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Oxytocin final

pharmacology of oxytocin and sex steroids

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Oxytocin final

  1. 1. Oxytocin Biosynthesis of Oxytocin Oxytocin is a cyclic nona peptide that differs from vasopressin by only two amino acids. It is synthesized as a larger precursor molecule in cell bodies of the paraventricular nucleus, and to a lesser extent, the supraoptic nucleus in the hypothalamus. The precursor is rapidly converted by proteolysis to the active hormone and its neurophysin, packaged into secretory granules as an oxytocin-neurophysin complex, and secreted from nerve endings that terminate primarily in the posterior pituitary gland (neurohypophysis).
  2. 2. • Oxytocin (OT) – from paraventricular nucleus Target = smooth muscle in uterus and breast Effect = contraction of muscle (labor, milk ejection, sexual arousal – “cuddle” hormone.) Regulation = hormonal changes during pregnancy, suckling • Clinical summary: • Oxytocin is used to induce labor or to augment its progression. After delivery, oxytocin also can be used to increase uterine tone and diminish postpartum hemorrhage. • In contrast, the oxytocin receptor antagonist, atosiban, can be used to suppress uterine contractions in the setting of premature labor; its precise role relative to other drugs is still under evaluation.
  3. 3. • Stimuli for oxytocin secretion include sensory stimuli arising from dilation of the cervix and vagina and from suckling at the breast. • Increases in circulating oxytocin in women in labor are difficult to detect, partly because of the pulsatile nature of oxytocin secretion and partly because of the activity of circulating oxytocinase. • Nevertheless, increased oxytocin in maternal circulation is detected in the second stage of labor, likely triggered by sustained distension of the uterine cervix and vagina. • Estradiol stimulates oxytocin secretion, whereas the ovarian polypeptide relaxin inhibits release. The inhibitory effect of relaxin appears to be the net result of a direct stimulatory effect on oxytocin-producing cells and an inhibitory action mediated indirectly by endogenous opioids.
  4. 4. • Physiological Roles of Oxytocin Uterus. The human uterus has a very low level of motor activity during the first two trimesters of pregnancy. • During the third trimester, spontaneous motor activity increases progressively until the sharp rise that constitutes the initiation of labor. Oxytocin stimulates the frequency and force of uterine contractions. • Uterine responsiveness to oxytocin roughly parallels this increase in spontaneous activity and is highly dependent on estrogen, which increases the expression of the oxytocin receptors. • An eightfold increase in uterine sensitivity to oxytocin occurs in the last half of pregnancy, mostly in the last 9 weeks, accompanied by a thirtyfold increase in oxytocin receptor number between early pregnancy and early labor
  5. 5. The finding that the oxytocin antagonist atosiban (TRACTOCILE) is effective in suppressing preterm labor further supports the physiological importance of oxytocin in this setting. • Breast. Oxytocin plays an important physiological role in milk ejection. Stimulation of the breast through suckling or mechanical manipulation induces oxytocin secretion, causing contraction of the myoepithelium that surrounds alveolar channels in the mammary gland. This action forces milk from the alveolar channels into large collecting sinuses, where it is available to the suckling infant. Mechanism of Action Oxytocin acts via specific G protein-coupled receptors closely related to the V1a and V2 vasopressin receptors. In the human myometrium, these receptors couple to Gq and G11, activating the PLCb-IP3-Ca2+ pathway and enhancing activation of voltage-sensitive Ca2+ channels. Oxytocin also increases local prostaglandin production, which further stimulates uterine contractions.
  6. 6. • Clinical Use of Oxytocin Induction of Labor. Uterine-stimulating agents are used most frequently to induce or augment labor in selected pregnant women. • Indications for induction of labor include situations in which the risk of continued pregnancy to the mother or fetus is considered to be greater than the risks of delivery or of pharmacological induction. • Such circumstances include premature rupture of the membranes, isoimmunization, fetal growth restriction, and uteroplacental insufficiency (as in diabetes, preeclampsia, or eclampsia). • Oxytocin (PITOCIN, SYNTOCINON) is the drug of choice for labor induction. It is administered by intravenous infusion of a diluted solution (typically 10 mIU/mL), preferably by means of an infusion pump.
  7. 7. • Augmentation of Labor. Because the resulting uterine hyperstimulation often is too forceful and sustained to be compatible with the safety of the mother and fetus, oxytocin generally should not be used to augment labor that is progressing normally. • To augment hypotonic contractions in dysfunctional labor, it rarely is necessary to exceed an infusion rate of 10 mIU/minute, and doses of >20 mIU/minute rarely are effective when lower concentrations fail. • Third Stage of Labor and Puerperium. Postpartum hemorrhage is a significant problem in developed nations and is of even greater importance in underdeveloped countries. After delivery of the fetus or after therapeutic abortion, a firm, contracted uterus greatly reduces the incidence and extent of hemorrhage. Oxytocin (10 IU/minute intramuscularly) often is given immediately after delivery to help maintain uterine contractions and tone.
  8. 8. • Oxytocin Challenge Test. In patients whose pregnancy holds increased risk for maternal or fetal complications (e.g., maternal diabetes mellitus or hypertension), an oxytocin challenge test can be used to assess fetal well-being. • Oxytocin is infused intravenously, initially at a rate of 0.5 mIU/minute; this rate is increased slowly until 3 uterine contractions occur in 10 minutes. • Oxytocin-Receptor Antagonists Peptide analogs that competitively inhibit the interaction of oxytocin with its membrane receptor have been developed, and one such antagonist, atosiban, has been introduced in a number of countries for the treatment of preterm labor. • In clinical trials, atosiban decreased the frequency of uterine contractions and increased the number of women who remained undelivered, with at least comparable efficacy to b adrenergic agonists but with a lower incidence of side effects
  9. 9. • Oxytocin is a peptide hormone of the posterior pituitary gland. It stimulates the contractions of the pregnant uterus, which becomes much more sensitive to it at term. Patients with posterior pituitary disease(diabetes insipidus) can, however, go into labour normally. • Oxytocin is structurally close to vasopressin and it is no surprise that it also has antidiuretic activity. Serious water intoxication can occur with prolonged i.v. infusions, especially where accompanied by large volumes of fluid. • The association of oxytocin with neonatal jaundice appears to be due to increased erythrocyte fragility causing haemolysis. Oxytocin has been supplanted by the Methylergometrine (Methergin®), as the prime treatment of postpartum haemorrhage. • Oxytocin is reflexly released from the pituitary following suckling (also by manual stimulation of the nipple) and causes almost immediate contraction of the myoepithelium of the breast.
  10. 10. Oxytocin is used i.v. in the induction of labour. It produces, almost immediately, rhythmic contractions with relaxation between, i.e. it mimics normal uterine activity. The decision to use oxytocin requires special skill. It has a t1/2 of 6 min and is given by i.v. infusion using a pump; it must be closely supervised; the dose is adjusted by the results; overdose can cause uterine tetany and even rupture. Atosiban is a modified form of oxytocin that inhibits the action of this hormone on the uterus, leading to a cessation of contractions. It is used i.v. as a tocolytic to halt premature labor. Barusiban is three to four times more potent antagonist than atosiban with higher affinity and selectivity for the oxytocin receptor
  11. 11. Adreno corticotropic hormones • Corticotropin Releasing Hormone (CRH) Target = anterior pituitary gland Effect = stim. release of adrenocorticotropic hormone (ACTH) Regulation = blood glucose levels, stress, interleukin -1
  12. 12. • ADRENOCORTICOTROPIC HORMONE; Adrenocorticotropic hormone (ACTH, also called corticotropin) and the steroid hormone products of the adrenal cortex are considered together because the major physiological and pharmacological effects of ACTH result from its action to increase the circulating levels of adrenocortical steroids. • Synthetic derivatives of ACTH are used principally in the diagnostic assessment of adrenocortical function. Because all known therapeutic effects of ACTH can be achieved with corticosteroids, synthetic steroid hormones generally are used therapeutically instead of ACTH. • Corticosteroids and their biologically active synthetic derivatives differ in their metabolic (glucocorticoid) and electrolyte-regulating (mineralocorticoid) activities. These agents are employed at physiological doses for replacement therapy when endogenous production is impaired.
  13. 13. • ACTH is synthesized as part of a larger precursor protein, pro- opiomelanocortin (POMC), and is liberated from the precursor through proteolytic cleavage at dibasic residues by the enzyme prohormone convertase 1 . • Impaired processing of POMC due to a mutation in prohormone convertase 1 has been implicated in the pathogenesis of a human disorder that presents with adrenal insufficiency, childhood obesity, hypogonadotropic hypogonadism, and diabetes. • A number of other biologically important peptides, including endorphins, lipotropins, and the melanocyte-stimulating hormones (MSH), also are produced from the same POMC precursor. • The actions of ACTH and the other melanocortins liberated from POMC are mediated by their specific interactions with five melanocortin receptor (MCR) subtypes comprising a distinct subfamily of G protein-coupled receptors
  14. 14. • Actions on the Adrenal Cortex. Acting via MC2R, ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and the androgen precursor dehydroepiandrosterone (DHEA) that can be converted peripherally into more potent androgens. • The adrenal cortex histologically and functionally can be separated into three zones that produce different steroid products under different regulatory influences. • The outer zona glomerulosa secretes the mineralocorticoid aldosterone, the middle zona fasciculata secretes the glucocorticoid cortisol, and the inner zona reticularis secretes DHEA and its sulfated derivative. • In the absence of the anterior pituitary, the inner zones of the cortex atrophy, and the production of glucocorticoids and adrenal androgens is markedly impaired.
  15. 15. 15 Adrenal (suprarenal) glands • Each is really two endocrine glands – Adrenal cortex (outer) – Adrenal medulla (inner) • Unrelated chemicals but all help with extreme situations
  16. 16. • Persistently elevated levels of ACTH, due either to repeated administration of large doses of ACTH or to excessive endogenous production, induce hyperplasia and hypertrophy of the inner zones of the adrenal cortex, with overproduction of cortisol and adrenal androgens. • Adrenal hyperplasia is most marked in congenital disorders of steroidogenesis, in which ACTH levels are continuously elevated as a secondary response to impaired cortisol biosynthesis. • Mechanism of Action. ACTH stimulates the synthesis and release of adrenocortical hormones. As specific mechanisms for steroid hormone secretion have not been defined and since steroids do not accumulate appreciably in the gland, it is believed that the actions of ACTH to increase steroid hormone production are mediated predominantly at the level of de novo biosynthesis.
  17. 17. • Extra-Adrenal Effects of ACTH. In large doses, ACTH causes a number of metabolic changes in adrenalectomized animals, including ketosis, lipolysis, hypoglycemia (immediately after treatment), and resistance to insulin (later after treatment). • Because of the large doses of ACTH required, the physiological significance of these extra-adrenal effects is questionable. ACTH also improves learning in experimental animals; this latter effect appears to be non-endocrine and mediated via distinct receptors in the central nervous system. • Regulation of ACTH Secretion. Hypothalamic-Pituitary- Adrenal Axis. The rate of glucocorticoid secretion is determined by fluctuations in the release of ACTH by the pituitary corticotropes. These corticotropes, in turn, are regulated by corticotropin-releasing hormone (CRH), a peptide hormone released by CRH neurons of the endocrine hypothalamus.
  18. 18. • Central Nervous System. The central nervous system integrates a number of positive and negative influences on ACTH secretion that are conveyed by several neurotransmitters. • These signals converge on the CRH neurons, which are clustered largely in the parvocellular region of the paraventricular hypothalamic nucleus and make axonal connections to the median eminence of the hypothalamus. • Arginine Vasopressin. Arginine vasopressin (AVP) also acts as a secretagogue for corticotropes, significantly potentiating the effects of CRH. Like CRH, AVP is produced in the parvocellular neurons of the paraventricular nucleus and secreted into the pituitary plexus from the median eminence. • Negative Feedback of Glucocorticoids. Glucocorticoids inhibit ACTH secretion via direct and indirect actions on CRH neurons to decrease CRH mRNA levels and CRH release and via direct effects on corticotropes.
  19. 19. • The Stress Response. Stress overcomes negative feedback regulation of the HPA axis, leading to a marked rise in corticosteroid production. Examples of stress signals include injury, hemorrhage, severe infection, major surgery, hypoglycemia, cold, pain, and fear. • Assays for ACTH. Initially, ACTH levels were assessed by bioassays that measured induced steroid production or the depletion of adrenal ascorbic acid. • Radioimmunoassays that subsequently were developed to quantitate ACTH levels in individual patients were not always reproducible and did not clearly differentiate between low and normal levels of ACTH. • Immunochemiluminescent assays that use two separate antibodies directed at distinct epitopes on the ACTH molecule now are widely available.
  20. 20. • Therapeutic Uses and Diagnostic Applications of ACTH. There are anecdotal reports that selected conditions respond better to ACTH than to corticosteroids (e.g., multiple sclerosis), and some clinicians continue to advocate therapy with ACTH. • Despite this, ACTH currently has only limited utility as a therapeutic agent. Therapy with ACTH is less predictable and less convenient than therapy with corticosteroids • Testing the Integrity of the HPA Axis. The major clinical use of ACTH is in testing the integrity of the HPA axis. Other tests used to assess the HPA axis include the insulin tolerance test and the metyrapone test. Cosyntropin (CORTROSYN, SYNACTHEN) is a synthetic peptide that corresponds to residues 1 to 24 of human ACTH.
  21. 21. • CRH Stimulation Test. Ovine CRH (corticorelin [ACTHREL]) and human CRH are available for diagnostic testing of the HPA axis. • In patients with documented ACTH-dependent hypercorticism, CRH testing may help differentiate between a pituitary source (i.e., Cushing's disease) and an ectopic source of ACTH. • At the recommended dose, CRH generally is well tolerated, although flushing may occur, particularly if the dose is administered as a bolus. • Patients with Cushing's disease respond to CRH with either a normal or an exaggerated increase in ACTH, whereas ACTH levels do not increase in patients with ectopic sources of ACTH.
  22. 22. • In this test, an inferior petrosal/peripheral ratio of >2.5 supports a pituitary source of ACTH. When performed by a skilled neuroradiologist, this procedure increases diagnostic accuracy with a tolerable risk of complications from the catheterization procedure . Absorption and Fate. ACTH is readily absorbed from parenteral sites. The hormone rapidly disappears from the circulation after intravenous administration; in humans, the half-life in plasma is about 15 minutes, primarily due to rapid enzymatic hydrolysis. Toxicity of ACTH. Aside from rare hypersensitivity reactions, the toxicity of ACTH is primarily attributable to the increased secretion of corticosteroids. Cosyntropin generally is less antigenic than native ACTH; thus cosyntropin is the preferred agent for clinical use.
  23. 23. 23 Adrenal Gland • Adrenal cortex – Secretes lipid-based steroid hormones, called “corticosteroids” – “cortico” as in “cortex” • MINERALOCORTICOIDS-Aldosterone is the main one • GLUCOCORTICOIDS-Cortisol (hydrocortisone) is the main Adrenal medulla:Secretes epinephrine& norepinephrine Aldosterone (main mineral corticoid)Secreted by adrenal cortex in response to a decline in either blood volume or blood pressure (e.g. severe hemorrhage) – Is terminal hormone in renin-angiotensin mechanism • Prompts distal and collecting tubules in kidney to reabsorb more sodium:-Water passively follows -Blood volume thus increases
  24. 24. 24 Cortisol, the most important glucocorticoid Glucocorticoid receptors are found in the cells of most vertebrate tissues) • It is essential for life • Helps the body deal with stressful situations within minutes – Physical: trauma, surgery, exercise – Psychological: anxiety, depression, crowding – Physiological: fasting, hypoglycemia, fever, infection • Regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions including water balance People with adrenal insufficiency: these stresses can cause hypotension, shock and death: must give glucocorticoids, eg for surgery or if have infection, etc.
  25. 25. 25 Cortisol, continued • Keeps blood glucose levels high enough to support brain’s activity – Forces other body cells to switch to fats and amino acids as energy sources • Catabolic: break down protein • Redirects circulating lymphocytes to lymphoid and peripheral tissues where pathogens usually are • In large quantities, depresses immune and inflammatory response – Used therapeutically – Responsible for some of its side effects
  26. 26. 26 Hormonal stimulation of glucocorticoids HPA axis (hypothalamic/pituitary/adrenal axis) • With stress, hypothalamus sends CRH to anterior pituitary (adenohypophysis) • Pituitary secretes ACTH • ACTH goes to adrenal cortex where stimulates glucocorticoid secretion – Sympathetic nervous system can also stimulate it • Adrenal cortex also secretes DHEA (dehydroepiandrosterone) – Converted in peripheral tissues to testosterone and estrogen (also steroid hormones) – Unclear function in relation to stress
  27. 27. Adrenal Glands Cortex – 80-90% Derived from mesoderm Produce over 2 dozen steroid hormones essential to life from cholesterol. 3 zones: Zona glomerulosa – outer zone Produces mineralcorticoids – affect Na+ & K+ Aldosterone – 95% • Acts on kidney tubules • Causes resorption of Na+ which also increases resorption of Cl-, HCO3 - & H2O
  28. 28. – adrenocortical steroids Introduction The adrenal cortex synthesizes two classes of steroids: the corticosteroids (glucocorticoids and mineralocorticoids), which have 21 carbon atoms, and the androgens, which have 19. The actions of corticosteroids historically were described as glucocorticoid (carbohydrate metabolism-regulating) and mineralocorticoid (electrolyte balance-regulating), reflecting their preferential activities. In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the main mineralocorticoid Although the adrenal cortex is an important source of androgen precursors in women, patients with adrenal insufficiency can be restored to normal life expectancy by replacement therapy with glucocorticoids and mineralocorticoids. Nevertheless, some recent studies have shown that addition of DHEA to the standard replacement regimen in women with adrenal insufficiency improved subjective well-being and sexuality
  29. 29. • Physiological Functions and Pharmacological Effects Physiological Actions. The effects of corticosteroids are numerous and widespread, and include alterations in carbohydrate, protein, and lipid metabolism; maintenance of fluid and electrolyte balance; and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. In addition, corticosteroids endow the organism with the capacity to resist such stressful circumstances as noxious stimuli and environmental changes. The actions of corticosteroids are interrelated to those of other hormones. For example, in the absence of lipolytic hormones, cortisol has virtually no effect on the rate of lipolysis by adipocytes. Likewise, in the absence of glucocorticoids, epinephrine and norepinephrine have only minor effects on lipolysis.
  30. 30. • Corticosteroids are grouped according to their relative potencies in Na+ retention, effects on carbohydrate metabolism (i.e., hepatic deposition of glycogen and gluconeogenesis), and antiinflammatory effects. • In general, potencies of steroids as judged by their ability to sustain life in adrenalectomized animals closely parallel those determined for Na+ retention, while potencies based on effects on glucose metabolism closely parallel those for antiinflammatory effects. • The effects on Na+ retention and the carbohydrate/ antiinflammatory actions are not closely related and reflect selective actions at distinct receptors. • Some steroids that are classified predominantly as glucocorticoids (e.g., cortisol) also possess modest but significant mineralocorticoid activity and thus may affect fluid and electrolyte handling in the clinical setting.
  31. 31. • General Mechanisms for Corticosteroid Effects. Corticosteroids interact with specific receptor proteins in target tissues to regulate the expression of corticosteroid- responsive genes, thereby changing the levels and array of proteins synthesized by the various target tissues . • As a consequence of the time required to modulate gene expression and protein synthesis, most effects of corticosteroids are not immediate but become apparent after several hours. • The receptors for corticosteroids are members of the nuclear receptor family of transcription factors that transduce the effects of a diverse array of small, hydrophobic ligands, including the steroid hormones, thyroid hormone, vitamin D, and retinoids. • These receptors share two highly conserved domains: a region of approximately 70 amino acids forming two zinc- binding domains, called zinc fingers.
  32. 32. • Glucocorticoid Receptor. The GR resides predominantly in the cytoplasm in an inactive form until it binds glucocorticoids . • Steroid binding results in receptor activation and translocation to the nucleus. The inactive GR is complexed with other proteins, including heat-shock protein (HSP) • Regulation of Gene Expression by Glucocorticoids. After ligand binding, the GR dissociates from its associated proteins and translocates to the nucleus. There, it interacts with specific DNA sequences within the regulatory regions of affected genes. • The short DNA sequences that are recognized by the activated GR are called glucocorticoid responsive elements (GREs) and provide specificity to the induction of gene transcription by glucocorticoids.90, a member of the heat- shock family of stress-induced protein.
  33. 33. • The recognition that the metabolic effects of glucocorticoids generally are mediated by transcriptional activation, while the antiinflammatory effects largely are mediated by transrepression, suggests that selective GR ligands may maintain the antiinflammatory actions while lessening the metabolic side effects. • Regulation of Gene Expression by Mineralocorticoids. Like the GR, MR also is a ligand-activated transcription factor and binds to a very similar, if not identical, hormone-responsive element. • Although its actions have been studied in less detail than the GR, the basic principles of action appear to be similar; in particular, the MR also associates with HSP90 and activates the transcription of discrete sets of genes within target tissues.
  34. 34. • Aldosterone exerts its effects on Na+ and K+ homeostasis primarily via its actions on the principal cells of the distal renal tubules and collecting ducts, while the effects on H+ secretion largely are exerted in the intercalated cells. • Receptor-Independent Mechanism for Corticosteroid Specificity. The availability of cloned genes encoding the GR and MR led to the surprising finding that aldosterone (a classic mineralocorticoid) and cortisol (generally viewed as predominantly glucocorticoid) binds the MR with equal affinity. • Carbohydrate and Protein Metabolism. Corticosteroids profoundly affect carbohydrate and protein metabolism. Teleologically, these effects of glucocorticoids on intermediary metabolism can be viewed as protecting glucose-dependent tissues (e.g., the brain and heart) from starvation. They stimulate the liver to form glucose from amino acids and glycerol and to store glucose as liver glycogen.
  35. 35. • The mechanisms by which glucocorticoids inhibit glucose utilization in peripheral tissues are not fully understood. • Glucocorticoids decrease glucose uptake in adipose tissue, skin, fibroblasts, thymocytes, and polymorphonuclear leukocytes; these effects are postulated to result from translocation of the glucose transporters from the plasma membrane to an intracellular location. • These peripheral effects are associated with a number of catabolic actions, including atrophy of lymphoid tissue, decreased muscle mass, negative nitrogen balance, and thinning of the skin. • Lipid Metabolism. Two effects of corticosteroids on lipid metabolism are firmly established. The first is the dramatic redistribution of body fat that occurs in settings of endogenous or pharmacologically induced hypercorticism, such as Cushing's syndrome.
  36. 36. • Electrolyte and Water Balance. Aldosterone is by far the most potent endogenous corticosteroid with respect to fluid and electrolyte balance. • Thus, electrolyte balance is relatively normal in patients with adrenal insufficiency due to pituitary disease, despite the loss of glucocorticoid production by the inner cortical zones. • Mineralocorticoids act on the distal tubules and collecting ducts of the kidney to enhance reabsorption of Na+ from the tubular fluid; they also increase the urinary excretion of K+ and H+. • These actions on electrolyte transport, in the kidney and in other tissues (e.g., colon, salivary glands, and sweat glands), appear to account for the physiological and pharmacological activities that are characteristic of mineralocorticoids.
  37. 37. • Thus, the primary features of hyperaldosteronism are positive Na+ balance with consequent expansion of extracellular fluid volume, normal or slight increases in plasma Na+ concentration, hypokalemia, and alkalosis. • Mineralocorticoid deficiency, in contrast, leads to Na+ wasting and contraction of the extracellular fluid volume, hyponatremia, hyperkalemia, and acidosis. • Glucocorticoids also exert effects on fluid and electrolyte balance, largely due to permissive effects on tubular function and actions that maintain glomerular filtration rate. • Glucocorticoids play a permissive role in the renal excretion of free water; the ability to excrete a water challenge was used at one time to diagnose adrenal insufficiency. In part, the inability of patients with glucocorticoid deficiency to excrete free water results from the increased secretion of AVP, which stimulates water reabsorption in the kidney.
  38. 38. • Cardiovascular System. The most striking effects of corticosteroids on the cardiovascular system result from mineralocorticoid-induced changes in renal Na+ excretion, as is evident in primary aldosteronism. • The resultant hypertension can lead to a diverse group of adverse effects on the cardiovascular system, including increased atherosclerosis, cerebral hemorrhage, stroke, and hypertensive cardiomyopathy. • The second major action of corticosteroids on the cardiovascular system is to enhance vascular reactivity to other vasoactive substances. • Conversely, hypertension is seen in patients with excessive glucocorticoid secretion, occurring in most patients with Cushing's syndrome and in a subset of patients treated with synthetic glucocorticoids (even those lacking any significant mineralocorticoid action).
  39. 39. Skeletal Muscle. Permissive concentrations of corticosteroids are required for the normal function of skeletal muscle, and diminished work capacity is a prominent sign of adrenocortical insufficiency. In patients with Addison's disease, weakness and fatigue are frequent symptoms that may reflect an inadequacy of the circulatory system. Excessive amounts of either glucocorticoids or mineralocorticoids also impair muscle function. • Central Nervous System. Corticosteroids exert a number of indirect effects on the CNS, through maintenance of blood pressure, plasma glucose concentrations, and electrolyte concentrations. Increasingly, direct effects of corticosteroids on the CNS have been recognized, including effects on mood, behavior, and brain excitability.
  40. 40. Patients with adrenal insufficiency exhibit a diverse array of psychiatric manifestations, including apathy, depression, and irritability; some patients are frankly psychotic. Formed Elements of Blood. Glucocorticoids exert minor effects on hemoglobin and erythrocyte content of blood, as evidenced by the frequent occurrence of polycythemia in Cushing's syndrome and of normochromic, normocytic anemia in adrenal insufficiency. More profound effects are seen in the setting of autoimmune hemolytic anemia, in which the immunosuppressive effects of glucocorticoids can diminish the self-destruction of erythrocytes. Antiinflammatory and Immunosuppressive Actions. In addition to their effects on lymphocyte number, corticosteroids profoundly alter the immune responses of lymphocytes
  41. 41. • These effects are an important facet of the antiinflammatory and immunosuppressive actions of the glucocorticoids. Glucocorticoids can prevent or suppress inflammation in response to multiple inciting events, including radiant, mechanical, chemical, infectious, and immunological stimuli. • Stresses such as injury, infection, and disease result in the increased production of cytokines, a network of signaling molecules that integrate actions of macrophages/monocytes, T lymphocytes, and B lymphocytes in mounting immune responses. • Among these cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor-a (TNF-a) stimulate the HPA axis, with IL-1 having the broadest range of actions. IL-1 stimulates the release of CRH by hypothalamic neurons, interacts directly with the pituitary to increase the release of ACTH, and may directly stimulate the adrenal gland to produce glucocorticoids
  42. 42. • Absorption, Transport, Metabolism, and Excretion Absorption. Hydrocortisone and numerous congeners, including the synthetic analogs, are orally effective. • Certain water-soluble esters of hydrocortisone and its synthetic congeners are administered intravenously to achieve high concentrations of drug rapidly in body fluids. More prolonged effects are obtained by intramuscular injection of suspensions of hydrocortisone, its esters, and congeners. • Transport, Metabolism, and Excretion. After absorption, 90% or more of cortisol in plasma is reversibly bound to protein under normal circumstances. Only the fraction of corticosteroid that is unbound can enter cells to mediate corticosteroid effects. Two plasma proteins account for almost all of the steroid- binding capacity: corticosteroid-binding globulin (CBG; also called transcortin), and albumin.
  43. 43. • All of the biologically active adrenocortical steroids and their synthetic congeners have a double bond in the 4,5 position and a ketone group at C 3. • As a general rule, the metabolism of steroid hormones involves sequential additions of oxygen or hydrogen atoms, followed by conjugation to form water-soluble derivatives. • Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites, yielding inactive compounds. Subsequent reduction of the 3-ketone substituent to the 3-hydroxyl derivative, forming tetrahydrocortisol, occurs only in the liver. • Synthetic steroids with an 11-keto substituent, such as cortisone and prednisone, must be enzymatically reduced to the corresponding 11b-hydroxy derivative before they are biologically active.
  44. 44. adrenocortical steroids synthetic analogues. • Structure-Activity Relationships Chemical modifications to the cortisol molecule have generated derivatives with greater separations of glucocorticoid and mineralocorticoid activity; for a number of synthetic glucocorticoids, the effects on electrolytes are minimal even at the highest doses used . • In addition, these modifications have led to derivatives with greater potencies and with longer durations of action. • Changes in chemical structure may alter the specificity and/or potency due to changes in affinity and intrinsic activity at corticosteroid receptors, and alterations in absorption, protein binding, rate of metabolic transformation, rate of excretion, or membrane permeability
  45. 45. • The 17a-hydroxyl group on ring D is a substituent on cortisol and on all of the currently used synthetic glucocorticoids. While steroids without the 17a-hydroxyl group (e.g., corticosterone) have appreciable glucocorticoid activity, the 17a-hydroxyl group gives optimal potency. Introduction of an additional double bond in the 1,2 position of ring A, as in prednisolone or prednisone, selectively increases glucocorticoid activity (approximately fourfold compared to hydrocortisone), resulting in an enhanced glucocorticoid/mineralocorticoid potency ratio. This modification also results in compounds that are metabolized more slowly than hydrocortisone. Fluorination at the 9a position on ring B enhances both glucocorticoid and mineralocorticoid activity, possibly related to an electron-withdrawing effect on the nearby 11b-hydroxyl group. It is used in mineralocorticoid replacement therapy and has no appreciable glucocorticoid effect at usual daily doses of 0.05 mg to 0.2 mg.
  46. 46. • Other Substitutions. 6a Substitution on ring B has somewhat unpredictable effects. 6a-Methylcortisol has increased glucocorticoid and mineralocorticoid activity, whereas 6a- methylprednisolone has somewhat greater glucocorticoid activity and somewhat less mineralocorticoid activity than prednisolone. • A number of modifications convert the glucocorticoids to more lipophilic molecules with enhanced topical/systemic potency ratios. • Examples include the introduction of an acetonide between hydroxyl groups at C 16 and C 17, esterification of the hydroxyl group with valerate at C 17, esterification of hydroxyl groups with propionate at C 17 and C 21, and substitution of the hydroxyl group at C 21 with chlorine.
  47. 47. • Toxicity of Adrenocortical Steroids Two categories of toxic effects result from the therapeutic use of corticosteroids: those resulting from withdrawal of steroid therapy and those resulting from continued use at supraphysiological doses. • The side effects from both categories are potentially life- threatening and mandate a careful assessment of the risks and benefits in each patient. Withdrawal of Therapy. The most frequent problem in steroid withdrawal is flare-up of the underlying disease for which steroids were prescribed. There are several other complications associated with steroid withdrawal. The most severe complication of steroid cessation, acute adrenal insufficiency, results from overly rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis
  48. 48. • Continued Use of Supraphysiological Glucocorticoid Doses. These include fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, osteoporosis, myopathy, behavioral disturbances, cataracts, growth arrest, and the characteristic habitus of steroid overdose, including fat redistribution, striae, and ecchymoses. Fluid and Electrolyte Handling. Alterations in fluid and electrolyte handling can cause hypokalemic alkalosis, edema, and hypertension, particularly in patients with primary hyperaldosteronism secondary to an adrenal adenoma or in patients treated with potent mineralocorticoids Metabolic Changes. Hyperglycemia with glycosuria usually can be managed with diet and/or insulin, and its occurrence should not be a major factor in the decision to continue corticosteroid therapy or to initiate therapy in diabetic patients.
  49. 49. • Immune Responses. Because of their multiple effects to inhibit the immune system and the inflammatory response, glucocorticoid use is associated with an increased susceptibility to infection and a risk for reactivation of latent tuberculosis • Possible Risk of Peptic Ulcers. There is considerable debate about the association between peptic ulcers and glucocorticoid therapy. Most patients who develop gastrointestinal bleeding while receiving corticosteroids also received nonsteroidal antiinflammatory agents, which are known to promote ulceration, such that the pathogenic role of corticosteroids remains open to debate. Myopathy. Myopathy, characterized by weakness of proximal limb muscles, can occur in patients taking large doses of corticosteroids and also is part of the clinical picture in patients with endogenous Cushing's syndrome. It can be of sufficient severity to impair ambulation and is an indication for withdrawal of therapy.
  50. 50. • Behavioral Changes. Behavioral disturbances are common after administration of corticosteroids and in patients who have Cushing's syndrome secondary to endogenous hypercorticism; these disturbances may take many forms, including nervousness, insomnia, changes in mood or psyche, and overt psychosis. Suicidal tendencies are not uncommon. • Cataracts. Cataracts are a well-established complication of glucocorticoid therapy and are related to dosage and duration of therapy. Patients on long-term glucocorticoid therapy at doses of prednisone of 10 to 15 mg/day or greater should receive periodic slit-lamp examinations to detect glucocorticoid-induced posterior subcapsular cataracts. Osteoporosis. A reasonable estimate is that 30% to 50% of all patients who receive chronic glucocorticoid therapy ultimately will develop osteoporotic fractures. Glucocorticoids preferentially affect trabecular bone and the cortical rim of the vertebral bodies; the ribs and vertebrae are the most frequent sites of fracture.
  51. 51. • Glucocorticoids decrease bone density by multiple mechanisms, including inhibition of gonadal steroid hormones, diminished gastrointestinal absorption of Ca2+, and inhibition of bone formation due to suppressive effects on osteoblasts and stimulation of resorption due to effects on osteoclasts mediated by changes in the production of osteoprotegerin and RANK ligand. In addition, glucocorticoid inhibition of intestinal Ca2+ uptake may lead to secondary increases in parathyroid hormone, thereby increasing bone resorption. Osteonecrosis. Osteonecrosis (also known as avascular or aseptic necrosis) is a relatively common complication of glucocorticoid therapy. The femoral head is affected most frequently, but this process also may affect the humeral head and distal femur. Joint pain and stiffness usually are the earliest symptoms, and this diagnosis should be considered in patients receiving glucocorticoids who abruptly develop hip, shoulder, or knee pain.
  52. 52. • Regulation of Growth and Development. Growth retardation in children can result from administration of relatively small doses of glucocorticoids. • Therapeutic Uses With the exception of replacement therapy in deficiency states, the use of glucocorticoids largely is empirical. Based on extensive clinical experience, a number of therapeutic principles can be proposed. Given the number and severity of potential side effects, the decision to institute therapy with glucocorticoids always requires a careful consideration of the relative risks and benefits in each patient. • In an attempt to dissociate therapeutic effects from undesirable side effects, various regimens of steroid administration have been utilized. To diminish HPA axis suppression, the intermediate-acting steroid preparations (e.g., prednisone or prednisolone) should be given in the morning as a single dose
  53. 53. • Replacement Therapy. Adrenal insufficiency can result from structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison's disease) or from structural or functional lesions of the anterior pituitary or hypothalamus (2O). • Acute Adrenal Insufficiency. This life-threatening disease is characterized by gastrointestinal symptoms (nausea, vomiting, and abdominal pain), dehydration, hyponatremia, hyperkalemia, weakness, lethargy, and hypotension • The immediate management of patients with acute adrenal insufficiency includes intravenous therapy with isotonic sodium chloride solution supplemented with 5% glucose and corticosteroids and appropriate therapy for precipitating causes such as infection, trauma, or hemorrhage. Because cardiovascular function often is reduced in the setting of adrenocortical insufficiency, the patient should be monitored for evidence of volume overload such as rising central venous pressure or pulmonary edema
  54. 54. Acute adrenal insufficiency Waterhouse-Friderichsen syndrome Prostration= very strong fatique Causes: - infection - trauma - hemorhage - thrombosis
  55. 55. Chronic Adrenal Insufficiency. Patients with chronic adrenal insufficiency present with many of the same manifestations seen in adrenal crisis, but with lesser severity. These patients require daily treatment with corticosteroids Standard doses of glucocorticoids often must be adjusted upward in patients who also are taking drugs that increase their metabolic clearance (e.g., phenytoin, barbiturates, or rifampin). Dosage adjustments also are needed to compensate for the stress of intercurrent illness, and proper patient education is essential for the execution of these adjustments. All patients with adrenal insufficiency should wear a medical alert bracelet or tag that lists their diagnosis and carries information about their steroid regimen.
  56. 56. Congenital Adrenal Hyperplasia. This term denotes a group of genetic disorders in which the activity of one of the several enzymes required for the biosynthesis of glucocorticoids is deficient. The impaired production of cortisol and the consequent lack of negative feedback inhibition lead to increased release of ACTH. In a subset of patients with classical CAH, the enzymatic deficiency is sufficiently severe to compromise aldosterone production. Such patients are unable to conserve Na+ normally and thus are called "salt wasters." These patients can present with cardiovascular collapse secondary to volume depletion.
  57. 57. Therapeutic Uses in Nonendocrine Diseases. The dosage of glucocorticoids varies considerably depending on the nature and severity of the underlying disorder. Rheumatic Disorders. Glucocorticoids are used widely in the treatment of a variety of rheumatic disorders and are a mainstay in the treatment of the more serious inflammatory rheumatic diseases, such as systemic lupus erythematosus, and a variety of vasculitic disorders, such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, and giant cell arteritis. Renal Diseases. Patients with nephrotic syndrome secondary to minimal change disease generally respond well to steroid therapy, and glucocorticoids clearly are the first-line treatment in both adults and children.
  58. 58. Allergic Disease. The onset of action of glucocorticoids in allergic diseases is delayed, and patients with severe allergic reactions such as anaphylaxis require immediate therapy with epinephrine: for adults, 0.3 to 0.5 ml of a 1:1000 solution intramuscularly or subcutaneously. Bronchial Asthma and Other Pulmonary Conditions. They sometimes are employed in chronic obstructive pulmonary disease (COPD), particularly when there is some evidence of reversible obstructive disease. Data supporting the efficacy of corticosteroids are much more convincing for bronchial asthma than for COPD. In many patients, inhaled steroids (e.g., beclomethasone dipropionate [VANCERIL], triamcinolone acetonide [AZMACORT], fluticasone [FLOVENT], flunisolide [AEROBID],
  59. 59. Infectious Diseases. Although the use of immunosuppressive glucocorticoids in infectious diseases may seem paradoxical, there are a limited number of settings in which they are indicated in the therapy of specific infectious pathogens. One dramatic example of such beneficial effects is seen in AIDS patients with Pneumocystis carinii pneumonia and moderate to severe hypoxia; addition of glucocorticoids to the antibiotic regimen increases oxygenation and lowers the incidence of respiratory failure and mortality. Ocular Diseases. Ocular pharmacology, including some consideration of the use of glucocorticoids. Glucocorticoids frequently are used to suppress inflammation in the eye and can preserve sight when used properly.
  60. 60. Skin Diseases. Glucocorticoids are remarkably efficacious in the treatment of a wide variety of inflammatory dermatoses. As a result, a large number of different preparations and concentrations of topical glucocorticoids of varying potencies are available. A typical regimen for an eczematous eruption is 1% hydrocortisone ointment applied locally twice daily. Gastrointestinal Diseases. Glucocorticoid therapy is indicated in selected patients with inflammatory bowel disease (chronic ulcerative colitis and Crohn's disease. Patients who fail to respond to more conservative management (i.e., rest, diet, and sulfasalazine) may benefit from glucocorticoids; steroids are most useful for acute exacerbations. Oral administration of budesonide in delayed-release capsules (ENTOCORT, 9 mg/day)
  61. 61. Hepatic Diseases. Glucocorticoids clearly are of benefit in autoimmune hepatitis, where as many as 80% of patients show histological remission when treated with prednisone (40 to 60 mg daily initially, with tapering to a maintenance dose of 7.5 to 10 mg daily after serum transaminase levels fall). Malignancies. Glucocorticoids are used in the chemotherapy of acute lymphocytic leukemia and lymphomas because of their anti-lymphocytic effects. Most commonly, glucocorticoids are one component of combination chemotherapy administered under scheduled protocols. Cerebral Edema. Corticosteroids are of value in the reduction or prevention of cerebral edema associated with parasites and neoplasms, especially those that are metastatic.
  62. 62. • INHIBITORS OF THE BIOSYNTHESIS AND ACTION OF ADRENOCORTICAL STEROIDS Five pharmacologic agents are useful inhibitors of adrenocortical secretion. Mitotane (o,p'-DDD), an adrenocorticolytic agent. The other inhibitors of steroid hormone biosynthesis- metyrapone, aminoglutethimide, ketoconazole, and trilostane. • Metyrapone, aminoglutethimide, and ketoconazole inhibit cytochrome P450 enzymes involved in adrenocorticosteroid biosynthesis. Differential selectivity of these agents for the different steroid hydroxylases provides some degree of specificity to their actions. • Trilostane is a competitive inhibitor of the conversion of pregnenolone to progesterone, a reaction catalyzed by 3b- hydroxysteroid dehydrogenase. In addition, agents that act as glucocorticoid receptor antagonists (anti-glucocorticoids)
  63. 63. • Aminoglutethimide. Aminoglutethimide (a-ethyl-p-aminophenyl- glutarimide; CYTADREN) primarily inhibits CYP11A1, which catalyzes the initial and rate-limiting step in the biosynthesis of all physiological steroids. • As a result, the production of all classes of steroid hormones is impaired. Aminoglutethimide also inhibits CYP11B1 and the enzyme aromatase, which converts androgens to estrogens. • Because of its actions to inhibit aromatase, aminoglutethimide also has been evaluated as a therapeutic agent for the treatment of hormonally responsive tumors such as prostate and breast cancer, although more effective agents such as tamoxifen and the aromatase inhibitors are preferred. • ANTI-GLUCOCORTICOIDS :The progesterone receptor antagonist mifepristone [RU-486; (11b-4-dimethylaminophenyl)-17b-hydroxy- 7a-(propyl-1-ynyl)estra-4,9-dien-3-one] has received considerable attention because of its use as an antiprogestagen that can terminate early pregnancy
  64. 64. • Metyrapone. Metyrapone (METOPIRONE) is a relatively selective inhibitor of CYP11B1 (11b-hydroxylase), which converts 11-deoxycortisol to cortisol in the terminal reaction of the glucocorticoid biosynthetic pathway. • Because of this inhibition, the biosynthesis of cortisol is markedly impaired, and the levels of steroid precursors (e.g., 11-deoxycortisol) are markedly increased. • Metyrapone also is used to diagnose patients with Cushing's syndrome who respond equivocally to the formal dexamethasone suppression test. Those with pituitary- dependent Cushing's syndrome exhibit a normal response, whereas those patients with ectopic secretion of ACTH exhibit no changes in ACTH or 11-deoxycortisol levels. Therapeutically, metyrapone has been used to treat the hypercorticism resulting from either adrenal neoplasms or tumors producing ACTH ectopically.
  65. 65. × ×
  66. 66. Estrogens and Progestins • Estrogens and progestins are hormones that produce many physiological actions • In women, –Developmental effects (estrogens are largely responsible for pubertal changes in girls and secondary sexual characteristics) –Neuroendocrine actions involved in: Control of ovulation and the preparation of the reproductive tract for fertilization and implantation –Major Actions on: Minerals, Carbohydrates, Proteins, and Lipid Metabolism • In men, effects: –Bone –Spermatogenesis –Behavior
  67. 67. • Estrogens and progestins are endogenous hormones that produce numerous physiological actions. • In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism. • Estrogens also have important actions in males, including effects on bone, spermatogenesis, and behavior. • Estrogens also may be produced from androgens via aromatase in the central nervous system (CNS) and other tissues and exert local effects near their production site (e.g., in bone they affect bone mineral density).
  68. 68. Estrogens • A group of steroid hormones that readily diffuse across the cell membrane • Inside the cell, they interact with estrogen receptors. In boys, estrogen deficiency diminishes the pubertal growth spurt and delays skeletal maturation and epiphyseal closure so that linear growth continues into adulthood. Estrogen deficiency in men leads to elevated gonadotropins, macroorchidism, and increased testosterone levels and also may affect carbohydrate and lipid metabolism and fertility in some individuals Estriol Estradiol Estrone A A A D D D
  69. 69. Estrogen Synthesis • Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta • Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries • Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts • The ovaries are the principal source of circulating estrogen in premenopausal women, with estrodiol being the main secretory product • In postmenopausal women, the principal circulating estrogen estrone, which is synthesized from dehydroepiandrosterone and secreted by the adrenals
  70. 70. Estrogen Synthesis • The most potent naturally occurring estrogen in humans for both the Estrogen Receptor alpha- and beta-mediated actions is 17beta-estradiol, followed by estrone and estriol • Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D • The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors • Synthesis of estrogen begins from the synthesis of androstenedione from cholesterol • Androstenedione crosses the basal membrane into surrounding granulosa cells, where its converted to estrone or estradiol wither immediately or through testosterone • The conversion is catalyzed by aromatase
  71. 71. • The variety of steroidal estrogens derived from animal sources, numerous nonsteroidal estrogens have been synthesized. • Many phenols are estrogenic, and estrogenic activity has been identified in such diverse forms of life as those found in ocean sediments. Estrogen-mimetic compounds (flavonoids) are found in many plants, including saw palmetto, and soybeans and other foods. • During pregnancy, a large amount of estrogen is synthesized by the fetoplacental unit—consisting of the fetal adrenal zone, secreting androgen precursor, and the placenta, which aromatizes it into estrogen. The estriol synthesized by the fetoplacental unit is released into the maternal circulation and excreted into the urine.
  72. 72. In general, the hormone undergoes rapid hepatic biotransformation, with a plasma half-life measured in minutes.Estradiol is converted primarily by 17b- hydroxysteroid dehydrogenase to estrone, which undergoes conversion by 16a-hydroxylation and 17-keto reduction to estriol, the major urinary metabolite. A variety of sulfate and glucuronide conjugates also are excreted in the urine.The 2- and 4-hydroxycatechols are largely inactivated by catechol-O-methyl transferases (COMTs).Half life range between 13-26 minutes . Estrogens also undergo enterohepatic recirculation via (1) sulfate and glucuronide conjugation in the liver, (2) biliary secretion of the conjugates into the intestine, and (3) hydrolysis in the gut (largely by bacterial enzymes) followed
  73. 73. Estrogen Receptors• Estrogens exert their effects by interaction with receptors that are members of the super family of nuclear receptors • The two estrogen receptor (ER) genes are located on separate chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta • Both ERs are estrogen-dependent nuclear transcription factors that have different tissue distributions and transcriptional regulatory effects on target genes • Both ERs are ligand-activated transcription factors that increase or decrease the transcription of target genes • After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus • In the nucleus, the ER is present as an inactive monomer bound to heat-shock proteins, and upon binding estrogen, a change in ER confirmation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA
  74. 74. • Estrogen and progesterone levels vary daily – Changes are dependent on the pituitary gonadotropic hormones FHS and LH • On day 1 of an average 28-day cycle, secretions of FSH and LH begin to increase – This release is caused by a reduction in the blood levels of estrogen and progesterone, which normally inhibit their release • Estrogens are largely responsible for the changes that take place during puberty – Synthetic estrogens can be used for therapy and conception – The most common side effects of estrogen therapy are nausea and vomiting • Other side effects include uterine bleeding, vaginal discharge, edema, thrombophlebitis, weight gain, and hypertension
  75. 75. Estrogens • Estrogen therapy may also promote endometrial carcinoma in postmenopausal women – This risk may be cancelled out by administration of a progestin • Effect on oral tissues • Changes in sex hormone levels are related to – Gingivitis at puberty – During pregnancy – After menopause • The increase in gingival inflammation may occur even with a decrease in the amount of plaque
  76. 76. Anti-estrogens and SERMs • Anti-estrogens – Pure antagonists – Clomiphene is for treatment of infertility in anovulatory women – Fulvestrant is used for the treatment of breast cancer • Selective Estrogen Receptor Modulators (SERMs) – Compounds with tissue- selective actions – The goal of these drugs is to produce beneficial estrogenic actions in certain tissues (ex. Brain, bone, liver) during postmenopausal hormone therapy – Tamoxifen, Raloxifen, Toremifine
  77. 77. Tamoxifen is given orally, and peak plasma levels are reached within 4 to 7 hours after treatment. This drug displays two elimination phases with half-lives of 7 to 14 hours and 4 to 11 days. Due to the prolonged half-life, 3 to 4 weeks of treatment are required to reach steady-state plasma levels. The parent drug is converted largely to metabolites within 4 to 6 hours after oral administration. Tamoxifen is metabolized in humans by multiple hepatic CYPs, some of which it also induces Raloxifene is adsorbed rapidly after oral administration and has an absolute bioavailability of about 2%. The drug has a half-life of about 28 hours and is eliminated primarily in the feces after hepatic glucuronidation; it does not appear to undergo significant biotransformation by CYPs.
  78. 78. Clomiphene is well absorbed following oral administration, and the drug and its metabolites are eliminated primarily in the feces and to a lesser extent in the urine. The long plasma half-life (5 to 7 days) is due largely to plasma- protein binding, enterohepatic circulation, and accumulation in fatty tissues. Other active metabolites with long half-lives also may be produced. Fulvestrant is administered monthly by intramuscular depot injections. Plasma concentrations reach maximal levels in 7 days and are maintained for a month. Numerous metabolites are formed in vivo, possibly by pathways similar to endogenous estrogen metabolism, but the drug is eliminated primarily (90%) via the feces in humans. •
  79. 79. Progestins • Progestins include the naturally occurring hormone progesterone, 17-acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives (estranges), and norgestrel and related compounds in the gonane series progesterone 17-acetoxyprogesterone 19-nortestosterone norgestrel levonorgestrel
  80. 80. The corpus luteum is the primary source of progesterone during the normal female sexual cycle – Progesterone promotes secretory changes in the endometrium and prepares the uterus for implantation of the fertilized ovum • If implantation does not occur, progesterone secretion declines and menstruation occurs • If implantation takes place, the trophoblast secretes chorionic gonadotropin, which sustains the corpus luteum, maintaining progesterone and estrogen levels and preventing menstruation • Progestins are used in a variety of dose forms – Parenteral medroxyprogesterone (Depo-Provera) is administered every 3 months as a contraceptive – Progestin-only “minipills” are used orally – A progestational agent can be administered as an intrauterine device (IUD) or implant under the skin of the arm
  81. 81. Physcical Actions of Progesterone • In the reproductive tract, progesterone decreases estrogen- driven endometrial proliferation and leads to the development of a secretory endometrium • The abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation • Progesterone is very important for the maintenance of pregnancy • It suppresses menstruation and uterine contractility • The elimination half-life of progesterone is approximately 5 minutes, and the hormone is metabolized primarily in the liver to hydroxylated metabolites and their sulfate and glucuronide conjugates, which are eliminated in the urine.
  82. 82. The Progestin Receptor •Unlike the ER receptor, which requires a phenolic ring for binding, the PR favors a non-phenolic ring structure •There is a single gene that encodes two isoforms of the progesterone receptor (PR): PR-A and PR-B •Since the ligand-binding domains of the two PR isoforms are identical, there is no difference in ligand binding •However, the biological activities of PR-A and PR-B are distinct and depend on the target gene in question •PR-B mediates the stimulatory activities of progesterone •PR-A strongly inhibits this action of PR-B •Upon binding progesterone, the heat-shock proteins dissociate, and the receptors are phosphorylated and subsequently form dimers (homo- and hetero-) that bind with high selectivity to progesterone response elements located on target genes
  83. 83. Anti-progestins • Anti-progestin, first discovered in 1981, is mifepristone, used to terminate pregnancy – In the presence of progesterone, mifepristone acts as a competitive receptor antagonist for both progesterone receptors • When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blocking uterine progesterone receptors, which leads to detachment of the blastocyst, decreasing hCG production Mifepristone Therapeutic Uses and Prospects. Mifepristone (MIFEPREX), in combination with misoprostol or other prostaglandins , is available for the termination of early pregnancy.
  84. 84. Oral contraceptives are the most common dose forms of hormonal contraceptives and consist of estrogens and progestins in various combinations – These are the most common birth control pills and are more than 99% effective • The combination type of oral contraceptive is taken for 21 days of each month – The seven pills in the fourth week contain no active ingredient • Seasonale is the newest in combination oral contraceptives – An extended cycle contraceptive • The contraceptive vaginal ring is a new dose form that introduces hormonal contraception into the body • An injectable contraceptive is also available
  85. 85. Combination Contraceptives • This type is the most frequently used in the United States, which contain both an estrogen and a progestin • The theoretical efficacy is 99.9% • Ethinyl estradiol (a synthetic estrogen) and mestranol are the estrogens most frequently used • Levonorgestrel is the most common progestin used worldwide • Currently, this type of contraceptives have lowered doses of estrogen (“low-dose”)
  86. 86. Forms of Combination Contraceptives • The Pill • The Patch • Vaginal Ring Estrogens are most commonly used to treat vasomotor disturbances ("hot flashes") in postmenopausal women. Other important benefits are amelioration of the effects of urogenital atrophy, a decreased incidence of colon cancer, and prevention of bone loss. Estrogens have proven efficacy for prevention of bone fractures at all sites in normal women, although when used solely for this purpose they should not be considered first-line because of possible untoward side effects including breast cancer, stroke, and coronary heart disease (CHD).
  87. 87. • Pharmacologic Effects • MECHANISM OF ACTION:The combinations of estrogens& progestins exert their contraceptive effect largely through selective inhibition of pituitary fxn hence inhibition of ovulation. • The combination agents also produce a change in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease the likelihood of conception and implantation. • The continuous use of progestins alone does not always inhibit ovulation. The other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used.
  88. 88. Estrogens tend to increase excitability in the brain, whereas progesterone tends to decrease it. The thermogenic action of progesterone and some of the synthetic progestins is also thought to occur in the central nervous system. • Combined contraceptives Mechanism of Action – Act by preventing ovulation – Measurements of plasma hormone levels indicate that LH and FSH levels are suppressed – The mid-cycle surge of LH is absent – Endogenous steroid levels are diminished – Thus, ovulation does not occur – The multiple actions of estrogens and progestins on the hypothalamic-pituitary-ovarian axis during the menstrual cycle and the efficacy of these agents all contribute to the blockade of ovulation
  89. 89. Progestin-Only Contraceptives:Progesterone is rapidly absorbed following administration by any route. Its half-life in the plasma is approximately 5 minutes, and small amounts are stored temporarily in body fat. It is almost completely metabolized in one passage through the liver, and for that reason it is quite ineffective when the usual formulation is administered orally. • They contain progestins only, termed “mini pills” • Slightly less effective, with 99% efficacy • Forms – Pills – Injectables • Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration and impairs implantation
  90. 90. Medroxyprogesterone acetate, 10–20 mg orally twice weekly—or intramuscularly in doses of 100 mg/m2 every 1–2 weeks—will prevent menstruation, but it will not arrest accelerated bone maturation in children with precocious puberty. • Emergency Contraceptives :Multiple mechanisms are likely to contribute to the efficacy of these agents, however, the exact mechanism is unknown • These mechanisms include: – Ovulation is inhibited or delayed, alterations in endometrial receptivity for implantation – Interference with functions of the corpus luteum that maintain pregnancy – Production of a cervical mucus that decreases sperm penetration – Alterations in tubular transport of sperm, egg, or embryo – Effects on fertilization • Emergency contraceptives do not interrupt pregnancy after implantation
  91. 91. Emergency Contraceptives • The FDA has approved two preparations • PLAN-B includes 2 doses of levonorgestrel separated by 12 hours (progestin-only) • PREVEN is a 2 pill dose of a high-dose oral contraceptive (levonorgestrel and ethinyl estradiol) separated by 12 hours • The first dose of these drugs should be taken 72 hours after intercourse PLAN B
  92. 92. Hormonal contraceptives are associated with a significant increase in the frequency of dry sockets after extractions • Contraindications for use of oral contraceptives include thromboembolitic disorders, significant dysfunction of the liver, known or suspected carcinoma of the breast or other estrogen-dependent neoplasm, and undiagnosed genital bleeding • Certain antibiotics have been said to reduce the effectiveness of hormonal contraceptives – They are thought to do so by indirectly suppressing the intestinal flora and thus diminishing the availability of hydrolytic enzymes to regenerate the parent steroid molecule – Consequently, plasma concentrations of steroids are said to be abnormally low, and the steroid is cleared more rapidly from the body than under normal circumstances
  93. 93. • Beneficial Effects of Oral Contraceptives:Treatment with oral contraceptives has also been shown to be associated with many benefits unrelated to contraception. • These include a reduced risk of ovarian cysts, ovarian and endometrial cancer, and benign breast disease. There is a lower incidence of ectopic pregnancy. Iron deficiency and rheumatoid arthritis are less common, and premenstrual symptoms, dysmenorrhea, endometriosis, acne, and hirsutism may be ameliorated with their use • Estrogens enhance the coagulability of blood. Many changes in factors influencing coagulation have been reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III, partially as a result of the hepatic effects
  94. 94. • MILD ADVERSE EFFECTS • 1. Nausea, mastalgia, breakthrough bleeding, and edema are related to the amount of estrogen in the preparation. These effects can often be alleviated by a shift to a preparation containing smaller amounts of estrogen or to agents containing progestins with more androgenic effects. • 2. Changes in serum proteins and other effects on endocrine function must be taken into account when thyroid, adrenal, or pituitary function is being evaluated. Increases in sedimentation rate are thought to be due to increased levels of fibrinogen. • 3. Headache is mild and often transient. However, migraine is often made worse and has been reported to be associated with an increased frequency of cerebrovascular accidents. When this occurs or when migraine has its onset during therapy with these agents, treatment should be discontinued. • 4. Withdrawal bleeding sometimes fails to occur—most often with combination preparations—and may cause confusion with regard to pregnancy. If this is disturbing to the patient, a different preparation may be tried or other methods of contraception used
  95. 95. • MODERATE ADVERSE EFFECTS • Any of the following may require discontinuance of oral contraceptives: 1. Breakthrough bleeding is the most common problem in using progestational agents alone for contraception.. 2. Weight gain is more common with the combination agents containing androgen-like progestins.. 3. Increased skin pigmentation may occur, especially in dark-skinned women 4. Acne may be exacerbated by agents containing androgen-like progestins , whereas agents containing large amounts of estrogen usually cause marked improvement in acne. 5. Hirsutism may also be aggravated by the "19-nortestosterone" derivatives, and combinations containing nonandrogenic progestins are preferred in these patients. 6. Ureteral dilation similar to that observed in pregnancy has been reported, and bacteriuria is more frequent. 7. Vaginal infections are more common and more difficult to treat in patients who are receiving oral contraceptives. 8. Amenorrhea occurs in some patients.
  96. 96. • SEVERE ADVERSE EFFECTS • Vascular Disorders,VENOUS THROMBOEMBOLIC DISEASE • MYOCARDIAL INFARCTION, CEREBROVASCULAR DISEASE, Depression,Cancer,Gastrointestinal Disorders • Many cases of cholestatic jaundice have been reported in patients taking progestin-containing drugs. • Other: These include alopecia, erythema multiforme, erythema nodosum, and other skin disorders. • Contraindications & Cautions: thrombophlebitis, thromboembolic phenomena, and cardiovascular and cerebrovascular disorders • They should not be used to treat vaginal bleeding when the cause is unknown. They should be avoided in patients with known or suspected tumors of the breast or other
  97. 97. Other Agents that Affect Sex Hormone Systems • Clomiphene has the ability to induce ovulation in some anovulatory women • Leuprolide is used in the management of endometriosis and to treat infertility • Tamoxifen is indicated in the palliative treatment of breast cancer in postmenopausal women • Danazol is used to treat endometriosis and fibrocystic disease in women • Aromatase inhibitors reduce almost the entire amount of estrogen made in the bodies of postmenopausal women
  98. 98. Pharmacological effects (1) Development of the male sexual apparatus and secondary sex characteristics (2) Necessary for normal spermatogenesis (3) Increasing protein anabolism (4) Promoting growth of blood cells in bone marrow, especially for red blood cells (EPO ) (5)Other effects: immune regulation, antiinflammation effects,CVS effects Clinical uses (1) Replacement therapy in men: hypogonadism (2)Female disorders: dysfunctional uterine bleeding, endometriosis, advanced breast and ovarian cancers (3) Anemia: aplastic or other anemia (largely replaced by recombinant erythropoietin ) (4) Infirmity: anabolic steroids (5) Others: male contraception, osteoporosis(either alone or in conjunction with estrogens. Replaced by bisphosphonates) etc. A. Androgens and antiandrogens
  99. 99. Male Sex Hormones Androgens • Testosterone, the main androgen, has both androgenic and anabolic effects • Androgens are responsible for the development of secondary male sex characteristics • Androgens are used illicitly for muscle mass gain – Androgenic steroids are schedule III controlled substances because of their abuse • Side effects of androgenic steroids include nausea, cholestatic jaundice, hepatocellular neoplasms, increased serum cholesterol, habituation, and depression and excitation
  100. 100. Adverse effects - due largely to their masculinizing actions and are most noticeable in women and prepubertal children. (1) Sex dysfunction: • virilisation in female(hirsutism, acne, amenorrhea, clitoral enlargement, and deepening of the voice, testosterone> 200–300 mg of per month) • increased libido in male (2) Hepatic toxicity • occurs early in the course of treatment, the degree is proportionate to the dose. bilirubin levels ↑ Contraindications 1. pregnant women, infants and young children (somatotropin is more appropriate to produce a growth spurt). 2. male patients with carcinoma of the prostate or breast. 3. renal or cardiac disease predisposed to edema • Caution: Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. Erythropoietin and colony-stimulating factors should be used instead. A. Androgens and antiandrogens
  101. 101. Androgens
  102. 102. Synthesis of Testosterone. In men, testosterone is the principal secreted androgen. The Leydig cells synthesize the majority of testosterone . In women, testosterone also is probably the principal androgen and is synthesized both in the corpus luteum and the adrenal cortex by similar pathways. The testosterone precursors androstenedione and dehydroepiandrosterone are weak androgens that can be converted peripherally to testosterone. Metabolism of Testosterone to Active and Inactive Compounds. Testosterone has many different effects in tissues. One of the mechanisms by which the varied effects are mediated is the metabolism of testosterone to two other active steroids, dihydrotestosterone and estradiol.
  103. 103. Physiological and Pharmacological Effects of Androgens The biological effects of testosterone can be considered by the receptor it activates and by the tissues in which effects occur at various stages of life. Testosterone can act as an androgen either directly, by binding to the androgen receptor, or indirectly by conversion to dihydrotestosterone, which binds to the androgen receptor even more avidly than testosterone. Testosterone also can act as an estrogen by conversion to estradiol, which binds to the estrogen receptor. Other kinds of androgen receptor mutations may explain why prostate cancer that is treated by androgen deprivation eventually becomes androgen-independent.
  104. 104. Men tend to have a better sense of spatial relations than do women and to exhibit behavior that differs in some ways from that of women, including being more aggressive. Adulthood. The serum testosterone concentration and the characteristics of the adult male are largely maintained during early adulthood and midlife. One change during this time is the gradual development of male pattern baldness, beginning with recession of hair at the temples and the vertex. Two changes that can occur in the prostate gland during adulthood are of much greater medical significance. One is the gradual development of benign prostatic hyperplasia, which occurs to a variable degree in almost all men, sometimes obstructing urine outflow by compressing the urethra as it passes through the prostate
  105. 105. The consequences of androgen deficiency depend on the stage of life during which the deficiency first occurs and on the degree of the deficiency. During Fetal Development. Testosterone deficiency in a male fetus during the first trimester in utero causes incomplete sexual differentiation. Deficiency of LH secretion because of pituitary or hypothalamic disease does not result in testosterone deficiency during the first trimester, presumably because Leydig cell secretion of testosterone at that time is regulated by placental hCG. Before Completion of Puberty. When a boy can secrete testosterone normally in utero but loses the ability to do so before the anticipated age of puberty, the result is failure to complete puberty.
  106. 106. After Completion of Puberty. When testosterone secretion becomes impaired after puberty is completed, regression of the pubertal effects of testosterone depends on both the degree and the duration of testosterone deficiency. In Women. Loss of androgen secretion in women results in a decrease in sexual hair, but not for many years. Androgens may have other important effects in women, and the loss of androgens (especially with the severe loss of ovarian and adrenal androgens that occurs in panhypopituitarism) would result in the loss of these effects. Therapeutic Androgen Preparations The need for a creative approach to pharmacotherapy with androgens arises from the fact that ingestion of testosterone is not an effective means of replacing testosterone deficiency.
  107. 107. Testosterone Esters. Esterifying a fatty acid to the 17a hydroxyl group of testosterone creates a compound that is even more lipophilic than testosterone itself. When an ester, such as testosterone enanthate (heptanoate). Alkylated Androgens. Consequently, 17a-alkylated androgens are androgenic when administered orally; however, they are less androgenic than testosterone itself, and they cause hepatotoxicity , whereas native testosterone does not. Transdermal Delivery Systems. Recent attempts to avoid the first-pass inactivation of testosterone by the liver have employed novel delivery systems; chemicals called excipients are used to facilitate the absorption of native testosterone across the skin in a controlled fashion.
  108. 108. Therapeutic Uses of Androgens Male Hypogonadism. The best-established indication for administration of androgens is for the treatment of male hypogonadism (testosterone deficiency in men). Any of the transdermal testosterone preparations or testosterone esters described above can be used to treat testosterone deficiency Side Effects. All androgens suppress gonadotropin secretion when taken in high doses and thereby suppress endogenous testicular function. This results in diminished fertility. If administration continues for many years, testicular size may diminish. Testosterone and sperm production usually return to normal within a few months of discontinuation but may take longer. doses of androgens also cause erythrocytosis.
  109. 109. • Catabolic and Wasting States. Testosterone, because of its anabolic effects, has been used in attempts to ameliorate catabolic and muscle-wasting states, but this has not been generally effective. Treatment of men with AIDS-related muscle wasting and subnormal serum testosterone concerations their muscle mass and strength Angioedema. The disease is caused by hereditary impairment of C1- esterase inhibitor or acquired development of antibodies against it. The 17a-alkylated androgens, such as stanozolol and danazol, stimulate the hepatic synthesis of the esterase inhibitor. In women, virilization is a potential side effect. In children, virilization and premature epiphyseal closure prevent chronic use of androgens for prophylaxis, for to treat acute episodes. Blood Dyscrasias. Androgens such as danazol still are used occasionally as adjunctive treatment for hemolytic anemia and idiopathic thrombocytopenic purpura that are refractory to first-line agents.
  110. 110. • ANTI-ANDROGENS Introduction Because some effects of androgens are undesirable, at least under certain circumstances, agents have been developed specifically to inhibit androgen synthesis or effects. Other drugs, originally developed for different purposes, have been accidentally found to be anti-androgens and now are used intentionally for this indication. Inhibitors of Testosterone Secretion. Both agonists and antagonists of the GnRH receptor are used to reduce testosterone secretion. Analogs of GnRH effectively inhibit testosterone secretion by inhibiting LH secretion. GnRH "superactive" analogs, given repeatedly, down-regulate the GnRH receptor and are available for treatment of prostate cancer.
  111. 111. • Inhibitors of Androgen Action :These drugs inhibit the binding of androgens to the androgen receptor or inhibit 5a- reductase. Androgen Receptor Antagonists. Flutamide, Bicalutamide, and Nilutamide. These relatively potent androgen receptor antagonists have limited efficacy when used alone because the increased LH secretion stimulates higher serum testosterone concentrations. • They are used primarily in conjunction with a GnRH analog in the treatment of metastatic prostate cancer. In this situation, they block the action of adrenal androgens, which are not inhibited by GnRH analogs. • Spironolactone. Spironolactone (ALDACTONE)is an inhibitor of aldosterone that also is a weak antagonist at the androgen receptor and a weak inhibitor of testosterone synthesis, apparently inhibiting CYP17.
  112. 112. • When used to treat fluid retention or hypertension in men, gynecomastia is a common side effect. • 5a-Reductase Inhibitors. Finasteride (PROSCAR) is an antagonist of 5a-reductase, especially type II; dutasteride (AVODART) is an antagonist of types I and II; both drugs block the conversion of testosterone to dihydrotestosterone, especially in the male external genitalia.. • Cyproterone Acetate. Cyproterone acetate is a progestin and a weak anti-androgen by virtue of binding to the androgen receptor. It is moderately effective in reducing hirsutism alone or in combination with an oral contraceptive
  113. 113. • Antigonizing androgen receptor; inhibiting hypothalamus-pituitary axis: LH↓, FSH↓, testosterone↓ • Used for treatment of prostatic cancer, severe acne and hersulism, and contraception A. Androgens and antiandrogens Antiandrogens Cyproterone Adverse effects 1. Antiandrogenic action gynecomastia (breast growth), galactorrhea (milk outflow), and erectile dysfunction. 2.Liver toxicity high dose (200–300 mg/day). 3. Increased risk of DVT ( in combination with ethinylestradiol ) 4. Other reactions •Depressive mood changes •Suppression of adrenal function and reduced response to ACTH •Osteoporosis- suppresses production of estrogen due to its antigonadotrophic effect
  114. 114. Sildenafil citrate(Viagra) B. Drugs used to treat erectile dysfunction • Acts by inhibiting cGMP-specific PDE5, an enzyme that delay degradation of cGMP, which regulates blood flow in the penis • The prime treatment for erectile dysfunction in all settings, including diabetes.
  115. 115. Clinical uses (1) Sexual dysfunction (2) Pulmonary arterial hypertension (PAH) • relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure→workload of the right ventricle ↓, symptoms of right-sided heart failure↑ • acts selectively in the lungs and penis without inducing vasodilation in other areas of the body →PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis (3) Altitude sickness • prevention and treatment of high-altitude pulmonary edema associated with altitude sickness -such as that suffered by mountain climbers. B. Drugs used to treat erectile dysfunction
  116. 116. B. Drugs used to treat erectile dysfunction Adverse effects 1.Headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred (lead to vision impairment in rare cases) - the most common adverse effects • 2. Priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss -rare but serious Contraindications 1. Administration of nitric oxide donors 2. Recent stroke or heart attack, or in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors 3. Hypotension (low blood pressure) 4. Severe hepatic/ renal function impairment 5. Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

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