Pharmacology – DRUGS FOR PITUITARY AND THYROID DISORDERS (MADE EASY)

In this lecture we’re gonna cover the pharmacology of drugs used in treatment of pituitary and thyroid disorders, so let’s get right into it. Joined at the base of the brain, hypothalamus and pituitary gland are the key players in the endocrine system. The pituitary, which is controlled by the hypothalamus, is often called “The Master Gland” due to its function to control the secretion or inhibition of hormones. Hormones are the most potent chemical messengers in our bodies, telling the body what to do and when. That’s why imbalanced or poorly functioning hormones can cause a variety of medical problems. Now, the “master” pituitary gland consists of an anterior lobe, which contains specialized cells that produce and secrete hormones in response to hormones released from the hypothalamus, and a posterior lobe, which contains neuronal projections extending from the hypothalamus that produce and then directly secrete hormones into the circulation. So as you can see, hypothalamic hormones can be broadly classified into two groups. The first group includes the hormones that act on the anterior pituitary gland such as thyrotropin-releasing hormone (TRH) that stimulates specialized endocrine cells called thyrotrophs (T) to release thyroid stimulating hormone (TSH), which in turn stimulates thyroid gland to produce and release thyroid hormones; the next one is gonadotropin-releasing hormone (GnRH) that stimulates gonadotrophs (G) to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulate the reproductive functioning of the ovaries and testes; the next one is corticotropin-releasing hormone (CRH) that stimulates corticotrophs (C) to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to produce and secrete certain steroid hormones; the next one is growth hormone-releasing hormone (GHRH) that stimulates somatotrophs (S) to release growth hormone (GH), which in turn stimulates the liver and other tissues to produce growth stimulants called insulin-like growth factors; and lastly we have two inhibiting hormones that is growth hormone-inhibiting hormone (GHIH), which inhibits somatotrophic cell release of growth hormone, and prolactin-inhibiting hormone (PIH), which is simply the neurotransmitter dopamine that acts on lactotrophs (L) to inhibit the secretion of prolactin. Now, moving on to the second group of hypothalamic hormones, which are transported down the axons of the same neurons that synthesize them to the posterior pituitary from where they’re released into the circulation. These are: anti-diuretic hormone (ADH), which acts primarily on the kidney to regulate water balance in the body; and oxytocin, which regulates uterine contractions and milk ejection. All right, so as you can see, hormones produced by the hypothalamus and pituitary play a crucial role in regulating metabolism, growth, and reproduction. And because of that, many drugs have been developed to either mimic or block their effects in order to treat various endocrine disorders. So, now let’s take a closer look at how these drugs work to produce their therapeutic effects, starting with agents targeting thyroid gland. To gain better understanding of the mechanism of drugs action, first we need to review the mechanism by which thyroid hormones are synthesized in the thyroid follicle, that is the functional unit of thyroid gland. The thyroid follicle, which is composed of intrafollicular colloid and follicular cells, serves as both factory and warehouse for production of thyroid hormones. The recipe for making thyroid hormones calls for two principle ingredients: the first one is a glycoprotein called thyroglobulin, which is synthesized in the rough endoplasmic reticulum of follicular cell, and then is secreted into the colloid; the second ingredient is an iodide, which is actively pumped into the cell by sodium-iodide symporter, and then is passively transported into the colloid along with thyroglobulin. In the colloid, with the help of an enzyme called thyroid peroxidase, iodide (I-) is oxidized to iodine (I0) and hormone synthesis begins with the addition of iodine to tyrosyl residues on the thyroglobulin molecules in a process called iodination. Next, through conjugation, adjacent tyrosyl residues are paired together and the entire complex re-enters the follicular cell. Back inside the cell, proteolytic enzymes digest thyroglobulin thus liberating free thyroid molecules, thyroxine known as T4 and triiodothyronine known as T3, which are then released into the circulation

where they quickly bind to carrier proteins for transport to target cells. Now, free extracellular T4 and T3 enter the target cell through transporter proteins. Once inside the cell, the amount of T3, which has greater biological activity than T4, is regulated by deiodinase enzymes 1 and 2 abbreviated D1 and D2 that catalyze the conversion of T4 to T3 thereby increasing intracellular levels of the active hormone. On the other hand, deiodinase 3 (abbreviated as D3) serves to inactivate T4 by converting it to so-called reverse T3 (rT3 for short), therefore limiting the amount of T4 that can be used to form T3. In the final step, T3 moves to the nucleus and binds to the thyroid hormone receptors (TR), which then form heterodimers with the retinoid X receptor (RXR) to induce transcription of target genes known as thyroid response elements. This leads to synthesis of various regulatory proteins, which then mediate various physiological responses. Now, the drugs used in treatment of thyroid disorders can be generally divided into two groups. The first group includes agents that treat the condition in which there is inadequate production of thyroid hormones, known as hypothyroidism. Medications used to treat hypothyroidism include Levothyroxine, which is a synthetic version of T4, Liothyronine, T3, Liotrix, which is a synthetic combination of T4 and T3, and desiccated natural thyroid, which is a natural thyroid hormone prepared from dried porcine thyroid containing mix of T4 and T3. Now, moving on to the second group that includes agents used to treat the condition in which there is overproduction of thyroid hormones, known as hyperthyroidism. Medications used to treat hyperthyroidism include Propylthiouracil and Methimazole, which work by inhibiting thyroid peroxidase that is required for oxidation of iodide as well as inhibiting coupling of iodotyrosines in thyroglobulin that is necessary for thyroid hormone synthesis. In addition to this, Propylthiouracil also inhibits deiodinase 1 (D1), which prevents conversion of T4 to T3. All right, now that we discussed drugs acting on thyroid gland, it’s time to move on to our next pharmacological target that is gonadotropin-releasing hormone receptor (GnRHR). So, the hypothalamic hormone, GnRH, is released and transported to the anterior pituitary in a pulsatile manner, where it binds to the receptors expressed by the pituitary gonadotrophs. The frequency of GnRH pulses changes under various physiological conditions, and varying pulse frequencies have been shown to regulate the secretion of LH and FSH. In order to modulate the GnRH effects for therapeutic purposes, a number of GnRH analogs have been developed to either downregulate or upregulate the secretion of LH and FSH. The GnRH agonists such as Goserelin, Histrelin, Leuprolide, and Nafarelin are more potent and have longer half-life than natural GnRH. They produce an initial stimulation of pituitary gonadotrophs that results in increased secretion of LH and FSH, followed by downregulation and inhibition of the pituitary-gonadal axis. In comparison to GnRH agonists, GnRH antagonists such as Degarelix, Elagolix, Ganirelix and Cetrorelix promptly suppress pituitary gonadotropin by competitively blocking GnRH-receptor, thereby avoiding the initial stimulatory phase of the agonists. The resulting suppression of LH and FSH in turn leads to profound inhibition of estrogen and androgen synthesis, which makes these agents effective in treatment of hormone-sensitive cancers as well as various gynecological disorders. On the other hand, the deficiency of both LH and FSH as a result of hypothalamic or pituitary disease can cause infertility or subfertility both in men and women. To address this problem, variety of pharmaceutical preparations of LH and FSH have been developed to stimulate spermatogenesis in men and to induce follicle development and ovulation in women. These preparations include Menotropins, which consist of a purified mixture of LH and FSH; Urofollitropin, which is a purified form of human FSH; Follitropin, which is a form of recombinant human FSH; Lutropin, which is a recombinant form of human LH; and Choriogonadotropin alfa, chorionic gonadotropin (hCG), a hormone naturally produced by the placenta during pregnancy

that shares structural similarities with LH and thus binds to and activates the same receptor. All right, moving on to our next pharmacological target that is the adrenal cortex. So, the main action of adrenocorticotropic hormone (ACTH) on the adrenal cortex is to stimulate the synthesis and release of adrenocortical and androgen hormones. Specifically, inside the cells of the adrenal cortex, stimulation by ACTH activates cholesterol side-chain cleavage enzyme, which in turn catalyzes the conversion of cholesterol to pregnenolone, the precursor of all adrenocortical hormones including mineralocorticoids, glucocorticoids, androgens, and estrogens. Now, in general, diseases affecting adrenal gland can be divided into disorders of hormone deficiency and disorders of hormone excess. Addison’s disease is the classic example of adrenocortical insufficiency characterized by inadequate secretion of cortisol, and often, aldosterone as well. Treatment for adrenocortical insufficiency involves replacing the missing hormone aldosterone with the synthetic analog such as Fludrocortisone, and replacing the missing cortisol with the synthetic analogs such as Hydrocortisone or Prednisone. On the other hand, Cushing’s syndrome is the example of excessive cortisol production. Treatment for excessive cortisol production involves either stopping corticosteroid medications that cause the symptoms or if an adrenal tumor is identified, medications such as Ketoconazole, Mitotane and Metyrapone can be used to inhibit enzymes involved in cortisol synthesis. All right, now let’s move on to discussing the pharmacology of the growth hormone also called somatotropin. So, growth is a very complex process that requires coordinated action of several hormones. Growth hormone, although it has largely indirect effect on growth, is the most important hormone involved in the growth process. The pituitary secretes growth hormone in response to the hypothalamus releasing growth-hormone releasing hormone and the stomach releasing ghrelin. The major role of the growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete insulin-like growth factor-1 (IGF-1). IGF-1, in turn, stimulates proliferation of cartilage cells, resulting in bone growth, as well as formation of new proteins particularly in skeletal muscle cells, resulting in muscle growth. In addition to that, growth hormone can also directly bind to its receptors on target cells such as fat cells, causing them to break down triglycerides and suppresses their ability to take up and accumulate circulating lipids. Now, deficiency in growth hormone can lead to developmental disorders such as growth retardation or dwarfism. To treat these disorders, a synthetic somatotropin can be injected into the body to compensate for insufficient levels of growth hormone. In addition to that, pediatric patients with growth failure and severe IGF-1 deficiency who are not responsive to treatment with somatotropin, can be treated with a recombinant human IGF-1 product called Mecasermin. Now, the body’s primary mechanism of regulating growth hormone is to release growth hormone-inhibiting hormone also known as somatostatin. Somatostatin secreted from the hypothalamus simply inhibits the pituitary gland's secretion of growth hormone. In disorders of excessive growth hormone secretion, which can lead to gigantism in children and acromegaly in adults, synthetic forms of somatostatin can be used to reduce blood levels of growth hormone. Examples of such agents are Octreotide and Lanreotide, which work by binding to somatostatin receptors located on the surface of different cell types to cause inhibition of growth hormone secretion and its effects on target tissue. Now let’s move on to discussing drugs that affect prolactin secretion. So, the secretion of prolactin is regulated by dopamine, which is secreted by hypothalamic dopaminergic neurons into the anterior pituitary via portal vessel. Dopamine that is released by these neurons acts on lactotrophs through D2-receptors causing inhibition of prolactin secretion. Now, the pathophysiology of prolactin can include either insufficient prolactin levels, which results in failure to lactate, or excessive galactorrhea and infertility. Two types of drugs can be used to treat these disorders. The first type includes dopamine receptor antagonist such as Metoclopramide, which works by blocking D2 receptors from being stimulated, thereby increasing prolactin secretion. The second type includes dopamine receptor agonists such as Bromocriptine and Cabergoline, which stimulate D2

receptors thereby inhibiting prolactin secretion. All right, finally before we end, let’s briefly discuss pharmacology of the posterior pituitary hormones that is anti-diuretic hormone also known as vasopressin, and oxytocin. So, in regards to the first hormone, when there’s a change in plasma osmolality, volume, or redistribution of blood, osmoreceptors located within hypothalamus as well as pressure receptors in veins, atria, and caro-tids stimulate the release of vasopressin into the circulation. Vasopressin action is mediated primarily by binding to the V2 receptors (V2R) on cells in the distal tubules and collecting ducts of the kidney, which in turn stimulates insertion of water-permeable channels called aquaporins into the luminal membrane. This allows water to be reabsorbed down an osmotic gradient and the urine to become more concentrated. In addition to that, vasopressin can act directly on blood vessels by binding to the V1 receptors (V1R) on a vascular smooth muscle to cause vasoconstriction. Now, in terms of therapeutic options, we have natural vasopressin available in injection form as well as synthetically modified selective V2 receptor agonist called Desmopressin (DDAVP) that is also available in oral and nasal formulations. Vasopressin and Desmopressin are treatments of choice for diabetes insipidus, certain bleeding disorders and nocturnal involuntary urination. On the other hand, for conditions associated with increased vasopressin levels we have vasopressin receptor antagonists, such as Conivaptan and Tolvaptan, which work mainly by blocking V2 receptors thereby effectively correcting hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone. Now, moving onto our last hormone that is oxytocin. So, oxytocin has been best known for its roles in female reproduction. For instance, in the late stage of pregnancy, stretching of tissues in the uterus and cervix causes local stretch receptors to send nerve impulses to the hypothalamus, which in turn causes the pituitary to secrete oxytocin into the circulation. Oxytocin then travels to the uterus and causes the muscles in uterine walls to contract, thereby bringing the baby downwards, stretching the cervix even more, and repeating the cycle until birth occurs. After the birth, oxytocin release is stimulated by the suckling of an infant at the breast, which again, triggers the synthesis and release of the oxytocin into the circulation. This time, oxytocin travels to the breast where it stimulates receptors in the cells of the milk ducts to initiate a contracting action that results in forcing milk down the duct. Now in terms of therapeutic uses, exogenous oxytocin can be administered to induce labor and to inhibit postpartum bleeding. And with that I wanted to thank you for watching, I hope you enjoyed this presentation and as always stay tuned for more.