Pharmacodynamic Evaluation: Endocrinology PDF

Pharmacodynamic Evaluation: Endocrinology Michael A. B. Naafs Abstract Thiazolidinediones................

Pharmacodynamic Evaluation: Endocrinology Michael A. B. Naafs Abstract Thiazolidinediones................................... 3 In this chapter, pharmacodynamic evaluations DPP-4 Inhibitors..................................... 4 for the most common clinical endocrine disor- GLP-1 Agonists...................................... 4 ders are discussed. SGLT-2 Inhibitors................................... 4 Special attention is given to new classes of oral antidiabetics and new sophisticated insulin Prandial Glucose Regulators........................ 4 analogues. Amylin Analogues................................... 5 Clinical pharmacology in endocrine disor- Insulin Types and Forms............................ 5 ders is reviewed along the classical hypothala- mus-pituitary- adrenal-gonadal axis, while Glucagon.............................................. 5 thyroid disorders are viewed separately. Pituitary-Hypothalamus............................. 6 There is a focus on the hormone receptor ACTH................................................. 6 interaction similarities and the drug-ligand- Growth Hormone.................................... 6 receptor binding. The concept of hormone agonists and antag- Prolactin.............................................. 6 onists has a prominent place. Somatostatin.......................................... 7 Neuroendocrinology pharmacodynamic eval- Melanocyte-Stimulating Hormones................ 7 uation is not included in this chapter. Oxytocin.............................................. 7 Antidiuretic Hormone............................... 8 Contents The Thyroid Gland: Hyper- and Introduction.......................................... 2 Hypothyroidism.................................. 8 Diabetes Mellitus..................................... 2 Methimazole.......................................... 8 Metformin-Biguanides............................... 2 Propylthiouracil...................................... 9 Sulfonylureas......................................... 3 The Parathyroids.................................... 9 Alpha-Glucosidase Inhibitors....................... 3 The Adrenals......................................... 9 Epinephrine.......................................... 10 The Renin-Angiotensin-Aldosterone System...... 11 M.A.B. Naafs (*) Naafs International Health Consultancy, Oldenzaal, Netherlands e-mail: [email protected] # Springer International Publishing AG 2017 1 F.J. Hock, M.R. Gralinski (eds.), Drug Discovery and Evaluation: Methods in Clinical Pharmacology, https://doi.org/10.1007/978-3-319-56637-5_35-1 2 M.A.B. Naafs The Gonadal Sex Steroids........................... 11 Diabetes Mellitus Antiandrogens........................................ 12 Pharmacodynamics in DM can be studied at a Estrogens and Progestogens........................ 13 population level, a mechanism-based mode, a Conclusion............................................ 13 metric model, or a drug-targeted-mediated phar- References and Further Reading................... 13 macodynamic model (Salahudeen and Nishtala 2017). In this section, the clinical pharmacody- namics of the most used oral antidiabetics, insu- Introduction lins, and its analogues will be viewed shortly. Endocrinology is the communication science in internal medicine. Metformin-Biguanides Communication takes place by “classical” hor- mones and paracrine and intracrine mechanisms Metformin improves glucose tolerance in patients and by neuroendocrine signals. Hormones are with type 2 DM lowering both basal and postpran- classified traditionally as amines, peptides, pro- dial plasma glucose by decreasing hepatic glucose teins, and steroids. production, intestinal absorption of glucose, and Endocrinology focuses primarily on the endo- insulin sensitivity by increasing peripheral glu- crine organs that secrete hormones as the pituitary, cose uptake and utilization (Thonos and Gregg thyroid, adrenals, ovaries, testes, and pancreas. 2017). Endocrine diseases are disorders of deficiency, Metformin does not produce hypoglycemia excess, or end-organ resistance to one or more under normal circumstances. Absolute bioavail- hormones. Most endocrine diseases are chronic ability is around 50–60%. Increasing doses results diseases that need lifelong treatment. Diabetes in decreased absorption. Food delays the absorp- mellitus is one of the most common as is hypo- tion of metformin. Peak plasma levels are thyroidism and metabolic syndrome, including achieved at a median 7 h. Metformin has a negli- obesities and dyslipidemia. gible protein bound and is excreted unchanged by Hormones exert their effect in the body by tubular secretion in the urine. No hepatic metabo- binding to a hormone-receptor complex. These lites have been found. The elimination half-life is are a wide family of proteins made up of receptors approximately 17 h. Plasma half-life is 6 h. Met- located on the cell surface as insulin and steroid formin uses the erythrocyte mass as a compart- hormone receptors or in the cytoplasma, so-called ment of distribution. intracellular or nuclear receptors, used, for exam- In elderly the total plasma clearance of metfor- ple, by testosterone. min is delayed due to an age-related decline in After hormone binding to the receptor com- renal function. No pharmacokinetic studies of plex, several pathways can be signaled and acti- metformin have been done in patients with hepatic vate the target cells. This process frequently insufficiency. shows similarities with the process of ligand Metformin is contraindicated in severe renal (drug), receptor, and ligand-receptor interaction impairment (eGFR below 30 ml/min.), known in pharmacodynamics (Salahudeen and Nishtala hypersensitivity to metformin, and acute or 2017). chronic metabolic acidosis, including diabetic In this chapter, the latest pharmacodynamic ketoacidosis. Elderly, debilitated, or malnourished developments for the most common endocrine patients and those with adrenal or pituitary insuf- disorders will be discussed. ficiency are susceptible to the hypoglycemic effects. Beta-adrenergic blockers can mask this effect. Lactic acidosis can be an infrequent complica- tion in metformin users. Metformin decreases Pharmacodynamic Evaluation: Endocrinology 3 liver uptake of lactate. Risk factors are renal admission. Undesired weight gain due to increas- impairment; use of carbonic anhydrase inhibitors, ing insulin secretion is around 2 kg. Sulfonylureas topiramate, and radiologic contrast agents; hyp- act directly on beta cells leading to progressive oxia; and alcohol intoxication. worsening of DM at the end. This phenomenon is In a minority of patients, metformin can lead to called “secondary failure.” Since ATP-potassium- vitamin B12 depletion, mostly without clinical dependent channels are present in cardiac cells symptoms. In these cases, metformin interferes and coronary vessels, sulfonylureas if present at with vitamin B12 absorption from the the time of a myocardial infarction may impair B12-intrinsic factor complex. adequate vasodilatation, resulting in a greater area of myocardial damage (Riddle 2017). Sulfonylureas Alpha-Glucosidase Inhibitors Sulfonylureas are insulin secretagogues which means they work by causing the body to secrete Alpha-glucosidase inhibitors (AGIs) sometimes insulin (Riddle 2017). Sulfonylureas bind to a referred as starch blockers are antidiabetic medicines channel of proteins in the pancreas. This is an that help to reduce post-meal blood glucose levels ATP-potassium channel. Glucose-generated ATP (Laar van de 2008).They do not have a direct effect is the ligand in the pancreatic beta cell to produce on insulin secretion or sensitivity. They work by insulin. slowing down the digestion of carbohydrates Members of this drug class are glimepiride found in starchy foods. Examples of AGIs include (Amaryl), glibenclamide (Daonil), gliclazide acarbose (Glucobay) and miglitol (Glyset). AGIs are (Diamicron), glipizide (Glibenese), and tolbuta- normally used as a single treatment but can be taken mide (Rastinon). Another class of diabetes drugs in combination with sulfonylureas. AGIs slow down which work in this way is the prandial glucose digestion by blocking enzymes in the small intestine regulators, the meglitinides. that break down carbohydrates. All sulfonylureas are absorbed by the intestine, Pharmacokinetic evaluation of acarbose is dif- each one with its specific absorption and bioavail- ficult because only 2% is absorbed. Acarbose ability. After absorption, sulfonylureas bind almost reversely binds to pancreatic-alpha-glucoside completely to plasma proteins on an average of hydrolases. Those enzymes inhibit hydrolysis of 95%. The volume of distribution is about 0.2 l/kg. complex starches to oligosaccharides. Acarbose The biological effect of sulfonylureas lasts raises the glucagon-like peptide (GLP-1) response much longer than their plasma half-life because due to inhibiting gastric emptying. The use of of receptor interaction and formation of active AGIs is limited by gastrointestinal side effects as metabolites persisting 24 h or more. Moreover meteorism, flatulence, and diarrhea. Unexplained their half-life is prolonged in renal failure. severe liver function test disturbances have been Genetic differences can also change the response reported. to sulfonylureas. Some of these gene polymor- phisms were identified in the genes encoding the potassium-ATP channel (KNCJ11 andABCC8). Thiazolidinediones These mutations cause a change in insulin secretion and insulin response to treatment. The thiazolidinediones are also called TZDs or Most sulfonylureas are characterized by renal glitazones. TZDs work by targeting the PPAR- excretion. Gliclazide and above all cliquidone gamma receptor which activates a number of show a predominant biliary clearance. Sulfonylureas genes in the body and plays an important role lower blood glucose by 20% and HbA1C by 1–2%. how the body metabolizes glucose and fat The most common side effect is hypoglycemia, (Marathur et al. 2016). TZDS can therefore help sometimes lasting for hours and requiring hospital boost insulin sensitivity. Pioglitazone (Actos) is 4 M.A.B. Naafs the most known member of this group. Peroxi- GLP-1 agonists stimulate the release of insulin some proliferate-activated receptors (PPARs) are and inhibit the release of glucagon and slow glu- structural similar to steroid or thyroid hormone cose absorption by slowing gastric emptying. The receptors and are subcellular organelles found in GLP-1 receptor is a cell surface receptor which most plant and animal cells. internalizes after stimulation and exerts its effect TZDs are high-affinity ligands for PPAR- by the second messenger adenylyl cyclase. The gamma, a nuclear receptor. PPAR-gamma has GLP-1 receptor is expressed in pancreatic beta been known to regulate adipocyte differentiation, cells and also in the brain where it is involved in fatty acid storage, and glucose metabolism and is the control of appetite. The GLP-1 receptor binds a target of antidiabetic drugs. PPAR-gamma ago- glucagon-like peptide (GLP-1) and glucagon as nists improve insulin resistance by opposing the its natural agonist. effect of tumor necrosis factor-alpha (TNF-alpha) Members of this drug class are exenatide in adipocytes. (Byetta), lixisenatide (Lyxumia), dulaglutide Pioglitazone can be used in type 2 DM alone or (Trulicity), and liraglutide (Victoza). in combination with metformin, a sulfonylurea or in combination with insulin. Pioglitazone has been linked to a significant risk of bladder cancer SGLT-2 Inhibitors in long-time users (Marathur et al. 2016). SGLT-2 inhibitors are a new class of type 2 DM medications They are also called the glifozins. DPP-4 Inhibitors They block the reabsorption of glucose in the kidney, increase glucose excretion, and lower DPP-4 inhibitors are also called gliptins. Gliptins blood glucose levels (Zou et al. 2017). work by blocking the action of dipeptidyl SGLT-2 is a low-affinity, high-capacity glu- peptidase-4 (DPP-4), an enzyme which destroys cose transporter located in the proximal tubule in a group of gastrointestinal hormones called the the kidneys. The pharmacodynamic response to incretins (Hippisley-Cox and Compland 2016; SGLT-2 inhibitors as assessed by urinary glucose Karagiannis et al. 2012). Incretins stimulate the excretion declines with increasing severity of production of insulin after eating and reduce the renal impairment. SGLT-2 inhibitors have a production of glucose by the liver during diges- rapid oral absorption, a long elimination half- tion by its effect on glucagon. life, and an extensive hepatic metabolism mainly Oral glucose stimulates the release of the via glucuronidation to inactive metabolites and a endogenous incretins glucagon-like peptide low renal excretion as a parent drug. (GLP-1) and glucose-dependent insulin-releasing Drugs in this class are dapagliflozin (Forxiga) peptide (GIP).The incretin effect is diminished in and empagliflozin (Jardiance). Adverse effects are type 2 DM. Drugs in this class include sitagliptin yeast infections, urinary tract infections, and dia- (Januvia), vildagliptin (Galvas), and saxagliptin betic ketoacidosis. (Onglyza). DPP-4 inhibitors have been linked with an increased risk of pancreatitis. Prandial Glucose Regulators GLP-1 Agonists Prandial glucose regulators or “glinides” are insu- lin secretagogues working similar like sulfonyl- The GLP-1 agonists are also known as the incretin ureas by the ATP-potassium channel but at a mimetics. These drugs work by mimicking the different site. Unlike sulfonylureas, they have a functions of the natural incretin hormones that rapid onset but relatively short effect. Drugs in help lower post-meal blood sugars (Lovshin this class are repaglinide (Prandin) and 2017). nateglinide (Starlix) (Mondoza et al. 2013). Pharmacodynamic Evaluation: Endocrinology 5 Amylin Analogues All insulins use the insulin receptor, a trans- membrane tyrosine kinase receptor, acting by the Amylin analogues or agonists are injectable drugs phosphorylation pathway. Ligands for this recep- that work similar to the hormone amylin and can tor are insulin; IGF-1 (insulin growth factor); be used in both type 1 and type 2 DM (Marathur IGF-2; the relaxin peptides 1, 2, and 3; and the et al. 2016). Amylin is released by the pancreas at insulin-like peptides 3–6. the same time as insulin but in much smaller There are important pharmacokinetic and phar- quantities, about 1% compared to insulin. macodynamic differences between the long- It inhibits the release of glucagon, slows food acting and rapid-acting insulin analogues emptying from the stomach, and curbs appetite. (Mondoza et al. 2013). These depend on the site Pramlintide acetate (Symlin) is the best known of injection, concentration of the insulin formula, member of this drug class. Symlin is unbound in volume of the injected dose, depth of injection, plasma. The half-life is around 50 min. thickness of the subcutaneous fat layer, exercise, local massage, heat exposure, and finally intrinsic properties of the insulins (Lispkak et al. 2017). Insulin Types and Forms Insulin is usually cleared by receptor-mediated uptake and intracellular degradation. The main Until the 1980s, animal insulin was the only treat- site of plasma extraction is the liver with smaller ment for insulin-dependent DM. Nowadays, largely contributions by adipose tissue and muscle. human insulins and human insulin analogues are used. These are rapid, short-acting, intermediate, and long-acting insulins (Lispkak et al. 2017). Glucagon Examples of rapid-acting insulins are insulin lispro (Humalog) and insulin aspart (Novorapid). Glucagon is produced by the alpha cells and raises Action starts at 15–20 min after s.c. injection and the blood glucose. Glucagon and insulin are part lasts 2–5 h. of a feedback system that keeps blood glucose Short-acting insulins are Actrapid, Humulin S, levels stable. and Velosulin. Action starts at 20 min and lasts Glucagon belongs to the secretin families of 6–8 h. hormones. Blood glucose is elevated by promot- Intermediate insulins are represented by the ing gluconeogenesis and glycogenolysis. Gluca- premixed insulin Humulin I, a human insulin gon also regulates the role of glucose production made up of 30% short-acting (neutral) insulin through lipolysis. Glucagon induces lipolysis and 70% intermediate-acting (isophane) insulin. under conditions of insulin suppression such as It has a peak activity between 1 and 8 h with a type 1 DM. duration of action lasting to 22 h. The glucagon receptor is a membrane G- Long-acting insulins have no peak activity protein-coupled receptor using the adenylate which allows for a basal delivery through the cyclase system as a second messenger. Secretion day. Examples of long-acting insulins are insulin of glucagon is merely stimulated by hypoglyce- glargine (Lantus), insulin detemir (Levemir) or mia and epinephrine and inhibited by insulin and insulin degludec (Tresiba). Lantus has a consis- somatostatin. tent activity of 24 h. The duration of Levemir is Glucagon (GlucaGen) is used as an emergency slightly shorter than Lantus and therefore is often medicine to treat severe hypoglycemia in diabetic injected twice daily. Tresiba has an action duration patients treated with insulin, who have passed out of more than 42 h. or cannot take some form of sugar by the mouth. In addition, there are also premixed human Alternatively, an epinephrine emergency kit insulin analogues which combine a rapid and a (Epipen) can be used in these circumstances long-acting insulin. Examples are Humalog Mix (Posner and Camarga 2017). 25, Humalog Mix 50, and Novomix 30. 6 M.A.B. Naafs Abnormally elevated levels of glucagon may Owing to the fact that GH has a short half-life, be caused by pancreatic tumors, such as several approaches have been taken to create glucagonoma, which include necrolytic erythema long-term agonists. These include the migrans. It may occur alone or in the context of pegylation-sustained release formulations and the genetic multiple endocrine neoplasia (MEN) ligand-receptor fusion proteins. Pegylation of a type 1 syndrome. GH analogue (pegvisomant, Somavert) forms the basis of a successful treatment of acromegaly (Freda et al. 2015). Pituitary-Hypothalamus GH receptor expression can be modified by insulin, thyroid hormones, and sex hormones. The pituitary gland produces various hormones. Pharmacodynamic response to GH analogue In the anterior pituitary gland, ACTH, TSH, LH, injection in GH-deficient children is measured FSH, PRL, GH, and MSH are produced, which act by plasma GH levels, IGF-1 (insulin-like growth on different target glands or cells. The posterior factor), glucose, and free fatty acid (FFA) levels. pituitary produces ADH and oxytocin. The hypo- Synthetic human growth hormone is used in thalamus releases ADH, CRH, GnRH, GHRH, children with HGH deficiency or insufficiency, GHIH (somatostatin), oxytocin, PRH or PIH children born small for gestational age, and girls (dopamine), and TRH. with Turner syndrome, Prader-Willi syndrome, and chronic kidney disease. In adults, the use of HGH includes HGH deficiency to rare pituitary ACTH tumors or their treatment, short bowel syndrome, or muscle wasting associated with HIV/AIDS. ACTH (Synachten) is used as a diagnostic aid in However, the most common use is doping in the assessment of suspected adrenocortical hypo- combination with other performance drugs as ana- function, Addison’s disease. The binding sites of bolic steroids in an attempt to build muscle and ACTH are located in the adrenal cortex where it improve athletic performance. Yet HGH’s effect becomes bound to a specific receptor. By activat- on athletic performance is unknown. ing the adenylate cyclase pathway, the pregneno- Members of the somatotropin drug class are lone is synthesized from cholesterol. From Norditropin, Nutropin, Humatrope, Genotropin, pregnenolone various corticosteroids are formed. and Saizen. Pharmacodynamics are measured as the corti- sol response at 0, 30, and 60 min after intravenous administration of 250 microgram synachten. Prolactin Prolactin (PRL) is a hormone that promotes lacta- Growth Hormone tion in mammals. Prolactin is produced in the front portion of the pituitary. Production of PRL Human growth hormone (GH) is secreted by is controlled by two hormones, dopamine and somatotrope cells in the anterior pituitary in a estrogen. Dopamine inhibits and estrogen pulsatile fashion. The secretion is regulated by increases PRL production. two hypothalamic peptides, growth hormone- Hyperprolactinemia leads to menstrual distur- releasing hormone (GHRH) which stimulates bances, estrogen and testosterone deficiency GH secretion and somatostatin which inhibits reproduction, and disease. Naturally occurring GH secretion by backregulation. GnRH has a half-life of 2–4 min. GnRH agonists The growth hormone receptor belongs to the have substitutions for glycine which significantly family of transmembrane proteins that includes increases the plasma half-life (Niamh 2013). the prolactin receptor. Signal transduction is by GnRH agonists can be used in pulsatile or tyrosine phosphorylation. continuous regimen to treat estrogen-dependent Pharmacodynamic Evaluation: Endocrinology 7 conditions as endometriosis, uterine leiomyomas, Melanocyte-Stimulating Hormones precocious puberty, and menorrhagia. GnRH ana- logues are used extensively during in vitro fertil- The melanocyte-stimulating hormones, alpha, ization cycles to prevent an LH surge and allow beta, and gamma MSH, are collectively known for retrieval of the mature oocytes (Singh et al. as the melanotropins. MSH is produced in the 2014). hypothalamus. Acting in the hypothalamus, The GnRH receptor belongs to the G-protein- alpha MSH suppresses appetite and contributes coupled transmembrane intracellular receptor to sexual arousal. Keratinocytes in the skin use family. They are also present in the gonads. the melanocortin receptor to produce melanin. In men GnRH agonists are used in the treat- An increase in MSH will cause darker skin. ment of prostate carcinoma by reducing the levels MSH increases in humans during pregnancy. of testosterone (Shipley et al. 2017). This causes increased pigmentation in pregnancy. Members of this drug class are goserelin MSH and ACTH share the same precursor mole- (Zoladex) and leuprorelin (Lupron). Pharmacody- cule proopiomelanocortin (POMC). namic response is measured by suppressed testos- For these reasons, patients with Cushing’s dis- terone and PSA (prostate-specific antigen) levels. ease, due to excess ACTH, can have hyper- In women GnRH antagonists are used in infer- pigmentation as acanthosis nigricans. Patients tility treatment. Members of this drug class are with primary Addison’s disease can have ganirelix acetate (Ganirelix) and cetrorelix hyperpigmentation too. (Cetrotide) (37). Different levels of MSH are not the major Pharmacodynamic response is measured by cause of racial variation in skin color. However, LH, FSH, and E2 concentrations. in many red-headed people and other people who do not tan well, there are variations in their hor- mone receptors, causing them not to respond to Somatostatin MSH in the blood. Alpha-MSH analogues as Melanolux are pri- Somatostatin is also known as growth hormone- marily used for their tan-stimulating effect and in inhibiting hormone (GHIH). Somatostatin erythropoietic porphyria. Melatonin is an alpha- inhibits insulin and glucagon secretion. Somato- MSH antagonist and is produced in the hypofyse statin is produced by the hypothalamus and uses from tryptophan precursors. Synthetic melatonin the membrane G-protein-coupled receptor and the (Bio-Melatonin) is used in insomnia and jet lag adenylate cyclase system as a second messenger. (De Leo et al. 2016). Somatostatin is also produced by the delta cells in the pyloric antrum, the duodenum, and the pancreatic islets. Somatostatin inhibits the release Oxytocin of growth hormone by opposing growth hormone- releasing hormone (GHRH), inhibits TSH, and Oxytocin is a hormone that causes contractions inhibits the release of prolactin (PRL). It further during labor and helps shrink the uterus after deliv- inhibits the release of gastrin, cholecystokinin, ery. Oxytocin orders the body to let down milk motilin, vasoactive intestinal polypeptide (VIP), when the baby suckles. It is also known as the gastric inhibitory polypeptide (GIP), and “cuddle hormone” because it is released when peo- enteroglucagon. It also suppresses the exocrine ple snuggle up or bond socially (Zanos et al. 2017). action of the pancreas. The oxytocin receptor is a member of the G- Octreotide (Sandostatin) is a synthetic somato- protein-coupled receptor family. Oxytocin recep- statin analogue used in the treatment of acromegaly, tors are expressed by the myoepithelial cells of the carcinoid syndrome, insulinomas, glucagonomas, mammary and in both the myometrium and endo- and the VIPomas (Freda et al. 2015; metrium at the end of pregnancy. Oxytocin recep- Der-Nigoghossian et al. 2017). tors are also present in the central nervous system. 8 M.A.B. Naafs Oxytocin is used in inducing labor in problem- and the pituitary communicate to maintain T3 and atic pregnancies or in helping to abort the fetus in T4 balance. The hypothalamus produces cases of incomplete abortion or miscarriage. TSH-releasing hormone (TRH) to tell the pituitary Oxytocin (Pitocin) is usually used as an intra- to release thyroid-stimulating hormone (TSH). venous infusion. Pitocin is also used as a nasal When T3 and T4 levels are low in the blood as spray in the treatment of autism. in hypothyroidism, the pituitary releases more Pharmacodynamics of oxytocin are measured TSH to order the thyroid gland to produce more by clinical outcomes. After prolonged exposure, T3 and T4. If T3 and T4 levels are high as in desensitization of oxytocin receptors can occur. hyperthyroidism, the pituitary gland releases less TSH to the thyroid gland to slow the production of these hormones (Campbell et al. 2015). Antidiuretic Hormone The thyroid hormone receptor is a nuclear ret- inoid X receptor. Antidiuretic hormone (ADH) or vasopressin acts Symptoms of hyperthyroidism are anxiety, irri- on the kidney and blood vessels. Vasopressin tability, moodiness, palpitations, sweating, eye helps prevent loss of water from the body by symptoms as exophthalmus, hand trembling, hair reducing urine output and helping the kidneys loss, weight loss, and missed or light menstrual reabsorb water. Vasopressin is used to treat diabe- periods. tes insipidus which is caused by a lack of naturally Symptoms of hypothyroidism are trouble in occurring pituitary hormone (Christ-Crain and sleeping, tiredness and fatigue, difficulty in con- Fenske 2016). centrating, dry coarse skin, weight gain, depres- Vasopressin receptors belong to the G-protein- sion, sensitivity to cold temperature, frequent coupled receptor family. They are located in the heavy periods, and joint and muscle pain. basolateral membrane of the kidney collecting Hyperthyroidism can be treated with antithy- ducts, pituitary gland, and vascular smooth roid medication, thyreostatics, primarily muscle. methimazole (Strumazol) and propylthiouracil Vasopressin is used as an intravenous infusion (PTU). Another option is radioactive iodine or (Pitressin) or as a nasal spray (desmopressin). surgery. Vasopressin antagonists (VRAs) are drugs that block vasopressin receptors. Most commonly VRAs are used to treat hyponatremia caused by Methimazole the syndrome of inappropriate secretion of anti- diuretic hormone (SIADH), congestive heart fail- Thiamazole inhibits the enzyme thyroperoxidase ure (CHF), and cirrhosis (Alagiakrishnan 2016). which normally acts in thyroid hormone synthesis Members of this drug class are the “vaptans” as by oxidizing the anion iodide (I-) to iodine I2, conivaptan (Vaprisol) and tolvaptan (Jinarc). hypoiodous acid (HOI), and enzyme-linked hypo- Pharmacodynamic response can be measured by iodite (EOI) facilitating iodine’s addition to tyro- serum electrolytes and serum and urine osmolar- sine residues on the hormone precursor ities (Streeten et al. 2017). thyroglobulin (TBG) to synthesize T3 and T4. It does not inhibit the sodium-dependent iodide transporter in the thyroid follicular cells. Inhibi- The Thyroid Gland: Hyper- tion of this step requires competitive inhibitors as and Hypothyroidism perchlorate or thiocyanate. Potassium perchlorate is used in the treatment The thyroid gland controls metabolism, the way of amiodarone (Cordarone), an iodide-containing your body uses energy. The thyroid uses iodine in cardiac arrhythmic-induced thyrotoxicosis. your food to make two hormones, triiodothyro- Pharmacodynamic response of the thyreostatics nine (T3) and thyroxine (T4). The hypothalamus are measured by T4 and TSH levels. Pharmacodynamic Evaluation: Endocrinology 9 Propylthiouracil muscles or even tetany. The condition can be inherited, but it is also encountered after thyroid Propylthiouracil (PTU) is mainly used in patients or parathyroid surgery. Teriparatide injection can with hypersensitivity or allergic reactions to be used as a treatment. Calcium replacement and methimazole. PTU inhibits the conversion of T4 vitamin D can ameliorate the symptoms but can to T3 in peripheral tissues and may therefore be an increase the risk of kidney stones and chronic effective treatment for thyroid storm. kidney disease (Black and Rosen 2016). Hypothyroidism is treated with levothyroxine There are a number of rare but well-described (Thyrax) or triiodothyronine (Cytomel). Cytomel genetic conditions affecting PTH metabolism, is used in patients allergic to L-thyroxine. including pseudohypoparathyroidism, familial Pharmacodynamic responses are measured by hypocalciuric hypercalcemia (FHH), and autoso- serum T4, T3, and TSH levels. mal dominant hypocalciuric hypocalcemia. In osteoporotic women, administration of the exogenous 1-34 PTH analogue teriparatide The Parathyroids (Forsteo) by daily s.c. injection in conjunction with estrogens produced increases in bone mass Parathyroid hormone (PTH) is secreted by the and reduced vertebral and non-vertebral fractures. chief cells of the parathyroid glands and acts to The intact1-84 PTH analogue Natpara is also used increase the concentration of ionic calcium. In the in the treatment of osteoporosis. These analogues blood calcitonin, a hormone produced by the C can be used in sequential courses with anti- cells of the thyroid decreases ionic calcium con- resorptive bone agents as the bisphosphonates centration. The PTH receptor is located in the (Loriaux 2017; Rossi et al. 2017). The bone and the kidney. bisphosphonate drug class includes APD PTH reduces the reabsorption of phosphate in (Pamidronate), alendronate (Fosamax), the proximal tubulus of the kidney and stimulates risedronate (Actonel), and ibandronate (Boniva). 1,25 dihydroxyvitamin D, the active vitamin D Bisphosphonates inhibit the digestion of bone metabolite, from 25-hydroxyvitamin D by its by stimulating the osteoclast to undergo apoptosis effect on renal 1 alpha-hydroxylase. PTH or cell death. While bone formation and bone increases calcium absorption in the intestine in resorption are normally coupled and are in bal- conjunction with vitamin D3. ance, the net effect will be increased bone PTH is important in bone remodeling and has a formation. direct stimulating effect on the osteoblast and an Calcitonin (Miacalcin Nasal) has a modest indirect inhibiting effect on the osteoclast. place in the treatment of osteoporosis, because PTH uses the G-protein-coupled protein recep- more effective drugs as bisphosphonates are avail- tor with the adenylyl cyclase system as the second able in the prevention of bone loss. messenger. Hyperparathyroidism, the presence of excess PTH in the blood, occurs in two distinct clinical The Adrenals circumstances. Primary hyperparathyroidism is due to abnormal levels of PTH from the parathy- The adrenal cortex produces glucocorticoids, roid glands by either hyperplasia or an adenoma. mineralocorticoids, androgens, estrogens, and Secondary hyperparathyroidism is due to an inap- progestins. propriate high PTH level seen as a physiological Glucocorticoids have a broad physiological response to hypocalcemia, as seen in renal insuf- role in the regulation of glucose metabolic path- ficiency and vitamin D deficiency. ways, stress, and modulation of the immune sys- Hypoparathyroidism is a decreased function of tem. Mineralocorticoids are key regulators of the parathyroids with low PTH levels leading to mineral and water balance. hypocalcemia, causing cramping and twitching of 10 M.A.B. Naafs Cholesterol is the precursor to all steroid bio- and cortisol have similar affinity to the mineralo- synthesis and is converted to a variety of steroid corticoid receptor. molecules in a series of reactions catalyzed by Primary hyperaldosteronism, Conn’s syn- several cytochrome P450 enzymes. The vast drome, is caused by either adrenal hyperplasia or majority of cholesterol is taken up from the LDL by an adrenal adenoma. This results in hyperten- cholesterol pool. sion and edema due to excessive sodium and Cortisol levels are highest in the morning and water retention and accelerated excretion of potas- are increased by stress or severe infection. Too sium ions (Steinman et al. 2017). much cortisol from any cause lead to Cushing’s Secondary hyperaldosteronism is caused by syndrome, the symptoms and signs of which extra adrenal stimuli, such as renal hypoperfusion, include fat redistribution to the face, upper back, which stimulates the renin-angiotensin-aldoste- and abdomen, weight gain, stretch marks, bruis- rone system (RAAS) with resultant hyper- ing, extra hair growth, irregular periods in women, secretion of aldosterone and edematous disorders loss of muscle, and trouble in sleeping (Posner as congestive heart failure cirrhosis with ascites and Camarga 2017). and nephrotic syndrome. Causes of reduced renal Too little cortisol is part of the syndrome called blood flow include obstructive renal artery disease Addison’s disease marked by low energy, joint and (atheroma, fibromuscular dysplasia of the renal abdominal pain, weight loss, diarrhea, fever, and artery). electrolyte disturbances. If the adrenals make too Important antimineralocorticoids are little cortisol, ACTH levels rise. If the pituitary is spironolactone (Aldactone) and amiloride not working, both ACTH and cortisol levels are low. (Midamor). The glucocorticoid receptor is a G-protein- Mitotane (Lysodren) is a steroidogenesis inhib- coupled nuclear receptor. The receptor is itor used in the treatment of Cushing’s syndrome expressed in almost every cell of the body. and adrenocortical carcinoma. It inhibits the Glucocorticosteroids are used as classical enzymes 11-beta-hydroxylase, 18-beta-hydroxy- glucosteroids or as glucocorticosteroid lase, and 3-beta-hydroxysteroidgenase. (GR) agonists that can be divided in selective and nonselective agonists. Classical glucocorti- coids are hydrocortison, prednisone, predniso- Epinephrine lone, and methylprednisolone. Beclomethasone is a potent nonselective glu- Epinephrine also known as adrenalin is a hor- cocorticoid agonist. Fluticasone is a highly selec- mone, a neurotransmitter, and a drug. tive GR agonist. It plays a role in the fight-or-flight response by Mifepristone and ketoconazole, an anti- increasing blood flow to muscles, output of the mycoticum, are GR antagonists used in the treat- heart, pupil dilation, and blood sugar. It does by ment of Cushing’s syndrome. Mifepristone has a binding to adrenergic alpha- and beta-receptors. fourfold higher affinity for the glucocorticoid As a medication, it is used in anaphylaxis, receptor than dexamethasone being in essential cardiac arrest, and superficial bleeding by i.m. or an antiprogestin. For this reason, it is used to i.v. administration. Inhaled epinephrine may be abort early pregnancies (Singh et al. 2014). used in croup and asthma. Epinephrine is widely The primary mineralocorticoid is aldosterone. used as a nasal decongestant. In anaphylaxis, it is Aldosterone is involved in the retention by sodium used as an Epipen Autoclick. Side effects include by active reabsorption in the collecting tubule of anxiety, shakiness, sweating, and sometimes the kidney, while potassium is actively secreted by broad complex ventricular tachycardia (Kuiper the collecting tubule, and water is passively et al. 2016). reabsorbed. Aldosterone production is under the Norepinephrine is a sympathomimetic drug. influence of ACTH. The mineralocorticoid recep- When given by i.v. injection, it increases heart tor is located in the cytosol in the cell. Aldosterone rate and force and constricts blood vessels making Pharmacodynamic Evaluation: Endocrinology 11 it very useful in the treatment of shock. Sympa- cleaving off two amino acids by the angiotensin- thomimetic and sympatholytic drugs mimic or converting enzyme (ACE) found in the capillaries block the effects of norepinephrine. These are in the body, the lungs, and the epithelial cells of called beta- and alpha-blockers. the kidney. Beta-blockers are used in the treatment of Angiotensin-2 is a potent vasoconstrictor that hypertension, atrial fibrillation, angina pectoris, causes arterioles to constrict resulting in increased congestive heart failure, and performance anxiety arterial blood pressure. Angiotensin-2 also stimu- (Bangalore 2017). Members of this drug class are lates the secretion of aldosterone from the adrenal atenolol (Tenormin), acebutolol (Sectral), meto- cortex.Angiotensin-2 stimulates the release of anti- prolol (Lopressor), pindolol (Viskeen), and pro- diuretic hormone (ADH), also called vasopressin, pranolol (Inderal). a vasoconstrictor too, mainly stimulating water Alpha-blockers are used in the treatment of reabsorption in the kidney and the sense of thirst. hypertension and benign prostate hyperplasia ACE inhibitors, angiotensin receptor blockers through their relaxing effect on the muscles of (ARBs), and direct renin blockers are used in the the neck of the bladder and help in the expulsion treatment of hypertension and congestive heart of bladder stones. They are also used in the treat- failure, preventing stroke, preventing nephropa- ment of anxiety disorders, panic disorders, and thy including diabetic nephropathy, or preventing posttraumatic stress disorders (PTSD). recurrent atrial fibrillation (Boggish et al. 2017). Alpha-blockers include doxazosin mesylate Members of the class of ACE inhibitors are (Cardura), prazosin hydrochlorie (Minipress), captopril (Capoten), enalapril (Renitec), quinapril and dutasteride (Avodart). (Accupril), and ramipril (Altace). Alpha-1-adrenoceptor agonists act as systemic Members of the class of ARBs are valsartan vasoconstrictors. Members of this class are nose (Diovan), losartan (Cozaar), and candesartan and eye drops (Neo-Synephrine, Mydrin). Alpha- (Atacand). 2-adrenoceptor agonists are antihypertensive Aliskiren (Tekturna) is an example of a direct drugs such as clonidine (Catapresan) and alpha- renin inhibitor. methyldopa (Aldomet). Pheochromocytomas are rare adrenal medulla tumors oversecreting the catecholamines epineph- The Gonadal Sex Steroids rine and norepinephrine. Sometimes they are part of a genetic syndrome of multiple endocrine neo- Testosterone and its more potent metabolites dihy- plasia (MEN) type 2 syndrome. drotestosterone, progesterone, and estradiol are classified as sex steroids. Cholesterol is the pre- cursor for these hormones like it is for cortisol and The Renin-Angiotensin-Aldosterone aldosterone. The nonsteroidal hormones, System luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hor- The renin-angiotensin-aldosterone system mones, are usually not regarded as sex hormones, (RAAS) is a hormone system that is involved in although they play major sex-related roles. the regulation of the plasma sodium concentration Natural sex steroids are made by the gonads, and arterial blood pressure. When the plasma ovaries, and testes, by adrenal glands, or by con- sodium concentration is lower than normal or the version from other sex steroid in other tissues as the renal blood flow is reduced, the juxtaglomerular liver or fat. Sex steroids include the androgens cells in the kidney convert prorenin, an intracel- consisting of androstenedione and dehydroepian- lular protein, into renin. Plasma renin then cuts a drosterone (DHEA). Estrogens include estradiol, short ten-amino acid-long peptide off a plasma estriol, and estrone. Progesterone belongs to the protein known as angiotensinogen. This short progestogens. Synthetic sex steroids as synthetic peptide is then converted to angiotensin-2 by androgens are often referred to as anabolic steroids. 12 M.A.B. Naafs Testosterone induces male secondary sex char- clotting factors 2, 5, 7, and 10 as well as pro- acteristics. It has an effect on spermatogenesis and longing prothrombin time. has an androgenic anabolic effect in the mainte- Gynecomastia can occur as a result of the aro- nance of muscle mass. matization of testosterone and AASs. Acne and Androgen agonist steroids (AASs) are syn- male baldness are greatly exacerbated by most thetic modifications of testosterone that are more AASs in susceptible individuals. Worsening or less anabolic or more or less androgenic, hav- benign prostate hyperplasia (BPH) occurs ing different affinity for the testosterone receptor. frequently. The testosterone receptor is an intracellular cyto- AASs as nandrolone decanoate are used in sol receptor. These receptors are located in tissues hemodialysis in combination with recombinant as the scalp, prostate, and skin. erythropoietin (EPO) to treat the anemia of Androgenic effects are likely mediated under chronic renal disease. the influence of dihydrotestosterone (DHT), which is produced by the conversion of testoster- one by the enzyme 5-alpha reductase. DHT has an Antiandrogens affinity for the testosterone receptor three to four times higher than testosterone. Antiandrogens are also known as androgen antag- Other mechanisms of direct and indirect ana- onists or testosterone blockers. They act by bolic effects include anti-glucocorticoid effects by blocking the androgen receptor and/or inhibiting displacement of glucocorticoids from their recep- or suppressing androgen production. tor and increases in circulating insulin-like growth In men antiandrogens are used in the treatment factor (IGF-1) as well as upregulation of IGF-1 of prostate cancer, BHP, androgenic alopecia, receptors. hypersexuality, paraphilias, and precocious Clinically, AASs have been used to treat a host puberty. of conditions including many forms of anemia, In women antiandrogens are used to treat acne, acute and chronic wounds, protein malnutrition, seborrhea, hidradenitis suppurativa, hirsutism, severe burns, short stature, osteoporosis, primary and hyperandrogenism as seen in polycystic or secondary hypogonadism, catabolic states due ovary syndrome (PCOS). Antiandrogens are also to long-term use of corticosteroids, and HIV used in the hormone replacement therapy for wasting syndrome. Testosterone and AASs have transgender women. been used and abused by individuals to augment In males the major side effects are their anabolic and androgenic potential. By doing demasculinization and feminization. The side so, these persons aim to boost their physical per- effects of antiandrogens in woman are minimal. formance in athletic endeavors or improve their A number of antiandrogens have been associ- physique (Taylor et al. 2017; Kshirsagar and ated with hepatotoxicity. Cyproterone acetate, Wankhede 2017). flutamide, and aminoglutethimide are known Common testosterone esters include testoster- for this. one propionate, testosterone enanthate, testoster- Androgen synthesis inhibitors include one cypionate, and methyltestosterone. aminoglutethimide which inhibits the cholesterol Methyltestosterone can be aromatized to the side-cleaving enzyme CYP11A1 which is respon- potent estrogen 17-alpha-methylestradiol. sible for the conversion of cholesterol into preg- Adverse effects are numerous. Cardiovascular nenolone. Ketoconazol and abiraterone are side effects include increased heart rate, increased inhibitors of the enzyme CYP17A1 which con- blood pressure, lowering HDL cholesterol and verts pregnenolone into androgens, mineralocor- increasing LDL cholesterol, lower left ventricular ticoids, and glucocorticoids. To prevent adrenal mass, and ventricular arrhythmias. Nearly all oral insufficiency, Addison’s disease, all these inhibi- AAAs are hepatotoxic in a dose-dependent man- tors require concomitant treatment with a ner. AAAs use also results in suppression of glucocorticoid. Pharmacodynamic Evaluation: Endocrinology 13 5-alpha-reductase inhibitors such as finasteride antiprogestin. Antiprogestins bind strongly to and dutasteride are inhibitors of 5-alpha reduc- both progesterone and glucocorticoid receptors. tase, the enzyme that converts testosterone to Although antiprogestins delay ovulation, this dihydrotestosterone (Woljee et al. 2017). effect is inconsistent unless high doses are given. Antigonadotrofins are drugs which suppress Under these circumstances, the antiprogestin the GnRH-mediated secretion of LH and FSH effect is associated with unopposed estrogen (Crew et al. 2017). action. GnRH agonists and GnRH antagonists are Antiestrogens are mainly used as a means of powerful antigonadotrofins that are able to sup- estrogen deprivation therapy in the treatment of press androgen levels by 95% in men. As men- ER-positive breast cancer. They are also used to tioned before leuprorelin (Lupron) and goserelin treat infertility, male hypogonadism, and gyneco- (Zoladex) are examples of GnRH agonists. An mastia in men and in the hormone replacement for example of a GnRH antagonist is cetolix transgender men. (cetrorelix). Antiestrogens include selective receptor mod- ulators (SERMs) like tamoxifen, clomifene, and raloxifene and selective estrogen receptor Estrogens and Progestogens degraders (SERDs) such as fulvestrant and aro- matase inhibitors (Ais) like anastrozole and pro- Estrogens are the primary female sex hormones gestogens and GnRH analogues. and are important in the estrous cycle in females. Natural estrogens are steroid hormones, while some synthetics are nonsteroidal. Enzymatic Conclusion actions produce estradiol from testosterone while estrone is made from androstenedione. This endocrinology pharmacodynamic evaluation Phytoestrogens have analogous effects of clearly shows the enormous impact of endocrinol- human estrogens in serving to reduce menopausal ogy in nearly all areas of medicine. If you could symptoms as well the risk of osteoporosis and take a look in the medicine cabinet of an older heart disease. Western patient, you would recognize all classes Progesterone is a steroid hormone involved in of medicines that came along in this review. the luteal phase of the menstrual cycle. Progester- one is produced in the ovaries and adrenals and in pregnancy and is synthesized from pregnenolone. 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Circulation 135:1991–2002 Campbell EJ, Campbell GM, Hanley DA (2015) The effect progesterone levels is possibly one step that facil- of parathyroid hormone and teriparatide on fracture itates the onset of labor. healing. Expert Opin Biol Ther 15(1):119–129 The combined oral contraceptive pill contains Christ-Crain M, Fenske W (2016) Copeptin in the diagno- estrogens and progestogens. Morning-after pills sis of vasopressin-dependent disorders of fluid homeo- stasis. Nat Rev Endocrinol 12:168–176 and abortion pills contain only progestogens as Mifepristone and Misoprostol. Mifepristone is an 14 M.A.B. Naafs Crew KD, Albain KS, Horshman Dl et al (2017) How do Mondoza G, Piroletta A, Jiminez-Ceja LM (2013) The role we do increase uptake of tamoxifen and other anti- of nateglinide and repaglinide, derivatives of estrogens for breast cancer prevention. 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