HORMONAL PREPARATIONS OF POLYPEPTIDE STRUCTURE (hormones of pituitary, thyroid, parathyroid, pancreatic glands). Antidiabetic drugs (Adiurecrinum, Oxytocinum, Pituitrinum, L-thyroxinum, Triiodthyronini hydrochloridum, Mercasolilum, Kalii iodum (Calcitrinum, Myocalcik, Insulinum pro injectionibus, Suspensio Zinc-insulinum, Humulinum (Insulin human), Suspensio insulini semilente, Suspensio insulini ultralente, Butamidum, Glibenclamidum (Maninilum), Chlorpropamidum, Bucarbanum, Metforminum)
HORMONAL PREPARATIONS OF STEROID STRUCTURE 1 (Desoxicorticosteroni acetas, Cortisoni acetas, Hydrocortisoni acetas, Prednisolonum, Dexametasonum, triamcinolonum, Flumetasoni pivalas, Synaflanum (Fluocinaloni acetonis, Beclometasoni dipropionas) HORMONAL PREPARATIONS OF STEROID STRUCTURE -2 SEX HORMONS (Estronum, Estradioli dypropionas, Ethynilestradiolum, Synestrolum, Tamoxofenum, Progesteronum, Oxiprogesteroni capronas, pregninum, Turinalum, Mifipristonum, Non-ovlonum, Marvelonum, Postinor, Depo-provera, Testosteroni propionas, Methylprednisolonum, Retabolilum)
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. The pituitary weighs about
The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from which they are released into the circulation.
Hypothalamic and pituitary hormones (and their synthetic analogs) have pharmacologic applications in three areas: (1) as replacement therapy for hormone deficiency states; (2) as drug therapy and (3) as diagnostic tools for performing stimulation tests.
Hypothalamic & Anterior Pituitary Hormones
Hypothalamic regulatory hormones include growth hormone-releasing hormone (GHRH); a growth hormone-inhibiting hormone (somatostatin); thyrotropin-releasing hormone (TRH); corticotropinreleasing hormone (CRH); gonadotropin-releasing hormone (GnRH), also called luteinizing hormone-releasing hormone (LHRH); and prolactin-inhibiting hormone (dopamine).
Anterior pituitary hormones include growth hormone (GH), thyrotropin (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and adrenocorticotropin (ACTH). Another peptide, -lipotropin ( -LPH), is derived from the same prohormone, proopiomelanocortin, as ACTH. -LPH is secreted from the pituitary (along with ACTH), and is a precursor of the opioid peptide –endorphin.
Mechanisms of Hormone Action
The hypothalamic and pituitary hormones are all peptides that exert their effects by binding to target cell surface membrane receptors with high specificity and affinity.
Clinical Pharmacology of Octreotide (Somatostatin Analog)
Somatostatin has limited therapeutic usefulness because of its short duration of action and its multiple effects on many secretory systems. Octreotide is 45 times more potent than somatostatin in inhibiting growth hormone 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 greater potency of octreotide as compared with somatostatin is not due to differences in affinity for somatostatin receptors. Rather, it appears to be due to octreotide’s much lower clearance and longer half-life. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer in humans than the half-life of somatostatin. Octreotide, in doses of 50–200 g 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 suspension (octreotide long-acting release; Sandostatin LAR) is a slow-release formulation in which octreotide is incorporated into microspheres. It is instituted only after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. The microspheres must be carefully put into suspension and immediately injected into a gluteal muscle. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 20–40 mg.
Octreotide is extremely costly.
Adverse effects of therapy include nausea with or without 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.
Thyroid-Stimulating Hormone (Thyrotropin, TSH) & Thyrotropin Alpha (rhTSH)
Thyrotropin is an anterior pituitary hormone that stimulates the thyroid to produce and synthesize thyroxine (T4), triiodothyronine (T3), and thyroglobulin.
Thyrotropin alpha is a commercially available analog of TSH that is used to help detection of metastatic differentiated thyroid carcinoma; it is also known as recombinant human TSH (rhTSH).
Chemistry & Pharmacokinetics
Structure
Thyrotropin is a glycoprotein consisting of two peptide (alpha and beta) subunits joined noncovalently. The TSH-alpha subunit in humans has 89 amino acids and is virtually identical to that of the alpha subunit of FSH, LH, and hCG. The TSH-beta subunit has 112 amino acids and confers thyroid specificity. Carbohydrate side chains glycosylate each subunit prior to secretion and are important for hormone action. Native TSH is actually secreted as a mixture of glycosylation variants, having both sialylated and sulfated forms. Thyrotropin alpha is a purified synthetic analog of native pituitary TSH that is produced in a Chinese hamster ovary cell line cotransfected with recombinant plasmids containing DNA sequences that encode the alpha and beta subunits of TSH. Like native TSH, thyrotropin alpha is a heterodimeric glycoprotein containing an alpha subunit of 92 amino acids with two glycosylation sites and a beta subunit of 118 amino acids with one glycosylation site. These subunits are slightly longer than those of pituitary TSH but contain amino acid sequences identical to those of native TSH. Like pituitary TSH, synthetic thyrotropin alpha is a mixture of glycosylated variants, but with only sialylated forms.
Absorption, Metabolism, and Excretion
Following an intramuscular injection of thyrotropin alpha (0.9 mg), the peak rhTSH concentration is reached in about 10 hours (range, 3–24 hours). The mean elimination half-life of thyrotropin alpha is 22 hours. Pituitary TSH is cleared by the kidneys and liver. Little unchanged thyrotropin is found in the urine.
Pharmacodynamics
Thyrotropin alpha has the biologic properties of pituitary TSH. It binds to TSH receptors on both normal thyroid and differentiated thyroid cancer cells. The TSH-activated receptor stimulates intracellular adenylyl cyclase activity. Increased cAMP production causes increased iodine uptake and increased production of thyroid hormones and thyroglobulin.
Clinical Pharmacology
Diagnostic Uses
Patients with well-differentiated (papillary or follicular) thyroid carcinoma are treated with surgical resection of the cancer along with total or near-total thyroidectomy. Total thyroidectomy normally reduces the serum levels of thyroid hormones and thyroglobulin to undetectable levels. Postoperatively, these patients must take oral thyroid hormone in order to maintain clinical euthyroidism and to suppress pituitary TSH secretion, thereby preventing any stimulation of tumor growth by TSH. Since thyroid cancer can recur years after apparent cure, such patients should have follow-up TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations. However, the aggressiveness of follow-up surveillance must be individualized according to each patient’s risk of recurrence. Traditionally, patients have had to endure prolonged withdrawal of thyroid hormone replacement for many weeks before these tests in order to allow their TSH levels to rise high enough to stimulate any remaining tumor cells to resume their uptake of 131I and their secretion of thyroglobulin. The use of thyrotropin alpha can obviate the need for cessation of
thyroid hormone replacement prior to the diagnostic whole-body 131I scan and serum thyroglobulin determination.
Therapeutic Uses
Treatment of metastatic differentiated thyroid cancer requires the administration of large doses of 131I (30–200 mCi) in the presence of persistently high serum levels of TSH. Patients must withdraw from thyroid hormone replacement in order to achieve this. For treatment purposes, thyrotropin alpha administration cannot substitute for thyroid hormone withdrawal.
Adrenocorticotropin (Corticotropin, ACTH, ACTH1–24)
Adrenocorticotropin is a peptide hormone produced in the anterior pituitary. Its primary endocrine function is to stimulate synthesis and release of cortisol by the adrenal cortex. Corticotropin can be used therapeutically, but a synthetic derivative is more commonly—and almost exclusively—used to assess adrenocortical responsiveness. A substandard adrenocortical response to exogenous corticotropin administration indicates adrenocortical insufficiency.
Chemistry & Pharmacokinetics
Structure
Human ACTH is a single peptide chain of 39 amino acids. The amino terminal portion containing amino acids 1–24 is necessary for full biologic activity. The remaining amino acids (25–39) confer species specificity. Synthetic human ACTH1–24 is known as cosyntropin. The amino terminal amino acids 1–13 are identical to melanocyte-stimulating hormone ( -MSH), which has been found in animals but not in humans. In states of excessive pituitary ACTH secretion (Addison’s disease or an
ACTH-secreting pituitary tumor), hyperpigmentation—caused by the -MSH activity intrinsic to ACTH—may be noted. ACTH from animal sources is assayed biologically by measuring the depletion of adrenocortical ascorbic acid that follows subcutaneous administration of the ACTH.
Absorption, Metabolism, and Excretion
Both porcine and synthetic corticotropin are given parenterally. Corticotropin cannot be administered orally because of gastrointestinal proteolysis. The biologic half-lives of ACTH1–39 and ACTH1–24 are under 20 minutes. Tissue uptake occurs in the liver and kidneys. ACTH1–39 is transformed into a biologically inactive substance, probably by modification of a side chain. ACTH is not excreted in the urine in significant amounts. The effects of long-acting repository forms of porcine corticotropin persist for up to 18 hours with a gelatin complex of the peptide and up to several days with a zinc hydroxide complex.
Pharmacodynamics
ACTH stimulates the adrenal cortex to produce glucocorticoids, mineralocorticoids, and androgens. ACTH increases the activity of cholesterol esterase, the enzyme that catalyzes the rate-limiting step of steroid hormone production: cholesterol pregnenolone. ACTH also stimulates adrenal hypertrophy and hyperplasia. When given chronically in pharmacologic doses, corticotropin causes increased skin pigmentation.
Clinical Pharmacology
Diagnostic Uses
ACTH stimulation of the adrenals will fail to elicit an appropriate response in states of adrenal insufficiency. A rapid test for ruling out adrenal insufficiency employs cosyntropin (see below). Plasma cortisol levels are measured before and either 30 minutes or 60 minutes following an intramuscular or intravenous injection of 0.25 mg of cosyntropin. A normal plasma cortisol response is a stimulated peak level exceeding 20 g/dL. A subnormal response indicates primary or secondary adrenocortical insufficiency that can be differentiated using endogenous plasma ACTH levels (which are increased in primary adrenal insufficiency and decreased in the secondary form). An incremental rise in plasma aldosterone generally occurs in secondary but not primary adrenal insufficiency after cosyntropin stimulation. ACTH stimulation may distinguish three forms of “late-onset” (nonclassic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism, all of which may be associated with hirsutism. In patients with deficiency of 21-hydroxylase, ACTH stimulation results in an incremental rise in plasma 17-hydroxyprogesterone, the substrate for the deficient enzyme. Patients with 11-hydroxylase deficiency manifest a rise in 11-deoxycortisol, while those with 3 -hydroxy- 5 steroid dehydrogenase deficiency show an increase of 17-hydroxypregnenolone in response to ACTH stimulation.
Therapeutic Uses
Corticotropin therapy has been virtually abandoned since it has no therapeutic advantage over directadministration of glucocorticoids.
Dosage
Cosyntropin is the preferred preparation for diagnostic use. The standard diagnostic test dose of 0.25 mg is equivalent to 25 units of porcine corticotropin. ACTH is rarely indicated but is available for use in doses of 10–20 units four times daily. Repository ACTH, 40–80 units, may be administered every 24–72 hours.
Toxicity & Contraindications
The toxicity of therapeutic doses of ACTH resembles that of the glucocorticoid with the added adverse effect of hyperandrogenism in women. The occasional development of antibodies to animal ACTH or to depot cosyntropin (a preparatioot currently available in the
Posterior Pituitary Hormones
Two posterior pituitary hormones are known: vasopressin and oxytocin. Their structures are very similar. Posterior pituitary hormones are synthesized in the hypothalamus and then transported to the posterior pituitary, where they are stored and then released into the circulation.
Oxytocin
Oxytocin is a peptide hormone secreted by the posterior pituitary that elicits milk ejection in lactating women. It may contribute to the initiation of labor. Oxytocin is released during sexual orgasm.
Chemistry & Pharmacokinetics
Structure
Oxytocin is a nine-amino-acid peptide composed of a six-amino-acid disulfide ring and a threemembered tail (Figure 37–2). Oxytocin and vasopressin differ from vasotocin—the only posterior pituitary hormone found ionmammalian vertebrates—by only one amino acid residue each.
Absorption, Metabolism, and Excretion
Oxytocin is usually administered intravenously for stimulation of labor. It is also available as a nasal spray to induce lactation postpartum. It is inactive if swallowed, because it is destroyed in the stomach and intestine. Oxytocin is not bound to plasma proteins and is catabolized by the kidneys and liver, with a circulating half-life of 5 minutes.
Pharmacodynamics
Oxytocin alters transmembrane ionic currents in myometrial smooth muscle cells to produce sustained uterine contraction. The sensitivity of the uterus to oxytocin increases during pregnancy. Oxytocin-induced myometrial contractions can be inhibited by -adrenoceptor agonists, magnesium sulfate, or inhalation anesthetics. Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. Oxytocin has weak antidiuretic and pressor activity.
Clinical Pharmacology
Diagnostic Uses
Oxytocin infusioear term will produce uterine contractions that decrease the fetal blood supply. The fetal heart rate response to a standardized oxytocin challenge test provides information about placental circulatory reserve. An abnormal response suggests intrauterine growth retardation and may warrant immediate cesarean delivery.
Therapeutic Uses
Oxytocin is used to induce labor and augment dysfunctional labor for (1) conditions requiring early vaginal delivery (eg, Rh problems, maternal diabetes, or preeclampsia), (2) uterine inertia, and (3) incomplete abortion. Oxytocin can also be used for control of postpartum uterine hemorrhage. Impaired milk ejection may respond to nasal oxytocin. Synthetic peptide and nonpeptide oxytocin antagonists that can prevent premature labor are being investigated.
Dosage
Oxytocin is frequently given to induce and maintain labor after the cervix has ripened naturally or with the aid of misoprostol. For induction of labor, oxytocin should be administered intravenously via an infusion pump with appropriate fetal and maternal monitoring. An initial infusion rate of 1 mU/min is increased every 15–30 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units is added to
Toxicity & Contraindications
When oxytocin is used properly, serious toxicity is rare. Among the reported adverse reactions are maternal deaths due to hypertensive episodes, uterine rupture, water intoxication, and fetal deaths. Afibrinogenemia has also been reported. Contraindications include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.
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.
Chemistry & Pharmacokinetics
Structure
Vasopressin is a nonapeptide with a six-amino-acid ring and a three-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 (Figure 37–2).
Absorption, Metabolism, and Excretion
Vasopressin is administered by intravenous, intramuscular, or intranasal routes; oral absorption is slight. The half-life of circulating ADH is approximately 20 minutes, with renal and hepatic catabolism via reduction of the disulfide bond and peptide cleavage. A small amount of vasopressin is excreted as such in the urine.
Pharmacodynamics
Vasopressin interacts with two types of receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules. Extrarenal V2-like receptors mediate release of coagulation factor VIIIc and von Willebrand factor.
Desmopressin acetate (DDAVP, 1-desamino-8-D-argininevasopressin) is a long-acting synthetic analog of vasopressin with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin.
Clinical Pharmacology
Vasopressin and desmopressin are the alternative treatments of choice for pituitary diabetes insipidus. Bedtime desmopressin therapy ameliorates nocturnal enuresis by decreasing nocturnal urine production. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.
Dosage
Aqueous Vasopressin
Synthetic aqueous vasopressin is a short-acting preparation for intramuscular, subcutaneous, or intravenous administration. The dose is 5–10 units subcutaneously or intramuscularly every 3–6 hours for transient diabetes insipidus and 0.1–0.5 units/min intravenously for gastrointestinal bleeding.
Desmopressin Acetate
This is the preferred treatment for most patients with central diabetes insipidus. Desmopressin may be administered intranasally, intravenously, subcutaneously, or orally. The typical nasal dosage is 10–40 g (0.1–0.4 mL) daily in one to three divided doses. 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 made to deliver a more precise dose. Injectable desmopressin is approximately ten times more bioavailable than intranasal desmopressin. The dosage by injection is 1–4 g (0.25–1 mL) daily every 12–24 hours as needed for polyuria, polydipsia, or hypernatremia. For nocturnal enuresis, desmopressin, 10–20 g (0.1–0.2 mL) intranasally at bedtime, is used.
Desmopressin is also available as an oral preparation. The usual dose is 0.1–0.2 mg every 12–24 hours. Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand’s disease (see Chapter 34: Drugs Used in Disorders of Coagulation).
Toxicity & Contraindications
Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Therapy can result in hyponatremic convulsions. 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.
Thyroid & Antithyroid Drugs
Thyroid & Antithyroid Drugs: Introduction
The normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine)—to 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. Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism
Homeostasis.
Iodide Metabolism
The recommended daily adult iodide (I–)* intake is
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 (Figure 38–1). 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 (
Iodide is then 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 (see below).
Transport of Thyroid Hormones
T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form. Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remaiormal, reflecting feedback control.
Peripheral Metabolism of Thyroid Hormones
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.
Thyroid-Pituitary Relationships
Hypothalamic & Pituitary Hormones. Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38–3). 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.
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 (Figure 38–1). In certain disease states (eg, Hashimoto’s thyroiditis), this can result in inhibition of thyroid hormone synthesis and hypothyroidism.
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].
Thyroid Hormones
Chemistry
The structural formulas of thyroxine and triiodothyronine as well as reverse triiodothyronine (rT3) are shown in Figure 38–2. All of these 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.
Pharmacokinetics
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 Lthyroxine 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 halflives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin) 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.
Mechanism of Action
A model of thyroid hormone action is depicted in Figure 38–4, which shows the free forms of thyroid hormones, T4 and T3, dissociated from thyroid-binding proteins, entering the cell by diffusion or possibly by active transport. 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-erboncogene family, which also includes the steroid hormone receptors and receptors for vitamins A and D. The T3 receptor exists in two forms, and . 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.
Effects of Thyroid Hormones
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 thyrotoxicosis or hypothyroidism. 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 dwarfism—symptoms 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 receptors or enhanced amplification of the 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.
Thyroid Preparations
See the Preparations Available section at the end of this chapter for a list of available preparations.
These preparations may be synthetic (levothyroxine, liothyronine, liotrix) or of animal origin (desiccated thyroid). 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 can be used because they provide comparable efficacy and are more cost-effective than branded preparations. Although liothyronine 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 (
Antithyroid Agents
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.
Thioamides
The thioamides methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis.
In the
Pharmacokinetics
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 60% of iodine organification for 7 hours. Since a single 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 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. Of the two, propylthiouracil is preferable in pregnancy because it is more strongly protein-bound and therefore crosses the placenta less readily. In addition, it is not secreted in sufficient quantity in breast milk to preclude breast-feeding.
Pharmacodynamics
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 (Figure 38–1). 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. The most common adverse effect is a maculopapular pruritic rash, at times accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash, vasculitis, arthralgia, a lupus-like reaction, cholestatic jaundice, hepatitis, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. The most dangerous complication is agranulocytosis, an infrequent but potentially fatal adverse reaction. It occurs in 0.3–0.6% of patients taking thioamides, but the risk may be increased in older patients and in those receiving high-dose methimazole therapy (over 40 mg/d). The reaction is usually rapidly reversible when the drug is discontinued, but antibiotic therapy may be necessary for complicating infections. The crosssensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended.
Anion Inhibitors
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 has been shown to cause aplastic anemia.
Iodides
Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy.
Pharmacodynamics
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 daily), the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis. Rapid improvement in thyrotoxic symptoms occurs within 2–7 days—hence 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.
Clinical Use of Iodide
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 thyroidblocking 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.
Iodinated Contrast Media
The iodinated contrast agents—ipodate and iopanoic acid by mouth, or diatrizoate intravenously— are 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 oral administration of 0.5–1 g/d. 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.
Radioactive Iodine
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 rays with an effective half-life of 5 days and a penetration range of 400–2000 m. 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 30 years of clinical experience with radioiodine. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it crosses the placenta and is excreted in breast milk.
Adrenoceptor-Blocking Agents
Beta blockers without intrinsic sympathomimetic activity are effective therapeutic adjuncts in the management of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the -blocker most widely studied and used in the therapy of thyrotoxicosis.
Hypothyroidism
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. The etiology and pathogenesis of hypothyroidism are outlined. 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 (or low free thyroxine index) 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.
Management of Hypothyroidism
Except for hypothyroidism caused by drugs, which can be treated by simply removing the depressant agent, the general strategy of replacement therapy is appropriate. The most satisfactory preparation is levothyroxine. 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 g/kg/d, whereas the average dosage for an adult is about 1.7 g/kg/d. There is some variability in the absorption of thyroxine, so this dosage may vary from patient to patient. Because of the long half-life of thyroxine, the dose can be given once daily. Children should be monitored for normal growth and development. Serum TSH and free thyroxine should be measured at regular intervals and maintained within the normal range. 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 dosage. In such adult patients, levothyroxine is given in a dosage of 12.5–25 g/d for 2 weeks, increasing the daily dose by
Special Problems in Management of Hypothyroidism
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.
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 intravenously— usually 300–400 g initially, followed by
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, a modest increase in the thyroxine dose (about 20–30%) is required to normalize the serum TSH level during pregnancy. Because of the elevated maternal TBG, the free thyroxine index (FT4I) or free thyroxine (FT4) and TSH must be used to monitor maternal thyroxine dosages.
Hyperthyroidism
Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone.
Graves’ Disease
Pathophysiology
Graves’ disease is considered to be an autoimmune disorder in which there is a genetic defect in suppressor T lymphocytes, and 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 the thyroid cell. Spontaneous remission occurs but may require 1 to 15 years.
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 (1–2 years), and there is a 60–70% incidence of relapse. Antithyroid drug therapy is usually begun with large 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 30–40 mg; once-daily dosing may enhance adherence. Maintenance therapy requires 5–15 mg once daily. Alternatively, therapy is started with propylthiouracil, 100–150 mg every 6 or 8 hours, followed after 4–8 weeks 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 T3 by RIA, FT4 or FT4I,
and serum TSH.
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. TSH release can be prevented by the daily administration of 50–150 g 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.
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 2 weeks 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.
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 Ci/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. When hypothyroidism develops, prompt replacement with oral levothyroxine, 50–150 g daily, should be instituted.
Adjuncts to Antithyroid Therapy
During the acute phase of thyrotoxicosis, -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 -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.
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 T3 by RIA 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.
Subacute Thyroiditis
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 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.
Special Problems
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 (eg, sodium ipodate,
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 (see below). 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
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 daily), 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.
Neonatal Graves’ Disease
Graves’ disease may occur in the newborn infant, either due to passage of 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 TSH—in 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.
Nontoxic Goiter
Nontoxic goiter is a syndrome of thyroid enlargement without excessive thyroid hormone production. Enlargement of the thyroid gland is usually due to TSH stimulation from inadequate thyroid hormone synthesis. The most common cause of nontoxic goiter worldwide is iodide deficiency, but in the
Goiter due to iodide deficiency is best managed by prophylactic administration of iodide. The optimal daily iodide intake is 150–200 g. 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 therapy—150–200 g/d orally—will 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. Some adenomas will regress following thyroxine therapy; those that do not should be rebiopsied or surgically removed. 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 requires withdrawal of thyroxine replacement for 4–6 weeks— accompanied 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.
Adrenocorticosteroids & Adrenocortical Antagonists
The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. Both natural and synthetic corticosteroids are used for diagnosis and treatment of disorders of adrenal function. They are also used—more often and in much larger doses—for treatment of a variety of inflammatory and immunologic disorders. Secretion of adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt-retaining hormone aldosterone is primarily under the influence of angiotensin. Corticotropin has some actions that do not depend upon its effect on adrenocortical secretion. However, its pharmacologic value as an anti-inflammatory agent and its use in testing adrenal function depend on its secretory action.
Inhibitors of the synthesis or antagonists of the action of the adrenocortical steroids are important in the treatment of several conditions. These agents are described at the end of this chapter.
Adrenocorticosteroids
The adrenal cortex releases a large number of steroids into the circulation. Some have minimal biologic activity and function primarily as precursors, and there are some for which no function has been established. The hormonal steroids may be classified as those having important effects on intermediary metabolism (glucocorticoids), those having principally salt-retaining activity (mineralocorticoids), and those having androgenic or estrogenic activity. In humans, the major glucocorticoid is cortisol and the most important mineralocorticoid is aldosterone. Quantitatively, dehydroepiandrosterone (DHEA) in its sulfated form (DHEAS) is the major adrenal androgen, since about 20 mg is secreted daily. However, DHEA and two other adrenal androgens, androstenediol and androstenedione, are weak androgens or estrogens, mostly by peripheral conversion to testosterone and dehydrotestosterone or
estradiol and estrone. Adrenal androgens constitute the major endogenous precursors of estrogen in women after menopause and in younger patients in whom ovarian function is deficient or absent.
The Naturally Occurring Glucocorticoids; Cortisol (Hydrocortisone)
Pharmacokinetics
Cortisol (also called hydrocortisone, compound F) exerts a wide range of physiologic effects, including regulation of intermediary metabolism, cardiovascular function, growth, and immunity.
Its synthesis and secretion are tightly regulated by the central nervous system, which is very sensitive to negative feedback by the circulating cortisol and exogenous (synthetic) glucocorticoids. Cortisol is synthesized from cholesterol (as shown in Figure 39–1).
In the normal adult, in the absence of stress, 10–20 mg of cortisol is secreted daily. The rate of secretion follows a circadian rhythm governed by pulses of ACTH that peak in the early morning hours and after meals (Figure 39–2). In plasma, cortisol is bound to circulating proteins.
Corticosteroid-binding globulin (CBG), an 2-globulin synthesized by the liver, binds 90% of the circulating hormone under normal circumstances. The remainder is free (about 5–10%) or loosely bound to albumin (about 5%) and is available to exert its effect on target cells. When plasma cortisol levels exceed 20–30 g/dL, CBG is saturated, and the concentration of free cortisol rises rapidly. CBG is increased in pregnancy and with estrogen administration and in hyperthyroidism. It is decreased by hypothyroidism, genetic defects in synthesis, and protein deficiency states. Albumin has a large capacity but low affinity for cortisol, and for practical purposes albumin-bound cortisol should be considered free. Synthetic corticosteroids such as dexamethasone are largely bound to albumin rather than CBG.
The half-life of cortisol in the circulation is normally about 60–90 minutes; half-life may be increased when hydrocortisone (the pharmaceutical preparation of cortisol) is administered in large amounts or when stress, hypothyroidism, or liver disease is present. Only 1% of cortisol is excreted unchanged in the urine as free cortisol; about 20% of cortisol is converted to cortisone by 11- hydroxysteroid dehydrogenase in the kidney and other tissues with mineralocorticoid receptors (see below) before reaching the liver. Most cortisol is inactivated in the liver by reduction of the 4,5 double bond in the A ring and subsequent conversion to tetrahydrocortisol and tetrahydrocortisone
by 3-hydroxysteroid dehydrogenase. (See Figure 39–4 for carboumbering.) Some is converted to cortol and cortolone by reduction of the C20 ketone. There are small amounts of other metabolites. About one third of the cortisol produced daily is excreted in the urine as dihydroxy ketone metabolites and is measured as 17-hydroxysteroids. Many cortisol metabolites are conjugated with glucuronic acid or sulfate at the C3 and C21 hydroxyls, respectively, in the liver; they then reenter
the circulation and are excreted in the urine. In some species (eg, the rat), corticosterone is the major glucocorticoid. It is less firmly bound to protein and therefore metabolized more rapidly. The pathways of its degradation are similar to those
Mechanism of Action
Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors that includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). All these receptors interact with the promoters of—and regulate the transcription of—target genes (Figure 39–3). In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with heat shock proteins (Hsp). Themost important of these are two molecules of Hsp90, though other proteins are certainly involved. Free hormone from the plasma and interstitial fluid enters the cell and binds to the receptor, inducing conformational changes that allow it to dissociate from the heat shock proteins. The ligand-bound receptor complex then is actively transported into the nucleus, where it interacts with DNA and nuclear proteins. As a homodimer, it binds to glucocorticoid receptor elements (GRE) in the promoters of responsive genes. The GRE is composed of two palindromic sequences that bind to the hormone receptor dimer.
These transcription factors have broad actions on the regulation of growth factors, proinflammatory cytokines, etc, and to a great extent mediate the anti-growth, anti-inflammatory, and immunosuppressive effects of glucocorticoids. These factors represent new targets in the development of a new generation of glucocorticoid agonists or antagonists with response selectivity or tissue selectivity.
Physiologic Effects
The glucocorticoids have widespread effects because they influence the function of most cells in the body. The major metabolic consequences of glucocorticoid secretion or administration are due to direct actions of these hormones in the cell. However, some important effects are the result of homeostatic responses by insulin and glucagon. Although many of the effects of glucocorticoids are dose-related and become magnified when large amounts are administered for therapeutic purposes, there are also other effects—called “permissive” effects—in the absence of which many normal functions become deficient. For example, the response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts of this glucocorticoid. Furthermore, the lipolytic responses of fat cells to catecholamines, ACTH, and growth hormone are attenuated in the absence of glucocorticoids.
Metabolic Effects
The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associatedwith their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism.
Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis.
The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation.
The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain.
Catabolic and Antianabolic Effects
Although glucocorticoids stimulate protein and RNA synthesis in the liver, they have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, fat, and skin. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin.
Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing’s syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids. In children, glucocorticoids reduce growth. This effect may be partially prevented by administration of growth hormone in high doses.
Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflammation. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation. Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue. These events are mediated by a complex series of interactions of white cell adhesion molecules with those on endothelial cells and are inhibited by glucocorticoids. After a single dose of a short-acting glucocorticoid, the circulating concentration of neutrophils increases while the lymphocytes (T and B cells), monocytes, eosinophils, and basophils in the circulation decrease iumber. The changes are maximal at 6 hours and are dissipated in 24 hours. The increase in neutrophils is due both to the increased influx into the blood from the bone marrow and decreased migration from the blood vessels, leading to a reduction in the number of cells at the site of inflammation. The reduction in circulating lymphocytes, monocytes, eosinophils, and basophils is primarily the result of their movement from the vascular bed to lymphoid tissue.
Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells.
The ability of these cells to respond to antigens and mitogens is reduced. The effect on macrophages is particularly marked and limits their ability to phagocytose and kill microorganisms nd to produce tumor necrosis factor- , interleukin-1, metalloproteinases, and plasminogen ctivator. Both macrophages and lymphocytes produce less interleukin-12 and interferon- , mportant inducers of TH1 cell activity, and cellular immunity.
Other Effects
Glucocorticoids have important effects on the nervous system. Adrenal insufficiency causes marked slowing of the alpha rhythm of the EEG and is associated with depression. Increased amounts of glucocorticoids often produce behavioral disturbances in humans: initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoids may increase intracranial pressure (pseudotumor cerebri).
Glucocorticoids given chronically suppress the pituitary release of ACTH, GH, TSH, and LH.
Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobacter pylori. They also promote fat redistribution in the body, with increase of visceral, facial, nuchal, and supraclavicular fat, and they appear to antagonize the effect of vitamin D on calcium absorption
The glucocorticoids also have important effects on the hematopoietic system. In addition to their effects on leukocytes described above, they increase the number of platelets and red blood cells.
In the absence of physiologic amounts of cortisol, renal function (particularly glomerular filtration) is impaired, vasopressin secretion is augmented, and there is an inability to excrete a water load normally.
Glucocorticoids have important effects on the development of the fetal lungs. Indeed, the structural and functional changes in the lungs near term, including the production of pulmonary surface-active material required for air breathing (surfactant), are stimulated by glucocorticoids.
Synthetic Corticosteroids
Glucocorticoids have become important agents for use in the treatment of many inflammatory, allergic, hematologic, and other disorders. This has stimulated the development of many synthetic steroids with anti-inflammatory and immunosuppressive activity.
Pharmacokinetics
Source
Pharmaceutical steroids are usually synthesized from cholic acid (obtained from cattle) or steroid sapogenins, in particular diosgenin and hecopenin, found in plants of the Liliaceae and Dioscoreaceae families. Further modifications of these steroids have led to the marketing of a large group of synthetic steroids with special characteristics that are pharmacologically and therapeutically important.
Disposition
The metabolism of the naturally occurring adrenal steroids has been discussed above. The synthetic corticosteroids are in most cases rapidly and completely absorbed when given by mouth. Although they are transported and metabolized in a fashion similar to that of the endogenous steroids, important differences exist. Alterations in the glucocorticoid molecule influence its affinity for glucocorticoid and mineralocorticoid receptors as well as its protein-binding avidity, side chain stability, rate of reduction, and metabolic products. Halogenation at the 9 position, unsaturation of the 1–2 bond of the A ring, and methylation at the 2 or 16 position prolong the half-life by more than 50%. The compounds are excreted in the free form. In some cases, the agent given is a prodrug—eg, prednisone is rapidly converted to the active product prednisolone in the body.
Pharmacodynamics
The actions of the synthetic steroids are similar to those of cortisol (see above). They bind to the specific intracellular receptor proteins and produce the same effects but have different ratios of glucocorticoid to mineralocorticoid potency.
Clinical Pharmacology
Diagnosis and Treatment of Disturbed Adrenal Function
Use of Glucocorticoids for Diagnostic Purposes
It is sometimes necessary to suppress the production of ACTH in order to identify the source of a particular hormone or to establish whether its production is influenced by the secretion of ACTH. In these circumstances, it is advantageous to employ a very potent substance such as dexamethasone because the use of small quantities reduces the possibility of confusion in the interpretation of hormone assays in blood or urine. For example, if complete suppression is achieved by the use of 50 mg of cortisol, the urinary 17-hydroxycorticosteroids will be 15–18 mg/24 h, since one third of the dose given will be recovered in urine as 17-hydroxycorticosteroid. If an equivalent dose of 1.5 mg of dexamethasone is employed, the urinary excretion will be only 0.5 mg/24 h and blood levels will be low. The dexamethasone suppression test is used for the diagnosis of Cushing’s syndrome and has also been used in the differential diagnosis of depressive psychiatric states. As a screening test, dexamethasone, 1 mg, is given orally at 11 PM, and a plasma sample is obtained in the morning. In normal individuals, the morning cortisol concentration is usually less than 3 g/dL, whereas in Cushing’s syndrome the level is usually greater than 5 g/dL. The results are not reliable in the
presence of depression, anxiety, concurrent illness, and other stressful conditions or if the patient receives a medication that enhances the catabolism of dexamethasone in the liver. To distinguish between hypercortisolism due to anxiety, depression, and alcoholism (pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a combined test is carried out, consisting of dexamethasone (0.5 mg orally every 6 hours for 2 days) followed by a standard corticotropin-releasing hormone (CRH) test (1 mg/kg given as a bolus intravenous infusion 2 hours after the last dose of dexamethasone).
In patients in whom the diagnosis of Cushing’s syndrome has been established clinically and confirmed by a finding of elevated free cortisol in the urine, suppression with large doses of dexamethasone will help to distinguish patients with Cushing’s disease from those with steroidproducing tumors of the adrenal cortex or with the ectopic ACTH syndrome. Dexamethasone is given in a dosage of 0.5 mg orally every 6 hours for 2 days, followed by 2 mg orally every 6 hours for 2 days, and the urine is then assayed for cortisol or its metabolites (Liddle’s test); or dexamethasone is given as a single dose of 8 mg at 11 PM and the plasma cortisol is measured at 8 AM the following day. In patients with Cushing’s disease, the suppressant effect of dexamethasone will usually produce a 50% reduction in hormone levels. In patients in whom suppression does not occur, the ACTH level will be low in the presence of a cortisol-producing adrenal tumor and elevated in patients with an ectopic ACTH-producing tumor.
Corticosteroids and Stimulation of Lung Maturation in the Fetus
Lung maturation in the fetus is regulated by the fetal secretion of cortisol. Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone, 12 mg, followed by an additional dose of 12 mg 18–24 hours later, is commonly used. Betamethasone is chosen because maternal protein binding and placental metabolism of this corticosteroid is less than that of cortisol, allowing increased transfer across the placenta to the fetus.
Corticosteroids and Nonadrenal Disorders
The synthetic analogs of cortisol are useful in the treatment of a diverse group of diseases unrelated to any known disturbance of adrenal function. The usefulness of corticosteroids in these disorders is a function of their ability to suppress inflammatory and immune responses, as described above. In disorders in which host response is the cause of the major manifestations of the disease, these agents are useful. In instances where the inflammatory or immune response is important in controlling the pathologic process, therapy with corticosteroids may be dangerous but
justified to prevent irreparable damage from an inflammatory response—if used in conjunction with specific therapy for the disease process. Since the corticosteroids are not usually curative, the pathologic process may progress while clinical manifestations are suppressed. Therefore, chronic therapy with these drugs should be undertaken with great care and only when the seriousness of the disorder warrants their use and less hazardous measures have been exhausted.
In general, attempts should be made to bring the disease process under control using medium- to intermediate-acting glucocorticoids such as prednisone and prednisolone, as well as all ancillary measures possible to keep the dose low. Where possible, alternate-day therapy should be utilized. Therapy should not be decreased or stopped abruptly. When prolonged therapy is anticipated, it is helpful to obtain chest x-rays and a tuberculin test, since glucocorticoid therapy can reactivate dormant disease. The presence of diabetes, peptic ulcer, osteoporosis, and psychological disturbances should be taken into consideration, and cardiovascular function should be assessed.
Toxicity
The benefits obtained from use of the glucocorticoids vary considerably. Use of these drugs must be carefully weighed in each patient against their widespread effects on every part of the organism.
The major undesirable effects of the glucocorticoids are the result of their hormonal actions (see above), which lead to the clinical picture of iatrogenic Cushing’s syndrome (see below). When the glucocorticoids are used for short periods (less than 2 weeks), it is unusual to see serious adverse effects even with moderately large doses. However, insomnia, behavioral changes (primarily hypomania), and acute peptic ulcers are occasionally observed even after only a few days of treatment. Acute pancreatitis is a rare but serious acute adverse effect of high-dose glucocorticoids.
Metabolic Effects
Most patients who are given daily doses of 100 mg of hydrocortisone or more (or the equivalent amount of synthetic steroid) for longer than 2 weeks undergo a series of changes that have been termed iatrogenic Cushing’s syndrome. The rate of development is a function of the dose and the genetic background of the patient. In the face, rounding, puffiness, fat deposition, and plethora usually appear (moon facies). Similarly, fat tends to be redistributed from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. There is an increased growth of fine hair over the face, thighs and trunk. Steroid-induced punctate acne may appear, and insomnia and increased appetite are noted. In the treatment of dangerous or disabling disorders, these changes may not require cessation of therapy. However, the underlying metabolic changes accompanying them can be very serious by the time they become obvious. The continuing breakdown of protein and diversion of amino acids to glucose production increase the need for insulin and over a period of time result in weight gain; visceral fat deposition; myopathy and muscle wasting; thinning of the skin, with striae and bruising; hyperglycemia; and eventually the development of osteoporosis, diabetes, and aseptic necrosis of the hip. Wound healing is also impaired under these circumstances.
When diabetes occurs, it is treated by diet and insulin. These patients are often resistant to insulin but rarely develop ketoacidosis. In general, patients treated with corticosteroids should be on highprotein and potassium-enriched diets.
Other Complications
Other serious side effects include peptic ulcers and their consequences. The clinical findings associated with certain disorders, particularly bacterial and mycotic infections, may be masked by the corticosteroids, and patients must be carefully watched to avoid serious mishap when large doses are used. The frequency of severe myopathy is greater in patients treated with long-acting glucocorticoids. The administration of such compounds has been associated with nausea, dizziness, and weight loss in some patients. It is treated by changing drugs, reducing dosage, and increasing potassium and protein intake.
Deoxycorticosterone (DOC)
DOC, which also serves as a precursor of aldosterone (Figure 39–1), is normally secreted in amounts of about 200 g/d. Its half-life when injected into the human circulation is about 70 minutes. Preliminary estimates of its concentration in plasma are approximately 0.03 g/dL. The control of its secretion differs from that of aldosterone in that the secretion of DOC is primarily under the control of ACTH. Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450c11 or P450c17 activity.
Effects of Progesterone
Progesterone has little effect on protein metabolism. It stimulates lipoprotein lipase activity and seems to favor fat deposition. The effects on carbohydrate metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to glucose. There is usually nomanifest change in carbohydrate tolerance. In the liver, progesterone glycogen storage, possibly by facilitating the effect of insulin. Progesterone also promotes ketogenesis.
Progesterone can compete with aldosterone for the mineralocorticoid receptor of the renal tubule, causing a decrease in Na+ reabsorption. This leads to an increased secretion of aldosterone by the romotes adrenal cortex (eg, in pregnancy). Progesterone increases body temperature in humans. The mechanism of this effect is not known, but an alteration of the temperature-regulating centers in the hypothalamus has been suggested. Progesterone also alters the function of the respiratory centers.
The ventilatory response to CO2 is increased (synthetic progestins with an ethinyl group do not have respiratory effects). This leads to a measurable reduction in arterial and alveolar PCO2 during pregnancy and in the luteal phase of the menstrual cycle. Progesterone and related steroids also have depressant and hypnotic effects on the brain. Progesterone is responsible for the alveolobular development of the secretory apparatus in the breast. It also participates in the preovulatory LH surge and causes the maturation and secretory changes in the endometrium that are seen following ovulation (Figure 40–1).
Clinical Uses of Progestins
Therapeutic Applications
The major uses of progestational hormones are for hormone replacement therapy (see above) and hormonal contraception (see below). In addition, they are useful in producing long-term ovarian suppression for other purposes. When used alone in large doses parenterally (eg, medroxyprogesterone acetate, 150 mg intramuscularly every 90 days), prolonged anovulation and amenorrhea result. This therapy has been employed in the treatment of dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated, and for contraception.
The major problem with this regimen is the prolonged time required in some patients for ovulatory function to return after cessation of therapy. It should not be used for patients planning a pregnancy in the near future. Similar regimens will relieve hot flushes in some menopausal women and can be used if estrogen therapy is contraindicated. Medroxyprogesterone acetate, 10–20 mg orally twice weekly—or intramuscularly in doses of 100 mg/m2 every 1–2 weeks—will prevent menstruation, but it will not arrest accelerated bone maturation in children with precocious puberty.
Progestins do not appear to have any place in the therapy of threatened or habitual abortion. Early reports of the usefulness of these agents resulted from the unwarranted assumption that after several abortions the likelihood of repeated abortions was over 90%. When progestational agents were administered to patients with previous abortions, a salvage rate of 80% was achieved. It is now recognized that similar patients abort only 20% of the time even when untreated. On the other hand, progesterone was experimentally given recently to delay premature labor with encouraging results.
Progesterone and medroxyprogesterone have been used in the treatment of women who have difficulty in conceiving and who demonstrate a slow rise in basal body temperature. There is no convincing evidence that this treatment is effective.
Preparations of progesterone and medroxyprogesterone have been used to treat premenstrual syndrome. Controlled studies have not confirmed the effectiveness of such therapy except when doses sufficient to suppress ovulation have been used.
Diagnostic Uses
Progesterone can be used as a test of estrogen secretion. The administration of progesterone, 150 mg/d, or medroxyprogesterone, 10 mg/d, for 5–7 days, is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens. A combination of estrogen and progestin can be given to test the responsiveness of the endometrium in patients with amenorrhea.
Hormonal Contraception (Oral, Parenteral, & Implanted Contraceptives)
A large number of oral contraceptives containing estrogens or progestins (or both) are now available for clinical use. These preparations vary chemically and pharmacologically and have many properties in common as well as definite differences important for the correct selection of the right agent.
Two types of preparations are used for oral contraception: (1) combinations of estrogens and progestins and (2) continuous progestin therapy without concomitant administration of estrogens. The combination agents are further divided into monophasic forms (constant dosage of both components during the cycle) and biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle). The preparations for oral use are all adequately absorbed, and in combination preparations the pharmacokinetics of neither drug is significantly altered by the other.
Only one implantable contraceptive preparation is available at present. Norgestrel, also utilized as the progestin component of some oral contraceptive preparations, is an effective suppressant of ovulation when it is released from subcutaneous implants. Intramuscular injection of large doses of medroxyprogesterone also provides contraceptive action of long duration.
Mechanism of Action
The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results in inhibition of ovulation. The combination agents also produce a change in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease the likelihood of conception and implantation.
The continuous use of progestins alone does not always inhibit ovulation. The other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used.
Effects on the Ovary
Chronic use of combination agents depresses ovarian function. Follicular development is minimal, and corpora lutea, larger follicles, stromal edema, and other morphologic features normally seen in ovulating women are absent. The ovaries usually become smaller even when enlarged before
therapy.
Effects on the Uterus
After prolonged use, the cervix may show some hypertrophy and polyp formation. There are also important effects on the cervical mucus, making it more like postovulation mucus, ie, thicker and less copious.
Agents containing both estrogens and progestins produce further morphologic and biochemical changes of the endometrial stroma under the influence of the progestin, which also stimulates glandular secretion throughout the luteal phase. The agents containing “19-nor” progestins— particularly those with the smaller amounts of estrogen—tend to produce more glandular atrophy and usually less bleeding.
Effects on the Breast
Stimulation of the breasts occurs in most patients receiving estrogen-containing agents. Some enlargement is generally noted. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation. When the doses are small, the effects on breast feeding are not appreciable. Studies of the transport of the oral contraceptives into breast milk suggest that only
small amounts of these compounds cross into the milk, and they have not been considered to be of
importance.
Other Effects of Oral Contraceptives
Effects on the Central Nervous System
The central nervous system effects of the oral contraceptives have not been well studied in humans. A variety of effects of estrogen and progesterone have beeoted in animals. Estrogens tend to increase excitability in the brain, whereas progesterone tends to decrease it. The thermogenic action of progesterone and some of the synthetic progestins is also thought to occur in the central nervous system. It is very difficult to evaluate any behavioral or emotional effects of these compounds in humans.
Effects on Endocrine Function
The inhibition of pituitary gonadotropin secretion has been mentioned. Estrogens also alter adrenal structure and function. Estrogens given orally or at high doses increase the plasma concentration of the 2-globulin that binds cortisol (corticosteroid-binding globulin). Plasma concentrations may be more than double the levels found in untreated individuals, and urinary excretion of free cortisol is elevated.
These preparations cause alterations in the renin-angiotensin-aldosterone system. Plasma renin
Effects on Blood
Serious thromboembolic phenomena occurring in women taking oral contraceptives have given rise to a great many studies of the effects of these compounds on blood coagulation. A clear picture of such effects has not yet emerged. The oral contraceptives do not consistently alter bleeding or clotting times. The changes that have been observed are similar to those reported in pregnancy.
There is an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III. Increased amounts of coumarin anticoagulants may be required to prolong prothrombin time in patients taking oral contraceptives.
Contraception with Progestins Alone
Small doses of progestins administered orally or by implantation under the skin can be used for contraception. They are particularly suited for use in patients for whom estrogen administration is undesirable. They are about as effective as intrauterine devices or combination pills containing 20–30 g of ethinyl estradiol. There is a high incidence of abnormal bleeding. Effective contraception can also be achieved by injecting 150 mg of depot medroxyprogesterone acetate (DMPA) every 3 months. After a 150 mg dose, ovulation is inhibited for at least 14 weeks.Almost all users experience episodes of unpredictable spotting and bleeding, particularly during the
first year of use. Spotting and bleeding decrease with time, and amenorrhea is common. This preparation is not desirable for women planning a pregnancy soon after cessation of therapy because ovulation suppression can persist for as long as 18 months after the last injection. However, ovulation usually returns in a much shorter time. Long-term DMPA use reduces menstrual blood loss and is associated with a decreased risk of endometrial cancer. Suppression of endogenous estrogen secretion may be associated with a reversible reduction in bone density, and changes in plasma lipids are associated with an increased risk of atherosclerosis.
The progestin implant method utilizes the subcutaneous implantation of capsules containing a progestin (L-norgestrel). These capsules release one fifth to one third as much steroid as oral agents, are extremely effective, and last for 5–6 years. The low levels of hormone have little effect on lipoprotein and carbohydrate metabolism or blood pressure. The disadvantages include the need for surgical insertion and removal of capsules and some irregular bleeding rather than predictable menses. An association of intracranial hypertension with implanted norgestrel has been observed in a small number of women. Patients experiencing headache or visual disturbances should be checked for papilledema.
Contraception with progestins is useful in patients with hepatic disease, hypertension, psychosis or mental retardation, or prior thromboembolism. The side effects include headache, dizziness, bloating and weight gain of 1–2 kg, and a reversible reduction of glucose tolerance.
Postcoital Contraceptives
Pregnancy can be prevented following coitus by the administration of estrogens alone or in combination with progestins (“morning after” contraception). When treatment is begun within 72 hours, it is effective 99% of the time. The hormones are often administered with antiemetics, since 40% of the patients have nausea or vomiting. Other adverse effects include headache, dizziness, breast tenderness, and abdominal and leg cramps. receptor and is
extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It
is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7–14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10–20 mg twice daily. Hot flushes and nausea and Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen vomiting occur in 25% of patients, and many other minor adverse effects are observed. Toremifene is astructurally similar compound with very similar properties, indications, and toxicities. Prevention of the expected loss of lumbar spine bone density and plasma lipid changes consistent with a reduction in the risk for atherosclerosis have also been reported in tamoxifen-treated patients following spontaneous or surgical menopause. However, this agonist activity also affects the uterus and increases the risk of endometrial cancer.
Raloxifene is another partial estogen agonist-antagonist at some but not all target tissues. It has similar effects on lipids and bone but appears not to stimulate the endometrium or breast. Because of its apparent tissue selectivity it has been described as a selective estrogen receptor modulator (SERM), a term that could also be applied to tamoxifen and toremifene. Although subject to a high first-pass effect, raloxifene has a very large volume of distribution and a long half-life (> 24 hours),
Mifepristone
Mifepristone (RU 486) is a “19-norsteroid” that binds strongly to the progesterone receptor and inhibits the activity of progesterone. A single dose of 600 mg is an effective emergency postcoital contraceptive, though it may result in delayed ovulation in the following cycle.
Testosterone, when administered by mouth, is rapidly absorbed. However, it is largely converted to inactive metabolites, and only about one sixth of the dose administered is available in active form.
Testosterone can be administered parenterally, but it has a more prolonged absorption time and greater activity in the propionate, enanthate, undecanoate, or cypionate ester forms. These derivatives are hydrolyzed to release free testosterone at the site of injection. Testosterone derivatives alkylated at the 17 position, eg, methyltestosterone and fluoxymesterone, are active when given by mouth.
Testosterone and its derivatives have been used for their anabolic effects as well as for the treatment of testosterone deficiency. Although testosterone and other known active steroids can be isolated in pure form and measured by weight, biologic assays are still used in the investigation of new compounds. In some of these studies in animals, the anabolic effects of the compound as measured by trophic effects on muscles or the reduction of nitrogen excretion may be dissociated from the other androgenic effects. This has led to the marketing of compounds claimed to have anabolic activity associated with only weak androgenic effects. Unfortunately, this dissociation is less
marked in humans than in the animals used for testing, and all are potent androgens. Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men. Even in the presence of pituitary deficiency, androgens are used rather than gonadotropin except when normal spermatogenesis is to be achieved. In patients with hypopituitarism, androgens are not added to the treatment regimen until puberty, at which time they are instituted in gradually increasing doses to achieve the growth spurt and the development of secondary sex characteristics. In these patients, therapy should be started with long-acting agents
such as testosterone enanthate in doses of 50 mg intramuscularly, initially every 4, then every 3, and finally every 2 weeks, with each change taking place at 3-month intervals. The dose is then doubled to 100 mg every 2 weeks until maturation is complete. Finally, it is changed to the adult replacement dose of 200 mg at 2-week intervals. Testosterone propionate, though potent, has a short duration of action and is not practical for long-term use. Testosterone undecanoate can be given orally, administering large amounts of the steroid twice daily (eg, 40 mg/d); however, this is not recommended because oral testosterone administration has been associated with liver tumors.
Testosterone can also be administered transdermally; skin patches or gels are available for scrotal or other skin area application. Two applications daily are usually required for replacement therapy.
Implanted pellets and other longer-acting preparations are under study. The development of polycythemia or hypertension may require some reduction in dose.
Anabolic Steroid and Androgen Abuse in Sports
The use of anabolic steroids by athletes has received worldwide attention. Many athletes and their coaches believe that anabolic steroids—in doses 10–200 times larger than the daily normal production—increase strength and aggressiveness, thereby improving competitive performance.
Although such effects have been demonstrated in women, many studies have failed to unequivocally demonstrate them in men. Placebo effects and the potential impact of minimal changes in championship competitions make evaluation of these studies very difficult. However, the adverse effects of these drugs clearly make their use inadvisable.
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), whose metabolic function remains undefined; 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”.
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. In the
Type 2 Diabetes Mellitus
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 high-density lipoprotein (HDL) levels.
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 have a slowly progressing type 1, and ultimately will require full insulin replacement. Although persons with type 2 diabetes ordinarily will 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 “non-ketotic 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.
Type 3 Diabetes Mellitus
The type 3 designation refers to multiple other specific causes of an elevated blood glucose: nonpancreatic diseases, drug therapy, etc.
Type 4 Diabetes Mellitus
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
The Insulin Receptor
Once insulin has entered the circulation, 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 subunit, which is entirely extracellular and constitutes the recognition site, and a subunit that spans the membrane (Figure 41–3). The subunit contains a tyrosine kinase. The binding of an insulin molecule to the subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic subunits into closer proximity thereby facilitating phosphorylation of tyrosine residues and tyrosine kinase activity.
Characteristics of Available Insulin Preparations
Commercial insulin preparations differ in a number of ways, including differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action. In 2003, seventeen insulin formulations were available in the
Principal Types and Duration of Action of Insulin Preparations
Four principal types of 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. 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. All other commercial insulins have been modified to provide prolonged action and are, with the exception of insulin glargine, dispensed as turbid suspensions at neutral pH with either protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins). Insulin glargine is the only soluble long-acting insulin. The goal of subcutaneous insulin therapy is to replace the normal basal (overnight, fasting, and between meal) as well as prandial (mealtime) insulin. Current regimens generally use intermediate- or long-acting insulins to provide basal or background coverage, and rapid-acting or short-acting insulin to meet the mealtime requirements. The latter insulins are given as supplemental doses to correct high blood sugars. 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 or intermediate-acting insulins with multiple boluses of rapid-acting or short-acting insulin. Conventional therapy presently consists of split-dose injections of mixtures of rapid- or short-acting and intermediate-acting insulins.
Rapid-Acting Insulin
Two rapid-acting insulin analogs are commercially available: insulin lispro and insulin aspart.
Short-Acting Insulin
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
Intermediate-Acting and Long-Acting Insulins
Lente Insulin
Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc ions in acetate buffer that has a relatively rapid onset of action) with 70% ultralente insulin (a poorly soluble crystal of zinc insulin that has a delayed onset and prolonged duration of action). These two components provide a combination of relatively rapid absorption with sustained long action, making lente insulin a useful therapeutic agent. As with regular insulin, the time of onset, time to peak, and duration of action are dose-dependent.
NPH (Neutral Protamine Hagedorn, or Isophane) Insulin NPH insulin is an intermediate-acting insulin wherein absorption and the onset of action is 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.
Ultralente Insulin
There has recently been a resurgence in the use of ultralente insulin, in combination with multiple injections of rapid-acting insulin, as a means of attempting optimal control in patients with type 1 diabetes. Human insulin (Humulin U [Lilly]) is the only ultralente insulin available in the
Mixtures of Insulins
Since intermediate-acting insulins require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of lispro, aspart, or regular insulin before meals.
For convenience, these are often mixed together in the same syringe before injection. When regular insulin is used, NPH is preferred to lente insulin as the intermediate-acting component in these mixtures because increased proportions of lente to regular insulin may retard the rapid action of admixed regular insulin, particularly if not injected immediately after mixing. This is due to precipitation of the regular insulin by excess zinc. Premixed formulations of 70%/30% NPH and regular and 50%/50% NPH and regular are available in the
Species of Insulin
Beef and Pork Insulins
Historically, commercial insulin in the
Human insulin, which is now less expensive than monospecies pork insulin and is also less immunogenic, has supplanted purified pork insulins.
Human Insulins
Mass production of human insulin by recombinant DNA techniques is now carried out by inserting the human proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the human insulin molecule.
Human insulin from E coli is available for clinical use as Humulin (Lilly) and dispensed as either regular, NPH, lente, or ultralente Humulin. Human insulin prepared biosynthetically in yeast is marketed by Novo Nordisk as human insulin injection in regular, lente, and NPH forms: Novolin R, Monotard Human Insulin (Novolin L), and Novolin N. The same company also produces a human insulin marketed as Velosulin (regular) that contains a phosphate buffer. This reduces aggregation of regular insulin molecules when used in infusion pumps. However, because of the tendency of phosphate to precipitate zinc ions, Velosulin should not be mixed with any of the lente insulins.
Human insulins appear to be as effective as—and considerably less immunogenic in diabetic patients than—beef-pork insulin mixtures and slightly less immunogenic than pork insulin.
Complications of Insulin Therapy
Hypoglycemia
Mechanisms and Diagnosis
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 frequent 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 develop—confusion, weakness, bizarre behavior, coma, seizures—at 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.
Treatment of Hypoglycemia
All of 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, orange juice, 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 will usually restore 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.
Insulin Allergy
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 highly purified and human insulins have markedly reduced the incidence of insulin allergy, especially local reactions.
Immune Insulin Resistance
A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligable extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies will lead to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus.
Lipodystrophy at Injection Sites
Injection of older 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 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, even with the purified insulins, 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
Four categories of oral antidiabetic agents are now available in the
The thiazolidinediones, under development since the early 1980s, are very effective agents that reduce insulin resistance. -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
Mechanism of Action
The major action of sulfonylureas is to increase insulin release from the pancreas
Two additional mechanisms of action have been proposed—a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissues. The latter is of unknown clinical significance.
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 use in 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 toproducts 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 in excess of 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 is required, the dose should be divided and given twice daily. Dosages larger than 1000 mg daily do not further improve the degree of blood glucose control.
Second-Generation Sulfonylureas
The second-generation sulfonylureas are more frequently prescribed in the
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.
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, since 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 longeracting glyburide without showing any demonstrable therapeutic advantages over the latter (which can be obtained as a generic drug).
Because of its shorter half-life, 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 therefore 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 since the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site. Unlike the sulfonylureas, they have no direct effect on insulin exocytosis.
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.
Biguanides
The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the
Mechanisms of Action
A full explanation of the biguanides’ mechanism of action remains elusive. Their blood glucoselowering action does not depend on the presence of 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) direct stimulation of glycolysis in tissues, with increased glucose removal from blood; (2) reduced hepatic and renal gluconeogenesis; (3) slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes; and (4) reduction of plasma glucagon levels.
Toxicities
The most frequent 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
Thiazolidinediones (Tzds) act to decrease insulin resistance. Their primary action is the nuclear regulation of genes involved in glucose and lipid metabolism and adipocyte differentiation. Tzds are ligands of peroxisome proliferator-activated receptor-gamma (PPAR- ), part of the steroid and thyroid superfamily of nuclear receptors. These PPAR receptors are found in muscle, fat, and liver.
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 may have PPAR- as well as PPAR- 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 estrogencontaining 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. 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 or sulfonylurea. 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) .
This digestion is facilitated by enteric enzymes, including pancreatic -amylase, and –glucosidases that are attached to the brush border of the intestinal cells. Acarbose and miglitol are competitive inhibitors of the intestinal -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 -glucosidases: sucrase, maltase, glycoamylase, dextranase. Miglitol alone has effects on isomaltase and on -glucosidases, which split -linked sugars such as lactose. Acarbose alone has a small effect on -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 use in individuals with type 2 diabetes as monotherapy and in combination with sulfonylureas, where the glycemic effect is additive. Both acarbose and miglitol are taken in doses of 25–100 mg just prior to ingesting the first portion of each meal; therapy should be initiated with the lowest dose and slowly titrated upward.
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 -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 cases of severe insulin resistance may benefit from the addition of one of the biguanides, thiazolidinediones, or – glucosidase inhibitors. In some cases, multiple oral agents have been required together with insulin.
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