PHARMACOTHERAPY OF ENDOCRINE DISORDERS
HYPOTHALAMIC & PITUITARY HORMONES
INTRODUCTION
The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: (1) as replacement therapy for hormone deficiency states; (2) as antagonists for diseases that result from excess production of pituitary hormones; and (3) as diagnostic tools for identifying several endocrine abnormalities.
ANTERIOR PITUITARY HORMONES & THEIR HYPOTHALAMIC REGULATORS
All of the hormones produced by the anterior pituitary except prolactin (PRL) are key participants in hormonal systems in which they regulate the production by peripheral tissues of hormones that perform the ultimate regulatory functions. In these systems, the secretion of the pituitary hormone is under the control of a hypothalamic hormone. Each hypothalamic-pituitary-endocrine gland system or axis provides multiple opportunities for complex neuroendocrine regulation of growth, development, and reproductive functions.
ANTERIOR PITUITARY & HYPOTHALAMIC HORMONE RECEPTORS
The anterior pituitary hormones can be classified according to hormone structure and the types of receptors that they activate. Growth hormone and prolactin, single-chain protein hormones with significant homology, form one group. Both hormones activate receptors of the JAK/STAT superfamily. Three pituitary hormones¾thyroid-stimulating hormone (TSH, thyrotropin), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)¾are dimeric proteins that activate G protein-coupled receptors. Thyroid-stimulating hormone, FSH, and LH share a common a chain. Their b chains, although somewhat similar to each other, differ enough to confer receptor specificity. Finally, adrenocorticotropic hormone (ACTH), a single peptide that is cleaved from a larger precursor that also contains the peptide b-endorphin, represents a third category. It does, however, like TSH, LH, and FSH, act through a G protein-coupled receptor.
Thyroid-stimulating hormone, FSH, LH, and ACTH share similarities in the regulation of their release from the pituitary. All are under the control of a hypothalamic peptide that stimulates their production by acting on G protein-coupled receptors. Thyroid-stimulating hormone release is regulated by thyrotropin-releasing hormone (TRH), whereas the release of LH and FSH (known collectively as gonadotropins) is stimulated by pulses of gonadotropin-releasing hormone (GnRH). Adrenocorticotropin release is stimulated by corticotropin-releasing hormone (CRH). The final important regulatory feature shared by these three structurally related hormones is that they and their hypothalamic releasing factors are subject to feedback inhibitory regulation by the hormones whose production they control. Thyroid-stimulating hormone and TRH production is inhibited by the two key thyroid hormones, thyroxine and triiodothyronine. Gonadotropin and GnRH production is inhibited in women by estrogen and progesterone, and in men by androgens such as testosterone. Production of ACTH is inhibited by cortisol. Feedback regulation is critical to the physiologic control of thyroid, adrenal cortical, and gonadal function and is also very important in pharmacologic treatments that affect these systems.
The hypothalamic hormonal control of GH and prolactin differs from the regulatory system for TSH, FSH, LH, and ACTH. The hypothalamus secretes two hormones that regulate GH; growth hormone-releasing hormone (GHRH) stimulates growth hormone production, whereas the peptide somatostatin (SST) inhibits growth hormone production. Growth hormone (GH) and its primary peripheral mediator, insulin-like growth factor-1 (IGF-1), also provide feedback to inhibit GH release. Prolactin production is inhibited by the catecholamine dopamine acting through the D2 subtype of dopamine receptors. The hypothalamus does not produce a hormone that stimulates prolactin production.
Whereas all of the pituitary and hypothalamic hormones described above are available for use in humans, only a few are of major clinical importance. Because of the greater ease of administration of target endocrine gland hormones or their synthetic analogs, the related hypothalamic and pituitary hormones (TRH, TSH, CRH, ACTH, GHRH) are either not used clinically or are used rarely for specialized diagnostic testing. In contrast, GH, somatostatin, LH, FSH, GnRH, and dopamine or analogs of these hormones are commonly used and are described in the following text.
Growth hormone, one of the peptide hormones produced by the anterior pituitary, is required during childhood and adolescence for attainment of normal adult size and has important effects throughout postnatal life on lipid and carbohydrate metabolism, and on lean body mass. Its effects are primarily mediated via insulin-like growth factor 1 (IGF-1, somatomedin C) and to a lesser extent both directly and through insulin-like growth factor 2 (IGF-2). Individuals with congenital or acquired deficiency in GH during childhood or adolescence fail to reach their predicted adult height and have disproportionately increased body fat and decreased muscle mass. Adults with GH deficiency also have disproportionately small lean body mass.
Chemistry & Pharmacokinetics
A. STRUCTURE
Growth hormone (somatotropin) is a 191-amino-acid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin. In the past, medicinal GH was isolated from the pituitaries of human cadavers. However, this form of GH was found to be contaminated with prions that could cause Creutzfeldt-Jakob disease. For this reason, it is no longer used.
Two types of recombinant human growth hormone (rhGH) are approved for clinical use. Somatropin has a 191-amino-acid sequence that is identical with the predominant native form of human growth hormone. Somatrem has 192 amino acids consisting of the 191 amino acids of GH plus an extra methionine residue at the amino terminal end. The two preparations appear to be equipotent.
B. ABSORPTION, METABOLISM, AND EXCRETION
Circulating endogenous GH has a half-life of 20-25 minutes and is predominantly cleared by the liver. Recombinant human GH is administered subcutaneously 3-6 times per week. Peak levels occur in 2-4 hours and active blood levels persist for approximately 36 hours.
Somatropin injectable suspension is a long-acting preparation of rhGH enclosed within microspheres. These microspheres degrade slowly after subcutaneous injection such that the rhGH is released over about 1 month.
Pharmacodynamics
Growth hormone mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily. Dimerization of two GH receptors is stimulated by a single GH molecule and activates signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs. Growth hormone has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism. The growth-promoting effects are mediated through an increase in the production of IGF-1. Much of the circulating IGF-1 is produced in the liver. Growth hormone also stimulates production of IGF-
A. GROWTH HORMONE DEFICIENCY
Growth hormone deficiency can have a genetic basis or can be acquired as a result of damage to the pituitary or hypothalamus by a tumor, infection, surgery, or radiation therapy. In childhood, GH deficiency presents as short stature and adiposity. (Neonates with isolated GH deficiency are of normal size at birth, presumably because fetal GH is not required for normal prenatal growth.) Another early sign of GH deficiency is hypoglycemia due to unopposed action of insulin, to which young children are especially sensitive. Criteria for diagnosis of GH deficiency usually include (1) a growth rate below 4 cm per year and (2) the absence of a serum GH response to two GH secretagogues. The incidence of congenital GH deficiency is approximately 1:4000 live births. Therapy with rhGH permits many children with short stature due to GH deficiency to achieve normal adult height.
In the past, it was believed that adults with GH deficiency did not exhibit a significant syndrome. However, more detailed studies suggest that adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, and reduced cardiac output. GH-deficient adults who have been treated with GH have been shown to experience a reversal of many of these manifestations.
B. GROWTH HORMONE TREATMENT OF PEDIATRIC PATIENTS WITH SHORT STATURE
Although the greatest improvement in growth occurs in patients with GH deficiency, exogenous GH has some effect on height in children with short stature that is due to factors other than GH deficiency. Growth hormone has been approved for several conditions and has been used experimentally or off-label in many others. Prader-Willi syndrome is an autosomal dominant genetic disease that is associated with growth failure, obesity, and carbohydrate intolerance. In pediatric patients with Prader-Willi syndrome and growth failure, GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.
Growth hormone treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome, the syndrome associated with a 45, XO karyotype. In clinical trials, GH treatment has been shown to increase final height in girls with Turner syndrome by 10-15 cm (4-6 inches). Because girls with Turner syndrome also have either absent or rudimentary ovaries, GH must be judiciously combined with gonadal steroids to achieve the maximal height effect.
Other conditions of growth failure for which GH treatment is approved include chronic renal failure in pediatric patients and small-for-gestational-age condition at birth in which the child has failed to catch up by age 2. In all of these pediatric patients as well as in patients with GH deficiency, it is critical to start GH treatment before the long bone epiphyses have closed.
The most controversial approved use of GH is for children with idiopathic short stature, also known as non-growth hormone-deficient short stature. This is a heterogeneous population that is defined clinically by a height that is 2.25 standard deviations or more below the national norm for children of the same age. Eligible children also have growth rates that are unlikely to result in an adult height in the normal range and the absence of a condition known to be associated with impaired growth. In this group of children, multiple years of GH therapy results in an average increase in adult height of 4-7 cm (1.57-2.76 inches) at an average cost of $35,000 per inch of height gained. The complex issues involved in the cost-risk-benefit relationship of this use of GH are important because an estimated 400,000 children in the USA fit the diagnostic criteria for idiopathic short stature.
Treatment of children with short stature should be carried out by specialists experienced in the use of GH. Treatment is begun with 0.025 mg/kg daily and may be increased to a maximum of 0.045 mg/kg daily. Somatropin injectable suspension is a long-acting preparation of rhGH that is administered subcutaneously in doses of 1.5 mg/kg monthly or 0.75 mg/kg twice monthly. Children must be observed closely for slowing of growth velocity, which could indicate a need to increase the dosage or the possibility of epiphyseal fusion or intercurrent problems such as hypothyroidism or malnutrition. Children with Turner syndrome or chronic renal insufficiency require somewhat higher doses.
Growth hormone affects many organ systems and also has a net anabolic effect. It has been tested in a number of conditions that are associated with a severe catabolic state and is approved for the treatment of wasting in patients with AIDS. In 2004, GH was approved for treatment of patients with short bowel syndrome who are dependent on total parenteral nutrition (TPN). After intestinal resection or bypass, the remaining functional intestine in many patients undergoes extensive adaptation that allows it to adequately absorb nutrients. However, other patients fail to adequately adapt and develop a malabsorption syndrome. Growth hormone has been shown in experimental animals to increase intestinal growth and improve its function. Results of GH treatment of patients with short bowel syndrome and dependence on total parenteral nutrition have been mixed in the clinical studies that have been published to date. Growth hormone is administered with glutamine, which also has trophic effects on the intestinal mucosa.
Toxicity & Contraindications
Children generally tolerate GH treatment well. A rarely reported side effect is intracranial hypertension, which may manifest as vision changes, headache, nausea, or vomiting. Some children develop scoliosis during rapid growth. Patients with Turner syndrome have an increased risk of otitis media while taking GH. Hypothyroidism is commonly discovered during GH treatment, so periodic assessment of thyroid function is indicated. Pancreatitis, gynecomastia, and nevus growth have occurred in patients receiving GH. Adults tend to have more adverse effects from GH therapy. Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. Growth hormone treatment increases the activity of cytochrome P450 isoforms, which could reduce the serum levels of drugs metabolized by that enzyme system. There has beeo increased incidence of malignancy among patients receiving GH therapy, but GH treatment is contraindicated in a patient with a known malignancy. Proliferative retinopathy may rarely occur. Growth hormone treatment of critically ill patients appears to increase mortality.
Side effects of the long-acting somatropin injectable suspension have included injection-site nodules that persist for 5-7 days (96%), edema, arthralgias, transient fatigue (24%), mild-moderate nausea (24%), and headache (36%).
A small number of children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and development of neutralizing antibodies to GH. In 2005, the FDA approved mecasermin for treatment of severe IGF-1 deficiency that is not responsive to GH. Mecasermin is a complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). The IGF-1 activates transmembrane receptors that, like insulin and EGF receptors, manifest tyrosine kinase activity at their intracellular domains. The binding protein rhIGFBP-3 is needed to maintain an adequate half-life of rhIGF-1. Normally, over 80% of the circulating IGF-1 is bound to IGFBP-3, which is produced by the liver under the control of GH. Patients with severe IGF-1 deficiency that is secondary to aberrant GH signaling also have deficiency of IGFBP-3, and so it is important to supply this with the IGF-1 replacement. Mecasermin is administered subcutaneously twice daily at a recommended starting dosage of 0.04-0.08 mg/kg and increased weekly up to a maximum twice daily dosage of 0.12 mg/kg. The most important adverse effect observed with mecasermin is hypoglycemia. To avoid hypoglycemia, the prescribing instructions require consumption of a meal or snack 20 minutes before or after mecasermin administration. Several patients have experienced intracranial hypertension and asymptomatic elevation of liver enzymes.
The need for antagonists of GH stems from the tendency of GH-producing cells (somatotrophs) in the anterior pituitary to form secreting tumors. Pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas cause acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract. Acromegaly adversely affects the skeletal, muscular, cardiovascular, respiratory, and metabolic systems.
When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to the rare condition, gigantism. Small GH-secreting adenomas can be treated with GH antagonists. Octreotide, a somatostatin analog, and bromocriptine, a dopamine receptor agonist (described below) reduce the production of GH, whereas pegvisomant prevents GH from activating its receptor. Larger pituitary adenomas, which produce greater amounts of GH and also can impair visual and central nervous system function by encroaching oearby brain structures, are treated with transsphenoidal surgery or radiation.
Somatostatin, a 14-amino-acid peptide, is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract. It inhibits the release of GH, glucagon, insulin, and gastrin.
Exogenous somatostatin is rapidly cleared from the circulation, with an initial half-life of 1-3 minutes. The kidney appears to play an important role in its metabolism and excretion.
Somatostatin has limited therapeutic usefulness because of its short duration of action and its multiple effects in many secretory systems. Octreotide, an analog of somatostatin, is 45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic B cells, hyperglycemia rarely occurs during treatment. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer in humans than that of somatostatin.
Octreotide, 50-200 mcg given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly; the carcinoid syndrome; gastrinoma; glucagonoma; nesidioblastosis; the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and diabetic diarrhea. Somatostatin receptor scintigraphy, using radiolabeled octreotide, is useful in localizing neuroendocrine tumors having somatostatin receptors and helps predict the response to octreotide therapy. Octreotide is also useful for the acute control of bleeding from esophageal varices.
Octreotide acetate injectable long-acting suspension is a slow-release microsphere formulation. It is instituted only after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 20-40 mg. Octreotide is extremely costly.
Adverse effects of octreotide therapy include nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6 months of use in 20-30% of patients. However, the yearly incidence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B12 deficiency may occur with long-term use of octreotide.
Acromegaly
Pegvisomant is a GH receptor antagonist that is useful for the treatment of acromegaly. Pegvisomant is the polyethylene glycol (PEG) derivative of a mutant GH, B2036, which has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site. This allows dimerization of the receptor but blocks the conformational changes required for signal transduction. Pegvisomant is a less potent GH receptor antagonist than is B2036, but pegylation reduces its clearance and improves its overall clinical effectiveness. When pegvisomant was administered subcutaneously to 160 patients with acromegaly daily for 12 months or more, serum levels of IGF-1 fell into the normal range in 97%; two patients experienced growth of their GH-secreting pituitary tumors, and two patients developed increases in liver enzymes.
THE GONADOTROPINS¾FOLLICLE-STIMULATING HORMONE & LUTEINIZING HORMONE¾& HUMAN CHORIONIC GONADOTROPIN
The gonadotropins are produced by a single type of pituitary cell, the gonadotroph. These hormones serve complementary functions in the reproductive process. In women, the principal function of FSH is to direct ovarian follicle development. Both FSH and LH are needed for ovarian steroidogenesis. In the ovary, LH stimulates androgen production by theca cells in the follicular stage of the menstrual cycle, whereas FSH stimulates the conversion by granulosa cells of androgens to estrogens. In the luteal phase of the menstrual cycle, estrogen and progesterone production is primarily under the control first of LH and then, if pregnancy occurs, under the control of human chorionic gonadotropin (hCG). Human chorionic gonadotropin is a placental proteiearly identical to LH; its actions are mediated through LH receptors.
In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for the production of testosterone by Leydig cells. FSH helps to maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein by Sertoli cells. FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen.
FSH, LH, and hCG are commercially available in several different forms. They are used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women. Their most common clinical use is for the controlled ovulation hyperstimulation that is the cornerstone of assisted reproductive technologies such as in vitro fertilization (IVF, see below).
All three hormones¾FSH, LH, and hCG¾are dimers that share an identical a chain in addition to a distinct b chain that confers receptor specificity. The b chains of hCG and LH are nearly identical, and these two hormones are used interchangeably. All of the gonadotropin preparations are administered by subcutaneous or intramuscular injection, usually on a daily basis. Half-lives vary by preparation and route of injection from 10 to 40 hours.
A. MENOTROPINS
The first commercial gonadotropin product was extracted from the urine of postmenopausal women, which contains a substance with FSH-like properties (but with 4% of the potency of FSH) and an LH-like substance. This purified extract of FSH and LH is known as menotropins, or human menopausal gonadotropins (hMG).
B. FOLLICLE-STIMULATING HORMONE
Three forms of purified FSH are available. Urofollitropin, also known as uFSH, is a purified preparation of human FSH that is extracted from the urine of postmenopausal women. Virtually all of the LH activity has been removed through a form of immunoaffinity chromatography that uses anti-hCG antibodies. Two recombinant forms of FSH (rFSH) are also available: follitropin alfa and follitropin beta. The amino acid sequences of these two products are identical to that of human FSH. These preparations differ from each other and urofollitropin in the composition of the carbohydrate side chains. The rFSH preparations have a shorter half-life than preparations derived from human urine but stimulate estrogen secretion at least as efficiently and, in some studies, more efficiently. The rFSH preparations are considerably more expensive.
C. LUTEINIZING HORMONE
Lutropin, recombinant human LH (rLH), was introduced in the USA in 2004. When given by subcutaneous injection, it has a half-life of about 10 hours. Lutropin has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency. It has not been approved for use with the other preparations of FSH nor for simulating the endogenous LH surge that is needed to complete follicular development and precipitate ovulation.
D. HUMAN CHORIONIC GONADOTROPIN
Human chorionic gonadotropin is produced by the human placenta and excreted into the urine, whence it can be extracted and purified. It is a glycoprotein consisting of a 92-amino-acid a chain virtually identical to that of FSH, LH, and TSH, and a b chain of 145 amino acids that resembles that of LH except for the presence of a carboxyl terminal sequence of 30 amino acids not present in LH. Choriogonadotropin alfa (rhCG) is a recombinant form of hCG. Because of its greater consistency in biologic activity, the rhCG is packaged and dosed on the basis of weight rather than units of activity. All of the other gonadotropins, including rFSH, are packaged and dosed on the basis of units of activity. The preparation of hCG that is purified from human urine is administered by intramuscular injection, whereas rhCG is administered by subcutaneous injection.
The gonadotropins and hCG exert their effects through G protein-coupled receptors. LH and FSH have complex effects on reproductive tissues in both sexes. In women, these effects change over the time course of a menstrual cycle as a result of a complex interplay between concentration-dependent effects of the gonadotropins, cross-talk between LH, FSH, and gonadal steroids, and the influence of other ovarian hormones. A coordinated pattern of FSH and LH secretion during the menstrual cycle is required for normal follicle development, ovulation, and pregnancy.
During the first 8 weeks of pregnancy, the progesterone and estrogen required to maintain pregnancy are produced by the ovarian corpus luteum. For the first few days after ovulation, the corpus luteum is maintained by maternal LH. However, as maternal LH concentrations fall owing to increasing concentrations of progesterone and estrogen, maintenance of the corpus luteum must be taken over by hCG produced by the placenta.
A. OVULATION INDUCTION
The gonadotropins are used to induce ovulation in women with anovulation due to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes. Because of the high cost of gonadotropins and the need for close monitoring during their administration, gonadotropins are generally reserved for anovulatory women who fail to respond to other less complicated forms of treatment (eg, clomiphene, aromatase inhibitors, metformin). Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. A number of protocols make use of gonadotropins in ovulation induction and controlled ovulation hyperstimulation, and new ones are continually being developed to improve the rates of success and to decrease the two primary risks of ovulation induction: multiple pregnancies and the ovarian hyperstimulation syndrome (OHSS; see below). Although the details differ, all of these protocols are based on the complex physiology that underlies a normal menstrual cycle. Like a menstrual cycle, ovulation induction is discussed in relation to a cycle that begins on the first day of a menstrual bleed. Shortly after the first day (usually on day 3), daily injections with one of the FSH preparations (hMG, urofollitropin) are begun and are continued for approximately 7-12 days. In women with hypogonadotropic hypogonadism, follicle development requires treatment with a combination of FSH and LH because these women do not produce the basal level of LH that is required for adequate ovarian estrogen production and normal follicle development. The dose and duration of FSH treatment are based on the response as measured by the serum estradiol concentration and by ultrasound evaluation of ovarian follicle development and endometrial thickness. When exogenous gonadotropins are used to stimulate follicle development, there is risk of a premature endogenous surge in LH owing to the rapidly changing hormonal milieu. To prevent this, gonadotropins are almost always administered in conjunction with a drug that blocks the effects of endogenous GnRH¾either continuous administration of a GnRH agonist, which down-regulates GnRH receptors, or a few days of treatment with a GnRH receptor antagonist.
When appropriate follicular maturation has occurred, the FSH and GnRH agonist or GnRH antagonist injections are discontinued; the following day, hCG (5000-10,000 IU) is administered intramuscularly to induce final follicular maturation and, in ovulation induction protocols, ovulation. The hCG administration is followed by insemination in ovulation induction and by oocyte retrieval in assisted reproductive technology procedures. Because use of GnRH agonists or antagonists during the follicular phase of ovulation induction suppresses endogenous LH production, it is important to provide exogenous hormonal support of the luteal phase. In clinical trials, exogenous progesterone, hCG, or a combination of the two have been effective at providing adequate luteal support. However, progesterone is preferred because hCG for luteal support carries a higher risk of the ovarian hyperstimulation syndrome (see below).
B. MALE INFERTILITY
Most of the signs and symptoms of hypogonadism in males (eg, delayed puberty, maintenance of secondary sex characteristics after puberty) can be adequately treated with exogenous androgen; however, treatment of infertility in hypogonadal men requires the activity of both LH and FSH. For many years, conventional therapy has consisted of initial treatment for 8-12 weeks with injections of 1000-2500 IU hCG several times per week. After the initial phase, hMG is injected at a dose of 75-150 units three times per week. In men with hypogonadal hypogonadism, it takes an average of 4-6 months of such treatment for sperm to appear in the ejaculate. With the more recent availability of urofollitropin, rFSH, and rLH, a number of alternative protocols have been developed. An advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner. With the advent of ICSI, the minimum threshold of spermatogenesis required for pregnancy is greatly lowered.
Toxicity & Contraindications
In women treated with gonadotropins and hCG, the two most serious complications are the ovarian hyperstimulation syndrome and multiple pregnancies. Overstimulation of the ovary during ovulation induction often leads to uncomplicated ovarian enlargement that usually resolves spontaneously. The ovarian hyperstimulation syndrome is a more serious complication that occurs in 0.5-4% of patients. It is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock. Hemoperitoneum (from a ruptured ovarian cyst), fever, and arterial thromboembolism can occur.
The probability of multiple pregnancies is greatly increased when ovulation induction and assisted reproductive technologies are used. In ovulation induction, the risk of multiple pregnancy is estimated to be 15-20%, whereas the percentage of multiple pregnancies in the general population is closer to 1%. Multiple pregnancies carry an increased risk of complications, such as gestational diabetes, preeclampsia, and preterm labor. In IVF, the risk of multiple pregnancy is primarily determined by the number of embryos transferred to the recipient. A strong trend in recent years has been to transfer fewer embryos.
Other reported adverse effects of gonadotropin treatment are headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG. In men treated with gonadotropins, the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment. An association between ovarian cancer and fertility drugs has been reported. However, it is not known which, if any, fertility drugs are causally related to cancer.
GONADOTROPIN-RELEASING HORMONE & ITS ANALOGS
Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotroph cells. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.
Sustained, nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism. GnRH agonists are used to produce gonadal suppression in men with prostate cancer. They are also used in women who are undergoing assisted reproductive technology procedures or have a gynecologic problem that is benefited by ovarian suppression.
A. STRUCTURE
GnRH is a decapeptide found in all mammals. Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic analogs include goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting thaative GnRH and gonadorelin.
B. PHARMACOKINETICS
Gonadorelin can be administered intravenously or subcutaneously. GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to a number of years for treatment of metastatic prostate cancer. Therefore, preparations have been developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms).
The pharmacodynamic actions of GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty. This is not surprising in view of the complex physiologic role that GnRH plays in normal reproduction, particularly in female reproduction. Pulsatile GnRH release occurs and is responsible for stimulating LH and FSH production during the fetal and neonatal period. However, from the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary simultaneously exhibits very low sensitivity to the GnRH that is produced. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs. In early puberty, pituitary sensitivity to GnRH increases. This is due in part to the effect of increasing concentrations of gonadal steroids. In females, it usually takes several months to a year after the onset of puberty for the hypothalamic-pituitary system to produce an LH surge and ovulation. By the end of puberty, the system is well established so that menstrual cycles proceed at relatively constant intervals. The amplitude and frequency of GnRH pulses also vary in a regular pattern through the menstrual cycle with the highest amplitudes occurring during the luteal phase and the highest frequency occurring late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin and inhibin have complex modulatory effects on the gonadotropin response to GnRH.
In the pharmacologic use of GnRH and its analogs, pulsatile intravenous administration of gonadorelin every 1-4 hours stimulates FSH and LH secretion. Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. During the first 7-10 days, an agonist effect occurs that results in increased concentrations of gonadal hormones in males and females. This initial phase is referred to as a flare. After this period, the continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids. The inhibitory action is due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH.
The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release.
1. Female infertility¾ In the current era of widespread availability of gonadotropins and assisted reproductive technology, the use of pulsatile GnRH administration to treat infertility has become less common. Although pulsatile GnRH is less likely than gonadotropins to cause multiple pregnancies and the ovarian hyperstimulation syndrome, the inconvenience and cost associated with continuous use of an intravenous pump and difficulties obtaining native GnRH (gonadorelin) are barriers to pulsatile GnRH. When this approach is used, a portable battery-powered programmable pump and intravenous tubing deliver pulses of gonadorelin every 90 minutes.
Gonadorelin or a GnRH agonist analog can be used to precipitate an LH surge and ovulation in women with infertility who are undergoing ovulation induction with gonadotropins. Traditionally, hCG has been used to precipitate ovulation in this situation. However, there is some evidence that gonadorelin or a GnRH agonist is less likely than hCG to cause multiple ova to be released and less likely to cause the ovarian hyperstimulation syndrome.
2. Male infertility¾ It is possible to use pulsatile gonadorelin for infertility in men with hypothalamic hypogonadotropic hypogonadism. A portable pump infuses gonadorelin intravenously every 90 minutes. Serum testosterone levels and semen analyses must be done regularly. At least 3-6 months of pulsatile infusions are required before significant numbers of sperm are seen. The preferable alternative to intravenous gonadorelin treatment is the gonadotropin treatment described above.
3. Diagnosis of LH responsiveness¾ GnRH can be useful in determining whether delayed puberty in a hypogonadotropic adolescent is due to constitutional delay or to hypogonadotropic hypogonadism. The LH response (but not the FSH response) to a single dose of GnRH can distinguish between these two conditions. Serum LH levels are measured before and at various times after an intravenous or subcutaneous bolus of GnRH. An increase in serum LH with a peak that exceeds 15.6 mIU/mL is normal and suggests impending puberty. An impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease, but does not rule out constitutional delay of adolescence.
B. SUPPRESSION OF GONADOTROPIN PRODUCTION
1. Controlled ovarian hyperstimulation¾ In the controlled ovarian hyperstimulation that provides multiple mature oocytes for assisted reproductive technologies such as IVF, it is critical to suppress an endogenous LH surge that could prematurely trigger ovulation. This suppression is most commonly achieved by daily subcutaneous injections of leuprolide or daily nasal applications of nafarelin. For leuprolide, treatment is commonly initiated with 1.0 mg daily for about 10 days or until menstrual bleeding occurs. At that point, the dose is reduced to 0.5 mg daily until hCG is administered. For nafarelin, the beginning dosage is generally 400 mcg twice a day, which is decreased to 200 mcg when menstrual bleeding occurs. In women who respond poorly to the standard protocol, alternative protocols that use shorter courses and lower doses of GnRH agonists may improve the follicular response to gonadotropins.
2. Endometriosis¾ Endometriosis is a syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of estrogen-sensitive endometrium-like tissue located outside the uterus. The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the concentrations of estrogen and progesterone that are a normal part of the menstrual cycle. The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and progesterone concentrations and prevents cyclical changes. The recommended duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone density. Leuprolide, goserelin, and nafarelin are approved for this indication. Leuprolide and goserelin are administered as depot preparations that provide 1 or 3 months of continuous GnRH agonist activity. Nafarelin is administered twice daily as a nasal spray at a dose of 0.2 mg per spray.
3. Uterine leiomyomata (uterine fibroids)¾ Uterine leiomyomata are benign, estrogen-sensitive, fibrous growths in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Treatment for 3-6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. Leuprolide, goserelin, and nafarelin are approved for this indication. The doses and routes of administration are similar to those described for treatment of endometriosis.
4. Prostate cancer¾ Antiandrogen therapy is the primary medical therapy for prostate cancer. Combined antiandrogen therapy with continuous GnRH agonist and an androgen receptor antagonist such as flutamide is as effective as surgical castration in reducing serum testosterone concentrations. Leuprolide, goserelin, histrelin, and triptorelin are approved for this indication. The preferred formulation is one of the long-acting depot forms that provide 1, 3, 4, 6, or 12 months of active drug therapy. During the first 7-10 days of GnRH analog therapy, serum testosterone levels increase because of the agonist action of the drug; this can precipitate pain in patients with bone metastases, and tumor growth and neurologic symptoms in patients with vertebral metastases. It can also temporarily worsen symptoms of urinary obstruction. Such tumor flares can usually be avoided with the concomitant administration of bicalutamide or one of the other androgen receptor antagonists. Within about 2 weeks, serum testosterone levels fall to the hypogonadal range.
5. Central precocious puberty¾ Continuous administration of a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 8 years in girls or 9 years in boys). Before administering a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal, not childhood, gonadotropin response to GnRH and a bone age at least 1 year beyond chronologic age. Pretreatment evaluation must also include gonadal steroid levels compatible with precocious puberty and not congenital adrenal hyperplasia; an hCG level that is low enough to exclude a chronic gonadotropin-secreting tumor; an MRI of the brain to exclude an intracranial tumor; and ultrasound examination of the adrenals and ovaries or testes to exclude a steroid-secreting tumor.
Treatment can be carried out with injections of leuprolide or nasal application of nafarelin. Leuprolide treatment is usually initiated at a dosage of 0.05 mg/kg body weight injected subcutaneously daily and then adjusted on the basis of the clinical response. Pediatric depot preparations of leuprolide are also available. The recommended initial dosage of nafarelin for central precocious puberty is 1.6 mg/d. This is achieved with two unit dose sprays (each spray contains 0.1 mL, 0.2 mg) into each nostril twice daily. Treatment with a GnRH agonist is generally continued to age 11 in females and age 12 in males.
6. Other¾ Other clinical uses for the gonadal suppression provided by continuous GnRH agonist treatment include advanced breast and ovarian cancer; thinning of the endometrial lining in preparation for an endometrial ablation procedure in women with dysfunctional uterine bleeding; and treatment of amenorrhea and infertility in women with polycystic ovary disease.
Toxicity
Gonadorelin can cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitivity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness have been reported following administration of GnRH to a patient with a gonadotropin-secreting pituitary tumor.
Continuous treatment of women with a GnRH analog (leuprolide, nafarelin, goserelin) causes the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks; however, the cysts may persist and require discontinuation of therapy. Reduced bone density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Depending on the condition being treated with the GnRH agonist, it may be possible to ameliorate the signs and symptoms of the hypoestrogenic state without losing clinical efficacy by adding back a small dose of a progestin and an estrogen. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.
In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, and injection site reactions. GnRH analog treatment of children is generally well tolerated. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Nafareliasal spray may cause or aggravate sinusitis.
Two synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix and cetrorelix inhibit the secretion of FSH and LH in a dose-dependent manner. Both are approved for use in controlled ovarian hyperstimulation as part of an assisted reproductive procedure such as IVF.
Ganirelix and cetrorelix are absorbed rapidly after subcutaneous injection. Administration of 0.25 mg daily maintains GnRH antagonism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours.
GnRH antagonists are approved for preventing the LH surge during controlled ovarian hyperstimulation. They offer several advantages over continuous treatment with a GnRH agonist. Because they produce an immediate antagonist effect, their use can be delayed until day 6-8 of the IVF cycle and thus the duration of administration is shorter. They also appear to have a less negative impact on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. Finally, GnRH antagonists are associated with a lower risk of ovarian hyperstimulation syndrome, which can lead to cycle cancellation. On the other hand, because their antagonist effects reverse more quickly after their discontinuation, adherence to the treatment regimen is critical. The antagonists produce a more complete suppression of gonadotropin secretion than agonists. There is concern that the suppression of LH may inhibit ovarian steroidogenesis to an extent that impairs follicular development when recombinant or the purified form of FSH is used during the follicular phase of an IVF cycle. Clinical trials have shown a slightly lower rate of pregnancy in IVF cycles that used GnRH antagonist treatment compared with cycles that used GnRH agonist treatment.
Toxicity
The GnRH antagonists are well tolerated. The most common adverse effects are nausea and headache. When used for ovulation induction in combination with gonadotropins, the most serious toxicity is the ovarian hyperstimulation syndrome.
Prolactin is a 198-amino-acid peptide hormone produced in the anterior pituitary. Its structure resembles that of GH. Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. A deficiency of prolactin¾which can occur in rare states of pituitary deficiency¾is manifested by failure to lactate or by a luteal phase defect. In rare cases of hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of dopamine (prolactin-inhibiting hormone) to the pituitary. Much more commonly, however, prolactin is elevated as a result of prolactin-secreting adenomas. Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men. In the case of large tumors (macroadenomas), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release.
No preparation of prolactin is available for use in prolactin-deficient patients. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release.
Adenomas that secrete excess prolactin usually retain the sensitivity to inhibition by dopamine exhibited by the normal pituitary. Bromocriptine, cabergoline, and pergolide are ergot derivatives with a high affinity for dopamine D2 receptors. Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D2 receptor affinity.
Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia. Growth hormone release is reduced in patients with acromegaly, although not as effectively. Cabergoline, bromocriptine, and pergolide are also used in Parkinson’s disease to improve motor function and reduce levodopa requirements.
All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. They can also be absorbed systemically after vaginal insertion of tablets. Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action. Pergolide and quinagolide have half-lives of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. Following vaginal administration, serum levels peak more slowly.
A. HYPERPROLACTINEMIA
A dopamine agonist is the standard medical treatment for hyperprolactinemia. These drugs shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas. Cabergoline is initiated at 0.25 mg twice weekly orally or vaginally. It can be increased gradually, according to serum prolactin determinations, up to a maximum of 1 mg twice weekly. Bromocriptine is generally taken daily after the evening meal at the initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients require 2.5-7.5 mg daily. Long-acting oral bromocriptine formulations (Parlodel SRO) and intramuscular formulations (Parlodel L.A.R.) are available outside the USA.
In doses of 0.15-0.6 mg/d orally, quinagolide suppresses prolactin and shrinks most prolactinomas. Quinagolide is sometimes better tolerated than ergot-derived dopamine agonists. It is not available in the USA.
B. PHYSIOLOGIC LACTATION
Dopamine agonists were used in the past to prevent breast engorgement when breast feeding was not desired. Their use for this purpose has been discouraged because of toxicity.
C. ACROMEGALY
A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly. The doses required are higher than those used to treat hyperprolactinemia. For example, patients with acromegaly require 20 to 30 mg/d of bromocriptine and seldom respond adequately
Toxicity & Contraindications
Dopamine agonists can cause nausea, headache, light-headedness, orthostatic hypotension, and fatigue. Psychiatric manifestations occasionally occur, even at lower doses, and may take months to resolve. Erythromelalgia occurs rarely. High dosages of ergot-derived preparations can cause cold-induced peripheral digital vasospasm. Pulmonary infiltrates have occurred with chronic high-dosage therapy. Cabergoline appears to cause nausea less often than bromocriptine. Vaginal administration can reduce nausea, but may cause local irritation.
Dopamine agonist therapy during the early weeks of pregnancy has not been associated with an increased risk of spontaneous abortion or congenital malformations. Although there has been a longer experience with the safety of bromocriptine during early pregnancy, there is growing evidence that cabergoline is also safe in women with macroadenomas who must continue a dopamine agonist during pregnancy. In patients with small pituitary adenomas, dopamine agonist therapy is discontinued upon conception because growth of microadenomas during pregnancy is rare. Patients with very large adenomas require vigilance for tumor progression and often require a dopamine agonist throughout pregnancy. There have been rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation.
The two posterior pituitary hormones¾vasopressin and oxytocin¾are synthesized ieuronal cell bodies in the hypothalamus and then transported via their axons to the posterior pituitary, where they are stored and then released into the circulation. Each has limited but important clinical uses.
Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.
A. STRUCTURE
Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide cross-link (Figure 37-5). Its amino acid sequence differs from that of vasopressin at positions 3 and 8. Vasotocin is similar to oxytocin and vasopressin and is found ionmammalian vertebrates.
B. ABSORPTION, METABOLISM, AND EXCRETION
Oxytocin is administered intravenously for initiation and augmentation of labor. It also can be administered intramuscularly for control of postpartum bleeding. Oxytocin is not bound to plasma proteins and is eliminated by the kidneys and liver, with a circulating half-life of 5 minutes.
Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and force of uterine contractions. At higher doses, it produces sustained contraction.
Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.
Oxytocin is used to induce labor for conditions requiring early vaginal delivery such as Rh problems, maternal diabetes, preeclampsia, or ruptured membranes. It is also used to augment abnormal labor that is protracted or displays an arrest disorder. Oxytocin has several uses in the immediate postpartum period, including the control of uterine hemorrhage after vaginal or cesarean delivery. It is sometimes used during second-trimester abortions.
Before delivery, oxytocin is usually administered intravenously via an infusion pump with appropriate fetal and maternal monitoring. For induction of labor, an initial infusion rate of 0.5-2 mU/min is increased every 30-60 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min. For postpartum uterine bleeding, 10-40 units are added to 1 L of 5% dextrose, and the infusion rate is titrated to control uterine atony. Alternatively, 10 units of oxytocin can be administered by intramuscular injection after delivery of the placenta.
During the antepartum period, oxytocin induces uterine contractions that transiently reduce placental blood flow to the fetus. The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve. Oxytocin is infused at an initial rate of 0.5 mU/min, then doubled every 20 minutes until uterine contractions decrease the fetal blood supply. An abnormal response, seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery.
When oxytocin is used judiciously, serious toxicity is rare. The toxicity that does occur is due either to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors. Excessive stimulation of uterine contractions before deliver can cause fetal distress, placental abruption, or uterine rupture. These complications can be detected early by means of standard fetal monitoring equipment. High concentrations of oxytocin with activation of vasopressin receptors can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death. Bolus injections of oxytocin can cause hypotension. To avoid hypotension, oxytocin is administered intravenously as dilute solutions at a controlled rate.
Contraindications to oxytocin include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.
Atosiban is an antagonist of the oxytocin receptor that has been approved outside the USA as a treatment for preterm labor (tocolysis). Atosiban is a modified form of oxytocin that is administered by IV infusion for 2-48 hours. In a small number of published clinical trials, atosiban appears to be as effective as b-adrenoceptor-agonist tocolytics and to produce fewer adverse effects. However, in one placebo-controlled trial, the subject group that received atosiban had more infant deaths than the placebo group. In 1998, the FDA decided not to approve atosiban based on concerns about efficacy and safety.
VASOPRESSIN (ANTIDIURETIC HORMONE, ADH)
Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. Vasopressin possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus.
A. STRUCTURE
Vasopressin is a nonapeptide with a 6-amino-acid ring and a 3-amino-acid side chain. The residue at position 8 is arginine in humans and in most other mammals except pigs and related species, whose vasopressin contains lysine at position 8. Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Desmopressin is modified at position 1 and contains a D-amino acid at position 8. Like vasopressin and oxytocin, desmopressin has a disulfide linkage between positions 1 and 6.
B. ABSORPTION, METABOLISM, AND EXCRETION
Vasopressin is administered by intravenous or intramuscular injection; oral administration is not effective because the peptide is inactivated by digestive enzymes. The half-life of circulating vasopressin is approximately 15 minutes, with renal and hepatic metabolism via reduction of the disulfide bond and peptide cleavage.
Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally. The half-life of circulating desmopressin is 1.5-2.5 hours. Nasal desmopressin is available as a unit dose spray that delivers 0.1 mL per spray; it is also available with a calibrated nasal tube that can be used to deliver a more precise dose. Nasal bioavailability of desmopressin is 3-4%, whereas oral bioavailability is less than 1%.
Vasopressin activates two subtypes of G protein-coupled receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor.
Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus. The dosage of desmopressin is 10-40 mcg (0.1-0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1-0.2 mg two to three times daily. The dosage by injection is 1-4 mcg (0.25-1 mL) every 12-24 hours as needed for polyuria, polydipsia, or hypernatremia. Bedtime desmopressin therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing nocturnal urine production. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.
Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand’s disease.
Toxicity & Contraindications
Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Therapy can result in hyponatremia and seizures.
Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease. Nasal insufflation of desmopressin may be less effective wheasal congestion is present.
A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both V1a and V2 receptors. Tolvaptan has 30-fold higher affinity for V2 than for V1 receptors. In several clinical trials, both agents relieved symptoms and reduced objective signs of hyponatremia and heart failure. Conivaptan has been approved by the FDA for intravenous administration in hyponatremia but not in congestive heart failure. Several other nonselective nonpeptide vasopressin receptor antagonists are being investigated for these conditions.
The normal thyroid gland secretes sufficient amounts of the thyroid hormones¾triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine)¾to normalize growth and development, body temperature, and energy levels. These hormones contain 59% and 65% (respectively) of iodine as an essential part of the molecule.
Iodide Metabolism
The recommended daily adult iodide (I–)* intake is 150 mcg (200 mcg during pregnancy).
Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished.
Biosynthesis of Thyroid Hormones
Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that convert it into active thyroid hormone. The first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter (NIS). This can be inhibited by such anions as thiocyanate (SCN–), pertechnetate (TcO4–), and perchlorate (ClO4–). At the apical cell membrane a second I– transport enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the cochlea of the inner ear and if deficient or absent, a syndrome of deafness and goiter, called Pendred’s syndrome, ensues. At the apical cell membrane, iodide is oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs.
Two molecules of DIT combine within the thyroglobulin molecule to form L-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3. In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity. Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT are deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine.
The primary pathway for the peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3¢-triiodothyronine (T3), which is three to four times more potent than T4. Alternatively, deiodination may occur in the inner ring, producing 3,3¢,5¢-triiodothyronine (reverse T3, or rT3), which is metabolically inactive. Drugs such as amiodarone, iodinated contrast media, b blockers, and corticosteroids, and severe illness or starvation inhibit the 5¢-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. The low serum levels of T3 and rT3 iormal individuals are due to the high metabolic clearances of these two compounds.
A. THYROID-PITUITARY RELATIONSHIPS Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH)). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH.
B. AUTOREGULATION OF THE THYROID GLAND
The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification. In certain disease states (eg, Hashimoto’s thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism. Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter).
C. ABNORMAL THYROID STIMULATORS
In Graves’ disease (see below), lymphocytes secrete a TSH receptor-stimulating antibody (TSH-R Ab [stim]), also known as thyroid-stimulating immunoglobulin (TSI). This immunoglobulin binds to the TSH receptor and turns on the gland in the same fashion as TSH itself. The duration of its effect, however, is much longer than that of TSH. TSH receptors are also found in orbital fibrocytes, which may be stimulated by high levels of TSH-R Ab [stim].
I. BASIC PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS
The structural formulas of thyroxine and triiodothyronine – naturally occurring molecules are levo (L) isomers. The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the L isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism.
Thyroxine is absorbed best in the duodenum and ileum; absorption is modified by intraluminal factors such as food, drugs, and intestinal flora. Oral bioavailability of current preparations of L-thyroxine averages 80%. In contrast, T3 is almost completely absorbed (95%). T4 and T3 absorption appears not to be affected by mild hypothyroidism but may be impaired in severe myxedema with ileus. These factors are important in switching from oral to parenteral therapy. For parenteral use, the intravenous route is preferred for both hormones.
In patients with hyperthyroidism, the metabolic clearances of T4 and T3 are increased and the half-lives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, imatinib, protease inhibitors) increase the metabolism of both T4 and T3. Despite this change in clearance, the normal hormone concentration is maintained in euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients receiving T4 replacement medication may require increased dosages to maintain clinical effectiveness. A similar compensation occurs if binding sites are altered. If TBG sites are increased by pregnancy, estrogens, or oral contraceptives, there is an initial shift of hormone from the free to the bound state and a decrease in its rate of elimination until the normal hormone concentration is restored. Thus, the concentration of total and bound hormone will increase, but the concentration of free hormone and the steady-state elimination will remaiormal. The reverse occurs when thyroid binding sites are decreased.
Within the cell, T4 is converted to T3 by 5¢-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, a and b. Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on different tissues.
Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis, eg, increased formation of Na+/K+ ATPase. This is consistent with the observation that the action of thyroid is manifested in vivo with a time lag of hours or days after its administration.
Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine), while few receptor sites occur in hormone-unresponsive tissues (spleen, testes). The brain, which lacks an anabolic response to T3, contains an intermediate number of receptors. In congruence with their biologic potencies, the affinity of the receptor site for T4 is about ten times lower than that for T3. The number of nuclear receptors may be altered to preserve body homeostasis. For example, starvation lowers both circulating T3 hormone and cellular T3 receptors.
The thyroid hormones are responsible for optimal growth, development, function, and maintenance of all body tissues. Excess or inadequate amounts result in the signs and symptoms of hyperthyroidism or hypothyroidism, respectively. Since T3 and T4 are qualitatively similar, they may be considered as one hormone in the discussion that follows.
Thyroid hormone is critical for nervous, skeletal, and reproductive tissues. Its effects depend on protein synthesis as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and dwarfism¾symptoms typical of congenital cretinism.
Effects on growth and calorigenesis are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.
Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardiovascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity. Possible explanations include increased numbers of b receptors or enhanced amplification of the b receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of symptoms is seen in hypothyroidism.
These preparations may be synthetic (levothyroxine, liothyronine, liotrix) or of animal origin (desiccated thyroid).
Thyroid hormones are not effective and can be detrimental in the management of obesity, abnormal vaginal bleeding, or depression if thyroid hormone levels are normal. Anecdotal reports of a beneficial effect of T3 administered with antidepressants have not been confirmed with a controlled study.
Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration. In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones. Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations.
Although liothyronine (T3) is three to four times more potent than levothyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours), which requires multiple daily doses; its higher cost; and the greater difficulty of monitoring its adequacy of replacement by conventional laboratory tests. Furthermore, because of its greater hormone activity and consequent greater risk of cardiotoxicity, T3 should be avoided in patients with cardiac disease. It is best used for short-term suppression of TSH. Because oral administration of T3 is unnecessary, use of the more expensive mixture of thyroxine and liothyronine (liotrix) instead of levothyroxine is never required.
The use of desiccated thyroid rather than synthetic preparations is never justified, since the disadvantages of protein antigenicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of low cost. Significant amounts of T3 found in some thyroid extracts and liotrix may produce significant elevations in T3 levels and toxicity. Equivalent doses are 100 mg of desiccated thyroid, 100 mcg of levothyroxine, and 37.5 mcg of liothyronine.
The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination. The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.
Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, by agents that modify the tissue response to thyroid hormones, or by glandular destruction with radiation or surgery. Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). The antithyroid compounds used clinically include the thioamides, iodides, and radioactive iodine.
The thioamides methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis. In the United Kingdom, carbimazole, which is converted to methimazole in vivo, is widely used. Methimazole is about ten times more potent than propylthiouracil.
Propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50-80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Most of an ingested dose of propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours.
In contrast, methimazole is completely absorbed but at variable rates. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of propylthiouracil. Excretion is slower than with propylthiouracil; 65-70% of a dose is recovered in the urine in 48 hours.
The short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for methimazole) has little influence on the duration of the antithyroid action or the dosing interval because both agents are accumulated by the thyroid gland. For propylthiouracil, giving the drug every 6-8 hours is reasonable since a single 100 mg dose can inhibit iodine organification by 60% for 7 hours. Since a single 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to moderate hyperthyroidism.
Both thioamides cross the placental barrier and are concentrated by the fetal thyroid, so that caution must be employed when using these drugs in pregnancy. Because of the risk of fetal hypothyroidism, both thioamides are classified as pregnancy category D (evidence of human fetal risk based on adverse reaction data from investigational or marketing experience). Of the two, propylthiouracil is preferable in pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. In addition, methimazole has been, albeit rarely, associated with congenital malformations. Both thioamides are secreted in low concentrations in breast milk but are considered safe for the nursing infant.
The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland. Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral deiodination of T4 and T3. Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before stores of T4 are depleted.
Toxicity
Adverse reactions to the thioamides occur in 3-12% of treated patients. Most reactions occur early, especially nausea and gastrointestinal distress. An altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4-6%), at times accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. Hepatitis (more common with propylthiouracil) and cholestatic jaundice (more common with methimazole) can be fatal; although asymptomatic elevations in transaminase levels also occur.
The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3), an infrequent but potentially fatal adverse reaction. It occurs in 0.1-0.5% of patients taking thioamides, but the risk may be increased in older patients and in those receiving high-dose methimazole therapy (> 40 mg/d). The reaction is usually rapidly reversible when the drug is discontinued, but broad-spectrum antibiotic therapy may be necessary for complicating infections. Colony-stimulating factors (eg, G-CSF) may hasten recovery of the granulocytes. The cross-sensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended.
Monovalent anions such as perchlorate (ClO4–), pertechnetate (TcO4–), and thiocyanate (SCN–) can block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism. Since these effects can be overcome by large doses of iodides, their effectiveness is somewhat unpredictable.
The major clinical use for potassium perchlorate is to block thyroidal reuptake of I– in patients with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia.
Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy.
Iodides have several actions on the thyroid. They inhibit organification and hormone release and decrease the size and vascularity of the hyperplastic gland. In susceptible individuals, iodides can induce hyperthyroidism (jodbasedow phenomenon) or precipitate hypothyroidism.
In pharmacologic doses (> 6 mg/d), the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis. Improvement in thyrotoxic symptoms occurs rapidly¾within 2-7 days¾hence the value of iodide therapy in thyroid storm. In addition, iodides decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as preoperative preparation for surgery.
Disadvantages of iodide therapy include an increase in intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks. Thus, iodides should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine seems likely. Iodide should not be used alone, because the gland will escape from the iodide block in 2-8 weeks, and its withdrawal may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic use of iodides in pregnancy should be avoided, since they cross the placenta and can cause fetal goiter. In radiation emergencies, the thyroid-blocking effects of potassium iodide can protect the gland from subsequent damage if administered before radiation exposure.
Toxicity
Adverse reactions to iodine (iodism) are uncommon and in most cases reversible upon discontinuance. They include acneiform rash (similar to that of bromism), swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely, anaphylactoid reactions.
4. Iodinated Contrast Media
The iodinated contrast agents¾diatrizoate orally and iohexol orally or intravenously¾are valuable in the treatment of hyperthyroidism, although they are not labeled for this indication. These drugs rapidly inhibit the conversion of T4 to T3 in the liver, kidney, pituitary gland, and brain. This accounts for the dramatic improvement in both subjective and objective parameters. For example, a decrease in heart rate is seen after only 3 days of administration of 0.5-1 g/d of oral contrast media. T3 levels often return to normal during this time. The prolonged effect of suppressing T4 as well as T3 suggests that inhibition of hormone release due to the iodine released may be an additional mechanism of action. Fortunately, these agents are relatively nontoxic. They provide useful adjunctive therapy in the treatment of thyroid storm and offer valuable alternatives when iodides or thioamides are contraindicated. Surprisingly, these agents may not interfere with 131I retention as much as iodides despite their large iodine content. Their toxicity is similar to that of the iodides, and their safety in pregnancy is undocumented.
131I is the only isotope used for treatment of thyrotoxicosis (others are used in diagnosis). Administered orally in solution as sodium 131I, it is rapidly absorbed, concentrated by the thyroid, and incorporated into storage follicles. Its therapeutic effect depends on emission of b rays with an effective half-life of 5 days and a penetration range of 400-2000 um. Within a few weeks after administration, destruction of the thyroid parenchyma is evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration. Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain. Fears of radiation-induced genetic damage, leukemia, and neoplasia have not been realized after more than 50 years of clinical experience with radioiodine. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland and is excreted in breast milk.
6. Adrenoceptor-Blocking Agents
Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the b blocker most widely studied and used in the therapy of thyrotoxicosis. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not alter thyroid hormone levels.
Hypothyroidism is a syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions. In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation.
Hypothyroidism can occur with or without thyroid enlargement (goiter). The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of a low free thyroxine and elevated serum TSH.
The most common cause of hypothyroidism in the USA at this time is probably Hashimoto’s thyroiditis, an immunologic disorder in genetically predisposed individuals. In this condition, there is evidence of humoral immunity in the presence of antithyroid antibodies and lymphocyte sensitization to thyroid antigens. Certain medications can also cause hypothyroidism.
Management of Hypothyroidism
Except for hypothyroidism caused by drugs, which can be treated in some cases by simply removing the depressant agent, the general strategy of replacement therapy is appropriate. The most satisfactory preparation is levothyroxine, administered as either a branded or generic preparation. Treatment with combination levothyroxine plus liothyronine has not been found to be superior to levothyroxine alone. Infants and children require more T4 per kilogram of body weight than adults. The average dosage for an infant 1-6 months of age is 10-15 mcg/kg/d, whereas the average dosage for an adult is about 1.7 mcg/kg/d. Older adults (> 65 years of age) may require less thyroxine for replacement. There is some variability in the absorption of thyroxine, so this dosage will vary from patient to patient. Since interactions with certain foods (eg, bran, soy) and drugs can impair its absorption, thyroxine should be administered on an empty stomach (eg, 30 minutes before meals or 1 hour after meals). Its long half-life of 7 days permits once daily dosing. Children should be monitored for normal growth and development. Serum TSH and free thyroxine should be measured at regular intervals and TSH maintained within an optimal range of 0.5-2.5 mU/L. It takes 6-8 weeks after starting a given dose of thyroxine to reach steady-state levels in the bloodstream. Thus, dosage changes should be made slowly.
In long-standing hypothyroidism, in older patients, and in patients with underlying cardiac disease, it is imperative to start treatment with reduced dosages. In such adult patients, levothyroxine is given in a dosage of 12.5-25 mcg/d for 2 weeks, increasing the daily dose by 25 mcg every 2 weeks until euthyroidism or drug toxicity is observed. In older patients, the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or cardiac arrhythmia develops, it is essential to stop or reduce the dose of thyroxine immediately. In younger patients or those with very mild disease, full replacement therapy may be started immediately.
The toxicity of thyroxine is directly related to the hormone level. In children, restlessness, insomnia, and accelerated bone maturation and growth may be signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss may be the presenting symptoms. If these symptoms are present, it is important to monitor serum TSH , which will determine whether the symptoms are due to excess thyroxine blood levels. Chronic overtreatment with T4, particularly in elderly patients, can increase the risk of atrial fibrillation and accelerated osteoporosis.
Special Problems in Management of Hypothyroidism
A. MYXEDEMA AND CORONARY ARTERY DISEASE
Since myxedema frequently occurs in older persons, it is often associated with underlying coronary artery disease. In this situation, the low levels of circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pectoris or myocardial infarction. Correction of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or acute myocardial infarction. If coronary artery surgery is indicated, it should be done first, prior to correction of the myxedema by thyroxine administration.
B. MYXEDEMA COMA
Myxedema coma is an end state of untreated hypothyroidism. It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death.
Management of myxedema coma is a medical emergency. The patient should be treated in the intensive care unit, since tracheal intubation and mechanical ventilation may be required. Associated illnesses such as infection or heart failure must be treated by appropriate therapy. It is important to give all preparations intravenously, because patients with myxedema coma absorb drugs poorly from other routes. Intravenous fluids should be administered with caution to avoid excessive water intake. These patients have large pools of empty T3 and T4 binding sites that must be filled before there is adequate free thyroxine to affect tissue metabolism. Accordingly, the treatment of choice in myxedema coma is to give a loading dose of levothyroxine intravenously¾usually 300-400 mcg initially, followed by 50-100 mcg daily. Intravenous T3 can also be used but may be more cardiotoxic and more difficult to monitor. Intravenous hydrocortisone is indicated if the patient has associated adrenal or pituitary insufficiency but is probably not necessary in most patients with primary myxedema. Opioids and sedatives must be used with extreme caution.
C. HYPOTHYROIDISM AND PREGNANCY
Hypothyroid women frequently have anovulatory cycles and are therefore relatively infertile until restoration of the euthyroid state. This has led to the widespread use of thyroid hormone for infertility, although there is no evidence for its usefulness in infertile euthyroid patients. In a pregnant hypothyroid patient receiving thyroxine, it is extremely important that the daily dose of thyroxine be adequate because early development of the fetal brain depends on maternal thyroxine. In many hypothyroid patients, an increase in the thyroxine dose (about 30-50%) is required to normalize the serum TSH level during pregnancy. Because of the elevated maternal TBG levels and, therefore, elevated total T4 levels, adequate maternal thyroxine dosages warrant maintenance of TSH between 0.5 and 3.0 mU/L and the total T4 at or above the upper range of normal.
D. SUBCLINICAL HYPOTHYROIDISM
Subclinical hypothyroidism, defined as an elevated TSH level and normal thyroid hormone levels, is found in 4-10% of the general population but increases to 20% in women older than age 50. The consensus of expert thyroid organizations concluded that thyroid hormone therapy should be considered for patients with TSH levels greater than 10 mU/L while close TSH monitoring is appropriate for those with lower TSH elevations.
E. DRUG-INDUCED HYPOTHYROIDISM
Drug-induced hypothyroidism can be satisfactorily managed with levothyroxine therapy if the offending agent cannot be stopped. In the case of amiodarone-induced hypothyroidism, levothyroxine therapy may be necessary even after discontinuance because of amiodarone’s very long half-life.
Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone.
The most common form of hyperthyroidism is Graves’ disease, or diffuse toxic goiter.
Pathophysiology
Graves’ disease is considered to be an autoimmune disorder in which helper T lymphocytes stimulate B lymphocytes to synthesize antibodies to thyroidal antigens. The antibody described previously (TSH-R Ab [stim]) is directed against the TSH receptor site in the thyroid cell membrane and has the capacity to stimulate growth and biosynthetic activity of the thyroid cell. Spontaneous remission occurs but some patients require years of antithyroid therapy.
In most patients with hyperthyroidism, T3, T4, FT4, and FT3 are elevated and TSH is suppressed. Radioiodine uptake is usually markedly elevated as well. Antithyroglobulin, thyroid peroxidase, and TSH-R Ab [stim] antibodies are usually present.
The three primary methods for controlling hyperthyroidism are antithyroid drug therapy, surgical thyroidectomy, and destruction of the gland with radioactive iodine.
A. ANTITHYROID DRUG THERAPY
Drug therapy is most useful in young patients with small glands and mild disease. Methimazole or propylthiouracil is administered until the disease undergoes spontaneous remission. This is the only therapy that leaves an intact thyroid gland, but it does require a long period of treatment and observation (12-18 months), and there is a 50-68% incidence of relapse.
Methimazole is preferable to propylthiouracil (except in pregnancy) because it can be administered once daily, which may enhance adherence. Antithyroid drug therapy is usually begun with divided doses, shifting to maintenance therapy with single daily doses when the patient becomes clinically euthyroid. However, mild to moderately severe thyrotoxicosis can often be controlled with methimazole given in a single morning dose of 20-40 mg initially for 4-8 weeks to normalize hormone levels. Maintenance therapy requires 5-15 mg once daily. Alternatively, therapy is started with propylthiouracil, 100-150 mg every 6 or 8 hours until the patient is euthyroid, followed by gradual reduction of the dose to the maintenance level of 50-150 mg once daily. In addition to inhibiting iodine organification, propylthiouracil also inhibits the conversion of T4 to T3, so it brings the level of activated thyroid hormone down more quickly than does methimazole. The best clinical guide to remission is reduction in the size of the goiter. Laboratory tests most useful in monitoring the course of therapy are serum FT3, FT4, and TSH levels.
Reactivation of the autoimmune process may occur when the dosage of antithyroid drug is lowered during maintenance therapy and TSH begins to drive the gland. In some cases TSH release can be prevented by the daily administration of 50-150 mcg of levothyroxine with 5-15 mg of methimazole or 50-150 mg of propylthiouracil for the second year of therapy. The relapse rate with this program is probably comparable to the rate with antithyroid therapy alone, but the risk of hypothyroidism and overtreatment is avoided.
Reactions to antithyroid drugs have been described above. A minor rash can often be controlled by antihistamine therapy. Because the more severe reaction of agranulocytosis is often heralded by sore throat or high fever, patients receiving antithyroid drugs must be instructed to discontinue the drug and seek immediate medical attention if these symptoms develop. White cell and differential counts and a throat culture are indicated in such cases, followed by appropriate antibiotic therapy.
B. THYROIDECTOMY
A near-total thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters. Patients are treated with antithyroid drugs until euthyroid (about 6 weeks). In addition, for 10-14 days prior to surgery, they receive saturated solution of potassium iodide, 5 drops twice daily, to diminish vascularity of the gland and simplify surgery. About 80-90% of patients will require thyroid supplementation following near-total thyroidectomy.
C. RADIOACTIVE IODINE
Radioiodine therapy utilizing 131I is the preferred treatment for most patients over 21 years of age. In patients without heart disease, the therapeutic dose may be given immediately in a range of 80-120 uCi/g of estimated thyroid weight corrected for uptake. In patients with underlying heart disease or severe thyrotoxicosis and in elderly patients, it is desirable to treat with antithyroid drugs (preferably methimazole) until the patient is euthyroid. The medication is then stopped for 5-7 days before the appropriate dose of 131I is administered. Iodides should be avoided to ensure maximal 131I uptake. Six to 12 weeks following the administration of radioiodine, the gland will shrink in size and the patient will usually become euthyroid or hypothyroid. A second dose may be required in some patients. Hypothyroidism occurs in about 80% of patients following radioiodine therapy. Serum FT4 and TSH levels should be monitored regularly. When hypothyroidism develops, prompt replacement with oral levothyroxine, 50-150 mcg daily, should be instituted.
D. ADJUNCTS TO ANTITHYROID THERAPY
During the acute phase of thyrotoxicosis, b-adrenoceptor blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20-40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. Propranolol is gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90-120 mg three or four times daily, can be used to control tachycardia in patients in whom b blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4 levels.
2. Toxic Uninodular Goiter & Toxic Multinodular Goiter
These forms of hyperthyroidism occur often in older women with nodular goiters. FT4 is moderately elevated or occasionally normal, but FT3 or T3 is strikingly elevated. Single toxic adenomas can be managed with either surgical excision of the adenoma or with radioiodine therapy. Toxic multinodular goiter is usually associated with a large goiter and is best treated by preparation with methimazole or propylthiouracil followed by subtotal thyroidectomy.
During the acute phase of a viral infection of the thyroid gland, there is destruction of thyroid parenchyma with transient release of stored thyroid hormones. A similar state may occur in patients with Hashimoto’s thyroiditis. These episodes of transient thyrotoxicosis have been termed spontaneously resolving hyperthyroidism. Supportive therapy is usually all that is necessary, such as b-adrenoceptor blocking agents without intrinsic sympathomimetic activity (eg, propranolol) for tachycardia and aspirin or nonsteroidal anti-inflammatory drugs to control local pain and fever. Corticosteroids may be necessary in severe cases to control the inflammation.
Thyroid Storm
Thyroid storm, or thyrotoxic crisis, is sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life-threatening syndrome. Vigorous management is mandatory. Propranolol, 1-2 mg slowly intravenously or 40-80 mg orally every 6 hours, is helpful to control the severe cardiovascular manifestations. If propranolol is contraindicated by the presence of severe heart failure or asthma, hypertension and tachycardia may be controlled with diltiazem, 90-120 mg orally three or four times daily or 5-10 mg/h by intravenous infusion (asthmatic patients only). Release of thyroid hormones from the gland is retarded by the administration of saturated solution of potassium iodide, 10 drops orally daily, or iodinated contrast media, 1 g orally daily. The latter medication will also block peripheral conversion of T4 to T3. Hormone synthesis is blocked by the administration of propylthiouracil, 250 mg orally every 6 hours. If the patient is unable to take propylthiouracil by mouth, a rectal formulation* can be prepared and administered in a dosage of 400 mg every 6 hours as a retention enema. Methimazole may also be prepared for rectal administration in a dose of 60 mg daily. Hydrocortisone, 50 mg intravenously every 6 hours, will protect the patient against shock and will block the conversion of T4 to T3, rapidly bringing down the level of thyroactive material in the blood.
Supportive therapy is essential to control fever, heart failure, and any underlying disease process that may have precipitated the acute storm. In rare situations, where the above methods are not adequate to control the problem, plasmapheresis or peritoneal dialysis has been used to lower the levels of circulating thyroxine.
Ophthalmopathy
Although severe ophthalmopathy is rare, it is difficult to treat. Management requires effective treatment of the thyroid disease, usually by total surgical excision or 131I ablation of the gland plus oral prednisone therapy. In addition, local therapy may be necessary, eg, elevation of the head to diminish periorbital edema and artificial tears to relieve corneal drying. Smoking cessation should be advised to prevent progression of the ophthalmopathy. For the severe, acute inflammatory reaction, a short course of prednisone, 60-100 mg orally daily for about a week and then 60-100 mg every other day, tapering the dose over a period of 6-12 weeks, may be effective. If steroid therapy fails or is contraindicated, irradiation of the posterior orbit, using well-collimated high-energy x-ray therapy, will frequently result in marked improvement of the acute process. Threatened loss of vision is an indication for surgical decompression of the orbit. Eyelid or eye muscle surgery may be necessary to correct residual problems after the acute process has subsided.
Dermopathy or pretibial myxedema will often respond to topical corticosteroids applied to the involved area and covered with an occlusive dressing.
Thyrotoxicosis during Pregnancy
Ideally, women in the childbearing period with severe disease should have definitive therapy with 131I or subtotal thyroidectomy prior to pregnancy in order to avoid an acute exacerbation of the disease during pregnancy or following delivery. If thyrotoxicosis does develop during pregnancy, radioiodine is contraindicated because it crosses the placenta and may injure the fetal thyroid. In the first trimester, the patient can be prepared with propylthiouracil and a subtotal thyroidectomy performed safely during the mid trimester. It is essential to give the patient a thyroid supplement during the balance of the pregnancy. However, most patients are treated with propylthiouracil during the pregnancy, and the decision regarding long-term management can be made after delivery. The dosage of propylthiouracil must be kept to the minimum necessary for control of the disease (ie, < 300 mg/d), because it may affect the function of the fetal thyroid gland. Methimazole is a potential alternative, although there is concern about a possible risk of fetal scalp defects.
Graves’ disease may occur in the newborn infant, either due to passage of maternal TSH-R Ab [stim] through the placenta, stimulating the thyroid gland of the neonate, or to genetic transmission of the trait to the fetus. Laboratory studies reveal an elevated free thyroxine, a markedly elevated T3, and a low TSH¾in contrast to the normal infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is usually found in the serum of both the child and the mother.
If caused by maternal TSH-R Ab [stim], the disease is usually self-limited and subsides over a period of 4-12 weeks, coinciding with the fall in the infant’s TSH-R Ab [stim] level. However, treatment is necessary because of the severe metabolic stress the infant experiences. Therapy includes propylthiouracil in a dose of 5-10 mg/kg/d in divided doses at 8-hour intervals; Lugol’s solution (8 mg of iodide per drop), 1 drop every 8 hours; and propranolol, 2 mg/kg/d in divided doses. Careful supportive therapy is essential. If the infant is very ill, oral prednisone, 2 mg/kg/d in divided doses, will help block conversion of T4 to T3. These medications are gradually reduced as the clinical picture improves and can be discontinued by 6-12 weeks.
Subclinical hyperthyroidism is defined as a suppressed TSH level (below the normal range) in conjunction with normal thyroid hormone levels. Cardiac toxicity (eg, atrial fibrillation), especially in older persons, is of greatest concern. The consensus of thyroid experts concluded that hyperthyroidism treatment is appropriate in those with TSH less than 0.1 mU/L, while close monitoring of the TSH level is appropriate for those with less TSH suppression.
Amiodarone-Induced Thyrotoxicosis
Approximately 3% of patients receiving amiodarone will develop hyperthyroidism. Two types of amiodarone-induced thyrotoxicosis have been reported: iodine-induced (type I), which often occurs in persons with underlying thyroid disease (eg, multinodular goiter); and an inflammatory thyroiditis (type II) that occurs in patients without thyroid disease due to leakage of thyroid hormone into the circulation. Treatment of type I requires thioamides while type II responds best to glucocorticoids. Since it is not always possible to differentiate between the two types, thioamides and glucocorticoids are often administered together. If possible, amiodarone should be discontinued; however, rapid improvement does not occur due to its long half-life.
Nontoxic goiter is a syndrome of thyroid enlargement without excessive thyroid hormone production. Enlargement of the thyroid gland is often due to TSH stimulation from inadequate thyroid hormone synthesis. The most common cause of nontoxic goiter worldwide is iodide deficiency, but in the USA, it is Hashimoto’s thyroiditis. Other causes include germline or acquired mutations in genes involved in hormone synthesis, dietary goitrogens, and neoplasms (see below).
Goiter due to iodide deficiency is best managed by prophylactic administration of iodide. The optimal daily iodide intake is 150-200 mcg. Iodized salt and iodate used as preservatives in flour and bread are excellent sources of iodine in the diet. In areas where it is difficult to introduce iodized salt or iodate preservatives, a solution of iodized poppyseed oil has been administered intramuscularly to provide a long-term source of inorganic iodine.
Goiter due to ingestion of goitrogens in the diet is managed by elimination of the goitrogen or by adding sufficient thyroxine to shut off TSH stimulation. Similarly, in Hashimoto’s thyroiditis and dyshormonogenesis, adequate thyroxine therapy¾150-200 mcg/d orally¾will suppress pituitary TSH and result in slow regression of the goiter as well as correction of hypothyroidism.
THYROID NEOPLASMS
Neoplasms of the thyroid gland may be benign (adenomas) or malignant. The primary diagnostic test is a fine needle aspiration biopsy and cytologic examination. Benign lesions may be monitored for growth or symptoms of local obstruction, which would mandate surgical excision. Management of thyroid carcinoma requires a total thyroidectomy, postoperative radioiodine therapy in selected instances, and lifetime replacement with levothyroxine. The evaluation for recurrence of some thyroid malignancies often involves withdrawal of thyroxine replacement for 4-6 weeks¾accompanied by the development of hypothyroidism. Tumor recurrence is likely if there is a rise in serum thyroglobulin (ie, a tumor marker) or a positive 131I scan when TSH is elevated. Alternatively, administration of recombinant human TSH (Thyrogen) can produce comparable TSH elevations without discontinuing thyroxine and avoiding hypothyroidism. Recombinant human TSH is administered intramuscularly once daily for 2 days. A rise in serum thyroglobulin or a positive 131I scan will indicate a recurrence of the thyroid cancer.
PANCREATIC HORMONES & ANTIDIABETIC DRUGS
The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least four hormone-producing cells are present. Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; and pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified.
The elevated blood glucose associated with diabetes mellitus results from absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories: type 1, insulin-dependent diabetes; type 2, noninsulin-dependent diabetes; type 3, other; and type 4, gestational diabetes mellitus (Expert Committee, 2003).
Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective B-cell destruction and severe or absolute insulin deficiency. Administration of insulin is essential in patients with type 1 diabetes. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage but only 10-15% of patients have a positive family history.
Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more B-cell deficiency, and the abnormalities may be mild or severe. Although insulin is produced by the B cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL).
Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control the blood glucose. It is likely that 10-20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1, and ultimately will require full insulin replacement. Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur as the result of stress such as infection or use of medication that enhances resistance, eg, corticosteroids. Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6-20 times the normal range and an altered mental state develops or the person loses consciousness. Urgent medical care and rehydration is required.
The type 3 designation refers to multiple other specific causes of an elevated blood glucose: nonpancreatic diseases, drug therapy, etc. For a detailed list the reader is referred to Expert Committee, 2003.
Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Gestational diabetes is diagnosed in approximately 4% of all pregnancies in the USA. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. Risk assessment for diabetes is suggested starting at the first prenatal visit. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until the 24th to 28th week of gestation.
Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids.
Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the B cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram.
Insulin is released from pancreatic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), certain amino acids (eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 and vagal activity are recognized.
The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35-40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30-40%. The half-life of circulating insulin is 3-5 minutes.
Basal insulin values of 5-15 uU/mL (30-90 pmol/L) are found iormal humans, with a peak rise to 60-90 uU/mL (360-540 pmol/L) during meals.
After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues, ie, liver, muscle, and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an a subunit, which is entirely extracellular and constitutes the recognition site, and a b subunit that spans the membrane. The b subunit contains a tyrosine kinase. The binding of an insulin molecule to the a subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic b subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the b subunits and tyrosine kinase activity directed at cytoplasmic proteins.
The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins, insulin receptor substrate-1 through -6 (IRS-1 to IRS-6). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases¾most significantly phosphatidylinositol-3-kinase¾which produce further phosphorylations or to an adaptor protein such as growth factor receptor-binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4-5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin’s second message and results in multiple effects, including translocation of glucose transporters to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division. The IRS-2 signaling pathway is associated with cellular proliferation and mitogenesis.
Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor b subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.
Effects of Insulin on Its Targets
Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues.
Characteristics of Available Insulin Preparations
Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action. In 2006, 17 insulin formulations were available in the USA.
A. PRINCIPAL TYPES AND DURATION OF ACTION OF INSULIN PREPARATIONS
Four principal types of injected insulins are available: (1) rapid-acting, with very fast onset and short duration; (2) short-acting, with rapid onset of action; (3) intermediate-acting; and (4) long-acting, with slow onset of action. An inhaled form of rapid-acting insulin also is marketed. Injected rapid-acting and short-acting insulins are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf-life. Inhaled rapid-acting human insulin is available as a powder for alveolar absorption. Injected intermediate-acting NPH insulins have been modified to provide prolonged action and are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin). Insulin glargine and insulin detemir are the soluble long-acting insulins. The goal of subcutaneous insulin therapy is to replace the normal basal (overnight, fasting, and between meal) as well as bolus or prandial (mealtime) insulin. Current regimens generally use long-acting insulins to provide basal or background coverage, and rapid-acting insulin to meet the mealtime requirements. The latter insulins are given as supplemental doses to correct transient hyperglycemia. Intensive therapy (“tight control”) attempts to restore near-normal glucose patterns throughout the day while minimizing the risk of hypoglycemia.
An exact reproduction of the normal glycemic profile is technically not possible because of the limitations inherent in subcutaneous administration of insulin. The most sophisticated insulin regimen delivers rapid-acting insulin through a continuous subcutaneous insulin infusion device; alternative intensive regimens referred to as multiple daily injections (MDI) use long-acting insulins with multiple boluses of rapid-acting insulin. Conventional therapy presently consists of split-dose injections of mixtures of rapid- or short-acting and intermediate-acting insulins.
1. Rapid-acting insulin¾ Three injected rapid-acting insulin analogs: insulin lispro, insulin aspart, and insulin glulisine, and one inhaled form of rapid-acting insulin, human insulin recombinant inhaled, are commercially available. The rapid-acting insulins permit more physiologic prandial insulin replacement because their rapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulin, and they have the additional benefit of allowing insulin to be taken immediately before the meal without sacrificing glucose control. Their duration of action is rarely more than 3-5 hours (with the exception of inhaled insulin, which may last 6-7 hours), which decreases the risk of late postmeal hypoglycemia. The injected rapid-acting insulins have the lowest variability of absorption (approximately 5%) of all available commercial insulins (compared to 25% for regular insulin and 25-50% for intermediate- and long-acting formulations). They are the preferred insulins for use in continuous subcutaneous insulin infusion devices.
Insulin lispro, the first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28. Reversing these two amino acids does not interfere in any way with insulin lispro’s binding to the insulin receptor, its circulating half-life, or its immunogenicity, which are similar to those of human regular insulin. However, the advantage of this analog is its very low propensity¾in contrast to human insulin¾to self-associate in antiparallel fashion and form dimers. To enhance the shelf-life of insulin in vials, insulin lispro is stabilized into hexamers by a cresol preservative. When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5-15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose.
Insulin aspart is created by the substitution of the B28 proline with a negatively charged aspartic acid. This modification reduces the normal ProB28 and GlyB23 monomer-monomer interaction, thereby inhibiting insulin self-aggregation. Its absorption and activity profile is similar to that of insulin lispro, and it is more reproducible than regular insulin, but has similar binding properties, activity, and mitogenicity characteristics to regular insulin and equivalent immunogenicity.
Insulin glulisine is formulated by substituting an asparagine for lysine at B3 and glutamic acid for lysine at B29. Its absorption, action, and immunologic characteristics are similar to the other injected rapid-acting insulins. After high-dose insulin glulisine-insulin receptor interaction, there may be downstream differences in IRS-2 pathway activation relative to human insulin. The clinical significance of such differences is unclear.
Inhaled human insulin is a powder form of rDNA human insulin that is administered through an inhaler device and is marketed for pre-prandial and blood sugar correction use in adults with type 1 and 2 diabetes. Because of concerns about lung safety, it is not approved for use in children, teenagers, or adults with asthma, bronchitis, emphysema, smokers, or those within 6 months of quitting smoking. Although this route of administration is well tolerated, studies have shown that less than 30% of users were able to achieve target blood glucoses after 6 months of therapy with inhaled human insulin.
2. Short-acting insulin¾ Regular insulin is a short-acting soluble crystalline zinc insulin made by recombinant DNA techniques to produce a molecule identical to human insulin. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and generally lasts 5-8 hours. In high concentrations, eg, in the vial, regular insulin molecules self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to create insulin hexamers. The hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action. After subcutaneous injection, the insulin hexamers are too large and bulky to be transported across the vascular endothelium into the bloodstream. As the insulin depot is diluted by interstitial fluid and the concentration begins to fall, the hexamers break down into dimers and finally monomers. This results in three rates of absorption of the injected insulin, with the final monomeric phase having the fastest uptake out of the injection site. The delayed absorption results in a mismatching of insulin availability with need.
Specifically, when regular insulin is administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Regular insulin should be injected 30-45 or more minutes before the meal to minimize the mismatching. As with all older insulin formulations, the duration of action as well as the time of onset and the intensity of peak action increase with the size of the dose. Clinically, this is a critical issue because the pharmacokinetics and pharmacodynamics of small doses of regular and NPH insulins differ greatly from those of large doses. Short-acting soluble insulin is the only type that should be administered intravenously because the dilution causes the hexameric insulin to immediately dissociate into monomers. It is particularly useful for intravenous therapy in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections.
3. Intermediate-acting and long-acting insulins¾
a. NPH (neutral protamine Hagedorn, or isophane) insulin¾ NPH insulin is an intermediate-acting insulin wherein absorption and the onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form (“isophane”). Protamine is a mixture of six major and some minor compounds of similar structure isolated from the sperm of rainbow trout. They appear to be basic, arginine-rich peptides with an average molecular weight of approximately 4400. To form an isophane complex (one in which neither component retains any free binding sites), approximately a 1:10 ratio by weight of protamine to insulin is required, representing approximately six molecules of insulin per molecule of protamine. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2-5 hours and duration of 4-12 hours; it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement in patients with type 1 diabetes. The dose regulates the action profile; specifically, small doses have lower, earlier peaks and a short duration of action with the converse true for large doses.
b. Insulin glargine¾ Insulin glargine is a soluble, “peakless” (ie, having a broad plasma concentration plateau), ultra-long-acting insulin analog. This product was designed to provide reproducible, convenient, background insulin replacement. The attachment of two arginine molecules to the B chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position created an analog that is soluble in an acidic solution but precipitates in the more neutral body pH after subcutaneous injection. Individual insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin. Insulin glargine has a slow onset of action (1-1.5 hours) and achieves a maximum effect after 4-6 hours. This maximum activity is maintained for 11-24 hours or longer. Glargine is usually given once daily, although some very insulin-sensitive individuals benefit from split (twice a day) dosing. To maintain solubility, the formulation is unusually acidic (pH 4.0) and insulin glargine should not be mixed with other insulins. Separate syringes must be used to minimize the risk of contamination and subsequent loss of efficacy. The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection, and this drug is associated with less immunogenicity than human insulin in animal studies. Glargine’s interaction with the insulin receptor is similar to that of native insulin and shows no increase in mitogenic activity in vitro. It has sixfold to sevenfold greater binding thaative insulin to the insulin-like growth factor-1 (IGF-1) receptor, but the clinical significance of this is unclear.
c. Insulin detemir¾ This insulin is the most recently developed long-acting insulin analog. The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. These modifications prolong the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. Insulin detemir has the most reproducible effect of the intermediate- and long-acting insulins, and its use is associated with less hypoglycemia than NPH insulin. Insulin detemir has a dose-dependent onset of action of 1-2 hours and duration of action of more than 24 hours. It is given twice daily to obtain a smooth background insulin level.
4. Mixtures of insulins¾ Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of rapid- or short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. However, premixed preparations have thus far been unstable. To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed. These intermediate insulins have been designated as “NPL” (neutral protamine lispro) and “NPA” (neutral protamine aspart) and have the same duration of action as NPH insulin. They have the advantage of permitting formulation as premixed combinations of NPL and insulin lispro, and as NPA and insulin aspart, and they have been shown to be safe and effective in clinical trials. The FDA has approved 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Additional ratios are available abroad. Insulin glargine and detemir must be given as separate injections. They are not miscible acutely or in a premixed preparation with any other insulin formulation.
B. INSULIN PRODUCTION
Human insulins¾ Mass production of human insulin and insulin analogs by recombinant DNA techniques is carried out by inserting the human or a modified proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules.
C. CONCENTRATION
All insulins in the USA and Canada are currently available in a concentration of 100 U/mL (U100). A limited supply of U500 regular human insulin is available for use in rare cases of severe insulin resistance in which larger doses of insulin are required.
The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. During the last three decades, much effort has gone into exploration of other means of administration, and inhaled insulin is now available.
A. PORTABLE PEN INJECTORS
To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. Disposable insulin pens are also available for selected formulations. These are regular insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, and several mixtures of NPH with regular, lispro, or aspart insulin. They have been well accepted by patients because they eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling.
B. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION DEVICES (CSII, INSULIN PUMPS)
Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results. Normally, the 24-hour background basal rates are relatively constant from day to day, although temporarily altered rates can be superimposed to adjust for a short-term change in requirement. For example, the basal delivery rate might need to be decreased for several hours because of the increased insulin sensitivity associated with strenuous activity. In contrast, the bolus amounts frequently vary and are used to correct high blood glucose levels and to cover mealtime insulin requirements based on the carbohydrate content of the food and concurrent activity. The pump¾which contains an insulin reservoir, the program chip, the keypad, and the display screen¾is about the size of a pager. It is usually placed on a belt or in a pocket, and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion set, although flanks and thighs are also used. The insulin reservoir, tubing, and infusion set need to be changed using sterile techniques every 2 or 3 days. CSII delivery is regarded as the most physiologic method of insulin replacement.
The use of these continuous infusion devices is encouraged for individuals who are unable to obtain target control while on multiple injection regimens and in circumstances in which excellent glycemic control is desired, such as during pregnancy. Their optimal use requires responsible involvement and commitment by the patient. Velosulin (a regular insulin) and insulin aspart, lispro, and glulisine are all specifically approved for pump use. Insulins aspart, lispro, and glulisine are preferred pump insulins because their favorable pharmacokinetic attributes allow glycemic control without increasing the risk of hypoglycemia.
C. INHALED INSULIN
The FDA has approved an inhaled insulin preparation of finely powdered and aerosolized human insulin. Insulin is readily absorbed into the bloodstream through alveolar walls, but the challenge has been to create particles that are small enough to pass through the bronchial tree without being trapped and still enter the alveoli in sufficient amounts to have a clinical effect. Insulin delivered by the inhaled route has pharmacokinetic and pharmacodynamic characteristics of both rapid- and short-acting insulin. It has a rapid onset and peak insulin levels (by 30 minutes) similar to insulin lispro, aspart, and glulisine, and peak effect (2-2.5 hours) and duration of action (6-8 hours) similar to regular insulin. Inhaled insulin can be used to cover mealtime insulin requirements or to correct high glucose levels, but not to provide background or basal insulin coverage. Less than 10% of the inhaled insulin dose (which ranges from 1 mg to 6 mg) is absorbed. One milligram of inhaled insulin is equivalent to 2-3 units of regular human insulin injected subcutaneously. Safety concerns include possible pulmonary fibrosis or hypertension, reduced lung volume or oxygen diffusing capacity, and excessive insulin antibody formation.
The current classification of diabetes mellitus identifies a group of patients who have virtually no insulin secretion and whose survival depends on administration of exogenous insulin. This insulin-dependent group (type 1) represents 5-10% of the diabetic population in the USA. Most type 2 diabetics do not require exogenous insulin for survival, but many need exogenous supplementation of their endogenous secretion to achieve optimum health.
Benefit of Glycemic Control in Diabetes Mellitus
The consensus of the American Diabetes Association is that intensive glycemic control associated with comprehensive self-management training should become standard therapy in type 1 patients. Exceptions include patients with advanced renal disease and the elderly, since the risks of hypoglycemia outweigh the benefit of tight glycemic control in these groups. In children under the age of 7 years, the extreme susceptibility of the developing brain to damage from hypoglycemia contraindicates attempts at intensive glycemic control. A similar conclusion regarding the benefits of tight control in type 2 diabetes was reached as the result of a large study in the United Kingdom.
BENEFITS OF TIGHT GLYCEMIC CONTROL IN DIABETES
A long-term randomized prospective study involving 1441 type 1 patients in 29 medical centers reported in 1993 that “near normalization” of blood glucose resulted in a delay in onset and a major slowing of progression of microvascular and neuropathic complications of diabetes during follow-up periods of up to 10 years (Diabetes Control And Complications Trial [DCCT] Research Group, 1993). In the intensively treated group, a mean glycated hemoglobin HbA1c of 7.2% (normal <6%) and a mean blood glucose of 155 mg/dL were achieved, whereas in the conventionally treated group, HbA1c averaged 8.9% with an average blood glucose of 225 mg/dL. Over the study period, which averaged 7 years, approximately a 60% reduction in risk of diabetic retinopathy, nephropathy, and neuropathy was noted in the tight control group compared with the standard control group.
The DCCT study, in addition, has introduced the concept of glycemic memory, which comprises the long-term benefits of any significant period of glycemic control. During a 6-year follow-up period, both the intensively and the conventionally treated groups had similar levels of glycemic control, and both had progression of carotid intimal-medial thickness. However, the intensively treated cohort had significantly less progression of intimal thickness.
The United Kingdom Prospective Diabetes Study (UKPDS) was a very large randomized prospective study carried out to study the effects of intensive glycemic control with several types of therapies and the effects of blood pressure control in type 2 diabetic patients. A total of 3867 newly diagnosed type 2 diabetic patients were studied over 10 years. A significant fraction of these were overweight and hypertensive. Patients were given dietary treatment alone or intensive therapy with insulin, chlorpropamide, glyburide, or glipizide. Metformin was an option for patients with inadequate response to other therapies. Tight control of blood pressure was added as a variable, with an angiotensin-converting enzyme inhibitor, b-blocker or, in some cases, a calcium channel blocker available for this purpose.
Tight control of diabetes, with reduction of HbA1c from 9.1% to 7%, was shown to reduce the risk of microvascular complications overall compared with that achieved with conventional therapy (mostly diet alone, which decreased HbA1c to 7.9%). Cardiovascular complications were not noted for any particular therapy; metformin treatment alone reduced the risk of macrovascular disease (myocardial infarction, stroke).
Tight control of hypertension also had a surprisingly significant effect on microvascular disease (as well as more conventional hypertension-related sequelae) in these diabetic patients. These studies show that tight glycemic control benefits both type 1 and type 2 patients.
The STOP-NIDDM trial followed up 1429 patients with impaired glucose tolerance who were randomized to treatment with acarbose or placebo over 3 years. This trial demonstrated that normalization of glycemic control in subjects with impaired glucose tolerance significantly diminished cardiovascular risk. The acarbose-treated group had a significant reduction in the development of major cardiovascular events and hypertension. A prospective placebo-controlled subgroup analysis has shown a marked decrease in the progression of intimal-medial thickness.
Complications of Insulin Therapy
A. HYPOGLYCEMIA
1. Mechanisms and diagnosis¾ Hypoglycemic reactions are the most common complication of insulin therapy. They may result from a delay in taking a meal, inadequate carbohydrate consumed, unusual physical exertion, or a dose of insulin that is too large for immediate needs.
Rapid development of hypoglycemia in individuals with intact hypoglycemic awareness causes signs of autonomic hyperactivity, both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger) and may progress to convulsions and coma if untreated.
In individuals exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. This dangerous acquired condition is termed “hypoglycemic unawareness.” When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop¾confusion, weakness, bizarre behavior, coma, seizures¾at which point they may not be able to procure or safely swallow glucose-containing foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes. An identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every diabetic who is receiving hypoglycemic drug therapy.
2. Treatment of hypoglycemia¾ All the manifestations of hypoglycemia are relieved by glucose administration. To expedite absorption, simple sugar or glucose should be given, preferably in a liquid form. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given. If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is to give 20-50 mL of 50% glucose solution by intravenous infusion over a period of 2-3 minutes. If intravenous therapy is not available, 1 mg of glucagon injected either subcutaneously or intramuscularly usually restores consciousness within 15 minutes to permit ingestion of sugar. If the patient is stuporous and glucagon is not available, small amounts of honey or syrup can be inserted into the buccal pouch. In general, however, oral feeding is contraindicated in unconscious patients. Emergency medical services should be called for all episodes of severely impaired consciousness.
B. IMMUNOPATHOLOGY OF INSULIN THERAPY
At least five molecular classes of insulin antibodies may be produced in diabetics during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. There are two major types of immune disorders in these patients:
1. Insulin allergy¾ Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to noninsulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.
2. Immune insulin resistance¾ A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus.
C. LIPODYSTROPHY AT INJECTION SITES
Injection of older animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. This type of immune complication is almost never seen since the development of human and analog insulin preparations of neutral pH. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours. Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoidance of that specific injection site or with liposuction.
ORAL ANTIDIABETIC AGENTS
INTRODUCTION
Four categories of oral antidiabetic agents are now available in the USA: insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives), biguanides, thiazolidinediones, and a-glucosidase inhibitors. The sulfonylureas and biguanides have been available the longest and are the traditional initial treatment choice for type 2 diabetes. Novel classes of rapidly acting insulin secretagogues, the meglitinides and D-phenylalanine derivatives, are alternatives to the short-acting sulfonylurea, tolbutamide. The thiazolidinediones, under development since the early 1980s, are very effective agents that reduce insulin resistance. Alpha-glucosidase inhibitors have a relatively weak antidiabetic effect and significant adverse effects, and they are used primarily as adjunctive therapy in individuals who cannot achieve their glycemic goals with other medications.
INSULIN SECRETAGOGUES: SULFONYLUREAS
The major action of sulfonylureas is to increase insulin release from the pancreas. Two additional mechanisms of action have been proposed¾a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissues.
A. INSULIN RELEASE FROM PANCREATIC B CELLS
Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor that is associated with a B-cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin.
B. REDUCTION OF SERUM GLUCAGON CONCENTRATIONS
Long-term administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic effect of the drugs. The mechanism for this suppressive effect of sulfonylureas on glucagon levels is unclear but appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit A-cell secretion.
C. POTASSIUM CHANNEL CLOSURE IN EXTRAPANCREATIC TISSUES
Insulin secretagogues bind to sulfonylurea receptors in potassium channels in extrapancreatic tissues, but the binding affinity varies among the drug classes and is much less avid than for the B-cell receptors. The clinical significance of extrapancreatic binding is not known.
Efficacy & Safety of the Sulfonylureas
In 1970, the University Group Diabetes Program (UGDP) in the USA reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide was excessive compared with either insulin-treated patients or those receiving placebos. Owing to design flaws, this study and its conclusions were not generally accepted. A study in the United Kingdom, the UKPDS, did not find an untoward cardiovascular effect of sulfonylurea usage in their large, long-term study.
The sulfonylureas continue to be widely prescribed, and six are available in the USA. They are conventionally divided into first-generation and second-generation agents, which differ primarily in their potency and adverse effects. The first-generation sulfonylureas are increasingly difficult to procure, and as the second-generation agents become generic and less expensive, the older compounds probably will be discontinued.
1. First-Generation Sulfonylureas
Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4-5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide.
Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; approximately 20-30% is excreted unchanged in the urine. Chlorpropamide also interacts with the drugs mentioned above that depend on hepatic oxidative catabolism, and it is contraindicated in patients with hepatic or renal insufficiency. Dosages higher than 500 mg daily increase the risk of jaundice. The average maintenance dosage is 250 mg daily, given as a single dose in the morning. Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group. Other side effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and dilutional hyponatremia. Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients.
Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dose should be divided and given twice daily.
2. Second-Generation Sulfonylureas
The second-generation sulfonylureas are more frequently prescribed in the USA than the first-generation agents because they have fewer adverse effects and drug interactions. These potent sulfonylurea compounds¾glyburide, glipizide, and glimepiride¾should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.
Glyburide is metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5-10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended. A formulation of “micronized” glyburide (Glynase PresTab) is available in a variety of tablet sizes. However, there is some question as to its bioequivalence with nonmicronized formulations, and the FDA recommends careful monitoring to retitrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs.
Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion, and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.
Glipizide has the shortest half-life (2-4 hours) of the more potent agents. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast, because absorption is delayed when the drug is taken with food. The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. When higher daily dosages are required, they should be divided and given before meals. The maximum total daily dosage recommended by the manufacturer is 40 mg/d, although some studies indicate that the maximum therapeutic effect is achieved by 15-20 mg of the drug. An extended-release preparation (Glucotrol XL) provides 24-hour action after a once-daily morning dose (maximum of 20 mg/d). However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over the latter (which can be obtained as a generic drug).
Because of its shorter half-life, the regular formulation of glipizide is much less likely than glyburide to produce serious hypoglycemia. At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with significant hepatic or renal impairment, who would be at high risk for hypoglycemia.
Glimepiride is approved for once-daily use as monotherapy or in combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. It has a long duration of effect with a half-life of 5 hours, allowing once-daily dosing and thereby improving compliance. It is completely metabolized by the liver to inactive products.
Secondary Failure & Tachyphylaxis to Sulfonylureas
Secondary failure, ie, failure to maintain a good response to sulfonylurea therapy over the long term, remains a disconcerting problem in the management of type 2 diabetes. A progressive decrease in B-cell mass, reduction in physical activity, decline in lean body mass, or increase in ectopic fat deposition in chronic type 2 diabetes also may contribute to secondary failure.
INSULIN SECRETAGOGUES: MEGLITINIDES
The meglitinides are a relatively new class of insulin secretagogues. Repaglinide, the first member of the group, was approved for clinical use in 1998. These drugs modulate B-cell insulin release by regulating potassium efflux through the potassium channels previously discussed. There is overlap with the sulfonylureas in their molecular sites of action because the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site.
Repaglinide has a very fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion, but the duration of action is 5-8 hours. It is hepatically cleared by CYP3A4 with a plasma half-life of 1 hour. Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions. The drug should be taken just before each meal in doses of 0.25-4 mg (maximum, 16 mg/d); hypoglycemia is a risk if the meal is delayed or skipped or contains inadequate carbohydrate. This drug should be used cautiously in individuals with renal and hepatic impairment. Repaglinide is approved as monotherapy or in combination with biguanides. There is no sulfur in its structure, so repaglinide may be used in type 2 diabetic individuals with sulfur or sulfonylurea allergy.
INSULIN SECRETAGOGUE: D-PHENYLALANINE DERIVATIVE
Nateglinide, a D-phenylalanine derivative, is the latest insulin secretagogue to become clinically available. Nateglinide stimulates very rapid and transient release of insulin from B cells through closure of the ATP-sensitive K+ channel. It also partially restores initial insulin release in response to an intravenous glucose tolerance test. This may be a significant advantage of the drug because type 2 diabetes is associated with loss of this initial insulin response. The restoration of more normal insulin secretion may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production. Nateglinide may have a special role in the treatment of individuals with isolated postprandial hyperglycemia, but it has minimal effect on overnight or fasting glucose levels. Nateglinide is efficacious when given alone or in combination with nonsecretagogue oral agents (such as metformin). In contrast to other insulin secretagogues, dose titration is not required.
Nateglinide is ingested just before meals. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is hepatically metabolized by CYP2C9 and CYP3A4 with a half-life of 1.5 hours. The overall duration of action is less than 4 hours.
Nateglinide amplifies the insulin secretory response to a glucose load but has a markedly diminished effect in the presence of normoglycemia. The incidence of hypoglycemia may be the lowest of all the secretagogues, and it has the advantage of being safe in individuals with very reduced renal function.
The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the USA because of its association with lactic acidosis and because there was no documentation of any long-term benefit from its use.
A full explanation of the biguanides’ mechanism of action remains elusive. Their blood glucose-lowering action does not depend on functioning pancreatic B cells. Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after biguanides; however, hypoglycemia during biguanide therapy is essentially unknown. These agents are therefore more appropriately termed “euglycemic” agents. Currently proposed mechanisms of action include (1) reduced hepatic and renal gluconeogenesis; (2) slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes; (3) direct stimulation of glycolysis in tissues, with increased glucose removal from blood; and (4) reduction of plasma glucagon levels.
Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin’s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication.
Biguanides have been most often prescribed for patients whose hyperglycemia is due to ineffective insulin action, ie, insulin resistance syndrome. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such individuals. The UKPDS reported that metformin therapy decreases the risk of macrovascular as well as microvascular disease; this is in contrast to the other therapies, which only modified microvascular morbidity. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. Metformin is useful in the prevention of type 2 diabetes; the landmark Diabetes Prevention Program concluded that metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner prediabetics.
The dosage of metformin is from 500 mg to a maximum of 2.55 g daily, with the lowest effective dose being recommended. A common schedule would be to begin with a single 500-mg tablet given with breakfast for several days. If this is tolerated without gastrointestinal discomfort and if hyperglycemia persists, a second 500-mg tablet may be added with the evening meal. If further dose increases are required after 1 week, an additional 500-mg tablet can be added to be taken with the midday meal, or the larger (850-mg) tablet can be prescribed twice daily or even three times daily (the maximum recommended dosage) if needed. Dosage should always be divided because ingestion of more than 1000 mg at any one time usually provokes significant gastrointestinal side effects.
Toxicities
The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, diarrhea) and occur in up to 20% of patients. They are dose-related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3-5% of patients because of persistent diarrhea. Absorption of vitamin B12 appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B12 levels and red blood cell parameters has been encouraged by the manufacturer to determine the need for vitamin B12 injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with metformin therapy than with phenformin therapy.
Biguanides are contraindicated in patients with renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction), because of an increased risk of lactic acidosis induced by biguanide drugs in the presence of these diseases.
Thiazolidinediones (Tzds) act to decrease insulin resistance. Their primary action is the regulation of genes involved in glucose and lipid metabolism and adipocyte differentiation. Tzds are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-g), part of the steroid and thyroid superfamily of nuclear receptors. These PPAR receptors are found in muscle, fat, and liver. PPAR-g receptors are complex and modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. The available Tzds do not have identical clinical effects, and new drug development will focus on defining PPAR effects and designing ligands that have selective action¾much like the selective estrogen receptor modulators.
In addition to targeting adipocytes, myocytes, and hepatocytes, Tzds also have significant effects on vascular endothelium, the immune system, the ovaries, and tumor cells. Some of these responses may be independent of the PPAR-g pathway.
In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation. Tzds also regulate adipocyte apoptosis and differentiation. Numerous other effects have been documented in animal studies but applicability to human tissues has yet to be determined.
Two thiazolidinediones are currently available: pioglitazone and rosiglitazone. Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. A third compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain. Pioglitazone has PPAR-a as well as PPAR-g activity. It is absorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites. The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estrogen-containing oral contraceptives; additional methods of contraception are advised. Pioglitazone may be taken once daily; the usual starting dose is 15-30 mg. The triglyceride lowering effect is more significant than that observed with rosiglitazone, presumably because of its PPAR-a binding characteristics. Pioglitaxone therapy reduces mortality and macrovascular events (myocardial infarction and stroke). Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.
Rosiglitazone is rapidly absorbed and highly protein-bound. It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 4-8 mg is the usual total dose. Rosiglitazone shares the common Tzd adverse effects but does not seem to have any significant drug interactions. The drug is approved for use in type 2 diabetes as monotherapy or in combination with a biguanide, sulfonylurea, in combination with a biguanide and sulfonylurea, and insulin.
Tzds are considered “euglycemics” and are efficacious in about 70% of new users. The overall response is similar to sulfonylurea and biguanide monotherapy. Individuals experiencing secondary failure to other oral agents should benefit from the addition (rather than substitution) of a Tzd. Because their mechanism of action involves gene regulation, the Tzds have a slow onset and offset of activity over weeks or even months. Combination therapy with sulfonylureas and insulin can lead to hypoglycemia and may require dosage adjustment. Long-term therapy is associated with a drop in triglyceride levels and a slight rise in HDL and low-density lipoprotein (LDL) cholesterol values. An adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema, especially when used in combination with insulin or insulin secretagogues. Some reports have suggested an increased risk of heart failure. Rarely, new or worsening macular edema has been reported in association with rosiglitazone treatment. Many users have a dose-related weight gain (average 1-3 kg), which may be fluid-related. These agents should not be used during pregnancy or in the presence of significant liver disease (ALT more than 2.5 ´ upper limit of normal), or if there is a concurrent diagnosis of heart failure. Anovulatory women may resume ovulation and should be counseled on the increased risk of pregnancy. Because of the hepatotoxicity observed with troglitazone, a discontinued Tzd, the FDA continues to require monitoring of liver function tests before initiation of Tzd therapy and periodically afterward. To date, hepatotoxicity has not been associated with rosiglitazone or pioglitazone.
Thiazolidinediones have an emerging benefit in the prevention of type 2 diabetes. The Diabetes Prevention Trial reported a 75% reduction in the diabetes incidence rate when troglitazone was administered to patients with prediabetes. Another study reported that troglitazone therapy significantly decreased the recurrence of diabetes mellitus in high-risk Hispanic women with a history of gestational diabetes. Other trials using clinically available Tzds are in progress.
Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into the bloodstream. Complex starches, oligosaccharides, and disaccharides must be broken down into individual monosaccharides before being absorbed in the duodenum and upper jejunum. This digestion is facilitated by enteric enzymes, including pancreatic a-amylase, and a-glucosidases that are attached to the brush border of the intestinal cells. Acarbose and miglitol are competitive inhibitors of the intestinal a-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides. Miglitol differs structurally from acarbose and is six times more potent in inhibiting sucrase. Although the binding affinity of the two compounds differs, acarbose and miglitol both target the a-glucosidases: sucrase, maltase, glycoamylase, and dextranase. Miglitol alone has effects on isomaltase and on b-glucosidases, which split b-linked sugars such as lactose. Acarbose alone has a small effect on a-amylase. The consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion (and thus absorption) of the ingested starch and disaccharides to the distal small intestine, thereby lowering postmeal glycemic excursions as much as 45-60 mg/dL and creating an insulin-sparing effect. Monotherapy with these drugs is associated with a modest drop (0.5-1%) in glycohemoglobin levels and a 20-25 mg/dL fall in fasting glucose levels. They are FDA-approved for persons with type 2 diabetes as monotherapy and in combination with sulfonylureas, in which the glycemic effect is additive. Both acarbose and miglitol are taken in doses of 25-100 mg just before ingesting the first portion of each meal; therapy should be initiated with the lowest dose and slowly titrated upward.
Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. These side effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of a-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. These drugs are contraindicated in patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention. Because both miglitol and acarbose are excreted by the kidneys, these medications should not be prescribed in individuals with renal impairment. Acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease.
The STOP-NIDDM trial demonstrated that a-glucosidase therapy in prediabetic individuals successfully prevented a significant number of new cases of type 2 diabetes and helped restore B-cell function, in addition to reducing cardiovascular disease and hypertension. Intervention with acarbose also reduced cardiovascular events in individuals with diabetes. Diabetes and cardiovascular disease prevention may become a further indication for this class of medications.
Pramlintide, a synthetic analog of amylin, is an injectable antihyperglycemic that modulates postprandial glucose levels and is approved for preprandial use in individuals with type 1 and type 2 diabetes. It is administered in addition to insulin in those individuals who are unable to achieve their target postprandial blood sugars. Pramlintide suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. Pramlintide is renally metabolized and excreted, but even at low creatinine clearance there is no significant change in bioavailability. It has not been evaluated in dialysis patients. The most reliable absorption is from the abdomen and thigh; arm administration is less reliable. Pramlintide should be injected immediately before eating; doses range from 15 mcg to 120 mcg subcutaneously. Therapy with this agent should be initiated with the lowest dose and titrated upward. Because of the risk of hypoglycemia, concurrent rapid- or short-acting mealtime insulin doses should be decreased by 50% or more. Pramlintide should always be injected by itself with a separate syringe; it cannot be mixed with insulin. The major side effects of pramlintide are hypoglycemia and gastrointestinal symptoms including nausea, vomiting, and anorexia.
As a synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes. Exenatide is approved as an injectable, adjunctive therapy in individuals with type 2 diabetes treated with metformin or sulfonylureas who still have suboptimal glycemic control. In clinical studies, exenatide therapy is shown to have multiple actions such as potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emptying and a central loss of appetite. The increased insulin secretion is speculated to be due in part to an increase in B-cell mass. It is not known whether the increased B-cell mass results from a decreased B-cell turnover, increased B-cell formation, or both.
Exenatide is absorbed equally from arm, abdomen, or thigh injection sites, reaching a peak concentration in approximately 2 hours with a duration of up to 10 hours. It undergoes glomerular filtration, and dosage adjustment is required only when the creatinine clearance is less than 30 mL/min. Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 mcg twice daily, with a maximum dosage of 10 mcg twice daily. When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. The major side effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage.
Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules. This drug appears likely to be approved for use in type 2 diabetes. In phase 2 and 3 clinical trials, sitagliptin was reported to have a bioavailability of approximately 80% and a half-life of 8-14 hours. Control of hyperglycemia and reductions in HbA1c were documented at doses of 100 mg orally once daily. Dosage should be reduced in patients with renal impairment. Hypoglycemic episodes were rare and the drug facilitated weight loss. Sitagliptin therapy can be combined with metformin, Tzds, or sulfonylureas. The drug will be marketed as Januvia.
Combination Therapy with Oral Antidiabetic Agents & Injectable Medication
A. COMBINATION THERAPY IN TYPE 2 DIABETES MELLITUS
1. Combination therapy with exenatide¾ Exenatide is approved for use in individuals who fail to achieve desired glycemic control on biguanides, sulfonylureas, or both. Although the combination of exenatide and Tzds, D-phenylalanine derivatives, meglitinides, a-glucosidase inhibitors, and insulin has not been studied, these regimens are clinically prescribed. Hypoglycemia is a risk when exenatide is used with an insulin secretagogue or insulin. The doses of the latter drugs have to be reduced at the initiation of exenatide therapy and subsequently titrated.
2. Combination therapy with pramlintide¾ Pramlintide is approved for concurrent mealtime administration in individuals with type 2 diabetes treated with insulin, metformin, or a sulfonylurea who are unable to achieve their postmeal glucose targets. Combination therapy results in a significant reduction in early postprandial glucose excursions; mealtime insulin or sulfonylurea doses usually have to be reduced to prevent hypoglycemia.
3. Combination therapy with insulin¾ Bedtime insulin has been suggested as an adjunct to oral antidiabetic therapy in patients with type 2 diabetes patients who have not responded to maximal oral therapy. Clinical practice has evolved to include sulfonylureas, meglitinides, D-phenylalanine derivatives, biguanides, thiazolidinediones, or a-glucosidase inhibitors given in conjunction with insulin.
Individuals unable to achieve glycemic control with bedtime insulin as described above generally require full insulin replacement and multiple daily injections of insulin. Insulin secretagogues are redundant when an individual is receiving multiple daily insulin injections, but persons with severe insulin resistance may benefit from the addition of one of the biguanides, thiazolidinediones, or a-glucosidase inhibitors. In some cases, multiple oral agents have been required together with insulin. When oral agents are added to the regimen of a person already taking insulin, the blood glucose should be closely monitored and the insulin dosage decreased as needed to avoid hypoglycemia.
B. COMBINATION THERAPY IN TYPE 1 DIABETES MELLITUS
1. Combination therapy with pramlintide¾ Pramlintide is approved for concurrent mealtime administration in individuals with type 1 diabetes who have poor glucose control after eating despite optimal insulin therapy. The addition of pramlintide leads to a significant reduction in early postprandial glucose excursions; mealtime insulin doses usually have to be reduced to prevent hypoglycemia.
2. Combination therapy with oral medications¾ There is no indication for combining insulin with insulin secretagogues (sulfonylureas, meglitinides, or D-phenylalanine derivatives) in individuals with type 1 diabetes. Type 1 diabetics with diets very high in starch may benefit from the addition of a-glucosidase inhibitors, but this is not typically practiced in the USA. Although not approved for use in type 1 diabetes, Tzds have been prescribed for type 1 individuals with significant insulin resistance and a combined type 1, type 2 phenotype, or latent autoimmune diabetes mellitus of adulthood (LADA). The insulin dose has to be reduced with the addition of Tzd therapy to prevent hypoglycemia.
Glucagon is synthesized in the A cells of the pancreatic islets of Langerhans. Glucagon is a peptide¾identical in all mammals¾consisting of a single chain of 29 amino acids, with a molecular weight of 3485. Selective proteolytic cleavage converts a large precursor molecule of approximately 18,000 MW to glucagon. One of the precursor intermediates consists of a 69-amino-acid peptide called glicentin, which contains the glucagon sequence interposed between peptide extensions.
Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Because of its rapid inactivation by plasma, chilling of the collecting tubes and addition of inhibitors of proteolytic enzymes are necessary when samples of blood are collected for immunoassay of circulating glucagon. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin.
Glicentin immunoreactivity has been found in cells of the small intestine as well as in pancreatic A cells and in effluents of perfused pancreas. The intestinal cells secrete enteroglucagon, a family of glucagon-like peptides, of which glicentin is a member, along with glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Unlike the pancreatic A cell, these intestinal cells lack the enzymes to convert glucagon precursors to true glucagon by removing the carboxyl terminal extension from the molecule.
The function of the enteroglucagons has not been clarified, although smaller peptides can bind hepatic glucagon receptors where they exert partial activity. A derivative of the 37-amino-acid form of GLP-1 that lacks the first six amino acids (GLP-1[7-37]) is a potent stimulant of insulin release. It represents the predominant form of GLP in the human intestine and has been termed “insulinotropin.” It has been considered as a potential therapeutic agent in type 2 diabetes. However, it requires continuous subcutaneous infusion to produce a sustained lowering of both fasting and postprandial hyperglycemia in type 2 diabetic patients; therefore, its clinical usefulness is limited. Exenatide (see above) is an analog of GLP-1.
Pharmacologic Effects of Glucagon
A. METABOLIC EFFECTS
The first six amino acids at the amino terminal of the glucagon molecule bind to specific receptors on liver cells. This leads to a Gs protein-coupled increase in adenylyl cyclase activity and the production of cAMP, which facilitates catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate pharmacologic result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. There is no effect on skeletal muscle glycogen, presumably because of the lack of glucagon receptors on skeletal muscle. Pharmacologic amounts of glucagon cause release of insulin from normal pancreatic B cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells.
B. CARDIAC EFFECTS
Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism described above. Thus, it produces an effect very similar to that of b-adrenoceptor agonists without requiring functioning b receptors.
C. EFFECTS ON SMOOTH MUSCLE
Large doses of glucagon produce profound relaxation of the intestine. In contrast to the above effects of the peptide, this action on the intestine may be due to mechanisms other than adenylyl cyclase activation.
A. SEVERE HYPOGLYCEMIA
The major use of glucagon is for emergency treatment of severe hypoglycemic reactions in patients with type 1 diabetes when unconsciousness precludes oral feedings and intravenous glucose is not possible. Recombinant glucagon is currently available in 1-mg vials for parenteral use (Glucagon Emergency Kit). Nasal sprays have been developed for this purpose but have not yet received FDA approval.
B. ENDOCRINE DIAGNOSIS
Several tests use glucagon to diagnose endocrine disorders. In patients with type 1 diabetes mellitus, a standard test of pancreatic B-cell secretory reserve uses 1 mg of glucagon administered as an intravenous bolus. Because insulin-treated patients develop circulating anti-insulin antibodies that interfere with radioimmunoassays of insulin, measurements of C-peptide are used to indicate B-cell secretion.
C. BETA-BLOCKER POISONING
Glucagon is sometimes useful for reversing the cardiac effects of an overdose of b-blocking agents because of its ability to increase cAMP production in the heart. However, it is not clinically useful in the treatment of cardiac failure.
D. RADIOLOGY OF THE BOWEL
Glucagon has been used extensively in radiology as an aid to x-ray visualization of the bowel because of its ability to relax the intestine.
Transient nausea and occasional vomiting can result from glucagon administration. These are generally mild, and glucagon is relatively free of severe adverse reactions.
ISLET AMYLOID POLYPEPTIDE (IAPP, AMYLIN)
Amylin is a 37-amino-acid peptide originally derived from islet amyloid deposits in pancreas material from patients with long-standing type 2 diabetes or insulinomas. It is produced by pancreatic B cells, packaged within B-cell granules in a concentration 1-2% that of insulin and co-secreted with insulin in a pulsatile manner and in response to physiologic secretory stimuli. Approximately 1 molecule of amylin is released for every 10 molecules of insulin. It circulates in a glycated (active) and nonglycated (inactive) form with physiologic concentrations ranging from 4-25 pmol/L and is primarily renally excreted. Amylin appears to be a member of the superfamily of neuroregulatory peptides, with 46% homology with the calcitonin gene-related peptide CGRP. The physiologic effect of amylin may be to modulate insulin release by acting as a negative feed back on insulin secretion. At pharmacologic doses, amylin reduces glucagon secretion, slows gastric emptying by a vagally medicated mechanism, and centrally decreases appetite. An analog of amylin, pramlintide (see above), differs from amylin by the substitution of proline at positions 25, 28, and 29. These modifications make pramlintide soluble and non-self-aggregating.
PREPARATIONS AVAILABLE
GROWTH HORMONE AGONISTS & ANTAGONISTS
Mecasermin rinfabate (Iplex)
Parenteral: 36 mg per 0.6 mL for subcutaneous injection
Mecasermin (Increlex)
Parenteral: 36 mg/mL for subcutaneous injection
Octreotide (Sandostatin)
Parenteral: 0.05, 0.1, 0.2, 0.5, 1.0 mg/mL for subcutaneous or IV administration
Parenteral depot injection (Sandostatin LAR Depot): 10, 20, 30 mg for IM injection
Pegvisomant (Somavert)
Parenteral: 10, 15, 29 mg powder to reconstitute for subcutaneous injection
Sermorelin (Geref)
Parenteral: 0.5, 1.0 mg for subcutaneous injection; 50 mcg powder to reconstitute for intravenous injection
Somatrem (Protropin)
Parenteral: 5, 10 mg for subcutaneous or IM injection
Somatropin (Genotropin, Humatrope, Nutropin, Nutropin AQ, Norditropin, Saizen, Serostim, Tev-tropin)
Parenteral: 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 5, 5.8, 6, 8, 8.8, 10, 12, 13.5, 13.8, 24 mg for subcutaneous or IM injection
GONADOTROPIN AGONISTS & ANTAGONISTS
Cetrorelix (Cetrotide)
Parenteral: 0.25, 3.0 mg in single-use vials for subcutaneous injection
Choriogonadotropin alfa [rhCG] (Ovidrel)
Parenteral: 250 mcg in single-dose prefilled syringes for subcutaneous injection
Chorionic gonadotropin [hCG] (generic, Profasi, Pregnyl, others)
Parenteral: powder to reconstitute 500, 1000, 2000 IU/mL for IM injection
Follitropin alfa [rFSH] (Gonal-f)
Parenteral: 82, 600, 1200 IU powder in single-dose vials or 415, 568, 1026 IU in prefilled pens with needles for subcutaneous injection
Follitropin beta [rFSH] (Follistim)
Parenteral: 37.5, 150 IU powder in sign-dose vials or 175, 350, 650, 975 IU in a solution of benzyl alcohol in cartridges for subcutaneous injection
Ganirelix (Antagon)
Parenteral: 500 mcg/mL in prefilled syringes for subcutaneous injection
Gonadorelin hydrochloride [GnRH] (Factrel)
Parenteral: 100, 500 mcg for subcutaneous or intravenous injection
Goserelin (Zoladex)
Parenteral: 3.6, 10.8 mg subcutaneous implant
Histrelin acetate (Vantas)
Parenteral: 50 mg subcutaneous implant
Leuprolide (generic, Eligard, Lupron)
Parenteral: 5 mg/mL in multiple-dose vials, or 7.5 mg powder in a single-use kit, or 30 mg (4-month depot), 45 mg (6-month depot) in a single-dose kit for subcutaneous injection
Parenteral depot polymeric delivery system (Eligard): 7.5, 22.5, 30, 45 mg in a single-dose kit for subcutaneous injection
Parenteral depot microspheres suspension (Lupron Depot, Depot-Ped, Depot-3, Depot-4): 3.75, 7.5, 11.25, 15, 22.5, 30 mg in a single-dose kit for IM injection
Parenteral implant: 72 mg for subcutaneous implant
Lutropin [rLH] (Luveris)
Parenteral: 82.5 IU powder for subcutaneous injection
Menotropins [hMG] (Menopur, Repronex)
Parenteral: 75 IU FSH and 75 IU LH activity, 150 IU FSH and 150 IU LH activity for subcutaneous or IM injection
Nafarelin (Synarel)
Nasal: 2 mg/mL (200 mcg/spray)
Urofollitropin (Bravelle)
Parenteral: 75 IU FSH for subcutaneous injection
PROLACTIN ANTAGONISTS (DOPAMINE AGONISTS)
Bromocriptine (generic, Parlodel)
Oral: 2.5 mg tablets, 5 mg capsules
Cabergoline (generic, Dostinex)
Oral: 0.5 mg scored tablets
Pergolide (generic, Permax)
Oral: 0.05, 0.25, 1.0 mg tablets
OXYTOCIN
Oxytocin (generic, Pitocin)
Parenteral: 10 units/mL for intravenous or IM injection
VASOPRESSIN AGONISTS AND ANTAGONISTS
Conivaptan (Vaprisol)
Parenteral: 5 mg/mL solution for IV injection
Desmopressin (DDAVP, generic, Minirin, Stimate)
Nasal: 0.1, 1.5 mg/mL solution
Nasal: 0.1 mg/mL spray pump and rhinal tube delivery system
Parenteral: 4 mcg/mL solution for IV or subcutaneous injection
Oral: 0.1, 0.2 mg tablets
Vasopressin (generic, Pitressin)
Parenteral: 20 pressor IU/mL for IM or subcutaneous administration
OTHER
Corticorelin ovine (Acthrel)
Parenteral: 100 mcg for IV injection
Corticotropin (H.P. Acthar Gel)
Parenteral: 80 units/mL
Cosyntropin (Cortrosyn)
Parenteral: 0.25 mg/vial for IV or IM injection
Thyrotropin alpha (Thyrogen)
Parenteral: 1.1 mg (4 IU) for IM injection
Triptorelin (Trelstar)
Parenteral: 3.75, 11.25 mg microgranules for IM injection
THYROID AGENTS
Levothyroxine [T4] (generic, Levoxyl, Levo-T, Levothroid, Levolet, Novothyrox, Synthroid, Unithroid)
Oral: 0.025, 0.05, 0.075, 0.088, 0.1, 0.112, 0.125, 0.137, 0.15, 0.175, 0.2, 0.3 mg tablets
Parenteral: 200, 500 mcg per vial (100 mcg/mL when reconstituted) for injection
Liothyronine [T3] (generic, Cytomel, Triostat)
Oral: 5, 25, 50 mcg tablets
Parenteral: 10 mcg/mL
Liotrix [a 4:1 ratio of T4:T3] (Thyrolar)
Oral: tablets containing 12.5, 25, 30, 50, 60, 100, 120, 150, 180 mcg T4 and one fourth as much T3
Thyroid desiccated [USP] (generic, Armour Thyroid, Thyroid Strong, Thyrar, S-P-T)
Oral: tablets containing 15, 30, 60, 90, 120, 180, 240, 300 mg; capsules (S-P-T) containing 120, 180, 300 mg
ANTITHYROID AGENTS
Diatrizoate sodium (Hypaque)
Parenteral: 25% (150 mg iodine/mL); 50% (300 mg iodine/mL) (unlabeled use); 250 g powder for reconstitution (oral use is unlabeled)
Iodide (131I) sodium (Iodotope, Sodium Iodide I 131 Therapeutic)
Oral: available as capsules and solution
Iohexol (Omnipaque)
Parenteral: 140, 180, 240, 300, 350 mg iodine/mL (unlabeled use)
Methimazole (Tapazole)
Oral: 5, 10 mg tablets
Potassium iodide
Oral solution (generic, SSKI): 1 g/mL
Oral solution (Lugol’s solution): 100 mg/mL potassium iodide plus 50 mg/mL iodine
Oral syrup (Pima): 325 mg/5 mL
Oral controlled action tablets (Iodo-Niacin): 135 mg potassium iodide plus 25 mg niacinamide hydroiodide
Oral potassium iodide tablets (generic, IOSAT, RAD-Block, Thyro-Block): 65, 130 mg
Propylthiouracil [PTU] (generic)
Oral: 50 mg tablets
Thyrotropin; recombinant human TSH (Thyrogen)
Parenteral: 0.9 mg per vial
SULFONYLUREAS
Chlorpropamide (generic, Diabinese)
Oral: 100, 250 mg tablets
Glimepiride (Amaryl)
Oral: 1, 2, 4 mg tablets
Glipizide (generic, Glucotrol, Glucotrol XL)
Oral: 5, 10 mg tablets; 5, 10 mg extended-release tablets
Glyburide (generic, Diabeta, Micronase, Glynase PresTab)
Oral: 1.25, 2.5, 5 mg tablets; 1.5, 3, 4.5, 6 mg Glynase PresTab, micronized tablets
Tolazamide (generic, Tolinase)
Oral: 100, 250, 500 mg tablets
Tolbutamide (generic, Orinase)
Oral: 500 mg tablets
MEGLITINIDE & RELATED DRUGS
Repaglinide (Prandin)
Oral: 0.5, 1, 2 mg tablets
Nateglinide (Starlix)
Oral: 60, 120 mg tablets
BIGUANIDE
Metformin (generic, Glucophage, Glucophage XR)
Oral: 500, 850, 1000 mg tablets; extended-release (XR): 500 mg tablets; 500 mg/5 mL solution
METFORMIN COMBINATIONS
Glipizide plus metformin (Metaglip)
Oral: 2.5/250, 2.5/500, 5/500 mg tablets
Glyburide plus metformin (Glucovance)
Oral: 1.25/250, 2.5/500, 5/500 mg tablets
Rosiglitazone plus metformin (Avandamet)
Oral: 1/500, 2/500, 4/500; 2/1000, 4/1000 mg tablets
THIAZOLIDINEDIONE DERIVATIVES
Pioglitazone (Actos)
Oral: 15, 30, 45 mg tablets
Rosiglitazone (Avandia)
Oral: 2, 4, 8 mg tablets
THIAZOLIDINEDIONE COMBINATIONS
Rosiglitazone plus glimeperide (Avandaryl)
Oral: 4/1, 4/2, 4/4 mg rosiglitazone/mg glimeperide tablets
ALPHA-GLUCOSIDASE INHIBITORS
Acarbose (Precose)
Oral: 25, 50, 100 mg tablets
Miglitol (Glyset)
Oral: 25, 50, 100 mg tablets
AMYLIN ANALOGS
Pramlintide (Symlin)
Parenteral: vial: 0.6 mg/mL (2.5 units [15 mcg] to 20 units [120 mcg])
GLUCAGON-LIKE POLYPEPTIDE-1 ANALOGS
Exenatide (Byetta)
Parenteral: 5, 10 mcg/dose pen injectors
GLUCAGON
Glucagon (generic)
Parenteral: 1 mg lyophilized powder to reconstitute for injection
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