Pharmacology Lecture 6: Pituitary and Thyroid Hormones PDF

Pharmacology Pituitary and thyroid hormones Lec 6 Pharmacology | Pituitary and thyroid hormones Contents : Introduction 3 Hypotalamic and anterior pituitary horomones 4 Adrenocorticotropic hormone (corticotropin) 8 Growth hormone (somatotropin) 14 Somatostatin (growth hormone-inhibiting hormone) 22...

Pharmacology Pituitary and thyroid hormones Lec 6 Pharmacology | Pituitary and thyroid hormones Contents : Introduction 3 Hypotalamic and anterior pituitary horomones 4 Adrenocorticotropic hormone (corticotropin) 8 Growth hormone (somatotropin) 14 Somatostatin (growth hormone-inhibiting hormone) 22 Gonadotropins 26 Prolactin 31 HORMONES OF THE POSTERIOR PITUITARY 34 THYROID HORMONES 40 Pharmacology | Pituitary and thyroid hormones The endocrine system releases hormones into the bloodstream, which carries chemical messengers to target cells throughout the body. Hormones have a much broader range of response time than do nerve impulses, requiring from seconds to days, or longer, to cause a response that may last for weeks or months. An important function of the hypothalamus is to connect the nervous system with the endocrine system via the pituitary gland. Note: Nerve impulses generally act within milliseconds Pharmacology | Pituitary and thyroid hormones HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES The hormones secreted by the hypothalamus and the pituitary are peptides or glycoproteins that act by binding to specific receptor sites on target tissues. The hormones of the anterior pituitary are regulated by neuropeptides that are called either "releasing" or "inhibiting" factors or hormones. These are produced in the hypothalamus, and they reach the pituitary by the hypophyseal portal system. Pharmacology | Pituitary and thyroid hormones Pharmacology | Pituitary and thyroid hormones The interaction of the releasing hormones with receptors results in the activation of genes that promote the synthesis of protein precursors. The protein precursors then undergo posttranslational modification to produce hormones, which are released into the circulation. Each hypothalamic regulatory hormone controls the release of a specific hormone from the anterior pituitary. Pharmacology | Pituitary and thyroid hormones Pituitary hormone preparations are currently used for specific hormonal deficiencies, although most of the agents have limited therapeutic applications. Hormones of the anterior pituitary are administered intramuscularly (IM), subcutaneously, or intranasally because their peptidyl nature makes them susceptible to destruction by proteolytic enzymes of the digestive tract. Pharmacology | Pituitary and thyroid hormones A. Adrenocorticotropic hormone (corticotropin) Corticotropin-releasing hormone (CRH) is responsible for the synthesis and release of the peptide proopiomelanocortin by the pituitary. Adrenocorticotropic hormone (ACTH) or corticotropin is a product of the posttranslational processing of this precursor polypeptide. Note: CRH is used diagnostically to differentiate between Cushing syndrome and ectopic ACTH-producing cells. Pharmacology | Pituitary and thyroid hormones Normally, ACTH is released from the pituitary in pulses with an overriding diurnal rhythm, with the highest concentration occurring in early morning and the lowest in late evening. Stress stimulates its secretion, whereas cortisol acting via negative feedback suppresses its release Pharmacology | Pituitary and thyroid hormones Mechanism of action ACTH binds to receptors on the surface of the adrenal cortex, thereby activating G protein-coupled processes that ultimately stimulate the rate-limiting step in the adrenocorticosteroid synthetic pathway (cholesterol to pregnenolone). This pathway ends with the synthesis and release of adrenocorticosteroids and the adrenal androgens. Pharmacology | Pituitary and thyroid hormones Therapeutic uses The availability of synthetic adrenocorticosteroids with specific properties has limited the use of corticotropin mainly to serving as a diagnostic tool for differentiating between: Primary adrenal insufficiency (Addison disease, associated with adrenal atrophy) and secondary adrenal insufficiency (caused by inadequate secretion of ACTH by the pituitary). Pharmacology | Pituitary and thyroid hormones Therapeutic corticotropin preparations are extracts from the anterior pituitaries of domestic animals or synthetic human ACTH. The latter, cosyntropin, is preferred for the diagnosis of adrenal insufficiency. ACTH is also used in the treatment of infantile spasms and multiple sclerosis. Pharmacology | Pituitary and thyroid hormones Adverse effects Short-term use of ACTH for diagnostic purposes is usually well tolerated. With longer use, toxicities are similar to glucocorticoids and include hypertension, peripheral edema, hypokalemia, emotional disturbances, and increased risk of infection. Pharmacology | Pituitary and thyroid hormones B. Growth hormone (somatotropin) Somatotropin is released by the anterior pituitary in response to growth hormone (GH)-releasing hormone. Conversely, secretion of GH is inhibited by the hormone somatostatin. GH is released in a pulsatile manner, with the highest levels occurring during sleep. Pharmacology | Pituitary and thyroid hormones With increasing age, GH secretion decreases, accompanied by a decrease in lean muscle mass. Somatotropin influences a wide variety of biochemical processes (for example, cell proliferation and bone growth). Synthetic human GH (somatropin) is produced using recombinant DNA technology. Pharmacology | Pituitary and thyroid hormones Mechanism of action Although many physiologic effects of GH are exerted directly at its targets, others are mediated through the somatomedins-insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). GH is a large peptide, the exogenous one, synthesized by gene technology and used as injection; the animal one is ineffective for human. Over secretion of GH before puberty causes Gigantism Over secretion of GH after puberty causes Acromegaly Reduced secretion of GH causes Dwarfism. Pharmacology | Pituitary and thyroid hormones Function of the growth hormones : 1. Glycogenolysis (catabolism of glycogen)→↑ blood sugar 2. - Lipolysis (catabolism of lipid) 3. - protein synthesis 4. - Increase the no of cells and their density including bone and cartilage. Pharmacology | Pituitary and thyroid hormones Therapeutic uses Somatropin is used in the treatment of: 1. GH deficiency. 2. Growth failure in children. 3. treatment of HIV patients with cachexia. 4. GH replacement in adults with confirmed deficiency. Pharmacology | Pituitary and thyroid hormones The synthetic GH (somatrem has longer t1/2 =25 min than natural GH, this drug is given to dwarf patients before puberty because after puberty the closure of long bones epiphysis occur, so administration of GH after puberty causes acromegaly, which characterized by thick skin & bone ,large nose and lower jaw and extremities specially fingers. Pharmacology | Pituitary and thyroid hormones Adverse effects Adverse effects of somatropin include pain at the injection site, edema, arthralgias, myalgias, nausea, and an increased risk of diabetes. Somatropin should not be used in pediatric patients with closed epiphyses, patients with diabetic retinopathy, or obese patients with Prader-Willi syndrome Pharmacology | Pituitary and thyroid hormones C. Somatostatin (growth hormone-inhibiting hormone) In the pituitary, somatostatin binds to receptors that suppress GH and thyroid-stimulating hormone (TSH) release. Originally isolated from the hypothalamus, somatostatin is a small polypeptide found in neurons throughout the body as well as in the intestine, stomach, and pancreas. Somatostatin not only inhibits release of GH but also insulin, glucagon, and gastrin. Pharmacology | Pituitary and thyroid hormones Octreotide and lanreotide are synthetic analogs of somatostatin with longer half-lives. Depot formulations of these agents allow for administration every 4 weeks. They have found use in the treatment of acromegaly and in severe diarrhea/flushing episodes associated with carcinoid tumors. An intravenous infusion of octreotide is also used for the treatment of bleeding esophageal varices. Pharmacology | Pituitary and thyroid hormones Adverse effects Adverse effects of octreotide include bradycardia, diarrhea, abdominal pain, flatulence, nausea, and steatorrhea. Gallbladder emptying is delayed, and asymptomatic cholesterol gallstones can occur with long-term treatment. Pharmacology | Pituitary and thyroid hormones D. Gonadotropins The gonadotropins (FSH and LH) are produced in the anterior pituitary. The regulation of gonadal steroid hormones depends on these agents. They used in the treatment of infertility. Menotropins (also known as human menopausal gonadotropins or hMG) are obtained from urine of postmenopausal women and marketed under trade name (pergonal R) and contain both FSH and LH. Pharmacology | Pituitary and thyroid hormones Pharmacology | Pituitary and thyroid hormones Urofollitropin is FSH obtained from postmenopausal women and is devoid of LH. Follitropin alfa and follitropin beta are human FSH products manufactured using recombinant DNA technology. Human chorionic gonadotropin (hCG) is a placental hormone that is excreted in urine of pregnant women isolated and marketed under trade name R(pregenyl).. Pharmacology | Pituitary and thyroid hormones The effects of hCG and choriogonadotropin alfa (made using recombinant DNA technology) are essentially identical to those of LH. Both preparations administered as IM injection as follow: For infertile women: Give menotropin at 5-12 days of menstrual cycle (for growth and maturation of follicals) followed by HCG at day 13-15 from period for ovulation. For infertile men: Give HCG for maturation of external sexual organs followed by menotropin for induction of spermatogenesis. Pharmacology | Pituitary and thyroid hormones Adverse effects Adverse effects include ovarian enlargement and possible ovarian hyperstimulation syndrome, which may be life threatening. Multiple births can occur. Pharmacology | Pituitary and thyroid hormones E. Prolactin Prolactin is a peptide hormone secreted by the anterior pituitary. Its primary function is to stimulate and maintain lactation. In addition, it decreases sexual drive and reproductive function. Thyrotropinreleasing hormone stimulates the release of prolactin, and secretion is inhibited by dopamine acting at D2 receptors. Note: Drugs that act as dopamine antagonists (for example, metoclopramide and some antipsychotics) can increase the secretion of prolactin Pharmacology | Pituitary and thyroid hormones Hyperprolactinemia, which is associated with galactorrhea and hypogonadism, is treated with D2 receptor agonists, such as bromocriptine and cabergoline. Both of these agents also find use in the treatment of pituitary microadenomas. Bromocriptine is also indicated for treatment of type 2 diabetes. Among their adverse effects are nausea, headache and, less frequently, psychosis. Pharmacology | Pituitary and thyroid hormones Pharmacology | Pituitary and thyroid hormones HORMONES OF THE POSTERIOR PITUITARY In contrast to the hormones of the anterior lobe of the pituitary, those of the posterior lobe, vasopressin and oxytocin, are not regulated by releasing hormones. Instead, they are synthesized in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity or parturition. Both hormones are administered intravenously and have very short half-lives. Pharmacology | Pituitary and thyroid hormones A. Oxytocin Oxytocin is used in obstetrics to stimulate uterine contraction and induce labor. Oxytocin also causes milk ejection by contracting the myoepithelial cells around the mammary alveoli. Although toxicities are uncommon with proper drug use, hypertension, uterine rupture, water retention, and fetal death may occur. Its antidiuretic and pressor activities are much less than those of vasopressin Pharmacology | Pituitary and thyroid hormones B. Vasopressin Vasopressin (antidiuretic hormone) is structurally related to oxytocin. Vasopressin has both antidiuretic and vasopressor effects. In the kidney, it binds to the V2 receptor to increase water permeability and reabsorption in the collecting tubules. Thus, the major use of vasopressin is to treat diabetes insipidus. Pharmacology | Pituitary and thyroid hormones It also finds use in septic shock and in controlling bleeding due to esophageal varices. Other effects of vasopressin are mediated by the V1 receptor, which is found in the liver, vascular smooth muscle (where it causes constriction), and other tissues. The major toxicities of vasopressin are: water intoxication and hyponatremia. Abdominal pain, tremor, and vertigo can also occur. Pharmacology | Pituitary and thyroid hormones Desmopressin, an analog of vasopressin, has minimal activity at the V1 receptor, making it largely free of pressor effects. This analog is longer acting than vasopressin and is preferred for the treatment of diabetes insipidus and nocturnal enuresis. For these indications, desmopressin is administered intranasally or orally. Note: The nasal spray should not be used for enuresis due to reports of seizures in children using this formulation.] Local irritation may occur with the nasal spray. THYROID HORMONES Pharmacology | Pituitary and thyroid hormones THYROID HORMONES The thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for normal function. The two major thyroid hormones are triiodothyronine (T3; the most active form) and thyroxine (T4). Pharmacology | Pituitary and thyroid hormones Normal TH concentration called Euthyroid. High TH concentration called hyperthyroidism or Graves disease or thyrotoxicosis. Low TH concentration called cretinism in children. Low TH concentration called myxoedema in adults. Note: Hyper or hypothyroidism may or not associated with goiter formation. The t1/2 of T3 is 2days, while the: The t1/2 of T4 in euthroid is 7 days The t1/2 of T4 in hyperthyroidism is 3 days The t1/2 of T4 in hypothyroidism is 14 days Pharmacology | Pituitary and thyroid hormones myxoedema Graves disease Pharmacology | Pituitary and thyroid hormones A. Thyroid hormone synthesis and secretion The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with thyroglobulin (the storage form of thyroid hormone). Thyroid function is controlled by TSH (thyrotropin), which is synthesized by the anterior pituitary. TSH action is mediated by cAMP and leads to stimulation of iodide. Pharmacology | Pituitary and thyroid hormones Pharmacology | Pituitary and thyroid hormones Steps of TH synthesis: 1. iodide trapping: active uptake of iodide from circulation into thyroid cells, the concentration of iodide in the thyroid gland is 25 times more than concentration in the blood. 2. Oxidation of iodide to iodine……. 2 I- = I2 3. Coupling of iodide with tyrosine (a.a) forming mono iodic tyrosine in the presence of peroxidase enzyme. Note: The hypothalamic thyrotropin-releasing hormone (TRH) governs the generation of TSH. Pharmacology | Pituitary and thyroid hormones 4. Condensation of 2 molecules of mono iodic tyrosine forming di-iodic tyrosine and then tri iodic tyrosine and tetra-iodic tyrosine in the presence of peroxidase enzyme. About 80% 0f T4 converted to T3 which is biologically 5 times more active than T4. Both T3 and T4 are highly protein binding forming thyroglobulin (TG), especially T4. Both are metabolized by cytochrome p-450 in the liver so they affected by enzyme inducers and inhibitors…… Pharmacology | Pituitary and thyroid hormones B. Mechanism of action Most circulating T3 and T4 is bound to thyroxine-binding globulin in the plasma. The hormones must dissociate from thyroxine-binding globulin prior to entry into cells. In the cell, T4 is enzymatically deiodinated toT3, which enters the nucleus and attaches to specific receptors. The activation of these receptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4. Pharmacology | Pituitary and thyroid hormones C. Pharmacokinetics Both T4 and T3 are absorbed after oral administration. Food, calcium preparations, iron salts, and aluminumcontaining antacids can decrease the absorption of T4. Deiodination is the major route of metabolism of T4. T3 also undergoes sequential deiodination. The hormones are also metabolized via conjugation with glucuronides and sulfates and excreted into bile. Pharmacology | Pituitary and thyroid hormones D. Treatment of hypothyroidism Hypothyroidism usually results from autoimmune destruction of the gland and is diagnosed by elevated TSH. Levothyroxine (T4) is preferred over T3 (liothyronine) or T3/T4 combination products (liotrix) for the treatment of hypothyroidism. Levothyroxine is better tolerated than T3 preparations and has a longer half-life Pharmacology | Pituitary and thyroid hormones It is dosed once daily, and steady state is achieved in 6 to 8 weeks. Toxicity is directly related to T4 levels and manifests as nervousness, palpitations and tachycardia, heat intolerance, and unexplained weight loss. Drugs that induce the cytochrome P-450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of thyroid hormones and may decrease the effectiveness. Pharmacology | Pituitary and thyroid hormones E. Treatment of hyperthyroidism (thyrotoxicosis) Graves’ disease, an autoimmune disease that affects the thyroid, is the most common cause of hyperthyroidism. In these situations, TSH levels are low due to negative feedback. The goal of therapy is to decrease synthesis and/or release of additional hormone. Note: Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone, which, in turn, decreases secretion of TSH. Pharmacology | Pituitary and thyroid hormones This can be accomplished by removing part or all of the thyroid gland, by inhibiting synthesis of the hormones, or by blocking release of hormones from the follicle. 1. Removal of the thyroid This can be accomplished surgically or by destruction of the gland with radioactive iodine (131I), which is selectively taken up by the thyroid follicular cells. Most patients become hypothyroid after radioactive iodine and require treatment with levothyroxine. Pharmacology | Pituitary and thyroid hormones 2. Inhibition of thyroid hormone synthesis The thioamides, propylthiouracil (PTU) and methimazole, are concentrated in the thyroid, where they inhibit both the oxidative processes required for iodination of tyrosyl groups and the condensation (coupling) of iodotyrosines to form T3 and T4. PTU also blocks the peripheral conversion of T4 to T3. Methimazole is preferred over PTU because it has a longer half-life, allowing for once-daily dosing, and a lower incidence of adverse effects. Note: These drugs have no effect on thyroglobulin already stored in the gland. Therefore, clinical effects may be delayed until thyroglobulin stores are depleted. Pharmacology | Pituitary and thyroid hormones However, PTU is recommended during the first trimester of pregnancy due to a greater risk of teratogenic effects with methimazole. PTU has been associated with hepatotoxicity and, rarely, agranulocytosis. Pharmacology | Pituitary and thyroid hormones 3. Blockade of hormone release A pharmacologic dose of iodide inhibits the iodination of tyrosine ("Wolff-Chaikoff effect"), but this effect lasts only a few days. More importantly, iodide inhibits the release of thyroid hormones from thyroglobulin by mechanisms not yet understood. Iodide is employed to treat thyroid storm or prior to surgery, because it decreases the vascularity of the thyroid gland. Pharmacology | Pituitary and thyroid hormones Iodide, administered orally, is not useful for long-term therapy; the thyroid ceases to respond to the drug after a few weeks. Adverse effects include sore mouth and throat, swelling of the tongue or larynx, rashes, ulcerations of mucous membranes, and metallic taste. Pharmacology | Pituitary and thyroid hormones 4. Thyroid storm Thyroid storm presents with extreme symptoms of hyperthyroidism. The treatment of thyroid storm is the same as for hyperthyroidism, except that the drugs are given in higher doses and more frequently. β-blockers, such as metoprolol or propranolol, are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. Pharmacology | Pituitary and thyroid hormones but beta blockers can't be considered as anti-hyperthyroid drugs because: 1. β-blockers don't change the lab-biochemical test results. 2. β-blockers don't treat or block all metabolic effects of TH. 3. β-blockers don't change the course of disease.