Power point presentation on Endocrine drugs-1.ppt

A precise presentation on introduction to endocrine system and the drugs thereby

1. Hypothalamic & Pituitary
Hormones

2. Introduction
•The hypothalamus and pituitary gland produce
hormones that play critical roles in regulation of:
–metabolism,
–growth,
–reproduction.
•Several endocrine disorders are treated using:
–Preparations of hypothalamus and pituitary
hormones,
•including products made by recombinant DNA technology
– and drugs that mimic or block their effects

3. •Classification of the hypothalamic and pituitary hormones and their
antagonists is often done according to the anatomic site of release of
the hormone that they mimic or block:
–1) the hypothalamus;
•Growth hormone releasing hormone
•Gonadotropin-releasing hormone (GnRH);
–2) the anterior pituitary:
•growth hormone (GH),
•the 2 gonadotropins; luteinizing hormone (LH) and follicle-stimulating
hormone (FSH),
•prolactin;
–3) the posterior pituitary;
•Oxytocin
•vasopressin (antidiuretic hormone [ADH]).
The hypothalamic-pituitary endocrine system:
Figure 37-1
Table 37–1
Introduction

4. Anterior Pituitary Hormones & Their Hypothalamic Regulators
•Growth Hormone (GH) agonist: Somatropin
–Somatropin is a recombinant form of human GH;
–It’s a GH agonist:
–Acts through GH receptors to increase the production
of insulin like growth factor-1 (IGF-1)
–GH functions:
» normal growth during childhood and adolescence
»Lifetime regulator of lipid and carbohydrate
metabolism and lean body mass.
–The effects of GH are primarily mediated through
production of insulin-like growth factor 1 (IGF-1) and 2
(IGF-2) in peripheral tissues

5. •Uses:
–Replacement in GH deficiency; leads to
increased final adult height in children with
certain conditions associated with short
stature;
–wasting in HIV infection;
–short bowel syndrome
Anterior Pituitary Hormones & Their Hypothalamic Regulators

6. •IGF-1 agonist: Mecasermin
–Mecasermin is a recombinant form of IGF-1 that
stimulates IGF-1 receptors
–Use:
•Replacement in IGF-1 deficiency that is not responsive to
exogenous GH
Anterior Pituitary Hormones & Their Hypothalamic Regulators

7. •Growth hormone antagonists:
–These are used to treat conditions of excess GH;
•Acromegally resulting from Growth hormone-secreting
pituitary adenomas
–Acromegally: A syndrome of growth hormone (GH) excess in adults
that is characterized by abnormal growth of tissues—particularly
connective tissue—metabolic abnormalities, and cardiac dysfunction
–Somatostatin analogs: Octreotide
•Somatostatin inhibits the release of GH, glucagon, insulin, and
gastrin
•Octreotide and other somatostatin analogs are agonists of
somatostatin receptors
•Use: acromegaly, gastrinoma, glucagonoma, and other
endocrine tumors
–GH receptor antagonist: Pegvisomant
•used in treatment of acromegaly
Anterior Pituitary Hormones & Their Hypothalamic Regulators

8. •Follicle-Stimulating Hormone (FSH),
Luteinizing Hormone, and their Analogs
–In women,
•FSH directs follicle development,
•FSH and LH collaborate in the regulation of ovarian
steroidogenesis: synthesis of estrogens and progestins
–In men,
•FSH is the primary regulator of spermatogenesis,
•LH is the main stimulus for testicular steroidogenesis:
androgen production.
Anterior Pituitary Hormones & Their Hypothalamic Regulators

9. –Use:
•The gonadotropins and their analogs are used in combination
to;
–stimulate spermatogenesis in infertile men
–induce ovulation in women with anovulation that is not
responsive to less complicated treatments
–Preparations:
•Menotropins: a mixture of FSH and LH purified from the
urine of postmenopausal women
–Postmenopausal women produce high levels of FSH and LH owing
to the disinhibition of pituitary gonadotropin production that
results from cessation of ovarian steroidogenesis
•FSH and its analogs: Urofollitropin
•LH analogs: Lutropin, Human chorionic gonadotropin (hCG)
Anterior Pituitary Hormones & Their Hypothalamic Regulators

10. •Gonadotropin-Releasing Hormone (GnRH)
agonist: Leuprolide
–Leuprolide is a Gonadotropin-Releasing Hormone
(GnRH) agonist
–Endogenous GnRH, produced in the hypothalamus
stimulates production of gonadotropins (FSH and
LH) in the anterior pituitary
•However, when administered continuously as a drug,
GnRH and its analogs inhibit LH and FSH release by
downregulating GnRH receptors in the pituitary cells
that normally release gonadotropins
Anterior Pituitary Hormones & Their Hypothalamic Regulators

11. –Use: Continuous GnRH agonist treatment is used
to suppress endogenous gonadotropin secretion
in:
•women undergoing ovulation induction with
gonadotropins,
•women with gynecologic disorders that benefit from
ovarian suppression (e.g, endometriosis, uterine
leiomyomata),
•children with precocious puberty,
•men with advanced prostate cancer.
Anterior Pituitary Hormones & Their Hypothalamic Regulators

12. •Gonadotropin-Releasing Hormone (GnRH) Antagonists:
Ganirelix and cetrorelix
–These can be used during ovulation induction in place of GnRH
agonists to suppress endogenous gonadotropin production.
•Prolactin Antagonists (Dopamine D
2 Receptor Agonists):
Bromocriptine
–Prolactin is an anterior pituitary hormone that regulates lactation
–Dopamine serves as the physiologic inhibitor of prolactin release
–Bromocriptine and other dopamine agonists inhibit prolactin
release
–Use:
•hyperprolactinemia and an associated syndrome of infertility and
galactorrhea resulting from prolactin-secreting adenomas
Anterior Pituitary Hormones & Their Hypothalamic Regulators

13. Posterior Pituitary Hormones
•Oxytocin
–Oxytocin is synthesized in hypothalamus and
transported to the posterior pituitary.
–It is an effective stimulant of uterine contraction
and is used intravenously to induce or reinforce
labor.

14. •Vasopressin (Antidiuretic Hormone [ADH])
–Vasopressin is synthesized in the hypothalamus and
released from nerve terminals in the posterior pituitary
–acts through V
2 receptors to increase the insertion of water
channels in the apical membranes of collecting duct cells in
the kidney
•thereby providing an antidiuretic effect.
–Extrarenal effects:
•V
2-like receptors regulate the release of coagulation factor VIII and
von Willebrand factor
–Desmopressin
•a selective agonist of V
2
receptors,
•Use:
–pituitary diabetes insipidus
–mild hemophilia A or von Willebrand disease.
Posterior Pituitary Hormones

15. Gonadal Hormones & Inhibitors

16. Introduction
•The gonadal hormones:
–steroids of the ovary: estrogens and progestins
–Steroids of the testis: testosterone

17. •The ovarian steroids are widely used,
–with many synthetic estrogens and progestins having been
produced, including;
•synthesis inhibitors,
•receptor antagonists,
•some drugs with mixed effects (ie, agonist effects in some tissues
and antagonist effects in other tissues).
–Selective estrogen receptor modulators (SERMs)
•These are mixed agonists with estrogenic effects
–Androgens:
•Synthetic androgens are also available for clinical use.
–Antiandrogens:
•Important in the treatment of prostate cancer and benign prostatic
hyperplasia in men and hyperandrogenism in women.
Introduction

18. Ovarian Hormones
•Ovary
–the primary source of gonadal hormones in women
during the childbearing years i.e., between puberty and
menopause
•A normal menstrual cycle is regulated by follicle-
stimulating hormone (FSH) and luteinizing hormone
(LH) from the pituitary, consisting of the following
events:
–Maturation of a follicle in the ovary; the follicle
secretes increasing amounts of estrogen,
–Release of an ovum from the follicle,
–Transformation of the follicle into a
progesterone-secreting corpus luteum.

19. •In absence of fertilization and implantation of
the ovum;
–the corpus luteum degenerates;
–the uterine endometrium, which has
proliferated under the stimulation of
estrogen and progesterone, is shed as part
of the menstrual flow,
–and the cycle repeats.
Ovarian Hormones

20. Estrogens
•Estrogen forms:
–Natural:
•Estradiol: the major ovarian estrogen in women
•Estrone
•estriol
–Synthetic estrogens
•ethinyl estradiol,
•mestranol

21. •Effects:
–Female maturation:
–Estrogen is essential for normal female reproductive
development;
–It is responsible for growth of the genital structures (vagina,
uterus, and uterine tubes) during childhood and for the
appearance of secondary sexual characteristics and the growth
spurt associated with puberty.
–Metabolic effects:
•Estrogen modifies serum protein levels and reduces bone
resorption.
•It increases plasma triglyceride levels while reducing low-
density lipoprotein (LDL) cholesterol and increasing high-
density lipoprotein (HDL) cholesterol.
Estrogens

22. •Effects on blood coagulation:
•Estrogen enhances coagulability of blood
–When administered continuously, especially in
combination with a progestin, estrogen inhibits the
secretion of gonadotropins from the anterior
pituitary;
•This forms the basis for its use as a contraceptive
Estrogens

23. •Clinical use: see Table 40–1
–treatment of hypogonadism in young females.
–Hormone replacement therapy (HRT) in women with
estrogen deficiency resulting from premature ovarian
failure, menopause, or surgical removal of the ovaries.
•HRT is useful in:
–hot flushes and atrophic changes in the urogenital tract.
–Prevention of bone loss and osteoporosis.
–Estrogens combined with progestins in hormonal
contraceptives;
•Estrogen is used in combination with a progestin to prevent
estrogen-induced endometrial cancer
Estrogens

24. •Adverse effects:
–Moderate adverse effects:
•Breakthrough bleeding,
•nausea,
•breast tenderness
–Serious adverse effects :
•Thromboembolism,
•gallbladder disease,
•hypertriglyceridemia,
•migraine headache,
•hypertension,
•depression
•In postmenopausal women:
–breast cancer,
–endometrial hyperplasia
Estrogens

25. Estrogens
•Drug interactions:
–Gonadal steroids and their derivatives are
metabolized primarily by the cytochrome P450
3A4 (CYP3A4) family of enzymes,
•hence, combination with cytochrome P450 inducers
can lead to breakthrough bleeding and reduced
contraceptive efficacy
–cytochrome P450 inducers:
•barbiturates, carbamazepine, corticosteroids,
griseofulvin, phenytoin, pioglitazone, rifampin, and
rifabutin

26. Progestins
•Natural progestins:
–The major progestin in humans: Progesterone
–Besides its hormonal effects, progesterone is also
the precursor to estrogens, androgens, and
adrenocortical steroids
–Progesterone is synthesized in ovaries, testis and
adrenal cortex from circulating cholesterol

27. •Forms:
–Oral progesterone preparations for HRT
–vaginal progesterone containing creams
–Synthetic progestins:
•hydroxyprogesterone,
•medroxyprogesterone,
•megestrol,
•dimethisterone
•desogestrel
•gestodene
•Norgestimate
–Most synthetic progestins vary in their degree of
androgenic effects.
Progestins

28. •Effects
–Maintenance of pregnancy
•Through its induction of secretory changes in the
endometrium, progesterone plays an important role in the
maintenance of pregnancy.
•Though the other progestins also have a stabilizing effect in
the endometrium, they lack in the pregnancy supportive
function.
–Metabolic effects:
•Progestins affect carbohydrate metabolism and stimulate the
deposition of fat, but lack significantly effects on plasma
proteins
–Progestins in high doses suppress gonadotropin
secretion
•and often cause anovulation in women.
Progestins

29. •Clinical Use
–Contraceptive use,
•Progestins are used either alone or in combination with
an estrogen for contraception.
–Hormone Replacement Therapy (HRT)
•Progestins are used in combination with an estrogen in
HRT to prevent estrogen-induced endometrial cancer.
–Infertility problems:
•Progesterone is used in assisted reproductive technology
methods to promote and maintain pregnancy.
Progestins

30. •Adverse effects
–Increase in blood pressure
–Decrease in HDL
–Reversible decrease in bone density associated
with long-term use of high doses in premenopausal
women;
•a secondary effect of ovarian suppression and decreased
ovarian production of estrogen
•resumption of ovulation is also delayed after termination
of therapy.
Progestins

31. Hormonal Contraceptives
•Hormonal contraceptives:
–Combined oral contraceptives (COCs): estrogen
and a progestin
–Progestin only contraceptives (POCs).
•Several preparations available:
–oral pills,
–long-acting injections,
–transdermal patches,
–vaginal rings,
–intrauterine devices (IUDs) (Table 40–1).

32. •Emergency contraception/postcoital
contraceptives;
–prevent pregnancy if administered within 72 h after
unprotected intercourse.
–Oral preparations:
•progestin (L-norgestrel) alone,
•estrogen alone,
•combination of an estrogen and a progestin
–The progestin-only preparation have a lower
incidence of side effects compared to the estrogen-
containing preparations.
Hormonal Contraceptives

33. •Mechanism of Action
–hormonal contraceptives produce several actions:
• inhibition of ovulation (the primary action)
•effects on the cervical mucus glands, uterine tubes, and
endometrium that decrease the likelihood of fertilization
and implantation.
–The Progestin-only agents do not always inhibit
ovulation
•And instead act through the other mechanisms mentioned
above.
–Postcoital contraceptives;
•Their mechanisms not well understood.
•They inhibit ovulation when administered before the LH
surge,
•They also affect:
–cervical mucus, tubal function, and the endometrial lining.
Hormonal Contraceptives

34. •Other clinical uses and beneficial effects
–COCs used in young women with primary
hypogonadism to prevent estrogen deficiency.
–COCS and POCs used to treat:
•acne,
•hirsutism,
•dysmenorrhea,
•endometriosis.
Hormonal Contraceptives

35. –Use of COCs reduces risks of:
•ovarian cysts,
•Ovarian and endometrial cancer,
•benign breast disease,
•pelvic inflammatory disease
•ectopic pregnancy,
•iron deficiency anemia,
• rheumatoid arthritis.
Hormonal Contraceptives

36. •Adverse effects:
–The incidence of dose-dependent toxicity has been
reduced with the introduction of the low-dose
combined oral contraceptives
–Major Adverse effects:
•Thromboembolism:
–Risk of myocardial infarction, stroke, deep vein thrombosis,
pulmonary embolism increased in older women, smokers,
women with a personal or family history of such problems,
and women with genetic predisposition to clotting malfunction
•Breast cancer
Hormonal Contraceptives

37. •Other adverse effects:
–breakthrough bleeding, especially during the first few
months of therapy;
–nausea,
–breast tenderness,
–headache,
–skin pigmentation,
–depression.
–weight gain, acne, and hirsutism: associated with
progestins with more androgenic effects
Hormonal Contraceptives

38. Antiestrogens
•Selective Estrogen Receptor Modulators (SERMs)
–These are mixed estrogen agonists that have estrogen
agonist effects in some tissues and act as partial
agonists or antagonists of estrogen in other tissues.
Drugs:
–Tamoxifen:
•effective in the treatment of hormone-responsive breast
cancer, where it acts as an antagonist to prevent receptor
activation by endogenous estrogens
–Clomiphene:
•a nonsteroidal compound used to induce ovulation in
anovulatory women with infertility problems
•It selectively blocks estrogen receptors in the pituitary, thereby
reducing negative feedback and increasing FSH and LH output.
•Increased levels of gonadotropins stimulates ovulation

39. •Pure Estrogen Receptor Antagonists
–Fulvestrant
•A pure estrogen receptor antagonist (in all tissues).
•used in the treatment of women with breast cancer that has
developed resistance to tamoxifen.
•Synthesis inhibitors:
–Anastrozole
•Reduces estrogen synthesis by inhibiting aromatase enzyme
•Use: Adjuvant treatment of hormone-responsive breast cancer
•GnRH agonist: Leuprolide,
–discussed earlier
• GnRH receptor antagonist:Ganirelix, cetrorelix
–Discussed earlier
Antiestrogens

40. Antiprogestins
•Mifepristone
–Progestin and glucocorticoid receptor antagonist
–Used in combination with a prostaglandin (eg,
misoprostol) for medical abortion

41. Androgens
•Production of testosterone and other androgens occurs in the
–testis, the adrenal cortex, and, to a small extent, the ovary.
•Precursors to testosterone synthesis:
–progesterone and dehydroepiandrosterone (DHEA).
•Testosterone is converted in several organs (eg, prostate) to
the active hormone
–Dihydrotestosterone (DHT),
•Androgens:
–Testosterone
–Fluoxymesterone, methyltestosterone
–Testosterone esters (eg, testosterone cypionate)
–Anabolic steroids (eg, oxandrolone, nandrolone decanoate)
•Uses:
–Male hypogonadism;
–weight gain in patients with wasting syndromes

42. Antiandrogens
•5-reductase inhibitors
–Finasteride
•Inhibits the 5-reductase enzyme that converts
testosterone to dihydrotestosterone, the active
form of testosterone
•Uses:
–Benign prostatic hyperplasia (BPH),
–male-pattern hair loss

43. •Receptor antagonists
–Flutamide
•Causes competitive inhibition of androgen receptor
•use:
–Advanced prostate cancer
•Synthesis inhibitor
–Ketoconazole
•Causes inhibition of cytochrome P450 enzymes involved
in androgen synthesis
•Use:
–Advanced prostate cancer that is resistant to first-line
antiandrogen drugs
Antiandrogens

44. Thyroid & Antithyroid Drugs

45. Introduction
•2 types of hormones secreted by the thyroid:
–iodine-containing amino acids:
•Thyroxine (T4)
•Triiodothyronine (T3)
–a peptide (calcitonin).
•Thyroxine and triiodothyronine have effects on:
–growth,
–development,
–metabolism.
•Calcitonin is important in calcium metabolism
•Drugs discussed in this section Include those used in
treatment of hypothyroidism and hyperthyroidism.

46. •Synthesis of thyroid hormones (Thyroxine
and triiodothyronine) requires iodine
obtained from food or iodide supplements.
•Conversion of iodine to elemental iodine
–The thyroid gland actively takes up iodide
ion to be converted to
elemental iodine through the action of
thyroidal peroxidase
See Figure 38–1
Introduction

47. •Iodine organification:
–Tyrosine residues in thyroglobulin are iodinated to form:
•monoiodotyrosine (MIT) or diiodotyrosine (DIT)
•T
4 : combination of 2 molecules of DIT
•T
3 : 1 molecule of MIT plus DIT
–T
4 and T
3 are then liberated from the thyroglobulin
through proteolysis and subsequently released from the
thyroid.
–The T
4 and T
3 that have been released are then
transported in the blood by thyroxine-binding globulin,
a protein synthesized in the liver.
Introduction

48. Effects of Thyroid Hormone:
•Thyroid hormones mediate important organ-level
actions:
–normal growth and development of the nervous, skeletal,
and reproductive systems
–control of metabolism of fats, carbohydrates, proteins, and
vitamins.
•Excess or inadequate amounts of thyroid hormones
result in the signs and symptoms of hyperthyroidism or
hypothyroidism, respectively (Table 38–4)
•Note:
–The potency of T
3
is about 10 times more than T4 .
–T
4
is converted to T
3
in target cells, the liver, and the
kidneys,
•Hence most of the effect of circulating T
4
is probably due to T
3
Introduction

49. Clinical use of thyroid hormones
•Thyroid hormone therapy is indicated in hypothyroidism:
–The therapy can be accomplished with either T4 or T
3
–Synthetic forms are available for these:
•levothyroxine (T
4
)- usually the form of choice.
•T
3
( liothyronine )- faster acting but has a shorter half-life and is more
expensive.
•Adverse effects:
–Manifestation of toxicity of thyroid hormone therapy
presents with features of thyrotoxicosis
–Patients at advanced age or those with cardiovascular
disease, and those with longstanding hypothyroidism are
highly sensitive to the stimulatory effects of T4 on the heart,
–hence they should receive lower initial doses of T
4
.

50. Antithyroid Drugs
•Figure 38-1 locates the various sites of action for
antithyroid drugs:
•Antithyroid drugs are indicated in hyperthyroidism
•1) Thioamides
–Propylthiouracil (PTU), Methimazole
•Inhibit thyroid peroxidase reactions, iodine organification, and
peripheral conversion of T4 to T
3
•2) Iodides
–Lugol's solution (ioidine and Potassium iodide)
•Inhibit iodine organification and hormone release;
•reduce size and vascularity of thyroid gland in preparation for
surgical thyroidectomy

51. 3) Radioactive iodine (
131
I)
•Sodium
131
I
•The radioactive isotope is rapidly absorbed and
concentrated in the thyroid where it emits rays resulting to
radiation-induced destruction of thyroid parenchyma
4) Beta blockers
–Propranolol
•useful in controlling the tachycardia and other cardiac
abnormalities of severe thyrotoxicosis through inhibition of
beta receptors.
•It also inhibits the peripheral conversion of T4 to T
3.

52. Adrenocorticosteroids &
Adrenocortical Antagonists

53. Introduction
•Corticosteroids:
–steroid hormones produced by the adrenal cortex.
•They exist in 2 major physiologic and pharmacologic
groups:
–(1) glucocorticoids;
•have important effects on intermediary metabolism,
catabolism, immune responses, and inflammation;
•e.g: cortisol
–(2) mineralocorticoids,
•regulate sodium and potassium reabsorption in the
collecting tubules of the kidney.
•e.g: aldosterone

54. •Addison's disease
–Condition characterized by partial or complete loss of
adrenocortical function, including loss of glucocorticoid and
mineralocorticoid function
•Adrenal suppression
–A condition characterized by suppression of the ability of the
adrenal cortex to produce corticosteroids.
–Most commonly occurs as a result of prolonged exogenous
glucocorticoid treatment
•Cushing's syndrome
–A metabolic disorder arising from excess secretion of
adrenocorticoid steroids;
•Occurs most commonly due to increased amounts of
adrenocorticotropic hormone (ACTH)
Introduction

55. Glucocorticoids
•Organ and Tissue Effects
–1) Metabolic Effects
•Stimulation of gluconeogenesis, resulting
to;
– increase in blood glucose levels
–Catabolism of muscle protein
–insulin secretion
–Stimulation of both lipolysis and
lipogenesis, with a net increase of fat
deposition in certain areas (e.g, the face
and the shoulders and back).

56. –2) Catabolic Effects
–muscle protein catabolism;
–High concentration of the steroids
may lead to: lymphoid and connective
tissue, fat, and skin wasting
–Osteoporosis may result from
catabolic effects on bone.
–In children, the steroids may lead to
growth inhibition.
Glucocorticoids

57. •3) Immunosuppressive Effects
–Glucocorticoids cause inhibition of cell-mediated
immunologic functions, especially those dependent
on lymphocytes.
–They are important in the treatment of
hematologic cancers due to their active
lymphotoxic effect
–Glucocorticoids are also useful in delaying rejection
reactions for transplanted organs;
•They do not interfere with the development of normal
acquired immunity
Glucocorticoids

58. •4) Anti-Inflammatory Effects
–Glucocorticoids affect the distribution and
function of leukocytes in a dramatic way:
•they increase neutrophils and decrease lymphocytes,
eosinophils, basophils, and monocytes.
–They also inhibit migration of leukocytes
–Cellular mechanisms: inhibition of phospholipase
A
2 and other inflammatory processes
Glucocorticoids

59. •5) Other Effects
–Some glucocorticoids like cortisol perform a role in
normal renal excretion of water loads;
•deficiency of cortisol leads to impaired renal function
(particularly glomerular filtration), augmented vasopressin
secretion, and diminished ability to excrete a water load
–Glucocorticoids also have effects on the CNS;
•High doses of the drugs may cause profound behavioral
changes;
–initially insomnia and euphoria and subsequently
depression
–Increase in gastric acid secretion and decreased
resistance to ulcer formation may also be observed
with large doses
Glucocorticoids

60. Important Glucocorticoids
•1) Cortisol (hydrocortisone)
–The major natural glucocorticoid
–secretion of cortisol is physiologically regulated by
adrenocorticotropin (ACTH)
•circadian rhythm: pattern of secretion varies during the
day;
–the peak occurs in the morning and the trough occurs about
midnight
Glucocorticoids

61. •2) Synthetic glucocorticoids:
–The representative synthetic glucocorticoids:
•Prednisone (active metabolite, prednisolone),
•dexamethasone,
•Triamcinolone
–compared with cortisol, these steroids have:
•longer half-life and duration of action,
•reduced salt-retaining effect,
•better penetration of lipid barriers for topical activity
See Table 39–1 for a comparative summary of effects
Glucocorticoids

62. •For Asthma and other conditions in which
good surface activity on mucous membranes
or skin is needed with minimal systemic
effects, special glucocorticoids have been
developed:
–Beclomethasone and budesonide
•These readily penetrate the airway mucosa but
have very short half-lives after they enter the
blood, so that systemic effects and toxicity are
greatly reduced.
Glucocorticoids

63. •Adverse effects:
–metabolic effects which may be life
threatening (growth inhibition,
diabetes, muscle wasting, osteoporosis),
–salt retention
–psychosis.
Glucocorticoids

64. •Minimizing the toxicities associated with
corticosteroids:
–local application (e.g, aerosols for asthma),
–alternate-day therapy (to reduce pituitary
suppression),
–tapering the dose soon after achieving a
therapeutic response.
•Slow tapering, over the course of several months, is
necessary for patients who have been in long term
therapy to allow recovery of normal adrenal function.
Glucocorticoids

65. Clinical uses of glucocorticoids;
•Adrenal uses:
–chronic adrenal cortical insufficiency
(Addison's disease)
–acute adrenal insufficiency associated
with life-threatening shock, infection,
or trauma.
Glucocorticoids

66. •Nonadrenal uses:
–Several inflammatory or immunologic
conditions:
•asthma, organ transplant rejection,
collagen diseases, rheumatic
disorders
–Hematologic cancers
–neurologic disorders,
–chemotherapy-induced vomiting,
Glucocorticoids

67. –hypercalcemia,
–mountain sickness.
–premature labor:
• Betamethasone, is given to pregnant women
in order to hasten maturation of the fetal lungs.
Note:
•The degree of benefit for use of corticosteroids
varies considerably in different disorders,
–and the toxicity of the drugs may limit their
chronic use.

68. Mineralocorticoids
1) Aldosterone
•The major natural mineralocorticoid in humans
•Aldosterone secretion is regulated by ACTH
and by the renin-angiotensin system
–It plays an important role in regulation of blood
volume and blood pressure
–Aldosterone has a short half-life and little
glucocorticoid activity
See Table 39-1

69. 2) Other Mineralocorticoids
•Fludrocortisone: also has significant
glucocorticoid activity
•Deoxycorticosterone (the naturally occurring
precursor of aldosterone)
•Fludrocortisone has a long duration of action;
–Hence preferred for replacement therapy after
adrenalectomy and in other conditions in which
mineralocorticoid therapy is needed.
Mineralocorticoids

70. Corticosteroid Antagonists
•1) Receptor Antagonists
–Aldosterone antagonists:
•Spironolactone and eplerenone
–Mifepristone (RU-486):
•a competitive inhibitor of glucocorticoid receptors as well
as progesterone receptors;
–used in the treatment of cushing's syndrome.
•2) Synthesis Inhibitors
–Include drugs that inhibit adrenal steroid synthesis;
•ketoconazole, aminoglutethimide, and metyrapone.

71. Drugs That Affect Bone Mineral
Homeostasis

72. Introduction
•Calcium and phosphorus,
–the 2 major elements of bone,
–also required for the normal function of
many other cells in the body.

73. •Calcium and phosphate homeostasis.
–Primary regulators:
•Parathyroid hormone (PTH) and vitamin D
See Figure 42–1
–Secondary regulators:
•calcitonin, glucocorticoids, and estrogens.
–Various bone mineral disorders (eg, osteoporosis,
rickets, osteomalacia etc),
•are treated with the above hormones or their analogs or
antagonists
Introduction

74. Hormonal regulators of bone mineral homeostasis
•Parathyroid hormone (PTH)
–produced in the para-thyroid gland
–It stimulates the production of the active metabolite of
vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)
2
D)
•The active metabolites of Vit D leads to increased serum
concentrations of calcium and phosphate
–PTH causes a net increase in calcium and decrease in
phosphate
–synthesis and secretion of PTH is primarily regulated by
the serum concentration of free ionized calcium;
•a drop in free ionized calcium stimulates PTH release.
–Active metabolites of vitamin D inhibit PTH synthesis

75. •Vitamin D
–Vitamin D, a fat-soluble vitamin
–Sources:
•synthesized in the skin from 7-
dehydrocholesterol under the influence
of ultraviolet light
•absorbed from the diet in the:
–natural form (vitamin D3 ,
cholecalciferol ) or
–the plant form (vitamin D2 ,
ergocalciferol ).
Hormonal regulators of bone mineral homeostasis

76. –Conversion into active form:
•Active metabolites of Vit D are
formed in:
– the liver: 25-hydroxyvitamin D or
calcifediol
–kidney : 1,25-dihydroxyvitamin D
or calcitriol
Hormonal regulators of bone mineral homeostasis

77. –Functions of the active vitamin D metabolites
•cause a net increase in serum concentrations
of calcium and phosphate by
–increasing intestinal absorption and bone
resorption and decreasing renal excretion
•required for normal mineralization of bone;
–deficiencies cause rickets in growing
children and adolescents and osteomalacia
in adults.
•inhibit PTH secretion directly and indirectly, by
increasing serum calcium
Hormonal regulators of bone mineral homeostasis

78. –Use of Vit D
•treatment of Vit D deficiency states,
including
–nutritional deficiency, intestinal
osteodystrophy, chronic kidney or liver
disease, hypoparathyroidism, and
nephrotic syndrome.
•used, in combination with calcium
supplementation, to prevent and treat
osteoporosis in older women and men.

79. •Calcitonin
–a peptide hormone secreted by the thyroid gland,
that decreases serum calcium and phosphate by
•inhibiting bone resorption and inhibiting reabsorption of
these minerals in the kidneys
–Used in osteoporosis
•Estrogens
–Estrogens and selective estrogen receptor modulators
(SERMs; eg, raloxifene ) prevent or delay bone loss in
postmenopausal women through inhibition of PTH-
stimulated bone resorption
Hormonal regulators of bone mineral homeostasis

80. Bibliography
–Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2013) Pharmacology- Examination And
Board Review 10th ed., McGraw Hill, Lange
–Katzung B.G (2007) Basic & Clinical Pharmacology,
11th ed, McGraw Hill, Lange