actions on liver, muscle, and adipose tissue are most important (Table 36.1). 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. Insulin is among the drugs highlighted by the Institute for Safe Medication Practices as having an increased risk for patient harm

710

Gastrointestinal and Endocrine Systems

SE C T I O N V

TABLE 36.2  Insulin Preparations

Preparation

Onset (hr)

Peak (hr)

Effective Duration (hr)

Aspart Glulisine Lispro Regular

<0.25 <0.25 <0.25 0.5–1.0

0.5–1.5 0.5–1.5 0.5–1.5 2–3

3–4 3–4 3–4 4–6

NPH

1–4

6–10

10–16

Detemir Glargine

1–4 1–4

—a —a

20–24 20–24

75/25–75% protamine lispro, 25% lispro 70/30–70% protamine aspart, 30% aspart 50/50–50% protamine lispro, 50% lispro 70/30–70% NPH, 30% regular

<0.25 <0.25 <0.25 0.5–1

1.5 1.5 1.5 Dualb

Up to 10–16 Up to 10–16 Up to 10–16 10–16

Short-acting

Intermediate-acting Long-acting

Insulin combinations

Relative plasma insulin level

NPH, Neutral protamine Hagedorn. a Glargine and detemir have minimal peak activity. b Dual: two peaks, one at 2 to 3 hours; the second one several hours later. Copyright 2004 American Diabetes Association. Adapted with permission from Skyler JS. Insulin treatment. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus. Alexandria, VA: American Diabetes Association; 2004.

Aspart, lispro (4-6 hr) Extended zinc insulin (18-24 hr) Regular (6-10 hr) NPH (12-20 hr) Glargine (20-24 hr)

0

2

4

6

8

10

12

14

16

18

20

22

24

Hours

• Fig. 36.1

  Pharmacokinetic profiles of human insulin and insulin analogs. The approximate relative duration of action of the various forms of insulin is shown. Duration varies widely both between and within individuals. (From Hirsch IB. Insulin analogues. N Engl J Med. 2005;352:174–183.)

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.

CHAPTER 36  Endocrine Pharmacology



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.

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.3 Insulin glulisine has similar properties.

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.

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.

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 therapy4: • 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

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

Morning Afternoon Evening Night

Glargine B

L

S

HS

Insulin analog

A

B

B

Glargine (or detemir)

B • Fig. 36.2

Morning Afternoon Evening Night

Insulin effect

Night

Insulin effect

Insulin effect

Morning Afternoon Evening

L

S Regular

711

HS

B

Bolus Bolus Bolus Basal infusion

B

L

S

NPH

C

  Commonly used insulin regimens. A, Administration of a long-acting insulin-like glargine (detemir could also be used but often requires twice-daily administration) to provide basal insulin and a short-acting insulin analog before meals. B, A less intensive insulin regimen with twice-daily injection of neutral protamine Hagedorn (NPH) insulin providing basal insulin and regular insulin or an insulin analog providing mealtime insulin coverage. Only one type of shorting-acting insulin would be used. C, The insulin level attained after subcutaneous insulin (short-acting insulin analog) by an insulin pump programmed to deliver different basal rates. At each meal, an insulin bolus is delivered. Upward arrows show insulin administration at mealtime. B, Breakfast; HS, bedtime; L, lunch; S, supper. (Copyright 2008 American Diabetes Association. From Kaufman FR, ed. Medical Management of Type 1 Diabetes. 5th ed. Modified with permission from the American Diabetes Association.)

HS

B

712

SE C T I O N V

Gastrointestinal and Endocrine Systems

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. Intermediateacting 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+ [KATP]) channels in the β cells, causing calcium ion (Ca2+) 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 peroxisomeproliferator–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.5 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.6 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.7 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.8 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.9 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.10,11 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 KATP channels in pancreatic β cells

CHAPTER 36  Endocrine Pharmacology

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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 glucosedependent 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.12 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.13 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.

↓ GI glucose absorption Prolong endogenous GLP-1 action ↑ Insulin secretion

α-Glucosidase inhibitorsb

Low-calorie, low-fat diet, exercise

↓ Insulin, resistance ↑ Insulin secretion

Medical nutrition therapy and physical activityb

1–3

0.25–0.5

0.5–1.0

Not limited

0.5

0.5–1.4

1–2

Other health benefits

Reduce postprandial glycemia Weight loss

Weight loss

Known safety profile

Short onset of action Lower postprandial glucose Lower insulin requirements

Weight neutral Do not cause hypoglycemia Inexpensive Reduce postprandial glycemia Do not cause hypoglycemia Inexpensive

Agent-Specific Advantages

Injection Nausea ↑ Risk of hypoglycemia with insulin secretagogues Pancreatitis Injection Nausea ↑ Risk of hypoglycemia with insulin Compliance difficult Long-term success low?

Injection Weight gain Hypoglycemia

Peripheral edema CHF Weight gain Fractures Macular edema Rosiglitazone may increase risk of CV disease Constipation Dyspepsia Abdominal pain Nausea ↑ Triglycerides Interfere with absorption of other drugs Intestinal obstruction

Hypoglycemia Weight gain Hypoglycemia

Flatulence Liver function tests

Diarrhea Nausea Lactic acidosis

Agent-Specific Disadvantages

Agents that also slow gastrointestinal motility

Renal disease, agents that also slow gastrointestinal motility, pancreatitis

CHF, liver disease

Renal/liver disease

Reduce dose with renal disease Renal/liver disease

GFR < 50 mL/min, congestive heart failure, radiographic contrast studies, seriously ill patients, acidosis Renal/liver disease

Contraindications

GFR, Glomerular filtration rate; CHF, congestive heart failure; CV, cardiovascular; GI, gastrointestinal; GLP-1, glucagon-like peptide 1. 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. Adapted with permission from Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.

Pramlintide

Slow gastric emptying ↓ Glucagon

Exenatide, liraglutide

See text

Amylin agonistsb,c

GLP-1 agonistsb

Insulin

↑ Glucose utilization ↓ Hepatic glucose production and other anabolic actions ↑ Insulin ↓ Glucose Slow gastric emptying Satiety

Bind bile acids; mechanism of glucose lowering not known

Bile acid sequestrantsb

Parenteral

Rosiglitazone, pioglitazone

↓ Insulin resistance ↑ Glucose utilization

Thiazolidinedionesb

Colesevelam

Repaglinide, nateglinide

↑ Insulin secretion

0.5–1.0

Saxagliptin, sitagliptin, vildagliptin See text 1–2

0.5–0.8

1–2

HbA1c Reduction (%)a

Acarbose, miglitol

Metformin

Examples

SE C T I O N V

Dipeptidyl peptidase-4 inhibitorsb Insulin secretagogues -sulfonylureasb Insulin secretagoguesnonsulfonylureasb

↓ Hepatic glucose absorption

Biguanidesb

Oral

Mechanism of Action

TABLE 36.3  Therapeutic Agents for Diabetes Mellitus

714 Gastrointestinal and Endocrine Systems



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.2,14 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.

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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. Longterm somatostatin analog use can lead to biliary abnormalities and gastrointestinal symptoms.

DRUGS TO TREAT DISORDERS OF THE HYPOTHALAMIC-PITUITARY-END-ORGAN AXIS

Thyroid Hormones The physiology of the thyroid gland and of the hypothalamicpituitary-thyroid axis is discussed in Chapter 30.

Clinical Pharmacology and Clinical Application

Basic Pharmacology

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.

The endogenous thyroid hormones thyroxine (T4) and triiodothyronine (T3) can be used as pharmacologic agents. T4 is the prohormone product of the thyroid gland.15,12 The thyroid secretes 80 to 100 µg of T4 daily; its half-life in the circulation is 6 to 7 days. Thus missing a morning dose of replacement T4 on the morning of surgery has minimal impact. T4 is metabolized to biologically active T3 or biologically inactive reverse T 3. T3 (3,5,3-triiodothyronine) is formed by extrathyroidal deiodination of T4 (80%) and by direct thyroid secretion (20%). It is more potent and less protein bound than T4; its half-life in the circulation is 24 to 30 hours. T3 mediates most of the effects of thyroid hormones.

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

Clinical Pharmacology Thyroxine (levothyroxine sodium) (T4) is the hormone of choice for thyroid hormone replacement owing to its consistent potency and its duration of action. Usually given orally, 50% to 80% of the administered dose of thyroxine is absorbed in the small intestine. Absorption is increased by fasting and decreased by administration of a number of drugs including sucralfate, cholestyramine, and mineral supplements. Levothyroxine supplementation is monitored by assay of serum TSH levels, with a goal of achieving a normal TSH concentration. Most patients require 75 to 150 µg/day. Dose adjustments take approximately 5 weeks to induce a new serum steady state. In older patients and patients with cardiac disease, low-dose thyroxine supplementation should be started initially, with subsequent slow titration upward to avoid myocardial ischemia or arrhythmias. If enteral access is not possible, thyroxine can be prepared from a lyophilized powder and administered intravenously at 50% of the enteral dose.

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Liothyronine sodium (T3) is the salt of triiodothyronine. It is available in tablet and injectable forms. The average daily dose is 50 to 75 µg. Liothyronine is usually not used as primary replacement therapy because of its relatively short half-life. Thyrotropin alfa is recombinant TSH and is administered intramuscularly. It is used as an adjunctive diagnostic tool for testing of serum thyroglobulin and in association with radioiodine for ablation of remnants of thyroid tissue in patients with thyroid cancer. Common adverse effects include nausea and headache, paresthesias, arrhythmias, and hypersensitivity reactions.

Clinical Application Myxedema coma is a rare, extreme form of hypothyroidism. It usually occurs in older women with undiagnosed hypothyroidism, especially in the setting of intercurrent illness. It can present with mental status changes and severe metabolic derangements, including hyponatremia and hypoglycemia, and can lead to hypotension and hypoventilation. Myxedema coma is associated with relatively high mortality. Therapy includes mechanical ventilation and rewarming and administration of IV levothyroxine and hydrocortisone, the latter because 5% to 10% of patients also have adrenal insufficiency.

Thioureylene Antithyroid Drugs

than 300 to 400 mg of PTU or 30 to 40 mg of methimazole are usually not required. Thyrotoxicosis usually improves within 3 to 6 weeks. Pretreatment serum T3 concentrations, size of the goiter, and dose of medication administered all affect the rate of resolution of symptoms. Once the patient is euthyroid, typically within 3 months, the dose of antithyroid medication can be reduced. The drugs are usually not stopped, however, to reduce risk of recurrence of hyperthyroidism. Hypothyroidism can develop and necessitates reduction in dosage or even the administration of thyroid hormone supplementation. Some have advocated a “block and replace” technique, which involves administration of a full dose of antithyroid medication to completely suppress the thyroid gland, followed by supplementation with thyroid hormone once a euthyroid state has been reached. Neither the “gradual dose titration” nor the “block and replace” technique is unequivocally superior. Thyroid storm is a rare life-threatening exacerbation of hyperthyroidism that can be precipitated by surgical stress or intercurrent illness. It is more likely to occur with undiagnosed or untreated hyperthyroidism. It manifests as hyperthermia, agitation, confusion, and tachycardia. Patients can develop arrhythmias, myocardial ischemia, and congestive heart failure. The differential diagnosis includes pheochromocytoma and malignant hyperthermia, and light anesthesia can mimic some of the features. Treatment of thyroid storm often requires multiple antithyroid agents administered simultaneously.

Basic and Clinical Pharmacology

Other Antithyroid Drugs

Clinically used antithyroid drugs belong to the thioureylene class and include propylthiouracil (PTU), methimazole, and carbimazole. Carbimazole, used in Europe, is a prodrug of methimazole.15 Thioureylenes interfere with the incorporation of iodine into tyrosyl residues of thyroglobulin and inhibit the coupling of tyrosyl residues to form iodotyrosines. Blockade of the peroxidase enzyme prevents oxidation of iodide or iodotyrosyl groups to the active state. The coupling reaction might be more sensitive to antithyroid drugs than the iodination reaction. Inhibition of thyroid hormone synthesis leads to depletion of thyroid hormone stores and subsequently to a decrease in serum concentrations. PTU, but not methimazole, also inhibits peripheral conversion of T4 to T3 and has theoretical advantages in thyroid storm wherein such blockade of peripheral T3 production is useful. Both PTU and methimazole must be given enterally. Both drugs, but especially methimazole, can produce agranulocytosis, which seems to be dose related and can develop rapidly. The development of fever or pharyngitis in patients taking antithyroid medication should prompt evaluation including a complete blood cell count. The most common adverse effect of these drugs, however, is a mild, urticarial rash. Joint pain, headache, paresthesias, nausea, alopecia, and rarely vasculitis can also occur. Both drugs cross the placenta and appear in breast milk, although transfer is lower with PTU, making PTU the preferred agent in parturients and breastfeeding mothers.

β Blockers (see Chapter 13) can be used as adjunctive therapies to improve the signs and symptoms of hyperthyroidism. β Blockers blunt tachycardia, tremor, and anxiety associated with the condition but do not affect synthesis or secretion of T3 or T4. They should not be used as single-agent therapy except for brief periods before sodium iodide [131I] administration or before surgery. Iodide has been used for many years for the treatment of hyperthyroidism and was the only therapy available before the introduction of the antithyroid drugs. Administration of large doses of iodide acutely inhibits synthesis of iodotyrosines and thyroid hormones (known as the Wolff-Chaikoff effect). The mechanism of the acute Wolff-Chaikoff effect is unclear but might be due to antagonism of TSH and cAMP-stimulated thyroid hormone release or generation of organic iodo-compounds within the thyroid. Inorganic iodine (e.g., Lugol’s solution, which contains 5% iodine and 10% potassium iodide, or saturated solution of potassium iodide) is used in preparation for thyroidectomy in patients with thyrotoxicosis. Administered enterally, iodine is converted to iodide in the intestine. It can be given alone, but is usually given 7 to 10 days immediately preoperatively after thyrotoxicosis has been controlled with an antithyroid drug. Doses are determined empirically and range from 1 to 5 drops three times per day. Inorganic iodide decreases the uptake of radioactive iodine, with uptake being inversely proportional to serum iodine concentration. Iodide was administered to populations at risk after the Chernobyl nuclear accident as protection against thyroid cancer. Iodinated contrast agents (e.g., iopanoic acid, ipodate sodium) can be used as temporary treatment for hyperthyroidism of any cause. These agents block peripheral conversion of T4 to T3 and are useful for very symptomatic hyperthyroidism and thyroid storm. They are not currently available in the United States. Of the radioisotopes of iodine, 131I has been used most commonly as an antithyroid medication.16 It has a half-life of 8 days, meaning that the vast majority of its radioactivity has decayed within 60 days.

Clinical Application Antithyroid drugs are used as definitive treatment for hyperthyroidism, in conjunction with radioiodine for the treatment of Graves disease, and to control hyperthyroidism in preparation for surgical treatment. PTU is started at a dose of 100 mg every 8 hours or 150 mg twice daily. Methimazole, because of its relatively long duration of action, is given as a single daily dose. Doses of greater



It emits both β particles and gamma rays. 131I is administered orally in capsule or solution form, is taken up into the thyroid in the same manner as nonradioactive iodide, and is incorporated into monoiodotyrosine and diiodotyrosine and subsequently into thyroid hormones that are stored in the thyroid follicles. Radioactivity damages thyroid parenchymal cells. Carefully chosen doses of radioactive iodine cause destruction of the thyroid gland without damage to adjacent tissues. 131I is used to treat hyperthyroidism and is often the therapy of choice for Graves disease, especially in older patients and those in whom the disease has been difficult to control. Complete ablation of the thyroid is often recommended, with subsequent supplementation with L-thyroxine. More than half of patients to whom 131I is administered require only one dose, but in others second or subsequent doses are required. Even when complete ablation of the thyroid gland is not desired, many patients develop hypothyroidism. Administration of PTU, but not methimazole, reduces the effectiveness of 131I, presumably by blocking incorporation into thyroid hormone. 131I is contraindicated in pregnancy because of concern for damage to the fetal thyroid gland. Theoretically the drug can cause cancer, and so there are concerns about its administration to younger patients. However, extensive experience with 131I, as documented in the Cooperative Thyrotoxicosis Therapy Follow-up Study Group, has not demonstrated an increase in cancer mortality after 131I treatment for Graves disease.17 Another radioisotope of iodine, 129I, primarily emits gamma rays, has a shorter half-life than 131I, and is used for imaging of the thyroid gland.

Preparing a Patient With Hyperthyroidism for Surgical Intervention The steps to be taken to prepare a patient with hyperthyroidism for surgical intervention will depend on the urgency of the procedure. If emergency surgery is required, initiation of an esmolol infusion may be all that time allows, with titration to heart rate and blood pressure control. If cases are urgent rather than emergent, antithyroid medications may be administered, followed a few hours later by iodide. Elective surgery may be prepared for by administration of antithyroid drugs, Lugol’s iodine, and oral β blockers.

Drugs Used in the Treatment of Pheochromocytoma Basic and Clinical Pharmacology α Antagonists Phenoxybenzamine is a nonselective α-adrenergic receptor antagonist used in patients with pheochromocytoma or paraganglionoma. The drug blunts the effects of catecholamines released from the tumor and is usually administered preoperatively in preparation for pheochromocytoma resection. Phenoxybenzamine can cause a reflex tachycardia by inhibition of presynaptic α2 adrenoceptors at postganglionic neurons, resulting in increased release of norepinephrine. It also causes orthostatic hypotension, which can be mitigated by liberal salt and fluid intake. Despite the use of phenoxybenzamine, significant elevations of blood pressure can still occur, especially with intraoperative tumor manipulation. Once a pheochromocytoma has been isolated from the circulation and removed, hypotension is common, and the residual effects of phenoxybenzamine contribute to this hypotension as drug effects dissipate over about 36 hours. Phenoxybenzamine is usually

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administered in the outpatient setting at an initial dose of 10 mg orally twice daily, increased in 10-mg increments daily until arterial blood pressure has stabilized and symptoms have reduced. Average dose is 44 mg/day (range 10–240 mg/day), and most patients require 10 to 14 days of therapy.18 Selective α1-receptor antagonists include terazosin and prazosin. They do not cause reflex tachycardia, decreasing the need for preoperative β-receptor antagonists. They have a shorter duration of action, allowing adjustment before surgery and a shorter duration of hypotension after pheochromocytoma resection. In addition to their use in the management of patients with pheochromocytoma, selective α1 antagonists can also be used in the treatment of benign prostatic hyperplasia. Side effects include dizziness and muscle weakness. Doxazosin is a long-acting α1 blocker administered once daily. Use of doxazosin before pheochromocytoma resection provides hemodynamic control similar to phenoxybenzamine.19 Phentolamine is an α1 antagonist that can be given intravenously or intramuscularly. It can be used for management of hypertension associated with pheochromocytoma, especially in the perioperative period, when it is given intravenously in 5-mg doses. It has also been used for pralidoxime-associated hypertension. Phentolamine can also be administered subcutaneously in diluted form to decrease the effects of extravasation of α-adrenergic agonists and to reverse the effects of subcutaneously administered local anesthetics. The drug is metabolized in the liver and excreted in the urine.

α-Methyl-para-tyrosine (Metyrosine) α-Methyl-para-tyrosine is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the production of catecholamines. Administration reduces tumor stores of catecholamines, and can be used in the long-term management of patients with pheochromocytoma when surgery is contraindicated or when long-term management of malignant pheochromocytoma is required. It can also be used in the preoperative preparation of patients with pheochromocytoma. Metyrosine can be especially useful for patients with congestive heart failure in whom α blockers cause tachycardia and β blockers worsen congestive heart failure. The dose is 0.5 to 4 mg/day.

Clinical Application The optimal regimen for the preoperative preparation of a patient undergoing pheochromocytoma or paraganglionoma resection is controversial. Preoperative α blockade is widely—although not universally—considered necessary to minimize extreme perioperative hypertension and allow for a smoother perioperative course.20,21 The agents decrease blood pressure, prevent paroxysmal hypertensive episodes, increase intravascular volume, decrease myocardial dysfunction, and are thought to allow resensitization of adrenergic receptors. Published guidelines from the Endocrine Society recommend the use of α antagonists, but there have been reports (including a large case series) of successful pheochromocytoma resections in the absence of α blockade.20,21 Whether to use a selective or nonselective α blocker is also uncertain. Weingarten et al. compared preoperative regimens using either the nonselective agent phenoxybenzamine or a selective agent (prazosin, doxazosin, or terazosin) and found differences in the need for intraoperative pressors and volume administration but no differences in surgical outcome or length of hospital stay.22 Achieving satisfactory hemodynamic and symptom control in patients with pheochromocytoma can also involve use of calcium channel antagonists and β blockers. β Blockers are usually administered after α blockade has been established. They are

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contraindicated in the absence of α1 blockade because vasoconstriction may occur without opposition by vasodilating β2 receptors. β Blockade should be used cautiously in patients with catecholamineinduced cardiomyopathy. Calcium antagonists may be used on the basis that calcium is essential for catecholamine release from the adrenal medulla and norepinephrine-mediated transmembrane calcium influx influences tone in vascular smooth muscle. An international group described two different preoperative preparatory regimens for pheochromocytoma resection. 23 The authors advocated for the use of combination therapy with phenoxybenzamine, α and β blockers, and perhaps α-methyl paratyrosine in “high-risk” patients. In “low-risk” patients, α-methyl paratyrosine and calcium channel blockers might be sufficient.22 Intraoperative blood pressure control often requires use of readily titratable, rapidly acting vasodilators such as sodium nitroprusside and nicardipine (see Chapter 24) in addition to esmolol and the combined α and β antagonist, labetalol.

mineralocorticoids more powerfully cause distal renal tubular absorption of Na+. Many steroids have both properties. Hydrocortisone is synthetically produced cortisol, the primary glucocorticoid in humans, and is used as the reference steroid (Table 36.4). Transport of the steroid into the cytoplasm allows binding to cytoplasmic receptors, which translocate to the nucleus where they interact with glucocorticoid response elements in genes. Glucocorticoids repress or activate specific genes, interact with other transcription factors, modulate messenger ribonucleic acid, and alter protein production.25

Clinical Pharmacology Corticosteroid effects include alterations in protein, carbohydrate and lipid metabolic processes, preservation of cardiovascular and metabolic homeostasis, and actions on the nervous, endocrine, and immune systems.26 Steroids increase blood glucose, promote hepatic glycogen synthesis, and decrease sensitivity to insulin. Muscle tissue can be degraded, leading to negative nitrogen balance. Antiinflammatory effects are mediated by stabilization of lysozymes, diminishing leucocyte response to local inflammation, promoting the formation of inhibitor of nuclear factor κB (IκB), and inhibition of proliferation of activated T cells (Fig. 36.3). In plasma, glucocorticoids are bound to albumin and transcortin, the levels of which are altered by states such as liver disease or pregnancy. Free, unbound glucocorticoid exerts physiologic effects. Glucocorticoids are metabolized primarily in the liver where they undergo oxidation-reduction reactions to form dihydrocortisol and tetrahydrocortisol. These metabolites are conjugated with glucuronide or sulfate to water-soluble metabolites that are excreted in the urine. A small proportion of the water-soluble metabolites are eliminated via the intestine. The serum half-lives of the synthetic glucocorticoids vary considerably. Hydrocortisone has a half-life of 80 minutes, whereas dexamethasone has a half-life of 270 minutes. The duration of physiologic effects is determined by the effects on gene regulation, which usually last significantly longer than the half-life. Glucocorticoids can be

Corticosteroids In the 1940s, Kendall and Hench at Mayo Clinic used products of the adrenal gland, especially cortisol (hydrocortisone), to treat rheumatoid arthritis, opening the door to widespread use of “steroids” in medicine.24 The physiology of the hypothalamicpituitary-adrenal axis (HPAA) is described in Chapter 35.

Basic Pharmacology All steroids, both endogenous and synthetic, are based on the cyclopentanophenanthrene ring, to which side group substitutions can be added to alter the pharmacodynamic and pharmacokinetic profile. The adrenal cortex synthesizes two classes of steroids: the corticosteroids and the androgens. Corticosteroids have traditionally been divided into glucocorticoids and mineralocorticoids according to their relative effects on carbohydrate metabolism, sodium ion (Na+) retention, and inflammation. Glucocorticoids have more effect on carbohydrate metabolism and more potent antiinflammatory effects, whereas

TABLE 36.4  Pharmacokinetics and Pharmacodynamics of Commonly Used Steroids

Steroid

Antiinflammatory Potency

Equivalent Dose (mg)

Elimination Half-Time (hr)

Duration of Action (hr)

Sodium-Retaining Potency

Route of Administration

Cortisol

1

20

1.5–3.0

8–12

1

O, T, IV, IM, IA

Cortisone

0.8

25

0.5

8–36

0.8

O, T, IV, IM, IA

Prednisolone

4

5

2–4

12–36

0.8

O, T, IV, IM, IA

Prednisone

4

5

2–4

12–36

0.8

O

Methylprednisolone

5

4

2–4

12–36

0.5

O, T, IV, IM, IA, E

5

36–54

0

O, T, IV, IM, IA,

Betamethasone

25

0.75

Dexamethasone

25

0.75

3.5–5.0

36–54

0

O, T, IV, IM, IA

3.5

12–36

0

O, T, IV, IM, E

Triamcinolone

5

4

Fludrocortisone

10

2

Aldosterone

24

0

E, Epidural; IA, intraarticular; IM, intramuscular; IV, intravenous; O, oral; T, topical. From Elisha S, Ouellette RG, Joyce J. Pharmacology for Nurse Anesthesiology. Sudbury, MA: Jones and Bartlett Learning; 2011. Table 18.3.

250 3000

O, T, IV, IM

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Cortisol HO

NF-κB–activating signals TNF-α Interleukin 1 Lipopolysaccharide Viral proteins Cell membrane

CH2OH C=O OH

Membranebound receptors

O

Cortisone

ENDOTHELIAL CELL Cytoplasm

Type 2 IIβhydroxysteroid dehydrogenase

P Glucocorticoid receptor

p65

Nongenomic activation

HSP

Glucocorticoid receptor

Degraded IκB

κB

Anti-inflammatory proteins

p50

Inhibition

Induction

Inflammatory proteins

HSP

P

Repression

Nucleus

Genomic signaling

Glucocorticoidresponsive element

mRNA DNA-dependent regulation

P

P

Glucocorticoid receptors NF-κB element

p50 P

No mRNA

p65

Glucocorticoid receptors P

Protein inference mechanisms

• Fig. 36.3

  Antiinflammatory mechanisms of action of glucocorticoids. The three major antiinflammatory mechanisms are (1) nongenomic activation mediated by cytoplasmic glucocorticoid receptors, (2) genomic signaling involving DNA-dependent gene regulation via glucocorticoid receptor interaction with glucocorticoid response elements, and (3) protein interference mechanisms (e.g., nuclear factor kappa B [NF-κB] elements). Black arrows denote activation; the red line denotes inhibition; the red dashed arrows denote repression; and the red X denotes lack of product (i.e., no mRNA). HSP, Heat shock protein; mRNA, messenger RNA; P, phosphate; TNF, tumor necrosis factor. (From Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–1723.)

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TABLE 36.5  Tissue-Specific Side Effects of High-Dose or Prolonged Glucocorticoid Therapy

Tissue

Side Effects

Adrenal gland

Adrenal atrophy, Cushing syndrome

Cardiovascular system

Dyslipidemia, hypertension, thrombosis, vasculitis

Central nervous system

Changes in behavior, cognition, memory, and mood (i.e., glucocorticoid-induced psychoses, cerebral atrophy)

Gastrointestinal tract

Gastrointestinal bleeding, pancreatitis, peptic ulcer

Immune system

Broad immunosuppression, activation of latent viruses

Integument

Atrophy, delayed wound healing, erythema, hypertrichosis, perioral dermatitis, petechiae, glucocorticoid-induced acne, striae rubrae distensae, telangiectasia

Musculoskeletal system

Bone necrosis, muscle atrophy, osteoporosis, retardation of longitudinal bone growth

Eyes

Cataracts, glaucoma

Kidney

Increased sodium retention and potassium excretion

Reproductive system

Delayed puberty, fetal growth retardation, hypogonadism

From Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–1723.

administered orally, intravenously, and intramuscularly. Preparations are specifically designed for topical use, and steroids can also be administered into the epidural space, synovial spaces, conjunctiva, and respiratory tract. If the enteral route is not available, an equivalent dose can be administered intravenously. The intravenous route is used as first-line therapy for allergic reactions (including anaphylaxis), and in severely ill patients. Inhaled steroids are commonly used for reactive airways disease (usually by metered-dose inhaler), epidural steroids are a mainstay of therapy in certain pain disorders, and topical steroid preparations are used in dermatologic conditions. Fludrocortisone is the mineralocorticoid most commonly used in clinical practice. It is administered in association with glucocorticoids for primary and secondary adrenocortical insufficiency and for treatment of salt-losing adrenogenital syndrome. It is administered orally, and absorption is rapid and complete. The dose is 0.05 to 0.2 mg/day, although there is considerable interpatient variability. Its half-life is 18 to 36 hours. Side effects include congestive heart failure, hypertension, and edema.

Adverse Effects High-dose and/or long-term corticosteroid therapy can cause side effects in many organs (Table 36.5). Hypertension is caused by renal Na+ retention and potentiation of vasopressor responses to angiotensin II and catecholamines. In children, corticosteroids interfere with the proliferation and longevity of chondrocytes, thus slowing longitudinal growth. In adults, osteoporosis and an increased risk of fracture occur owing to adverse effects on osteoblast function. Corticosteroid-induced immunosuppressant effects on lymphocytes predispose to infection and interfere with wound healing. Although corticosteroids are used in the treatment of allergic reactions, patients can have allergic reactions to synthetic steroids. An allergy to a specific steroid can mean that the patient has an allergy to other synthetic steroids. Negative feedback effects of exogenous steroids can blunt the function of the HPAA, leading to absolute or relative adrenal suppression. This can lead to problems in stressful situations, such as during illness or in the perioperative period (see later text).

Clinical Application Adrenal Insufficiency Corticosteroid therapy is vital in patients with Addison disease. Hydrocortisone, a short-acting agent, is often used. Dosing recommendations include 5 mg/m2 body surface area three times per day, 10 mg in the morning and 5 mg in the evening, and 15 to 25 mg per day administered in two or three doses. These dosing regimens attempt to mimic physiologic steroid secretion, but early morning relative adrenal insufficiency can still occur. Longer-acting steroid preparations (prednisone, dexamethasone) can also be used, especially in those who are noncompliant with multiple dose regimens. Mineralocorticoids might also need to be administered, usually in the form of fludrocortisone, as mentioned earlier. Reactive Airways Disease Asthma and chronic obstructive pulmonary disease are inflammatory conditions in which corticosteroids are often used. Inhaled glucocorticoids are the agents of choice in the treatment of persistent asthma according to the National Asthma Education and Prevention Program. Regular treatment with steroids reduces symptom frequency, improves quality of life, decreases risk of serious exacerbations, and modulates bronchial hyperresponsiveness. In randomized controlled trials, inhaled budesonide decreases the incidence of asthma exacerbations more than placebo and inhaled terbutaline.27,28 Inhaled glucocorticoids can be administered by metered-dose inhaler, dry powder inhaler, or nebulizer. Oral and intravenous corticosteroids are also administered for exacerbations of asthma and chronic obstructive pulmonary disease, and oral agents can be used on a long-term basis for severe reactive airways disease. Corticosteroid Therapy in Neurologic Critical Care Glucocorticoids (usually dexamethasone) are administered in relatively large doses for the treatment and prevention of cerebral edema in patients with brain tumors and certain patients with bacterial meningitis.29 Despite encouraging experimental results, they have not been shown to improve outcome when administered to patients with ischemic stroke, intracerebral hemorrhage,



aneurysmal subarachnoid hemorrhage, and traumatic brain injury. Previously, methylprednisolone was often administered in the acute phase of spinal cord injury, although the evidence to support this was controversial, and current guidelines recommend against such practice.30–32

Nausea and Vomiting Dexamethasone is often used as prophylaxis against nausea and vomiting in the perioperative setting and in patients receiving chemotherapy, a practice supported by clinical trials and metaanalyses.33 In the perioperative period it works best when administered early in the surgical procedure, suggesting that its effects might be due to a decrease in the inflammatory effects of surgery.34 Modulation of endorphins might also play a role. Dexamethasone might also have a central effect on the chemoreceptor trigger zone. Immunosuppression Corticosteroids are used extensively for induction of immunosuppression in patients receiving solid organ transplants. They are given in high doses (e.g., methylprednisolone 500 mg) in the operating room and continued at lower doses for an indefinite period. Treatment of Inflammatory Conditions Steroids are used to treat rheumatoid arthritis, connective tissue diseases (e.g., polyarteritis nodosa, Goodpasture syndrome, Wegener granulomatosis), ocular inflammation (e.g., iritis, uveitis), myasthenia gravis, inflammatory bowel disease, and cutaneous disorders. In addition to systemic therapy, steroids can be administered rectally and topically for bowel and cutaneous disorders, respectively. Steroids are usually used in conjunction with other immunosuppressants to allow use of the lowest effective dose of each agent to minimize side effects. Airway Edema Corticosteroids (usually dexamethasone) are often administered prophylactically in the setting of surgical procedures that cause airway swelling (e.g., tonsillectomy, maxillofacial procedures) to decrease swelling and avoid airway compromise. Dexamethasone can also be administered as a treatment for airway compromise following extubation. A metaanalysis suggested that such a practice is supported by clinical data.35 Allergy Corticosteroids are important in the treatment of allergic reactions. In the perioperative and critical care setting, intravenous administration of hydrocortisone is a key component in the treatment of anaphylaxis. Perioperative Steroid Supplementation Worldwide, 1% to 3% of adults use long-term corticosteroids to manage a chronic condition. As many as 20% of these patients have taken oral glucocorticoids for more than 6 months and almost 5% of patients continue oral steroid therapy for more than 5 years.36 Such patients are at risk of adrenal suppression causing relative adrenal insufficiency in the perioperative period. Major surgery increases the daily production of cortisol from the usual 15 to 20 mg to 75 to 150 mg. There is considerable debate about the necessity of administering perioperative “stress” doses of steroids. Since the 1950s, there have been reports of perioperative deaths in patients with adrenal insufficiency. The incidence of hypotensive crises caused by adrenal insufficiency is low (1%–2%),

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but steroid supplementation has been justified on the basis that the risk of death is significant. Many have expressed concern, however, that perioperative steroid supplementation is overused. Patients can be divided into those likely or unlikely to have suppression of the HPAA. Patients taking the equivalent of 20 mg of prednisone per day or more or those who have a cushingoid appearance are likely to have adrenal suppression and should receive perioperative steroid supplementation. On the other hand, those taking steroids for less than 3 weeks and those using long-term alternate-day therapy are unlikely to have suppression of the HPAA axis and do not need perioperative supplementation. For intermediate doses of steroids when the state of the HPAA axis is indeterminate, consideration can be given to the performance of an ACTH test or patients can simply receive perioperative steroid supplementation. Recommended doses for steroid supplementation depend on the nature of the surgical procedure.37–39 For minor procedures (e.g., hernia repair) the usual morning steroid dose should be taken and no additional supplementation is required. For patients undergoing a procedure associated with moderate surgical stress (e.g., joint replacement), hydrocortisone 50 mg can be given before the procedure, and hydrocortisone 25 mg given every 8 hours for 24 hours postoperatively. Subsequently the patient should receive the usual steroid dose. If a major surgical procedure is being performed (e.g., esophagectomy), 100 mg of hydrocortisone should be given before induction and hydrocortisone 50 mg IV administered every 8 hours for 24 hours. Subsequent steroid supplementation should be tapered relatively quickly to baseline levels.

Adrenocorticotropic Hormone and Steroid Antagonists Corticotropin or ACTH is used diagnostically in the ACTH test for adrenal insufficiency and therapeutically for a variety of conditions, including acute exacerbations of multiple sclerosis, infantile spasms, and many rheumatologic and connective tissue diseases. Adverse effects are similar to those of the corticosteroids and include adrenal insufficiency after acute withdrawal. Spironolactone is a potassium-sparing diuretic that acts to antagonize the actions of aldosterone on distal renal tubules.40 It is used in the treatment of congestive heart failure, primary hyperaldosteronism, hypertension, and peripheral edema. Side effects include hyperkalemia, renal impairment, and gynecomastia. It is associated with tumor development in animals. Eplerenone is another aldosterone antagonist used to modify the renin-angiotensin-aldosterone system in patients with heart failure. It lacks the sexual side effects of spironolactone but might be more likely to cause hyperkalemia. Metyrapone and aminoglutethimide inhibit steroid synthesis. Metyrapone inhibits the 11-β-hydroxylation reaction, leading to a decrease in cortisol secretion and accumulation of 11-deoxycortisol. Mineralocorticoid deficiency does not occur because production of 11-deoxycorticosterone (a mineralocorticoid) is increased. It can be used in situations of excess glucocorticoid production from adrenal or extraadrenal tumors. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme (a desmolase), leading to a decrease in both cortisol and aldosterone production. Like metyrapone it is used in the treatment of tumor-induced steroid excess. The commonly used induction agent etomidate blunts steroid production by inhibiting 11-β-hydroxylation, and there has been considerable controversy regarding the appropriateness of its use in patients with septic shock, with metaanalyses producing conflicting results.41–43

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Posterior Pituitary Hormones, Analogs, and Antagonists The posterior pituitary (neurohypophysis) secretes oxytocin and antidiuretic hormone. The latter is also known as arginine vasopressin (AVP) or vasopressin. These agents, their analogs, and their antagonists are used in clinical practice, especially in obstetrics and critical care.

Basic and Clinical Pharmacology Vasopressin and Desmopressin AVP, a 9–amino acid peptide with a 6–amino acid ring and 3–amino acid side chain, is a powerful vasoconstrictor that works by stimulating specific G-protein–coupled receptors (V1 receptors) in the vasculature. It also acts on the renal collecting ducts where it increases permeability to water and results in the production of more concentrated urine. This effect is mediated by V2 receptors. V3 receptors (formerly called V1b receptors) are found in the anterior pituitary and are coupled to various second-messenger systems. They have a role in the secretion of ACTH.34,44 Other vasopressin-like receptors regulate the release of factor VIII and von Willebrand factor. Desmopressin acetate (also known as DDAVP) is a long-acting synthetic analog of vasopressin that has a much more pronounced antidiuretic effect and much weaker vasopressor properties than vasopressin. Compared with vasopressin, in desmopressin the first amino acid has been deaminated and the arginine at the eighth position is the dextro rather than levo form. Vasopressin can be administered intramuscularly or intravenously. It has a half-life in the circulation of about 15 minutes and is metabolized in the kidneys and the liver. Desmopressin can be given intravenously, subcutaneously, orally, or intranasally. It has a half-life of 1.5 to 2.5 hours. Oral bioavailability is less than 1%, but when given by the nasal route it is 3% to 4%. Adverse effects associated with use of vasopressin include headache and agitation. Abdominal pain and nausea can occur as the result of stimulation of abdominal smooth muscle and increased peristalsis. Allergic reactions, which include rashes, urticaria, and anaphylaxis, are rare. Hyponatremia with subsequent seizure activity can occur if an inappropriately high dose is administered. Thrombocytopenia can be caused by AVP-induced platelet aggregation mediated by V1 receptors.45 Extravasation can lead to skin necrosis and gangrene. Myocardial ischemia can occur at relatively high doses. Oxytocin Oxytocin is a cyclic nonapeptide structurally similar to AVP. The hormones differ by only two of their nine amino acids. An oxytocin precursor is produced by the paraventricular and supraoptic nuclei of the hypothalamus. After proteolysis, oxytocin is secreted by the posterior pituitary. There is also minor oxytocin release from regions of the hypothalamus, brainstem, and spinal cord. Oxytocin is synthesized to a significantly lesser extent in the ovary, uterus, and placenta. It is released in response to cervical dilation and suckling at the breast. Oxytocin plays an important role in pregnancy and labor, in which it stimulates the force and frequency of uterine contractions and milk ejection. It acts through G-protein–coupled receptors that are closely related to vasopressin receptors (see Chapter 30). Oxytocin is used to induce or augment labor in selected pregnant women.46,47 Adverse effects of oxytocin include water retention and hyponatremia; when used at high doses in patients to whom hypotonic fluids are administered, this can lead to seizures and coma. Intravenous administration of oxytocin causes vasodilation with subsequent

hypotension and reflex tachycardia. Hypotension can be severe in hypovolemic patients and in patients under anesthesia in whom compensatory reflexes are blunted. In contrast to the effects on the systemic vasculature, coronary vasoconstriction can occur.

Clinical Application Vasopressin and Desmopressin Both vasopressin and desmopressin can be used for treatment of pituitary DI, which can occur as the result of disruption of the posterior pituitary after neurosurgery or trauma or in the setting of postpartum hemorrhage. Desmopressin is typically used in a dose of 10 to 40 µg/day in two or three divided doses delivered by intranasal spray. It can also be given orally or intravenously. In the ICU it can be given intravenously in a dose of 1 to 4 µg once or twice daily as needed to treat polyuria, polydipsia, and hypernatremia of pituitary origin. Vasopressin has also been used in critically ill patients with bleeding esophageal varices or bleeding colonic diverticula. The doses required are relatively high and can cause coronary ischemia. Alternative therapies are more typically used now. In doses larger than those used for the treatment of DI, vasopressin causes vasoconstriction and increases in both systemic and pulmonary blood pressure by direct effects on vascular smooth muscle. When vascular tone is low, the vasoconstrictive effects are more powerful. Studies of AVP serum concentrations in shock states have shown there is relative AVP deficiency in patients with vasodilatory shock states such as sepsis. Administration of vasopressin in vasodilatory shock caused a dramatic increase in systemic blood pressure, even with acidemia, in which the effectiveness of catecholamines is reduced.48 Vasopressin use in critically ill patients has increased over the past 2 decades. It is used as an infusion at a dose of 0.03 units/min in septic shock. Its exact role has been debated; recommendations are that it be used as an adjunct to catecholamines rather than as a first-line single agent.49–51 The results of a large prospective study (Vasopressin and Septic Shock Trial [VASST]) comparing low-dose vasopressin to norepinephrine in patients with septic shock failed to show a significant difference in 28-day mortality (Fig. 36.4). 52 Vasopressin was introduced into algorithms for the treatment of cardiac arrest based on a prospective study that demonstrated effectiveness similar to that of epinephrine.53 A subsequent randomized control trial in patients who had sustained an out-of-hospital cardiac arrest, however, failed to demonstrate improved survival with vasopressin, and the drug has been removed from the most recent cardiac arrest management algorithms.50,54,55 In addition to its role in the treatment of DI, desmopressin is also used in patients with uremia, liver disease, and some types of hemophilia to improve hemostatic function. It releases von Willebrand factor, prostaglandins, and tissue plasminogen activator from endothelial cells via V2 receptors, increasing platelet adhesiveness. It can be used in the treatment of hemophilia A, mild to moderate von Willebrand disease type 1, and uremic platelet dysfunction. It is also used in the perioperative period, although the effectiveness of such therapy is debatable.56 Oxytocin Oxytocin is administered by intravenous infusion. A starting dose of 0.5 to 2 mU/min can be titrated upward in increments of 1 to 2 mU/min until the desired contraction pattern is established, and decreased when a satisfactory contraction pattern and adequate cervical dilation are present. Infusion rates of 6 mU/min provide

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Probability of survival

1.0 P = 0.127 at day 28

0.9

P = 0.10 at day 90

0.8 0.7 Vasopressin

0.6 0.5 0.4 0.0

Norepinephrine 0

10

20

30

40

50

60

70

80

90

• Fig. 36.4  Kaplan-Meier survival curves for patients with septic shock randomly asigned to receive vasopressin or norepinephrine. The dashed vertical line marks day 28. There was no significant difference in mortality rate calculated with the log-rank test. (From Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–887.)

Days since initiation of the study drug No. at risk Vasopressin 397 301 272 249 240 234 232 230 226 220 Norepinephrine 382 289 247 230 212 205 200 194 193 191

oxytocin levels similar to those of spontaneous labor; rates greater than 9 to 10 mU/min are rarely required, although high-dose oxytocin strategies have been used with doses of more than 20 mU/ min. As increased uterine contraction occurs, so too does an increase in the associated pain, and additional analgesia or adjustment of epidural analgesia might be required. Hyperstimulation leads to very frequent or sustained uterine contractions that can necessitate discontinuation of the infusion. Cessation of the infusion usually leads to rapid resolution of hyperstimulation because the plasma half-life of intravenous oxytocin is about 3 minutes. A low-dose oxytocin infusion administered as an “oxytocin challenge test” is performed in some pregnant women to assess fetal well-being. Oxytocin is also used as a therapy for postpartum hemorrhage.57 Ten units can be given intramuscularly, or 20 to 40 units diluted in a liter of crystalloid can be administered intravenously. If oxytocin fails to cause uterine contraction and postpartum hemorrhage is ongoing, administration of methylergonovine and/or prostaglandin F2 might be required.

Other Agents Terlipressin is a vasopressin analog, not currently available in the United States, with a longer duration of action than vasopressin. It is used with albumin administration for treatment of hepatorenal syndrome. Although it can improve short-term renal function and survival in patients with type 1 hepatorenal syndrome, there is a paucity of evidence demonstrating an effect on overall mortality.58,59 Vaptans are relatively new drugs that antagonize the effects of AVP.60 Tolvaptan selectively antagonizes the effects of AVP at V2 receptors in the renal collecting ducts, causing a marked, dosedependent increase in solute-free water excretion.61 In two multicenter trials, oral tolvaptan was effective in patients with euvolemic or hypervolemic hyponatremia, and is approved for the treatment of hyponatremia and heart failure.45,62 Conivaptan antagonizes V1a and V2 receptors, which, in conditions associated with increased vasopressin levels, decreases renal water excretion. It is used to treat hyponatremia and has been used successfully to treat hyponatremia in liver transplant candidates.63 Use of vaptans for the treatment of hyponatremia allows avoidance of fluid restriction and continuation of natriuretic diuretics (for treatment of ascites) and prevents development of hepatic encephalopathy. Conivaptan is not approved for treatment of congestive heart failure. The most frequent side effect of the vaptans is thirst. They can also theoretically cause rapid hypernatremia and renal failure owing to depletion of intravascular water.

Carbetocin is an analog of oxytocin, still under investigation, that has a longer duration of action than oxytocin. Atosiban is a peptide agent that antagonizes the actions of oxytocin for the treatment of preterm labor. Its clinical utility is still under consideration. Neither drug is currently available in the United States.64

GROWTH HORMONE, PROLACTIN, AND RELATED DRUGS

Growth Hormone Basic Pharmacology GH is secreted from the anterior pituitary in a pulsatile manner. Secretion is high in childhood, maximal around the time of puberty, and decreases with age. Pituitary secretion is under the control of GH-releasing hormone (GHRH) and somatostatin from the hypothalamus, which increase and decrease GH secretion, respectively. Ghrelin (from the stomach) and IGF-1 (which mediates GH effects in the periphery) negatively feed back on GH release. GH is actually a mixture of peptides. A polypeptide of 191 amino acids is most prominent, and a 176–amino acid polypeptide makes up approximately 10% of secreted GH. These are bound to a number of GH-binding proteins. GH binds to specific cell surface receptors that are widely distributed. The hormone stimulates the longitudinal growth of bones, increases bone density when the epiphyses have closed, stimulates chondrocyte formation, and increases muscle mass. GH acts on the liver to stimulate gluconeogenesis and on fat cells to promote fat breakdown. It stimulates production of IGF-1 in liver and many tissues, and it is through IGF-1 that its anabolic action is mediated.

Clinical Pharmacology Pharmaceutical GH is now produced by recombinant techniques, which has increased the safety of administration. Pharmacologic preparations include somatropin whose sequence matches that of native GH, and somatrem, a GH derivative. They have similar biologic activity but differ slightly in their method of preparation. The half-life of GH is less than 30 minutes, but its biologic half-life is up to 18 hours. GH is administered subcutaneously, once daily, or every second day, usually in the evening. Some preparations can also be given intramuscularly.

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Adverse effects of GH administration include raised intracranial pressure manifesting as nausea, vomiting, headache, and visual changes. This is a rare complication but warrants periodic ophthalmoscopy to assess for the presence of papilledema. There could be an increased risk of cancers including leukemia, although the link is tenuous. GH is antagonistic to insulin and administration increases the risk of type 2 DM. Scoliosis and epiphyseal injuries have been associated with excessively rapid growth. In adults, arthralgias, myalgias, carpal tunnel syndrome, and peripheral edema can occur.

Clinical Application GH is used as replacement therapy in children with short stature and severe GH deficiency. In addition, GH can be used in other conditions associated with short stature, including Prader-Willi syndrome, Turner syndrome, and (somewhat controversially) in idiopathic short stature. It is also used in wasting associated with AIDS and for patients with short bowel syndrome. Measurement of serum IGF-1 levels is used to monitor response in the initial phase of administration; later, change in height is assessed. The duration of GH therapy must be individualized, although some children with GH deficiency require continuation of GH supplementation into adulthood.

Drugs Related to Growth Hormone Sermorelin acetate is a synthetic analog of GHRH also available for treatment of GH deficiency. It is less effective than GH and not suitable for GH deficiency of pituitary origin. Recombinant human IGF-1 is also available for use in patients with GH resistance. Mecasermin is a complex of recombinant human IGF-1 and recombinant human IGF-binding protein-3 (rhIGFBP-3) used to treat children with severe IGF-1 deficiency unresponsive to GH. The rhIGFBP-3 is used to maintain an adequate half-life of the biologically active IGF-1. Subcutaneous administration can cause hypoglycemia and so should be given only around food ingestion. Elevations in intracranial pressure and liver blood tests can also occur. Pegvisomant is a GH receptor antagonist used in the treatment of acromegaly.65 It is administered subcutaneously once daily with dosage adjusted to serum IGF-1 levels. It can cause liver dysfunction and, theoretically, loss of negative feedback of GH and IGF-1 can lead to increased growth of GH-secreting tumors. Tesamorelin is an analog of GHRH used to treat HIV-associated lipodystrophy.

Drugs Affecting Prolactin Physiology Dopamine acts as an inhibitory transmitter for prolactin release. The release of prolactin from prolactin-secreting adenomas is also inhibited by dopamine and dopamine receptor agonists. Bromocriptine and cabergoline are ergot derivatives that act as dopaminereceptor agonists. Usually administered orally, they are useful in the treatment of hyperprolactinemia caused by prolactin-secreting pituitary tumors and in Parkinson disease, and can also be of use at higher doses in the suppression of GH release in acromegaly.66 The half-life of bromocriptine (7 hours) is shorter than that of cabergoline (65 hours). Longer-acting preparations of bromocriptine are available outside the United States. Side effects of dopamine agonists include headache, nausea and vomiting, postural hypotension, digital vasospasm, nasal congestion, nightmares, and insomnia. At high doses, pulmonary infiltrates and cardiac valvulopathies

can develop. Bromocriptine was used for suppression of lactation and decrease of breast size when breast feeding was not desired, but this is no longer recommended because of the potential for coronary thrombosis and stroke. Pramipexole is a dopamine agonist used in the treatment of Parkinson disease and restless legs syndrome.67

Sex Hormones and Related Drugs Because many of these drugs are essentially identical to their endogenous hormone counterparts, their basic and clinical pharmacology behavior (i.e., structure-activity, mechanism, metabolism, pharmacokinetics, and clinical effects) mimic those of the endogenous hormones. Sex steroids include androgens, estrogens, and progestins. Their physiology is reviewed in Chapter 30.

Basic and Clinical Pharmacology The Gonadotropins Gonadotropins include follicle-stimulating hormone (FSH) and luteinizing hormone (LH). They are produced by the gonadotroph cells in the anterior pituitary. In women, both LH and FSH are involved in the production of ovarian steroids and in the regulation of the ovarian cycle. In men, FSH regulates spermatogenesis and supports developing sperm. LH stimulates testosterone production by Leydig cells. Human chorionic gonadotropin (hCG) controls estrogen and progesterone production during pregnancy. The three hormones have identical α chains and unique β chains, although the β chains of LH and hCG are very similar. The gonadotropins are used in the treatment of infertility. They can stimulate spermatogenesis in men and induce ovulation in women. Preparations of FSH include urofollitropin (a purified preparation of FSH extracted from the urine of postmenopausal women), and follitropin α and follitropin β (recombinant preparations). Lutropin α is recombinant human LH. It is used in association with follitropin α to stimulate follicle development in infertile women with LH deficiency. FSH and LH are also contained in human menopausal gonadotropin, which is another extract obtained from the urine of postmenopausal women. hCG is purified from the urine of pregnant women or made by recombinant techniques when it is known as choriogonadotropin α. The former preparation is administered intramuscularly, the latter subcutaneously. It is typically used to cause final maturation of follicles and timed ovulation in assisted reproduction techniques. Adverse effects of gonadotropin treatment include depression and emotional lability, headache, edema, and antibody production. Gynecomastia can be associated with gonadotropin treatment in men and is related to the level of treatment-associated testosterone production. Sex Steroids Androgens and Androgen Antagonists

Androgens include testosterone, dihydrotestosterone, and related compounds. They act through a specific androgen receptor. Hepatic metabolism limits the systemic availability of orally administered drug, so parenteral preparations are commonly used. Testosterone is used when there is a deficiency of endogenous testosterone, in males with delayed puberty and hypogonadism, and for inoperable breast cancer. A variety of compounds that activate the androgen receptor are also used in clinical practice. Therapeutic uses include catabolic and wasting states and, controversially, enhancement of athletic performance. Male contraception is a potential use for



androgen administration but such therapy is still being refined. Administration of androgens is used to prevent attacks in both male and female patients with angioedema caused by C1-esterase inhibitor deficiency. Stanozolol and danazol, both of which are 17α-alkylated androgens, stimulate hepatic synthesis of the inhibitor. Danazol 200 mg is administered orally two to three times per day initially, with subsequent decrease in the long-term dose. If an attack occurs, dosage is increased by up to 200 mg/day. Side effects include hepatotoxicity and, rarely, benign intracranial hypertension. The drugs are also used to treat endometriosis and fibrocystic breast disease in women. Nilutamide, bicalutamide, and flutamide are androgen receptor antagonists used in the treatment of metastatic prostate cancer. Nilutamide commonly causes visual changes and is associated with interstitial pneumonitis in 2% of recipients. All three drugs can cause hepatotoxicity and gynecomastia. Cyproterone is a weak antiandrogen used to reduce hirsutism. Finasteride and dutasteride antagonize the enzyme (5α-reductase) that converts testosterone to dihydrotestosterone. They are used in the treatment of benign prostatic hyperplasia and male-pattern baldness. Impotence and gynecomastia can occur as a result of their use. Estrogens and Estrogen Antagonists

Estrogens and progestins are endogenous hormones that produce numerous physiologic actions, including developmental effects, control of ovulation and cyclical changes in the female reproductive tract, and actions on carbohydrate, protein, lipid, and mineral metabolism.68 Estrogens can be administered via oral, parenteral, transdermal, or topical routes. Oral drugs include estradiol, conjugated estrogens (including conjugated equine estrogens), esters of estrone and other estrogens, and ethinyl estradiol. The delivery of estrogens by transdermal patch allows a slow, sustained release of hormone to the systemic circulation. Preparations in oil are most suitable for intramuscular administration and have a prolonged duration of action. Estradiol and preparations of conjugated estrogen have been prepared for topical (vaginal) use. Systemic estrogens are bound to plasma proteins in varying degrees and metabolized in the liver. They also undergo enterohepatic circulation. Adverse effects of pharmacologic estrogen administration include nausea and vomiting, migraine headaches, breast tenderness, exacerbation of endometriosis, alterations in triglyceride and lipoprotein metabolism, increased risk of gynecologic malignancies, and increased risk of thromboembolic disease, especially in smokers.69,70 In addition to thromboembolic disease, use of oral contraceptives is associated with hypertension, cholelithiasis, and the development of benign hepatomas. Progestins and Progestin Antagonists

The progestins are compounds with actions similar to those of progesterone.68 They include progesterone, a naturally occurring hormone, pregnanes (17α-acetoxyprogesterone derivatives), estranes (19-nortestosterone derivatives), and gonanes (norgestrel and related compounds). The progestins are used for contraception, either alone or in association with an estrogen, and are administered with estrogen as hormone replacement therapy in postmenopausal women. Progestins can be used in the diagnosis of secondary amenorrhea and can be used to reduce endometrial hyperplasia induced by unopposed estrogens. Levonorgestrel is used as an emergency contraceptive measure. Mifepristone is an antiprogestin that can be used for termination of pregnancy. It is a derivative of the 19-norprogestin norethindrone and acts as a competitive

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antagonist at progesterone receptors. Mifepristone is orally active, has good bioavailability, and undergoes liver metabolism and enterohepatic circulation. Effects depend on the phase of the cycle in which it is administered. It can cause breakdown of the decidua, delay or prevent ovulation, and impair the development of a secretory endometrium. Ulipristal is another 19-norprogestin derivative that acts as a selective progesterone receptor modulator. It can be used as an emergency contraceptive for at least 72 hours after unprotected intercourse. Adverse effects include nausea, abdominal pain, and headache.

Clinical Application Gonadotropins In women with anovulation (e.g., those with polycystic ovarian syndrome or hypogonadotropic hypogonadism), gonadotropins are used to induce ovulation. They are also used for controlled ovarian hyperstimulation in assisted reproduction techniques. Careful monitoring of their effects using blood hormone concentrations and ultrasound visualization of the ovaries is required as they can cause ovarian hyperstimulation syndrome and multiple pregnancies. Ovarian hyperstimulation occurs in up to 4% of patients and, on occasion, a cycle might need to be abandoned because of the risk of hyperstimulation. Ovarian hyperstimulation results in painful ovarian enlargement, ascites, pleural effusions, and potentially intravascular volume depletion. Fever, ovarian cyst rupture, and thromboembolism can also occur. Treatment of infertility in men who have hypogonadism requires stimulation of FSH and LH by gonadotropins. hCG and human menopausal gonadotropins are administered for this purpose, although recombinant FSH and recombinant LH have been used more recently. Estrogens Estrogens are administered to decrease vasomotor symptoms, bone fractures, and urogenital atrophy in menopausal women. The long-term effects of estrogens on cardiovascular risk in postmenopausal women are a matter of debate.71,72 In addition, estrogens are commonly administered as a component (with progestins) of combination oral contraceptive regimens. The combination of hormones inhibits ovulation by a negative feedback mechanism that prevents release of FSH and LH. A less frequent, but accepted, indication for estrogen treatment is in the setting of failure of ovarian development (e.g., Turner syndrome) in which estrogens are administered to induce puberty. Selective estrogen receptor modulators are drugs that produce beneficial estrogen effects in some tissues (e.g., bone) and antagonize estrogen effects in others (e.g., breast), also with beneficial intent. Tamoxifen, administered orally, is the hormonal therapy of choice in women with early and advanced breast cancer and is used as palliative therapy in women with advanced breast cancer who have estrogen receptor–positive tumors. Adverse effects include hot flashes and increased risk of thromboembolic disease and endometrial cancer. It is metabolized in the liver by cytochrome P450 and induces the activity of some isoforms. Metabolism to its more potent 4-hydroxy metabolite is influenced by genetic polymorphisms. Toremifene is similar to tamoxifen in structure and activity. Raloxifene is used to reduce the risk of breast cancer in postmenopausal women and in the prevention and treatment of osteoporosis. It inhibits proliferation of estrogen receptor–positive breast cancer cells and has an antiresorptive effect on bone that leads to a reduction in the incidence of vertebral fractures.

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Clomiphene and fulvestrant antagonize the action of estrogen in all tissues. The former is used in the treatment of female infertility owing to anovulation. Administered orally, it increases gonadotrophin levels and enhances follicular recruitment. Adverse effects of clomiphene include ovarian hyperstimulation, multiple births, ovarian cysts, hot flashes, and visual changes. Prolonged use might increase the risk of ovarian cancer. Fulvestrant is used in patients with advanced breast cancer.

Hormonal Contraceptives Most oral contraceptives use a combination of an estrogen and a progestin, with a theoretical efficacy of greater than 99.9%.68 They are usually presented in 28-day packs, with pills for days 22 to 28 being inert. Preparations are monophasic, biphasic, or triphasic, depending on the relative amounts of estrogens and progestins, in an attempt to more closely mimic the natural menstrual cycle and limit the amount of hormone administered. Most preparations contain 30 to 35 µg of estrogen; those containing less than 35 µg are referred to as “low-dose.” Preparations containing a combination of norelgestromin and ethinyl estradiol are available as patches and as an intravaginal ring. Combination contraceptives act by influencing the hypothalamicpituitary-ovarian axis at multiple levels, but ultimately prevent ovulation, especially by suppressing FSH and LH. Adverse effects of combination oral contraceptives are related to the dose of estrogen used and newer low-estrogen preparations have decreased risks.73 Side effects include increased risk of venous thromboembolic disease, especially in women who smoke; myocardial infarction in smokers and those with other risk factors; hepatic adenomas and hepatocellular carcinoma; and cervical cancer in long-term oral contraceptive users who also have human papilloma virus infection. Combination oral contraceptives decrease the risk of endometrial and ovarian cancers. An association with breast cancer is controversial. Combination oral contraceptives are contraindicated in patients with active or previous thromboembolic disease, cerebrovascular disease, myocardial infarction, congenital hyperlipidemia, liver tumors or significant dysfunction, and certain cancers. The risk of cardiovascular side effects is significantly increased if combination oral contraceptives are administered to smokers older than 35 years. Progestin-only preparations are also available. They block ovulation in only 60% to 80% of cycles but cause a thickening of cervical mucus that decreases sperm penetration and causes endometrial alterations that impair implantation. They have a slightly decreased theoretical efficacy (99%) compared with combination preparations. They are taken in pill form, administered intramuscularly or placed subdermally or intravaginally. Side effects include breakthrough bleeding, headache, and alterations in lipid metabolism. The progestin-only preparations are contraindicated in liver disease, breast cancer, and undiagnosed vaginal bleeding.

Parathyroid Hormone and Drugs Affecting Calcium Metabolism Parathyroid hormone (PTH) helps regulate extracellular fluid Ca2+ concentration.74 It influences bone osteoclast activity, renal distal tubular reabsorption of Ca2+, and gastrointestinal Ca2+ absorption, the latter through its regulation of the synthesis of 1,25 dihydroxycholecalciferol (calcitriol). PTH also affects renal absorption of phosphate and bicarbonate. PTH secretion is regulated primarily by serum [Ca2+] and is influenced by phosphate, magnesium ion, and catecholamine levels.75 The actions of PTH on metabolism

are shown in Fig. 36.5. See Chapter 30 for a more detailed discussion of PTH physiology. PTH is derived from pre-proparathyroid hormone, and subsequently from proparathyroid hormone, neither of which appears in plasma. During periods of hypocalcemia, PTH secretion is increased. The half-life of PTH in the plasma is 2 to 5 minutes. It is cleared mainly by the liver and kidneys. The physiologic effects of PTH on target tissues are mediated by PTHspecific G-protein–coupled receptors. With high levels of circulating PTH (e.g., in primary hyperparathyroidism), bone demineralization and osteopenia occur. PTH can be administered intermittently, however, and this promotes bone growth. Teriparatide is recombinant human PTH 1-34 (a 34–amino acid terminal PTH fragment) used for the treatment of osteoporosis in postmenopausal women at high risk for fracture, as well as hypogonadal or primary osteoporosis in men and osteoporosis resulting from glucocorticoid administration.76 Teriparatide reduces the risk of vertebral and nonvertebral fractures. Given via the subcutaneous route, it causes an increased serum Ca2+ that peaks at 4 to 6 hours. Adverse effects include transient hypercalcemia, orthostatic hypotension, chest pain, and syncope as well as gastrointestinal upset. It is also associated with the development of osteosarcoma in animals. Vitamin D is used therapeutically for prevention and treatment of osteoporosis; prophylaxis against, and cure of, nutritional rickets; treatment of chronic renal failure metabolic rickets osteomalacia; and hypoparathyroidism. A number of preparations are available. Calcitriol (1,25-dihydroxy cholecalciferol) is administered orally or by injection. Doxercalciferol (1α-hydroxyvitamin D2) is administered orally or intravenously for the treatment of secondary hyperparathyroidism. It requires activation in the liver by 25-hydroxylation. Dihydrotachysterol is another form of vitamin D that requires activation in the liver. At high doses it mobilizes bone mineral and is used in the treatment of hypoparathyroidism. Ergocalciferol is used for prevention of vitamin D deficiency as well as therapeutically for the treatment of hypoparathyroidism, certain types of rickets, and familial hypophosphatemia. Calcitonin is a single-chain peptide hormone secreted by the parafollicular C cells of the thyroid. It circulates in very low concentrations in plasma and causes hypocalcemia and hypophosphatemia by inhibition of osteoclastic bone resorption. The actions of calcitonin oppose those of PTH, although it does not appear essential for Ca2+ homeostasis. It is used pharmacologically to treat hypercalcemia (especially hypercalcemia related to malignancy), osteoporosis, and Paget disease. The therapeutic agent is derived from salmon or eel and administered subcutaneously, intramuscularly, or intranasally. Side effects are usually associated with the nasal route of administration and include rhinitis, flushing, back pain, and rare allergic reactions. Cinacalcet mimics the effect of Ca2+ to inhibit PTH secretion (i.e., it is a calcimimetic) and lowers the concentration of Ca2+ at which PTH secretion is suppressed. It is used for the treatment of secondary hyperparathyroidism owing to chronic renal disease and for patients with hypercalcemia associated with parathyroid carcinoma. Cinacalcet can cause hypocalcemia, which is especially problematic in patients prone to seizures. Pyrophosphate analogs with two phosphate groups attached to a central carbon are known as bisphosphonates.77 The bisphosphonates have a strong affinity for bone because their physical structure allows them to chelate Ca2+. They inhibit bone resorption by concentrating at sites of active remodeling where they are absorbed into the bone matrix and subsequently inhibit osteoclasts. They also decrease osteoclast numbers. Members of this class include

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CaSR Parathyroid cell

Low serum Ca2+ sensed through CaSRs

Low Ca2+

Parathyroid glands

PTH

Intestine

PTH Bone resorption Bone

1,25(OH)2D

Increased Ca2+ reabsorption, decreased PO43– reabsorption

Increased Ca2+ and PO43–

25(OH)D

Kidney Increased Ca2+ and PO43– into serum (normal range restored)

• Fig. 36.5  Control of mineral metabolism by parathyroid hormone. Levels of serum ionized calcium (Ca2+) are tightly controlled through the action of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25[OH]2D). Both the rate and magnitude of changes in serum ionized Ca2+ concentration are detected by extracellular Ca2+-sensing receptors (CaSRs) expressed on parathyroid cells. When ionized Ca2+ decreases, release of PTH is triggered. Conversely, when ionized Ca2+ levels increase, PTH secretion is suppressed. PTH stimulates bone resorption, which delivers Ca2+ and phosphorus (PO43−) into the circulation. In the kidney, PTH stimulates renal reabsorption of Ca2+ and promotes phosphate excretion. PTH also enhances the conversion of 25-hydroxyvitamin D (25[OH]D) to the active vitamin D metabolite 1,25(OH)2D, which increases transepithelial transport of Ca2+ and PO43− through actions in intestinal cells. In concert, these steps restore ionized Ca2+ to the normal range, and through the actions of PTH and other factors (e.g., fibroblast-derived growth factor 23) in the kidney, reset the level of serum PO43− within the normal range. When the actions of PTH are reduced or lost, subsequent steps in the maintenance of homeostasis are impaired, resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. (From Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008;359:391–403.)

etidronate, zoledronate, pamidronate, alendronate, tiludronate, and risedronate. Bisphosphonates have limited bioavailability (1%–6%) when given orally because they are very poorly absorbed from the gastrointestinal tract and can be given intravenously to avoid this problem. Excretion is primarily renal, and poor renal function is a relative contraindication. Zoledronate can be nephrotoxic. The bisphosphonates—especially the first-generation bisphosphonate etidronate— can cause osteomalacia and esophagitis. Although hypocalcemia associated with their use is unusual, it can occur especially in patients with malignancy. Intravenous administration can cause myalgias and fevers. Oral bisphosphonates increase phosphate retention in the tubules. The bisphosphonates are used in postmenopausal osteoporosis, Paget disease, corticosteroidassociated bone loss, and hypercalcemia due to malignancy.78 They are also used for patients with multiple myeloma and metastatic breast cancer. They can be given as infrequently as weekly or monthly.

Emerging Developments Glycemic Control in the Perioperative Period and in the Critically Ill There is considerable controversy regarding optimal blood glucose concentration in the perioperative period and in critically ill patients.79 Significant hyperglycemia is associated with multiple adverse effects including increased incidence of surgical site infections. Certain patient populations are adversely affected by hyperglycemia (e.g., patients with acute myocardial infarction, neurologic injury). In 2001, a single-center study suggested that targeting “tight” glycemic control (80–110 mg/dL; 4.4–6.1 mM) in critically ill patients improved outcomes.80 Over the course of the subsequent decade, glycemic control targets were lowered and the use of insulin infusions in the ICU became commonplace. Many practitioners extrapolated these data and targeted tighter

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glycemic control in the operating room. Quality initiatives also encouraged tighter glycemic control. However, the potential for hypoglycemia exists when intensive insulin therapy is used. Hypoglycemia is associated with adverse neurologic outcomes and is a feared perioperative complication. Further data suggested that hypoglycemia in critically ill patients was independently associated with poor outcome. A number of studies and metaanalyses failed to demonstrate beneficial effects of “tight” glycemic control and raised the question of whether the practice was, in fact, detrimental. For example, the VISEP (Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis) study was stopped early because the use of intensive insulin therapy to maintain normoglycemia was associated with adverse events in patients with sepsis.81 The NICE-SUGAR (Normoglycemia in Intensive Care Evaluation– Survival Using Glucose Algorithm Regulation) study, a prospective multicenter, multinational randomized controlled trial comparing tight glycemic control (target glucose 81–108 mg/dL; 4.5–6 mM) with conventional glycemic control (target glucose <180 mg/dL; 10 mM) failed to demonstrate a beneficial effect of intensive insulin therapy and, in fact, demonstrated increased mortality in the intensive insulin therapy group (Fig. 36.6).82 Current guidelines suggest that in-hospital glucose levels should be kept between 140 and 180 mg/dL (7.8–10 mM).83

107

142

Intensive control

0.030

Density

0.025 0.020 Conventional control

0.015 0.010 0.005 0.000

A

0

50

100

150

200

250

Time-weighted mean blood glucose level (mg/dL)

Probability of survival

1.0

Steroid Supplementation During Critical Illness Steroid supplementation in the setting of severe sepsis and septic shock has also been a topic of debate over the past decade. Adrenal insufficiency can be a feature of the so-called endocrinopathy of critical illness. A “functional” or “relative” adrenal insufficiency has been described and called critical illness-related corticosteroid insufficiency, though there is considerable debate regarding its definition.84 Initial data suggested that supplementation with hydrocortisone and fludrocortisone in patients with septic shock improved outcomes.85 The choice and dose of steroids, the need for performance of an ACTH test (and the dose of ACTH if performed), the duration of steroid use, and the choice of patients in whom steroid supplementation is necessary are controversial. Recent multicenter studies, however, have failed to demonstrate any benefit to steroid administration in septic shock unless the patient has preexisting adrenal insufficiency.86,87 The CORTICUS (Corticosteroid Therapy of Septic Shock) study was a multicenter, randomized, double-blind placebo controlled trial of 499 patients enrolled within 72 hours of the onset of septic shock. Hydocortisone administration did not improve 28-day mortality overall, nor was there improvement in the subgroups of patients with and without adequate adrenal reserve.86 Steroid administration lead to a faster reversal of shock but may have contributed to an increased risk of infection. Analysis of data from almost 9000 patients in the Surviving Sepsis Campaign database demonstrated an increase in mortality in patients treated with steroids.88 The HYPRESS (Hydrocortisone for Prevention of Septic Shock) study demonstrated that in patients with sepsis, but without septic shock, use of hydrocortisone did not reduce the risk of shock.89 High-dose corticosteroid administration in the early phase of the acute respiratory distress syndrome (ARDS) does not offer significant advantages. Low-dose steroids have been used in the fibroproliferative stage of ARDS to decrease the fibrosing alveolitis. The multicenter LASRS (Late Steroid Rescue Study) demonstrated that in patients in whom ARDS had been present for 7 days, administration of a course of methylprednisolone allowed earlier liberation from mechanical ventilatory support, but ultimately no difference in outcome.90 Glucorticoids are useful, however, in ARDS

40

0.035

0.9

0.8

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0.6 0.0

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10

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30

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50

60

70

80

90

Days after randomization

B

No. at risk Conventional control Intensive control

3014 3016

2379 2337

2304 2227

2261 2182

• Fig. 36.6

  A, Density plot for the mean time-weighted blood glucose levels for individual patients in the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) study. Dashed lines indicate the modes in the intensive control group (blue) and the conventional control group (purple), as well as the upper threshold for severe hypoglycemia (40 mg/dL). B, Kaplan-Meier plots demonstrating improved survival with conventional glycemic control versus intensive glycemic control (P = 0.03) in the NICE-SUGAR study. (From NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297.)

caused by certain conditions, including acute eosinophilic pneumonia and engraftment syndrome after hematopoietic stem cell transplantation, when they should be administered in high doses.

Hormone Supplementation in Potential Organ Donors Brain death leads to derangement of the hypothalamic-pituitary axis, and hormonal supplementation has been advocated as a means to maintain hemodynamic stability and metabolic homeostasis. Such management might ultimately result in an increase in the number of organs available for procurement from suitable patients and subsequent transplantation.91 Corticosteroids are thought to attenuate the effects of inflammatory cytokines generated as a result

CHAPTER 36  Endocrine Pharmacology



of brain death and seem to improve oxygenation in donor lungs.92,93 Whether they improve survival of donor kidneys or hearts is uncertain. Vasopressin has beneficial effects on hemodynamics, and desmopressin is useful in the treatment of DI to help with sodium management. Although numerous case series and retrospective audits reported a beneficial effect of thyroid hormone administration to patients in whom brain death had occurred, a metaanalysis of four placebo-controlled randomized trials failed to show an advantage.94,95 Nonetheless, the practice continues based on theoretical grounds. In general, there is a paucity of good evidence on which to decide whether or not to administer hormonal supplementation to potential

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organ donors in whom brain death has occurred. The evidence is further confounded by the variety of drugs and doses that have been used.96 In an attempt to standardize practice, a consensus statement has been published by critical care and organ procurement organizations.97 Recommendations include administration of four drugs: methylprednisolone, 15 mg/kg91; T3 (4-µg bolus, then an infusion at 3 µg/hr) or T4 (20 µg bolus, followed by an infusion at 10 µg/hr); arginine vasopressin (0.01–0.04 IU/min) for hemodynamic support and/or desmopressin (initial dose 1–4 µg); and insulin (titrated according to institutional protocols for hyperglycemia).94 Further data are expected.

Key Points • Endocrinologic therapeutic interventions range from supplementation of missing endogenous hormones (e.g., insulin in DM) to complex manipulations of hormones and receptors using synthetic drugs (e.g., assisted reproduction techniques). • Treatments for hyperglycemia include administration of insulin in patients with type 1 and type 2 DM and a variety of insulin secretagogues and other OHAs in patients with type 2 DM. • Thyroid hormone supplementation includes administration of T4 (usually) or T 3. Antithyroid medications are used in hyperthyroidism. • Management of pheochromocytoma and paraganglioma involves the use of α- and β-adrenoreceptor antagonists, inhibitors of catecholamine synthesis, and direct-acting vasodilators.

• Corticosteroids are among the most widely used pharmaceuticals. Perioperatively, careful consideration must be given to appropriate adrenal supplementation in patients with adrenal suppression. • Oxytocin, a hormonal product of the posterior pituitary, has long been used in obstetric practice. There is considerable recent interest in use of the other posterior pituitary hormone, arginine vasopressin, in patients with hemodynamic instability and septic shock. • Finely regulated Ca2+ homeostasis is influenced by parathyroid hormone and vitamin D analogs and by calcitonin and the bisphosphonates.

Key References

plasma levels are inappropriately low in vasodilatory shock, which led to a new therapeutic intervention. (Ref. 48). NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283–1297. An international prospective randomized control trial of more than 6000 critically ill adults comparing intensive glucose control with conventional glucose control. This landmark study demonstrated that, contrary to previous data, intensive glycemic control increased mortality. (Ref. 82). Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124. A multicenter, randomized, double-blind, placebo-controlled trial that compared administration of intravenous hydrocortisone with placebo in patients with septic shock. Hydrocortisone did not improve survival or reversal of shock either overall or in patients who did not have a response to ACTH. (Ref. 86). Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–1684. A prospective, randomized trial from the Acute Respiratory Distress Syndrome Network (ARDSNet) in 180 patients with persistent ARDS that demonstrated lack of benefit and potential harm from the nonselective use of steroids. (Ref. 90).

Banting FG, Best CH, Collip JB, et al. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J. 1922;12:141–146. The original description of the use of insulin for the treatment of diabetes mellitus, work that resulted in a Nobel Prize. (Ref. 1). Haahtela T, Jarvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med. 1991;325:388–392. A prospective, randomized trial in patients with recently diagnosed, mild asthma, demonstrating the superiority of antiinflammatory therapy with inhaled budesonide over the use of inhaled terbutaline. (Ref. 28). Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever, and certain other conditions. Arch Intern Med (Chic). 1950;85:545–666. The original description of the use of corticosteroids for the treatment of rheumatoid arthritis and other inflammatory conditions, which resulted in a Nobel Prize. (Ref. 24). Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613. In a study of more than 2700 postmenopausal women with established coronary disease, administration of estrogen and progesterone did not reduce the overall rate of cardiovascular events (Ref. 71). Kotloff RM, Blosser S, Fulda GJ, et al. Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement. Crit Care Med. 2015;43:1291– 1325. A consensus statement involving members of the intensive care and transplant communities focusing on maximizing use of organs recovered from donors in whom brain death has occurred. Specific recommendations for hormonal supplementation have been incorporated into many management protocols. (Ref. 97). Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122– 1125. A small but important study demonstrating that vasopressin

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CHAPTER 36  Endocrine Pharmacology

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