Endocrinology

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Chapter 14 Endocrinology

α-Glucosidase Inhibitors (AGIs)

Description

α-Glucosidase inhibitors (AGIs) are agents that reduce blood glucose by inhibiting the breakdown of carbohydrates to glucose in the gut.

Prototype and Common Drugs

image Prototype: acarbose
image Others: miglitol, voglibose

MOA (Mechanism of Action)

image Glucosidases (GSs) such as maltase, dextranase, sucrase, and glucoamylase aid in carbohydrate absorption by cleaving complex carbohydrates to yield glucose. Only monosaccharides such as glucose or fructose can be absorbed into the bloodstream (Figure 14-1).
image The AGIs are carbohydrate analogues that bind reversibly and with much greater affinity than carbohydrates to these GS enzymes.
image The competitive inhibition of these GSs delays the absorption of carbohydrates along the gastrointestinal (GI) tract. These agents are therefore useful in reducing the spike in blood sugar that occurs after a meal.
image The different AGIs differ slightly in the target enzymes they inhibit. Acarbose also has a small effect on α-amylase, whereas miglitol inhibits isomaltase and β-glucosidases. The β-glucosidases cleave β-linked sugars such as lactose.
image

Figure 14-1

Pharmacokinetics

image Acarbose is meant to act locally in the GI tract and therefore has minimal systemic bioavailability (approximately 2%).
image Metabolism occurs within the GI tract, by the action of intestinal bacteria and digestive enzymes.

Indications

image Diabetes mellitus (type 2), for:

image Predominantly postprandial hyperglycemia
image New-onset diabetes with mild hyperglycemia

Contraindications

image Irritable bowel syndrome (IBS), inflammatory bowel disease: The GI side effects associated with the use of AGIs (see later) may exacerbate the symptoms of IBS.

Side Effects

image GI (flatulence, bloating, abdominal discomfort, diarrhea): GI side effects are all caused by the actions of bacteria on undigested carbohydrates that reach the large intestine. The carbohydrate load that reaches the large intestine is a substrate for bacteria, which generate gas when they consume the carbohydrate. This side effect seems to be reduced with time, possibly because of an up-regulation of α-glucosidase enzymes in the distal small intestine.
image Hypoglycemia: Hypoglycemia is typically seen only with concomitant administration of sulfonylureas. The hypoglycemia should be managed with glucose and not sucrose, as the breakdown of sucrose might be inhibited by the actions of the α-glucosidase inhibition.

Rare

image Increased serum aminotransferases: Reversible elevations in aminotransferase levels (one of the liver enzymes) have been seen with these agents, although this is considered to be a rare phenomenon.

Important Notes

image The effects of AGIs are generally considered additive to those of other antidiabetics.
image Acarbose has been shown in some studies to have potential beneficial cardiovascular effects beyond that of simply lowering blood glucose.
image Because of their mechanism of action, namely reducing postprandial glucose levels, there has been considerable interest in the potential for AGIs to prevent onset of type 2 diabetes mellitus. Postprandial hyperglycemia is considered to be an early warning sign for development of type 2 diabetes. The STOP-NIDDM trial was a large (N = 1429 participants) double-blind randomized controlled trial that found that the number needed to treat (NNT) for preventing one new case of diabetes over 3 years was 11 for acarbose. Given that these results are from only one study, they should be interpreted with caution; however these findings do suggest further investigation is warranted.

Evidence

α-Glucosidase Inhibitors versus Placebo or Other Antidiabetics in Type 2 Diabetes Mellitus

image A 2005 Cochrane review (41 trials, N = 8130 patients) included studies largely 24 to 52 weeks in duration, with all the various AGIs. Few data on mortality, morbidity, or quality of life were available. The AGIs improved surrogate markers such as HbA1c (−0.8%), fasting blood glucose (−1.1 mmol/L), and postload blood glucose (−2.3 mmol/L) versus placebo.

FYI

image Lactase is a β-glucosidase that breaks down lactose, a disaccharide composed of glucose and galactose. Because acarbose is specific for α-glucosidases, the metabolism of lactose is unaffected.

Biguanides

Description

Biguanides reduce blood glucose without stimulating insulin secretion.

Prototype

image Metformin

MOA (Mechanism of Action)

image There are several proposed mechanisms behind the glucose-reducing effects of biguanides (Figure 14-2):

image Reduced gluconeogenesis

• Gluconeogenesis is the formation of glucose from noncarbohydrate precursors.
• Adenosine monophosphate (AMP) kinase is believed to mediate some of this effect by inhibiting enzymes involved in gluconeogenesis.
• AMP kinase plays a role in energy homeostasis and has become a focal point for research into new therapies for diabetes mellitus and other metabolic conditions.

image Increased action of insulin in muscle and fat

• This is also believed to occur through stimulation of the actions of AMP kinase.

image Delayed glucose absorption from GI tract
image Direct stimulation of glycolysis in tissue with increased glucose removal from blood

• Glycolysis is the breakdown of glucose.

image Reduced plasma glucagon

• Glucagon is a hormone that increases glucose levels by breaking down glycogen.

image

Figure 14-2

Pharmacokinetics

image Metformin is not metabolized and is excreted in urine unchanged. Renal clearance occurs mainly through tubular secretion.

Indication

image Type 2 diabetes mellitus

Contraindication

image Metabolic acidosis: See Side Effects.

Side Effects

image GI: Abdominal pain, nausea, diarrhea. Mechanism unknown.
image Reduced absorption of vitamin B12 and folate: Mechanism is unknown, but the risk of reduced vitamin B12 appears to increase with dose and duration of therapy.
image Hypoglycemia: There is a low risk of hypoglycemia.

Serious

image Lactic acidosis (rare): Typically not seen at recommended doses. Patients who have renal impairment are at higher risk. Metformin must be discontinued if this occurs.

Important Notes

image Because metformin does not stimulate the release of insulin, it is less likely to cause hypoglycemia than the oral hypoglycemics.
image Metformin is also used in the management of polycystic ovarian syndrome (PCOS). Hyperinsulinemia is believed to contribute to PCOS by stimulating excess testosterone production by the ovaries and decreasing synthesis of sex hormone binding globulin in the liver. Metformin reduces insulin levels, therefore inhibiting this process.
image Lactic acidosis was a major concern with this drug class, as an original member of this class (phenformin) was withdrawn from the market in the 1970s because of this potentially fatal side effect. The incidence of lactic acidosis with metformin is actually very low (less than one case per 1000 patient years). This risk can increase substantially if metformin is given with other agents that cause acidosis or in patients with renal impairment.

Advanced

image There is increasing evidence from animal and now human studies that metformin may have beneficial effects that extend beyond its known effects in reducing blood glucose. In particular, metformin may have beneficial cardiovascular effects, including a reduction in microvascular complications and improved endothelial function.

Evidence

Metformin Monotherapy in Type 2 Diabetes Mellitus

image A 2005 Cochrane review compared metformin with sulfonylureas (13 trials, N = 1167 participants), placebo (12 trials, N = 702), diet (three trials, N = 493), thiazolidinediones (TZDs) (three trials, N = 132), insulin (two trials, N = 439), meglitinides (two trials, N = 208), and glucosidase inhibitors (two trials, N = 111). Obese participants with type 2 diabetes who were treated with intensive metformin therapy had a reduced risk for any clinical endpoint related to type 2 diabetes, including all-cause mortality and stroke compared with intensive therapy with chlorpropamide, glibenclamide, or insulin. The authors described metformin as eliciting a strong benefit for HbA1c compared with placebo or diet.

FYI

image The biguanides originated from the French lilac plant, which had been used for centuries to treat symptoms of diabetes mellitus. Guanidine is believed to be a major active ingredient in the plant, and two molecules were joined together to form the biguanides.

Incretins

Description

Incretins are oral hypoglycemic agents.

Prototypes and Common Drugs

Dipeptidyl Peptidase (DPP)–4 Inhibitors (Also Known As the “Gliptins”)

image Prototype: sitagliptin
image Others: saxagliptin, vildagliptin

Incretin Mimetics

image Prototype: exenatide

MOA (Mechanism of Action)

image Patients with type 2 diabetes mellitus appear to have an impaired insulin response (insulin resistance) and an inappropriate increase in glucagon release compared with normal individuals. Glucagon is a hormone that does the opposite of insulin—it increases blood glucose.
image Incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) lower blood glucose. They accomplish this by a number of mechanisms:

image GLP-1 and GIP stimulate insulin release from pancreatic beta cells under conditions of normal or elevated blood glucose.
image GLP-1 also lowers glucagon secretion from alpha cells, reduces appetite, slows gastric emptying, and regulates beta-cell growth (Figure 14-3).

image The DPP-4 enzyme inactivates incretin hormones, and therefore agents that overcome the actions of this enzyme enhance the effects of incretins (see Figure 14-3).
image Two approaches have been taken to enhance incretin hormones. Incretin mimetics are GLP-1 analogues that are not degraded by DPP-4 and thus act as GLP-1 agonists. The gliptins work by inhibiting the DPP-4 enzyme, which prevents the breakdown of incretins, thus enhancing their actions.
image The net effects of incretins are an increase in insulin release and a decrease in glucagon.
image

Figure 14-3

Pharmacokinetics

image Exenatide is administered by subcutaneous injection. It has a circulating half-life of 60 to 90 minutes.
image Unlike exenatide, the gliptins are administered orally.

Indication

image Diabetes mellitus (type 2)

Contraindications

image None of major significance

Side Effects

image The incretins are generally well tolerated.
image Hypersensitivity reactions: DPP-4 contributes to the activation of T cells, so inhibition of the activity of this enzyme might affect immune function.
image Increased incidence of infection: This was observed with sitagliptin in clinical trials, but the mechanism has not been explained. Once again, there might be a connection with immune function.

Important Notes

image The first indication that incretins exist came from the observation that an oral glucose load is more effective at stimulating insulin secretion than glucose given intravenously. It was subsequently discovered that two hormones (GIP and GLP-1) that are released from the upper and lower bowel enhance glucose-dependent insulin release. This increased effect of oral glucose on insulin secretion is identified as the incretin effect.

Advanced

Pregnancy

image The safety of sitagliptin in pregnancy has not been established.

Evidence

DPP-4 Inhibitors versus Other Antidiabetics and Placebo in Type 2 Diabetes Mellitus

image A 2008 Cochrane review included studies of sitagliptin (11 trials, N = 6743 patients) and vildagliptin (14 trials, N = 6121 patients) from 12 to 52 weeks’ duration. No data were published for mortality, diabetic complications, or quality of life. Compared with placebo, absolute reductions in HbA1c were sitagliptin 0.7% and vildagliptin 0.6%. Compared with the effects of other agents, no improvements in metabolic control were detected.
image All-cause infections increased with sitagliptin and with vildagliptin, but the difference was statistically significant only with sitagliptin. Otherwise the agents were well tolerated.

FYI

image Exenatide is a synthetic analogue of exendin-4, a peptide found in the venom of the Gila monster, a large lizard.
image Original attempts to use GLP-1 therapeutically were thwarted by its rapid inactivation by DPP-4. The actions on GLP-1 lasted for only a few minutes; therefore it had to be administered by continuous infusion. Exenatide acts as an agonist at GLP-1 receptors but is not broken down to an appreciable extent by DPP-4; thus it represents the first clinically feasible incretin analogue.

Insulins

Description

Insulin is a naturally occurring hormone that reduces blood glucose.

Prototypes and Common Drugs

Short-Acting Insulin

image Prototype: insulin R (regular)
image Others: insulin aspart, insulin lispro, insulin glulisine

Intermediate-Acting Insulin

image Prototype: Neutral Protamine Hagedorn (NPH) insulin
image Others: insulin Lente

Long-Acting Insulin

image Prototype: insulin ultralente
image Others: insulin protamine zinc, insulin glargine, insulin detemir

MOA (Mechanism of Action)

image Insulin is a hormone secreted by beta cells of the islets of Langerhans in the pancreas. It has several functions, many of which serve to lower blood glucose (Figure 14-4):

image Controls the uptake, use, and storage of cellular nutrients:

• The most widely known function of insulin is to promote the uptake of glucose by cells. Insulin does this by mobilizing glucose transporters (GLUT-4) on the surface of muscle and adipose tissue.
• In the liver and in muscle, insulin leads to increased glycogen deposition by increasing its synthesis and inhibiting its degradation. Glycogen is the primary means for storing glucose in the body.
• In the liver, insulin inhibits the synthesis of glucose (gluconeogenesis).
• In muscle, insulin facilitates uptake of amino acids, promoting protein synthesis.
• In adipose, insulin promotes synthesis of triglycerides and inhibits lipolysis.

image Aside from its multiple metabolic effects, insulin also binds to the insulin-like growth factor receptor (IGF-1) and appears to have growth-promoting effects.
image

Figure 14-4

Pharmacokinetics

image As is the case with most peptides, insulin cannot be administered orally. It is most frequently delivered parenterally, typically subcutaneously.
image An inhaled formulation of insulin is now available in some jurisdictions.
image A wide variety of insulins is available, characterized by onset and duration of action, summarized in Table 14-1.
image There is considerable interindividual variability in the pharmacokinetics of insulin, thus creating variability and unpredictability in the time to peak hypoglycemic effect.
image The Lente insulins absorb more slowly because of their crystal size.

TABLE 14-1 Insulin Formulations

image

Indication

image Diabetes mellitus (type 1 and type 2)

Contraindications

image None of major significance

Side Effects

image Hypoglycemia: seen with overdose or a missed meal; signs and symptoms include:

image Sweating
image Tachycardia
image Tremor
image Weakness
image Hunger
image Blurred vision
image Confusion
image Convulsions
image Coma

image Most of these signs and symptoms are secondary to the release of counterregulatory hormones such as epinephrine, glucagon, growth hormone (GH), cortisol, and norepinephrine, with epinephrine and glucagon playing the most important roles.
image Mild hypoglycemia is typically managed by patients with intake of sugar, preferably glucose. More severe cases can be managed with intravenous glucose, or with glucagon, a hormone with actions opposite to those of insulin.
image Lipodystrophy: Insulin injections can lead to localized atrophy of subcutaneous fat (lipoatrophy) or enlargement of fat deposits (lipohypertrophy). Lipoatrophy may be caused by an immune response, whereas lipohypertrophy may be caused by generation of fat cells.
image Edema: Edema is attributed to Na+ retention.

Important Notes

image Recombinant human insulin was a very early example of the use of biotechnology in drug development. Insulins were originally derived from beef (bovine) or pork (porcine) sources, and these forms of insulin are still used in some areas of the world. As they were not of human origin, bovine and porcine insulins elicited immune responses that either made their administration unpredictable or in some cases led to hypersensitivity reactions. Porcine insulin differs from human by one amino acid, and bovine by three amino acids; therefore bovine insulin is more prone to cause immunogenic reactions.
image The beta cells of the pancreas actually secrete a 110–amino acid polypeptide called preproinsulin, which is cleaved to proinsulin in the endoplasmic reticulum and then to insulin in the Golgi and secretory granules. Insulin is composed of two polypeptide chains: an A chain of 21 amino acids and a B chain of 30 amino acids. Modification of these chains has yielded several different analogues of insulin with different onset times and duration.

Advanced

image The use of units for insulin dosages dates back to the time when insulin had to be standardized because of the use of impure hormone. One unit of insulin was the amount required to lower blood glucose in a fasting rabbit to 2.5 mM (45 mg/dL).
image Homogeneous preparations of human insulin contain 25 to 30 units/mg, and most insulin preparations are supplied in concentrations of 100 units/mL, or about 3.6 mg/mL.

Evidence

Short-Acting Analogues versus Regular Insulin

image A 2006 Cochrane review (49 trials, N = 8274 participants) assessed the effects of short-acting insulin analogues versus regular human insulin. There were minimal differences in efficacy. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was −0.1% in favor of short-acting insulin analogues versus insulin, and in patients with type 2 diabetes there was no difference. In type 1 diabetes the incidence of severe hypoglycemia was lower for insulin analogues versus insulin (median 22 versus 46 episodes per 100 person-years). In type 2 diabetes there were also fewer severe hypoglycemia events with analogues versus insulin (median 0.3 versus 1.4 per 100 person-years).

Gestational Diabetes Mellitus

image A 2009 Cochrane review (eight trials, N = 1418 women) compared the effects of various treatment policies with one another or with routine antenatal care for gestational diabetes mellitus (GDM) on both maternal and infant outcomes. Intensive management (including dietary advice and insulin) reduced the risk of preeclampsia compared with results of routine antenatal care (relative risk [RR] 0.65), based on one trial of 1000 participants. The risk of the composite outcome of perinatal morbidity (death, shoulder dystocia, bone fracture, and nerve palsy) was also reduced for those on intensive therapy for mild GDM versus routine antenatal care (RR 0.32), based on one trial of 1030 infants. Note that gestational diabetes leads to large babies, which can then experience complications in the birthing process because of their size.

FYI

image Lente means slow in Italian.
image Banting and Best are credited with the discovery of insulin in the 1920s. In essence, they were the first to isolate and identify insulin and to use this “pancreatic extract” in patients. This built on work that had begun in the late 1880s, when the pancreas had been identified as playing a role in diabetes, and work at the turn of the century that had first used pancreatic extracts to treat diabetic animals and (unsuccessfully) patients.
image The islets of Langerhans have other specialized cells that are responsible for the secretion of glucagon (alpha cells) and somatostatin (delta cells).
image NPH insulin is created by treating regular insulin with protamine and zinc at a neutral pH (7.2). This results in a fine precipitate of protamine zinc insulin that provides for slow and even absorption when administered subcutaneously. Hagedorn (the H in NPH) was the name of the scientist who created the formulation.
image In an attempt to create a long-acting heparin injection, protamine was also originally added to heparin. However, the two chemicals formed a precipitate, and it was this discovery that led to the use of protamine as a reversal agent for heparin.
image Protamine is manufactured from salmon sperm.

Meglitinides

Description

Meglitinides are oral agents that lower blood glucose by increasing insulin secretion.

Prototype and Common Drugs

image Prototype: repaglinide
image Others: nateglinide

MOA (Mechanism of Action)

image The meglitinides are insulin secretagogues, stimulating the release of insulin from pancreatic beta cells in a manner similar to that of the sulfonylureas (Figure 14-5).
image They bind to a beta cell sulfonylurea receptor (SUR-1) that is associated with an inward rectifier adenosine triphosphate (ATP)–sensitive potassium channel. Binding leads to depolarization, which then opens a voltage-gated calcium channel, leading to calcium influx and insulin release.
image Meglitinides therefore rely on functioning beta cells in order to achieve their pharmacologic effect. They are thus not useful in type 1 diabetes mellitus.
image

Figure 14-5

Pharmacokinetics

image The meglitinides are rapidly and completely absorbed, achieving peak plasma concentrations in less than 1 hour after oral administration.
image They are metabolized in the liver, and have a short elimination half-life of 1 to 2 hours. Dose adjustments should be considered in patients with impaired liver function.
image Nateglinide acts more quickly than repaglinide and also has a shorter duration of action. Because both of these agents have a rapid onset and offset, they are typically administered just before meals for the management of postprandial hyperglycemia.
image Food increases the absorption of nateglinide but has minimal impact on repaglinide absorption.

Indication

image Diabetes mellitus (type 2)

Contraindication

image Concomitant gemfibrozil and repaglinide: Gemfibrozil (a fibrate) significantly reduces the metabolism of repaglinide, leading to as much as an eightfold increase in repaglinide levels. In some cases this has lead to severe episodes of hypoglycemia. Gemfibrozil is used to lower cholesterol; multiple risk-reduction strategies are frequently used in patients with multiple risk factors for atherosclerosis and thus there is a risk that these two drugs can be co-administered.

Side Effects

image Hypoglycemia: Although less common than with the sulfonylureas, hypoglycemia still occurs in approximately 1% of patients. This side effect is treated in the same manner as hypoglycemia seen with other insulin secretagogues.

Important Notes

image The rapid onset of action of the meglitinides, particularly nateglinide, makes them useful agents in the management of postprandial hyperglycemia. Patients can take these agents just before eating, allowing them flexibility in choosing the timing of their meals. The sulfonylureas do not allow for this much flexibility.

Evidence

Meglitinides versus One Another, Metformin, and Placebo

image A 2007 Cochrane review (15 trials, N = 3781 patients) did not find any studies that reported on morbidity or mortality. Compared with the effects of placebo, HbA1c was reduced by both repaglinide (0.1% to 2.1%) and nateglinide (0.2% to 0.6%). In trials comparing the two agents, repaglinide performed better than nateglinide with respect to reducing HbA1c. Repaglinide had similar reductions in HbA1c to metformin (three studies, N = 248 patients), whereas nateglinide had similar or slightly less of an effect on HbA1c compared to metformin (one study, N = 355 patients).
image Weight gain was generally greater with meglitinides versus metformin; diarrhea occurred less frequently and hypoglycemia more frequently with meglitinides versus metformin.

FYI

image The meglitinides were approved 40 years after the approval of the first sulfonylurea, tolbutamide.

Sulfonylureas

Description

Sulfonylureas are oral agents that lower blood glucose by increasing insulin secretion.

Prototypes and Common Drugs

First-Generation Agents

image Prototype: Tolbutamide
image Others: Chlorpropamide, tolazamide, acetohexamide

Second-Generation Agents

image Prototype: Glyburide
image Others: Glipizide, gliclazide, glimepiride

MOA (Mechanism of Action)

image Patients with type 2 diabetes mellitus appear to have an impaired insulin response (insulin resistance) and an inappropriate increase in glucagon release compared with normal individuals. Glucagon is a hormone that does the opposite of insulin—it increases blood glucose.
image The sulfonylureas are insulin secretagogues, meaning that they stimulate insulin release from the beta cells of the pancreas.
image They bind to a beta-cell sulfonylurea receptor (SUR-1) that is associated with an inward rectifier ATP-sensitive potassium channel. Binding leads to depolarization, which then opens a voltage-gated calcium channel, leading to calcium influx and insulin release (Figure 14-6).
image Sulfonylureas also reduce serum glucagon levels. Although the mechanism behind this has not been definitively established, sulfonylureas enhance the release of insulin and somatostatin, and it is believed that one or both of these effects may in turn lead to a reduction in glucagon release from pancreatic alpha cells.
image

Figure 14-6

Pharmacokinetics

image The elimination half-lives of first-generation agents vary considerably, whereas the half-lives of second-generation agents are typically short (3 to 5 hours). However, the biologic half-lives, the amount of time for which they are effective, is longer than their elimination half-lives would suggest, for reasons that are still unknown.
image All sulfonylureas are metabolized by the liver and excreted in urine. Because of the risk of hypoglycemia, dose adjustments must be considered in patients with hepatic impairment. A small proportion is also excreted unchanged in urine, therefore caution should also be exercised in patients with renal impairment.

Indication

image Diabetes mellitus (type 2)

Contraindications

None of major significance.

Side Effects

image Hypoglycemia: Hypoglycemia is caused by oversecretion of insulin and occurs more frequently with glyburide. Glyburide may impair the body’s ability to prevent endogenous insulin secretion during hypoglycemia.
image Flushing: Flushing occurs when these drugs are taken with alcohol and is more common with older agents like chlorpropamide.
image Weight gain: Weight gain is caused by increased insulin activity in adipose. It occurs less frequently with the second-generation sulfonylureas.

Rare, Serious

image Hematologic toxicities: Anemias and thrombocytopenias occur and are mainly seen with chlorpropamide.

Important Notes

image Because of concerns over hypoglycemia, the sulfonylureas, particularly glyburide, should be initiated at a low dose, and patients should be observed carefully for changes in blood glucose over the first few weeks of therapy. Patients with irregular diets or who drink ethanol to excess are at increased risk for hypoglycemia.
image The hypoglycemic effects of the sulfonylureas tend to diminish with time. The most likely explanation for this reduced response is progressive loss of beta cells from diabetes.
image Patients with type 1 diabetes mellitus are unable to secrete appreciable amounts of insulin; therefore a drug that promotes insulin secretion will not work in these patients.

Advanced

Pregnancy

image Patients with gestational diabetes should not be treated with sulfonylureas, but should instead be treated with insulin.

Evidence

Glyburide for Hypoglycemic Events and Cardiovascular Risk

image A 2007 systematic review (21 trials, N = 7047 patients) compared glyburide with other insulin secretagogues and insulin for hypoglycemic and cardiovascular events. The authors found that glyburide was associated with a greater risk of experiencing a hypoglycemic event compared with other secretagogues (RR 1.52) or other sulfonylureas (1.83). Glyburide was not associated with an increased risk of cardiovascular events, death, or end-of-trial weight gain compared with other secretagogues.

FYI

image The sulfonylureas were the first oral agents for type 2 diabetes and have been in use for over 50 years.
image After a large study conducted in the 1970s found increased cardiovascular mortality with sulfonylureas, for many years there was an association drawn between this class and elevated cardiovascular risk. Subsequent studies have not found this association, although this class is still believed in some circles to carry this risk.

Thiazolidinediones

Description

The thiazolidinediones (TZDs) are oral agents that lower blood glucose by increasing the sensitivity of cells to insulin.

Prototype And Common Drugs

image Prototype: rosiglitazone
image Others: pioglitazone

MOA (Mechanism Of Action)

image The TZDs are peroxisome proliferator–activated receptor–gamma (PPAR-γ) agonists.
image The PPAR-γ receptors are a complex family of receptors found in the cell nucleus in muscle, fat, and liver. Among other roles, they regulate expression of genes responsible for lipid and protein metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. It is through a combination of these effects that they are thought to decrease insulin resistance, although the relative importance of each has not been established (Figure 14-7).
image The TZDs are thought to exert their effects at PPAR-γ receptors in adipose tissue by promoting uptake and storage of free fatty acids (FFAs) in adipose tissue. They accomplish this by increasing the number of small adipocytes that store FFAs while decreasing the number of large adipocytes that release FFAs. Through a variety of poorly understood mechanisms, high concentrations of FFAs are thought to promote insulin resistance.
image The TZDs also promote the expression and translocation of glucose transporters in muscle and adipose tissue. This increases glucose uptake into muscle and adipose tissue. The TZDs also may reduce hepatic production of glucose, although the mechanism by which this is accomplished is unclear.
image Activation of the PPAR-γ receptor also has several other effects, including inhibition of proinflammatory genes and cytokine production, as well as increased adiponectin production. Adiponectin is thought to play several protective roles in the body, stimulating glucose uptake in muscle, protecting against atherosclerosis and endothelial cell apoptosis, and stabilizing plaques.
image

Figure 14-7

Pharmacokinetics

image Rosiglitazone peak plasma levels are seen 1 hour after administration, and absorption is not significantly affected by food.
image Pioglitazone reaches its peak in 2 hours. It has two active metabolites (M-III and M-IV).
image Both rosiglitazone and pioglitazone are metabolized by hepatic CYP450 enzymes. They do not appear to induce or inhibit any CYP450 isozymes.

Indication

image Diabetes mellitus (type 2)

Contraindication

image Heart failure: See Side Effects.

Side Effects

image Weight gain: Weight gain is caused by redistribution of adipocytes from visceral to subcutaneous regions.
image Edema: TZDs promote retention of sodium and water by up-regulating tubular transporters for sodium and reducing glomerular filtration rate (GFR).
image Cardiovascular: Heart failure is likely caused by the edema described previously, observed with rosiglitazone in a large clinical trial. Myocardial ischemia has also been reported with rosiglitazone.
image Fractures: TZDs appear to impair osteoblasts, and higher fracture rates (upper arm, hand, or foot) in female subjects were observed in a large clinical trial.

Important Notes

image The PPAR-γ receptor has an extensive list of biologic actions, making it difficult to sort out the actions of agonists such as the TZDs. The most difficult effects to sort out are the cardiovascular effects. The TZDs initially appeared to have beneficial cardiovascular effects, but recently adverse cardiovascular effects, specifically heart failure, have emerged.

Advanced

image The TZDs appear to have variable effects on triglycerides and LDL, although they consistently raise HDL. Pioglitazone appears to have greater beneficial effects on lipid profiles compared with rosiglitazone.

Pregnancy

image Oral antidiabetics are generally not recommended. Insulin is the recommended treatment for diabetes during pregnancy.

Lactation

image Pioglitazone is secreted in breast milk in rats, and although human studies have not been performed, the TZDs are not recommended for breastfeeding women.

Drug Interactions

image Rosiglitazone is extensively metabolized by CYP2C8, with a minor contribution from CYP2C9.
image Pioglitazone is extensively metabolized by CYP2C8 and CYP3A4.

Evidence

Rosiglitazone versus Oral Antidiabetics or Placebo in Type 2 Diabetes Mellitus

image A 2007 Cochrane review (18 trials, N = 3888 patients) found no improvement in mortality, morbidity, adverse effects, and quality of life in trials with a follow-up of at least 24 weeks. HbA1c was not improved by rosiglitazone compared with other oral antidiabetic agents. Edema occurred significantly more frequently in rosiglitazone-treated patients, and the ADOPT study identified an increased risk of cardiovascular events with rosiglitazone. Data from ADOPT and another trial, PROactive, suggest increased risk of fractures in women treated with rosiglitazone.

Pioglitazone versus Oral Antidiabetics or Placebo in Type 2 Diabetes Mellitus

image A 2006 Cochrane review (22 trials, N = 6200 patients) did not find convincing evidence of improvement in mortality, morbidity, adverse effects, and health-related quality of life. Improvements in HbA1c were similar with pioglitazone compared with other oral antidiabetics. Edema occurred significantly more frequently with pioglitazone.

FYI

image The PPAR-γ receptor is very large and has several different distinct ligands, including warfarin, monounsaturated and polyunsaturated fats, some nonsteroidal antiinflammatory drugs (NSAIDs), and the angiotensin receptor blocker (ARB) telmisartan.
image The first marketed TZD, troglitazone, was removed from the market because of concerns over hepatotoxicity.
image Dual PPAR-α and PPAR-γ agonists are being developed in order to maximize the benefits of PPAR agonism on both lipids and glucose. PPAR-α agonists (fibrates) are used to treat hypercholesterolemia.

Glucagon

Description

Glucagon is an endogenous hormone that generally opposes the actions of insulin.

Prototype

image Glucagon

MOA (Mechanism of Action)

image Glucagon is a 29–amino acid protein secreted from the alpha cells in the pancreas and has significant homology with secretin, vasoactive intestinal peptide (VIP), and GI inhibitory polypeptide.
image Glucagon secretion is under the control of the sympathetic system and is regulated by the following:

image Dietary amino acids, glucose, and fatty acids (stimulation)
image Hypoglycemia
image Ketones (inhibition)

image The main effects of glucagon are on the liver, mediated by G protein–linked glucagon receptors and increased intracellular cyclic adenosine monophosphate (cAMP). The important specific actions include the following (Figure 14-8):

image Increased glycogenolysis via cAMP-stimulated phosphorylation
image Decreased glycogen synthesis via phosphorylation of glycogen synthase, which inactivates the enzyme
image Increased glycolysis via reduction in levels of fructose-2,6-bisphosphate, which is an important regulator in the rate-limiting step for glycolysis
image Increased ketogenesis
image Because glucagon acts to increase blood sugar, it works against insulin, which acts to lower blood sugar.
image In cardiac tissue glucagon binds a glucagon receptor and raises cAMP, resulting in a positive inotropic (contractility) and chronotropic (heart rate) effect on the heart. This is the mechanism by which it is therapeutic in β-blocker and calcium channel blocker overdoses; importantly, its action is independent of β receptors or calcium channels.
image Secretion of different pancreatic hormones influences other hormones:

image Glucagon stimulates endogenous insulin secretion.
image Insulin and somatostatin both inhibit glucagon secretion (see also the section on somatostatin analogs in this chapter).

image

Figure 14-8

Pharmacokinetics

image As a peptide, glucagon cannot be given orally because it will be digested into amino acids.
image Glucagon has a short half-life of 3 to 6 minutes. It is usually given as an intravenous infusion.

Indications

image Refractory hypoglycemia (not corrected by glucose administration)

image Oral hypoglycemia overdose
image Hyperinsulin states

• Insulin overdose
• Insulinoma (islet cell tumor that secretes insulin)

image Drug overdoses

image β-Blockers
image Calcium channel blockers

image Intestinal relaxation

image To facilitate some radiologic investigations of the GI tract

Contraindication

image Pheochromocytomas: These are rare catecholamine-secreting tumors and are sensitive to glucagon, which promotes catecholamine secretion from these tumors.

Side Effects

image Hyperglycemia
image Hypokalemia
image Nausea and vomiting, caused by delaying gastric emptying and hypotonicity

Important Notes

image Intravenous or oral glucose is the first-line treatment for hypoglycemia. Glucagon is the second-line treatment. Insulin overdoses are usually not treated with glucagon unless hypoglycemia is refractory to glucose administration.
image Glucagon decreases hepatic glycogen but does not decrease skeletal muscle glycogen because there are no glucagon receptors on skeletal muscle.
image Although some drugs that treat acute heart failure result in an increase in cAMP (β agonists and phosphodiesterase inhibitors), glucagon is not used for treating heart failure despite its similar action on cAMP.

Advanced

image Proglucagon is the precursor to glucagon and if cleaved at different locations also gives rise to glucagon-like peptides (GLP-1 and GLP-2), called incretins. Incretins are themselves a class of drugs used for diabetes management. GLP-1 and GLP-2 are secreted from intestinal cells and are involved with insulin and glucagon secretion, gastric emptying, intestinal blood flow, and permeability and appetite satiety.

Evidence

image There are no human controlled studies of glucagon use in β-blocker or calcium channel blocker therapy. However, “the available animal data, human clinical experience, and minimal adverse effect profile support the use of glucagon early in the course of both β-blocker and calcium channel blocker toxicity.”

FYI

image With the discovery that propranolol did not prevent the positive inotropic action of glucagon in cats and dogs, it was suggested that there was the possibility that glucagon may be useful in the treatment of heart failure induced by β-blockers; subsequently the logic was extended to the treatment of calcium channel blocker overdose.

Estrogens

Description

Estrogen is one of the endogenous female sex hormones. See also the discussions of progestins and hormone contraception.

Common Drugs

image Bioidentical estrogens: estrone sulfate (E1), estropipate (E1), 17β-estradiol (E2), estriol (E3)
image Esterified estrogens: ethinyl estradiol, mestranol, quinestrol, equilin
image Conjugated equine estrogens (CEEs): dienestrol

MOA (Mechanism of Action)

image Estrogens are transcription factors; they modify messenger RNA (mRNA) synthesis directly.
image Estrogens enter the cell passively (no receptor required) and bind to estrogen receptors in the nucleus, which then dimerize and bind DNA directly to regions called estrogen-responsive elements (EREs) and influence gene transcription.
image Important effects of estrogen include the following (Figure 14-9):

image Reproductive:

• Female sexual maturation (neonatal and pubescent)
• Endometrial growth stimulation
• Breast tissue stimulation

image Hematologic:

• Increased tendency for clotting via increased circulating levels of factors II, VII, IX, and X (vitamin K–dependant factors) and decreased antithrombin III

image Skin and mucosa:

• Increased pigmentation (melasma)
• Increased skin collagen content and skin thickness
• Maintenance of skin moisture by increasing acid mucopolysaccharides and hyaluronic acid

image Metabolic:

• Decreased bone resorption via antagonism of parathyroid hormone and interleukin-6 (IL-6)
• Increased high-density lipoprotein (HDL); decreased low-density lipoprotein (LDL); increased triglycerides

image

Figure 14-9

Pharmacokinetics

image Estrogen preparations include oral tablets, creams, and patches.

Indications

image Prevention of pregnancy (contraception)
image Menopausal hormone replacement therapy (HRT)
image Endometriosis
image Dysfunctional uterine bleeding (DUB)
image Urogenital atrophy: thinning and drying of vaginal mucosa
image Anti-androgen therapy: acne, hirsutism
image Infertility
image Polycystic ovarian syndrome (PCOS)

Contraindications

image Hypercoagulable states: Estrogen is a procoagulant, and estrogen administration is a risk factor for pathologic thromboses (deep vein thrombosis [DVT] and pulmonary embolus [PE]).
image Cancers that could demonstrate increased growth in response to estrogen: breast, ovarian, uterine, endometrial.
image Strong risk factors for atherosclerosis: hypertension (HTN), diabetes, high cholesterol, family history.

Side Effects

image Migraine headaches
image Water retention

image Abdominal bloating
image Weight gain

image Stimulation of reproductive organ tissues:

image Vaginal bleeding or spotting (because of growth of endometrial tissue)
image Enlarged fibroids
image Breast tenderness

image Gall bladder disease (primarily stones)
image Nausea (this is particularly common with higher doses used with postintercourse contraception, also called the “morning after” pill)
image Thrombosis: (estrogen is a procoagulant)

image DVT and PE
image Stroke
image Coronary heart disease

image Skin rashes
image Increased triglycerides

Important Notes

image Progesterone is often co-administered with estrogen.
image Estrogen stimulates endometrial growth and can also stimulate cancers of reproductive tissues.
image Estrogens do not cause HTN at the doses in which they are currently prescribed but can cause HTN at very high doses.
image Estrogen is prothrombotic. It increases the probability of clot formation. Bleeding is a potential complication of natural childbirth, and the prothrombotic effects of estrogen are therefore beneficial during this time.
image The natural progression of sex hormone synthesis is as follows: progestins → androgens → estrogens (Figure 14-10). The similarity to aldosterone probably accounts for the water retention properties of sex hormones.
image

Figure 14-10

Advanced

image The cause of water retention is not fully understood, but it is possibly mediated by the following:

image Changes in the thresholds for antidiuretic hormone (ADH) secretion and osmotic thirst, resulting in increased body water
image Increases in the renin-angiotensin-aldosterone system by estrogen or progesterone
image Nitric oxide–mediated vasodilation (thus increasing total blood volume) because of estrogen

image The mechanism by which estrogens increase the prevalence of migraines is complex, but it probably involves the following:

image Vasodilation mediated by nitric oxide
image Neuronal excitability mediated by increased calcium and decreased magnesium

Evidence

(Note that many studies also include progesterone.)

image Many studies, often with different methodologies, have resulted in many results; summarizing is difficult because of the heterogeneity of studies that exists. Patient differences (age, gravida status, time since menopause) and drug differences (estrogen only versus estrogen with progesterone, dose, duration, estrogen formulation, estrogen delivery method) are some examples of the differences among studies. A very small subset of the evidence is presented here.

image Endometrial cancer risk: An analysis of 45 RCTs with 38,702 postmenopausal women demonstrated that unopposed estrogen (without any progesterone coadministered) of any dose for a duration of only 1 year increases risk of endometrial hyperplasia (and by extension, endometrial cancer) in patients being treated for menopausal symptoms. This effect increased with increasing dose of estrogen and increasing duration of administration.
image Cardiovascular risk: A single large double-blind RCT of 10,739 postmenopausal women comparing estrogen with placebo demonstrated no difference in myocardial infarction or cardiac death. However, the hazard ratio for stroke was 1.39, indicating an almost 40% increase in risk for stroke. Average follow-up time was 6.8 years.
image Bone health (bone density, fractures):

• An analysis in 2008 of 13 RCTs (two were placebo controlled), provides evidence that combined hormone oral contraceptives does not affect bone health. Depot progesterone alone (depot medroxyprogesterone acetate or DMPA) was associated with decreased bone density. Note that oral contraceptives would be administered to women of childbearing age.
• A single large double blind RCT of 10,739 postmenopausal women comparing estrogen with placebo demonstrated a hazard ratio of 0.61 for hip fractures (reduction of risk by 40%) and 0.70 for all fractures in the estrogen group. Average follow-up time was 6.8 years.

image DVT risk: In a 2006 RCT, 10,739 women followed for an average of 7.1 years demonstrated a rate of venous thrombosis of 3.0 per 1000 person-years in the estrogen group versus 2.2 in the placebo group. This represents a statistically significant hazard ratio of 1.47 (47% more likely to get a blood clot if on estrogen). Compared with estrogen plus progesterone, it appears that the risk is greater with combination therapy versus estrogen alone.
image Cognitive function: A meta-analysis in 2007 of 16 studies with 10,114 women with normal brain function demonstrated no benefit in prevention of cognitive decline over a period of 3 to 5 years compared with placebo. In fact, there was a slight trend toward better function with placebo. It has been previously suggested that estrogen deficiency is associated with decreased cognitive function.
image Weight gain: An analysis of available literature in 2008 included five RCTs (957 women) comparing hormone with placebo and did not find strong evidence to support an association between weight gain and the use of oral contraceptives; however, most studies were not designed to study this particular outcome.
image Acne: A meta-analysis in 2009 found 25 trials evaluating combined hormones and acne treatment. Of the 25, seven were placebo controlled, and these studies showed improvement in acne with hormone therapy. The remaining studies compared different hormone combinations and doses. Hormones containing cyproterone acetate might be superior in treating acne, but data are somewhat conflicting.

FYI

image A state of estrus in mammals (excluding humans) is the time around ovulation when the female is receptive to sexual activity (being in heat); estrogen peaks right before this time in the cycle.
image Simplified memory tip: Estrogen is like fertilizer for the endometrium. Progesterone is like the lawnmower.
image Fibroids are benign tumors of the uterus, composed of myometrium.
image Gravida status refers to the number of previous pregnancies.
image Dysfunctional uterine bleeding is defined as bleeding outside the normal menstrual period.
image Menorrhagia is heavy menstrual bleeding.
image Dysmenorrhea is a condition of having excessively painful menstrual periods.

Estrogen Receptor Antagonists

Description

Estrogen receptor antagonists are drugs that block estrogen receptors. See also the section on aromatase inhibitors (AIs) in this chapter for drugs that inhibit estrogen synthesis.

Prototype and Common Drugs

Selective Estrogen Receptor Modulators (SERMs)

image Prototype: tamoxifen
image Others: toremifene, raloxifene

Estrogen Receptor Antagonists

image Prototype: clomiphene
image Others: fulvestrant

MOA (Mechanism of Action)

image There are several forms of estrogen, but 17β-estradiol is the predominant form intracellularly. Estrogens have multiple effects in females, from maintaining bone to regulating the menstrual cycle and development. Important effects of estrogen include the following:

image Reproductive:

• Female sexual maturation (neonatal and pubescent)
• Endometrial growth stimulation
• Breast tissue stimulation

image Hematologic:

• Increased tendency for clotting via increased circulating levels of factors II, VII, IX, and X (vitamin K–dependant factors) and decreased antithrombin III

image Skin and mucosa

• Increased pigmentation (melasma)
• Increased skin collagen content and skin thickness
• Maintenance of skin moisture by increasing acid mucopolysaccharides and hyaluronic acid

image Metabolic:

• Decreased bone resorption via antagonism of parathyroid hormone and IL-6
• Increased HDL; decreased LDL; increased triglycerides

image Estrogens also mediate cell proliferation, in both normal and malignant cells. There are two estrogen receptors (ERα and ERβ), both of which either increase or decrease transcription of target genes.
image On binding of estrogen, the receptors dimerize (join together) and then bind to EREs, typically found in the promoter region of target genes. A promoter is a region of a gene that facilitates transcription. Binding of agonist to the estrogen receptor also recruits coactivators, which help to stimulate transcription. The net effect of all of this is to initiate transcription (Figure 14-11).
image Estrogen receptor antagonists inhibit transcription by promoting the binding of co-repressors (CoRs) to the ERE. CoRs inhibit transcription.
image The SERMs are partial agonists, antagonizing the effects of estrogen in some tissues (breast) and stimulating estrogen receptors in others (bone, brain, liver). This is in contrast to the estrogen antagonists (e.g., clomiphene), which block estrogen receptors in all tissues.
image Some breast cancers express estrogen receptors, and estrogen antagonists are used to treat these tumors.
image Clomiphene has a unique mechanism in that it stimulates the release of follicle-stimulating hormone (FSH). It does this by antagonizing the negative feedback of estrogen on gonadotropin-releasing hormone (GnRH). Estrogen normally has an inhibitory effect on GnRH, so through blocking of this inhibitory effect, more FSH is released, promoting ovulation in patients with infertility.
image

Figure 14-11

Pharmacokinetics

image Tamoxifen’s elimination is biphasic, as the parent drug has a much shorter half-life (6 hours) than the active metabolite (5 to 10 days). The major route of elimination for tamoxifen is through metabolism by CYP3A4 and CYP2D6.
image Toremifene is an active metabolite of tamoxifen.
image Raloxifene and clomiphene do not undergo extensive CYP metabolism. Clomiphene has a long elimination half-life of 5 to 7 days.
image Fulvestrant is available in a depot injection, which can be administered on a monthly basis.

Indications

image Breast cancer (estrogen-receptor positive)
image Prevention of breast cancer in high-risk women
image Osteoporosis
image Infertility

Contraindications

Pregnancy

image Estrogen plays an important role in maintenance of pregnancy.

Side Effects

image Endometrial: Some of the partial agonists have estrogen agonist effects on the endometrium, leading to abnormal cell growth. This can manifest as increased endometrial thickness, endometrial polyps, leiomyomas, and even endometrial cancer.
image Thromboembolism: Increased risk of thromboembolic events, including pulmonary embolism, have been observed in large studies.
image Stroke: Stroke has been observed in large studies.
image Hot flashes: Hot flashes mimic the physiology of menopause.
image Nausea, vomiting
image Menstrual irregularities: Oligomenorrhea (infrequent periods) and amenorrhea (absent periods) may occur.
image Cataracts

Important Notes

image Although they are all partial agonists, the SERMs are a heterogeneous drug class because they have different effects (agonist or antagonist) depending on the tissue they target.
image Raloxifene does not have the endometrial side effects seen with tamoxifen (see Side Effects).
image Raloxifene began as an investigational drug for treatment of breast cancer but was first approved for its beneficial effects in osteoporosis in postmenopausal women. Since then it has been “rediscovered” as a preventive therapy for postmenopausal women at high risk of invasive breast cancer.
image Several large trials have reported a benefit of tamoxifen in the prevention of breast cancer, particularly in high-risk groups. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial randomized 13,388 high-risk women to either tamoxifen or placebo. The risk of estrogen receptor–positive breast cancer was reduced by 69% at 5 years. The International Breast Cancer Intervention Study (IBIS) randomized 7154 women to tamoxifen or placebo and also found a 32% reduction in the overall risk of breast cancer.

Evidence

Tamoxifen and Breast Cancer Treatment

image A 1998 meta-analysis (55 trials, N = 37,000) clearly established the role of tamoxifen in the treatment of estrogen receptor–positive breast cancer. The analysis included women with early breast cancer, finding that adjuvant tamoxifen for approximately 5 years reduced breast cancer recurrence by 42% and mortality by 22%.

Aromatase Inhibitors (AIs)

Description

AIs block the synthesis of estrogen.

Prototype and Common Drugs

image Prototype: first- and second-generation AIs are discussed in the FYI section.
image Others: third-generation AIs:

image Steroid (type I): exemestane
image Nonsteroids (type II): anastrozole, letrozole

MOA (Mechanism of Action)

image Aromatization is the process of converting a nonaromatic ring into an aromatic ring and is catalyzed by aromatase, a P450 enzyme. Aromatization converts androgens into estrogens. Estrogens contain an aromatic six-carbon ring. Androgens do not (Figure 14-12).
image Steroid-type AIs have an androgen structure and bind the substrate binding site in a noncompetitive, irreversible fashion.
image Nonsteroid-type AIs bind the cytochrome P450 moiety of the enzyme and are competitive and reversible.
image Aromatase inhibition results in the following:

image Lower levels of estradiol, estrone, and estrone sulfate. This is beneficial for conditions that require lower estrogen levels, including breast cancer and precocious puberty.
image Decreased negative feedback on the hypothalamic-pituitary axis by estrogen, leading to increased FSH secretion and resultant ovarian follicle growth, which is the mechanism by which AIs are beneficial for infertility.
image Higher androgen levels in the ovary, which might promote follicular growth and also help with infertility.

image

Figure 14-12

Pharmacokinetics

image AIs and tamoxifen, a SERM, are frequently coadministered for cancer therapy. Tamoxifen induces CYP enzymes and so reduces the levels of AIs.

Indications

image Hormone-sensitive breast cancers
image Precocious puberty (early puberty in young children)
image Endometriosis
image Infertility due to anovulation (absence of ovulation)

Contraindication

image Pregnancy (which is a physiologic state requiring increased estrogen)

Side Effects

image Reduced bone density and increased fractures

image Bone protection measures should be taken. These include bisphosphonates, vitamin D, calcium, and exercise.

image Hot flushes from estrogen deficiency (which mimics perimenopausal symptoms)
image Nonspecific: nausea, fatigue, increased sweating, peripheral edema, and increased appetite

Important Notes

image Comparisons between AIs and SERMs:

image AIs inhibit estrogen synthesis; SERMs do not. Therefore estrogen metabolites (which could act on tumors) would also be reduced with AIs but not necessarily blocked with SERMs.
image AIs will not block exogenous estrogens (e.g., phytoestrogens); SERMs will.
image AIs do not bind to the estrogen receptor; SERMs do. Progesterone receptor up-regulation in tumors has been observed with SERMs but not with AIs, and this could be a mechanism of tumor resistance.

image Aromatase is present in many tissues, including the ovaries, brain, placenta, adipose tissue, muscle, liver, breast, and estrogen-dependent breast cancer. Adipose is the primary source of estrogen production in both men and postmenopausal women.

Advanced

image Aromatase converts:

image Testosterone into estradiol
image Androstenedione into estrone

image Type I (steroid) AIs are actually prodrugs; when they bind aromatase, the enzyme converts them to a structure that permanently binds and destroys the enzyme. They are called suicide inhibitors because the enzyme is destroyed by the chemical it creates.

Evidence

Advanced Breast Cancer

image A meta-analysis in 2007 (25 studies, N = 9416 women) showed a pooled hazard ratio for survival of 0.89 (11% benefit) of AIs over other therapy (progesterones or SERMs).

Early Breast Cancer

image An RCT in 2004 with follow-up in 2007 demonstrated that postmenopausal women who were cancer free while on tamoxifen at the 2- to 3-year mark (postsurgery) had increased survival (3.3% absolute increase) at 5 years if they switched to exemestane versus staying on tamoxifen.

Anovulation

image A 2008 review (9 studies, N = 2573 women) examined the impact of adding letrozole to conventional infertility treatments. There were no statistically significant improvements in ovulatory cycles nor pregnancies per ovulatory cycle. Large RCTs are required to clarify the roles of AIs for anovulation therapy.

Endometriosis

image Data are currently too limited to recommend AI use with endometriosis, but it is being tried in advanced cases.

FYI

image The prototype first-generation (aminoglutethimide) and second-generation (fadrozole and formestane) AIs are no longer used because of low potency, lack of specificity, and side effects.
image The nonsteroidal AIs contain a triazole structure. An azole is a five-membered ring that includes at least one noncarbon atom. Triazoles have three nitrogens. There is also a class of antifungals called “azoles” whose mechanism of action is also inhibition of a P450 enzyme (Figure 14-13).
image Total body aromatization of plasma androstenedione increased from 0.5% to 10% with a rise in body weight from 100 to 400 pounds in women.
image An aromatic ring contains an odd number of “lone electrons.” It is a very stable structure.
image Patients with PCOS have reduced aromatase activity within the ovary, which is probably responsible for the production of multiple small follicles, resulting in multiple cysts.
image

Figure 14-13

Progestins

Description

Progestins (also called progestogens) are one of the endogenous female sex hormones. See the discussions of estrogens and hormone contraception.

Common Drugs

image Bioidentical: progesterone
image First-generation pregnanes: megestrol acetate, medroxyprogesterone acetate (MPA)
image Second-generation estranes: norethindrone, norethindrone acetate, ethynodiol, lynestrenol
image Third-generation gonanes: norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene, dienogest
image Nonsteroidal: drospirenone

MOA (Mechanism of Action)

image Progestins are transcription factors; they modify mRNA synthesis directly.
image Progestins enter the cell passively (no receptor required) and bind to progesterone receptors in the nucleus, which then dimerize and bind DNA directly and influence gene transcription.
image Important effects of progesterone include the following:

image Reproductive:

• Part of feedback loop with luteinizing hormone (LH) and FSH
• Abrupt decline determines onset of menstruation
• Changes endocervical glands from watery to viscous; this reduces sperm entry into the uterus
• Maintenance of pregnancy
• Increased body temperature because of preovulatory surge in progesterone
• Mild sedating effects

image Metabolic:

• Increased insulin secretion and peripheral insulin resistance
• Increased lipase activity
• Possible increased fat deposition
• Increased LDL; decreased HDL (the opposite of estrogen)

Pharmacokinetics

image There are multiple routes of administration: oral, subcutaneous, and depot subcutaneous.
image Additional routes of administration include insertion of foreign bodies that contain and slowly release progesterone. These include implants (which are placed surgically in the arm), intrauterine devices (IUDs), and vaginal rings.

Indications

image Prevention of pregnancy (contraception)
image Menopausal HRT
image DUB

Contraindications

image Risks for DVT or PE
image Severe migraine headache: There are relationships among estrogen, progesterone, and serotonin levels. Serotonin is implicated in migraine pathophysiology; administration of estrogen or progesterone can potentially exacerbate (or alleviate) migraines.
image Unexplained vaginal bleeding: Prolonged progesterone administration can cause vaginal bleeding; it is important to diagnose any pathologic causes of bleeding before starting treatment that could confound other bleeding.
image Breast cancer: Female sex hormones can stimulate breast tissue growth.
image Active liver disease
image Conditions of concern for hypoestrogenic effects and reduced HDL levels, theoretically increasing cardiovascular risk:

image HTN with vascular disease
image Current and history of ischemic heart disease
image History of stroke
image Diabetes for over 20 years or with nephropathy, retinopathy, neuropathy, or vascular disease

Side Effects

image Androgenic activity: Because of the similarity of progestins to androgens and the conversion of progestins to androgens, androgenic side effects are not uncommon. Levonorgestrel is the most androgenic. Third-generation progestins are less androgenic than second-generation progestins.

image Acne and hirsutism are the most common signs.
image Increased LDL and insulin resistance are also seen.

image DVT: Third-generation progestins may be associated with a higher incidence of DVT than second-generation progestins.
image Vaginal bleeding: The mechanism is not completely understood.

Important Notes

image Progesterone is secreted by the ovary, mainly by the corpus luteum during the luteal phase (second half) of the menstrual cycle. See Figure 14-9.
image Bioidentical hormones are hormones that are chemically identical to what is naturally produced in the human body. Because minor chemical changes can result in a change in function, some women experience fewer side effects with bioidentical hormones.
image Drospirenone is derived from spironolactone (an aldosterone antagonist) and also has antialdosterone effects.

image Reduces estrogen-induced water retention
image Also has antiandrogen effects

image Progestins can be administered alone or in combination with estrogens for birth control. Long-term contraception (e.g., depot injections, implants, IUDs) are progestin only. Their use is associated with menstrual irregularities, including abnormal bleeding.
image HRT is administered as estrogen only or a combination of estrogen and progesterone, but not progesterone alone.
image Subcutaneous rods can deliver progestins for as long as 5 years.

Advanced

Chemical Structure

image Pregnanes have an extra methyl group at C6, which decreases first-pass hepatic metabolism and thus makes these formulations orally available.
image Estranes have lost the methyl group at C19, which decreases androgenic activity.
image Gonanes have replaced the methyl group at C13 with an ethyl group, which again decreases androgenic activity.

Evidence

Hormone Replacement Therapy and Cardiovascular Outcomes

image A Cochrane review in 2005 (10 studies, N = 24,000 women) compared HRT (estrogen only and estrogen combined with progesterone) with placebo or no treatment and found that there were no protective effects of HRT on all-cause mortality, cardiovascular death, or myocardial infarction. However, there was an increased risk of DVT and PE (RR 2.15) and stroke (RR 1.44) in patients treated with HRT.

FYI

image Gestation refers to pregnancy. The man who co-discovered progesterone in the 1930s, American medical student Willard H. Allen (later to become an obstetrician), described a pregestational proliferation of the uterus and coined the names progestin and progesterone.
image The word root -sterone refers to steroid ketones, which testosterone is, but estrogen is not. This similarity of progesterone to testosterone is the reason for the androgenic side effect profile of progesterones.

image There is no aromatic ring in progesterone (as there is in estrogen). Instead, there is a ketone group (C=O) on the A ring (similar to testosterone).
image In addition to the four-ring, 19-carbon steroid structure, there are an extra two carbons at C17 (named 17α), to make the structure a C21 steroid.
image See Figure 14-10.

Hormone Contraception

Description

Hormone contraceptives are estrogen and progestin preparations used for the purpose of preventing pregnancy. See also the two sections on estrogens and progestins for further details.

Common Drugs

image Multiple combinations of different estrogens and progestins

image Estrogens: ethinyl estradiol, mestranol
image Progestins: many different types

MOA (Mechanism of Action)

Progestins

image Progestins are primarily responsible for the contraceptive activity.
image They prevent the LH surge that is required for release of the ovum; thus the ovum is not released from the ovary.
image They thicken cervical mucus, which impedes sperm entry into uterus.
image They decrease tubal motility, which impedes sperm transit through fallopian tubes.
image They thin the endometrium, which reduces probability of implantation.

Estrogens

image Estrogens are primarily responsible for cycle control (bleeding) and to a lesser extent demonstrate some contraceptive activity.
image They stabilize the endometrium, minimizing irregular shedding (bleeding).
image They inhibit release of FSH, preventing the development of the dominant follicle.
image They potentiate the progestin’s inhibition of the LH surge.

Combined Hormone versus Progestin-Only Preparations

image Most preparations are a combination of an estrogen plus progestin; however, some preparations contain progestin only. Progestin-only preparations are used in women in whom estrogens are contraindicated or not tolerated.

Pharmacokinetics

image Estrogen is metabolized by CYP3A4 liver enzymes, and thus the birth control pill (BCP) can become less effective if coadministered with other drugs that are CYP3A4 inducers:

image Barbiturates (for seizures or, less commonly now, for sedation)
image Isoniazid (for tuberculosis treatment)

image The BCP is usually administered over a 28-day period:

image The pill is used for 21 days, followed by 7 days of no pill or placebo.
image Seven days of no hormone results in withdrawal bleed, creating a menstrual period.
image Some formulations extend the 21 days of hormone to 24 and shorten the placebo to 4 days.
image The duration of the hormone administration can be extended even more so that a woman will experience less frequent menstrual bleeding. Administration for 42 or 84 (plus 7 placebo) days of extended cycle hormone results in menstrual bleeding once every 2 or 4 months.

image The BCP can be packaged with different administration schedules:

image Monophasic: There is only one dose of hormone throughout the cycle.
image Multiphasic (biphasic or triphasic): There is more than one dose of hormone throughout the cycle.

image Other forms of hormonal contraception administration include the following:

image Depot: slow release injection once every 3 months
image Transdermal patch: changed once a week
image Vaginal ring: changed once a month
image IUDs: can be drug free or hormone eluting
image Implants: progestin-impregnated implants, placed under the skin in the inner arm between the bicep and tricep muscles.

Indications

image Planned prevention of conception: BCP, also called the oral contraceptive pill (OCP)
image Unplanned prevention of conception: the morning-after pill

Contraindications

image Smoking is a relative contraindication because of the increased risk of thrombus and atherosclerotic disease.
image Risk for thrombus should be considered an absolute contraindication:

image Familial factor V Leiden, the most common inherited coagulation cascade abnormality that gives rise to pathologic thrombi.
image Previous DVT or PE

image Also see the sections on estrogens and progestins for details.

Side Effects

image Side effects are related to the dosages and types of hormone used.
image Breakthrough bleeding is common when the BCP is started. Bleeding in cycle 1 (after starting the pill) is often reduced by cycle 4.
image Although doses are not routinely reported in this textbook, doses of hormones in BCPs are important and require mention:

image Side effects are usually attributed to the estrogen; the higher the dose, the higher the probability of side effects.
image Doses of ethinyl estradiol range from 20 mcg to 50 mcg.

• Doses of 20 to 25 mcg are considered ultra-low doses.

image Ethinyl estradiol 50 mcg has higher incidences of headache, breast tenderness, DVT, and nausea. This dose is rarely used anymore.
image 35 mcg of ethinyl estradiol is equivalent to 50 mcg of mestranol (both are estrogen compounds).
image Patients who develop intolerable estrogen-related side effects might be candidates for progestin-only BCPs.

image Progestin-related side effects are primarily androgenic: acne and hirsutism. Levonorgestrel is the most androgenic progestin.
image Different formulations and routes of administration are associated with slightly different side effect profiles:

image Extended cycle: Side effects include breakthrough bleeding and acne.
image Progestin only: Side effects include increased breakthrough bleeding and a slightly lower efficacy for preventing pregnancy.
image Depot (progestin only): Side effects include decreased bone density, which is reversible. Use should be limited to 2 years in adolescents, and all women on the depot injection should take supplemental calcium.
image Morning-after pill: Because of the high dose of estrogen, nausea is common. Progestin-only formulations are also used which do not carry the same risk of nausea.

Important Notes

image A few BCPs use iron pills instead of placebo pills during the 7 days of no hormone. This is to help maintain iron levels in women who have low iron stores because of regular menstrual blood loss.
image Ultra-low–dose estrogen should be avoided in adolescents because of the requirement for slightly higher estrogen levels for proper bone development.
image Side effects are the most common reason for discontinuing BCPs. They include the following:

image Dysmenorrhea, anemia, acne, hirsutism, ectopic pregnancy, benign breast disease, endometrial cancer, and ovarian cysts

image The estrogen-containing morning-after pill has about 3 to 5 times the dose of estrogen compared with the BCP. It is usually prescribed with an antinausea medication.
image Monophasic and triphasic regimens offer similar rates of abnormal bleeding, discontinuation, and adverse events.
image Extended cycle formulations are always monophasic.
image When used correctly, BCPs prevent pregnancy 99% of the time. However, because of incorrect use, the failure rate is about 2% to 3%. Twenty percent to 50% of adolescents do not take the BCP as directed; 20% of users miss one or two pills per cycle.

Evidence

Lactation

image A meta-analysis in 2008 with five included studies could not find evidence to support or refute an association between hormone contraception and lactation quality or quantity.

Breakthrough Bleeding

image A systematic review in 2007 did not find a clear association between type or dose of oral BCP and breakthrough bleeding; however, studies were heterogeneous with respect to methodology and reporting of bleeding. Bleeding in cycle 1 (first menstrual cycle after starting the BCP) was higher than in cycle 4.

FYI

image The BCP was on the front cover of Time magazine in 1967.
image Mestranol was the estrogen used in the first oral contraceptive.
image Many brands of BCP are named according to the dose of hormone. For example, 1/30 would represent 1000 mcg of a progestin formulation plus 30 mcg of an estrogen formulation.
image BCPs are also named according to phases. For example, if there are three different doses, each for 7 days, then 7/7/7 is used to denote this.
image Related to reproduction and the coagulation cascade, a hypercoagulable state can give rise to recurrent spontaneous abortions (also called miscarriages). The mechanism is utero-placental thrombi resulting in impaired circulation to the placenta. Affected women should be investigated for hypercoagulable states, such as the presence of factor V Leiden.
image Progestins are more closely related to androgens than are estrogens and therefore are the female hormones that give rise to androgenic side effects.

Oxytocin

Description

Oxytocin is a naturally occurring neuropeptide released from the posterior pituitary.

Prototype and Common Drugs

image Prototype: Oxytocin
image Others: Carbetocin, demoxytocin

MOA (Mechanism of Action)

image Oxytocin is produced in the hypothalamus but is secreted by the posterior pituitary and acts primarily on smooth muscle of breast and uterine tissue (Figure 14-14):

image Let-down reflex to release milk from the breast
image Myometrial (uterine) contraction during and after delivery
image In the uterus, oxytocin binds oxytocin receptors, which activates G proteins and results in:

image Increased intracellular calcium leading directly to increased contraction
image Increased levels of prostaglandin (PG) F2α, which is a potent vasoconstrictor and oxytocic (uterine constrictor)

image Increased uterine contraction helps to expel the fetus. After delivery, uterine contraction is critical to help stop bleeding; the uterus contracts down on intramyometrial vessels, which clamps them shut.
image Oxytocin is involved in a positive feedback loop: once labor has started, uterine contractions caused by oxytocin induce more oxytocin to be released from the cervix.
image

Figure 14-14

Pharmacokinetics

image Oxytocin is a peptide, so it cannot be given orally; it is given by intravenous or subcutaneous injection. The half-life of oxytocin is 3 minutes.
image Carbetocin is a synthetic, nonpeptide oxytocin analogue with a duration of action of 1 hour.
image When given to augment labor, oxytocin is given as an intravenous infusion, starting at a low dose and increasing approximately every 30 minutes (to a maximum dose).
image When given to prevent postpartum bleeding, it is given as a subcutaneous injection or intravenous infusion.

Indications

image Induction of labor
image Augmentation of labor
image Prevention and treatment of postpartum bleeding

Contraindication

image Previous uterine rupture

Side Effects

image Hypotension results when oxytocin is administered rapidly.
image Abnormally high uterine tone: Increased contraction can lead to decreased blood flow to the uterus and thus decreased oxygen delivery to the fetus. Uterine tone and oxytocin administered must be considered as a cause of fetal distress. Reducing the dose or discontinuing the oxytocin is required if oxytocin is thought to be the cause.
image Uterine rupture: This is a rare complication (in some reports, about 1 in 6000). Uterine stimulation is one risk factor for this complication. A scarred uterus (from previous caesarian sections) is another risk factor.
image Antidiuretic effect: This occurs because of the similarity of oxytocin to vasopressin (ADH).

Important Notes

image The first stage of labor is cervical dilation; the second stage is expulsion of the fetus once the cervix is fully dilated; the third stage is the period after the baby is delivered until the placenta is delivered.
image Uterine atony (loss of tone) is a very common cause of postpartum hemorrhage (PPH) and is treated with drugs that increase uterine tone:

image Oxytocin
image Prostaglandin (PGF2α)
image Ergotamine derivatives (ergometrine)

image Postpartum uterine atony can also be caused by prolonged uterine stimulation by exogenous oxytocin.
image Considering that the gravid uterus receives 20% of cardiac output, torrential blood loss can occur in the postpartum period. Blood loss of 500 mL is not unusual for caesarian sections or vaginal deliveries. Blood loss of >1000 mL becomes medically important.

Evidence

Postpartum Bleeding (Including the Third Stage of Labor)

image Oxytocin versus nothing: In a meta-analysis in 2004 (seven trials, N = 3000 women), prophylactic oxytocin was found to reduce blood loss with an RR of 0.50 for blood loss greater than 500 mL.
image Oxytocin versus ergot alkaloids: A meta-analysis in 2004 (six trials, N = 2800 women) demonstrated little difference. Manual placenta removals were less frequent with oxytocin (RR 0.57).
image Oxytocin versus oxytocin plus ergot alkaloids: A meta-analysis in 2007 (six trials, N = 9332 women) demonstrated that if blood loss was defined as >1000 mL, there was no difference, but if blood loss was defined as >500 mL, then there was a small reduction in blood loss with the combination therapy. Combination therapy significantly increased the following side effects: HTN, vomiting, and nausea.
image Carbetocin versus oxytocin: A meta-analysis in 2007 (four studies, N = 1032 women) did not demonstrate a difference in blood loss or risk of PPH. However, with carbetocin there was a reduction (RR 0.44) in the use of uterotonics and a reduction (RR 0.38) in the need for uterine massage (used to stimulate contraction). There was no difference in side effects.

Induction or Augmentation of Labor

image Oxytocin versus no treatment: A meta-analysis in 2001 (26 studies, N = 6660 women) showed that oxytocin reduced the rate of unsuccessful vaginal delivery within 24 hours: 8.3% versus 54% (RR 0.16), but the caesarean section rate was increased: 10.4% versus 8.9% (RR 1.17).
image Oxytocin versus vaginal PGs: A meta-analysis in 2001 (27 studies, N = 4649 women) showed that oxytocin was associated with increased unsuccessful vaginal deliveries within 24 hours (52% versus 28%, RR 1.85), irrespective of membrane status (ruptured or not ruptured). There was no difference in caesarean section rates.
image Oxytocin versus intracervical PGs: A meta-analysis in 2001 (13 studies, N = 1244 women) showed that oxytocin alone was associated with an increase in unsuccessful vaginal delivery within 24 hours (51% versus 35%, RR 1.49).

FYI

image Oxytocin, vasopressin (AVP), and the AVP analogue DDAVP are structurally very similar; they all contain nine amino acids (they are nonapeptides). There is one amino acid difference between AVP and DDAVP, and there are two amino acid differences between AVP and oxytocin.
image Octreotide has eight amino acids (a somatostatin analogue).
image Oxytocin and AVP evolved from a single peptide in nonmammals called vasotocin.
image Tocolysis is termination of uterine contractions; oxytocics and uterotonics are stimulants of uterine contraction.

Reproductive Prostaglandins (PGs)

Description

PGs are involved with many processes in the body; this section discusses reproductive uses of PGs.

Prototypes

image Misoprostol (PGE1)
image Dinoprostone (PGE2)
image Carboprost (PGF2α)

MOA (Mechanism of Action)

image PGs act on a family of receptors that are coupled to G proteins. Some G proteins are stimulatory and some are inhibitory, depending on the specific receptor type. Therefore the physiologic effect of a given PG depends on the receptor and the tissue type. The actions are ultimately mediated by changes in cAMP and intracellular calcium concentrations.
image PGs bind PG receptors:

image PGE binds EP receptors (four subtypes, 1 to 4)
image PGF binds FP receptors (two subtypes, A and B)

image Second messengers associated with PG receptors include G proteins, which link to adenylyl cyclase and phospholipase 3.
image The most dominant effects on the female reproductive system include the following (Figure 14-15):

image Cervical softening (the firm cervix relaxes before dilation, a necessary step in early labor)
image Increased uterine contraction
image The most dominant effects on the male reproductive system include the following:

image Vasodilation of the vessels in the corpus cavernosum of the penis

image

Figure 14-15

Pharmacokinetics

image Administration is by different routes:

image PGE1: orally or transurethrally
image PGE2: locally as a gel (vaginally, close to the cervix), suppository
image PGF2α: intramuscularly or intramyometrially

image Oral administration of PGF2α results in too many GI side effects for the agent to be useful.
image Topically administered PGs (in women, vaginal or intracervical route; in men, intraurethral route) will have minimal absorption.
image PGs have short half-lives; about 95% of the agent is inactivated after one circulation through the pulmonary circulation via enzymes that are specific for PGs.

Indications (Reproductive Only)

image PGE1 and PGE2

image Labor induction and cervical ripening
image Missed abortion (miscarriage with products of conception not yet expelled)
image Abortion

image PGE1 only

image Erectile dysfunction

image PGF2α only

image Treatment of postpartum hemorrhage, but not as first-line treatment
image Abortion

Contraindications

image Severe asthma: PGF2α is a potent bronchoconstrictor.
image Glaucoma: This is discussed in more detail in the ophthalmology section.
image Myocardial infarction: Myocardial infarction occurs because of the risk of vascular constriction to the myocardium.
image Relative contraindications that are obstetric related include unexplained vaginal bleeding, chorioamnionitis, ruptured membranes, and previous cesarean section.

Side Effects

image Smooth muscle contraction of the following:

image Airways, leading to an asthma-type reaction
image Vasculature, leading to HTN
image GI tract, leading to diarrhea, cramping, and vomiting. PG’s also promote movement of water and electrolytes into the intestine; this also increases diarrhea.

image Fever: Naturally occurring E type PGs are a key element in the fever response (with inflammation); the site of action is in the preoptic area of the hypothalamus. Administration of exogenous PGE2 therefore causes fever.

Important Notes

image Missed abortions are also commonly treated expectantly (wait for spontaneous passage of products of conception) or procedurally with dilatation and curettage (D&C), a procedure that involves mechanical dilation of the cervix and then gentle removal of intrauterine contents with a suction catheter or curettage, an instrument that scrapes away the endometrium.
image For erectile dysfunction, the PG must be injected into the penis or inserted into the urethra.
image Both PGE2 and PGF2α cross the uteroplacental barrier, but fetal toxicity is uncommon.

Advanced

image PG receptors are located in cell membranes and have seven transmembrane segments; they encompass a large family of receptors with four classes and at least 10 different subtypes.
image Dinoprostone comes prepackaged in a viscous gel of colloid with triacetin (antifungal). The syringe is connected to a soft-plastic catheter for intracervical administration.

Evidence

Induction of Labor

image Intravenous PGs versus oxytocin: A meta-analysis in 2004 (13 trials, N = 1165 women) showed that intravenous PG was associated with higher rates of uterine hyperstimulation, both with changes in the fetal heart rate (RR 6.76) and without (RR 4.25), compared with oxytocin. Use of PG was also associated with significantly more maternal side effects: GI effects, thrombophlebitis, and pyrexia. PG was no more likely to result in vaginal delivery than oxytocin.
image Vaginal PGs versus oxytocin: A meta-analysis in 2001 (27 studies, N = 4649 women) showed that vaginal PGs were associated with decreased unsuccessful vaginal deliveries within 24 hours (28% versus 52%, RR 0.54), irrespective of membrane status (ruptured or not ruptured). There was no difference in caesarean section rates.
image Intracervical PGs versus oxytocin: A meta-analysis in 2001 (13 studies, N = 1244 women) showed that intracervical PGs were associated with a decrease in unsuccessful vaginal delivery within 24 hours (35% versus 51%, RR 0.67).

Erectile Dysfunction

image PGE1 versus placebo or no treatment: A meta-analysis in 2009 (4 studies, N = 1873 men) demonstrated increased probability (odds ratio [OR] 7.22) of at least one successful intercourse. Adverse effects were most frequent in the treated groups and occurred more often and intensely as doses increased. Penile pain and minor urethral trauma were predominant.

FYI

image In 1934, Dr. Ulf von Euler found that extracts of sheep vesicular gland dramatically lowered blood pressure when injected into animals. Human seminal fluid also seemed to possess similar qualities. Von Euler named it prostaglandin, believing that it originated in the prostate gland.
image Nomenclature:

image Eicosa is Greek for 20. Eicosanoids have 20 carbon atoms. Eicosanoids include PGs, prostacyclins, leukotrienes, and thromboxane. Arachidonic acid is the most abundant precursor.
image The letter after PG represents a historical designation.

• Ether and phosphate buffer were first used to separate PGs in Sweden; the PGs that partitioned into ether were called PGE, and those in phosphate (spelled fosfat in Swedish) were called PGF.
• An additional test, using acid and base, gave rise to PGA and PGB.

image The subscripted number refers to the number of double bonds (C=C).

• PGE1 has a double bond at C5; PGE3 has double bonds at C5, C13, and C17.

image The α or β designates the orientation (pointing in front of the molecule or pointing behind) of the second hydroxyl (-OH) group on the ring. Most PGs have only a single hydroxyl group on the ring; PGF has two.

• PGF2α therefore was fractionated into phosphate, has two double bonds, and has a second hydroxyl group that is oriented behind the ring.

Nonsteroidal Androgen Antagonists (NSAAs)

Description

Nonsteroidal androgen antagonists (NSAAs) are androgen receptor antagonists.

Prototype and Common Drugs

image Prototype: Flutamide
image Others: Nilutamide, bicalutamide

MOA (Mechanism of Action)

image These are androgen receptor antagonists that act on androgen receptors in the prostate. As their name states, they are not steroids (unlike dihydrotestosterone [DHT], the agonist they block).
image Antagonism of androgen receptors in prostate tissue reduces growth stimulation of prostatic cancer because of their action on modifying transcription factors related to cellular growth.

Pharmacokinetics

image NSAAs are hepatically metabolized, so they are contraindicated in patients with severe hepatic dysfunction.
image Bicalutamide can be given orally once a day; its half-life is about 1 week. Flutamide has a shorter half-life and requires 3-times-a-day administration.

Indication

image Metastatic prostate cancer

Contraindication

image Severe hepatic dysfunction

Side Effects

image Direct antiandrogen effects: Breast pain, gynecomastia, and hot flushes may occur.
image Diarrhea, vomiting, and nausea may occur.
image Hematuria (blood in urine): Many patients with prostate cancer already have hematuria; this side effect has been described, but the drug probably does not cause the bleeding.
image Asthenia (decreased sensation in skin) and skin rashes may occur.

Important Notes

image Bicalutamide has essentially replaced flutamide because of once-daily dosing (flutamide administration was 3 times a day) and a lower incidence of diarrhea.
image NSAAs are usually used in combination therapy with either chemical or surgical castration in advanced metastatic prostate cancer.

image Chemical castration is accomplished with a GnRH agonist, which shuts down testicular function.

image NSAA therapy is not curative of prostate cancer. It is palliative. The goal of therapy is to improve both quality and duration of life.
image Estrogen antagonists and other androgens have been used to help reduce the incidence of antiandrogen side effects.

Evidence

A meta-analysis was conducted in 2000 (23 trials, N = 6320 men), looking at treatment of advanced prostate cancer with castration (surgical or chemical) versus castration plus NSAA. The analysis found an absolute 5% reduction with NSAA in mortality at 5 years, thus an NNT was of 20. There were more adverse events in the group receiving NSAAs, and 10% withdrew from treatment because of side effects.

FYI

image Gynecomastia is the feminization of men: breast development, hair pattern changes, and skin changes.

Androgens

Description

Androgens are male sex hormones.

Common Drugs

image Testosterone
image Testosterone esters: testosterone undecanoate, testosterone cypionate, testosterone enanthate
image 17α-alkylated androgens: danazol, methyltestosterone, oxandrolone, stanozolol, fluoxymesterone

MOA (Mechanism of Action)

image Testosterone can be converted in the body to DHT (another physiologically active androgen) and also to estradiol (an estrogen).
image Physiologic androgens will act on androgen receptors to produce the following:

image Male sex organ differentiation in utero
image Secondary sex characteristics during puberty, including libido (sex drive)
image Prostate gland stimulation (growth)

image It is important to note that exogenous androgen administration will result in inhibition of the physiologic sex hormone axis and will significantly inhibit production and secretion of naturally produced sex hormones in both men and women. See Figure 14-10.

Pharmacokinetics

image Androgens administered orally undergo extensive first-pass hepatic metabolism. Therefore modifications to the hormone and also alternative methods of delivery have been developed.
image Androgens can be administered via the oral, transdermal, sublingual, or injection route.
image Testosterone esters are more lipophilic and therefore well absorbed in fat (subcutaneous injections). A depot form of injection (slow release) is the ester testosterone undecanoate.
image 17α-Methylated androgens (they have a methyl group attached to the 17 carbon) demonstrate reduced hepatic metabolism but also are less androgenic and are hepatotoxic.

Indications

image Male hypogonadism (reduced testicular secretion of testosterone)
image Low libido states
image Heavy menstrual bleeding

Contraindications

image Prostate cancer: Androgens stimulate the growth of prostate tissue and thus would stimulate growth of prostate cancer. In fact, creating the opposite (hypoandronergic states) are part of prostate cancer therapy.

Side Effects

image Salt and water retention from the mild mineralocorticoid effect (remember that aldosterone is a similar steroid hormone)
image Hepatic toxicity with 17α-methylated androgens only
image Masculinization if used in women: hirsutism, deeper voice, baldness, amenorrhea, breast and uterine atrophy, and infertility
image Consequences of anabolic steroid abuse include the following:

image Central nervous system (CNS): Aggression and depression are associated but may also have been present before steroid abuse; difficult to differentiate
image Cardiovascular system: HTN, accelerated atherosclerosis, sudden death, cardiac hypertrophy, cardiac fibrosis
image Male endocrine: testicular atrophy, decreased sperm counts, increased number of abnormal sperm, infertility
image Hepatic: increased liver enzymes and gallstones
image Musculoskeletal system: premature bone growth plate fusion (shorter stature), tendon ruptures
image Skin: increased acne and baldness

Evidence

Female Libido Management

image A Cochrane meta-analysis in 2007 (35 RCTs, N = 4768 women) showed that the addition of testosterone to HRT effectively increased sexual function. Side effects were acne, hair growth, and lower HDL levels.

Heavy Menstrual Bleeding

image A meta-analysis in 2007 (9 RCTs, N = 353 women) showed weak evidence of the superiority of the use of an androgen over NSAIDs or a progesterone IUD for the treatment of heavy bleeding. However, the side effects were greater with the androgen.

FYI

image How to recognize a steroid abuser when you go to the gym:

image Back acne
image Hypogonadism
image Frequently looks at self in mirror
image Never shares weights

image Hirsutism is a male pattern of hair distribution on a woman (e.g., facial and chest hair).
image Amenorrhea is cessation of the menstrual cycle.
image Infertility in both men and women can persist for months or years after abuse of anabolic steroids, because of prolonged suppression of gonadal hormone production.
image Sterone means a ketone derived from a steroid ring. In addition to testosterone, progesterone and aldosterone are also ketone steroids.

Somatostatin Analogs

Description

Somatostatin analogs are modifications of somatostatin.

Prototype and Common Drugs

image Prototype: Octreotide
image Others: Lanreotide, vapreotide

MOA (Mechanism of Action)

image Somatostatin acts on somatostatin receptors; five subtypes have been identified, named SR1 through SR5. Octreotide acts primarily on SR2 and SR5.
image Somatostatin is secreted by the delta cells of the pancreatic islet cells and inhibits the release of the following:

image GH, insulin, glucagon, gastrin, VIP
image Pancreatic enzymes

image Somatostatin also lowers portal blood pressure, possibly through its inhibitory action of other vasodilating hormones, particularly glucagon. Inhibition of vasodilators results in vasoconstriction that reduces blood flow into the portal system and thus reduces the pressure in this system (Figure 14-16).
image

Figure 14-16

Pharmacokinetics

image Octreotide is an octapeptide (eight amino acids) and therefore must be given parenterally (intravenous or subcutaneous) because it would be digested if taken orally.
image Somatostatin has a half-life of 1 to 2 minutes; octreotide has a half-life of 2 hours.
image There are long-acting formulations of octreotide and lanreotide that require injections only once every 28 days.

Indications

image Variceal bleeding
image After pancreatic surgery (reduced suppression of pancreatic secretions)
image Suppression of hormones or transmitters:

image Acromegaly (GH)
image Symptomatic VIP or carcinoid tumors
image Functioning islet cell tumors (insulinoma and glucagonomas)

image Severe refractory chemotherapy-induced diarrhea
image Hepatorenal syndrome (renal failure in the setting of advanced liver failure)

Contraindication

image Caution with type 1 diabetes: altered glucose metabolism (hypoglycemia) can result.

Side Effects

image Cardiovascular: sinus bradycardia
image GI related: abdominal pain, diarrhea, nausea
image CNS related: headache, fatigue

Important Notes

image Variceal bleeding occurs when liver cirrhosis increases resistance to the passage of blood through the liver and hence causes portal HTN, resulting in dilated fragile veins in the esophagus, stomach, and rectum.
image Because of the actions on glucose-mediating hormones (primarily glucagon, insulin, and glucagon-like peptides), administration to patients with type 1 diabetes can result in reduced insulin requirements and thus a risk of hypoglycemia. Paradoxically, administration to patients with type 2 diabetes can result in hyperglycemia.

Advanced

image Somatostatin is also released from other tissues: hypothalamus, stomach, and duodenum.
image Octreotide has been used in patients with advanced cancer. Research is still ongoing.

Evidence

Variceal Bleeding

image A meta-analysis in 2007 (21 studies and 2588 patients) demonstrated no benefit of octreotide versus placebo with regard to mortality. Treated patients, on average, required slightly fewer red blood cell transfusions (0.7 units).

Refractory Diarrhea

image A systematic review in 2001 (30 studies and 712 patients) found that among the eight RCTs included in the review, there was a response (complete or partial resolution of diarrhea) of 64% to therapy compared with 34% in the placebo (control) group.

FYI

image Somatostatin’s inhibition of somatotropin (GH) is the origin of its name. Octreotide’s name arises from its octapeptide structure.
image Islets in the pancreas are multisecretory. In addition, glucagon is secreted from alpha cells and insulin from beta cells in the pancreas.
image Carcinoid tumors of the gut secrete serotonin, which causes flushing, diarrhea, wheezing, and abdominal pain.

Growth Hormone Antagonists

Description

GH antagonists block the action of GH.

Prototype

image Pegvisomant

MOA (Mechanism of Action)

image GH antagonists block the action of GH at the GH receptor in the liver.
image GH is a protein. The substitution of one amino acid converts endogenous GH into an antagonist. Commercial GH antagonists have multiple substitutions to enhance binding affinity.
image IGF-1 mediates the effects of GH; GH stimulates release of IGF-1 from the liver, and IGF-1 stimulates growth in bone and soft tissues (Figure 14-17).
image Biologic activities of GH include the following:

image Skeletal growth
image Soft tissue growth
image Insulin antagonism

image Pathologically high levels of GH result in gigantism (very large stature) and acromegaly, a condition of bone and soft tissue overgrowth that occurs with high GH levels after growth plates have been fused and vertical growth is finished.
image Because of the insulin antagonism, insulin resistance (diabetes) also occurs with GH overproduction.
image

Figure 14-17

Pharmacokinetics

image The addition of polyethylene glycol 500 (PEG-500) to GH (and thus also GH antagonists) increases its half-life from 30 minutes to about 2 days.
image As a protein, it cannot be taken orally; it is injected subcutaneously.

Indication

image Acromegaly: a rare condition, of which the most common cause is a benign GH (hyper)secreting pituitary adenoma

image For patients with persistently elevated IGF-1 despite other therapy
image Possibly as monotherapy (more research required)

Contraindication

image Severe liver disease (because of risk of liver damage)

Side Effect

image Elevated liver enzymes (transaminases) are seen in 25% of patients, indicating liver damage. Liver enzymes must be routinely monitored.

Important Notes

image Surgery, dopamine agonists, and somatostatin are standard first-line treatments for acromegaly. Dopamine agonists and somatostatin are inhibitors of GH secretion but are not direct antagonists of GH; therefore their mechanism of action is slightly different, and they act at a different location in the biochemical pathway.
image Some signs of acromegaly include coarse facial features (prominent brow, cheekbones, chin), large hands and fingers, large tongue (macroglossia), obstructive sleep apnea (because of the macroglossia), vocal changes, HTN, cardiomegaly, and insulin resistance.

image Life expectancy in active acromegaly is 10 years shorter than normal.

image IGF-1 levels are measured to help monitor effectiveness of acromegaly treatment. A drop in levels indicates that GH antagonism has occurred, and drug doses are titrated to IGF-1 levels. It is possible to lower IFG-1 levels to below normal, which is probably undesirable.

Advanced

image Nelson’s syndrome is a condition of rapid growth of the pituitary as a result of cortisol absence (lack of negative feedback). Concerns about the development of Nelson’s syndrome have been raised with regard to the use of GH antagonists and the resulting loss of negative feedback from IGF-1 on the pituitary. So far, Nelson’s syndrome has not been demonstrated.

Evidence

Biochemical Markers

image In an observational study in 2001 (N = 160), it was demonstrated that somatostatin normalizes IGF-1 levels in about 65% of patients. Pegvisomant normalized IGF-1 levels in 97% of patients and reduced insulin and resting glucose levels but not HbA1c. However, GH levels almost double. The mechanism of this increase is unknown, but it could be related to loss of negative feedback on the pituitary from IGF-1.

FYI

image Andre the Giant, a professional wrestler in the 1970s who passed away in 1993 from heart failure, had acromegaly.
image Acro– means top, height, or summit. The name would suggest that acromegaly means large height; however, the term gigantism is used instead. Acromegaly describes the non–height-related effects of GH excess.
image Somatotrophin is another name for endogenously produced GH; somatotropin is the name for synthetic GH.
image The name pegvisomant reflects the PEG and somatotrophin constituents of the drug.
image Laron dwarfism is caused by a deficiency of IGF-1. Approved in the United States, recombinant IGF-1 is currently being used to treat this condition.

Adrenocorticotropic Hormone (ACTH)

Description

Adrenocorticotropic hormone (ACTH) is secreted by the anterior pituitary and acts on the adrenal glands.

Prototype

image ACTH (cosyntropin)

MOA (Mechanism of Action)

image Corticotropin-releasing hormone (CRH) is released from the hypothalamus and stimulates the anterior pituitary.
image ACTH is produced and secreted from the anterior pituitary. ACTH binds ACTH receptors on the adrenal cortex. As a result, cortisol production and secretion from the adrenal cortex are increased (Figure 14-18).
image Activation of the ACTH receptor results in activation of the following signaling process: G proteins → increased cAMP → increased protein kinase A (PKA) → increased intracellular Ca2+, all of which result in:

image Increased uptake of lipoprotein and metabolism of cholesterol, for the synthesis of adrenal steroids (cortisol and aldosterone)
image Activation of transcription factors for enzymes required for steroid synthesis and release

image

Figure 14-18

Pharmacokinetics

image The half-life of ACTH is 10 minutes.

Indication

image ACTH test: to test adrenal gland function. This test stimulates (or attempts to stimulate) the adrenal gland. The appropriate response is a rise in serum cortisol.

Contraindications

image None

Side Effects

image Minimal when used as a single bolus test

Important Notes

image Cortisol insufficiency is rarely, if ever, treated with ACTH. It is usually treated with systemic steroids to replace the cortisol.
image Cortisol insufficiency can be caused by decreased ACTH secretion or dysfunctional adrenal glands.
image Cortisol insufficiency manifests as:

image Hypotension (aldosterone raises blood pressure)
image Hypoglycemia (cortisol raises blood sugar)
image Hyponatremia with hyperkalemia (aldosterone conserves Na+ and excretes K+ in the kidney, so deficiency causes Na+ wasting and K+ retention)
image Metabolic acidosis (aldosterone conserves bicarbonate in the kidney; deficiency results in bicarbonate wasting through the kidney, a condition called renal tubular acidosis or type 4 RTA)
image Hypercalcemia (probably from decreased renal excretion)

image Measurements of serum cortisol are difficult to interpret in different disease states because 90% of circulating cortisol is protein bound to corticosteroid-binding globulin. During severe illness, the corticosteroid-binding globulin drops by as much as 50%. Most assays measure total cortisol and so will not be able to measure free (unbound) cortisol, which is the fraction that is biologically available. This severely limits the ability to interpret the results.

Advanced

image ACTH is also (in smaller quantities) produced by the immune system, including T cells, B cells, and macrophages. Fighting off infection usually results in the body mounting an increased metabolic response, so the interplay between adrenal function and the immune system is logical.
image The ACTH test usually involves administration of 250 mcg of ACTH. This dose has been criticized for being far too large (supraphysiologic) to be sensitive. A more appropriate dose of 1 mcg has been suggested, but data to recommend the use of this dose are lacking.
image In severe illness, such as septic shock or acute respiratory distress syndrome (ARDS), ACTH stimulation tests are not recommended for identifying patients who require steroid therapy. Confounding the interpretation of this test is the fact that cortisol is protein bound and the active component is unbound. Most assays for serum cortisol measure both bound and unbound components, and in critical illness protein binding is abnormal, so it is difficult to know what the unbound (active) levels of cortisol are with these results.

FYI

image The adrenal glands sit on top of the kidneys. Originally named the suprarenal glands, they were renamed to the adrenal glands. Each is composed of a cortex and a medulla. Thus, adrenocortico refers to action primarily on the adrenal cortex.
image The zona glomerulosa, zona fasciculata, and zona reticularis are the three zones of the adrenal cortex.

image Aldosterone is produced in the zona glomerulosa.
image Cortisol is produced in zona fasciculata.
image Androgens are produced in the zona reticularis.

image Cortisol and aldosterone are referred to as glucocorticoids and mineralocorticoids, respectively; the corticoid part of the name is in reference to the adrenal cortex.
image The adrenal medulla produces epinephrine and norepinephrine.
image Former U.S. president John F. Kennedy had chronic adrenal insufficiency (Addison’s disease).

Thyroid Replacements

Description

Thyroid replacements compensate for low levels of endogenous thyroid hormone.

Prototypes

image Levothyroxine (T4)
image Liothyronine (T3)

MOA (Mechanism of Action)

image Exogenously administered thyroxine replaces deficient endogenous thyroid hormone, a condition called hypothyroidism.
image Thyroid-releasing hormone (TRH) from the hypothalamus stimulates the pituitary to release thyroid-stimulating hormone (TSH), which stimulates the thyroid gland to synthesize and release thyroid hormone. Thyroid hormone has negative feedback loop activity on both TRH and TSH.
image There are three major forms of thyroid hormone: T4, T3, and rT3 (reverse T3).

image T3 is far more active than T4, but T4 is more abundant.
image Peripheral (nonthyroid) tissues convert T4 to T3.
image rT3 is not active.
image T4 is the most common type of thyroid replacement. Exogenously administered T4 is converted (deiodinated) to the more active form of T3.
image T4 contains four iodine molecules. T3 and rT3 both contain three, but the orientation of the iodine is different in the T3 compared to rT3.

image Thyroid hormones bind intracellular nuclear thyroid hormone receptors (THRs) and influence RNA transcription directly. THRs have 10 times the affinity for T3 that they have for T4.
image Thyroid hormone influences many systems and processes in the body, including the following:

image Metabolic: energy levels, body temperature, weight, lipids, appetite
image Cardiovascular: heart rate, heart rhythm (normal sinus versus other), blood pressure, fluid distribution (because of hydrostatic pressures)
image Skin and hair: composition, thickness, texture
image GI: motility
image Musculoskeletal: bone growth, tendon reflexes
image Hematologic: erythropoiesis (red blood cell production)
image Reproductive: ovulation and spermatogenesis

Pharmacokinetics

image Thyroxine (T4) is administered daily and has good oral availability.
image It has a long half-life of 7 days, meaning that achievement of steady state (five half-lives) requires about 35 days; dose adjustments based on TSH levels should not be made before steady state is reached.
image In contrast, liothyronine (T3) has a half-life of 1 day, mandating more frequent administration.
image Thyroid hormone is deiodinized (iodine molecule removed) to inactive forms by the liver. Doses might require adjustment in liver disease.
image T4 is almost always administered orally. An indication for intravenous administration of T4 is severe life-threatening hypothyroidism (myxedema coma).
image Hypothyroidism decreases clearance of T3 and T4, whereas hyperthyroidism increases clearance.
image Thyroid hormone contains iodine. Therefore other iodinated agents such as amiodarone or iodinated contrast media can inhibit the 5’-deiodinase necessary for the conversion of T4 to T3. β-Blockers, corticosteroids, and severe illness or starvation can also produce the same effect. This results in more T4 being converted to the inactive form of rT3.
image Drugs that induce CYP enzymes can result in increased T4 metabolism to inactive forms.
image Thyroid hormone is strongly bound to thyroxine-binding globulin (TBG), which contributes to its long half-life. Only the unbound hormone is active. Therefore changes in the TBG level can strongly influence the overall activity level.

Indication

image Hypothyroidism from any cause

Contraindications

image Caution must be exercised in conditions in which tachycardia is dangerous (coronary artery disease, aortic stenosis, mitral stenosis) because of the risk of tachycardia if the dose of thyroid replacement is too high.

Side Effects

image Hyperthyroidism-related signs and symptoms

image Cardiac toxicity is one of the most important components:

• Tachycardia
• Atrial fibrillation: One must consider thyroid function as a cause of atrial fibrillation, including endogenous (not drug-related) hyperthyroidism.

Important Notes

image TSH is the most commonly used test to monitor hypothyroid states. In primary (thyroid gland dysfunction) hypothyroidism, TSH levels are elevated in an attempt to further stimulate the thyroid gland. Secondary hypothyroidism (pituitary gland dysfunction) would result in a low TSH.
image Adrenal and thyroid hypofunctioning can coexist. Thyroid hormone replacement without additional corticosteroids may precipitate acute adrenal insufficiency in patients with impaired adrenal function. The outcome can be fatal; however, patients are usually very sick if both adrenal function and thyroid function are significantly abnormal. This can occur in myxedema coma.
image T4 is preferred over T3 administration because T4 has a longer half-life, enabling daily administration, and has a lower potential for cardiac toxicity.
image Diseases associated with abnormal levels of thyroid hormones include the following:

image Grave’s disease: Grave’s disease consists of elevated T4 resulting from antibodies stimulating the TSH receptors on the thyroid.
image Hashimoto’s thyroiditis: Antibodies against the TSH receptor destroy the thyroid gland, eventually resulting in hypothyroidism. Through the destruction process, there can be episodes of increased release of thyroid hormone, causing episodic hyperthyroidism.
image Myxedema: Myxedema is a severe form of hypothyroidism that can be life-threatening. Adrenal function must also be assessed in this condition. Patients can manifest hypoglycemia, hyponatremia, hypothermia, bradycardia, hypotension, congestive heart failure, and coma.
image Cretinism: Cretinism is a severe hypothyroidism in children.
image Thyrotoxic storm: Thyrotoxic storm is severe hyperthyroidism. It is treated with antithyroid therapy.

Advanced

image Subclinical hypothyroidism is a condition of elevated TSH but with normal T3 and T4 levels. Patients are usually healthy and without symptoms.
image Sick euthyroid syndrome is a condition of normal TSH but with decreased T3. It is a term used in patients who are critically ill, but whose disease is not a primary thyroid disorder.
image T3 therapy is rarely ever required but has a faster onset of action than T4 because T4 first needs to be converted to T3. Myxedema coma would be the only indication for T3 administration, and evidence is lacking to support that T3 is superior to T4 in myxedema coma. In fact, cardiovascular toxicity (tachycardia and arrhythmias) can result from too high a dose or too fast an onset of action—a reason to consider avoiding intravenous T3 in critically ill patients.

Evidence

Subclinical Hypothyroidism

image A meta-analysis in 2007 (12 trials, 350 patients) compared levothyroxine replacement with placebo or no treatment for patients with subclinical hypothyroidism. No significant differences were found with respect to symptoms, survival or cardiac function. There was some evidence that thyroid replacement slightly improved lipid levels.

FYI

image Subclinical generally means asymptomatic or having too small an effect to be detected by tests.
image Thyroid hormone with all the iodine molecules removed (thus inactive) is called thyronine.

Antithyroids

Description

Antithyroids are used to treat hyperthyroidism.

Prototype and Common Drugs

Thioamides

image Prototype: propylthiouracil (PTU)
image Others: methimazole, carbimazole

Ablative Agents

image Prototype: radioactive iodine (131I)

MOA (Mechanism of Action)

image Synthesis of thyroid hormone requires the following steps:

image Uptake of iodide into the thyroid
image Through the action of thyroid peroxidase, the following occurs:

• Conversion of the ion iodide (I−) to an oxidized form iodine (I)
• Iodination (addition of iodine) of the tyrosine groups of thyroglobulin (Tg): addition of one iodine makes monoiodotyrosine (MIT); addition of two iodines makes diiodotyrosine (DIT). Coupling two DITs makes T4 (a total of four iodines). Coupling an MIT with a DIT makes T3 (a total of three iodines).

image Cleavage of T3 or T4 from thyroglobulin occurs via proteases in the lysosome.
image T3 or T4 is then released from the thyroid gland.
image Further deiodination (removal of iodine) of T4 to T3. This step occurs outside of the thyroid (peripheral conversion) and generates 80% of the total T3.

image A simplified way to think about synthesis is that thyroid hormone is really like two tyrosine amino acids combined together with either three or four iodine molecules. Thyroglobulin is the tyrosine amino acid supplier (Figure 14-19).
image Thioamides act primarily by blocking the synthesis of thyroid hormone. They do the following:

image Inhibit the thyroid peroxidase catalyzed reactions

• Block iodine oxidation (I− to I)
• Block coupling of the iodinated tyrosines
• Inhibit the peripheral deiodination of T3 and T4

image Do not block uptake of iodide by the gland
image Require about 3 to 4 weeks to exert their effects because of the thyroid precursors of thyroid synthesis that are stored inside the thyroid gland

image Radioactive iodine (131I) destroys the thyroid gland via radiation.

image 131I has a half-life of 8 days and emits primarily β-radiation, which penetrates to a depth of 2 mm.
image 131I preferentially destroys the thyroid gland because of the avid uptake of I by the thyroid.

image

Figure 14-19

Pharmacokinetics

image Antithyroids have good oral availability; dose adjustments are not required in renal or liver disease.

Indications

image Thioamides:

image Hyperthyroidism

image 131I

image Hyperthyroidism
image Thyroid cancer

Contraindications

image Thioamides penetrate the placental barrier and should be used with caution in pregnancy. If required, the lowest dose should be used.
image 131I is:

image Absolutely contraindicated in pregnancy because it can ablate the fetal thyroid gland. Furthermore, pregnancy must be avoided for 6 months following administration of 131I.
image Relatively contraindicated in children. There is a small risk of cancer.

Side Effects

Thioamides

image The most common side effects (in 6% to 10% of patients) are skin rash, fever, and arthralgia (sore joints).

Serious, Rare Side Effects

image Agranulocytosis: Patients can develop a serious reduction in the granulocyte count (neutrophil count), which severely impairs the immune system and results in high risk for serious life-threatening infections. Discontinuing the drug results in restoration of the blood count. A blood count should be performed before the drugs are started, and if the patient develops a fever, cough, sore throat, or urinary tract infection or other symptom that might be suggestive of infection, then a blood count must be repeated. The thioamides must be stopped if the granulocyte count is low.
image Hepatotoxicity: A small percent (0.2%) of patients develop liver damage, which is an allergic-type response and can result in liver failure, necessity for transplant, or death.
image Vasculitis: Vasculitis, an autoimmune process that results in inflammation of blood vessels, is very rare.
image If side effects occur with one thioamide, the probability of side effects occurring with another thioamide is about 50%; so if a severe reaction occurs, then all thioamides are absolutely contraindicated thereafter.

131I

image Hypothyroidism: Almost all patients require lifelong thyroid replacement after radioactive ablation.
image Sialadenitis: Inflammation of the salivary glands occurs because of uptake of 131I. Salivary damage can result in xerostomia (dry mouth), altered taste, increased dental caries, and pain.
image Cancer: Although very small, a risk of cancer arises from the radiation from the 131I.

Important Notes

image β-Blocker therapy is an important part of hyperthyroidism treatment. However, it treats the downstream effects (signs and symptoms) of hyperthyroidism but does not reduce thyroid production or secretion. β-Blocker therapy works within hours of the start of treatment and so is an important component of therapy, because antithyroid medication requires at least 3 to 4 weeks before lowering thyroid hormone levels.
image TSH levels should be tested on a monthly basis and then when symptoms are under control, every 1 to 3 months thereafter.
image Hyperthyroid remission can occur, so treatment with thioamides can be used without thyroid ablation or thyroidectomy. Choice of therapy is not always straightforward and must balance the risks and benefits of the three different options (surgery, 131I ablation, and suppressive therapy). If a patient could be predicted to go into remission, then suppressive therapy might be the best option; however, predicting remission is difficult.
image 131I has been suggested to be associated with increased cancer formation (nonthyroid cancers). The evidence is still under debate.

Advanced

image There are generally two different approaches to administering thioamides:

image Dose titration: Adjust the dose to effect.
image Block and replace: Give a high dose, and then give thyroid replacement.

image Potassium perchlorate is a competitive inhibitor of iodide transport and is used only in amiodarone-induced hyperthyroidism.

FYI

image Nomenclature:

image Antithyroid (-imazoles) should not be confused with -azoles (such as fluconazole), which are antifungal agents.
image Thioamides, as the name suggests, contain a sulfur (thio) and an amide (S = C-NH).

image Carbimazole is converted to methimazole in the body.
image Tyrosine is also the precursor for the synthesis of dopamine, norepinephrine, and epinephrine (see discussions of inotropes and pressors in Chapter 11).
image After 131I treatment, a patient can set off airport radiation alarms for a few months.
image 131I was released after the Chernobyl accident and is also released after nuclear bomb testing.

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