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174 Cards in this Set

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  • Back
What is endocrine pharmacology?
-Endocrine pharmacology is the study
of actions and mechanisms of drugs
that affect endocrine glands and the
substances they secret (hormones).
What are the differences between exocrine versus endocrine glands?
Endocrine:
-ductless
-secreting unto blood vessels
-actions depending on specific receptors
-long distance action
Exocrine:
-has duct
-secretes into body cavities or outside
-no specific receptor involvement
-short-distance action
What are the functions of the endocrine system?
• Maintain homeostasis.
• Support cell growth.
• Coordinate important physiological
events, i.e. development, metabolism
and reproduction.
• Facilitate responses to external stimuli.
What are hormones? Various structures?
-Chemicals that are secreted by endocrine glands and transported by the circulation to elicit
biological effects in distant organs.
-Amines, Peptides & proteins,
-Steroids
How are amines synthesized? storage? secretion?
-from tyrosine in cytoplasm
-storage exists
-exocytosis
How are peptides and proteins synthesized? storage? secretion?
-From amino acids in rough endoplasmic reticulum (ER)
-storage from ER and Golgi apparatus
-exocytosis
How are steroids synthesized? storage? secretion?
-from cholesterol in cytoplasm
-no storage
-passive diffusion
What is the plasma transportation of hormones?
-Highly dependent upon hormone physico-chemical properties.
• Water-soluble hormones (peptides, proteins and small
molecules) are mainly transporting in the free form.
• Water-insoluble hormones (steroids and thyroid
hormones) are largely transported by plasma proteins.
• In general, free hormone molecules are more active and
shorter in circulation than the bound molecules.
What is endocrine hyper-function? Treatment?
-overproduction of hormones (e.g.
tumors)
-abnormalities in
receptors expression, functions
and downstream signaling
pathways.
-Surgery:
Primary choice for most
endocrine adenomas.
• Anti-hormone drug
therapy:
-hormone receptor
antagonists, antibodies.
What is endocrine hypo-function? treatment?
-insufficiency in hormone
production (e.g. genetic defects)
-abnormalities in receptors
expression, functions and
downstream signaling pathways.
Hormone replacement
therapy:
-synthetic hormones or
receptor agonists.
What is the hypothalamus?
-a body located at the base of
3rd ventricle with neurosecretory cells to regulate pituitary hormone release.
What is the pituitary gland?
-a master gland beneath the
hypothalamus controlling most endocrine glands functions.
How is the pituitary gland physically connected to the hypothalamus?
(a) Blood vessels (portal venous
system) that drains the
hypothalamus and perfuses the
anterior pituitary.
(b) Neurosecretory fibers that
synthesize posterior pituitary
hormones and transport them to
the posterior pituitary where they are released
What are the common features of hypothalamic and pituitary hormones?
• All are peptide/protein hormones. Pituitary hormones generally
have two subunits, of which alpha unit is for function and beta
unit is for specificity.
• They require parenteral administration (i.v., i.m., s.c.).
• They all have relatively fast plasma clearance. I.V. injection
obtains the fastest action and shortest duration of action.
• Most of them generate biological effects via binding to cell
membrane receptors on the target cells and activating cAMP.
– Exceptions: Growth hormone and prolactin are through activating
tyrosine kinase receptor pathway.
• Largely produced by the recombinant technology.
What is growth hormone deficiency?
– In children: Dwarfism (short stature), reduced muscle mass, adiposity.
– In adults: reduced muscle mass, reduced cardiac output, obesity.
What is growth hormone overproduction?
– Most commonly in adults due to GH-secreting
adenomas: acromegaly
How is sermorelin used for growth hormone deficiency?
• GHRH analogue
• Applications
• GH deficiency (Dwarfism, reduced muscle mass, obesity),
usually given subcutaneously once daily at bedtime.
• GH deficiency diagnosis, usually given i.v.
• Not for cancer patients
What are somatropin and somatrem for use for growth hormone deficency?
• Recombinant human growth hormone
Application:
• For genetic (newborn) and acquired (adult) GH deficiency,
usually given subcutaneously once daily at bedtime.
• Long-acting injectable suspension available, usually given
subcutaneously once per month.
• Potential for abuse.
• Anti-aging drugs, banned drugs for athletes.
• Not for cancer patients.
What is Octreotide as a growth hormone antagonist for over-production?
• Somatostatin analogue.
Application:
• GH-secreting tumors leading to acromegaly (GH excess in
adults, manifested by enlargement of extremities), given
subcutaneously.
• Long-acting preparation: Octreotide acetate injectable
suspension, usually given by i.m. injection every 4 weeks.
What is pegvisomant as a growth hormone antagonist for over-production?
-Mutated growth hormone that has strong affinity for GH
receptor, but can not generate GH activities.
• Application: for acromegaly.
• Daily s.c. injection.
What is the mechanism of action of GnRH receptor agonists?
-The release of FSH and LH is increased by pulsatile releasing or dosing of GnRH (agonists)
and inhibited by sustained administration of GnRH (agonists) in both women and men.
What is the preparation of gonadorelin as a GnRH receptor agonist?
– Acetate of synthetic human GnRH.
What is the preparation of leuprolide (lupron) as a GnRH receptor agonist?
-GnRH analogues
-available in solution for daily s.c.
injection and or slow-releasing microsphere depot preparation.
What is the preparation of goserelin as a GnRH receptor agonist?
-a slow-releasing subcutaneous implantable
cylinder preparation.
What is the preparation of nafarelin as a GnRH receptor agonist?
-fast-acting nasal preparation.
What are GnRH receptor agonists used for? Side effects?
Stimulation of gonadotropin production:
• Infertility due to hypothalamic hypogonadism in both sexes by
pulsatile release of Gonadorelin or a GnRH agonist about every 90min.

Inhibition of gonadotropin production:
• Gonadal hormone-sensitive tumors (e.g. prostate, uterine and ovary tumors) by using long-acting depot preparations.
• Precocious puberty (onset of secondary sex characteristics before 8
years old in girls or 9 years old in boys) by daily s.c. injection or using
long-acting depot preparations.

Side effects:
• Initial flare symptoms
• Hypogonadal symptoms (menopause, depression, osteoporosis decreased libido, reduced bone density)
What is the biological function of follicle stimulating hormone (FSH)?
– Stimulating gametogenesis; follicular development in
women and spermatogenesis in men.
– Working together with LH in stimulating gonadal
steroids synthesis.
What is the biological function of luteinizing hormone (LH)?
– Primarily responsible for controlling gonadal steroids
synthesis.
– Inducing ovulation and progesterone release.
What are clinical preparations for FSH?
– Urinary FSH (uFSH), purified human FSH isolated from the urine
of postmenopausal women.
– Recombinant FSH (rFSH, Follitropin).
What are the clincial preparations for LH?
– Recombinant LH (rLH, Lutropin)
– Human chorionic gonadotropin (hCG), a hormone, with almost
identical structure to LH, that is produced by the placenta and
excreted into the urine. -Recombinant hCG (rhCG) is also
available.
What are the clinical applications for use of FSH and LH analogues?
– FSH and LH analogs are used together for infertility due to
hypogonadism in both sexes.
– May cause ovarian hyperstimulation and multiple pregnancies.
What are the dopamine receptor agonists for hormone regulation? mechanism of action? applications for use?
• Ergot derivatives:
– Bromocriptine, Cabergoline, Pergolide
– Can be given orally.
• Actions:
– Directly activating D2 receptors to inhibit prolactin release
• Applications:
– Hyperprolactinemia due to prolactin-secreting tumors
(prolactinomas)
– Acromegaly due to pituitary tumors secreting both growth
hormone and prolactin, in combination with GH inhibitors
– Parkinson’s disease
What is the mechanism of action of oxytocin as a posterior pituitary hormone? application for clinical use?
Actions:
-stimulating uterus contraction and milk ejection by activating oxytocin receptors on the uterine and breast smooth muscle cells, which increases cytoplasmic Ca2+ level.

Applications:
-inducing labor (by i.v.) and control of uterine
hemorrhage (by i.m).
What is the mechanism of action of vasopressin as a posterior pituitary hormone? drugs? application for clinical use?
Actions:
-increasing water resorption via activating V2 receptors on renal tubule cells; inducing vasoconstriction via activating V1 receptors on vascular smooth cells.
Drug:
-Vasopressin,
-Desmopressin ( a long-acting vasopressin analog with minimal vasoconstriction effects and potent antidiuretic activity).
Application:
-treatment of pituitary diabetes insipidus.
What is the mechansim of action of drugs used for thyroid stimulating hormones? Applications for use clinically?
-inhibits the production of thyroid stimulating hormone
Synthetic TRH:
-mainly usedfor diagnostic purpose.
Thyrotropin alpha:
• Synthetic TSH.
• Application: stimulating thyroid
tumor cells to uptake 131I for tumor
therapy.
What is the mechanism of action of drugs used for adrenocorticotropin hormones? applications for clinical use?
-inhibits the production of adrenocorticotropin
Synthetic human and sheep CRH:
-used for diagnosis.
Cosyntropin:
• Synthetic human ACTH1-24.
• Application: only for the diagnosis of adrenal insufficiency.
What are the pharmacokinetic properties of estrogen and progesterone?
• Not water-soluble, bound to sex hormone-binding globulin (SHBG) in circulation.
• Only free form is biologically active.
• Estradiol and Estrone are metabolized by the liver and other tissues to the less active Estriol.
• First-pass effect makes oral administration of estrogen less effective and progesterone almost ineffective.
• Enterohepatic circulation of Estradiol and its active metabolites often causes hepatic problems, which can be minimized by other routes of administration (injection, transdermal, vaginal).
• Estrogen & Progesterone are metabolized and conjugated with glucuronic
acid in the liver and excreted into the urine as glucuronide.
What are physological/pharmacological properties of estrogens?
• Female maturation:
– Growth of female genital structures.
– Appearance of secondary sexual characteristics and growth spurt during
puberty.
– Stromal development and ductal growth of breast.
– Endometrial proliferation.
• Metabolic effects:
– Inhibiting bone resorption.
– Stimulating the synthesis of various proteins and enzymes.
– Altering plasma lipid profile (increasing HDL, decreasing LDL and
cholesterol).
– Enhancing blood coagulability.
• CNS effects:
– Important in influencing human behavior and maintaining psychological
well-being.
What are physiological/pharmacological properties of progesterones?
• Effects in female reproductive cycle
– Inducing secretary changes in the endometrium.
– Responsible for the alveolobular development of the secretary
apparatus in the breast.
– Required for the maintenance of pregnancy.
• Metabolic effects
– Stimulating fat deposition.
– No significant effect on plasma proteins.
• CNS effects
– Depressant and hypnotic effects.
What are the types of estrogen drugs?
-steroidal and natural, steroidal and synthetic, and nonsteroidal and synthetic
-synthetic types and increased oral effectiveness, duration of activity, and decreased undesired effects
Whata re the types of progesterone drugs?
-progesterone, hydroxyprogesterone, medroxyprogesterone, norethindrone, and desodestrel
-synthetics have increased oral effectivness and duration of action
Whata re the clinical applications of for use of estrogen adn progestin type drugs?
-contraception
Whata re principle mechanism of estrogens and progestin type drugs as contraceptives?
-Administration of
Estrogen+Progestin provides
negative feedback, inhibiting
FSH and LH and therefore
ovulation
-decreasing the chance of
conception and
implantation by inducing
physical barriers
What are combination contraceptives as hormonal contraceptives? mechanism of action?
-Most widely used oral contraceptive.
• Containing a synthetic estrogen (ethinyl estradiol
in most cases) and a synthetic progestin (e.g. 19-
Norethindrone).
• Including monophasic forms (constant dosage of two components
during the 21-day drug period) and biphasic or triphasic forms
(dosage of one or both components changed once or twice during
the 21-day drug period).
• Biphasic and triphasic oral contraceptives minimize the overall dose
of hormone delivered and are designed to mimic the physiological
estrogen to progestin ratio.
mechanisms:
– Inhibition of ovulation through negative feedback

Mechanism.
– Decreasing the chance of fertilization and implantation by changing the cervical mucus, endometrium and the motility and secretion in the uterine tubes.
What are progestin-only contraceptives as hormonal contraceptives? side effects? mechnaims of action?
• Consisting of either 19-Norethindrone or 19-
Norgestrel.
• Progestin-only oral contraceptives are not
extensively used due to increased side effects and
slightly decreased contraceptive activity as
compared to the combination drugs.
• The side effects include irregular bleeding, weight
gain and mood changes.
• Progestin-only contraceptive devices are often
used, e.g. Norplant system (SC implantable 19-
Norgestrel), Mirena (intrauterine device releasing
19-Norgestrel for 5yrs).
• Mechanisms:
– Decreasing the chance of fertilization and implantation by changing the
cervical mucus, endometrium and the motility and secretion in the uterine
tubes.
– May (not) inhibit ovulation.
What are emergency contraceptives as hormonal contraceptives? mechanisms of action?
• High doses of synthetic progestin and/or a synthetic estrogen.
• Administration within 72h after unprotected intercourse.
• Two emergency contraceptive kits available: Plan B, Preven.
• Plan B is more effective and better tolerated than Preven.

Mechanisms: not well understood, might be related to changing the estrogen/progesterone ratio and inhibition of implantation.
What are the adverse effects and contraindications of contraceptives?
• Generally well tolerated. Only mild or moderate side
effects such as nausea, headache and weight gain.
• Severe adverse effects
– Cardiovascular and cerebrovascular diseases: venous thrombosis, myocardial infarction, stroke.
– Depression.
– Cancer: reducing endometrial and ovarian cancers, no effects
on breast cancer and still controversial on cervical cancer.
• Contraindications
– Women with cardiovascular and cerebrovascular diseases.
– Women with estrogen-dependent tumors (breast, ovarian…).
What is hormone replacement therapy by estrogen and progestin type drugs?
• Hormone replacement therapy is effective in alleviating
postmenopausal symptoms.
• Estrogens should be given in the smallest dosage consistent
with relief of symptoms.
• Estrogens should be given together with progestins in cancersusceptible
patients.
• Premarin (conjugated horse estrogens)
– The most commonly used oral estrogens in the treatment of
postmenopausal symptoms.
– A mixture of estrogen sulfates.
– Cleaved within the body to yield free, active estrogens.
• Oral progestins
– Only synthetic progestins (e.g. medroxyprogesterone) can be given orally.
Whata re adverse effects and contraindications of hormone replacement therapy by estrogen and progestin type drugs?
• Risk of cancers
– Breast cancer (major concern). Addition of progestins does
not protect.
– Endometrial cancer, which can be reduced by adding
progestins.
• Thrombosis formation
– Especially in older women, smokers and women with a
family history of this problem.
• Nausea, headache, weight gain, skin pigmentation.
• Contraindications
– Women with cardiovascular and cerebrovascular diseases.
– Women with estrogen-dependent tumors (breast,
ovarian…).
What is tamoxifen as an estrogen/progesterone antagonist? applications for use? adverse effects?
• Selective estrogen receptor modulator (SERM), partial
estrogen receptor agonist.
• Estrogen effects on the bone, heart and endometrium.
• Anti-estrogen effects on the breast.
• Applications:
– treatment and prevention of breast cancer with estrogen
receptor expression.
– Relieving postmenopausal syndromes
• Adverse effect:
– May increase the risk of endometrial cancer.
What is raloxifene as an estrogen/progesterone antagonist? application for use?
• Selective estrogen receptor modulator (SERM), partial
estrogen receptor agonist.
• Estrogen effects on the bone and heart.
• Anti-estrogen effects on the breast and endometrium.
• Applications
– Relieving postmenopausal syndromes
– treatment and prevention of breast cancer with estrogen
receptor expression.
What is clomiphene as an estrogen/progesterone antagonist? spplication for use? side effects?
• Selective estrogen receptor modulator, partial ER agonist.
• Stimulating ovulation by inhibiting estrogen negative
feedback in the pituitary.
• Application: treatment of infertility.
• Side effects: multiple births, ovarian cysts.
What is mifepristone as an estrogen/progesterone antagonists? application for use?
•• Analogue of progesterone
• Antagonist of progesterone and glucocorticoid receptors.
• Applications: inducing abortion, Cushing’s syndrome.
What sit he fucntion of the hypothalamus? Pituitary gland?
-hypothalamus:
(1) controlling anterior pituitary hormone release by releasing hypothalamic hormones
(2) producing posterior pituitary hormones and transporting them along nerve fibers to the posterior pituitary.

•Pituitary gland:
-controlling the peripheral endocrine function by releasing anterior and posterior pituitary hormones.
Whata re the hypothalimic hormones?
•Growth Hormone-Releasing Hormone (GHRH)
•Growth Hormone-Inhibiting Hormone (Somatostatin)
•Thyrotropin-Releasing Hormone (TRH)
•Corticotropin-Releasing Hormone (CRH)
•Gonadotropin-Releasing Hormone (GNRH)
•Prolactin-Inhibiting Hormone (PIH, Dopamine)
What are the anterior pituitary hormones?
•Growth Hormones (GH, Somatotropin)
•Thyroid-Stimulating Hormone (TSH, Thyrotropin)
•Adrenocorticotropin Hormone (ACTH, Corticotropin)
•Follicle-Stimulating Hormone (FSH)
•Luteinizing Hormone (LH)
•Prolactin (PRL)
What are the posterior pituitary hormones?
•Vasopressin (antidiuretic hormone, ADH)
•Oxytocin
Whata re the pharmacokinetic properties of hypothalimic/pituitary hormone replacers? mechanism of action?
-Pharmacokinetic properties:
•All are peptide/protein hormones and have relatively fast plasma clearance.
•All require parenteral administration, intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.). Typically i.v. injection leads to the fastest action and shortest duration of action.

-Mechanisms of action:
•All of them bind to G-protein coupled membrane receptors and elicit activities through the production of second messenger such as cGMP EXCEPT growth hormone and prolactin which bind to tyrosine kinase receptors.
How is growth hormone regulated?
•Hypothalamus: GH releasing hormone (GHRH); GH inhibiting hormone (Somatostatin)
•Negative feedback
•Released during sleep and after exercise.
Whata re the fucntions fo growth hormone?
-Stimulating longitudinal bone growth
•Stimulating protein synthesis and muscle growth (anabolic effect)
•Increasing lipolysis
•Increasing blood glucose level
How are gonodotropins regulated?
•Hypothalamus: GNRH
•Mostly negative feedback. Only during menstrual mid-cycle, the increase of estrogen induces the surge of LH and FSH through positive feedback.
•Pulsatile release of GNRH (or its analogs) stimulates the secretion of LH and FSH, whereas sustained administration of GNRH (or its analogs) inhibits the release of LH and FSH.
What are the functions of gonodotropins?
•FSH:
(1) stimulating gametogenesis, follicular development in women and spermatogenesis in men
(2) working together with LH in stimulating gonadal steroids synthesis.
•LH:
(1) primarily responsible for controlling gonadal steroids synthesis
(2) inducing ovulation and progesterone release.
How is prolactin regulated?
Hypothalamus: prolactin-Inhibiting hormone (dopamine)
What is the function of prolactin?
•Milk production, lactation
How is thyroid stimulating hormone regulated?
•Hypothalamus: thyrotropin-releasing hormone (TRH)
•Negative feedback
What is the function of thyroid stimulating hormone?
-stimulating thyroid glands to synthesize thyroid hormones by increasing iodide uptake and thyroid peroxidase activity.
How is adrenocorticotropin regulated?
•Hypothalamus: corticotropin-releasing hormone (CRH)
•Negative feedback
What is the fucntion fo adrenocorticotropin hormone?
-stimulating adrenal cortex to synthesize steroid hormones by activating cholesterol esterase, a rate-limiting enzyme for the synthesis of steroids.
What is the process of biosynthesis and secretion of thyroid hormones?
1. Iodide Trapping:
-Iodide is actively transported into the thyroid follicular cell (from the blood) by the sodium iodide symporter (NIS).
-The ratio of iodide in the thyroid to that in blood is about 25 to1. Iodide diffuses throughout the cell and is transported across the lumenal cell surface to the colloid.

2. Thyroglobulin Synthesis:
-The thyroglobulin protein (Tg) is synthesized in the rough endoplasmic reticulum, travels through the Golgi apparatus, and is secreted into the follicular lumen.

3. Iodination:
-The thyroid peroxidase enzyme (TPO), acting at the lumenal cell surface, converts iodide to iodine and covalently links it to tyrosine residues within the thyroglobulin protein.
-This reaction forms monoiodotyrosine (MIT) and diiodotyrosine (DIT). The major product is the DIT.

4. Coupling:
-Two iodinated tyrosine residues are coupled through an ether linkage.
-This yields the thyroglobulin-associated storage form of the thyroid hormones.

5. Reabsorption, Lysosomal Fusion, and Proteolysis: -Pseudopods reabsorb thyroglobulin into the cell.
-The reabsorbed thyroglobulin-containing vesicles fuse with lysosomes and proteases digest thyroglobulin into its constituent amino acids. Thyroid hormones (T3, T4) are released.

6. Secretion:
-T4, along with a small amount of T3, is secreted into the blood through exocytosis.

7. Deiodination and Recycling:
-MIT and DIT are reused.
How is thyroid hormone release regulated?
•The hypothalamic-pituitary-thyroid axis (negative feedback regulation).

•Auto-regulation of the thyroid gland by blood iodine level.

•Pathological thyroid stimulation (Graves’ disease)
How is thyroid hormone transported and metabolized?
Transportation:
• Transported in the blood by thyroxine-binding globulin (TBG).
• Only about 0.04% T4 and 0.4%T3 exist in the free, active form.

Metabolism:
• The major metabolism pathway is deiodination.
• T3 is about 10 times more potent than T4 and reverse T3 (rT3) is inactive.
• Both T3 and rT3 will be deiodinated to yield totally deiodinated thyronine (T0)
What are mechanisms of action of thyroid hormones?
-T4 and T3, dissociated from TBG, enter cells by passive diffusion or active transportation.
•T4 is converted to T3 in the target cells, which is about 10 times more potent than T4.
•T3 enters the nucleus and binds to T3 nuclear receptor, activates metabolic gene expression and protein synthesis.
What are the physiological effects of thyroid hormone?
-Virtually every cell in the body is affected by thyroid
hormones.
• Important in regulating basal metabolic rate.
• Inducing anabolic effects at lower levels and
catabolic effects at higher levels.
• Normal secretion is necessary for normal growth
and development of nervous, skeletal and reproductive systems.
Whata re the pharmacological effects of thyroid hormone?
-Maintain normal growth and development of nervous, skeletal and reproductive systems.
•Control metabolism of fats, carbohydrates, proteins and vitamins.
•Thyrotoxicosis (excess thyroid activity) vs hypothyroidism (decreased thyroid activity).
What is the cause of hypothyroidism? symptoms? treatment?
• Cause:
– Hashimoto’s thyroiditis (autoimmune destruction of thyroid).
• Symptoms:
– Goiter (enlargement of the thyroid gland) plus the hypothyroidism
symptoms in the previous slide.
• Treatment:
– Thyroid hormone replacement therapy.
What is therapeutic use of thyroid hormones for hypothyroidism?
The aim of therapy is to give replacement doses of the thyroid hormones to patients with low production of thyroid hormones.
1. The dose of thyroid hormones should be determined for each patient individually, as the requirement for each patient varies significantly.
2. Therapy should begin with low doses to avoid adverse cardiovascular effects, especially in elder patients.
4
What are the thyroid hormone applications for hypothyroidism? cautions?
• Thyroid hormone preparations
– Both Levothyroxine (T4) and Liothyronine (T3) available.
– Levothyroxine is the preparation of choice for thyroid
replacement therapy because of its long half-life, stability and low
cost.
– Liothyronine (T3) is only used in the emergency situation.
• Cautions
– Therapy should begin with low dose to avoid hyperthyroidism,
especially in patients with cardiovascular diseases.
What are the differences between levothyroxine (T4) and 3,3’,5’-Triiodothyronine (T3)?
-The differences between Levothyroxine (T4) and T3 can be easily understood by remembering that T4 may serve as a precursor or reservoir for the more active T3 molecule.
-Most of the hormone released by the thyroid is T4, which can be converted to T3 in peripheral tissues by a 5’-monodeiodinase enzyme.
-The total plasma concentration of T4 is higher than that of T3, but T3 has a higher affinity for the receptor and T3 is largely responsible for effects on target tissues.

2. Levothyroxine is the drug of choice for maintenance therapy because it has a long half-life, which results in a lower potential for large fluctuations in blood levels. T3 is less useful for maintenance because of its shorter half-life and thus shorter duration of action. Although it is used less frequently, T3 may be useful when rapid effects are required (e.g., in myxedema coma).
What are the adverse effects of using T4 (Levothyroxine) and T3 (3,3’,5’-Triiodothyronine) as replacement therapy for hypothyroidism?
-Hyperthyroidism, including cardiac symptoms such as tachycardia, arrhythmias, angina, or infarction.
What is the cause of hyperthyroidism? symptoms? treatment?
• Cause:
– Graves’ disease (autoimmune disease with the production
of TSH receptor-stimulating antibody).
– Thyroid tumors.
• Symptoms:
– See previous slide (Goiter occurs in the Graves’ patients).
• Treatment:
– Surgery or radiation with 131I isotope (often the first choice).
– Antithyroid drugs (leaving intact gland, but requiring a longterm
treatment, with high relapse rate)
What is the therapeutic purpose of antithyroid drugs?
-Inhibiting thyroid hormone secretion or reducing the amount of functional thyroid tissue.
What is the mechanism of radioactive iodide as an antithyroid drug? applications? adverse effects?
• Mechanisms:
– 131I accumulates in the thyroid
gland and destroys the thyroid
tissue by emitting beta particles.
• Applications:
– hyperthyroidism
• Adverse effects:
– hypothyroidism.
– Not for pregnant women
What are the thiozides of antithyroid drugs? mechanisms? applications? adverse effects?
Drugs:
– Propylthiouracil (PTU); Methimazole
• Mechanisms:
– Inhibiting thyroid peroxidase (TPO)
– Blocking the coupling of DIT and MIT
– Inhibiting T4 to T3 (PTU only)
-The effects of the drugs do not become fully manifest for several weeks because of the existence of thyroid hormone stored in the thyroid gland.
-For this reason, the drugs are usually initially administered at maximal doses.
-Once euthyroidism has been reached, the dose can be reduced to a maintenance level.
• Applications:
– Reducing hyperthyroid symptoms
before or after radioactive or surgical
ablation.
– PTU can be used in the thyrotoxic
crisis.
-In some patients with Grave’s disease, particularly patients with a small goiter and mild disease,
-Agranulocytosis (develops rapidly and may present as a fever or sore throat; incidence = 1/500-1/1000 patients), hepatitis, jaundice, and rash
What is the mechanism of iodide salts and iodine as an antithyroid hormone?
1.Mechanism:
•Inhibiting thyroid hormone release and iodination of tyrosine.
•Decreasing the size and vascularity of a hyperplastic thyroid gland.

2.Applications:
•Rarely used as a sole therapy after the introduction of thioamides.
•Used in the management of “thyroid storm” (a severe thyrotoxicosis) due to its rapid onset of action.
•Preparing patients for surgical resection of a hyperactive thyroid.
What is the mechanism of radioactive iodide as an antithyroid hormone? application? adverse effects?
1.Mechanism:
•Radioactive iodide is concentrated in the thyroid gland through normal iodide uptake mechanism
-it then destroys thyroid cells by emitting ionizing beta particles (with short tissue penetration).

2.Application:
•This therapy is used to destroy functional thyroid tissue in hyperthyroid patients.
-Symptoms of hyperthyroidism abate over 2-3 months.

3.Adverse effects:
•Hypothyroidism (Note that conversion of hyperthyroidism to hypothyroidism is frequently the desired effect, as hypothyroidism can be treated with Levothyroxine).
•Not for pregnant women as it can cause ablation of the fetal thyroid gland.
What is the mechanism of iodinated radiocontrast media ipodate and iopanoic acid? application?
1.Mechanism:
•Suppressing the conversion of T4 to T3 via 5’-deiodinase.
•Inhibiting hormone release.

2.Application:
•Adjunctive therapy in the treatment of thyroid storm.
What is the biochemical pathway of synthesis of estrogens and progesterone?
1. The precursor of all steroid hormones is pregnenolone, which derives from cholesterol.
2. Pregnenolone can be converted to progesterone.
3. Pregnenolone can also be converted to androgens (e.g., testosterone), which can be further converted to estrogens. The conversion from androgens to estrogens is catalyzed by the aromatase
What are the sites of estrogen and progesterone synthesis?
-The major site of estrogen and progesterone synthesis in premenopausal women is the ovary, except in pregnancy when it is the fetoplacental unit. A small amount of estrogen can also be synthesized in peripheral sites, such as adrenal glands and adipose tissues.
-Biological activity: Estradiol > Estrone >> Estriol
What is the regulation of synthesis of estrogen and progesterone?
•Production of estrogen and progesterone by the ovary is under the control of GNRH from the hypothalamus and FSH and LH from the pituitary.
•Estrogen and progesterone generally exert negative feedback to inhibit the secretion of GNRH, FSH and LH.
•ONLY during the menstrual midcycle, the increase of estrogen stimulates LH and FSH surge through positive feedback.
What are the pharmacokinetic properties of estrogens and progesterones?
•Natural estrogens and progestins are not water soluble and bound to sex-hormone globulin (SHBG) in circulation. Only the free form is able to bind to the nuclear receptor to generate activities.
•Because of significant first pass effect, natural estrogens and progestins can not be given orally to patients.
-Due to significant enterohepatic circulation, natural estrogens and progestins tend to accumulate in the liver, which causes undesirable hepatic effects (esp estrogen). -These problems can be minimized by parenteral administration.
•Natural estrogens and progestins are mainly metabolized in the liver to derivatives that are less active and more water soluble. For example, estradiol can be converted to estrone, which can be further metabolized to estriol. All of these chemicals will be conjugated with glucuronide or sulfate groups to increase water solubility and be excreted in the urine.
Whata re the physiological effects of estrogens and progesterone on the female reproductive system?
A.Secretion of estrogens and progesterone.
-Estrogen is secreted in the first half of the female reproductive cycle.
-Progesterone is additionally secreted during the second half of the cycle (after ovulation).

B.Female menstrual cycle
What is the follicular or proliferative stage of the menstrual cycle?
a. The initial high FSH level stimulates the development of multiple follicles, each containing an ovum (egg cell), and subsequent decrease in FSH causes only the dominant follicle to develop rapidly.

b. Follicular cells, including the outer theca and inner granulosa cells, secrete estrogen.

c. Estrogen stimulates the proliferation of endometrial cells that line the uterus. Estrogen also causes the cervical glands to secrete an abundant, watery secretion.
What is the luteal phase of the menstral cycle?
a. The LH/FSH surge at midcycle induced by high level of estrogen (positive feedback) triggers ovulation.

b. Following ovulation, the follicle becomes the corpus luteum and the follicular cells (including the theca and granulosa cells) start to secret progesterone in addition to estrogen.

c. Progesterone causes the uterus to convert to a secretory state, countering the effects of estrogen on the uterus. Progesterone also causes the secretions from the cervical glands to become scant and viscous.

d. If fertilization does not occur, the corpus luteum degenerates and progesterone levels fall, allowing menstruation. If fertilization does occur, the progesterone level is maintained throughout the pregnancy. Implantation is dependent upon the proper priming of the uterus (estrogen followed by progesterone); this is partially because estrogen causes an up-regulation of progesterone receptors. Implantation is also dependent upon an appropriate progesterone/estrogen ratio.
How are androgens synthesized?
• Most commonly secreted androgen is Testosterone.
• Man: 95% by Leydig cells in testes, 5% from adrenals.
• Woman: 30% from ovaries, 70% from adrenals.
• Two pathways: Delta-4, Delta-5 (dominant).
How are androgens metabolized? How are they regulated?
• 65% with SHBG, 33% with albumin, 2% free (active).
Target tissue metabolism:
• dihydrotestosterone (DHT) by 5α-reductase
• estradiol by P450 aromatase.
-0Metabolism: mainly metabolized in the liver becoming
inactive metabolites (first pass effect).
-Elimination: mainly excreted through urine.
What are physiological effects of androgens?
•Responsible for most changes associated with male puberty: -general growth promotion (anabolic effect)
-thickening of skin and increases in sebaceous gland activity -thickening of vocal cords
-skeletal growth and epiphysial closure of long bones
-maturation of prostate and seminal vesicles
-stimulation and maintenance of sexual function
-increase in lean body mass.
•Supporting the development of secondary sex characteristics: pubic hair, axillary hair…
What is the mechanism of action of androgens?

Like other steroid hormones, androgens are highly lipophilic and enter cells by passive diffusion.

Target cells are those cells that express the androgen receptor (AR).
•AR is a member of nuclear receptor superfamily.
-The androgen-receptor complex binds to specific sequences of DNA in target genes (hormone response element), and activates target gene expression.
•Regulation of target gene expression results in the execution of physiologic effects.
What are the clinical applications of androgens?
•Androgen Replacement Therapy: hypopituitarism and hypogonadism
•Growth stimulation: delayed puberty in males
•As a protein anabolic agent following trauma or surgery
•Osteoporosis: Alone or with estrogens (Not often used)
•Anemia: stimulating erythropoietin production (rarely used now)
•Treatment of mammary hyperplasia and breast cancer (rarely used now)
•Anabolic abuse in sports
•Potential abuse as anti-aging drugs: counteracting the natural decline in androgens
What are the testosterone esters as androgenic testosterone derivatives?
-More gradual absorption and
longer activity than testosterone. -Given parenterally
includes:
– T-proprionate
– T-enanthanate
– T-cypionate
What are the alkylated testosterones as androgenic testosterone derivatives?
-Orally active
– Methyltestosterone
– Fluoxymesterone
What are the transdermal systems as androgenic testosterone derivatives?
– Testoderm (patch)
– Androderm (patch)
– Androgel (topical gel)
What are the adverse effects of use of androgenic testosterone derivatives?
-Masculinization and hirsutism of women and pre-pubertal children (major limiting factor for application in females and children).
•Disruption of CNS development in early life
•Alkyl-substituted androgens are associated with hepatic dysfunction
•Associated with increased water-retention and edema
•Androgens like estrogens will increase the expression and activity of the cytochrome P450 enzyme, particularly in the liver. -This may in turn increase the metabolism of other drugs, thereby decreasing their efficacy.
What are the contraindications and cautions of use of androgenic testosterone derivatives?
•Contraindicated in pregnant women and infants
•Contraindicated in male patients with carcinoma of the prostate or breast.
•Special caution when using androgens in children and patients with liver problems
What is the theraputic application of adrogen suppressors and antiandrogens? therapeutic approches?
Therapeutic application: prostate cancer.
Therapeutic approaches:
• Suppression of androgen release.
• Inhibition of steroid synthesis
• Inhibition of androgen conversion
•Androgen receptor antagonists
What theraputic agents are used for suppression of androgen release? adverse effects?
•GNRH analogs: Leuprolide, Goserelin, Nafarelin.
•Continuous administration of GNRH analogs inhibits the release of LH and gonadal hormones (both androgens and estrogens)
•Used for the treatment of prostate cancer or breast cancer.
•They can cause an initial increase in gonadal steroids production which is harmful for cancer patients (tumor flare). This can be inhibited by combining hormone receptor antagonists.
What therapeutic agents are used for the inhibition of steroid synthesis? How? Application for use?
•Ketoconazole, Spironolactone
•Decreasing adrenal and gonadal hormone level
by inhibiting steroid synthetases
•Mainly used for treating Cushing’s disease due to the overproduction of adrenal hormones
What therpautic agent is used for the inhibition of androgen conversion? How? application for use?
-Finasteride
•Inhibiting the conversion of testosterone to dihydrotestosterone (active form in the prostate) by inhibiting 5-α reductase
•Used for the treatment of benign prostatic hypertrophy (BPH) and prostate cancer
Whata re the therapeutic agents used for the antagonism of androgen receptors? How? application for use?
•Flutamide, Bicalutamide
•Inhibiting endogenous androgen activities by blocking androgen receptors.
•Both Flutamide and Bicalutamide are oral nonsteroidal antiandrogen drugs mainly used for the treatment of prostatic carcinoma.
-These drugs are most effective when used simultaneously with GNRH agonists such as Leuprolide. -Unlike Flutamide, Bicalutamide has a long plasma half-life that allows once-daily dosing compared to three times daily for Flutamide.
What are the adverse effects of androgen synthesis inhibitors and antiandrogens?
•Suppression of gonadal function, loss of libido.
•Disruption of male pubertal development..
What is the function of the adrenal cortex?
-secreting adrenocorticoids responsible for chronic stress response.
What is the function of the adrenal medulla?
-(neuro) secreting epinephrine (80%) & norepinephrine responsible
for acute stress response.
How are adrenocorticosteroids secreted?
• 10-20 mg of cortisol per day in normal adults.
• Steroids are not stored, freely diffuse out of cells after synthesis.
• The rate of secretion is controlled by the rate of synthesis, which is
under control of ACTH or Ang II (mineralocorticoids only).
How are adrenocorticosteroids distributed?
In plasma, 90% cortisol bound to corticosteroid-binding globulin
(CBG), 10% free or loosely bound to albumin (active form).
• CBG is synthesized in the liver.
How are adrenocorticosteroids metabolized?
• Relatively fast plasma clearance (half life 60-90 min) due to less
protein binding.
• Mainly inactivated in the liver by reduction of C4,5 double bond and
C3 keto group.
• Inactive metabolites are conjugated with glucuronic acid or sulfate and excreted in the urine.
How are adrenocorticalsteroids regulated?
• Physiological diurnal rhythm: peak in the early morning.
• Level of stress:
– Physiological stressors: hunger, fever, infections…
– Psychological stressors
• Controlled by the plasma corticotropin-releasing
hormone (CRH) and adrenocorticotropin hormone
(ACTH), which are under the negative feedback of plasma
adrenal hormone level.
• No significant change with aging.
What is the mechanism of action of adrenocorticosteroids?
• Free steroid hormones enter the
cells through passive diffusion.
• Binding to the receptors in the
cytoplasm.
• The hormone-receptor complex
enters the nucleus and binds to
the hormone-response element
(HRE) of the target gene.
• Promotion or inhibition of target
gene transcription.
• The effect will be executed
through the protein translation.
What are the metabolic effects of glucocorticoids on carbohydrates, proteins and fats?
Carbohydrates:
-increasing blood glucose and liver
glycogen by stimulating gluconeogenesis;
-inhibiting peripheral glucose uptake and utilization.
-The major effect is to maintain glucose supply to
the brain.
-The increased glucose level triggers insulin release.
Proteins:
-catabolic effects on muscle, bone, skin.
Fats:
-stimulating both lipolysis and lipogenesis with a net increase of fat deposition, esp in face (moon
face), shoulders and back (buffalo hump).
What are the immunosuppressive and anti-inflammatory effects of glucocorticoids? Other effects?
– Inhibiting the release of inflammatory cytokines and
chemokines; the extravasation and infiltration of leukocytes
(neutrophils, monocytes) and fibroblast DNA synthesis and
proliferation.
– Inhibiting the generation and functions of lymphocytes and
macrophages.
– The end result is the suppression of natural protective
response to the foreign substances.
– Salt retention, inducing peptic ulcer.
What are the important glucocorticoids?
•Natural glucocorticoids: Cortisol (Hydrocortisone), short-acting (8-12 hr).
•Synthetic glucocorticoids:
(1) medium-acting: prednisone (12-24 hr);
(2) Intermediate-acting: triamcinolone (20–36 hr);
(3) Long-acting: dexamethasone (24–48 hr).
What are the physiological effects of mineralocorticoids?
• Salt (sodium) and water retention.
• Excretion of potassium
What drug is used as a mineralocorticoid replacement?
-Fludrocortisone (a synthetic potent salt-retaining mineralocorticoid used for the treatment of adrenocortical insufficiency).
What are the clinical applications for use of corticosteroid replacement therapy?
Adrenocortical insufficiency:
– Chronic (Addison’s disease)
– Acute: out of adrenocortical capacity during infection, trauma, surgery.
Congenital adrenal hyperplasia
Cushing’s syndrome (maintaining normal adrenal function after surgery)
Non-adrenal diseases:
– Wide application in many inflammatory and
immunologic diseases such as allergy,
asthma, local and systemic infections, organ
transplant rejection…
– Only for symptom relieving, not curative.
What is the cuase of addison's disease? symptoms? treatment?
• Cause:
– partial or complete loss of adrenal function.
• Symptoms:
– Low cortisol: weakness, fatigue, hypoglycemia.
– Low aldosterone: polyuria, hypotension.
– Low androgen: loss of pubic and axillary hair in
females.
– High CRH and ACTH: skin hyperpigmentation.
• Treatment:
– Both glucocorticoids and mineralocorticoids.
How are corticosteroids administered?
-All glucocorticoids can be administered orally, many including cortisol, prednisolone and dexamethasone can be injected i.m. or s.c.
-Triamcinolone, dexamethasone, and cortisol can also be applied topically.
What are the toxic effects and cautions of use of corticosteroid replacement therapies?
• Extension of physiological actions, largely predictable, similar to Cushing’s syndrome.
• Can be severe, even life threatening.
• Highly dependent upon the dose, duration and patient genetic
background. Keeping the dose as low as possible and using
intermittent administration. Withdrawing dose gradually.
• Used with great caution in patients with peptic ulcer, hypertension, diabetes, osteoporosis and infections.
What is the cause of cushing's syndrome? symptoms? treatment?
• Cause:
– excessive secretion of adrenocorticoids due to an ACTHsecreting
pituitary tumor (Cushing’s disease) or other tumors
producing ACTH.
• Symptoms:
– High cortisol: moon face, buffalo hump; muscle wasting;
osteoporosis; dark, thin and easy bruising skin, poor wound
healing, diabetes, peptic ulcer, mental disorder.
– High ACTH: adrenal hyperplasia, skin hyperpigmentation
– High aldosterone: hypertension.
• Treatment:
– Surgery or radiation with a large dose of cortisol during and after
the procedure, decreasing dose gradually.
How is mifepristone used as a corticosteroid receptor antagonist? application for use?
• Glucocorticoids receptor & progesterone receptor
antagonist.
• Extensive and strong binding to albumin leading to a long
half life (~20h), no binding to CBG
• Application: Cushing’s syndrome in inoperable patients,
abortion.
How is spironolactone used as a corticosteroid receptor antagonist? application for use?
• Mineralocorticoid receptor & androgen receptor antagonist
• Application: aldosteronism, hypertension (as a potassiumkeeping
diuretic), hirsutism.
How is aminoglutethimide and ketoconazole used as a corticosteroid synthesis inhibitor? application for use?
Aminoglutethimide:
-Inhibiting the conversion of cholesterol to pregnenolone
and causing a reduction in the synthesis of all steroids.
Ketoconazole:
-Inhibiting Cyt P450 enzymes (e.g. 17α-, 11β-hydroxylase)
necessary for the synthesis of all steroids.
Application:
-Aminoglutethimide and Ketoconazole are
used alone or together in the treatment of Cushing’s
syndrome in inoperable patients.
What is calcium homeostasis?
Uptake:
- Calcium enters the body from the intestine. The absorption of calcium in the intestine is poor.
Storage:
-Calcium is mainly stored in the skeleton (99%) to provide structural support for the body. Although less than 1% calcium is in the extracellular fluid, it is important for maintaining cellular functions.
•Excretion:
-Calcium can be excreted from the kidney and intestine. In general, over 98% of filtered calcium is reabsorbed by the kidney.
•Regulation:
Two hormones (parathyroid hormone, vitamin D) are mainly responsible for the regulation of calcium. The net effect of parathyroid hormone and vitamin D is to increase blood calcium level.
What are disorders of calcium homeostasis?
1. Hypercalcemia
2. Hypocalcemia
3. Osteoporosis
What is the cause of hypercalcemia? symptoms? treatment plan?.
• Cause:
– Including hyperparathyroidism, Cancers, Thiazide therapy,
Vitamin D overdose.
• Symptoms:
– CNS symptoms: confusion, depression, coma.
– Other: Nauseal/vomiting, kidney stone, polyuria.
• Treatment Plans:
– Inhibit accelerated bone resorption.
– Diminish intestinal absorption of calcium
– Increase urinary calcium excretion
– Avoid hypercalcemic medications e.g. Thiazides, vitamin D
What are therapeutic agents for hypercalcemia?
• Bisphosphonates
• Calcitonin
• Plicamycin
• Glucocorticoids
• Diuretics
• Phosphates
What are bisphosphonates as treatment for hypercalcemia? mechanism? administrastion? adverse effects? common drugs?
• First choice therapy
• Mechanism:
– inhibition of accelerated bone resorption by
inducing cell death of osteoclasts.
• IV infusion for hypercalcemia.
• High safety and efficacy, occasional nephrotoxicity after repeated use.
-long half-life.
• Most common drugs:
– Pamidronate, Zoledronate
What is calcitonin as a therapeutic agent for hypercalcemia? mechanism? pharmacokinetics? adverse effects? application for use?
• A peptide hormone secreted by
thyroid gland C (parafollicular) cells
in response to high serum calcium.
• Salmon calcitonin has a longer activity
and is therefore used therapeutically.
Actions:
• binding to cell surface G-protein-coupled receptor
on osteoclasts, inhibiting bone resorption.
• reducing calcium, phosphate resorption.
pharmacokinetics:
a. most rapid onset of action of the available calcium-lowering drugs.
b. serum calcium falls in 2 to 6 hours, nadir in 12-24 hours.
c. relatively modest and transient effect due to development of resistance.
d. rapidly metabolized
• Very safe, useful for rapid effects in acute cases, often
used as ancillary treatment.
adverse effects:
-generally mild, transient flushing of the face and nausea, not seen with nasal spray.
Usefulness:
-adjunctive therapy; in severe cases in combination with the later-acting bisphosphonates or plicamycin for a more rapid and greater effect.
Other uses:
-osteoporosis,
-Paget’s disease.
What is the mechanism of action of plicamycin for use for hypercalcemia? adverse effects? applications for use?
Mechanism of action:
-a cytotoxic antibiotic that binds to DNA and inhibits osteoclasts proliferation, which decreases bone resorption.
Adverse effects:
-significant, high systemic toxicity to bone marrow, liver and kidneys.
Usefulness
-Because of significant side effects, plicamycin is a 3rd line agent and only used if other therapies fail.
What is the mechanism of action of glucocorticoids for use for hypercalcemia? adverse effects? application for use?
Mechanism of action:
-reduce gastrointestinal absorption of calcium by counteracting the activity of vitamin D;
-reduce the production of osteoclast-stimulating cytokines by lymphatic cells
-increase the excretion of calcium.
Adverse effects:
-often significant with long-term use (see Adrenocorticoids section). Long-term use of glucocorticoids can cause osteoporosis.
Usefulness:
limited to treatment for certain hypercalcemia of malignancy (myeloma) or diseases related to vitamin D excess.
What loop diuretics are used for treatment of hypercalcemia? mechanism of action? Cautions?
-furosemide.
Mechanism of action:
-enhances urinary calcium excretion by acting on the thick ascending loop of Henle to inhibit calcium reabsorption.
Cautions:
-often used in the severe and emergency cases; hydration first to prevent fluid depletion.
• Avoid Thiazides that enhance calcium resorption in
the distal tubule.
What is the cause of hypocalcemia? symptoms? treatment?
Cause:
– Hypoparathyroidism, Vitamin D deficiency, renal failure.
• Symptoms:
– Neuromuscular symptoms: tetany, muscle cramps, convulsions.
– Cardiovascular symptoms: bradycardia.
• Treatment:
– Mild cases: Oral calcium supplements (Calcium carbonate is
preferred for its high Ca content) with Vitamin D (e.g. 1,25 VD).
– Moderate to severe: IV calcium preparations. Calcium gluconate
is preferred for less irritation to veins.
What is the preparation of intravenous calcium salts for hypocalcemia? mechanism of action? adverse effects and contraindications?
1. Preparations:
a. calcium gluconate: treatment of choice for severe hypocalcemic tetany.
b. calcium gluceptate: can also be given by i.m.
c. calcium chloride: more calcium, more rapid effect, but more toxic to veins.
2. Mechanism of action: direct increase in serum calcium.
Adverse effects:
a. can cause venous irritation (calcium gluconate preferred over calcium chloride).
b. calcium chloride and gluconate should never be administered i.m.
c. caution should be used in the treatment of patients receiving digitalis.
What is the preparation of oral calcium supplements for hypocalcemia?
-Calcium carbonate,
-calcium citrate,
-calcium gluconate,
-calcium lactate.
What are the preoparations of vitamin d for hypocalcemia? mechanism of action?
Preparations: cholecalciferol (Vit D3), ergocalciferol (Vit D2), dihydrotachysterol (DHT), calcifediol (25(OH) Vit D3), calcitriol (1,25(OH)2 Vit D3).
Calcitriol has a rapid effect, does not require further metabolism and has the shortest half-life, but is very expensive.

Mechanism: increases serum calcium by stimulating intestinal absorption of calcium and mobilizing calcium from bone.
How does osteoporosis occur?
• Deficiency of Calcium and/or Vitamin D.
• Physiological changes.
• Drug-induced, e.g. glucocorticoids.
• Disease-induced, e.g. thyrotoxicosis.
What are therapeutic agents of osteoporosis?
• Calcium supplements
• Vitamin D
• Bisphosphonates
• Estrogen replacement therapy
• SERM
• Calcitonin
• Teriparatide (recombinant parathyroid
hormone)
What are preparations of calcium supplements for use for osetoporosis? absorption? adverse effects? other uses?
Preparations
– Calcium carbonate: highest calcium (40%), low cost.
– Calcium citrate: with best absorption, 21% calcium.
– Others: calcium lactate, calcium phosphate.
• Absorption
– Generally poor, especially in older patients.
– Often use together with Vitamin D.
• Adverse effects
– GI disturbance
– Not recommended for patients with kidney stones.
Other uses:
-hypocalcemia, osteomalacia, renal osteodystrophy.
What is the preparation of vitamin D for use for osteoporosis? mechanism of action? pharmacokinetics? adverse effect? other uses?
• Preparation
– Vitamins D2, D3, non-active form, cheap and efficient oral
supplements
– 1, 25-dihydroxy-vitamin D (Calcitriol), active form, expensive,
more rapid and shorter action
• Mechanism of action
– Nuclear hormone/receptor complex activating gene expression
leading to increased Ca absorption from intestine and Ca
resorption from the kidney and bone.
• Pharmacokinetics
– Good absorption, Bound to Vit D-binding protein in circulation.
– Vit D tends to be stored in the fat tissue.
• Adverse effect
– Vit D overdose causes hypercalcemia.
other uses:
hypocalcemia, hypoparathyroidism, renal osteodystrophy, osteomalacia, rickets.
What are the drugs of bisphosphonates used for osteoporosis? mechanism of action? absorption? side effects?
1. Alendronate (Fosamax) is a third generation drug (no interferencewith bone mineralization). Risedronate (Actonel) is a fourth generation drug.
2. Mechanism
a. antiresorptive agent, inhibits osteoclast activity by causing cell apoptosis.
b. increases bone mineral density and decreases fracture rate.
Absortpion:
-Gastrointestinal absorption is very poor (<1%) and oral administration must be taken on an empty stomach (no liquids other than water).
4. Side effects
a. gastrointestinal: possible irritation to esophagus & stomach.
b. concern about unknown long term effects (incorporated into the bone matrix).
What is estrogen replacement therapy for use for osteoporosis? Drugs involved? mechanism of action? administration? adverse effect and contraindications?
-no longer routinely recommended for long-term use in the prevention of chronic diseases.
Drugs:Conjugated equine estrogens (Premarin), and many other forms.
Mechanism of action:
a. Antiresorptive agent – reduces bone loss by regulating the proliferation and survival of both osteoclasts and osteoblasts. The effect is to increase bone mineral density and decrease fracture rates.
b. Nuclear hormone/receptor complex regulates gene expression in osteoclasts and osteoblasts.
administration: Oral or transdermal administration.
Averse effects/contraindications:
a.Must be used with a progestin to protect against increased risk of endometrial cancer.
b.Can cause nausea, weight gain, breast tenderness, menstrual bleeding.
c.Possible increased risk of cardiovascular disease, breast cancer, migraines, hypertension, blood clots.
What drugs is used for selective estrogen receptor modulator for use for osteoporosis? mechanism of action? side effects and contraindications?
-Raloxifene (Evista). Oral preparation.
Mechanism of action:
-agonist effect on bone
-antagonist in breast and uterus (may protect against breast cancer).
-Appears less effective than estrogen in increasing bone mineral density.
Side effects/contraindications:
a. may increase menopausal symptoms.
b. long-term safety and effectiveness not yet established, and direct comparisons with other drugs are lacking
What is calcitonin for use for osteoporosis? mechanism of action? administration? usefulness? adverse effects?
– safe but limited evidence for its effectiveness, 3rd line agent.
Mechanism of action:
a. inhibits bone resorption by inhibiting osteoclasts.
b. G-protein coupled membrane receptor stimulates second messengers in osteoclasts.
-Administer subcutaneously or by nasal spray daily. Plasma half-life is in minutes.
Usefulness:
-helpful for bone pain, high turnover osteoporosis.
Adverse effects:
-mild, gastrointestinal effects (nausea) but not with nasal spray.
What is teriparatide (forteo) for use for osteoporosis? mechanism of action? administration? adverse effects? other uses?
– recombinant parathyroid hormone, intermittent use (1X daily) has an anabolic effect on bone.
Mechanism of action:
-increases calcium reabsorption by stimulating vitamin D conversion in the kidney; increases bone formation by stimulating osteoblasts activity. However, excessive parathyroid hormone causes bone resorption.
-Very effective (better than bisphosphonates) at increasing bone mineral density.
Administer subcutaneously daily, peak concentration in 30 min after administration and cleared in 3 hours by liver.
-Adverse effects:
-hypercalcemia, hypercalciuria, elevated uric acid, hypomagnesmia, injection site reaction, orthostatic hypotension. -Expensive.
Other uses:
-hypoparathyroidism
What is insulin?
• A 51 amino acids peptide with two chains (A and B) linked by
disulfide bridges.
• Produced by cleavage of proinsulin.
• Proinsulin is a single-chain protein, processed within the Golgi
apparatus and packaged into granules where it is hydrolyzed
into insulin and C-peptide.
What is the process of synthesis of insulin the a pancreatic beta cell?
1. Mature insulin is a 51 amino acid protein composed of two polypeptide chains (A+ B chains) connected by disulfide links.
2. It is derived from proinsulin by cleavage of the C-peptide (connecting peptide).
3. Insulin (complexed with zinc) is stored in secretory granules in the pancreatic beta cell.
What is the process of secretion of insulin from the pancreatic beta cells?
1. Glucose is a potent stimulus for insulin secretion. Other sugars, and certain amino acids and fatty acids, also stimulate secretion.
2. Secretion occurs by exocytosis of the secretory granules. Exocytosis is triggered through an increase in ATP (stimulated for example by glucose). This increase causes a K+ channel to close, which prevents K+ exit and causes depolarization of the cell. This causes a Ca++ channel to open, and Ca++ promotes exocytosis.
3. Release occurs in two phases, rapid initial release followed by sustained release. C-peptide and small amounts of uncleaved proinsulin are released along with the insulin.
What is process of degradation of insulin
1.Insulin is released from the pancreas into the hepatic portal system.
-About 60% of the insulin released is degraded shortly in the liver.
-The rest will be degraded in the kidney.
-Injection of insulin will lead to more insulin degradation in the kidney.
2.Insulin levels in the blood decline rapidly (half-life of 5-8 minutes).
What is physiological effects of insulin?
1. Insulin promotes the uptake and utilization of glucose, lowering its concentration in the blood.
2. Insulin promotes the storage of glucose as glycogen, of amino acids as proteins, and of fatty acids as triglycerides. Furthermore, insulin inhibits the breakdown of glycogen, proteins, and fats. Thus, insulin promotes anabolism (the build-up and storage of cellular nutrients), and inhibits catabolism (breakdown).
What is th mechanism of action of insulin?
-Insulin triggers its effects by binding to a cell surface insulin receptor.
-This receptor consists of 2 alpha subunits and 2 beta subunits.
-The alpha subunits contain the insulin binding domains and the beta subunits have tyrosine kinase activity.
-Binding of insulin to the alpha subunits promotes autophosphorylation of the beta subunits.
-Thus activated, the beta subunits phosphorylate target proteins in the cell.
-A major target protein is IRS-1. -This and other target proteins can activate further cascades of phosphorylation and dephosphorylation.
-An immediate effect of insulin is the enhanced glucose uptake, which is due to the translocation of glucose transporters to the cell surface.
-Another rapid effect is the activation of specific enzymes and inactivation of others.
-Those that are activated are generally involved in anabolic processes while those that are inactivated are involved in catabolic processes.
-Longer term effects of insulin are caused by modifying the expression of specific genes.
What are the basic principles of therpapeutic use of insulin preparations?
-Insulin is a necessary drug for patients with Type 1 diabetes. -Here, dietary management is an integral part of therapy.
-Insulin can also be used for some Type 2 diabetes not controlled by other measures such as diet, exercise, weight loss, and oral agents.
-The objective of therapy is the normalization of glucose levels and of carbohydrate, protein, and lipid metabolism.
-This is carried out using a “basal-bolus” approach to provide both a basal level of insulin (to suppress hepatic glucose output) and additional bolus injections of insulin before meals.
-In standard therapy, insulin is administered subcutaneously. It is a protein and cannot be administered orally, although preparations for oral or nasal administration of encapsulated insulin are being tested experimentally.
-Regular insulin can be administered intravenously for emergencies, such as ketoacidosis and diabetic coma.
-Replacement of fluid and electrolytes is an integral part of therapy.
-Since insulin is normally secreted into the portal system, the liver is exposed to a higher concentration than is present in the circulation. -To suppress hepatic glucose output in the diabetic, it is usually necessary to maintain higher than normal blood levels of insulin.
What are the differences between type I and type II diabetes?
Type I:
– loss of Beta-cell function (autoimmuno
destruction).
– Low or absent insulin.
• Type II:
– Reduced sensitivity to insulin due to
receptor, signal transduction defects.
– High insulin.
What are complications of diabetes?
• Hyperglycemia leads to blood hyperosmolality, polyuria,
dehydration, Na+/K+ imblance, protein glycosylation.
• Microvascular diseases are the most common tissue
complications and the cause of death of diabetes.
• Ketoacidosis decreases blood pH and Hb avidity for
oxygen, causing hypoxic coma.
• Hypoglycemia can occur in treated diabetic patients with
the symptoms of tachycardia, sweating, convulsions
and coma
Whata re ultra-short acting insulin preparations?
• Insulin Lispro, used 0-15 min before meal.
• Insulin Aspart, often used in insulin pump.
What is the long-acting insulin preparation?
-Insulin Glargine (peakless insulin)
What are the various combined administrations of short and intermediate acting insulin drugs?
-Conventional “split-dose”
-Modified Conventional “split-dose”
-Multiple daily injections
-Continuous SC infusion
What are various insulin delivery systems?
• Conventional disposable needles & syringes
• Portable pen injectors
• Continuous SC insulin devices
• Inhaled insulin
What is the difference between regular insulin, insulin lispro, and insulin glargine for use for insulin replacement therapy?
-Regular insulin has a fairly rapid onset and a short duration of action. -Conjugation of insulin with zinc and/or protamine produces longer acting preparations.
-Insulin Lispro is a “designer” insulin with Lys and Pro reversed at amino acids 28 and 29 of the B chain of insulin
-Regular insulin is injected 30-60 minutes before a meal, to ensure that it is absorbed before the glucose increase from the meal. -Insulin Lispro is injected 0-15 minutes before a meal.
-Regular insulin forms aggregates (e.g. hexamers) that require time to disaggregate for absorption. Insulin -Lispro aggregates less, which accounts for its more rapid absorption.
-The more rapid absorption of ultra-short acting insulin preparations makes them very useful for decreasing postprandial (post-meal) hyperglycemia.
-Insulin Aspart is another ultra-short acting insulin.
-These ultra-short acting insulin preparations are often used in preference over regular insulin by many patients in insulin pumps.
-A long acting insulin is Insulin Glargine, which contains 2 arginine residues at the carboxyl terminus of the B chain and a glycine for asparagine substitution at position 21 of the A chain.
-Insulin Glargine precipitates upon subcutaneous administration.
-It is called a “peakless” insulin because it is absorbed slowly and there is no distinct peak in insulin level.
Whata re the complications of insulin treatment?
1. Hypoglycemia
2. Anti-insulin antibodies/insulin resistance/allergic reaction
Recombinant human insulin has lower antigenicity than pork or beef insulin.
3. Lipodystrophies at the site of injection
What are the various oral anti-diabetic drugs?
Insulin release stimulators (secretgogues)
– Sulfonylureas
– Meglitinides
– D-phenylalanine derivatives
• Gluconeogenesis blockers
– Biguanides
• Insulin-sensitizing agents
– Thiazolidinediones
• Carbohydrate absorption inhibitors
– α-glucosidases inhibitors: Acarbose.
What is the mechanism of action of sulfonylureas for use as an anti-diabetic drug?
-These drugs stimulate pancreatic beta cells to release pre-formed insulin.
-This is accomplished by binding to a cell surface sulfonylurea receptor. -This receptor appears to regulate potassium channels on the beta cell membrane.
-Inhibition of this K+ channel by sulfonylureas results in depolarization of pancreatic beta cells, which results in Ca++- triggered exocytosis of insulin. -Sulfonylureas can increase insulin secretion at submaximal concentrations of glucose as well as maximally stimulatory concentrations.
What are the therapeutic agents of sulfonylureas for use as anti-diabetic drugs?
-New second generation sulfonylureas:Glyburide and Glipizide
-less side effects and long action.
-In addition, non-sulfonylureas have been developed that also act by enhancing insulin secretion through binding to the sulfonylurea receptor to block K+ channel, but at a site different from that utilized by the sulfonylureas.
-These drugs include meglitinides (e.g. Repaglinide) and D-phenyialanine (e.g. Nateglinide).
What are meglitinides (e.g. Repaglinide) and D-phenyialanine (e.g. Nateglinide) for use as anti-diabetic drugs? Pharmacokinetics/metabolism? application for use? side effects?
– Fast onset of action and peak effect within 1 h
– Cleared in the liver, 4-5 h duration of action
Pharmacokinetics:
1. Readily absorbed from the G.I. tract
2. Highly bound to plasma proteins
3. Metabolized by the liver and excreted by the kidneys
• Application
– Type II diabetes treatment.
– Controlling post-meal glucose increase, taken right before
meal.
• side effects
– Hypoglycemia (applied to all anti-diabetic therapy)
– Weight gain.
-Some patients do not respond to sulfonylureas (primary failure). -Diabetes generally progresses in some patients that demonstrate an initial response (~5% per year secondary failure).
-Other rare side effects include hematological and hepatic effects, CNS effects (dizziness, confusion), and dermatological effects (rash). -One agent may be replaced with another to minimize these.
What is the mechanism of action of metformin for use as a anti-diabetic drug? pharmacokinetics? application for use? adverse effects?
– Mechanism: inhibiting gluconeogenesis, glucose absorption,
enhancing glucose uptake and use in muscle cells, etc.
– Pharmacokinetics: no plasma protein binding, not metabolized,
excreted intact in 2-5 h by kidney.
– Application:
• Used as a single agent, or in combination with other drugs, for Type
II diabetes.
• Without increasing weight and inducing hypoglycemia.
• Type II diabetes prevention.
– advsere effects:
• Mainly GI track symptoms: starting with a low dose and increasing
it gradually.
• Contraindicated in patients with renal and hepatic diseases.
What is the mechanism of action of rosiglitazone for use as an anti-diabetic drug? pharmacokinetics? application for use? adverse effects?
– Mechanism: Activating nuclear receptor peroxisome
proliferator-activated receptor (PPAR)-γ and generating
insulin-like effects.
-Decrease plasma glucose, insulin, triglyceride and free fatty acid levels.
– Pharmacokinetics: rapid absorption, protein bound,
metabolized in the liver, excreted by the kidney.
– Application:
• Monotherapy or in combination with metformin, sulfonylureas
and insulin for Type II diabetes.
• Slow onset and offset of activities (weeks to months)
• Hypoglycemia (rare), weight gain
– Toxicities
• Not for patients with hepatic and renal diseases.
• Fluid retention.
What is the mechanism of action of acarbose for use as an anti-diabetic drug? pharmacokinetics? application for use? adverse effects?
• Mechanism:
-competitively inhibiting α-glucosidases, no effect on fasting glucose level.
-This interferes with the absorption of carbohydrates.
-The delayed carbohydrate absorption decreases postprandial hyperglycemia. It can be used in combination with other agents such as sulfonylureas.
• Pharmacokinetics: not extensively absorbed.
• Application
– Monotherapy or in combination with metformin or sulfonylureas for
Type II diabetes, taken right before meal (starting with low dose)
• Toxicities:
– GI symptoms due to fermentation.
– Contraindicated in patients with intestinal disease.
What is type II diabetic treatment?
• Diet, weight control first.
• Initial drug therapy:
– monotherapy with a 2nd-generation sulfonylurea (glyburide,
glipizide, or glimepiride), less commonly metformin.
• Late drug therapy:
– Combination therapy including an insulin action enhancer
(metformin, a thiazolidinedione, or Acarbose) with insulin release
stimulator (insulin secretagogues or insulin).
– Long acting drugs (sulfonylureas, metformin, thiazolidinediones)
controlling both fasting and post-meal blood glucose.
– Short acting drugs (Meglitinides, Phenylalanines, Acarbose,
insulins) most effective in controlling post-meal glucose level.