Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 37–3 Controlled ovarian stimulation in preparation for an assisted reproductive technology such as in vitro fertilization. Follicular phase: Follicle development is stimulated with gonadotropin injections that begin about 2 days after menses begin. When the follicles are ready, as assessed by ultrasound measurement of follicle size, final oocyte maturation is induced by an injection of hCG. Luteal phase: Shortly thereafter oocytes are retrieved and fertilized in vitro. The recipient’s luteal phase is supported with injections of progesterone. To prevent a premature luteinizing-hormone surge, endogenous LH secretion is inhibited with either a GnRH agonist or a GnRH antagonist. In most protocols, the GnRH agonist is started midway through the preceding luteal cycle.


Pharmacology_Katzung

Pharmacology_Katzung. development. When exogenous gonadotropins are used to stimulate follicle development, there is risk of a premature endogenous surge in LH owing to the rapidly increasing serum estradiol levels. To prevent this, gonadotropins are almost always administered in conjunction with a drug that blocks the effects of endogenous GnRH—either continuous administration of a GnRH agonist, which downregulates GnRH receptors, or a GnRH receptor antagonist (see below and Figure 37–3).


Pharmacology_Katzung

Pharmacology_Katzung. When appropriate follicular maturation has occurred, the gonadotropin and the GnRH agonist or GnRH antagonist injections are discontinued and hCG (3300–10,000 IU) is administered subcutaneously to induce final follicular maturation and, in ovulation induction protocols, ovulation. The hCG administration is followed by timed intercourse or intrauterine insemination in ovulation induction and by oocyte retrieval in assisted reproductive technology procedures. Because use of GnRH agonists or antagonists during the follicular phase of ovulation induction suppresses endogenous LH production, it is important to provide exogenous hormonal support of the luteal phase. In clinical trials, exogenous progesterone, hCG, or a combination of the two have been effective at providing adequate luteal support. However, progesterone is preferred for luteal support because hCG carries a higher risk of OHSS in patients with high follicular response to gonadotropins. B. Male Infertility


Pharmacology_Katzung

Pharmacology_Katzung. Most of the signs and symptoms of hypogonadism in males (eg, delayed puberty, retention of prepubertal secondary sex characteristics after puberty) can be adequately treated with exogenous androgen; however, treatment of infertility in hypogonadal men requires the activity of both LH and FSH. For many years, conventional therapy has consisted of initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week. After the initial phase, hMG is injected at a dose of 75–150 units three times per week. In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate in up to 90% of patients, but often not at normal levels. Even if pregnancy does not occur spontaneously, the number of sperm is often sufficient that pregnancy can be achieved by insemination with the patient’s semen (intrauterine insemination) or with the help of an assisted reproductive technique such as in vitro fertilization with or


Pharmacology_Katzung

Pharmacology_Katzung. that pregnancy can be achieved by insemination with the patient’s semen (intrauterine insemination) or with the help of an assisted reproductive technique such as in vitro fertilization with or without intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian stimulation of a female partner. With the advent of ICSI, the minimum threshold of spermatogenesis required for pregnancy is greatly lowered.


Pharmacology_Katzung

Pharmacology_Katzung. C. Outdated Uses Chorionic gonadotropin is approved for the treatment of prepubertal cryptorchidism. Prepubertal boys were treated with intramuscular injections of hCG for 2–6 weeks. However, this clinical use is no longer supported because the long-term efficacy of hormonal treatment of cryptorchidism (~20%) is much lower than the long-term efficacy of surgical treatment (>95%), and because of concerns that early childhood treatment with hCG treatment has a negative impact on germ cells in addition to increasing the risk of precocious puberty.


Pharmacology_Katzung

Pharmacology_Katzung. In the United States, chorionic gonadotropin has a black-box warning against its use for weight loss. The use of hCG plus severe calorie restriction for weight loss was popularized by a publication in the 1950s claiming that the hCG selectively mobilizes body fat stores. This practice continues today, despite a preponderance of subsequent scientific evidence from placebo-controlled trials that hCG does not provide any weight loss benefit beyond the weight loss associated with severe calorie restriction alone.


Pharmacology_Katzung

Pharmacology_Katzung. In women treated with gonadotropins and hCG, the two most serious complications are OHSS and multiple pregnancies. Stimulation of the ovary during ovulation induction often leads to uncomplicated ovarian enlargement that usually resolves spontaneously. However, OHSS may occur and can be associated with ovarian enlargement, intravascular depletion, ascites, liver dysfunction, pulmonary edema, electrolyte imbalance, and thromboembolic events. Although OHSS is often self-limited, with spontaneous resolution within a few days, severe disease may require hospitalization and intensive care. Triggering the final oocyte maturation with hCG carries the risk of inducing OHSS. GnRH agonists also induce this final oocyte maturation by promoting the release of endogenous gonadotropin stores from the hypophysis and can be used as an alternative to hCG. Use of the GnRH agonist trigger dramatically reduces the risk of OHSS, owing to the short half-life of the GnRH agonist–induced endogenous LH surge.


Pharmacology_Katzung

Pharmacology_Katzung. The probability of multiple pregnancies is greatly increased when ovulation induction and assisted reproductive technologies are used. In ovulation induction, the risk of a multiple pregnancy is estimated to be 5–10%, whereas the percentage of multiple pregnancies in the general population is closer to 1%. Multiple pregnancies carry an increased risk of complications, such as gestational diabetes, preeclampsia, and preterm labor. For in vitro fertilization procedures, the risk of a multiple pregnancy is determined primarily by the number of embryos transferred to the recipient. A strong trend in recent years has been to transfer single embryos. Other reported adverse effects of gonadotropin treatment are headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG. In men treated with gonadotropins, the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotrophs. Pulsatile GnRH secretion is required to stimulate the gonadotrophs to produce and release LH and FSH. Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadotropic hypogonadism. GnRH agonists are used to induce gonadal suppression in men with prostate cancer or children with central precocious puberty. They are also used in women who are undergoing assisted reproductive technology procedures or who have a gynecologic problem that is benefited by ovarian suppression. A. Structure


Pharmacology_Katzung

Pharmacology_Katzung. A. Structure GnRH is a decapeptide found in all mammals. Gonadorelin is an acetate salt of synthetic human GnRH. Substitution of amino acids at the 6 position or replacement of the C-terminal glycine-amide produces synthetic agonists. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin. Such analogs of GnRH include goserelin, buserelin, histrelin, leuprolide, nafarelin, and triptorelin. B. Pharmacokinetics


Pharmacology_Katzung

Pharmacology_Katzung. B. Pharmacokinetics Gonadorelin can be administered intravenously or subcutaneously. Other GnRH agonists can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours. The duration of clinical uses of GnRH agonists varies from a few days for controlled ovarian stimulation to a number of years for treatment of metastatic prostate cancer. Therefore, preparations have been developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms).


Pharmacology_Katzung

Pharmacology_Katzung. The physiologic actions of GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty. This is not surprising in view of the complex role that GnRH plays in normal reproduction, particularly in female reproduction. Pulsatile GnRH release occurs and is responsible for stimulating LH and FSH production during the fetal and neonatal period. Subsequently, from the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary simultaneously exhibits very low sensitivity to GnRH. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitivity to GnRH increases, which is due in part to the effect of increasing concentrations of gonadal steroids. In females, it usually takes several months to a year after the onset of puberty for the hypothalamic-pituitary system to produce an LH surge and ovulation. By the end of puberty, the system


Pharmacology_Katzung

Pharmacology_Katzung. In females, it usually takes several months to a year after the onset of puberty for the hypothalamic-pituitary system to produce an LH surge and ovulation. By the end of puberty, the system is well established so that menstrual cycles proceed at relatively constant intervals. The amplitude and frequency of GnRH pulses vary in a regular pattern through the menstrual cycle with the highest amplitudes occurring during the luteal phase and the highest frequency occurring late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin, inhibin, and follistatin have complex modulatory effects on the gonadotropin response to GnRH.


Pharmacology_Katzung

Pharmacology_Katzung. In the pharmacologic use of GnRH and its analogs, pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion. Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare. After this period, the continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids (ie, hypogonadotropic hypogonadal state). The inhibitory action is due to a combination of receptor downregulation and changes in the signaling pathways activated by GnRH. The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release. A. Stimulation 1.


Pharmacology_Katzung

Pharmacology_Katzung. The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release. A. Stimulation 1. Female infertility—In the current era of widespread availability of gonadotropins and assisted reproductive technology, the use of pulsatile GnRH administration to treat infertility is uncommon. Although pulsatile GnRH is less likely than gonadotropins to cause multiple pregnancies and OHSS, the inconvenience and cost associated with continuous use of an intravenous pump and difficulties obtaining native GnRH (gonadorelin) are barriers to pulsatile GnRH. When this approach is used, a portable battery-powered programmable pump and intravenous tubing deliver pulses of gonadorelin every 90 minutes.


Pharmacology_Katzung

Pharmacology_Katzung. Gonadorelin or a GnRH agonist analog can be used to initiate an LH surge and ovulation in women with infertility who are undergoing ovulation induction with gonadotropins. Traditionally, hCG has been used to initiate ovulation in this situation. However, there is some evidence that gonadorelin or a GnRH agonist is less likely than hCG to cause OHSS. 2. Male infertility—It is possible to use pulsatile gonadorelin for infertility in men with hypothalamic hypogonadotropic hypogonadism. A portable pump infuses gonadorelin intravenously every 90 minutes. Serum testosterone levels and semen analyses must be done regularly. At least 3–6 months of pulsatile infusions are required before significant numbers of sperm are seen. As described above, treatment of hypogonadotropic hypogonadism is more commonly done with hCG and hMG or their recombinant equivalents. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Diagnosis of LH responsiveness—GnRH may be useful in determining whether delayed puberty in a hypogonadotropic adolescent is due to constitutional delay or to hypogonadotropic hypogonadism. The LH response (but not the FSH response) to a single dose of GnRH may distinguish between these two conditions; however, there can be significant individual overlap in the LH response between the two groups. Serum LH levels are measured before and at several times after an intravenous or subcutaneous bolus of GnRH. An increase in serum LH with a peak that is greater than 5–8 mIU/mL suggests early pubertal status. An impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease, but does not rule out constitutional delay of puberty. B. Suppression of Gonadotropin Production 1.


Pharmacology_Katzung

Pharmacology_Katzung. B. Suppression of Gonadotropin Production 1. Controlled ovarian stimulation—In the controlled ovarian stimulation that provides multiple mature oocytes for assisted reproductive technologies such as in vitro fertilization, it is critical to suppress an endogenous LH surge that could prematurely trigger ovulation. This suppression is most commonly achieved by daily subcutaneous injections of leuprolide or daily nasal applications of nafarelin. For leuprolide, treatment is commonly initiated with 1 mg daily for about 10 days until menstrual bleeding occurs. At that point, the dose is reduced to 0.5 mg daily until hCG is administered (Figure 37–3). For nafarelin, the beginning dosage is generally 400 mcg twice a day, which is decreased to 200 mcg when menstrual bleeding occurs. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Endometriosis—Endometriosis is defined as the presence of estrogen-sensitive endometrium outside the uterus that results in cyclical abdominal pain in premenopausal women. The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the concentrations of estrogen and progesterone that are a normal part of the menstrual cycle. The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and progesterone concentrations and prevents cyclical changes. The preferred duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone mineral density. When relief of pain from treatment with a GnRH agonist supports continued therapy for more than 6 months, the addition of add-back therapy (estrogen or progestins) reduces or eliminates GnRH agonistinduced bone mineral loss and provides symptomatic relief without reducing the efficacy of pain relief.


Pharmacology_Katzung

Pharmacology_Katzung. the addition of add-back therapy (estrogen or progestins) reduces or eliminates GnRH agonistinduced bone mineral loss and provides symptomatic relief without reducing the efficacy of pain relief. Leuprolide and goserelin are administered as depot preparations that provide 1 or 3 months of continuous GnRH agonist activity. Nafarelin is administered twice daily as a nasal spray at a dose of 0.2 mg per spray.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Uterine leiomyomata (uterine fibroids)—Uterine leiomyomata are benign, estrogen-sensitive, smooth muscle tumors in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. The effects of GnRH agonists are temporary, with gradual recurrent growth of leiomyomas to previous size within several months after cessation of treatment. GnRH agonists have been used widely for preoperative treatment of uterine leiomyomas, both for myomectomy and hysterectomy. GnRH agonists have been shown to improve hematologic parameters, shorten hospital stay, and decrease blood loss, operating time, and postoperative pain when given for 3 months preoperatively. 4.


Pharmacology_Katzung

Pharmacology_Katzung. Prostate cancer—Androgen deprivation therapy is the primary medical therapy for prostate cancer. Combined antiandrogen therapy with continuous GnRH agonist and an androgen receptor antagonist is as effective as surgical castration in reducing serum testosterone concentrations and effects. Leuprolide, goserelin, histrelin, buserelin, and triptorelin are approved for this indication. The preferred formulation is one of the long-acting depot forms that provide 1, 3, 4, 6, or 12 months of active drug therapy. During the first 7–10 days of GnRH analog therapy, serum testosterone levels increase because of the agonist action of the drug; this can precipitate pain in patients with bone metastases, and tumor growth and neurologic symptoms in patients with vertebral metastases. It can also temporarily worsen symptoms of urinary obstruction. Such tumor flares can usually be avoided with the concomitant administration of an androgen receptor antagonist (flutamide, bicalutamide, or nilutamide)


Pharmacology_Katzung

Pharmacology_Katzung. worsen symptoms of urinary obstruction. Such tumor flares can usually be avoided with the concomitant administration of an androgen receptor antagonist (flutamide, bicalutamide, or nilutamide) (see Chapter 40). Within about 2 weeks, serum testosterone levels fall to the hypogonadal range.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Central precocious puberty—Continuous administration of a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 7–8 years in girls or 9 years in boys). Before embarking on treatment with a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal gonadotropin response to GnRH or a “test dose” of a GnRH analog. Treatment is typically indicated in a child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age) or in whom the early development of pubertal secondary sexual characteristics or menses causes significant emotional distress. While central precocious puberty is most often idiopathic, it is important to rule out central nervous system pathology with MRI imaging of the hypothalamic-pituitary area.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment is most commonly carried out with either every month or every three months intramuscular depot injection of leuprolide acetate or with a once-yearly implant of histrelin acetate. Daily subcutaneous regimens and multiple daily nasal spray regimens of GnRH agonists also are available but are not recommended due to poor adherence. Treatment with a GnRH agonist is generally continued long enough to optimize adult height and allow pubertal development that is concurrent with peers. Typically treatment is continued until age 11 in females and age 12 in males. 6. Other—The gonadal suppression provided by continuous GnRH agonist treatment is used in the management of advanced breast and ovarian cancer. In addition, recently published clinical practice guidelines recommend the use of continuous GnRH agonist administration in early pubertal transgender adolescents to block endogenous puberty prior to subsequent treatment with cross-gender gonadal hormones.


Pharmacology_Katzung

Pharmacology_Katzung. Gonadorelin can cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitivity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness have been reported following administration of GnRH to a patient with a gonadotropinsecreting pituitary tumor.


Pharmacology_Katzung

Pharmacology_Katzung. Continuous treatment of women with a GnRH analog (leuprolide, nafarelin, goserelin) causes the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first month of therapy due to its flare effect on gonadotropin secretion and generally resolve after an additional 6 weeks. Reduced bone mineral density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Depending on the condition being treated with the GnRH agonist, it may be possible to ameliorate the signs and symptoms of the hypoestrogenic state without losing clinical efficacy by adding back a small dose of a progestin alone or in combination with a low dose of an estrogen. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.


Pharmacology_Katzung

Pharmacology_Katzung. In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, and injection site reactions. GnRH analog treatment of children is generally well tolerated. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Nafarelin nasal spray may cause or aggravate sinusitis. Four synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner. Ganirelix and cetrorelix are approved for use in controlled ovarian stimulation procedures, whereas degarelix and abarelix are approved for men with advanced prostate cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Ganirelix and cetrorelix are absorbed rapidly after subcutaneous injection. Administration of 0.25 mg daily maintains GnRH antagonism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours. Degarelix therapy is initiated with 240 mg administered as two subcutaneous injections. Maintenance dosing is with an 80-mg subcutaneous injection every 28 days. A. Suppression of Gonadotropin Production


Pharmacology_Katzung

Pharmacology_Katzung. GnRH antagonists are approved for preventing the LH surge during controlled ovarian stimulation. They offer several advantages over continuous treatment with a GnRH agonist. Because GnRH antagonists produce an immediate antagonist effect, their use can be delayed until day 6–8 of the in vitro fertilization cycle (Figure 37–3), and thus the duration of administration is shorter. They also appear to have a less suppressive effect on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. On the other hand, because their antagonist effects reverse more quickly after their discontinuation, adherence to the treatment regimen is critical. The antagonists produce a more complete suppression of LH secretion than agonists. The suppression of LH may impair follicular development when recombinant or the purified form of FSH is used during an in vitro fertilization cycle. Clinical trials have shown a slightly lower rate of


Pharmacology_Katzung

Pharmacology_Katzung. suppression of LH may impair follicular development when recombinant or the purified form of FSH is used during an in vitro fertilization cycle. Clinical trials have shown a slightly lower rate of pregnancy in in vitro fertilization cycles that used GnRH antagonist treatment compared with cycles that used GnRH agonist treatment.


Pharmacology_Katzung

Pharmacology_Katzung. B. Advanced Prostate Cancer Degarelix and abarelix are approved for the treatment of symptomatic advanced prostate cancer. These GnRH antagonists reduce concentrations of gonadotropins and androgens more rapidly than GnRH agonists and avoid the testosterone surge seen with GnRH agonist therapy. When used for controlled ovarian stimulation, ganirelix and cetrorelix are well tolerated. The most common adverse effects are nausea and headache. During the treatment of men with prostate cancer, degarelix caused injection-site reactions and increases in liver enzymes. Like continuous treatment with a GnRH agonist, degarelix and abarelix lead to signs and symptoms of androgen deprivation, including hot flushes and weight gain.


Pharmacology_Katzung

Pharmacology_Katzung. Prolactin is a 198-amino-acid peptide hormone produced in the anterior pituitary. Its structure resembles that of GH. Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate. No preparation of prolactin is available for use in prolactin-deficient patients.


Pharmacology_Katzung

Pharmacology_Katzung. In pituitary stalk section from surgery or head trauma, stalk compression due to a sellar mass, or rare cases of hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of dopamine (prolactin-inhibiting hormone) to the pituitary. Much more commonly, prolactin is elevated as a result of prolactin-secreting adenomas. In addition, a number of drugs elevate prolactin levels. These include antipsychotic and gastrointestinal motility drugs that are known dopamine receptor antagonists, estrogens, and opiates. Hyperprolactinemia causes hypogonadism, which manifests with infertility, oligomenorrhea or amenorrhea, and galactorrhea in premenopausal women, and with loss of libido, erectile dysfunction, and infertility in men. In the case of large tumors (macroadenomas), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia


Pharmacology_Katzung

Pharmacology_Katzung. it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release.


Pharmacology_Katzung

Pharmacology_Katzung. Adenomas that secrete excess prolactin usually retain the sensitivity to inhibition by dopamine exhibited by normal pituitary lactotrophs, prolactin secreting cells. Bromocriptine and cabergoline are ergot derivatives (see Chapters 16 and 28) with a high affinity for dopamine D2 receptors. Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D2 receptor affinity. The chemical structure and pharmacokinetic features of ergot alkaloids are presented in Chapter 16.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia and GH release is reduced in patients with acromegaly, although not as effectively. Bromocriptine has also been used in Parkinson’s disease to improve motor function and reduce levodopa requirements (see Chapter 28). Newer, nonergot D2 agonists used in Parkinson’s disease (pramipexole and ropinirole; see Chapter 28) have been reported to interfere with lactation, but they are not approved for use in hyperprolactinemia.


Pharmacology_Katzung

Pharmacology_Katzung. All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. They can also be absorbed systemically after vaginal insertion of tablets to avoid nausea due to oral administration. Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action. Quinagolide has a half-life of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. After vaginal administration, serum levels peak more slowly. A. Hyperprolactinemia


Pharmacology_Katzung

Pharmacology_Katzung. A. Hyperprolactinemia A dopamine agonist is the standard first-line treatment for hyperprolactinemia. These drugs shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas (Figure 37–4). Cabergoline is initiated at 0.25 mg twice weekly orally or vaginally. It can be increased gradually, according to serum prolactin determinations, up to a maximum of 1 mg twice weekly. Bromocriptine is generally taken daily after the evening meal at the initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients require 2.5–7.5 mg daily. Long-acting oral bromocriptine formulations (Parlodel SRO) and intramuscular formulations (Parlodel LAR) are available outside the United States. B. Physiologic Lactation


Pharmacology_Katzung

Pharmacology_Katzung. B. Physiologic Lactation Dopamine agonists were used in the past to prevent breast engorgement when breast-feeding was not desired. Their use for this purpose has been discouraged because of toxicity (see Toxicity & Contraindications). C. Acromegaly A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used


Pharmacology_Katzung

Pharmacology_Katzung. A Dopamine agonist therapy during the early weeks of pregnancy 0 2 4 6 8 1012141618202224 Weeks of cabergoline therapy has not been associated with an increased risk of spontaneous abortion or congenital malformations. Although there has been a longer experience with the safety of bromocriptine during early pregnancy, there is growing evidence that cabergoline is also safe in women with macroadenomas who must continue a dopamine agonist during pregnancy. In patients with small pituitary adenomas, dopamine agonist therapy is discontinued upon conception because growth of microadenomas during pregnancy is rare. Patients with very large adenomas require vigilance for tumor progression and often require a dopamine agonist throughout pregnancy. There have been rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation.


Pharmacology_Katzung

Pharmacology_Katzung. The two posterior pituitary hormones—vasopressin and oxytocin— are synthesized in neuronal cell bodies in the hypothalamus and transported via their axons to the posterior pituitary, where they are stored and then released into the circulation. Each has limited but % of patients FIGURE 37–4 Results from a clinical trial of cabergoline in women with hyperprolactinemia and anovulation. A: The dashed line indicates the upper limit of normal serum prolactin concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 37–4 Results from a clinical trial of cabergoline in women with hyperprolactinemia and anovulation. A: The dashed line indicates the upper limit of normal serum prolactin concentrations. B: Complete success was defined as pregnancy or at least two consecutive menses with evidence of ovulation at least once. Partial success was two menstrual cycles without evidence of ovulation or just one ovulatory cycle. The most common reasons for withdrawal from the trial were nausea, headache, dizziness, abdominal pain, and fatigue. (Adapted from Webster J et al: A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904.) to treat acromegaly. The doses required are higher than those used to treat hyperprolactinemia. For example, patients with acromegaly require 20–30 mg/d of bromocriptine and seldom respond adequately to bromocriptine alone unless the pituitary tumor secretes prolactin as well as GH.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine agonists can cause nausea, headache, light-headedness, orthostatic hypotension, and fatigue. Psychiatric manifestations occasionally occur, even at lower doses, and may take months to resolve. Erythromelalgia occurs rarely. High dosages of ergot-derived preparations can cause cold-induced peripheral digital vasospasm. Pulmonary infiltrates have occurred with chronic high-dosage therapy. Cabergoline treatment at high doses for Parkinson’s disease is associated with higher risk of valvular heart disease, but probably not at the lower dose used for hyperprolactinemia. Cabergoline appears to cause nausea less often than bromocriptine. Vaginal administration can reduce nausea, but may cause local irritation. important clinical uses.


Pharmacology_Katzung

Pharmacology_Katzung. important clinical uses. Oxytocin is a peptide hormone secreted by the posterior pituitary. Oxytocin stimulates muscular contractions in the uterus and myoepithelial contractions in the breast. Thus, it is involved in parturition and the letdown of milk. During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. A. Structure Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide cross-link (Figure 37–5). Its amino acid sequence differs from that of vasopressin at positions 3 and 8. B. Absorption, Metabolism, and Excretion Oxytocin is administered intravenously for initiation and augmentation of labor. It also can be administered intramuscularly for control of postpartum bleeding. Oxytocin is not bound to plasma proteins and is rapidly eliminated by the kidneys and liver, with a circulating half-life of 5 minutes.


Pharmacology_Katzung

Pharmacology_Katzung. Oxytocin acts through G protein–coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates the release of FIGURE 37–5 Posterior pituitary hormones and desmopressin. (Adapted, with permission, from Ganong WF: Review of Medical Physiology, 21st ed. McGraw-Hill, 2003. Copyright © The McGraw-Hill Companies, Inc.) prostaglandins and leukotrienes that augment uterine contraction. In small doses oxytocin increases both the frequency and the force of uterine contractions. At higher doses, it produces sustained contraction. Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk letdown. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.


Pharmacology_Katzung

Pharmacology_Katzung. Oxytocin is used to induce labor for conditions requiring expedited vaginal delivery such as uncontrolled maternal diabetes, worsening preeclampsia, intrauterine infection, or ruptured membranes after 34 gestational weeks. It is also used to augment protracted labor. Oxytocin can also be used in the immediate postpartum period to stop vaginal bleeding due to uterine atony. Before delivery, oxytocin is usually administered intravenously via an infusion pump with appropriate fetal and maternal monitoring. For induction of labor, an initial infusion rate of 0.5–2 mU/min is increased every 30–60 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units are added to 1 L of 5% dextrose, and the infusion rate is titrated to control uterine atony. Alternatively, 10 units of oxytocin can be administered by intramuscular injection.


Pharmacology_Katzung

Pharmacology_Katzung. During the antepartum period, oxytocin induces uterine contractions that transiently reduce placental blood flow to the fetus. The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve. An abnormal response, seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery.


Pharmacology_Katzung

Pharmacology_Katzung. When oxytocin is used judiciously, serious toxicity is rare. The toxicity that does occur is due either to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors. Excessive stimulation of uterine contractions before delivery can cause fetal distress, placental abruption, or uterine rupture. These complications can be detected early by means of standard fetal monitoring. High concentrations of oxytocin with activation of vasopressin receptors can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death. Bolus injections of oxytocin can cause hypotension. To avoid hypotension, oxytocin is administered intravenously as dilute solutions at a controlled rate. Contraindications to oxytocin include fetal distress, fetal malpresentation, placental abruption, and other predispositions for uterine rupture, including previous extensive uterine surgery.


Pharmacology_Katzung

Pharmacology_Katzung. Contraindications to oxytocin include fetal distress, fetal malpresentation, placental abruption, and other predispositions for uterine rupture, including previous extensive uterine surgery. Atosiban is an antagonist of the oxytocin receptor that has been approved outside the United States as a treatment (tocolysis) for preterm labor. Atosiban is a modified form of oxytocin that is administered by intravenous infusion for 2–48 hours. In a small number of published clinical trials, atosiban appears to be as effective as β-adrenoceptor-agonist tocolytics and to produce fewer adverse effects. In 1998, however, the FDA decided not to approve atosiban based on concerns about efficacy and safety. VASOPRESSIN (ANTIDIURETIC HORMONE, ADH)


Pharmacology_Katzung

Pharmacology_Katzung. VASOPRESSIN (ANTIDIURETIC HORMONE, ADH) Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. It possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus (see also Chapters 15 and 17). A. Structure Vasopressin is a nonapeptide with a 6-amino-acid ring and a 3-amino-acid side chain. The residue at position 8 is arginine in humans and in most other mammals except pigs and related species, whose vasopressin contains lysine at position 8 (Figure 37–5). Desmopressin acetate (DDAVP, 1-desamino-8-d-arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal pressor activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Desmopressin is modified at position 1 and contains a d-amino acid at position 8. Like vasopressin and oxytocin, desmopressin has a disulfide linkage between positions 1 and 6.


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Pharmacology_Katzung. B. Absorption, Metabolism, and Excretion Vasopressin is administered by intravenous or intramuscular injection. The half-life of circulating vasopressin is approximately 15 minutes, with renal and hepatic metabolism via reduction of the disulfide bond and peptide cleavage. Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally. The half-life of circulating desmopressin is 1.5–2.5 hours. Nasal desmopressin is available as a unit dose spray that delivers 10 mcg per spray; it is also available with a calibrated nasal tube that can be used to deliver a more precise dose. Nasal bioavailability of desmopressin is 3–4%, whereas oral bioavailability is less than 1%.


Pharmacology_Katzung

Pharmacology_Katzung. Vasopressin activates two subtypes of G protein–coupled receptors (see Chapter 17). V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction via the coupling protein Gq and phospholipase C. V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules via Gs and adenylyl cyclase. Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor, which increases platelet aggregation.


Pharmacology_Katzung

Pharmacology_Katzung. Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus. The dosage of desmopressin is 10–40 mcg (0.1–0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every 12–24 hours as needed for polyuria, polydipsia, or hypernatremia. Bedtime desmopressin therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing nocturnal urine production. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding. High-dose vasopressin as a 40-unit intravenous bolus injection may be given to replace epinephrine in the Advanced Cardiovascular Life Support (ACLS) resuscitation protocol for pulseless arrest. Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand disease (see Chapter 34).


Pharmacology_Katzung

Pharmacology_Katzung. Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand disease (see Chapter 34). Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Overdosage can result in hyponatremia and seizures. Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease. Nasal insufflation of desmopressin may be less effective when nasal congestion is present.


Pharmacology_Katzung

Pharmacology_Katzung. A group of nonpeptide antagonists of vasopressin receptors has been investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both V1a and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for V1 receptors. In several clinical trials, both agents promoted the excretion of free water, relieved symptoms, and reduced objective signs of hyponatremia and heart failure. Conivaptan, administered intravenously, and tolvaptan, given orally, are approved by the FDA for treatment of hyponatremia. Tolvaptan treatment duration is limited to 30 days due to risk of hepatotoxicity, including life-threatening liver failure. Several other nonselective nonpeptide vasopressin receptor antagonists are being investigated for these conditions (see Chapter 15). Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions


Pharmacology_Katzung

Pharmacology_Katzung. Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions Inhibits production of GH receptors and, to a lesser extent, of TSH, glucagon, insulin, and gastrin Acromegaly and several other hormone-secreting tumors • acute control of bleeding from esophageal varices SC or IV injection • long-acting formulation injected IM monthly • Toxicity: Gastrointestinal disturbances, gallstones, bradycardia, cardiac conduction problems • Lanreotide: Similar to octreotide; available as a long-acting formulation for acromegaly GONADOTROPINS: FOLLICLE-STIMULATING HORMONE (FSH) ANALOGS •FollitropinalfaActivatesFSHreceptorsMimicseffectsofendogenousFSHControlledovarianstimulation•infertilityduetohypogonadotropichypogonadisminmenSCinjection•Toxicity: Ovarianhyperstimulationsyndromeandmultiplepregnanciesinwomen•gynecomastiainmen•headache,depression,edemainbothsexes


Pharmacology_Katzung

Pharmacology_Katzung. Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains Urofollitropin: Human FSH purified from the urine of postmenopausal women Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity GONADOTROPINS: LUTEINIZING HORMONE (LH) ANALOGS Choriogonadotropin alfa: Recombinant form of hCG Lutropin: Recombinant form of human LH Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity


Pharmacology_Katzung

Pharmacology_Katzung. Choriogonadotropin alfa: Recombinant form of hCG Lutropin: Recombinant form of human LH Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS •GanirelixBlocksGnRHreceptorsReducesendogenousproductionofLHandFSHPreventionofprematureLHsurgeduringcontrolledovarianstimulationSCinjection•Toxicity: Nausea,headache • Desmopressin Relatively selective vasopressin V2 receptor agonist Acts in the kidney collecting duct cells to decrease the excretion of water • acts on extrarenal V2 receptors to increase factor VIII and von Willebrand factor Pituitary diabetes insipidus Oral, IV, SC, or intranasal • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. Oral, IV, SC, or intranasal • Toxicity: Gastrointestinal disturbances, headache, hyponatremia, allergic reactions • Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices • Conivaptan Antagonist of vasopressin V1a and V2 receptors • Tolvaptan: Similar but more selective for vasopressin V2 receptors; oral administration; treatment course limited to 30 days due to risk of hepatotoxicity 1See Tables 37–2 and 37–3 for summaries of the clinical uses of the rarely used hypothalamic and pituitary hormones not described in this table.


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Pharmacology_Katzung. GENERIC NAME AVAILABLE AS GROWTH FACTOR AGONISTS & ANTAGONISTS Lanreotide acetate Somatuline Depot Mecasermin Increlex Octreotide acetate Generic, Sandostatin, Sandostatin LAR Depot Pegvisomant Somavert Somatropin Genotropin, Humatrope, Norditropin, Nutropin, Omnitrope, Saizen, Serostim, Tev-tropin, Zorbtive GONADOTROPIN AGONISTS & ANTAGONISTS Abarelix Plenaxis* Cetrorelix acetate Cetrotide Choriogonadotropin alfa (rhCG) Ovidrel Chorionic gonadotropin (hCG) Generic, Profasi, Pregnyl Degarelix Firmagon Follitropin alfa (rFSH) Gonal-f Follitropin beta (rFSH) Follistim Ganirelix acetate Antagon Gonadorelin hydrochloride (GnRH) Factrel Goserelin acetate Zoladex Histrelin acetate Supprelin LA, Vantas Urofollitropin Bravelle*, Fertinex*PROLACTIN ANTAGONISTS (DOPAMINE AGONISTS) Cabergoline Generic, Dostinex OXYTOCIN GENERIC NAME AVAILABLE AS Leuprolide acetate Generic, Eligard, Lupron Lutropin alfa (rLH) Luveris*Menotropins (hMG) Menopur, Repronex Nafarelin acetate Synarel Triptorelin


Pharmacology_Katzung

Pharmacology_Katzung. Generic, Dostinex OXYTOCIN GENERIC NAME AVAILABLE AS Leuprolide acetate Generic, Eligard, Lupron Lutropin alfa (rLH) Luveris*Menotropins (hMG) Menopur, Repronex Nafarelin acetate Synarel Triptorelin pamoate Trelstar, Trelstar LA, Trelstar Depot Bromocriptine mesylate Generic, Parlodel, Cycloset Oxytocin Generic, Pitocin VASOPRESSIN AGONISTS AND ANTAGONISTS Conivaptan HCl Vaprisol Desmopressin acetate (DDAVP) Generic, Minirin, Stimate Tolvaptan Samsca Vasopressin Generic, Pitressin OTHER Corticorelin ovine triflutate Acthrel Corticotropin H.P. Acthar Gel Cosyntropin Generic, Cortrosyn, Cosyntropin Thyrotropin alfa Thyrogen PREP AR A TIONS A V AIL ABLE *Withdrawn from the USA.


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Pharmacology_Katzung. Abramovici A, Cantu J, Jenkins SM: Tocolytic therapy for acute preterm labor. Obstet Gynecol Clin North Am 2012;39:77. Al-Inany HG et al: Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2011;(5):CD001750. Beall SA, DeCherney A: History and challenges surrounding ovarian stimulation in the treatment of infertility. Fertil Steril 2012;97:795. Caldwell PH, Deshpande AV, Von Gontard A: Management of nocturnal enuresis. BMJ 2013;347:f6259. Carel JC et al: Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:752. Carel JC et al: Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: Preliminary report of the French SAGhE study. J Clin Endocrinol Metab 2012;97:416.


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Pharmacology_Katzung. Collett-Solberg PF et al: The role of recombinant human insulin-like growth factor-I in treating children with short stature. J Clin Endocrinol Metab 2008;93:10. Dong Q, Rosenthal SM: Endocrine disorders of the hypothalamus and pituitary. In: Swaiman KF, Ashwal S, Ferriero DM (editors): Pediatric Neurology, 5th ed. Mosby, Inc. (Elsevier, Inc.), 2011. Dreicer R et al: New data, new paradigms for treating prostate cancer patients— VI: Novel hormonal therapy approaches. Urology 2011;78(5 Suppl):S494. Gabe SG et al: Obstetrics: Normal and Problem Pregnancies, 6th ed. Churchill Livingstone, 2012. Han TS, Bouloux PM: What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol 2010;72:731. Hodson EM, Willis NS, Craig JC: Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev 2012;(2):CD003264.


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Pharmacology_Katzung. Hodson EM, Willis NS, Craig JC: Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev 2012;(2):CD003264. Katznelson L et al: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly—2011 update. Endo Pract 2011;s4:1. Lanning NJ, Carter-Su C: Recent advances in growth hormone signaling. Rev Endocr Metab Disord 2006;7:225. Melmed S et al (editors): Williams Textbook of Endocrinology, 13th ed. Elsevier, 2016. Papatsonis DN et al: Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2013;(10):CD005938. Penson D et al: Effectiveness of hormonal and surgical therapies for cryptorchidism: A systematic review. Pediatrics 2013;131:e1897. Richmond E, Rogol AD: Current indications for growth hormone therapy for children and adolescents. Endocr Dev 2010;18:92.


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Pharmacology_Katzung. Richmond E, Rogol AD: Current indications for growth hormone therapy for children and adolescents. Endocr Dev 2010;18:92. Rosenfeld RG, Hwa V: The growth hormone cascade and its role in mammalian growth. Horm Res 2009;71(Suppl 2):36. Sävendahl L et al: Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: Preliminary report of 3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab 2012;97:E213. Snyder PJ: Treatment of hyperprolactinemia due to lactotroph adenoma and other causes. Available online at: www.uptodate.com. Speroff L, Fritz MA: Clinical Gynecologic Endocrinology and Infertility, 8th ed. Lippincott Williams & Wilkins, 2010. Strauss JF, Barbieri RL: Yen & Jaffe’s Reproductive Endocrinology, 6th ed. Elsevier, 2009.


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Pharmacology_Katzung. Strauss JF, Barbieri RL: Yen & Jaffe’s Reproductive Endocrinology, 6th ed. Elsevier, 2009. Surrey ES: Gonadotropin-releasing hormone agonist and add-back therapy: What do the data show? Curr Opin Obstet Gynecol 2010;22:283. Taylor BE, Buchman TG: Is there a role for growth hormone therapy in refractory critical illness? Curr Opin Crit Care Med 2008;14:438. Tena-Sempere M: Deciphering puberty: Novel partners, novel mechanisms. Eur J Endocrinol 2012;167:733. Wales PW et al: Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database Syst Rev 2010;(16):CD006321. Webster J et al: A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904. Westhoff G, Cotter AM, Tolosa JE: Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev 2013;(10):CD001808.


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Pharmacology_Katzung. Westhoff G, Cotter AM, Tolosa JE: Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev 2013;(10):CD001808. Wit JM et al: Idiopathic short stature: Definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008;18:89. Youssef MA et al: Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev 2011;(1):CD008046.


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Pharmacology_Katzung. While growth hormone (GH) may have some direct growth-promoting effects, it is thought to mediate skeletal growth principally through production of insulin-like growth factor-I (IGF-I) at the epiphyseal plate, which acts mainly in an autocrine/paracrine manner. IGF-I may also promote statural growth through endocrine mechanisms. The findings of small testes and a microphallus in this patient suggest a diagnosis of hypogonadism, likely as a consequence of gonadotropin deficiency. This patient is at risk for multiple hypothalamic/pituitary deficiencies. He may already have or may subsequently develop ACTH/ cortisol and TSH/thyroid hormone deficiencies and thus may require supplementation with hydrocortisone and levothyroxine, in addition to supplementation with GH and testosterone. He should also be evaluated for the pres-ence of central diabetes insipidus and, if present, treated with desmopressin, a V2 vasopressin receptor–selective analog. Betty J. Dong, PharmD, FASHP, FCCP, FAPHA


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Pharmacology_Katzung. JP is a 33-year-old woman who presents with complaints of fatigue requiring daytime naps, weight gain, cold intoler-ance, and muscle weakness for the last few months. These complaints are new since she used to always feel “hot,” noted difficulty sleeping, and could eat anything that she wanted without gaining weight. She also would like to become preg-nant in the near future. Because of poor medication adherence to methimazole and propranolol, she received radioactive iodine (RAI) therapy, developed hypothyroidism, and was started on levothyroxine 100 mcg daily. Other medications include calcium carbonate three times daily to “protect her bones” and omeprazole for “heartburn.” On physical exami-nation, her blood pressure is 130/89 mm Hg with a pulse of 50 bpm. Her weight is 136 lb (61.8 kg), an increase of 10 lb (4.5 kg) in the last year. Her thyroid gland is not palpable and her reflexes are delayed. Laboratory findings include a thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL


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Pharmacology_Katzung. an increase of 10 lb (4.5 kg) in the last year. Her thyroid gland is not palpable and her reflexes are delayed. Laboratory findings include a thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL (normal 0.45–4.12 μIU/mL) and a free thyroxine level of 8 pmol/L (normal 10–18 pmol/L). Evaluate the management of her past history of hyperthyroidism and assess her current thyroid status. Identify your treatment recommendations to maximize control of her current thyroid status.


Pharmacology_Katzung

Pharmacology_Katzung. 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 and is discussed in Chapter 42. The recommended daily adult iodide (I−)† intake is 150 mcg (200 mcg during pregnancy and lactation and up to 250 mcg for children). * This chapter is dedicated to Dr. Francis S. Greenspan, co-author, mentor, colleague, and friend who will be sorely missed by his many colleagues and by his patients for his kindness, generosity, and expert care as chief of the Thyroid Clinic at UCSF. †In this chapter, the term “iodine” denotes all forms of the element; the term “iodide” denotes only the ionic form, I−


Pharmacology_Katzung

Pharmacology_Katzung. †In this chapter, the term “iodine” denotes all forms of the element; the term “iodide” denotes only the ionic form, I− Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished. Biosynthesis of Thyroid Hormones


Pharmacology_Katzung

Pharmacology_Katzung. Biosynthesis of Thyroid Hormones Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that incorporate 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 (NIS). This can be inhibited by large doses of iodides as well as anions (eg, thiocyanate (SCN−), pertechnetate (TcO4−), and perchlorate (CIO4−). At the apical cell membrane a second I− transport enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the cochlea of the inner ear. If pendrin is deficient or absent (SLC26A4 mutation), a hereditary syndrome of goiter and deafness, called Pendred syndrome (PDS), ensues. At the apical – – – −I−ProteolysisI°MIT-DIT-T3-T4 Transport PeroxidaseOrganification Thyroid gland Thyroglobulin Peripheral tissues T4, T3 Blood Iodides –Iodides, thioamides SCN–, ClO4


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Pharmacology_Katzung. SCN–, ClO4 T4, T3 – Radiocontrast media, °-blockers, corticosteroids, amiodarone FIGURE 38–1 Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown. cell membrane, iodide is oxidized by thyroidal peroxidase (TPO) 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. Gene expression of TPO is stimulated by thyroid-stimulating hormone (TSH).


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Pharmacology_Katzung. 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 then 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. Eighty percent of T3 circulating in the blood is derived from peripheral metabolism of thyroxine and the rest from direct thyroid secretion (see below, Figure 38–2). Transport of Thyroid Hormones


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Pharmacology_Katzung. Transport of Thyroid Hormones Thyroxine 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 (as FT4 and FT3). Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remain normal, reflecting feedback control. Peripheral Metabolism of Thyroid Hormones


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Pharmacology_Katzung. Peripheral Metabolism of Thyroid Hormones The primary pathway for the peripheral metabolism of thyroxine is deiodination by three 5′deiodinase enzymes (D1, D2, D3). 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. The D1 enzyme is responsible for about 24% of the circulating T3 while 64% of peripheral T3 is generated by D2, which also regulates T3 levels in the brain and pituitary. D3 deiodination produces metabolically inactive 3,3′,5′-triiodothyronine (reverse T3 [rT3]), (Figure 38–2). The low serum levels of T3 and rT3 in normal individuals are due to the high metabolic clearances of these two compounds.


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Pharmacology_Katzung. Drugs such as amiodarone, iodinated contrast media, β blockers, and corticosteroids, as well as severe illness or starvation, inhibit the 5′-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. A polymorphism in the D2 gene can reduce T3 activation and impair thyroid hormone response. The pharmacokinetics of thyroid hormones are listed in Table 38–1. Evaluation of Thyroid Function The tests used to evaluate thyroid function are listed in Table 38–2. FIGURE 38–2 Peripheral metabolism of thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.) A. Thyroid-Pituitary Relationships


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Pharmacology_Katzung. A. Thyroid-Pituitary Relationships Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. 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 thyrotropin (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. T3, the more active of the two hormones, acts in a negative feedback fashion in the pituitary to block the action of TSH and in the hypothalamus to TABLE 38–1 Summary of thyroid hormone kinetics. inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. B. Autoregulation of the Thyroid Gland


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Pharmacology_Katzung. inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. B. Autoregulation of the Thyroid Gland The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block; see Figure 38–1). In certain disease states (eg, Hashimoto’s thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism. Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter). C. Abnormal Thyroid Stimulators


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Pharmacology_Katzung. C. Abnormal Thyroid Stimulators In Graves’ disease (see below), lymphocytes secrete a TSH receptor–stimulating antibody (TSH-R Ab [stim]), also known as thyroid-stimulating immunoglobulin (TSI). This immunoglobulin binds to the TSH receptor and stimulates 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] and can cause ophthalmopathy. 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. TABLE 38–2 Typical adult values for thyroid function tests. 1Results may vary with different laboratories. 2Exception is central hypothyroidism.


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Pharmacology_Katzung. TABLE 38–2 Typical adult values for thyroid function tests. 1Results may vary with different laboratories. 2Exception is central hypothyroidism. The synthetic dextro (d) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the l-isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism. Thyroxine is absorbed best in the duodenum and ileum; absorption is modified by intraluminal factors such as food, drugs, gastric acidity, and intestinal flora. Oral bioavailability of current preparations of l-thyroxine averages 70 to 80% (Table 38–1). 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.


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Pharmacology_Katzung. In patients with hyperthyroidism, the metabolic clearances of T4 and T3 are increased and the half-lives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors) increase the metabolism of both T4 and T3 (Table 38–3). Despite this change in clearance, the normal hormone concentration is maintained in the majority of euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients dependent on 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 free hormone concentration is restored. Thus, the


Pharmacology_Katzung

Pharmacology_Katzung. 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 free 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 remain normal. The reverse occurs when thyroid binding sites are decreased.


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Mechanism of Action

Pharmacology_Katzung. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. 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 the active transporters (eg, monocarboxylate transporter 8 [MCT8], MCT10, and organic anion transporting polypeptide [OATP1C1]). Transporter mutations can result in a clinical syndrome of mental retardation, myopathy, and low serum T4 levels (Allan-Herndon-Dudley syndrome). Within the cell, T4 is converted to T3 by 5′-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 thyroid receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, α and β. Mutations in both α and β genes have been associated with generalized thyroid hormone resistance. Cigarette smoking and environmental agents (eg, polychlorinated biphenyls) also may interfere with receptor action.


Pharmacology_Katzung

Pharmacology_Katzung. α and β genes have been associated with generalized thyroid hormone resistance. Cigarette smoking and environmental agents (eg, polychlorinated biphenyls) also may interfere with receptor action. Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on these tissues.


Pharmacology_Katzung

Pharmacology_Katzung. 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. T4,T3


Pharmacology_Katzung

Pharmacology_Katzung. T4,T3 FIGURE 38–3 The hypothalamic-pituitary-thyroid axis. Acute psychosis or prolonged exposure to cold may activate the axis. Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary thyroid-stimulating hormone (TSH) release, while somatostatin and dopamine inhibit it. TSH stimulates T4 and T3 synthesis and release from the thyroid, and they in turn inhibit both TRH and TSH synthesis and release. Small amounts of iodide are necessary for hormone production, but large amounts inhibit T3 and T4 production and release. Solid arrows, stimulatory influence; dashed arrows, inhibitory influence. H, hypothalamus; AP, anterior pituitary.


Pharmacology_Katzung

Pharmacology_Katzung. 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. Under some conditions, 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 hyperthyroidism or hypothyroidism, respectively (Table 38–4). Since T3 and T4 are qualitatively similar, they may be considered as one hormone in the discussion that follows. Thyroid hormone is critical for the development and functioning of 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—typical of congenital cretinism.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. Thyroid hormone increases the numbers of β receptors and enhances amplification of the β-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 effects is seen in hypothyroidism (Table 38–4). 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).


Pharmacology_Katzung

Pharmacology_Katzung. Thyroid hormones are not effective and can be detrimental in the management of obesity, abnormal vaginal bleeding, or depression if thyroid hormone levels are normal. Recent meta-analysis of T3 co-administered with antidepressants showed some depression benefits, but the results were inconclusive and further confirmation for its optimal use is required.


Pharmacology_Katzung

Pharmacology_Katzung. 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 to weekly administration. In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones and T3 administration is unnecessary. Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations, It is preferable that patients remain on a consistent levothyroxine preparation between refills to avoid changes in bioavailability. A branded soft gel capsule (Tirosint) had faster, more complete dissolution and was less affected by gastric pH or coffee than a tablet formulation.


Pharmacology_Katzung

Pharmacology_Katzung. Although liothyronine (T3) is three to four times more potent than levothyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours), requiring multiple daily doses, and difficulty in monitoring its adequacy of TABLE 38–3 Drug effects and thyroid function. Inhibition of TRH or TSH secretion without induction of Bexarotene, dopamine, bromocriptine, cabergoline, levodopa, corticosteroids, hypothyroidism or hyperthyroidism somatostatin, octreotide, metformin, interleukin-6, heroin Inhibition of thyroid hormone synthesis or release Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide, with the induction of hypothyroidism (or occasionally tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors hyperthyroidism) Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH


Pharmacology_Katzung

Pharmacology_Katzung. Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH Increased TBG Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil, perphenazine Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, L-asparaginase, nicotinic acid Displacement of T3 and T4 from TBG with transient Salicylates, fenclofenac, mefenamic acid, intravenous furosemide, heparin Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not TSH levels (unless receiving thyroxine replacement therapy)


Pharmacology_Katzung

Pharmacology_Katzung. Increased hepatic metabolism, enhanced degradation Nicardipine, phenytoin, carbamazepine, primidone, phenobarbital, rifampin, rifabutin, of thyroid hormone tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), sertraline, quetiapine replacement by conventional laboratory tests. T3 should also be avoided in patients with cardiac disease due to significant elevations in peak levels and a greater risk of cardiotoxicity. Using the more expensive thyroxine and liothyronine fixed-dose combination (liotrix) and desiccated thyroid has not been shown to be more effective than T4 administration alone. T3 is best reserved for short-term TSH suppression. Research is ongoing to clarify whether T3 might be more appropriate in patients with a polymorphism in the D2 gene or in those who continue to report fatigue, weight gain, and mental impairment while on T4 alone.


Pharmacology_Katzung

Pharmacology_Katzung. 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 lower cost. Significant amounts of T3 found in some thyroid extracts may produce significant elevations in T3 levels and toxicity. Exact equi-effective doses have not been determined. Approximate equivalence of desiccated thyroid 60 mg (1 gr) to 80 to 100 mcg of levothyroxine, and approximately 37.5 mcg of liothyronine has been reported. Any dosage conversions should be re-titrated based on laboratory and clinical response. The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination. The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 38–4 Model of the interaction of T3 with the T3 receptor. A: Inactive phase—the unliganded T3 receptor dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase—T3 and T4 circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within the cytoplasm, T4 is converted to T3 by 5′-deiodinase (5′DI); T3 then moves into the nucleus. There it binds to the ligand-binding domain of the thyroid receptor (TR) monomer. This promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR) on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads to alteration in protein synthesis and cellular phenotype. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor


Pharmacology_Katzung

Pharmacology_Katzung. transcription, which leads to alteration in protein synthesis and cellular phenotype. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T3, triiodothyronine; T4, tetraiodothyronine, L-thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.) methimazole (other than agranulocytosis or hepatitis). The chemical structures of these compounds are shown in Figure 38–5. The The thioamides methimazole and propylthiouracil are major thiocarbamide group is essential for antithyroid activity. drugs for treatment of thyrotoxicosis. In the United Kingdom, carbimazole, which is converted to methimazole in vivo, is widely used. Methimazole is about ten times more potent than propylthiouracil and is the drug of choice in adults and


Pharmacology_Katzung

Pharmacology_Katzung. In the United Kingdom, carbimazole, which is converted to methimazole in vivo, is widely used. Methimazole is about ten times more potent than propylthiouracil and is the drug of choice in adults and children. Due Methimazole is completely absorbed but at variable rates. It is readily to a black box warning about severe hepatitis, propylthiouracil accumulated by the thyroid gland and has a volume of distribution should be reserved for use during the first trimester of pregnancy, similar to that of propylthiouracil. Excretion is slower than with pro-in thyroid storm, and in those experiencing adverse reactions to pylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 38–4 Manifestations of thyrotoxicosis and hypothyroidism. 1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic, hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase. FIGURE 38–5 Structure of thioamides. The thiocarbamide moiety is shaded in color. In contrast, 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.


Pharmacology_Katzung

Pharmacology_Katzung. The short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for methimazole) has little influence on the duration of the antithyroid action or the dosing interval because both agents are accumulated by the thyroid gland. For propylthiouracil, giving the drug every 6–8 hours is reasonable since a single 100 mg dose can inhibit iodine organification by 60% for 7 hours. Since a single 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to severe hyperthyroidism.


Pharmacology_Katzung

Pharmacology_Katzung. Both thioamides cross the placental barrier and are concentrated by the fetal thyroid, so that caution must be employed when using these drugs in pregnancy. Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D (evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, see Chapter 59). Of the two, propylthiouracil is preferable during the first trimester of pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. In addition, methimazole has been, albeit rarely, associated with congenital malformations. Both thioamides are secreted in low concentrations in breast milk but are considered safe for the nursing infant.


Pharmacology_Katzung

Pharmacology_Katzung. 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 but not methimazole also inhibits 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.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse reactions to the thioamides occur in 3–12% of treated patients. Most reactions occur early, especially nausea and gastrointestinal distress. An altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. An increased risk of severe hepatitis, sometimes resulting in death, has been reported with propylthiouracil (black box warning), so it should be avoided in children and adults unless no other options are available. Cholestatic jaundice is more common with methimazole than propylthiouracil. Asymptomatic elevations in transaminase levels can also occur.


Pharmacology_Katzung

Pharmacology_Katzung. The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3), an infrequent but potentially fatal adverse reaction. It occurs in 0.1–0.5% of patients taking thioamides, but the risk may be increased in older patients and usually within the first 90 days in those receiving more than 40 mg/d of methimazole. The reaction is usually rapidly reversible when the drug is discontinued, but broad-spectrum antibiotic therapy may be necessary for complicating infections. Colony-stimulating factors (eg, G-CSF; see Chapter 33) may hasten recovery of the granulocytes. The cross-sensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Monovalent anions such as perchlorate (ClO4−), pertechnetate (TcO4−), and thiocyanate (SCN−) can block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism. Since these effects can be overcome by large doses of iodides, their effectiveness is somewhat unpredictable. The major clinical use for potassium perchlorate is to block thyroidal reuptake of I− in patients with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia. Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy. Iodides have several actions on the thyroid. They inhibit organification and hormone release and decrease the size and vascularity of the hyperplastic gland. In susceptible individuals, iodides can induce hyperthyroidism (Jod-Basedow phenomenon) or precipitate hypothyroidism. In pharmacologic doses (>6 mg/d), the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis. Improvement in thyrotoxic symptoms occurs rapidly—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


Pharmacology_Katzung

Pharmacology_Katzung. 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 involving release of radioactive iodine isotopes, the thyroid-blocking effects of potassium iodide can protect the gland from subsequent damage if administered before radiation exposure.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 β rays with an effective half-life of 5 days and a penetration range of 400–2000 μm. Within a few weeks after administration, destruction of the thyroid parenchyma is evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration. Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain. Fears of radiation-induced genetic damage, leukemia, and neoplasia have not been realized after more than 50 years of clinical experience with radioiodine therapy for hyperthyroidism. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland and it


Pharmacology_Katzung

Pharmacology_Katzung. radioiodine therapy for hyperthyroidism. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland and it is excreted in breast milk.


Pharmacology_Katzung

Pharmacology_Katzung. Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the β blocker most widely studied and used in the therapy of thyrotoxicosis. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not typically alter thyroid hormone levels. Propranolol at doses greater than 160 mg/d may also reduce T3 levels approximately 20% by inhibiting the peripheral conversion of T4 to T3. Hypothyroidism is a syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions (Table 38–4). In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation.


Pharmacology_Katzung

Pharmacology_Katzung. The etiology and pathogenesis of hypothyroidism are outlined in Table 38–5. Hypothyroidism can occur with or without thyroid enlargement (goiter). The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of low free thyroxine and elevated serum TSH levels (Table 38–2). The most common cause of hypothyroidism in the United States 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. Genetic mutations as discussed previously and certain medications also can cause hypothyroidism (Table 38–5).


Pharmacology_Katzung

Pharmacology_Katzung. Except for hypothyroidism caused by drugs, which can be treated in some cases by simply removing the depressant agent, the general strategy of replacement therapy is appropriate. The most satisfactory preparation is levothyroxine, administered as either a branded or generic preparation. Multiple trials have documented that combination levothyroxine plus liothyronine is not superior to levothyroxine alone although some patients remain unwell on thyroxine alone. Genetic variations in deiodinases or hormone transporters may account for some of this lack of efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. There is some variability in the absorption of thyroxine; dosage will also vary depending on age and weight. Infants and children require more T4 per kilogram of body weight than adults. The average dosage for an infant 1–6 months of age is 10–15 mcg/kg per day, whereas the average dosage for an adult is about 1.7 mcg/kg per day (0.8 mcg/lb per day ) or 125 mcg/d. Older adults (>65 years of age) may require less thyroxine (1.6 mcg/kg per day or 0.7 mcg/lb per day ) for replacement as body mass declines. In patients requiring suppression therapy post-thyroidectomy for thyroid cancer, the average daily dosage of T4 is 2.2 mcg/kg or 1 mcg/lb. Higher thyroxine requirements have also been reported in patients with celiac disease and Helicobacter pylori gastritis; thyroxine doses may be lower following treatment. TABLE 38–5 Etiology and pathogenesis of hypothyroidism.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 38–5 Etiology and pathogenesis of hypothyroidism. 1Iodides, lithium, fluoride, thioamides, aminosalicylic acid, phenylbutazone, amiodarone, perchlorate, ethionamide, thiocyanate, cytokines (interferons, interleukins), bexarotene, tyrosine kinase inhibitors, etc. See Table 38–3. 2See Table 38–3 for specific pathogenesis.


Pharmacology_Katzung

Pharmacology_Katzung. 2See Table 38–3 for specific pathogenesis. Since interactions with certain foods (eg, bran, soy, coffee) and drugs (Table 38–3) can impair its absorption, thyroxine should be administered on an empty stomach (eg, 60 minutes before meals, 4 hours after meals, or at bedtime) to maintain TSH within an optimal range of 0.5–2.5 mIU/L. Its long half-life of 7 days permits once-daily dosing. Children should be monitored for normal growth and development. Serum TSH and free thyroxine should always be measured before a change in dosage to avoid transient serum alterations. 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.


Pharmacology_Katzung

Pharmacology_Katzung. In younger patients or those with very mild disease, full replacement therapy may be started immediately. In older patients (>50 years) without cardiac disease, levothyroxine can be started at a dosage of 50 mcg/d. In long-standing hypothyroidism and in older patients with underlying cardiac disease, it is imperative to start with reduced dosages of levothyroxine, 12.5–25 mcg/d for 2 weeks, before increasing by 12.5–25 mcg/d every 2 weeks until euthyroidism or drug toxicity is observed. In cardiac patients, the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or cardiac arrhythmia develops, it is essential to stop or reduce the thyroxine dosage immediately.


Pharmacology_Katzung

Pharmacology_Katzung. Thyroxine toxicity is directly related to the hormone level. In children, restlessness, insomnia, and accelerated bone maturation and growth may be signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss may be the presenting symptoms. If these symptoms are present, it is important to monitor serum TSH and FT4 levels (Table 38–2), which will determine whether the symptoms are due to excess thyroxine blood levels. Chronic overtreatment with T4, particularly in elderly patients, can increase the risk of atrial fibrillation and accelerated osteoporosis. Special Problems in Management of Hypothyroidism A. Myxedema and Coronary Artery Disease


Pharmacology_Katzung

Pharmacology_Katzung. Special Problems in Management of Hypothyroidism A. Myxedema and Coronary Artery Disease Since myxedema frequently occurs in older persons, it is often associated with underlying coronary artery disease. In this situation, the low levels of circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pectoris, atrial fibrillation, or myocardial infarction. Correction of myxedema must be done cautiously to avoid provoking these cardiac events. If coronary artery surgery is indicated, it should be done first, prior to correction of the myxedema by thyroxine administration. B. Myxedema Coma Myxedema coma is an end state of untreated hypothyroidism. It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 mcg initially, followed by 50–100 mcg daily. Intravenous T3 5–20 mcg initially, followed by 2.5–10 mcg every 8 hours also can be added but may be more cardiotoxic and more difficult to monitor. Lower T4 and T3 doses should be considered for smaller or older patients, or those with concomitant cardiac disease or arrhythmias. Intravenous hydrocortisone is indicated if the patient has associated adrenal or pituitary insufficiency but is probably not necessary in most patients with primary