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  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • are very many, diverse, and unrelated
  • are very many, diverse, and unrelated
  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • Potency relative to cortisol Glucocorticoids with significant antiinflammatory activity in blue Mineralocorticoids with significant sodium retaining activity in red
  • are very many, diverse, and unrelated
  • are very many, diverse, and unrelated
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • are very many, diverse, and unrelated
  • Slide 1

    1. 1. PHCL 766 BLOOD-ENDOCRINE Pharmacology
    2. 2. Drugs Used in the Treatment of Hypothalamic, Pituitary, Thyroid, and Adrenal Disorders <ul><li>General Considerations </li></ul><ul><ul><li>A hormone is a substance secreted by one tissue or gland that is transported via the circulation to a site where it exerts its effects on different tissues. </li></ul></ul><ul><ul><li>Uses for hormones and synthetic analogues </li></ul></ul><ul><ul><ul><li>Diagnostic tools in endocrine disorders </li></ul></ul></ul><ul><ul><ul><li>Replacement therapy in endocrine disorders </li></ul></ul></ul><ul><ul><ul><li>Treatment of nonendocrine disorders </li></ul></ul></ul>
    3. 3. Interactions among the hypothalamic, pituitary, and peripheral glands (+) = stimulant; (-) = inhibitor Breast Prolactin (+) Dopamine (-) PRH (+) Estrogen Progesterone Testosterone Gonads FSH (+) LH (+) GnRH or LHRH (+) T 4 , T 3 Thyroid TSH (+) TRH (+) Glucocorticoids, Mineralcorticoids Androgens Adrenal cortex ACTH (+) CRH (+) Somatomedins Liver GH (+) GHRH (+); SRIH (-) Target Organ Hormone Target Organ Pituitary Hypothalamic
    4. 4. Hypothalamic Hormones and Related Drugs <ul><li>Sermorelin (growth hormone–releasing hormone) </li></ul><ul><ul><li>Mechanism of action: causes rapid elevation of growth hormone in the blood </li></ul></ul><ul><ul><li>Use: assessment of responsiveness and treatment of growth hormone deficiency </li></ul></ul><ul><li>Somatostatin (growth hormone–inhibiting hormone) </li></ul><ul><ul><li>Octreotide (synthetic analogue) </li></ul></ul><ul><ul><li>Mechanism of action: inhibits release of pituitary and gastrointestinal hormones </li></ul></ul><ul><ul><li>Uses </li></ul></ul><ul><ul><ul><li>Symptomatic treatment of hormone-secreting tumors, including pituitary tumors, carcinoid tumors, insulinomas, vasoactive intestinal peptide tumors (VIPomas) </li></ul></ul></ul><ul><ul><ul><li>Esophageal varices ( octreotide ) </li></ul></ul></ul><ul><ul><li>Adverse effects: abdominal pain, diarrhea, nausea and vomiting </li></ul></ul>The ending –relin indicates a hypothalamic-related hormone
    5. 5. Hypothalamic Hormones and Related Drugs <ul><li>Protirelin (thyrotropin-releasing hormone; TRH) </li></ul><ul><ul><li>Mechanism of action: stimulates synthesis and release of thyrotropin and prolactin from the anterior pituitary </li></ul></ul><ul><ul><li>Use: assessment of thyroid function in patients with pituitary or hypothalamic dysfunction </li></ul></ul><ul><li>Corticotropin-releasing hormone (CRH; corticorelin ) </li></ul><ul><ul><li>Mechanism of action: stimulates release of corticotropin and  -endorphin from the anterior pituitary </li></ul></ul><ul><ul><li>Use: differentiation between hypothalamic and pituitary causes of corticotropin deficiency or excess </li></ul></ul>
    6. 6. Hypothalamic Hormones and Related Drugs <ul><li>Gonadotropin-releasing hormone (GnRH)–related preparations </li></ul><ul><ul><li>Examples: leuprolide, nafarelin, gonadorelin </li></ul></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Stimulate secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH): pulsatile intravenous administration every 1–4 hours </li></ul></ul></ul><ul><ul><ul><li>Inhibit gonadotropin release: continuous administration of longer-lasting synthetic analogues </li></ul></ul></ul><ul><ul><li>Uses </li></ul></ul><ul><ul><ul><li>Shorter-acting preparations : treatment of delayed puberty, induction of ovulation in women with hypothalamic amenorrhea, stimulation of spermatogenesis in men with hypogonadotropic hypogonadism (infertility) </li></ul></ul></ul><ul><ul><ul><li>Long-acting GnRH analogues : suppression of FSH and LH in polycystic ovary syndrome, endometriosis, precocious puberty, prostate cancer </li></ul></ul></ul><ul><ul><ul><li>May be effective in endometriosis, uterine fibrinoids in women, and prostate cancer in men. </li></ul></ul></ul><ul><ul><li>Adverse effects: menopausal symptoms, amenorrhea, testicular atrophy </li></ul></ul><ul><ul><li>GnRH antagonist: ganirelix, cetrorelix </li></ul></ul><ul><ul><ul><li>Used to prevent premature surges of LH during controlled ovarian hyperstimulation. </li></ul></ul></ul>
    7. 7. Anterior Pituitary Hormones and Related Drugs <ul><li>Growth hormone –related preparations </li></ul><ul><ul><li>Somatropin, somatrem , recombinant human growth hormone (rhGH) </li></ul></ul><ul><ul><li>Growth hormone is required for stimulating normal growth in children and adolescents as well as for controlling metabolism in adults. </li></ul></ul><ul><ul><li>Disorders characterized by an excess of growth hormone include gigantism ( before puberty) and acromegaly ( after fusion of epiphyseal plates of the long bones). </li></ul></ul><ul><ul><li>Disorders characterized by a deficiency of growth hormone include dwarfism . </li></ul></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Increase production of somatomedins in the liver and other tissues </li></ul></ul></ul><ul><ul><ul><ul><li>Insulin-like growth factor ( IGF-1 ) </li></ul></ul></ul></ul><ul><ul><ul><li>Oppose the actions of insulin </li></ul></ul></ul><ul><ul><li>Uses: hypopituitary dwarfism, cachexia, Turner’s syndrome (single X chromosome) </li></ul></ul><ul><ul><li>Adverse effects </li></ul></ul><ul><ul><ul><li>Impaired glucose tolerance may develop over long periods. </li></ul></ul></ul><ul><ul><ul><li>Only synthetic growth hormone is used today (Creutzfeldt-Jakob disease resulted from the use of cadaveric growth hormone). </li></ul></ul></ul><ul><ul><ul><li>Excess growth hormone production results in gigantism and acromegaly; deficiency results in dwarfism . </li></ul></ul></ul>
    8. 8. Mecasermin <ul><li>Mechanism of action </li></ul><ul><ul><li>Insulin-like growth factor ( IGF-1 ) produced by using recombinant DNA technology </li></ul></ul><ul><ul><li>It is a recombinant IGF-1 product that promotes growth </li></ul></ul><ul><li>Uses </li></ul><ul><ul><li>Growth failure in children with severe primary insulin-like growth factor-1 deficiency ( IGF-1 deficiency ) </li></ul></ul><ul><ul><li>Treatment of patients with GH gene deletions who have developed neutralizing antibodies to GH </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>Cardiac murmur </li></ul></ul><ul><ul><li>Hyper/hypoglycemia </li></ul></ul><ul><ul><li>Iron-deficiency anemia </li></ul></ul>
    9. 9. Pegvisomant <ul><li>Mechanism of action </li></ul><ul><ul><li>A protein of recombinant DNA origin covalently bound to polyethylene glycol (PEG) polymers </li></ul></ul><ul><ul><li>GH analogue that selectively binds GH receptors </li></ul></ul><ul><ul><li>Blocks the binding of endogenous GH </li></ul></ul><ul><ul><li>Leads to decreased serum concentrations of IGF-I and other GH-responsive proteins </li></ul></ul><ul><li>Use </li></ul><ul><ul><li>Acromegaly (patients resistant to or unable to tolerate other therapies) </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>Pain </li></ul></ul><ul><ul><li>Abnormal liver function tests </li></ul></ul>
    10. 10. Anterior Pituitary Hormones and Related Drugs <ul><li>Thyrotropin (thyroid-stimulating hormone; TSH) </li></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Stimulates growth of thyroid gland </li></ul></ul></ul><ul><ul><ul><li>Stimulates the synthesis and release of thyroid hormones </li></ul></ul></ul><ul><ul><li>Use: diagnosis of hypothyroidism </li></ul></ul>
    11. 11. Anterior Pituitary Hormones and Related Drugs <ul><li>Adrenocorticotropin (ACTH)–related preparations </li></ul><ul><ul><li>Examples: corticotropin, ACTH 1–24 , cosyntropin </li></ul></ul><ul><ul><li>Regulation of secretion </li></ul></ul><ul><ul><ul><li>Corticotropin levels undergo daily cyclic changes (circadian rhythms). </li></ul></ul></ul><ul><ul><ul><ul><li>Peak plasma levels occur about 6:00 am, and the lowest levels occur about 12:00 am. </li></ul></ul></ul></ul><ul><ul><li>Stress increases the release of corticotropin. </li></ul></ul><ul><ul><li>Mechanism of action </li></ul></ul><ul><ul><ul><li>Stimulate growth of the adrenal gland </li></ul></ul></ul><ul><ul><ul><li>Stimulate the production and release of glucocorticoids, mineralocorticoids, and androgens from the adrenal cortex </li></ul></ul></ul><ul><ul><li>Use: differentiation between primary (adrenal malfunction) and secondary (pituitary malfunction) adrenocortical insufficiency </li></ul></ul><ul><ul><li>Adverse effects (corticotropin or glucocorticoids): Cushing’s syndrome </li></ul></ul><ul><ul><ul><li>General: weight gain, cushingoid appearance (“moon face”), sodium retention, edema </li></ul></ul></ul><ul><ul><ul><li>Musculoskeletal: osteoporosis, myopathy, growth retardation (children) </li></ul></ul></ul><ul><ul><ul><li>Ophthalmic: cataracts, glaucoma </li></ul></ul></ul><ul><ul><ul><li>Other: diabetes mellitus, peptic ulcer disease, psychosis, decreased resistance to infection </li></ul></ul></ul>Stress markedly affects multiple hormonal systems <ul><ul><li>ACTH and glucocorticoids cause iatrogenic Cushing’s syndrome </li></ul></ul>Know
    12. 12. Anterior Pituitary Hormones and Related Drugs <ul><li>Prolactin and related preparations </li></ul><ul><ul><li>Prolactin </li></ul></ul><ul><ul><ul><li>Regulation of secretion </li></ul></ul></ul><ul><ul><ul><ul><li>Stress, suckling, phenothiazines ( dopamine antagonists ), and TRH stimulate the release of prolactin. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Dopamine and dopamine agonists in the central nervous system (CNS), such as bromocriptine, tonically inhibit the release of prolactin. </li></ul></ul></ul></ul><ul><ul><li>Mechanism of action: stimulates milk production </li></ul></ul><ul><ul><ul><li>Oxytocin stimulates milk ejection (“let-down”) </li></ul></ul></ul><ul><ul><li>Use: not available for clinical use </li></ul></ul><ul><ul><li>Inhibitors of prolactin release ( bromocriptine, Cabergoline ) </li></ul></ul><ul><ul><ul><li>Uses: prevention of breast tenderness and engorgement in women who are not breastfeeding; inhibition of lactation; treatment of amenorrhea and galactorrhea associated with hyperprolactinemia due to pituitary adenomas </li></ul></ul></ul>
    13. 13. Anterior Pituitary Hormones and Related Drugs: Follicle-stimulating hormone (FSH) <ul><li>Examples </li></ul><ul><ul><li>Uro follitropin </li></ul></ul><ul><ul><li>Follitropin alfa </li></ul></ul><ul><ul><li>Follitropin beta </li></ul></ul><ul><li>Sources </li></ul><ul><ul><li>Urofollitropin is a preparation of highly purified FSH extracted from the urine of postmenopausal women </li></ul></ul><ul><ul><li>Follitropin alfa and follitropin beta are recombinant preparations of FSH </li></ul></ul><ul><li>Mechanism of action </li></ul><ul><ul><li>Stimulates ovarian follicle growth (females) </li></ul></ul><ul><ul><li>Also, stimulates granulosa cell synthesis of aromatase for conversion of testosterone synthesized in the theca interna to estradiol </li></ul></ul><ul><ul><li>Stimulates spermatogenesis (males) </li></ul></ul><ul><li>Uses </li></ul><ul><ul><li>Infertility </li></ul></ul><ul><ul><li>Polycystic ovarian syndrome </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>Multiple births </li></ul></ul><ul><ul><li>Ovarian enlargement </li></ul></ul>-follitropin = FSH
    14. 14. Anterior Pituitary Hormones and Related Drugs: Luteinizing hormone (LH) <ul><li>Examples and sources </li></ul><ul><ul><li>Menotropins </li></ul></ul><ul><ul><ul><li>Extracted from urine of postmenopausal women (both FSH and LH activity) </li></ul></ul></ul><ul><ul><li>Chorionic gonadotropin (human) </li></ul></ul><ul><ul><ul><li>LH obtained from the urine of pregnant women </li></ul></ul></ul><ul><ul><li>Chorionic gonadotropin (recombinant) </li></ul></ul><ul><ul><ul><li>LH analogue produced by recombinant DNA techniques </li></ul></ul></ul><ul><ul><li>Lutropin alfa </li></ul></ul><ul><ul><ul><li>LH prepared using Chinese hamster cell ovaries </li></ul></ul></ul><ul><li>Mechanism of action </li></ul><ul><ul><li>Increases follicular estradiol secretion </li></ul></ul><ul><ul><li>Required for FSH induced follicular development </li></ul></ul><ul><ul><li>Preparations containing FSH and LH activity are used in various fertility paradigms. </li></ul></ul>
    15. 15. Anterior Pituitary Hormones and Related Drugs: Luteinizing hormone (LH) <ul><li>Uses </li></ul><ul><ul><li>Menotropins </li></ul></ul><ul><ul><ul><li>In conjunction with chorionic gonadotropins (human) to induce ovulation and pregnancy in infertile women </li></ul></ul></ul><ul><ul><ul><li>Stimulation of multiple follicle development in ovulatory patients as part of an assisted reproductive technology (ART) </li></ul></ul></ul><ul><ul><ul><li>Stimulation of spermatogenesis in primary or secondary hypogonadotropic hypogonadism in males </li></ul></ul></ul><ul><ul><li>Lutropin </li></ul></ul><ul><ul><ul><li>Stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency </li></ul></ul></ul><ul><ul><ul><li>Given in combination with follitropin alfa </li></ul></ul></ul><ul><ul><li>Chorionic gonadotropin (recombinant) </li></ul></ul><ul><ul><ul><li>As part of an ART program, induces ovulation in infertile females who have been pretreated with FSH </li></ul></ul></ul><ul><ul><ul><li>To induces ovulation and pregnancy in infertile females when the cause of infertility is functional </li></ul></ul></ul>
    16. 16. Posterior Pituitary Hormones and Related Drugs <ul><li>These hormones are produced in the hypothalamus and are transported to the posterior pituitary (neurohypophysis), where they are stored and released into the circulation </li></ul><ul><ul><li>Vasopressin (antidiuretic hormone; ADH) </li></ul></ul><ul><ul><li>Oxytocin </li></ul></ul><ul><ul><ul><li>This substance, which is secreted by the supraoptic and paraventricular nuclei on the hypothalamus, is used to induce labor and stimulate uterine contractions </li></ul></ul></ul>
    17. 17. Vasopressin <ul><li>General considerations </li></ul><ul><ul><li>The synthetic analogue is desmopressin (preferred for treating neurogenic diabetes insipidus). </li></ul></ul><ul><ul><li>Disorders characterized by an absence of ADH include diabetes insipidus (severe polyuria, hypernatremia). </li></ul></ul><ul><ul><li>Disorders characterized by an excess of ADH include syndrome of inappropriate antidiuretic hormone ( SIADH ), water retention, hyponatremia, and possible pulmonary disease. </li></ul></ul><ul><li>Regulation of secretion </li></ul><ul><ul><li>Increases in plasma osmolality (e.g., dehydration) result in increased secretion of ADH. </li></ul></ul><ul><ul><li>Decreases in blood pressure (e.g., due to hemorrhage) increase ADH secretion. </li></ul></ul><ul><li>Mechanism of action </li></ul><ul><ul><li>Modulates renal tubular reabsorption of water, increasing permeability of the distal tubule and collecting ducts to water </li></ul></ul><ul><ul><li>This effect is mediated by an increase in cAMP associated with stimulation of the V 2 receptor. </li></ul></ul><ul><ul><li>At high concentrations, causes vasoconstriction (helps maintain blood pressure during hemorrhage) </li></ul></ul><ul><ul><li>This effect occurs via the stimulation of the V 1 receptor coupled to the polyphosphoinositide pathway. </li></ul></ul>
    18. 18. Vasopressin <ul><li>Uses </li></ul><ul><ul><li>Central ( neurogenic ) diabetes insipidus </li></ul></ul><ul><ul><ul><li>Thiazide diuretics are used to treat nephrogenic diabetes insipidus because: </li></ul></ul></ul><ul><ul><ul><li>They cause a reduction in the polyuria of patients with diabetes insipidus by causing volume depletion, hence reducing glomerular filtration rate and volume of urine. </li></ul></ul></ul><ul><ul><li>Esophageal variceal bleeding and colonic diverticular bleeding (some cases) </li></ul></ul><ul><ul><li>Ventricular fibrillation or pulseless ventricular tachycardia </li></ul></ul><ul><li>Adverse effects: overhydration, hypertension </li></ul><ul><li>Drugs that affect the secretion or action of ADH </li></ul><ul><ul><li>Diuretics, carbamazepine, morphine, tricyclic antidepressants increase ADH release. </li></ul></ul><ul><ul><li>Ethanol decreases ADH release. </li></ul></ul><ul><ul><li>Lithium and demeclocycline , which reduce the action of ADH at the collection ducts of the nephron, are used to treat SIADH . </li></ul></ul>Excess ADH results in SIADH, water retention, hyponatremia, and possible pulmonary disease; absence of ADH results in diabetes insipidus .
    19. 19. Ovarian Function <ul><li>In human females the ovaries are quiescent during childhood </li></ul><ul><li>Ovarian function begins when the ovaries respond to pituitary gonadotropins ( FSH and LH ) at puberty ( menarche or gonadarche ) </li></ul><ul><li>Menarche is followed by 30-40 year period of menstrual cycles manifested as episodes of bleeding caused by ovarian secretion of estrogen and progesterone </li></ul><ul><li>At menopause cyclic bleeding stops when the ovaries fail to respond to the pituitary gonadotropins . </li></ul>
    20. 20. Regulation of Menstruation <ul><li>Menstrual cycles are automatically reactivated every 28-30 days by a neuronal ‘clock’ (hypothalamic arcuate nucleus) serving as a pulse generator that fires at regular intervals  </li></ul><ul><li>Releases GnRH periodically into the hypothalamic-pituitary portal vasculature  </li></ul><ul><li>GnRH acts on anterior pituitary to release LH & FSH  </li></ul><ul><li>LH & FSH stimulate ovaries to secrete estrogen & progesterone </li></ul><ul><li>Negative feedback regulation : </li></ul><ul><li>(A) estrogen acts on pituitary to decrease FSH and LH </li></ul><ul><li>(B) progesterone acts on hypothalamus to decrease GnRH </li></ul>
    21. 21. Menstrual Cycles <ul><li>As each cycle starts, vesicular follicles become larger  after 5-6 days a dominant follicle develops more rapidly  theca and granulosa cells multiply to release estrogens  estrogen secretion peaks just before midcycle  brief surge in LH and FSH release  ovulation </li></ul><ul><li>After ovulation, the follicular cavity fills with blood  luteinized theca and granulosa cells proliferate to form the corpus luteum which then produces estrogen and progesterone for the rest of the cycle </li></ul><ul><li>Normal ovulatory menstrual cycles are maintained by the pulsatile release of hormones (constant infusions of GnRH will stop LH and FSH release  decrease estrogen and progesterone  amenorrhea) </li></ul>
    22. 22. Estrogen Biosynthesis and Metabolism <ul><li>Three major estrogens normally secreted are: </li></ul><ul><ul><li>Estrone (E1) </li></ul></ul><ul><ul><li>Estradiol (estradiol-17b; E2) </li></ul></ul><ul><ul><li>Estriol (E3) </li></ul></ul><ul><li>Secretion of estradiol the major estrogen, varies widely during the menstrual cycle with the highest peak occurring at ovulation </li></ul><ul><li>Ovaries also produce some estrone, but estrone and estriol are mostly formed in the liver </li></ul><ul><li>Estradiol in the circulation is bound to sex hormone-binding globulin and albumin, converted in the liver to hydroxylated derivatives and conjugated metabolites which are excreted in bile </li></ul><ul><li>Stallions are the most prolific natural source of estrogens producing more than pregnant mares or women   </li></ul>
    23. 23. Estrogen Mechanism of Action <ul><li>Estrogen receptors are nuclear receptors (same superfamily that includes steroid, sterol, retinoic acid, and thyroid receptors) found mainly in the uterus, vagina, and ovary </li></ul><ul><li>Estrogen binds to two receptors ( ER  and ER   on heat shock proteins in the nucleus  </li></ul><ul><ul><li>Releases hormone-receptor complex to form homodimers that bind to estrogen response elements (EREs)  </li></ul></ul><ul><ul><li>EREs regulate gene transcription  </li></ul></ul><ul><ul><li>mRNA edited to form protein  estrogen effects </li></ul></ul>
    24. 24. Estrogen Effects <ul><li>Female maturation - estrogens stimulate: </li></ul><ul><ul><li>Development of the vagina, uterus, and fallopian tubes </li></ul></ul><ul><ul><li>Breast enlargement by stromal and ductal growth </li></ul></ul><ul><ul><li>Closing of epiphyses of long bones at puberty </li></ul></ul><ul><ul><li>Growth of axillary and pubic hair </li></ul></ul><ul><ul><li>Body fat distribution to produce female body contour </li></ul></ul><ul><ul><li>Skin pigmentation of nipples, areolae, and genitals </li></ul></ul><ul><ul><li>Growth of uterine muscle and development of endometrial lining </li></ul></ul><ul><ul><li>Continuous estrogen exposure  </li></ul></ul><ul><ul><li>endometrial hyperplasia  abnormal bleeding </li></ul></ul>
    25. 25. Estrogen Effects <ul><li>Cardiovascular and metabolic effects – </li></ul><ul><ul><li>Increased risk of thromboembolism </li></ul></ul><ul><ul><li>Metabolic changes in the liver causing increased circulating protein levels ( TBG, angiotensinogen, fibrinogen , clotting factors , etc) </li></ul></ul><ul><ul><li>Increased serum triglycerides and free & esterified cholesterol </li></ul></ul><ul><ul><li>On the contrary, some lipid effects are beneficial: </li></ul></ul><ul><ul><ul><li> HDL and  LDL  beneficial ratio! </li></ul></ul></ul><ul><ul><li>Lipid effects together with direct vasodilation may be protective  </li></ul></ul><ul><ul><ul><li>Cardiovascular diseases in older women reduced by 35-50% </li></ul></ul></ul><ul><ul><ul><li>This so-called protective effect has recently been contradicted </li></ul></ul></ul><ul><li>Blood coagulation – enhanced by increasing coagulation factors and plasminogen, and decreasing antithrombin and platelet adhesiveness </li></ul>
    26. 26. Compounds with Estrogenic Activity <ul><li>Natural estrogens - from which synthetic estrogens were derived </li></ul><ul><ul><li>Estradiol, estrone, estriol </li></ul></ul><ul><li>Synthetic estrogens - most commonly used in OCs </li></ul><ul><ul><li>Ethinyl estradiol, mestranol , quinestrol </li></ul></ul><ul><li>Synthetic nonsteroidal compounds with estrogenic activity - also have been used some clinically </li></ul><ul><ul><li>Diethylstilbestrol, chlorotrianisene, methallenestril </li></ul></ul>
    27. 27. Commonly Used Estrogens <ul><li>Are among the most commonly prescribed drugs in the US because of use for: </li></ul><ul><li>oral contraception (OC) and </li></ul><ul><li>estrogen (ERT) or hormone (HRT) replacement therapy </li></ul><ul><li>High ratio of hepatic to peripheral effects when given orally because significant amounts are excreted in bile and reabsorbed in the intestine </li></ul><ul><li>Hepatic effects are minimized by vaginal, trans-dermal, or parenteral administration </li></ul>Table 40–1 Commonly Used Estrogens. 3–9 mg/d Methallenestril 12–25 mg/d Chlorotrianisene 0.1–0.2 mg/week Quinestrol Patch    Transdermal 0.2–2 mg/d    Injectable 0.3–1.25 mg/d    Oral Conjugated, esterified, or mixed estrogenic substances: 1.25–2.5 mg/d Estropipate 2–20 mg every other week Estradiol valerate 2–5 mg every 3–4 weeks Estradiol cypionate 1–2 mg/d Micronized estradiol 0.005–0.02 mg/d Ethinyl estradiol Average Replacement Dosage Preparation
    28. 28. Clinical Uses of Estrogens <ul><li>Primary hypogonadism – </li></ul><ul><ul><li>For replacement therapy in estrogen-deficiencies due to undeveloped ovaries, premature menopause, castration or menopause </li></ul></ul><ul><ul><li>Treatment attempts to mimic physiology of puberty </li></ul></ul><ul><ul><li>Estrogen treatment usually starts at 11-13 years of age in order to </li></ul></ul><ul><ul><ul><li>Stimulate development of secondary sex characteristics and menses </li></ul></ul></ul><ul><ul><ul><li>Prevent osteoporosis </li></ul></ul></ul><ul><ul><ul><li>Avoid psychologic effects of delayed puberty and estrogen deficiency </li></ul></ul></ul><ul><li>Postmenopausal hormonal therapy – </li></ul><ul><ul><li>The main therapeutic indications are to prevent hot flushes and osteoporosis </li></ul></ul><ul><ul><li>Only the lowest possible doses should be used because of increased risks for breast and endometrial cancer </li></ul></ul><ul><ul><li>The so-called “protective effect against cardiovascular disease” is now contradicted by recent studies </li></ul></ul><ul><li>Other uses – combined with progestins to: </li></ul><ul><ul><li>Suppress ovulation in intractable dysmenorrhea </li></ul></ul><ul><ul><li>Suppress ovarian function for treatment of hirsutism and amenorrhea caused by excessive ovarian secretion of androgens </li></ul></ul>
    29. 29. Adverse Estrogen Effects <ul><li>Postmenopausal uterine bleeding – to avoid confusion with vaginal bleeding caused by endometrial cancer, use the smallest amounts of estrogen cyclically </li></ul><ul><li>Increased risks for breast and endometrial cancer </li></ul><ul><li>Nausea, breast tenderness, hyperpigmentation, migraine, cholestasis, gall bladder disease, and hypertension </li></ul><ul><li>Contraindicated in patients with: </li></ul><ul><ul><li>Breast or endometrial cancer </li></ul></ul><ul><ul><li>Undiagnosed genital bleeding </li></ul></ul><ul><ul><li>Liver disease </li></ul></ul><ul><ul><li>Thromboembolic disorders </li></ul></ul><ul><ul><li>Heavy smokers </li></ul></ul>
    30. 30. The PROGESTINS <ul><li>Progesterone , the natural progestin, is the most important human progestin </li></ul><ul><li>Aside from important hormonal effects, it serves as a precursor for estrogens, androgens, and adrenocortical steroids </li></ul><ul><li>It is synthesized from circulating cholesterol in the ovary, testis, adrenals, and placenta </li></ul><ul><li>It is produced  primarily by the corpus luteum in the ovary </li></ul><ul><ul><li>Plasma levels are elevated to peak in the third trimester of pregnancy </li></ul></ul>
    31. 31. Progesterone Pharmacokinetics <ul><li>Progesterone is rapidly absorbed from any route of administration with a plasma half-life of about 5 min and small amounts stored in body fat </li></ul><ul><li>Oral preparations are ineffective because it is completely metabolized after one passage through the liver where it forms pregnanediol, is conjugated with glucuronic acid, and then excreted in urine as pregnanediol glucuronide </li></ul><ul><li>Urinary pregnanediol is used as an index of progesterone secretion </li></ul><ul><li>Many synthetic progestins are commercially available and some are active when given orally (e.g., megestrol, dimethisterone, medroxyprogesterone ) </li></ul><ul><li>Third-generation progestins used primarily in oral contraceptives are 19-nortestosterone derivatives like desogestrel, norethynodrel, norethindrone, or norgestimate </li></ul>
    32. 32. Progesterone Action and Effects <ul><li>Mechanism of action - like other steroid hormones; </li></ul><ul><ul><li>It enters the cell </li></ul></ul><ul><ul><li>Binds to nuclear and cytoplasmic receptors </li></ul></ul><ul><ul><li>Forms a ligand-receptor complexinds to a progesterone response element (PRE) </li></ul></ul><ul><ul><li>Activates gene transcription </li></ul></ul><ul><li>It stimulates lipoprotein lipase to favor fat deposition </li></ul><ul><li>Effects on carbohydrate metabolism are more marked: </li></ul><ul><ul><li>It increases insulin and the insulin response to glucose </li></ul></ul><ul><ul><li>It promotes hepatic glycogen storage </li></ul></ul><ul><li>It competes with aldosterone for mineralocorticoid receptors in renal collecting tubules to decrease Na + reabsorption which in turn increases adrenal secretion of aldosterone </li></ul><ul><li>It also increases body temperature, respiratory responses to CO 2 , development of breast secretory mechanisms, endometrial maturation, etc </li></ul>
    33. 33. Clinical Uses of Progestins <ul><li>Therapeutic – mainly for: </li></ul><ul><ul><li>Hormone replacement therapy (HRT) </li></ul></ul><ul><ul><li>Oral contraception (OC) </li></ul></ul><ul><ul><li>Long-term ovarian suppression - injected in large doses IM medroxyprogesterone results in anovulation and amenorrhea </li></ul></ul><ul><ul><li>Treatment of dysmenorrhea, endometriosis, and bleeding disorders for which estrogen is contraindicated </li></ul></ul><ul><li>Diagnostic – to test for estrogen secretion; after treatment with progesterone or medroxyprogesterone in amenorrheic women, withdrawal bleeding occurs only when there has been endometrial stimulation by estrogen </li></ul>
    34. 34. ORAL CONTRACEPTIVES (OCs) <ul><li>Two types of preparations are used: </li></ul><ul><ul><li>Combinations of estrogens and progestins </li></ul></ul><ul><ul><li>Continuous progestin without concomitant estrogen </li></ul></ul><ul><li>OCs taken properly are 97-98% effective in reducing the risk of conception </li></ul><ul><li>Contraceptive failures occur when one or more doses are missed </li></ul><ul><li>Most commonly used estrogens are ethinyl estradiol or mestranol </li></ul><ul><li>Progestin-only contraceptives avoid adverse effects due to the estrogen component but are slightly less effective (96-97.5%) in reducing conception risk; some examples are: </li></ul><ul><ul><li>Oral norethindrone or norgestrel </li></ul></ul><ul><ul><li>Etonogestrel implantation </li></ul></ul><ul><ul><li>Medroxyprogesterone for IM injection </li></ul></ul>
    35. 35. GONADAL HORMONES AND INHIBITORS ANDROGENS DANAZOL FLUOXYMESTERONE METHYLTESTOSTERONE NANDROLONE OXANDROLONE TESTOLACTONE TESTOSTERONE ESTROGEN AND PROGESTIN COMBINATION Drospirenone and Estradiol (HRT; oral) Estradiol and Levonorgestrel (HRT; patch) Estradiol and Norethindrone (HRT; patch) Estradiol and Norgestimate (HRT; oral) Estrogens (Conjugated/Equine) and Medroxyprogesterone (HRT; oral) Estrogens (Esterified) and Methyltestosterone (HRT; oral) Ethinyl Estradiol and Desogestrel (OC) Ethinyl Estradiol and Drospirenone (OC) Ethinyl Estradiol and Ethynodiol Diacetate (OC) Ethinyl Estradiol and Etonogestrel (VRC) Ethinyl Estradiol and Levonorgestrel (OC) Ethinyl Estradiol and Norelgestromin (PC) Ethinyl Estradiol and Norethindrone (OC) Ethinyl Estradiol and Norgestimate (OC) Ethinyl Estradiol and Norgestrel (OC) Mestranol and Norethindrone (OC) ANTIPROGESTINS Mifepristone Danazol ESTROGEN DERIVATIVES ESTRADIOL ESTROGENS (CONJUGATED A/SYNTHETIC) ESTROGENS (CONJUGATED B/SYNTHETIC) ESTROGENS (CONJUGATED/EQUINE) ESTROGENS (ESTERIFIED) ESTROPIPATE
    36. 36. Monophasic OCs <ul><li>Fixed amounts of estrogen and progestin </li></ul><ul><li>Taken daily for 21 days </li></ul><ul><li>Followed by 7-day “pill-free” period </li></ul><ul><li>28 day packs with last 7 pills inert </li></ul><ul><li>The FDA approved Yasmin® for routine contraception. </li></ul><ul><li>Then the FDA approved for YAZ™, a low-estrogen formulation, for routine contraception. YAZ™ contains 3 mg of drospirenone, but only 20 mcg of ethinyl estradiol, compared to 30 mcg in Yasmin®; the dosage regimen of YAZ™ is unique in that it contains 24 days of active therapy, followed by 4 days of placebo, which may offer patients fewer hormone fluctuations than the traditional 21 days of active pills per 28 day cycle. </li></ul>Norethindrone Mestranol Norinyl 1/50 Ortho-Novum 1/50 Drospirenone Ethinyl estradiol Yasmin® YAZ™ Norgestrel Ethinyl estradiol Ovral 28 Desogestrel Ethinyl estradiol Desogen Norethindrone Ethinyl estradiol Loestrin, Brevicon, Modicon, Norinyl, Ortho-Novum, Ovcon Progestin Estrogen Preparation
    37. 37. Triphasic OCs <ul><li>Three different pills each taken daily for 7 days </li></ul><ul><li>Reduces steroid amounts </li></ul><ul><li>Approximates menstrual estrogen to progestin ratio more closely </li></ul>Norethindrone Ethinyl estradiol Estrostep 21, Ortho-Novum 7/ 7/ 7 Tri- Norinyl Norgestimate Ethinyl estradiol Ortho-Tri-Cyclen L-norgestrel Ethinyl estradiol Triphasil Tri-Leven Progestin Estrogen Preparation
    38. 38. Oral Combination Contraceptives <ul><li>Monophasic combination tablets </li></ul><ul><ul><li>Same combination of estrogen and progestin given for 21 days and stopped for 7 days each month </li></ul></ul><ul><li>Biphasic combination tablets </li></ul><ul><ul><li>Same estrogen dose for 21 days, with a higher progestin dose in the last 10 days of each month </li></ul></ul><ul><li>Triphasic combination tablets </li></ul><ul><ul><li>Generally the same estrogen dose for 21 days, with a varying progestin dose over the 3 weeks of administration </li></ul></ul><ul><li>24 Day pill regimen </li></ul><ul><ul><li>Loestrin 24 Fe; Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg for 24 days and ferrous fumarate for 4 days </li></ul></ul><ul><li>Extended cycle oral contraceptives </li></ul><ul><ul><li>One active tablet/day for 84 consecutive days, followed by 1 inactive tablet/day for 7 days </li></ul></ul><ul><ul><li>If all doses have been taken on schedule and one menstrual period is missed, pregnancy should be ruled out prior to continuing therapy. </li></ul></ul>
    39. 39. Transdermal (patch) Estrogen-Progestin Contraceptive <ul><li>Ethinyl estradiol and norelgestromin </li></ul><ul><li>Procedure </li></ul><ul><ul><li>Apply one patch each week for 3 weeks (21 total days) </li></ul></ul><ul><ul><li>Then one week patch-free </li></ul></ul><ul><ul><li>Apply each patch on the same day each week </li></ul></ul><ul><ul><li>Only one patch should be worn at a time </li></ul></ul><ul><ul><li>No more than 7 days patch-free interval </li></ul></ul><ul><li>FDA posted concerns that use of the ethinyl estradiol and norelgestromin transdermal patch may increase the risk of blood clots in some women </li></ul><ul><ul><li>The contraceptive patch may increase blood clots in some women since the area-under-the curve (AUC) is high in some women due to more extensive dermal absorption. </li></ul></ul>
    40. 40. Vaginal Ring (NuvaRing) <ul><li>Vaginal ring (NuvaRing) made of ethylene vinyl acetate provides 0.015 mg ethinyl estradiol and 0.12 mg etonogestrel daily, </li></ul><ul><li>Applied for 21 days and removed for one week ; does not interfere with intercourse </li></ul><ul><li>Mechanism of action, risks and failure rate similar to OCs </li></ul>
    41. 41. Intrauterine Devices <ul><li>Two types of IUDs are currently used in the US : </li></ul><ul><ul><li>Copper (TCu-380A) IUD </li></ul></ul><ul><ul><ul><li>A T-shaped device that is mostly spermicidal due to the sterile inflammatory reaction created secondary to a foreign body in the uterus </li></ul></ul></ul><ul><ul><ul><li>Copper salts are released to alter the endometrium and cervical mucus </li></ul></ul></ul><ul><ul><ul><li>White blood cells are attracted to kill the spermatozoa by phagocytosis and sperm transport is significantly impaired, </li></ul></ul></ul><ul><ul><li>Two hormone-containing IUDs : </li></ul></ul><ul><ul><ul><li>Progesterone-releasing device (Progestasert) releases progesterone released at a rate of 65 mg/d (approved for 1 year) to diffuse into the endometrial cavity, and cause decidualization and atrophy of the endometrium </li></ul></ul></ul><ul><ul><ul><li>Levonorgestrel-releasing device (Mirena) releases levonorgestrel gradually at a rate of 20  g/d (approved for 5 years) </li></ul></ul></ul><ul><li>The IUD should be placed within 7 days after onset of the menstrual cycle. Protection begins immediately after insertion and failure rates after the first year of use are for copper IUD 0.5–0.8%, Progestasert 1.3–1.6%, and Mirena 0.1–0.2%. </li></ul>
    42. 42. OC Multiple Mechanisms of Action <ul><li>Main action is selective inhibition of pituitary function to depress ovarian function and prevent ovulation </li></ul><ul><ul><li>Minimal follicular development </li></ul></ul><ul><ul><li>Corporea lutea, larger follicles, stromal edema, and other features of ovulation are absent </li></ul></ul><ul><ul><li>Ovaries usually become smaller </li></ul></ul><ul><li>Decrease likelihood of implantation and conception by changing cervical mucus, endometrium, and tubal motility and secretion </li></ul><ul><li>Uterine effects after prolonged OC use may include cervical hypertrophy and polyp formation </li></ul>
    43. 43. OC Pharmacologic Effects <ul><li>Ovarian depression – causing minimal follicular development, loss of corpora lutea, large follicles, stromal edema, and smaller ovaries </li></ul><ul><ul><li>Normal menstrual patterns resume when OCs are discontinued: </li></ul></ul><ul><ul><li>75% ovulate in the first post-treatment cycle and 97% by third cycle </li></ul></ul><ul><li>Uterine effects –after prolonged use: </li></ul><ul><ul><li>Cervical hypertrophy and polyp formation, </li></ul></ul><ul><ul><li>Cervical mucus thicker and less copious </li></ul></ul><ul><li>Breast stimulation – </li></ul><ul><ul><li>Breast enlargement with suppressed lactation </li></ul></ul>
    44. 44. Other OC effects (after prolonged use) <ul><li>CNS effects on mood and behavior </li></ul><ul><li>Endocrine effects may alter adrenal steroids, renin/angiotensin system, aldosterone, thyroxine, and androgens </li></ul><ul><li>Thromboembolism from changes in clotting factors and blood coagulation </li></ul><ul><li>Hepatic effects may alter drug excretion and metabolism </li></ul><ul><li>Lipid metabolism increases in serum triglycerides, phospholipids, and cholesterol </li></ul><ul><li>Carbohydrate metabolism reduced GI sugar absorption, increase in basal insulin </li></ul><ul><li>Cardiovascular effects : increases in BP, HR , and cardiac output </li></ul><ul><li>Skin effects : increase in pigmentation (chloasma) and decreased sebum formation, acne, and terminal hair growth </li></ul>
    45. 45. OC Adverse Effects <ul><li>Low incidence of serious toxicity but mild adverse effects are frequent </li></ul><ul><ul><li>Adverse effects are greatly reduced with use of smaller doses </li></ul></ul><ul><ul><li>With current low-dose OCs the risks of hypertension, myocardial infarction, or stroke are almost nil </li></ul></ul><ul><li>Mild effects include nausea, edema; transient headaches and worsened migraine </li></ul><ul><li>Moderate effects include: </li></ul><ul><ul><li>Breakthrough bleeding (especially when progestational agents are used alone), </li></ul></ul><ul><ul><li>Weight gain, increased skin pigmentation, ureteral dilation, vaginal fungal infections , galactorrhea, and amenorrhea </li></ul></ul><ul><ul><li>Acne and hirsutism may be aggravated by androgenic activity of many 19-nortesterone derivatives ( norethynodrel, norethindrone, norgestrel ) </li></ul></ul><ul><li>Severe effects include: </li></ul><ul><ul><li>Thromboembolism – 3X higher risk related to estrogen </li></ul></ul><ul><ul><li>Myocardial infarction - especially in obese, hypertensive, diabetic, or hyperlipidemic women; smoking markedly increases this risk (i.e., annual number of cases per 100,000 is 4 for non-smokers vs 40-44 for smokers) </li></ul></ul><ul><ul><li>Increased risk of strokes – especially over age 35 </li></ul></ul><ul><ul><li>GI disorders - cholestatic jaundice, gall bladder disease, hepatic adenomas </li></ul></ul><ul><ul><li>Depression </li></ul></ul><ul><ul><li>Cancer </li></ul></ul>
    46. 46. Beneficial Effects of Low dose OCs compared to women not on OCs <ul><ul><li>Lower risks of : </li></ul></ul><ul><ul><ul><li>Ovarian cysts </li></ul></ul></ul><ul><ul><ul><li>Ovarian and endometrial cancer </li></ul></ul></ul><ul><ul><ul><li>Benign breast disease </li></ul></ul></ul><ul><ul><li>Lower incidence of : </li></ul></ul><ul><ul><ul><li>Ectopic pregnancy </li></ul></ul></ul><ul><ul><ul><li>Iron deficiency </li></ul></ul></ul><ul><ul><ul><li>Rheumatoid arthritis </li></ul></ul></ul><ul><ul><li>Ameliorate : </li></ul></ul><ul><ul><ul><li>Premenstrual symptoms </li></ul></ul></ul><ul><ul><ul><li>Dysmenorrhea </li></ul></ul></ul><ul><ul><ul><li>Endometriosis </li></ul></ul></ul>
    47. 47. Continuous Progestins <ul><li>Daily progestin (norethindrone) tablets </li></ul><ul><ul><li>For patients whom estrogen administration is undesirable </li></ul></ul><ul><li>Etonogestrel implantation </li></ul><ul><ul><li>Implant 1 rod in the inner side of the upper arm; remove no later than 3 years after the date of insertion </li></ul></ul><ul><li>Continuous progestins are preferred as contraceptives in women who should not take estrogens (e.g., heavy smokers) </li></ul><ul><li>Progestin contraceptive mechanisms </li></ul><ul><ul><li>Thickening of cervical mucus </li></ul></ul><ul><ul><li>Inhibition of ovulation (but not always) </li></ul></ul><ul><ul><li>Inhibition of implantation </li></ul></ul><ul><ul><li>Not effective once the implantation process has occurred </li></ul></ul>
    48. 48. EMERGENCY CONTRACEPTION <ul><li>Postcoital contraception is used when a woman who believes she is at risk for unintended pregnancy because the contraceptive method has failed or she had unprotected intercourse. </li></ul><ul><li>High-dose OCs approved by FDA for postcoital contraception in 1997. </li></ul><ul><li>Combination method uses 2 doses of two tablets (Ovral: 50 μ g ethinyl estradiol, 0.5 mg norgestrel) 12 hours apart (total: 200 μ g ethinyl estradiol, 2 mg norgestrel). </li></ul><ul><li>Progestin-only method involves two doses of ten pills (Ovrette 0.075 mg) 12 hours apart </li></ul><ul><li>Maximum efficacy is achieved if the first dose is taken within 72 hours after intercourse and repeated in 12 hours. </li></ul><ul><li>The failure rate with combination formulas is 2–3% and with progestin only 1%. </li></ul>
    49. 49. Selective Estrogen Receptor Modulators (SERMS) <ul><li>SERMS are compounds with tissue-selective estrogenic activities acting only in tissues where their actions would be beneficial (as in bone, brain, or liver during postmenopausal hormone replacement) but not in tissues where estrogenic actions would be harmful (as in breast or endometrium) </li></ul><ul><li>Tamoxifen and toremifene are partial agonist inhibitors of estradiol </li></ul><ul><ul><li>For treatment of breast cancer in postmenopausal women </li></ul></ul><ul><ul><li>Inhibit breast cancer cells and tumor size, but stimulate endometrial proliferation and thickening, and may increase the risk of endometrial cancer </li></ul></ul><ul><ul><li>Prevent loss of bone density and reduce risk of atherosclerosis </li></ul></ul><ul><li>Raloxifene is a partial estrogen agonist-antagonist at some but not all target tissues </li></ul><ul><ul><li>Has beneficial effects on bone but without affecting the endometrium or breast </li></ul></ul><ul><ul><li>Used for preventing postmenopausal osteoporosis </li></ul></ul><ul><ul><li>Does increase the risk of thromboembolism </li></ul></ul>
    50. 50. OVULATION-INDUCING AGENT: Clomiphene <ul><li>Clomiphene is a partial estrogen agonist that acts by blocking estrogen receptors </li></ul><ul><li>Because estrogen normally inhibits the pituitary, by blocking estrogen >>>> clomiphene will: </li></ul><ul><ul><li>Reduce the negative feedback by estradiol  </li></ul></ul><ul><ul><li>Thus, increase FSH and LH secretion </li></ul></ul><ul><li>Used for stimulating ovulation in amenorrheic women who want to become pregnant </li></ul><ul><li>Ovarian stimulation usually results in enlarged ovaries </li></ul><ul><li>Most common adverse effects are: hot flushes; occasional eye symptoms, headache, constipation, skin allergies, and reversible hair loss </li></ul><ul><li>Stimulation of ovulatory menstrual cycles may cause nausea and vomiting, increased nervous tension, depression, fatigue, breast soreness, weight gain, urinary frequency, and heavy menses </li></ul>
    51. 51. <ul><li>A 30-year-old sexually active woman who has used combination oral contraceptives for 10 years and smokes two packs of cigarettes daily, would be at high risk for which of the following? </li></ul><ul><li>A. Ectopic pregnancy </li></ul><ul><li>B. Iron deficiency </li></ul><ul><li>C. Ovarian cancer </li></ul><ul><li>D. Rheumatoid arthritis </li></ul><ul><li>E. Myocardial infarction </li></ul>Ans = E Note the other foils are beneficial effects og OCs
    52. 52. <ul><li>For hormonal replacement therapy in postmenopausal women, which of the following estrogen preparations is least likely to elevate angiotensinogen? </li></ul><ul><li>Estradiol oral tablets </li></ul><ul><li>Esterified estrogen oral tablets </li></ul><ul><li>Ethinyl estradiol oral tablets </li></ul><ul><li>Diethylstilbestrol oral tablets </li></ul><ul><li>Estradiol vaginal cream </li></ul>Ans = E Because no first Pass through liver
    53. 53. TESTOSTERONE Synthesis & Secretion <ul><li>Testosterone, the principal androgen in men, is secreted mostly by Leydig cells in the testis (95%) and partly by the adrenal cortex (5%) </li></ul><ul><li>Testosterone secretion is much higher in males than in females and it accounts for most gender differences </li></ul><ul><li>Plasma testosterone levels of about 0.6 mg/dL in males after puberty, decline after </li></ul><ul><li>age 50 </li></ul><ul><li>In women the much lower plasma levels of 0.03 mg/dL are secreted by the adrenal cortex and corpus luteum </li></ul><ul><li>In men about 8 mg is produced daily from plasma cholesterol along with small amounts of two weak androgens: androstenedione and dehydroepiandrosterone (DHEA) ) </li></ul>
    54. 54. Testosterone Metabolism <ul><li>In target tissues, testosterone is converted into active and inactive metabolites </li></ul><ul><li>Two active steroids are formed: </li></ul><ul><ul><li>Dihydroxytestosterone </li></ul></ul><ul><ul><li>Estradiol </li></ul></ul><ul><li>Dihydrotestosterone (DHT) is the major active androgen in most tissues </li></ul><ul><li>Various tissue effects can be mediated by testosterone, dihydrotestosterone, or estradiol </li></ul><ul><li>In the liver, testosterone is metabolized to androsterone and etiocholanolone which are both biologically inactive </li></ul>
    55. 55. Physiologic Effects <ul><li>Testosterone and dihydrotestosterone cause many changes at puberty: </li></ul><ul><ul><li>General growth-promoting properties </li></ul></ul><ul><ul><li>Penile and scrotal growth: phallus enlarges in length and width, scrotum becomes rugated, and prostatic secretions begin </li></ul></ul><ul><ul><li>Thicker and oilier skin with more active sebaceous glands </li></ul></ul><ul><ul><li>Appearance of public, axillary, and beard hair </li></ul></ul><ul><ul><li>Laryngeal growth, thicker vocal cords  lower-pitched voice </li></ul></ul><ul><ul><li>Accelerated skeletal growth and epiphysial closure </li></ul></ul><ul><ul><li>Growth of prostate and seminal vesicles </li></ul></ul><ul><ul><li>Stimulating and maintaining male sexual function </li></ul></ul><ul><li>In early adulthood and midlife: </li></ul><ul><ul><li>Gradual development of male pattern baldness; begins with recession of hair at temples and vertex </li></ul></ul><ul><ul><li>Development of benign prostatic hyperplasia or prostatic cancer </li></ul></ul><ul><li>Serum testosterone declines gradually as men age so that by age 80 free testosterone concentration is about 40% of that at age 20 </li></ul><ul><ul><li>May be related to decreases in energy, libido, muscle mass/strength, and bone mineral density </li></ul></ul>
    56. 56. SYNTHETIC ANDROGENS <ul><li>Oral testosterone is rapidly absorbed but ineffective because it is catabolized in the liver ( high 1 st pass effect ) </li></ul><ul><li>Synthetic preparations as lipophilic esters dissolved in oil, bypass hepatic catabolism and in hypogonadal males are injected IM every 2-4 weeks </li></ul><ul><li>Propionate, enanthate, undecenoate, or cypionate esters with more prolonged and greater activity release free testosterone at injection sites </li></ul><ul><li>Used for: </li></ul><ul><ul><li>Anabolic effects </li></ul></ul><ul><ul><li>Treating testosterone deficiency </li></ul></ul><ul><li>All synthetic androgens that are used to improve athletic performance have potent androgenic effects and the increase in muscle strength is always accompanied by adverse effects </li></ul>
    57. 57. Pharmacologic Effects <ul><li>Bind to intracellular androgen receptors that initiate a series of events similar to those for estradiol and progesterone. </li></ul><ul><li>In adult males, large doses suppress gonadotropin secretion  testicular atrophy </li></ul><ul><li>Can produce secondary male characteristics in women </li></ul><ul><li>Use with great caution because of masculinizing effects </li></ul><ul><li>Urinary nitrogen excretion is reduced due to increased protein synthesis or decreased protein breakdown </li></ul>
    58. 58. Clinical Uses <ul><li>Androgen replacement therapy in hypogonadal males </li></ul><ul><li>Growth stimulator in boys with delayed puberty </li></ul><ul><li>Treatment in women of: </li></ul><ul><ul><li>Postpartum breast engorgement </li></ul></ul><ul><ul><li>Endometriosis </li></ul></ul><ul><ul><li>Endometrial bleeding (and to enhance libido) after menopause </li></ul></ul><ul><ul><li>Postmenopausal osteoporosis ( alone or combined with estrogens) </li></ul></ul><ul><ul><li>Chemotherapy of premenopausal breast tumors ( not much today) </li></ul></ul>
    59. 59. Clinical Uses <ul><li>As protein anabolic agents to reverse protein loss after trauma, surgery, or prolonged immobilization </li></ul><ul><li>Anabolic steroid abuse - athletes use doses 10-200 X higher than endogenous testosterone levels to improve competitive performance by increasing strength and aggressiveness; </li></ul><ul><ul><li>Will suppress endogenous testosterone and sperm production; </li></ul></ul><ul><ul><li>May cause gynecomastia and virilization </li></ul></ul><ul><li>Aging – to replace low androgen levels in elderly males: </li></ul><ul><ul><li>May worsen benign prostatic hyperplasia </li></ul></ul><ul><ul><li>Increase risk of prostatic cancer </li></ul></ul>
    60. 60. Adverse Effects <ul><li>Largely due to masculinizing actions that are most pronounced in women and prepubertal children </li></ul><ul><li>In women: </li></ul><ul><ul><li>Acne, hirsutism, amenorrhea, clitoral enlargement, deep voice; also alter serum lipids to increase atherosclerotic susceptibility </li></ul></ul><ul><li>In men: </li></ul><ul><ul><li>Acne, sleep apnea, erythrocytosis, gynecomastia, azoospermia, decreased testicular size </li></ul></ul>
    61. 61. Androgen Suppression and Antiandrogens <ul><li>Gonadotropin-releasing hormone analogs like goserelin and leuprolide are used for gonadal suppression in treatment of prostatic cancer </li></ul><ul><li>Ketoconazole (antifungal agent) is used to inhibit adrenal and gonadal steroid synthesis in situations of over-production </li></ul><ul><li>Finasteride & Dutasteride inhibit 5 α -reductase to reduce conversion of testosterone to dihydrotestosterone (DHT) and is used to reduce prostatic size in benign prostatic hyperplasia </li></ul><ul><ul><li>Infrequently causes impotence </li></ul></ul><ul><li>Flutamide, bicalutamide, and nilutamide are antiandrogens used for treatment of prostatic carcinoma </li></ul>
    62. 62. THYROID PHYSIOLOGY <ul><li>The thyroid gland maintains metabolic homeostasis by regulating: </li></ul><ul><ul><li>Growth and development , </li></ul></ul><ul><ul><li>Body temperature </li></ul></ul><ul><ul><li>Energy levels </li></ul></ul><ul><li>These multiple functions are accomplished through two hormones: </li></ul><ul><ul><li>Triiodothyronine or T 3 </li></ul></ul><ul><ul><li>Tetraiodothyronine or T 4 </li></ul></ul>
    63. 63. Iodinated Thyroid compounds
    64. 64. Two Thyroid Hormones MIT= monoiodotyrosine DIT= diiodotyrosine 5 1 Thyroglobulin ratio 65 59 Iodine content (%) two DIT one MIT plus one DIT Molecular composition T 4 or thyroxine T 3 Alias Tetraiodothyronine Triiodothyronine Hormones
    65. 65. Thyroid Hormone Biosynthesis <ul><li>Iodide (I - ) absorbed in the GIT enters an extracellular pool from which the thyroid gland removes 75 mg daily </li></ul><ul><li>Thyroid hormone synthesis proceeds as: </li></ul><ul><li>I - is taken up by thyroid follicular cells via a membrane Na + /I - transporter  </li></ul><ul><li>I - is coupled to tyrosine residues on the thyroglobulin molecule (organification)  </li></ul><ul><li>Formation of monoiodo- (MIT) and diiodo-tyrosine (DIT)  </li></ul><ul><li>Thyroid peroxidase catalyzes coupling of two molecules of DIT to form T 4 , and one molecule each of MIT and DIT to form T 3  </li></ul><ul><li>Thyroglobulin stored as colloid in the lumen  </li></ul><ul><li>TSH signals secretion to hydrolyze thyroglobulin to free MIT, DIT, T 3 & T 4  </li></ul><ul><li>MIT and DIT are deiodinated to recycle while T 3 & T 4 are released by exocytosis </li></ul>
    66. 66. Peripheral Metabolism of Thyroxine <ul><li>Plasma T 3 & T 4 are reversibly bound to thyroxine-binding globulin (TBG) </li></ul><ul><li>Thyroid hormone released mostly as T 4 because T 4 to T 3 ratio in thyroglobulin is 5:1 </li></ul><ul><li>Peripheral metabolism of T 4 is mainly by deiodination to form: </li></ul><ul><ul><li>T 3 which is 3-4 times more potent than T 4 , or </li></ul></ul><ul><ul><li>Reverse T 3 which is metabolically inactive </li></ul></ul><ul><li>Total serum levels for T 4 are higher because more of it is released and metabolic clearance of T 3 is much higher </li></ul>
    67. 67. Summary of Thyroid Hormone Kinetics 7 1 Half Life (days) 80 95 Oral absorption (%) 1 3-4 Biologic potency 64-132 1.5-2.9 Total Serum levels (nmol/L) 1.1 24 Daily Metabolic clearance (L) 75 25 Daily production (mg) T 4 T 3 Thyroid Hormones
    68. 68. Mechanisms for Thyroid Regulation <ul><ul><li>Hypothalamic-Pituitary Regulation </li></ul></ul><ul><ul><li>paraventricular nuclei in the hypothalamus secrete TRH  </li></ul></ul><ul><ul><li>TRH stimulates the anterior pituitary to release TSH   </li></ul></ul><ul><ul><li> </li></ul></ul><ul><ul><li>TSH acts on the thyroid to release T 3 & T 4  </li></ul></ul><ul><ul><li>T 3 & T 4 act by negative feedback to inhibit formation of TRH and TSH </li></ul></ul><ul><ul><li>Autoregulation within the thyroid modifies thyroid hormone synthesis through blood iodine levels: </li></ul></ul><ul><ul><li>high iodine levels  </li></ul></ul><ul><ul><li>inhibit iodide organification  </li></ul></ul><ul><ul><li>reduced T 3 & T 4 synthesis  </li></ul></ul><ul><ul><li>hypothyroidism </li></ul></ul>
    69. 69. Hormonal Mechanisms in Thyroid Disease <ul><li>Normal hypothalamic-pituitary axis </li></ul><ul><li>Stimulatory autoantibody in Graves’ disease causing increased thyroid hormone secretion and suppression of TRH and TSH </li></ul><ul><li>Destructive autoantibody in Hashimoto’s disease causing decreased thyroid hormone secretion, no negative feedback, and increased TRH and TSH </li></ul>
    70. 70. Thyroid Hormone Mechanism of Action <ul><ul><li>T 3 & T 4 are dissociated from thyroid-binding proteins ( TBPs )  </li></ul></ul><ul><ul><li>Enter target cells by diffusion or transport  </li></ul></ul><ul><ul><li>In the cytoplasm 5’-deiodinase converts T 4 to T 3  </li></ul></ul><ul><ul><li>T 3 enters the nucleus to bind to T 3 receptors  </li></ul></ul><ul><ul><li> Corepressor is released & coactivator bound </li></ul></ul><ul><ul><li>Gene expression is turned on </li></ul></ul><ul><ul><li>T 3 receptors belong to a superfamily of nuclear receptors (c- erb includes receptors for steroid hormones and vitamins A and D) </li></ul></ul><ul><ul><li>many T 3 receptors are found in responsive tissues like pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine </li></ul></ul>
    71. 71. Circulating Thyroid Hormone <ul><li>Circulating iodine is 95% organic iodine and 5% free iodide; of the organic iodine 95% is T 4 and 5% is T 3 </li></ul><ul><li>To protect circulating T 3 and T 4 they are mostly bound to thyroxin binding globulin (TBG) </li></ul><ul><li>Amounts of free or unbound hormones are minimal: 0.03% T 4 and 0.3% T 3 </li></ul><ul><li>Only the unbound hormones have metabolic activity </li></ul><ul><li>In peripheral tissues T 4 is converted to T 3 by iodothyronine 5’-deiodinase found mainly in liver, thyroid, and kidneys </li></ul><ul><li>The active hormone in most target tissues is T 3 </li></ul>
    72. 72. T 3 Mechanism of Action <ul><li>T 3 acts on intracellular thyroid hormone receptors (TRs) located in all cells of the body </li></ul><ul><li>TR monomers interact with retinoic acid X receptor (RXR) to form heterodimers </li></ul><ul><li>In the absence of T 3 the TR:RXR heterodimer associates with a corepressor complex that binds to DNA to inhibit gene expression </li></ul><ul><li>In the presence of T 3 , the corepressor complex dissociates, coactivators form to stimulate gene expression </li></ul><ul><li>Binding to TR dimers thus serves as a molecular switch from inhibition to activation of gene expression </li></ul>
    73. 73. Thyroid Hormone Effects <ul><li>Are generally responsible for optimal growth, development, function, and energy levels in all tissues </li></ul><ul><ul><li>Excess  hyperthyroidism (thyrotoxicosis) </li></ul></ul><ul><ul><li>Inadequacy  hypothyroidism (myxedema) </li></ul></ul><ul><li>Main effects include: </li></ul><ul><ul><li>Nervous, musculoskeletal, and reproductive tissues: nervousness, emotional lability, muscle weakness and fatigue, osteoporosis, menstrual irregularities </li></ul></ul><ul><ul><li>Calorigenic effect : increased oxygen consumption, sweating </li></ul></ul><ul><ul><li>Sympathetic hyperactivity due to increased  -adrenergic sensitivity  dramatic cardiovascular effects including: tachycardia, increased stroke volume and cardiac output, high-output heart failure, arrhythmia, angina </li></ul></ul><ul><ul><li>Metabolic effects : decreased cholesterol and triglycerides; increased basal metabolic rate, hyperglycemia, and appetite </li></ul></ul>
    74. 74. Thyroid Preparations <ul><li>Major clinical use of T 3 & T 4 is for hormone replacement therapy in hypothyroidism or cretinism </li></ul><ul><li>Four preparations now used clinically are: </li></ul><ul><ul><li>Synthetic levothyroxine [T 4 ] is the preparation of choice for replacement and suppression therapy because of its stability, uniform content, low cost, long half-life (7 days), and conversion to produce both T 3 & T 4 </li></ul></ul><ul><ul><li>Desiccated thyroid, though inexpensive, is not recommended for replacement therapy because of its antigenicity, instability, and variable hormone content </li></ul></ul><ul><ul><li>Liothyronine, [T 3 ], is 3-4 times more active than levothyroxine, but not recommended for routine replacement therapy because of its higher cost, shorter half-life (24 hours), and greater potential for cardiotoxicity </li></ul></ul><ul><ul><li>Liotrix , a 4:1 combination of synthetic T 4 and T 3 , is also expensive with the same disadvantages as liothyronine </li></ul></ul>
    75. 75. Antithyroid Drugs <ul><li>[1] Thioamides : </li></ul><ul><li>Methimazole </li></ul><ul><li>Propylthiouracil </li></ul><ul><li>[2] Iodides : potassium iodide solution </li></ul><ul><li>[3] Radioactive Iodine (RAI) </li></ul><ul><li>[4] Other Drugs : </li></ul><ul><li>anion inhibitors </li></ul><ul><li> -adrenergic blockers </li></ul>
    76. 76. Thioamides : Methimazole & Propylthiouracil <ul><li>Both accumulate readily in the thyroid gland for treatment of thyrotoxicosis </li></ul><ul><li>Methimazole is 10X more active that propylthiouracil </li></ul><ul><li>Plasma half-lives: 6 hr for methimazole and 1.5 hr for propylthiouracil </li></ul><ul><li>Slow onset of action requiring 3-4 weeks to deplete T 4 stores </li></ul><ul><li>Multiple mechanisms of action including: </li></ul><ul><ul><li>Major action to prevent hormone synthesis by inhibiting peroxidase reactions to block iodine organification </li></ul></ul><ul><ul><li>Block iodotyrosine coupling </li></ul></ul><ul><ul><li>Inhibit peripheral deiodination of T 3 & T 4 </li></ul></ul><ul><li>Adverse reactions occur in 3-12% of treated patients: </li></ul><ul><ul><li>Most common: maculopapular pruritic rash </li></ul></ul><ul><ul><li>Rarely: urticarial rash, vasculitis, arthralgia, lupus-like reaction, jaundice, hepatitis hypothrombinemia </li></ul></ul><ul><ul><li>Most dangerous – agranulocytosis </li></ul></ul>
    77. 77. Iodides : Potassium Iodide Solution <ul><li>Many thyroid actions including: </li></ul><ul><ul><li>Inhibition of hormone release by reducing thyroglobulin proteolysis </li></ul></ul><ul><ul><li>Decrease in size and vascularity of the hyperplastic gland </li></ul></ul><ul><li>Thyrotoxic symptoms improve within 2-7 days , but should not be used alone because the gland “escapes’ from iodide block after 2-8 weeks and withdrawal may result in severe thyrotoxicosis </li></ul><ul><li>Chronic use in pregnancy should be avoided as iodides cross the placenta and can cause fetal goiter </li></ul><ul><li>Advantages are: simplicity, inexpensive, relatively nontoxic, and absence of glandular destruction </li></ul><ul><li>Adverse reactions, though uncommon, include: acneiform rash, swollen salivary glands, mucous membrane ulceration, conjunctivitis, rhinorrhea, metallic taste, drug fever, bleeding disorders, anaphylaxis </li></ul><ul><li>Disadvantages are: “escape”, aggravation of thyrotoxicosis, allergic reactions, and increased intraglandular iodine which can delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks </li></ul>
    78. 78. Radioactive Iodine (RAI) <ul><li>RAI is the only isotope used for treatment of thyrotoxicosis </li></ul><ul><li>RAI is given as oral solution, 131 I is rapidly absorbed and concentrated in the thyroid gland </li></ul><ul><li>Thyroid parenchymal destruction becomes evident within weeks in form of epithelial swelling, necrosis, follicular disruption, edema, and leukocyte infiltration </li></ul><ul><li>The therapeutic effect depends on emission of beta rays with: </li></ul><ul><ul><li>Penetration range of 400-2000  m </li></ul></ul><ul><ul><li>Effective half-life of 5 days </li></ul></ul><ul><li>Advantages include easy administration, effectiveness, low expense, and absence of pain </li></ul><ul><li>Major disadvantage is induction of hypothyroidism </li></ul><ul><li>Main contraindication is pregnancy as RAI crosses the placenta and is excreted in breast milk </li></ul>
    79. 79. Anion Inhibitors &  -adrenergic Blockers <ul><li>Monovalent ions as perchlorate (ClO4-), pertechnetate (TcO4-), and thiocyanate (SCN-) block iodide uptake through competitive inhibition of the iodide transport mechanism, but their effectiveness is unpredictable </li></ul><ul><li>Potassium perchlorate is no longer used clinically because it causes aplastic anemia </li></ul><ul><li>Iodinated contrast media ( diatrizoate by mouth, or iohexol; IV or oral ) though not FDA approved, act by inhibiting conversion of T 4 to T 3 in liver, kidney, pituitary, and brain </li></ul><ul><li>Since many symptoms of thyrotoxicosis result from sympathetic hyperactivity,  -adrenergic blockers are also used for treatment </li></ul>
    80. 80. Drugs Affecting T 3 -T 4 Synthesis <ul><li>Anions (perchlorate, pertechnetate, and thiocyanate ) compete with I - uptake </li></ul><ul><li>RAI causes selective thyroid destruction </li></ul><ul><li>Iodide (high levels) reduce T 3 -T 4 release by inhibiting thyroglobulin proteolysis </li></ul><ul><li>Thioamides inhibit peroxidase to block organification </li></ul>
    81. 81. <ul><li>A 25-year-old woman complains of heat intolerance, excessive sweating, tremors, palpitations, difficulty in swallowing, and muscular weakness. Oral treatment with which of the following will produce relief within 2-7 days? </li></ul><ul><li>A. Dessicated thyroid </li></ul><ul><li>B. Levothyroxine </li></ul><ul><li>C. Methimazole </li></ul><ul><li>D. Propylthiouracil </li></ul><ul><li>E. Potassium iodide </li></ul>Ans = E Potassium iodide inhibits proteolysis and decreases TH levels in a couple of days; Takes 3 to 4 weeks to lower TH Levels with PTU
    82. 82. ADRENOCORTICAL SECRETIONS <ul><li>Endogenous adrenocortical hormones are steroid molecules normally produced and secreted from the adrenal cortex </li></ul><ul><li>The adrenal cortex has two functionally discrete compartments, which secrete distinctly different hormones: </li></ul><ul><ul><li>Outer zona glomerulosa secretes the mineralocorticoid  aldosterone </li></ul></ul><ul><ul><ul><li>Aldosterone secretion from the outer zona glomerulosa is regulated mainly by extracellular K + through angiotensin receptors </li></ul></ul></ul><ul><ul><li>Inner zonae fasciculata/reticularis secretes the glucocorticoid  cortisol , and adrenal androgens </li></ul></ul><ul><ul><ul><li>Inner zones do not have angiotensin receptors, but are regulated mainly by ACTH and glucocorticoid production is catalyzed by two enzymes: </li></ul></ul></ul><ul><ul><ul><ul><li>- 17 α -hydroxylase (P45017 α ) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>- 11 β -hydroxylase(P45011 β ) </li></ul></ul></ul></ul>
    83. 83. Adrenocortical Hormones *dehydroepiandrosterone Androgenic-estrogenic DHEA* Androgen Salt-retaining Aldosterone Mineralo corticoid Intermediary metabolism Cortisol Gluco corticoid Activity Hormone Class
    84. 84. Adrenocorticoid Biosynthesis <ul><li>Synthesis from cholesterol proceeds along three pathways: </li></ul><ul><ul><li>Mineralocorticoid </li></ul></ul><ul><ul><li>Glucocorticoid </li></ul></ul><ul><ul><li>Andro-estrogen </li></ul></ul><ul><li>Produce 3 major hormones (underlined): </li></ul><ul><ul><li>Aldosterone </li></ul></ul><ul><ul><li>Cortisol </li></ul></ul><ul><ul><li>Dehydroepi-androsterone (DHEA) </li></ul></ul>
    85. 85. CORTISOL (hydrocortisone) <ul><li>It is the naturally-occurring glucocorticoid </li></ul><ul><li>It comes from cholesterol </li></ul><ul><li>Synthesis and secretion are tightly regulated by the CNS which is very sensitive to negative feedback by: </li></ul><ul><ul><li>Circulating cortisol </li></ul></ul><ul><ul><li>Exogenous (synthetic) glucocorticoids </li></ul></ul><ul><li>10-20 mg secreted daily following a circadian rhythm regulated by ACTH </li></ul><ul><li>Half-life 60-90 min </li></ul><ul><li>90% bound by corticosteroid binding globulin (CBG) synthesized by the liver; 5-10 % free or loosely bound to albumin </li></ul><ul><li>Mostly inactivated in the liver: </li></ul><ul><ul><li>About 20% is converted to cortisone </li></ul></ul><ul><ul><li>Only 1% is excreted in urine </li></ul></ul>
    86. 86. Mechanism of Glucocorticoid Action - 1 <ul><li>Act on glucocorticoid receptors </li></ul><ul><li>There are two types: </li></ul><ul><ul><li>Type I – mineralocorticoid receptor ; expressed mainly in organs of excretion as kidney, colon, salivary glands, sweat glands </li></ul></ul><ul><ul><li>Type II – glucocorticoid receptor ; broader tissue distribution </li></ul></ul><ul><li>Glucocorticoid receptors are primarily cytoplasmic, in form of oligomeric complexes with two molecules of heat shock proteins (Hsp90); shown on next slide </li></ul>
    87. 87. Steroid-Receptor Interaction S = Steroid R = Receptor Hsp90 = Heat shock protein 90 <ul><li>Free steroid enters cell cytoplasm to release receptor from Hsp90  </li></ul><ul><li>Steroid-receptor receptor complex enters the nucleus  </li></ul><ul><li>Binds to the glucocorticoid response element (GRE)  </li></ul><ul><li>Regulates transcription by RNA polymerase and other factors  </li></ul><ul><li>mRNA edited and exported to cytoplasm to form protein </li></ul>
    88. 88. Mechanism of Glucocorticoid Action - 2 <ul><li>Most effects are mediated by widely distributed glucocorticoid receptors that regulate transcription of target genes </li></ul><ul><li>Glucocorticoids regulate 10-20% of the expressed genes in a cell </li></ul><ul><li>Glucocorticoid effects are mainly due to proteins synthesized from mRNA transcribed by their target genes </li></ul><ul><li>Glucocorticoids have anti-growth, anti-inflammatory, and immunosuppressive effects because the transcription factors affected have broad actions on growth factors and proinflammatory cytokines </li></ul><ul><li>These transcription factors represent targets for new drugs, glucocorticoid agonists or antagonists, that are response or tissue selective </li></ul>
    89. 89. Corticosteroid Effects <ul><li>Have many widespread effects on all tissues and organs because almost all cells in the body are affected </li></ul><ul><li>Most effects are direct while others are “permissive” </li></ul><ul><li>Major groups of effects are: </li></ul><ul><ul><ul><li>Anti-inflammatory and immunosuppressive </li></ul></ul></ul><ul><ul><ul><li>Metabolic </li></ul></ul></ul><ul><ul><ul><li>Catabolic and antianabolic </li></ul></ul></ul><ul><ul><ul><li>CNS </li></ul></ul></ul>
    90. 90. Anti-inflammatory & Immunosuppressive Effects <ul><li>Manifestations of inflammation are dramatically reduced by: </li></ul><ul><ul><li>Increasing neutrophils </li></ul></ul><ul><ul><ul><li>Inactivates neutrophil adhesion molecules causing marginating pool (pool normally adhering to endothelium) to become part of circulating pool </li></ul></ul></ul><ul><ul><li>Decreasing lymphocytes, monocytes, eosinophils, and basophils </li></ul></ul><ul><ul><li>Affecting concentration, distribution, and function of leukocytes </li></ul></ul><ul><ul><li>Suppressing cytokines, chemokines, and other lipid and glucolipid mediators of inflammation </li></ul></ul><ul><ul><li>Reducing synthesis of prostaglandins and leukotrienes </li></ul></ul><ul><ul><li>Suppressing mast cell degranulation to reduce histamine release to decrease capillary permeability </li></ul></ul><ul><li>These changes are responsible for not only for their major therapeutic use but also for serious adverse effects </li></ul>
    91. 91. Metabolic Effects <ul><li>These effects contribute to supply adequate glucose to the brain in the fasting state by: </li></ul><ul><ul><li>Increasing glucose from gluconeogenesis </li></ul></ul><ul><ul><li>Increasing amino acids from muscle catabolism </li></ul></ul><ul><ul><li>Inhibiting peripheral glucose uptake </li></ul></ul><ul><ul><li>Stimulating lipolysis </li></ul></ul><ul><li>These changes are generally beneficial, but can also cause serious adverse effects even when therapeutic doses are used. </li></ul><ul><li>Important dose-related effects on carbohydrate, protein, and fat metabolism are to: </li></ul><ul><ul><li>Stimulate gluconeogenesis and glycogen synthesis , </li></ul></ul><ul><ul><li>Release of amino acids during muscle catabolism , </li></ul></ul><ul><ul><li>Stimulate hormone-sensitive lipase and lipolysis , </li></ul></ul><ul><ul><li>Elevate serum glucose to stimulate insulin release and inhibit glucose uptake by muscle cells: </li></ul></ul><ul><ul><ul><li>The increased insulin secretion stimulates lipogenesis and inhibits lipolysis to cause increased fat deposition and release of fatty acids and glycerol into the circulation </li></ul></ul></ul>
    92. 92. Catabolic & Antianabolic Effects <ul><li>Occur in lymphoid and connective tissues, muscle, fat, and skin </li></ul><ul><li>Supraphysiologic amounts reduce muscle mass causing weakness and skin thinning </li></ul><ul><li>Bone effects cause osteoporosis in Cushing’s syndrome and limit long-term therapeutic use </li></ul><ul><li>Reduced growth in children can be partly prevented with high doses of growth hormone </li></ul>
    93. 93. CNS Effects <ul><li>Marked slowing of EEG alpha rhythm and depression </li></ul><ul><li>Behavioral disturbances initially as insomnia and euphoria followed by depression and/or psychosis </li></ul><ul><li>Large does may increase intracranial pressure (pseudotumor cerebri) </li></ul><ul><li>Suppressed pituitary release of ACTH, GH, TSH, and LH ; thus, multiple endocrine effects </li></ul>
    94. 94. Other Effects <ul><li>Development of peptic ulcer by suppressing local immune response to H. pylori </li></ul><ul><li>Promote fat redistribution to increase visceral, facial, nuchal (nape), and supraclavicular fat </li></ul><ul><li>Antagonize Vitamin D effect of calcium absorption </li></ul><ul><li>Increase numbers of platelets and erythrocytes </li></ul><ul><li>Cortisol deficiency impairs renal function and augments vasopressin secretion resulting in an inability to excrete a water load normally </li></ul><ul><li>Stimulate structural and functional development of fetal lungs including the production of pulmonary surface-active (surfactant) materials required for air breathing </li></ul>
    95. 95. Commonly Used Glucocorticoids
    96. 96. Synthetic Corticosteroids <ul><li>Traditionally grouped as: </li></ul><ul><ul><li>Glucocorticoids - affect glucose metabolism and inflammation </li></ul></ul><ul><ul><li>Mineralocorticoids - affect Na + retention </li></ul></ul><ul><li>The two groups of effects are usually not closely related and reflect distinct actions at two distinct receptors </li></ul><ul><li>Separation between classes is not perfect because many steroids classified as glucocorticoids (e.g., cortisol and prednisone) also have some mineralocorticoid activity, while others classified as mineralocorticoids (e.g., fludrocortisone) also affect glucose metabolism </li></ul><ul><li>Ratios of glucocorticoid to mineralocorticoid potency differ: </li></ul><ul><ul><li>Betamethasone & dexamthasone have strong anti-inflammatory but no salt-retaining activity </li></ul></ul><ul><ul><li>Desoxycorticosterone has salt-retaining but no anti-inflammatory activity </li></ul></ul><ul><li>Because glucocorticoids are widely used for treating various inflammatory, allergic, hematologic, and other disorders, many synthetic steroids with anti-inflammatory and immunosuppressive activity have been developed </li></ul><ul><li>Corticosteroids without salt-retaining activity should be used whenever electrolyte abnormalities are present </li></ul>
    97. 97. Synthetic Corticosteroid Potencies 250 10 Fludrocortisone 20 0 Desoxycorticosterone 0 30 Dexamethasone 0 25-40 Betamethasone 0 5 Triamcinolone 0 5 Methylprednisolone 0.3 5 Prednisolone 0.3 4 Prednisone 0.8 0.8 Cortisone 1 1 Cortisol Na + retention antiinflammatory corticosteroid
    98. 98. Therapeutic Uses of Corticosteroids I. Diagnosis and Treatment of Adrenal Disorders <ul><li>Adrenocortical insufficiency (Addison’s disease) – </li></ul><ul><ul><li>Requires life-long combined glucocorticoid and mineralocorticoid treatment; use hydrocortisone plus a mineralocorticoid like fludrocortisone </li></ul></ul><ul><ul><li>Do not use glucocorticoids that have no salt-retaining activity </li></ul></ul><ul><li>Bilateral adrenal hyperplasia (Cushing’s disease) – </li></ul><ul><ul><li>From an ACTH-secreting pituitary adenoma </li></ul></ul><ul><ul><li>Main characterics are rounded plethoric face, trunk obesity, muscle wasting, purple striae, skin bruising, and osteoporosis </li></ul></ul><ul><ul><li>Treat with large doses of hydrocortisone following surgical removal of the tumor </li></ul></ul><ul><li>Aldosteronism – aldosterone excess resulting from adrenal adenoma </li></ul><ul><ul><li>treat with spironolactone </li></ul></ul><ul><li>Dexamethasone suppression test –for diagnosis of Cushing’s syndrome characterized by high cortisol levels that are reduced to 50% by dexamethasone </li></ul>
    99. 99. Therapeutic Uses of Corticosteroids II. Treatment of Nonadrenal Disorders Atopic dermatitis, seborrheic dermatitis Skin Prevent rejection Organ transplant Allergic conjunctivitis, uveitis Ocular Inflammatory bowel disease, ulcerative colitis Gastrointestinal Lupus erythematosus, rheumatoid arthritis Collagen-vascular Cerebral edema CNS Angioneurotic edema, anaphylactic & drug reactions, bronchial asthma, hay fever, urticaria Allergy Examples Disorder
    100. 100. Nonadrenal Disorders <ul><li>Are very many, diverse, and unrelated </li></ul><ul><li>Glucocorticoids are not curative in nonadrenal disorders and whenever possible, should be used only to supplement specific treatment for the disease </li></ul><ul><li>Most commonly used glucocorticoids include: betamethasone, dexamethasone, hydrocortisone, prednisolone, methylprednisolone, and triamcinolone </li></ul><ul><li>For chronic use proceed carefully with low doses, intermittent administration (i.e., alternate day) and do not discontinue abruptly ; taper doses when stopping </li></ul><ul><li>Local administration can minimize systemic adverse effects as when using hydrocortisone enemas for ulcerative colitis or inhaled steroids for asthma </li></ul>
    101. 101. Toxicity of Synthetic Glucocorticoids <ul><li>When used for < 2 weeks serious adverse effects are infrequent but insomnia, behavioral changes, and acute peptic ulcers may occur occasionally </li></ul><ul><li>When given for longer periods major adverse effects include: </li></ul><ul><ul><li>Metabolic adverse effects resulting from the hormonal actions  iatrogenic Cushing’s syndrome manifested in form of moon facies, fat redistributed from extremities to trunk, punctate acne, obesity, muscle wasting, skin thinning, osteoporosis, diabetes, impaired wound healing, etc </li></ul></ul><ul><ul><li>Other complications include: peptic ulcer, myopathy, acute psychosis, depression, glaucoma, hypertension, fluid retention and edema, etc </li></ul></ul><ul><ul><li>Adrenal suppression resulting in anorexia, nausea or vomiting, weight loss, lethargy, headache, fever, joint pains, and postural hypotension </li></ul></ul><ul><li>Should be used with great caution in patients with peptic ulcer, heart disease, hypertension, psychoses, infections, diabetes, osteoporosis, glaucoma, etc </li></ul>
    102. 102. MINERALOCORTICOIDS <ul><li>Aldosterone , the most important mineralocorticoid in man, is synthesized in the zona glomerulosa </li></ul><ul><li>It binds to mineralocorticoid receptors in the distal convoluted and proximal collecting tubules to promote sodium reabsorption </li></ul><ul><li>Deoxycorticosterone , the precursor of aldosterone, is also normally synthesized and secreted </li></ul><ul><li>Synthetic fludrocorticosterone , the most commonly prescribed, has potent mineralocorticoid activity that is used for treating adrenocortical insufficiency associated with mineralocorticoid deficiency </li></ul>
    103. 103. ADRENOCORTICAL ANTAGONISTS <ul><li>Consisting of various unrelated agents: </li></ul><ul><ul><li>Metyrapone - a selective inhibitor of steroid synthesis commonly used for testing adrenal function; </li></ul></ul><ul><ul><li>Ketoconazole – an antifungal agent, which is also, a nonselective inhibitor of adrenal and gonadal steroid synthesis used for treatment of Cushing’s syndrome </li></ul></ul><ul><ul><li>Mifepristone (RU 486) - a glucocorticoid antagonist with strong antiprogestin activity and has been used as an abortifacient </li></ul></ul><ul><ul><li>Spironolactone - an aldosterone antagonist, widely used to prevent hypokalemia in treatment of hypertension and congestive heart failure </li></ul></ul><ul><ul><ul><li>Used to treat hirsutism in women (androgen antagonist) </li></ul></ul></ul>
    104. 104. <ul><li>In a 30-year-old woman with a long history of lupus erythematosus, oral treatment with dexamethasone tablets for 4 weeks may aggravate which of the following? </li></ul><ul><li>A. Anaphylactic reactions </li></ul><ul><li>B. Bronchial asthma </li></ul><ul><li>C. Inflammatory bowel disease </li></ul><ul><li>D. Seborrheic dermatitis </li></ul><ul><li>E. Diabetes mellitus   </li></ul>Ans = E Steroid-induced diabetes
    105. 105. <ul><li>For treatment of a 20-year-old asthmatic man who complains of chest tightness and shortness of breath when he exercises, which of the following is a corticosteroid that has no salt-retaining activity? </li></ul><ul><li>A. Cortisone </li></ul><ul><li>B. Desoxycorticosterone </li></ul><ul><li>C. Fludrocorticosterone </li></ul><ul><li>D. Prednisolone </li></ul><ul><li>E. Triamcinolone </li></ul>Ans = E Given by inhalation for asthma
    106. 106. Adverse Effects Adrenal suppression Growth inhibition Diabetes Muscle wasting Osteoporosis Salt retention Psychosis Cataracts <ul><li>Gluconeogenesis </li></ul><ul><li>Fat deposition </li></ul><ul><li>Muscle protein catabolism </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Anti-inflammatory </li></ul> 11- β -hydroxylase <ul><li>Lipocortin </li></ul><ul><li> COX-2 </li></ul>
    107. 107. Which of the following proteins is expected to be up-regulated when a 49-year-old woman with rheumatoid arthritis is treated with dexamethasone? <ul><li>Cyclooxygensae-2 </li></ul><ul><li>IgE </li></ul><ul><li>Lipocortin </li></ul><ul><li>Phospholipase A 2 </li></ul><ul><li>Thromboxane A 2 </li></ul>Answer: C Lipocortin inhibits phospholipase A2; Thus, decreasing arrachidonic acid levels  decreasing production of Inflammatory mediators
    108. 108. Which of the following is appropriate to reduce the signs and symptoms of Cushing’s syndrome in a 45-year-old man with an adrenal tumor? <ul><li>Betamethasone </li></ul><ul><li>Fludrocortisone </li></ul><ul><li>Hydrocortisone </li></ul><ul><li>Ketoconazole </li></ul><ul><li>Triamcinolone </li></ul>Answer: D Inhibits mammalian synthesis of glucocorticoids and steroid hormones by inhibiting the cytochrome P-450 system and 11 β -hydroxylase
    109. 109. ENDOCRINE PANCREAS <ul><li>The pancreas in adult humans </li></ul><ul><li>Consists of 1 million islets of Langerhans </li></ul><ul><li>Contains 4 cell types that synthesize and secrete a distinct hormone </li></ul>Facilitate digestion Pancreatic polypeptide < 2 F (PP) Inhibit secretory cells Somatostatin 3-5 D (delta) Storage and anabolic hormone Unknown INSULIN C-peptide amylin 75 B (beta) Mobilize glycogen Glucagon 20 A (alpha) Function Hormone % Islet Cell Cell type
    110. 110. HUMAN PROINSULIN <ul><li>Insulin comes from proinsulin synthesized in pancreatic B cells </li></ul><ul><li>Proinsulin is hydrolyzed to release: </li></ul><ul><ul><li>Insulin </li></ul></ul><ul><ul><li>C-peptide (no known function) </li></ul></ul><ul><li>Removal of C-peptide forms insulin, a small protein consisting of 51 amino acids arranged in two chains: </li></ul><ul><ul><li>A chain = 21 amino acids </li></ul></ul><ul><ul><li>B chain = 30 amino acids </li></ul></ul><ul><li>Insulin crystals are stored in secretory granules inside B cells </li></ul><ul><li>The human pancreas normally contains 8 mg (200 U) </li></ul>
    111. 111. Insulin Secretion <ul><li>Upon stimulation by hyperglycemia or insulin secretagogues </li></ul><ul><ul><li>Intracellular ATP increases to close K + channels in B cell </li></ul></ul><ul><ul><li>Opens voltage-gated Ca ++ channels </li></ul></ul><ul><ul><li>Ca ++ enters to increase intracellular Ca ++ </li></ul></ul><ul><ul><li>Insulin is secreted </li></ul></ul><ul><li>Secretion is increased by various stimuli (sugars, amino acids, secretagogues) </li></ul><ul><li>Glucose is the principal stimulus </li></ul>At rest , B cells have low ATP levels, ATP-gated K + channels are open, K + diffuses out to keep the cell fully polarized (negative) and insulin secretion is minimal
    112. 112. Circulating Insulin <ul><li>Blood levels detected by radioimmunoassay in normal subjects are: </li></ul><ul><ul><li>Basal values of 5-15 mU/mL (30-90 pmol/L) </li></ul></ul><ul><ul><li>Peak rise to 60-90 mU/mL (360-540 pmol/L) during meals </li></ul></ul><ul><li>Circulating insulin binds to specialized receptors located on cell membranes of: </li></ul><ul><ul><li>Liver </li></ul></ul><ul><ul><li>Muscle </li></ul></ul><ul><ul><li>Adipose tissues </li></ul></ul><ul><li>Circulating insulin has a half-life of 3-5 minutes </li></ul><ul><li>Removed from circulation by insulinase (glutathione insulin transhydrogenase) action in: </li></ul><ul><ul><li>Liver 60% </li></ul></ul><ul><ul><li>Kidney 35-40% </li></ul></ul>
    113. 113. Insulin Receptor IRS = insulin receptor substrate Tyr = tyrosine P = phosphate <ul><li>Consists of two covalently linked heterodimers each containing: </li></ul><ul><ul><li> subunit – extracellular </li></ul></ul><ul><ul><li> subunit - spans cell membrane </li></ul></ul><ul><li>Insulin binds to the  subunit, which sticks out like an antenna, to activate the receptor and bring the catalytic loops of the cytoplasmic  subunit closer together to facilitate tyrosine kinase activity  </li></ul><ul><li>Activated tyrosine kinase phosphorylates the docking proteins IRS to translate the insulin signal   </li></ul><ul><li>The phosphorylation network causes translocation of glucose transporters (GLUT4) to the cell membrane  </li></ul><ul><li>Increase glucose uptake, glycogen formation, and multiple effects of protein synthesis, lipolysis, and lipogenesis </li></ul>
    114. 114. Major Target Tissues: Liver, Fat, and Muscle
    115. 115. INSULIN EFFECTS <ul><li>Four main sites of action: </li></ul><ul><li>Glucose transporters to facilitate glucose movement across cell membranes; GLUT 4 is most important for hypoglycemia </li></ul><ul><li>Liver to increase storage of glycogen and decrease postabsorptive catabolism </li></ul><ul><li>Muscle to promote protein and glycogen synthesis </li></ul><ul><li>Adipose tissue to reduce free fatty acids and promote triglyceride storage </li></ul><ul><li>hypoglycemia results mainly from: inhibition of hepatic glucose production, and stimulation of glucose uptake & metabolism in liver, adipose tissues, and skeletal muscle </li></ul>
    116. 116. Outcomes of Diabetes Glycation of proteins     Type 1   Type 2 obesity 
    117. 117. INSULIN Preparations <ul><li>Usually injected SC with onset, peak, and duration of action dose related </li></ul><ul><li>Short-acting or ultrashort acting mimic the post-prandial rise in insulin and given IV for hyperglycemic emergencies or diabetic ketoacidosis </li></ul><ul><li>NPH, long, and ultra-long acting preparations mimic basal insulin </li></ul><ul><li>Mixtures used to produce desired times of onset, peak, and duration of action </li></ul><ul><li>Glargine and detemir are ultra-long-acting, produces a sustained “peakless” absorption profile, and can provide once-daily effective 24-hr plasma levels </li></ul>
    118. 118. Five Main Types of Insulin > 24 Glargine & detemir Ultralong-acting 18-24 NPH Intermediate-acting 5-7 Regular Short-acting 3-4 Lispro (Humalog) Aspart (Novolog) Glulisine Ultra-short-acting Duration (hrs) Preparations Insulin Type
    119. 119. Types of Diabetes Mellitus Heterogeneous, obesity related, reduced B cells Autoimmune disease of B cells Etiology Insulin resistant Lack of insulin Basic defect 90 (increases with age) 5-10 Incidence (%) Adult < 30 years Age group Type 2 (NIDDM) Type 1 (IDDM)
    120. 120. Insulin Therapy <ul><li>Insulin is currently the mainstay treatment in: </li></ul><ul><ul><li>All type 1 diabetics and </li></ul></ul><ul><ul><li>Type 2 diabetics not adequately controlled by diet and/or oral hypoglycemic drugs (20%) </li></ul></ul><ul><li>Injected subcutaneously (abdomen, buttock, anterior thigh, or dorsal arm) for long-term treatment, but may also be given IM or IV </li></ul><ul><li>Insulin injected SC differs from endogenously secreted insulin in two ways: </li></ul><ul><ul><li>Does not reproduce the rapid rise and fall occurring when insulin is secreted due to stimulation by ingested food, and </li></ul></ul><ul><ul><li>Diffuses into the systemic circulation instead of being secreted into the portal circulation (eliminates direct hepatic effects) </li></ul></ul><ul><li>Ideal goal - to normalize blood glucose and all aspects of glucose metabolism, but this is difficult to achieve </li></ul>
    121. 121. Insulin Hypoglycemia <ul><li>Most common complication resulting from delayed meals, unusual physical exertion, or insulin overdose </li></ul><ul><li>Main signs occurring with plasma glucose of 60-80 mg/dL: </li></ul><ul><ul><li>Neuroglycopenic - CNS impairment manifested as mental confusion, bizarre behavior, convulsions, or coma </li></ul></ul><ul><ul><li>Autonomic hyperactivity - </li></ul></ul><ul><ul><ul><li>Sympathetic (tachycardia, palpitations, sweating, tremors) </li></ul></ul></ul><ul><ul><ul><li>Parasympathetic (nausea, hunger) </li></ul></ul></ul><ul><li>Rapidly relieved by giving glucose </li></ul><ul><ul><li>In patients who can swallow -orange juice or any sugar-containing food or beverage </li></ul></ul><ul><ul><li>In unconscious patients - IV 50% glucose, 20-50 mL over 2-3 min; last resort glucagon </li></ul></ul>
    122. 122. ORAL ANTIDIABETIC DRUGS <ul><li>Used alone or with insulin for type 2 diabetes: </li></ul><ul><li>Four categories based on hypoglycemic mechanism: </li></ul><ul><ul><li>Insulin Secretagogues </li></ul></ul><ul><ul><ul><li>Sulfonylureas </li></ul></ul></ul><ul><ul><ul><li>Meglitinides </li></ul></ul></ul><ul><ul><li>Biguanides </li></ul></ul><ul><ul><ul><li>Metformin </li></ul></ul></ul><ul><ul><li>Thiazolidinediones (TZDs); -glitazones </li></ul></ul><ul><ul><ul><li>Rosiglitazone </li></ul></ul></ul><ul><ul><ul><li>Pioglitazone </li></ul></ul></ul><ul><ul><li>Alpha-glucosidase inhibitors </li></ul></ul><ul><ul><ul><li>Acarbose </li></ul></ul></ul><ul><ul><ul><li>Miglitol </li></ul></ul></ul>
    123. 123. Insulin Secretagogues <ul><li>Stimulate insulin release through closing K + channels in pancreatic B cells </li></ul><ul><li>Chemically may be either </li></ul><ul><ul><li>Sulfonylureas or </li></ul></ul><ul><ul><li>A meglitinide (repaglinide)  </li></ul></ul>
    124. 124. Sulfonylureas <ul><li>Bind to high-affinity receptors for K + channels in pancreatic B cells  </li></ul><ul><li>Inhibit K + efflux to cause depolarization   </li></ul><ul><li>Open voltage-gated Ca ++ channel  </li></ul><ul><li>Increase Ca ++ influx  </li></ul><ul><li>Release insulin </li></ul>Glyburide Tolbutamide Glipizide Tolazamide Gliclazide Chlorpropamide Glimepiride Acetohexamide Second generation First generation
    125. 125. Sulfonylurea Characteristics <ul><li>Also reduce serum glucagon levels </li></ul><ul><li>Used mainly for treating type 2 diabetics whose hyperglycemia cannot be controlled by diet alone </li></ul><ul><li>Second generation sulfonylureas are: </li></ul><ul><ul><li>More effective and cause fewer adverse effects; but more profound hypoglycemia </li></ul></ul><ul><ul><li>Should be used with caution in diabetics who are elderly or have cardiovascular disease </li></ul></ul><ul><li>Tolbutamide is safest for elderly diabetics because: </li></ul><ul><ul><li>Its duration of action is relatively short </li></ul></ul><ul><ul><li>Severe hypoglycemic episodes are unlikely </li></ul></ul>
    126. 126. Meglitinides <ul><li>Increase insulin release from B cells by regulating K + efflux through the K + channel </li></ul><ul><li>Those available are repaglinide and nateglinide </li></ul><ul><li>Their site of action includes: </li></ul><ul><ul><li>A unique binding site and </li></ul></ul><ul><ul><li>Two other sites in common with the sulfonylureas </li></ul></ul><ul><li>Used mainly for controlling postprandial glucose levels </li></ul><ul><li>Use cautiously in the presence of hepatic dysfunction </li></ul><ul><li>Can be used in type 2 diabetics who are allergic to sulfonylureas because the repaglinide & natglinide structures does not contain a sulfonamide moiety </li></ul>
    127. 127. Biguanides: Metformin <ul><li>Mechanism of action uncertain, but does not depend on functioning B cells; proposed mechanisms include: </li></ul><ul><ul><li>Direct stimulation of tissue glycolysis </li></ul></ul><ul><ul><li>Reduced hepatic gluconeogenesis </li></ul></ul><ul><ul><li>Reduced GI glucose absorption </li></ul></ul><ul><ul><li>Reduced plasma glucagon </li></ul></ul><ul><li>It is “euglycemic” or antihyperglycemic; does not cause hypoglycemia but reduces fasting or postprandial blood glucose levels </li></ul><ul><li>Used mainly in: </li></ul><ul><ul><li>Obese patients with ‘insulin resistance syndrome’ </li></ul></ul><ul><ul><li>Type 2 diabetics who do not respond to sulfonylureas alone </li></ul></ul><ul><li>Most frequent adverse effects (20% of patients) are gastrointestinal : anorexia, nausea, vomiting, abdominal discomfort, diarrhea </li></ul><ul><li>Increases the risk of lactic acidosis </li></ul><ul><li>Contraindicated in patients with renal or hepatic disease, alcoholism, or chronic cardiopulmonary dysfunction </li></ul>
    128. 128. Thiazolidinediones (Tzds): Rosiglitazone & Pioglitazone <ul><li>Diminish insulin resistance by enhancing the tissue sensitivity to insulin (i.e., increased glucose uptake and metabolism in muscle and adipose tissues) </li></ul><ul><ul><li>The –glitazones are insulin sensitizers </li></ul></ul><ul><li>TZDs are agonists of PPAR-  (peroxisome proliferator-activated receptor-gamma) nuclear receptors found in muscle, fat, and liver </li></ul><ul><li>PPAR-  activates insulin-responsive genes that regulate carbohydrate and lipid metabolism </li></ul><ul><li>The major site of TZD action in diabetics are adipose tissues </li></ul><ul><li>Some beneficial effects may be due to redistribution of body fat causing reduced visceral fat mass and loss of central obesity </li></ul><ul><li>Also “euglycemic” rather than hypoglycemic; restore normal blood glucose levels without causing hypoglycemia </li></ul><ul><li>The first one, troglitazone , was withdrawn because of liver damage </li></ul><ul><li>Rosiglitazone & pioglitazone are clinically effective in type 2 diabetes without producing hepatotoxicity </li></ul><ul><li>Adverse effects are: edema, anemia, expanded plasma volume; rosiglitazone has been associated with an increased risk of heart failure </li></ul>
    129. 129. Sitagliptin (Januvia™) <ul><li>An orally effective dipeptidyl-peptidase-IV (DPP-IV) inhibitor used in the treatment of type 2 diabetes mellitus </li></ul><ul><li>Potentiates the effects of the incretin hormones, glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulinotropic peptide (GIP), by inhibiting their breakdown by DPP-IV </li></ul><ul><li>Additionally, may improve beta-cell function </li></ul><ul><li>Indications include: </li></ul><ul><ul><li>Use as initial combination therapy with metformin in drug-naive patients </li></ul></ul><ul><ul><li>As add-on therapy to a sulfonylurea </li></ul></ul><ul><ul><li>As add-on therapy to a sulfonylurea plus metformin </li></ul></ul>
    130. 130. Exenatide (Byetta®) <ul><li>An incretin mimetic: </li></ul><ul><ul><li>Incretins are endogenous compounds, such as glucagon-like peptide-1 ( GLP-1 ), that improve glycemic control once released into the circulation via the gut </li></ul></ul><ul><li>A 39-amino acid GLP-1 agonist isolated from the salivary gland venom of the lizard Heloderma suspectum (Gila monster) </li></ul><ul><li>It mimics the enhancement of glucose-dependent insulin secretion and other antihyperglycemic actions of incretins </li></ul><ul><li>Indicated for the adjunct treatment of type 2 diabetes mellitus inadequately managed by the use of metformin, a sulfonylurea, a thiazolidinedione, or a combination of metformin plus a sulfonylurea or metformin plus a thiazolidinedione </li></ul><ul><li>It is given via subcutaneous administration </li></ul><ul><li>Can cause hypoglycemia especially when used with other hyoglycemic agents </li></ul><ul><li>Pancreatitis </li></ul><ul><ul><li>The FDA issued information on reports of acute pancreatitis occurring in patients taking exenatide. </li></ul></ul>
    131. 131. Pramlintide (Symlin®) <ul><li>It is a synthetic analog of amylin, a hormone co-secreted with insulin from pancreatic beta cells </li></ul><ul><li>Amylin secretion is absent in patients with type 1 diabetes mellitus and decreased in patients with type 2 diabetes mellitus </li></ul><ul><li>Amylin affects glucose concentrations by: </li></ul><ul><ul><li>Slowing of gastric emptying without altering the overall absorption of nutrients </li></ul></ul><ul><ul><li>Suppression of postprandial glucagon secretion </li></ul></ul><ul><ul><li>Centrally-mediated modulation of appetite leading to decreased caloric intake </li></ul></ul><ul><li>Indicated for: </li></ul><ul><ul><li>Adjunct treatment of type 1 diabetes mellitus in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy </li></ul></ul><ul><ul><li>Adjunct treatment of type 2 diabetes mellitus in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin </li></ul></ul><ul><li>Common adverse effects of pramlintide are: </li></ul><ul><ul><li>Hypoglycemia </li></ul></ul><ul><ul><li>Nausea </li></ul></ul><ul><ul><li>Cause weight loss rather than weight gain </li></ul></ul><ul><li>It is administered by subcutaneous injection </li></ul>
    132. 132. <ul><li>In a 26-year old woman with type 1 diabetes, treatment with which of the following insulin preparations has the longest duration of action? </li></ul><ul><li>A. Aspart </li></ul><ul><li>B. Glargine </li></ul><ul><li>C. Lispro </li></ul><ul><li>D. Regular </li></ul><ul><li>E. Ultralente </li></ul>Ans = B Glargine often referred to as “peak-less” insulin
    133. 133. <ul><li>A 65-year-old woman is 5’4”, weighs 120 kg, and has lab values of: fasting blood glucose = 225 mg/dL (normal < 115), glycosylated hemoglobin or HbA1 = 17% (normal 4-6%), and plasma triglycerides = 370 mg/dL (normal 35-160). Oral treatment with which of the following would reduce insulin resistance without damaging the liver in this patient? </li></ul><ul><li>A. Metformin </li></ul><ul><li>B. Miglitol </li></ul><ul><li>C. Proinsulin </li></ul><ul><li>D. Pioglitazone </li></ul><ul><li>E. Troglitazone </li></ul>Ans = D The –glitazone’s are “ insulin sensitizers”; Troglitazone removed from market because of hepatotoxicity
    134. 134.  Disulfiram effect Lactic acidosis Insulin sensitizers PPAR γ <ul><li>Risk of </li></ul><ul><li>Heart failure </li></ul>Repaglinide Nateglinide Pramlintide (Symlyn) = synthetic amylin; multiple effects including anorectic Exenatide (Byetta) GLP-1 from saliva of Gila monster; used when difficult to attain glycemic control Sitagliptin is an orally effective dipeptidyl-peptidase-IV (DPP-IV) inhibitor used in the treatment of type 2 diabetes mellitus
    135. 135. A 12-year-old boy with type 1 diabetes mellitus is brought to the Emergency Department complaining of dizziness. Laboratory findings revealed severe, hyperglycemia, ketoacidosis and a blood pH of 7.1. Which of the following medications is most appropriate to treat this boy? <ul><li>Glyburide </li></ul><ul><li>Metformin </li></ul><ul><li>Pioglitazone </li></ul><ul><li>Regular insulin </li></ul><ul><li>Ultralente insulin </li></ul>Answer: D IV regular insulin for this patient
    136. 136. Metformin is contraindicated in a alcoholic 49-year-old obese woman with type 2 diabetes mellitus because it may increase the risk of the following? <ul><li>A disulfiram-like effect </li></ul><ul><li>Excessive weight gain </li></ul><ul><li>Lactic acidosis </li></ul><ul><li>Severe hepatotoxicity </li></ul><ul><li>Severe hypoglycemia </li></ul>Answer: C Metformin can cause lactic acidosis when given to patients with: Liver disease Renal disease Cardio/pulmonary disease Alcoholics
    137. 137. BONE MINERAL HOMEOSTASIS <ul><li>Major mineral constituents of bone are calcium and phosphate with the largest amounts of both found in bone: of total amounts in the body, bones contain </li></ul><ul><ul><li>98% of calcium and </li></ul></ul><ul><ul><li>85% of phosphate </li></ul></ul><ul><li>Average American diets contain about the same amounts of both constituents, but intestinal absorption of phosphate is much higher than that of calcium </li></ul><ul><li>Renal reabsorption of both constituents is highly efficient averaging </li></ul><ul><ul><li>98% for calcium </li></ul></ul><ul><ul><li>85% for phosphate </li></ul></ul>
    138. 138. General Features of Calcium and Phosphate Homeostasis <ul><li>Total body content and amounts in US diet are almost the same </li></ul><ul><li>Bone serves as the principal reservoir through constant remodeling and mineral exchange with extracellular fluid </li></ul><ul><li>Larger amounts of calcium are present in bone and reabsorbed by the kidneys </li></ul><ul><li>Phosphate is more efficiently absorbed in the intestines </li></ul>85 98 Renal tubular reabsorption 70-90 15-25 Intestinal absorption (%) 600-1000 600-1000 Dietary amount (mg/day) 85 98 Body content in bone (%) 1 1-2 Total body content (kg) Phosphate Calcium Constituent Amounts
    139. 139. Daily Calcium Turnover <ul><li>Ca ++ enters the body only through the intestine resulting in daily absorption of about 300 mg </li></ul><ul><li>An obligatory loss of 150 mg/day occurs in mucosal and biliary secretions, and in sloughed intestinal cells; this plus the residual 500 mg remaining from unabsorbed intake adds to a total fecal loss of 650 mg/day </li></ul><ul><li>Urinary excretion of

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