PHM 1.05 - ENDOCRINE DRUGS HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS.pdf

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 OVERVIEW ENDOCRINE SYSTEM HYPOTHALAMIC – PITUITARY HORMONE DRUGS o GROWTH HORMONE o GROWTH HORMONE ANTAGONISTS o T...

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 OVERVIEW ENDOCRINE SYSTEM HYPOTHALAMIC – PITUITARY HORMONE DRUGS o GROWTH HORMONE o GROWTH HORMONE ANTAGONISTS o THE GONADOTROPINS o GONADOTROPIN-RELEASING HORMONE & ANALOGS o GnRH RECEPTOR ANTAGONISTS o PROLACTIN o DOPAMINE AGONISTS o OXYTOCIN o OXYTOCIN ANTAGONIST o VASOPRESSIN o VASOPRESSIN ANTAGONISTS  THYROID GLAND  THYROID DRUGS  ANTI – THYROID DRUGS ENDOCRINE SYSTEM   ITS ENDOCRINE PHARMACOLOGY  Endocrine disorders are unique in the sense that treatment can be targeted directly to the malfunctioning pathway.  Hormone replacement therapy in hypo functioning diseases  specific antihormone treatment in hyperfunctioning disorders are the hallmark of endocrine treatment. CASE STUDY o A 4-year-old boy (height 90 cm, –3 standard deviations [SD]; weight 14.5 kg, approximately 15th percentile) presents with short stature. o Review of the past history and growth chart demonstrates normal birth weight and birth length, but a progressive decrease in height percentiles relative to age-matched normal ranges starting at 6 months of age, and orthostasis with febrile illnesses. o Physical examination demonstrates short stature and mild generalized obesity. Genital examination reveals descended but small testes and a phallic length of –2 SD. o Laboratory evaluations demonstrate growth hormone (GH) deficiency and a delayed bone age of 18 months. o The patient is started on replacement with recombinant human GH at a dose of 40 mcg/kg per day subcutaneously. o After 1 year of treatment, his height velocity has increased from 5 cm/y to 11 cm/y. ❖ How does GH stimulate growth in children? ❖ What other hormone deficiencies are suggested by the patient’s history and physical examination? ❖ What other hormone replacements is this patient likely to require? 1 | Page PHARMACOLOGY ❖ The endocrine system is a complex network of glands and organs. ❖ It uses hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, and mood. ❖ The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. HOW DOES HORMONES WORK? ❖ Hormones are chemical messengers secreted into blood or extracellular fluid by one cell that affect the functioning of other cells. ❖ Most hormones circulate in blood, coming into contact with essentially all cells. ❖ However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone. In other words, a particular cell is a target cell for a hormone if it contains functional receptors for that hormone, and cells which do not have such a receptor cannot be influenced directly by that hormone. ❖ Hormone receptors are found either outside the cell (exposed on the surface of the cell) or inside/within the cell depending on the type of hormone binding of hormone to receptor triggers a cascade of reactions within the cell that affects function. Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 a. AGONISTS  molecules that bind the receptor and induce all the postreceptor events that lead to a biologic effect/ expected effect/ natural effect  In other words, they act like the "normal" hormone, although perhaps more or less potently.  Natural hormones/ endogenous hormones are themselves agonists and, in many cases, more than one distinct hormone binds to the same receptor.  For a given receptor, different agonists can have dramatically different potencies.  Drugs that are agonists bind to the receptor producing a similar response to the intended chemical and receptor just like a natural hormone. b. ANTAGONISTS  molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signaling events.  Antagonists are like certain types of bureaucrats - they don't themselves perform useful work, but block the activities of those that do have the capacity to contribute.  Hormone antagonists are widely used as drugs. PHARMACOLOGIC ACTION OF ENDOCRINE DRUGS ❖ Areas of Application: 1. Replacement therapy in hormonal deficiency states. 2. Antagonists of diseases caused by excess production of hormones. 3. Regulate normal endocrine function to achieve a desired effect. E.g., inhibition of ovulation 4. Diagnostic tools for identifying endocrine abnormalities. HYPOTHALAMIC-PITUITARY- TARGET ORGAN hypothalamus to the anterior pituitary. ❖ Releasing hormones stimulate anterior pituitary cells to produce their corresponding hormones o compared to the posterior lobe hormones, they are produced in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe ► from there they are stored and released into the circulation. ❖ Shown here are the target organs and their hormonal products POSTERIOR PITUITARY HORMONES Oxytocin Anti-diuretic hormone (ADH) 2 | Page TARGET ORGANS Breast, Uterus Kidneys PROBLEMS in the HYPOTHALAMIC-PITUITARY AREA ❖ HYPOPITUITARISM- disorders from hypothalamus and/or pituitary gland causing deficiency in one or more pituitary hormones a. GH deficiency o short stature, micropenis (children), fatigue, decreased sense of well-being (adults) b. TSH deficiency o low T4 and T3 – short stature, mental retardation, fatigue, weight gain c. ACTH deficiency o Low cortisol- adrenal crisis (hypotension, vomiting, low blood sugar, shock) d. LH, FSH deficiency o low estrogen and testosterone (delayed puberty, micropenis, undescended testis) e. Vasopressin (ADH) deficiency o diabetes insipidus (polyuria, hypotension, shock) f. Oxytocin deficiency o like inability to lactate, vaginal dryness, decreased libido, etc. CAUSES OF HYPOPITUITARISM ✓ tumors ✓ infiltrative diseases ✓ hydrocephalus ❖ The H and P gland is connected by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. ❖ The portal venous system carries small regulatory or releasing hormones from the PHARMACOLOGY ✓ genetic mutations ✓ chromosomal disorders ❖ HYPERPITUITARISM- primary hypersecretion pituitary hormones, typically from pituitary adenoma a. High GH level o acromegaly and gigantism b. High prolactin of Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 o galactorrhea, infertility, oligomenorrhea, amenorrhea c. High ACTH o high cortisol (Cushing syndrome) HYPOTHALAMIC- PITUITARY HORMONES/DRUGS PHARMACOLOGIC APPLICATION ❖ The following hypothalamic and pituitary hormones are infrequently used as treatments ✓ TRH, TSH ✓ GHRH ✓ CRH and ACTH o used for specialized diagnostic testing for stimulation in some hypo-/hyperfunctioning endocrine disorders ❖ GH, somatostatin, LH, FSH, GnRH, dopamine or analogs of these hormones are used frequently for treatment GROWTH HORMONE: SOMATOTROPIN CHEMISTRY & PHARMACOKINETICS PHARMACOLOGY ❖ Growth hormone (GH; somatotropin) is a 191-aminoacid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin. ❖ Somatropin, the recombinant form of GH, has a 191amino-acid sequence that is identical with the predominant native form of human GH.  In the past, medicinal GH was isolated from the pituitaries of human cadavers.  However, this form of GH was found to be contaminated with prions that could cause Creutzfeldt-Jakob disease.  For this reason, it is no longer used. ABSORPTION, METABOLISM, AND EXCRETION ❖ Circulating endogenous GH:  secretion: pulsatile (approx. 10 pulses per day)  secretion: pulsatile (approx. 10 pulses per day) and lasting approximately 90 minutes and separated by approximately 128 minutes.  half-life: 20 minutes  Clearance: liver ❖ Recombinant human GH (rhGH)  Administration: subcutaneously 6–7 times per week  Peak levels: 2–4 hours, and active blood levels persist for approximately 36 hours. PHARMACODYNAMICS ❖ GH mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily ❖ GH has complex effects: 1. Growth o mediated principally, but not solely, through an increase in the production of IGF-I. o Majority of IGF-1 is produced by the liver.  Growth hormone also stimulates production of IGF-I in bone, cartilage, muscle, kidney, and other tissues, where it has autocrine or paracrine roles stimulates production of IGF-1 in bones, cartilage, muscles, kidneys.  It stimulates longitudinal bone growth until the epiphyseal plates fuse—near the end of puberty. 2. Body composition o in both children and adults, GH has anabolic effects in muscle and catabolic effects in adipose cells that shift the balance of body mass to an increase in muscle mass and a reduction in adiposity. 3. Carbohydrate, protein, and lipid metabolism GROWTH HORMONE 3 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 TOXICITY ❖ Children generally tolerate growth hormone treatment well ❖ Adverse events are relatively rare o pseudotumor cerebri o slipped capital femoral epiphysis o progression of scoliosis o edema, hyperglycemia o increased risk of asphyxiation in severely obese patients with Prader-Willi syndrome (GH is an anabolic steroid that can cause further obesity) o upper airway obstruction or sleep apnea GROWTH HORMONE ANTAGONISTS ❖ used to reverse the effects of GH producing cells in the anterior pituitary (GH-secreting pituitary adenomas) = ↑ GH levels PHARMACOLOGY OCTREOTIDE ▪ most widely used somatostatin analog 45X more potent than somatostatin in inhibiting GH release half-life: about 80 minutes, 30 times longer than that of somatostatin indications: hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, insulinoma, VIPoma, and ACTH-secreting tumor. other therapeutic use: ✓ include diarrhea—secretory, HIV associated, diabetic, chemotherapy, or radiation induce. ✓ For acute control of bleeding from esophageal varices (portal hypertension) GONADOTROPINS (FOLLICLE-STIMULATING HORMONE & LUTEINIZING HORMONE) & HUMAN CHORIONIC GONADOTROPIN ❖ GONADOTROPINS (FSH & LH) o in women: ▬ FSH: stimulates ovarian follicle development ▬ LH: critical for ovulation, stimulation of androgens (the estradiol precursors) from theca cells, and maintenance of the corpus luteum o in men: ▬ FSH: primary regulator of spermatogenesis ▬ LH: stimulates testosterone production from the Leydig cells in the testes for virilization (developing male fetus) o Important for sexual development during puberty serve complementary functions in the reproductive process ❖ GIGANTISM o When a GH-secreting adenoma occurs before the long bone epiphyses close ❖ ACROMEGALY o characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract o Seen in adults SOMATOSTATIN ▪ a 14-amino-acid peptide found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract ▪ it primarily acts as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin ▪ it is rapidly cleared from the circulation, with a half-life of 1–3 minutes. PEGVISOMANT ▪ GH receptor antagonist used to treat acromegaly ▪ Polyethylene glycol (PEG) derivative of a mutant GH. LANREOTIDE ▪ another octapeptide somatostatin analog approved for the treatment of acromegaly 4 | Page ❖ HUMAN CHORIONIC GONADOTROPIN (hCG) o placental glycoprotein nearly identical with LH o its actions are mediated through LH receptors PHARMACOKINETICS ❖ heterodimers, share an identical α subunit ❖ LH and hCG have nearly identical β subunit ❖ Administration: subcutaneous or I.M. ❖ Half-lives vary by preparation and route of injection: 1040 hrs MENOTROPINS OR HUMAN MENOPAUSAL GONADOTROPIN (HMG) ▪ first commercial gonadotropin containing both LH and FSH extracted from urine of postmenopausal women ▪ 1960’s: for stimulation of follicle development in women Follicle stimulating hormone UROFOLLITROPIN ▪ from urine of postmenopausal women ▪ recombinant forms: follitropin alfa and follitropin beta Luteinizing hormone LUTROPIN ALFA ▪ first and only recombinant form of human LH Human chorionic gonadotropin PREGNYL Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 ▪ produced by human placenta and excreted in the urine where it is extracted and purified PHARMACODYNAMICS ❖ FSH, LH and hCG exert their effects through G proteincoupled receptors CLINICAL INDICATIONS: 1. Ovulation induction- in women with hypogonadotropic hypogonadism, polycystic ovarian syndrome 2. Controlled ovarian stimulation- in assisted reproductive technology procedures 3. Male infertility/ hypogonadism (micropenis; delayed puberty) 4. Prepubertal cryptorchidism- hCG induces testicular descent; not recommended at present for treatment of cryptorchidism because long term efficacy is much lower than that of surgical treatment 5. Stimulation test in the diagnosis of hypogonadismprimary vs secondary/central TOXICITY/ COMPLICATIONS 1. Ovarian hyperstimulation syndrome (OHSS) o ovarian enlargement, intravascular depletion, ascites, liver dysfunction, pulmonary edema, thromboembolic events o self-limited with spontaneous resolution within a few days o severe disease may require hospitalization and intensive care 2. Multiple pregnancies o 5-10% risk during ovulation induction GONADOTROPIN- RELEASING HORMONE (GnRH) AND ITS ANALOGS  Endogenous GNRH causes the pituitary gland to secrete gonadotropins (LH, FSH).  In childhood, GNRH levels are normally low. As puberty begins, GNRH levels will start to rise and secondary sexual development will start  When the testes and ovaries are fully developed, GNRH, LH and FSH production is being controlled by the level of testosterone, estrogen and progesterone ❖ GnRH is a decapeptide found in all mammals. 5 | Page PHARMACOLOGY ❖ 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 longerlasting than native GnRH ❖ GnRH analogs: goserelin, buserelin, histrelin, leuprolide, nafarelin, and triptorelin. PHARMACOKINETICS ❖ Administration o intravenously or subcutaneously (Gonadorelin) o Other GnRH agonists can be administered subcutaneously, intramuscularly, via nasal spray (Nafarelin), or as a subcutaneous implant. ❖ Half-life o subcutaneous and intranasal GnRH analogs: 3 hours o intravenous: 4 minutes ❖ Duration of clinical uses o varies from a few days for controlled ovarian stimulation to a number of years for treatment of metastatic prostate cancer. ❖ Preparations o developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms) PHARMACODYNAMICS ❖ GnRH binds to specific G protein coupled receptors in the pituitary – stimulating gonadotropin secretion and synthesis ❖ GnRH agonists induce an initial gonadotropin hypersecretion (flare-up), followed by pituitary desensitization and profound suppression of LH and FSH. ❖ Prolonged activation of GnRH receptors by GnRH leads to desensitization and consequently to suppressed gonadotropin secretion. This is the primary mechanism of action of agonistic GnRH analogues. GNRH CLINICAL INDICATIONS 1. Stimulation o Female infertility o Male infertility o Diagnosis of LH responsiveness in cases of delayed puberty 2. Suppression of gonadotropin production o Controlled ovarian stimulation o Endometriosis defined as the presence of estrogen-sensitive endometrium outside the uterus that results in cyclical abdominal pain in premenopausal women. 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 ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and progesterone concentrations and prevents cyclical changes. o Uterine leiomyomata/fibroids benign, estrogen-sensitive, smooth muscle tumors in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 - Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. 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. o Prostate cancer- androgen deprivation therapy is the primary medical treatment o Central precocious puberty- onset of puberty before 8 years old in girls and 9 years old in boys 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 concentration and effects o Others: advanced breast and ovarian cancer TOXICITY ❖ Headache, light-headedness, nausea and flushing ❖ Local swelling at injection site ❖ Osteoporosis and reduced bone mineral density GnRH RECEPTOR ANTAGONISTS PHARMACOLOGY ❖ Hyperprolactinemia- from pituitary prolactin-secreting adenoma DOPAMINE AGONISTS ❖ Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia; GH release is also reduced in patients with acromegaly, although not as effective as the somatostatins ❖ All available dopamine agonists (Bromocriptine and Cabergoline, quinagolide) BROMOCRIPTINE AND CABERGOLINE, QUINAGOLIDE PHARMACOKINETICS ▪ Administration: All available dopamine agonists are active as oral preparations  all are eliminated by metabolism c  an also be absorbed systemically after vaginal insertion of tablets to avoid nausea due to oral administration. ▪ Half-life o Cabergoline- 65 hrs. - longest duration of action o quinagolide- 20 hrs. o bromocriptine- 7 hrs. After vaginal administration, serum levels peak more slowly CLINICAL INDICATIONS 1. Hyperprolactinemia- dopamine agonist is the first-line treatment, and shrinks pituitary prolactin-secreting tumors 2. Physiologic lactation 3. Acromegaly - alone or in combination with pituitary surgery, radiation therapy or octreotide TOXICITY ❖ nausea, headache, hypotension and fatigue light-headedness, orthostatic OXYTOCIN ◼ 4 SYNTHETIC DECAPEPTIDES Ganirelix | Cetrorelix | Abarelix |Degarelix ▪ Inhibit the secretion of FSH and LH in a dose-dependent manner ▪ Administration: subcutaneous injection INDICATIONS: 1. Suppression of gonadotropin production- Controlled ovarian stimulation 2. Advance prostate cancer- degarelix and abarelix; reduce concentrations of gonadotropins and androgens more rapidly than GnRH agonists ▪ Toxicity: nausea and headache PROLACTIN CHEMISTRY & PHARMACOKINETICS: ❖ 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. 6 | Page ❖ secreted by the posterior pituitary. ❖ stimulates muscular contractions in the uterus and myoepithelial contractions in the breast. Thus, it is involved in parturition and the milk letdown. ❖ 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. (In preparation for parturition or labor) STRUCTURE ❖ 9-amino-acid peptide with an intrapeptide disulfide cross-link. Its amino acid sequence differs from that of vasopressin at positions 3 and 8. PHARMACOKINETICS ❖ Administration: Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 o Intravenous - labor initiation and augmentation o Intramuscular - Control of postpartum bleeding ❖ Elimination: Kidneys & Liver ❖ Half-life: 5 minutes PHARMACOKINETICS Vasopressin Desmopressin PHARMACODYNAMICS ❖ Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction. ❖ Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk letdown. Without oxytocin-induced contraction, normal lactation cannot occur. CLINICAL INDICATION 1. Induction of labor – for conditions requiring expedited vaginal delivery (worsening pre-eclampsia, ruptured membranes after 34 weeks gestation, uncontrolled maternal diabetes, intrauterine infection) 2. Immediate postpartum period to stop vaginal bleeding due to uterine atony. TOXICITY ❖ rare, when used judiciously ❖ Contraindications – fetal malpresentation, placental abruption distress, PHARMACOLOGY fetal OXYTOCIN ANTAGONIST ATOSIBAN ▪ antagonist of the oxytocin receptor that has been approved outside the United States as a treatment (tocolysis; anticontraction) for preterm labor. ▪ 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. o In 1998, however, the FDA decided not to approve atosiban based on concerns about efficacy and safety. VASOPRESSIN (ANTIDIURETIC HORMONE, ADH) ▪ peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. ▪ possesses antidiuretic and vasopressor properties. STRUCTURE ▪ DESMOPRESSIN ACETATE (DDAVP, 1-desamino-8-darginine vasopressin) o is a long-acting synthetic analog of vasopressin with minimal pressor activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. o 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. ADMINISTRATION HALF-LIFE I.V. / I.M. I.V., SQ., intranasal, oral 15 minutes 1.5–2.5 hours PHARMACODYNAMICS ❖ Vasopressin activates two subtypes of G protein–coupled receptors o V1 receptors: - vascular smooth muscle cells- vasoconstriction o V2 receptors: - on renal tubule cells ► reduce diuresis through increased water permeability and water resorption in the collecting tubules o Extrarenal V2-like receptors: - regulate the release of coagulation factor VIII and von Willebrand factor, which increases platelet aggregation. CLINICAL INDICATIONS 1. Central diabetes insipidus o treatment of choice o deficiency of vasopressin (tumors compressing the pituitary stalk, infiltrative diseases destroying the pituitary stalk, transection of pituitary stalk after surgery) causing polyuria. 2. Esophageal variceal bleeding and colonic diverticular bleeding 3. Treatment of coagulopathy in Hemophilia A and von Willebrand disease TOXICITY ❖ Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. ❖ OVERDOSAGE can result in hyponatremia and seizures because of water intoxication. When vasopressin is given (anti-diuretic) ► hindi n siya iihi for how many hours; and when the patient keeps on drinking ► WATER OVERLOAD ► dilution of sodium in the blood ► HYPONATREMIA and SEIZURES ❖ Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease. VASOPRESSIN ANTAGONISTS Conivaptan | Tolvaptan ❖ used in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin e.g. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) ❖ They promote excretion of free water, relieve symptoms, and reduced objective signs of hyponatremia and heart failure. ❖ Conivaptan- intravenous ❖ Tolvaptan- oral CASE STUDY ANSWER ✓ While growth hormone (GH) may have some direct growthpromoting effects, it is thought to mediate skeletal growth principally through production of insulin-like growth factorI (IGF-I) at the epiphyseal plate, which acts mainly in an 7 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 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 presence of central diabetes insipidus and, if present, treated with desmopressin, a V2 vasopressin receptor-selective analog. THYROID & ANTITHYROID DRUGS CASE STUDY o JP is a 33-year-old woman who presents with complaints of fatigue requiring daytime naps, weight gain, cold intolerance, 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. o She also would like to become pregnant 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.” o On physical examination, 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. o 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). o Evaluate the management of her past history of hyperthyroidism and assess her current thyroid status. o Identify your treatment recommendations to maximize control of her current thyroid status. THYROID GLAND PHARMACOLOGY - The hypothalamus produces TSH Releasing Hormone (TRH) that signals the pituitary to tell the thyroid gland to produce more or less of T3 and T4 by either increasing or decreasing the release of a hormone called thyroid-stimulating hormone (TSH). - When T3 and T4 levels are low in the blood, the pituitary gland releases more TSH to tell the thyroid gland to produce more thyroid hormones. - If T3 and T4 levels are high, the pituitary gland releases less TSH to the thyroid gland to slow the production of these hormones. ❖ Thyroid gland ▪ a butterfly-shaped organ located in the base of your neck. ❖ Thyroid hormones ▪ are critical determinants of brain and somatic development in infants; regulates metabolic activity such as: ▬ Breathing ▬ Heart rate ▬ Central and peripheral nervous systems ▬ Bodyweight ▬ Muscle strength ▬ Menstrual cycles ▬ Body temperature ▬ Cholesterol levels ▪ The two principal thyroid hormones are: THYROXINE TRIIODOTHYRONINE T4 or L-3,5,3',5'- T3 or L-3,5,3'tetraiodothyronine triiodothyronine solely a product of the a product of the thyroid and of thyroid gland many other tissues, in which it is produced by deiodination of T4 There are two biologically active thyroid hormones: thyroxine (T4) and (T3). composed of a phenyl ring attached via an ether linkage to a tyrosine molecule. Both have two iodine atoms on their tyrosine (inner) ring. T4 has two iodine atoms on its phenyl (outer) ring, whereas T3 has only one. The compound formed if an iodine atom is removed from the inner ring of T4 is the reverse T3 which has no biological activity. ❖ IODINE - essential for normal thyroid function. The only known physiologic role of iodine (or iodide [I−] in its ionized form) is in the synthesis of thyroid hormones. 8 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 THYROID HORMONE SYNTHESIS PHARMACOLOGY ✓ Normal levels of TSH, FT4, FT3) ▬ HYPERTHYROIDISM ✓ Increased levels of FT4, FT3 ✓ Decreased level of TSH ▬ HYPOTHYROIDISM ✓ Decreased levels of FT4, FT3 ✓ Increased level of TSH MECHANISM OF ACTION ❖ T4 and T3 dissociate from the binding proteins ► FT4 and FT3 ❖ Thyroid hormone synthesis includes the following steps: 1. iodide (I-) trapped by the thyroid follicular cells; 2. diffusion of iodide to the apex of the cells 3. transport of iodide into the colloid; 4. oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid; 5. combination of two DIT molecules to form tetraiodothyronine (T4) or of MIT with DIT to form T3; 6. uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT; 7. release of T4 and T3 into the circulation; and 8. deiodination of DIT and MIT to yield tyrosine. T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. TRANSPORT OF THYROID HORMONES: ❖ Thyroxine-binding globulin (TBG), thransthyretin, albumin and lipoproteins ❖ Only about 0.04% of total T4 and 0.4% of T3 exist in the free form (as FT4 and FT3) and it is the serum FT4 and FT3 concentrations that determine the hormones biological activity PERIPHERAL DEIODINATION: ❖ T4 is converted to T3 by deiodinases in the peripheral tissues such as the kidneys and liver. Produces majority of T3. T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form (as FT4 and FT3) and it is the serum-free t4 and free t3 concentrations that determine the hormones biological activity EVALUATION OF THYROID FUNCTION: ❖ serum TSH, FT4 and FT3 THYROID DRUGS LEVOTHYROXINE (T4) ▪ 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 ▪ long half-life (7 days) - permits once-daily to weekly administration ▪ Administration: Intravenous, oral ▪ T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones ▪ Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations ▪ preferable that patients remain on a consistent levothyroxine preparation between refills to avoid changes in bioavailability. ▪ has interactions with certain foods (eg, bran, soy, coffee) and drugs can impair its absorption ▪ thyroxine should be administered on an empty stomach (eg, 60 minutes before meals, 4 hours after meals, or at bedtime) ▪ maintain TSH within an optimal range of 0.5–2.5 mIU/L. ▪ half-life: 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. LIOTHYRONINE (T3) (not avail in the PH) ▪ 3-4x more potent than levothyroxine ▪ Short half-life: 24 hours, hence not recommended because it will require multiple daily doses and difficulty in monitoring its adequacy of replacement by laboratory tests ▪ Administration: intravenous, oral ▪ Reserved for short-term TSH suppression CLINICAL INDICATIONS: 1. Thyroid Hormone Replacement Therapy ❖ HYPOTHYROIDISM- defined as a low level or absence of thyroid hormones. It may be present at birth (congenital) or develop later in life (acquired). ▬ EUTHYROIDISM (Normal thyroid function) 9 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 PRIMARY HYPOTHYROIDISM ▬ due to defects in the thyroid gland itself, is the most common cause of hypothyroidism. SECONDARY or CENTRAL HYPOTHYROIDISM ▬ secondary to defects at the level of the pituitary gland or hypothalamus (hypopituitarism) CONGENITAL: ✓ thyroid gland dysgenesis ACQUIRED: ✓ Hashimoto’s thyroiditis, ✓ Iodine deficiency, ✓ after total thyroidectomy, ✓ after radiation therapy of the head and neck area, ✓ medication (lithium, amiodarone, anti-epileptic drugs) CONGENITAL: ✓ genetic mutations ACQUIRED: ✓ tumors, ✓ hydrocephalus, ✓ infiltrative diseases 2. TSH suppression ❖ T4 dose taken is large enough to suppress blood levels of TSH below the normal TSH range ❖ part of the treatment protocol for differentiated thyroid cancer to prevent recurrence after total thyroidectomy +/radioactive iodine therapy ANTI-THYROID DRUGS ❖ reduce thyroid activity and hormone effects by interfering with the production of thyroid hormones, or by glandular destruction with radiation or surgery. 1.Thioamides (Methimazole, Carbimazole and Propylthiouracil) 2. Iodides 3. Radioactive iodine THIOAMIDES Methimazole | Carbimazole | Propylthiouracil ❖ Methimazole is the active metabolite of Carbimazole ❖ Half-life: o Propylthiouracil (PTU) - 1.5 hrs o Methimazole - 6 hrs. ❖ Administration: o oral administration; o every 6-8 hrs for PTU o every 8 hrs to once a day dosing for methimazole ❖ They are selectively accumulated in the thyroid gland ❖ Both crosses the placenta o PTU is preferably given during the 1st trimester of pregnancy because it is strongly protein-bound hence crosses the placenta less readily PHARMACODYNAMIC ❖ Prevent hormone synthesis by: o inhibiting the thyroid peroxidasecatalyzed reactions o blocking iodine organification o blocking coupling of iodotyrosine ❖ PTU inhibits peripheral deiodination of T4 to T3 ❖ Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3–4 weeks before stores of T4 are depleted. 10 | Page Klem,Jenna,Cam,Charie,Apple PHARMACOLOGY TOXICITY ❖ ADVERSE REACTIONS: seen in 3-12% of treated patients o Maculopapular pruritis rash- most common o Severe hepatitis- reported in PTU o Cholestatic jaundice- more common with methimazole o Agranulocytosis ▪ most dangerous complication (0.1-0.5% of patients) ▪ granulocyte count < 500 cells/mm3 ▪ rapidly reversible when the drug is discontinued IODIDES ▪ Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy. ▪ Inhibits organification and hormone release through inhibition of thyroglobulin proteolysis ▪ Decreases the size and vascularity of hyperplastic thyroid gland ▪ Given orally CLINICAL INDICATION 1. Thyroid storm- thyrotoxic crisis; acute life-threatening, hypermetabolic state caused by excessive release of thyroid hormones. Improvement in thyrotoxic symptoms occurs rapidly with iodide—within 2–7 days 2. Preoperative preparation for thyroid surgery- decrease the vascularity, size, and fragility of a hyperplastic gland ❖ DISADVANTAGES of iodide therapy include an increase in intraglandular stores of iodine, which may delay the onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks. It should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine seems likely ❖ Chronic use of iodides in pregnancy should be avoided, since they cross the placenta and can cause fetal goiter. TOXICITY ❖ ADVERSE REACTIONS to iodine (IODISM) are uncommon and in most cases reversible upon discontinuance. ❖ They include acneiform rash, swollen salivary glands, mucous membrane, ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders, and rarely, anaphylactoid reactions RADIOACTIVE IODINE ▪ 131I is the only isotope used for treatment of thyrotoxicosis. ▪ 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: PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 ✓ 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 is excreted in breast milk. PHARMACOLOGY These are the different manifestations of thyroid disorders; I hope you remember them from your physiology lecture. A normal thyroid hormone level is very important, especially in neonates because undiagnosed and untreated congenital hypothyroidism causes mental retardation. Good news for babies born nowadays, newborn screening is mandatory so congenital hypothyroidism is diagnosed early hence treatment is initiated early also. CLINICAL INDICATIONS: ❖ HYPERTHYROIDISM (thyrotoxicosis) is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone a. Grave’s disease o most common form of hyperthyroidism; diffuse toxic goiter b. Toxic uni-/multinodular goiter c. Thyroid storm- thyrotoxic crisis d. Neonatal Grave’s disease o due to passage of maternal TSH-receptor antibody through the placenta stimulates the thyroid gland of the neonate 11 | Page Klem,Jenna,Cam,Charie,Apple CASE STUDY ANSWER The initial methimazole treatment was appropriate and preferable to propylthiouracil because of its longer duration of action allowing once daily dosing and its improved safety profile. JP presents with the typical signs and symptoms of hypothyroidism following RAI despite levothyroxine replacement. Either radioactive iodine or thyroidectomy are reasonable and effective strategies for definitive treatment of her hyperthyroidism, especially before becoming pregnant to avoid an acute hyperthyroid exacerbation during pregnancy or following delivery. Her hypothyroid symptoms should have been easily corrected by the addition of levothyroxine dosed correctly at 1.7 mcg/kg/ day or 100 mcg daily. Because she is young and has no cardiac disease, full replacement doses were appropriate to start. However, her elevated TSH level indicates inadequate levothyroxine replacement which may be related to nonadherence, or concomitant calcium and omeprazole co-administration. For optimal absorption, levothyroxine should be taken orally 60 minutes before meals on an empty stomach or at bedtime, and separated by 4 hours from her calcium administration. Lower thyroxine doses may also be sufficient if her omeprazole is stopped. Once weekly thyroxine injections may be effective in those with ongoing nonadherence. Thyroid function tests should be monitored after 6–8 weeks of therapy, obtained before thyroxine administration to avoid transient hormone alterations, and the dosage adjusted to achieve a normal TSH level and resolution of hypothyroid symptoms PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 CHECKPOINT 1. The most widely used somatostatin analog a. Somatropin b. Pegvisomant c. Octreotide 2. primarily act as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin a. Somatostatin b. Bromocriptine c. Pegvisomant 3. is a 198-amino-acid peptide hormone produced in the anterior pituitary. Its structure resembles that of GH. a. Prolactin b. Dopamine agonists c. Octreotide 4. first commercial gonadotropin containing both LH and FSH extracted from urine of postmenopausal women a. Menotropins or human menopausal gonadotropin (hMG) b. Human chorionic gonadotropin c. Follicle stimulating hormone 5. It is an antagonist of the oxytocin receptor that has been approved outside the United States as a treatment for preterm labor. a. Conivaptan b. Atosiban c. Ganirelix PHARMACOLOGY 6. Which of the following is the active metabolite of Carbimazole? a. Methimazole b. Propylthiouracil c. Levothyroxine 7. All of the following are toxicities associated with Thioamides, Except? a. Maculopapular pruritis rash b. Severe hepatitis c. Iodism 8. 131I is used in the following, Except? a. Thyroid storm b. Preoperative preparation for thyroid surgery c. Grave’s Disease d. Multinodular goiter 9. This condition is due to defects in the thyroid gland itself and the most common cause of hypothyroidism. a. Primary Hyperthyroidism b. Primary Hypothyroidism c. Secondary Hyperthyroidism 10. Most common cause of hyperthyroidism a. Hashimoto’s Thyroiditis b. Grave’s Disease C/A/A/A/B/A/C/B/B/B APPENDIX ENDOCRINE SYSTEM 1 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 PHARMACOLOGY HYPOTHALAMIC-PITUITARY- TARGET ORGAN SUMMARY HYPOTHALAMIC & PITUITARY HORMONES 2 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 3 | Page PHARMACOLOGY Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.05 ENDOCRINEDRUGS: HYPOTHALAMIC & PITUITARY HORMONES AND THYROID & ANTITHYROID DRUGS Lecturer: DR. SHARON GAWIGAWEN Date: FEBRUARY 23, 2023 PHARMACOLOGY SUMMARY DRUGS USED IN THE MANAGEMENT OF THYROID DISEASE 4 | Page Klem,Jenna,Cam,Charie,Apple