2013 ENDOCRINE PHARMACOLOGY word notes (Autosaved).pdf

8/9/2019 2013 ENDOCRINE PHARMACOLOGY word notes (Autosaved).pdf

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1 | E n d o c r i n e P h a r m a c o l o g y

ENDOCRINE PHARMACOLOGY Andrea Q. Carigma, M.D.

Faculty of Pharmacy

University of Santo Tomas

My dear student,

I know that these past few days have been a torture for you – thesis, other major subject requirements and all. And as

much as I want to put more information in your brain:

THE DISK IS RUNNING LOW ON SPACE. PLEASE DELETE SOME FILES.

Yep. I tried, pero ayaw na talaga mag-copy. I think an upgrade (or a transplant) is necessary.

I know that the semester’s schedule hasn’t been a big help either. The class suspensions, and endless faculty and OCD

meetings left me always wanting for time with you . (At parang magaling kayo magdasal at lalo ako nalalayo sa inyo.)

Hindi naman sa may separation anxiety ako no.. I am putting so much effort to teach you because I just truly believe

that you have it in you to learn the complexities of pharmacology even if it would take time for you to master them . I

truly do. I also believe that you have it in you to make yourself a better professional for your family, friends and

patients will serve in the future.

Ang tanong lang: Paano ka naman magigiling mahusay kung hindi ka magsusumikap na maging mahusay?

Laging tatandaan: Hindi lahat ng tao ay matalino, pero daig ng matiyaga ang matalino. At higit sa lahat: aanhin ang

talino kung wala namang puso?

I made this last set of notes for you as a parting gift since this will be the last time that we’ll be together in class. Just a

few chapters away, and you’ll FINALLY, (SA WAKASSSSSS!!!!) get rid of me, but I really do hope that I was able to give

you something valuable. I do hope that somehow, I was able to help you become a better person for the people you’ll

serve as you take your own journey ahead (as pharmacist, doctor, lawyer, entrepreneur, husband, wife, tambay sa

kanto – habang nakatambay ka, maglecture ka sa mga tao ng pharmacology. Magiging kapakipakinabang ka, for

sure).

Lectures will be lectures. In time, what I have taught you will be obsolete. The grade you get from this subject would

be insignificant in time. I hope that beside all the facts I have shared with you, you were able to learn the value of

diligence, integrity and DIGNITY. Show the world what you’re made of. Show them that aside from brain, you have a

heart.

Live. Love. Read. Learn.

Impress me.

Show me that you’re made up of something better.

Strive for greatness, always.

Dr. C


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An endocrine gland is a tissue that produces chemical substances

called hormones. These hormones are released into the

circulating blood and influence the function of cells at another

location in the body. The endocrine system is essential for cell- to-

cell communication for the maintenance of the following

functions:

Food seeking & satiety

Metabolism & caloric economy

Growth & Differentiation

Reproduction

Homeostasis

Response to environmental change

Arousal, defense, flight & secluding behaviors

The important endocrine glands include the following:

Pituitary gland

Thyroid gland

Parathyroid glands

Pancreas

Adrenal gland

Ovary/ testes

The hormones that are produced by the endocrine glands mediate the activity of the endocrine system. They exert their effects

by binding to specific receptors in the cells of the target organ.

Hormones may either be:

PEPTIDE HORMONES or

LIPOPHILIC (STEROID) HORMONES

The peptide hormones are water soluble. They have no specific transport

mechanism (that is, they are not bound to plasma proteins while they are

transported in the bloodstream). These hormones act by binding to

receptors on the cell membrane surface and they need 2nd messengers

to exert their action.


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The precursor is cholesterol (for most steroid hormones) or 7-dehydrocholesterol (for Vit D metabolites). These precursors

undergo a series of enzymatic transformations to form the final products.

Examples of steroid hormones include:

The reproductive hormones - estrogen, testosterone, progesterone

The hormones produced by the adrenal cortex – aldosterone, cortisol and dehydropiandrosterone

Steroid hormones are transported into the bloodstream bound to plasma proteins (e.g. estrogen and testosterone are bound

to SHBG (sex hormone binding globulin)

Since these hormones are lipophilic, they easily diffuse across the cell membrane and they exert their effects by binding to

receptors that are found in the cytoplasm or the nucleus.


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The pituitary gland is also called the hypophysis. It lies in the sella turcica, a bony cavity at the base of the brain. The pituitary

gland is connected to the hypothalamus, from which it receives neuroendocrine control (whether stimulatory or inhibitory).

The pituitary is divided into the:

ANTERIOR PITUITARY (adenohypophysis)

GROWTH HORMONE (GH)

Promotes somatic growth (protein formation, cell multiplication and differentiation)

ADRENOCORTICOTROPIC HORMONE (ACTH)

Regulates the production of adrenocortical hormones

THYROTROPIN/ THYROID STIMULATING HORMONE (TSH)

Modulates thyroid hormone production in the thyroid gland

PROLACTIN (PRL)

Promotes development of the mammary glands for lactation

FOLLICLE STIMULATING HORMONE (FSH)

Promotes development of oocyte/ spermatocyte

LUTEINIZING HORMONE (LH)

Promotes estrogen/ testosterone production

The hormones of the anterio pituitary gland. (figure above)


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POSTERIOR PITUITARY (neurohypophysis)

ANTI-DIURETIC HORMONE

Also known as vasopressin

Regulates water reabsorption in the collecting tubules (and the distal parts of the distal

convoluted tubules) of the kidneys

produce vasoconstriction (hence the name “vasopressin”)

OXYTOCIN

Uterine smooth muscle contraction

Milk letdown

The production of hormones by the pituitary gland is regulated by the HYPOTHALAMUS. Shown below is the organization of

the HYPOTHALAMIC-PITUITARY GLAND-TARGET ORGAN (HPO) AXIS. Hypothalamic hormones (usually named “releasing

hormones”) promote production, or they may inhibit production (e.g. Dopamine’s ef fect on prolactin production)

Growth hormone (GH) is important in the attainment of the normal adult size. GH plays an important role in lipid and

carbohydrate metabolism as well as muscle and bone development. It is a 191-amino acid peptide chain. The production of GH

is promoted by the hypothalamic GHRH (growth hormone releasing hormone) and is inhibited by somatostatin which is also

produced by the hypothalamus.

GH produces the following effects:

LONGITUDINAL BONE GROWTH (as long as the epiphyseal plates are still open)

MUSCLE MASS BUILD UP (anabolic effect)

LIPOLYSIS (breakdown of stored fats; hence, catabolic effect)

* GH may decrease insulin sensitivity, and this in turn, leads to a compensatory hyperinsulinemia.


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The effects of GH are due to the binding of GH with its receptor (which is a JAK-STAT receptor found on the cell membrane

surface). The growth-promoting effects are mediated through an increase in the production of IGF-1 (insulin-like growth

factor/ SOMATOMEDIN)

GH has a short half-life (20-25 minutes). When in reaches the liver, it gets cleaved by hepatic enzymes.

GH administration is beneficial for patients who exhibit GH deficiency

TREATMENT OF GROWTH HORMONE DEFICIENCY STATES

The recombinant form of GH, SOMATROPIN may be administered SUBCUTANEOUSLY for the treatment of GH deficiency

states (eg. Turner’s syndrome, Prader-Willi syndrome). It may be administered 3–7 times per week. Peak levels occur in 2–4

hours and active blood levels persist for approximately 36 hours.

Adverse effects of somatropin include:

o

Intracranial hypertension (which manifests with nausea, vomiting, headache, visual changes)

o Scoliosis (twisting of the spine within its axis)

o Otitis media (infection of the inner ear)

o Hypothyroidism

o

Pancreatitis

o Nevus (nunal) growth

o Edema, arthralgia, myalgia

The adverse effects of somatropin are more often seen in ADULTS than in children.

Another drug that may be used in the treatment of GH deficiency is MECASERMIN. This drug is useful in the treatment of

children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH.

Mecasermin is a complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding

protein-3 (rhIGFBP-3). It is administered SUBCUTANEOUSLY twice daily.

The most important adverse effect observed with mecasermin is hypoglycemia. Several patients have experienced intracranial

hypertension and asymptomatic elevation of liver enzymes.

TREATMENT OF GROWTH HORMONE OVERPRODUCTION

Pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas

cause ACROMEGALY, which is characterized by abnormal growth of cartilage and bone

tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract.

When a GH-secreting adenoma occurs

before the long bone epiphyses close, it

leads to the rare condition,

GIGANTISM.

Left: GIGANTISM; Right facial features of

a Patient with ACROMEGALY)


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Under normal physiologic conditions, GH production of the pituitary is controlled by SOMATOSTATIN (a hormone produced

by the hypothalamus). Somatostatin inhibits the pituitary production of GH. Somatostatin as a drug has very limited use

BECAUSE OF ITS SHORT HALF-LIFE (1-3 minutes). And so, efforts have been made to improve the pharmacokinetics of this

agent.

OCTREOTIDE, a somatostatin analogue, is 45 times more potent than somatostatin in inhibiting GH release but only twice

as potent in reducing insulin secretion. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer than

that of somatostatin. It is given SUBCUTANEOUSLY every 8 hours. It can also be given INTRAMUSCULARLY at 4-week intervals.

Adverse effects of octreotide include:

o

Nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements

o Biliary sludge and gallstones

o

Sinus bradycardia (25%) and conduction disturbances (10%).

o Pain at the site of injection is common, especially with the long-acting octreotide suspension.

o

Vitamin B12 deficiency may occur with long-term use of octreotide.

PEGVISOMANT is another useful drug for the treatment of GH excess.

Pegvisomant is a GH receptor antagonist that is useful for the treatment of acromegaly. Pegvisomant is the polyethylene

glycol (PEG) derivative of a mutant GH . It partially activates the GH receptor by allowing dimerization of the receptor but

blocking the conformational changes for signal transduction. (IN SIMPLER TERMS, it binds the GH receptor but it does not

activate it – it is an ANTAGONIST.) Adverse effects include: worsening of the GH-secreting pituitary tumors and increase in

levels of hepatic enzymes (AST and ALT).

Okay ka pa? Hinga muna. Puwede ding tumulala. 2 minutes.

…

Time’s up! Ok na?

Round two! GAME!

The gonadotrophs (cells in the pituitary gland) produce the gonadotropins FSH and LH.

LH = LUTEINIZING HORMONE

o promotes estrogen and progesterone production

o

promotes androgen production in the Theca and Leydig cells.

FSH = FOLLICLE STIMULATING HORMONE

o FSH is responsible for the ovarian follicle development (from the primary oocyte to the mature Graffian follicle) in

the the female. It also participates in the steroidogenesis.


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o

In the male, it promotes steroidogenesis

HUMAN CHORIOGONADOTROPIN (HCG) on the other hand is a placental hormone that primarily functions to maintain

estrogen and progesterone production necessary for pregnancy.

They are used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women. Their most

common clinical use is for the controlled ovulation hyperstimulation that is the cornerstone of assisted reproductive

technologies such as in vitro fertilization.

UROFOLLITROPIN

o also known as uFSH, is a purified preparation of human FSH that is extracted from the urine of postmenopausal

women.

FOLLITROPIN ALFA/ FOLLITROPIN BETA

o recombinant forms of FSH (rFSH)

o The rFSH preparations have a shorter half-life than preparations derived from human urine but stimulate

estrogen secretion at least as efficiently and, in some studies, more efficiently. The rFSH preparations are

considerably more expensive.

LUTROPIN ALFA

o the recombinant form of human LH

o

approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women

with profound LH deficiency.

CHORIOGONADOTROPIN ALFA (RHCG)

o is a recombinant form of HCG.

The gonadotropins exert their effects by binding to cell membrane receptors (that are G-protein coupled receptors) Their main

indication is for INDUCTION OF OVULATION in women and for the TREATMENT OF INFERTILITY in men. They are

administered SUBCUTANEOUSLY OR INTRAMUSCULARLY.

Adverse reactions include:

o ovarian enlargement (that resolves spontaneously)

o

multiple pregnancies

o

ovarian hyperstimulation syndrome (OHSS) occurs in 0.5-4% of patients.

characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in

shock. Hemoperitoneum (from a ruptured ovarian cyst), fever, and arterial thromboembolism can occur.

o Gynecomastia (male)

Gonadotropin-releasing hormone (GnRH) is secreted by neurons in the hypothalamus.

It is a decapeptide (10 amino acid) hormone that binds to G protein-coupled receptors on the plasma membranes of

gonadotroph cells of the pituitary gland. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to

produce and release LH and FSH.

Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in

both women and men, resulting in hypogonadism.


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Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.

Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH.

O BAKA MAKALIMUTAN MO. ISA PA ULIT.

Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.

Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH.

Ok na?

If you truly understand this concept and the use of the gonadotropins in the treatment of infertility, you can now predict that

the administration of pulsatile GnRH will be useful for the same purpose since it will also increase FSH and LH that will

promote oocyte development in the female and spermatogenesis in the male.

GONADORELIN is an acetate salt of synthetic human GnRH. Synthetic analogs include GOSERELIN, HISTRELIN,

LEUPROLIDE, NAFARELIN, TRIPTORELIN.

Gonadorelin can be administered intravenously or subcutaneously.

GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a

subcutaneous implant.

Adverse effects of PULSATILE GnRH analogue administration includes:

o Gonadorelin can cause headache, light-headedness, nausea, and flushing.

o

Local swelling often occurs at subcutaneous injection sites.

o

Generalized hypersensitivity dermatitis

In the event that these analogues are administered CONTINUOUSLY, a negative effect is observed in FSH and LH levels. And

this supression is useful in certain disease conditions:

Endometriosis

Endometriosis is a syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of

estrogen-sensitive endometrium-like tissue outside the uterus.

The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and

progesterone concentrations and prevents cyclical changes.

Uterine Leiomyomata (Uterine Fibroids)/ Myoma

Uterine leiomyomata are benign, estrogen-sensitive, fibrous growths in the uterus that can cause menorrhagia, with

associated anemia and pelvic pain. Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, whencombined with supplemental iron, improves anemia. Leuprolide, goserelin, and nafarelin are approved for this

indication.

Prostate Cancer

Antiandrogen therapy is the primary medical therapy for prostate cancer. Combined antiandrogen therapy with

continuous GnRH agonist and an androgen receptor antagonist such as flutamide (see Chapter 40) is as effective as


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surgical castration in reducing serum testosterone concentrations and effects. Leuprolide, goserelin, histrelin, and

triptorelin are approved for this indication.

Adverse effects of CONTINUOUS GnRH analogue administration includes:

o

typical symptoms of menopause, which include

hot flushes, sweats, and headaches.

Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur.

o ovarian cysts

o

reduced bone density and osteoporosis may occur with prolonged use.

Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner.

GANIRELIX and CETRORELIX are approved for use in controlled ovarian hyperstimulation procedures, whereas ABARELIX and

DEGARELIX are approved for men with advanced prostate cancer.

Ganirelix and cetrorelix are absorbed rapidly after subcutaneous injection.

Abarelix is absorbed slowly after intramuscular injection.

RELIX. RELIX. RELIX. INHIBITOR OF RELEASE. “X” RELEASE RELIX

Adverse effects:

o

most common adverse effects are nausea and headache

o

allergy

o Like continuous treatment with a GnRH agonist, abarelix leads to signs and symptoms of androgen deprivation,

including hot flushes and sweats, gynecomastia, decreased libido, decreased hematocrit, and reduced bone

density.

I bet sinusumpa nyo na ko ngayon. Pero may paniniwala akong gumagana pa at hindi pa lubusang kinakalawang ang

neurons nyo.

Prolactin is a 198-amino-acid peptide hormone produced in the anterior pituitary. Prolactin is the principal hormone

responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens,progestins, corticosteroids, and insulin are present.

Prolactin = PRO-LACTATION.

The pituitary production of prolactin is regulated by DOPAMINE that is released from the hypothalamus. DOPAMINE INHIBITS

PROLACTIN RELEASE.


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Prolactin is elevated as a result of prolactin-secreting adenomas. Hyperprolactinemia produces a syndrome of amenorrhea

and galactorrhea in women, and loss of libido and infertility in men.

Kung sobra, bawasan.

Kung kulang dagdagan.

Kung sobra sa prolactin, e di bawasan: BIGYAN NG DOPAMINE. Dopamine inhibits prolactin release.

NGUNIT, PERO. SUBALIT, DAPATWAT….

Dopamine has a very short half-life and is available only for IV infusion. That’s why we use dopamine agonists instead – drugs

that promote dopamine receptor activation.

BROMOCRIPTINE and CABERGOLINE are ergot derivatives with a high affinity for dopamine D2 receptors. D2 receptor

activation suppress prolactin release very effectively in patients with hyperprolactinemia. These drugs shrink pituitary

prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with

microadenomas and 30% of women with macroadenomas.

Adverse effects:

o Dopamine agonists can cause nausea, headache, light-headedness, insomnia, orthostatic hypotension, and

fatigue.

o Psychiatric manifestations occasionally occur, even at lower doses, and may take months to resolve.

The posterior pituitary produces TWO HORMONES:

TWO.

OXYTOCIN and ANTI-DIURETIC HORMONE (aka VASOPRESSIN)

Isa pa.



O. baka makalimutan mo pa.



Ang magkamali, panget.

OXYTOCIN is a 9-amino-acid peptide that participates in labor and delivery and elicits milk ejection in lactating women.

Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction. It is administered intravenously at

regulated rate.


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Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract

uterine smooth muscle. Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine

contraction.

Oxytocin is used to

o

induce labor for conditions requiring early vaginal delivery such as incompatibility problems, maternal diabetes,

preeclampsia, or ruptured membranes.

o used to augment abnormal labor that is protracted or displays an arrest disorder.

o

Oxytocin has several uses in the immediate postpartum period, including the control of uterine hemorrhage

after vaginal or cesarean delivery.

Adverse effects:

o Excessive stimulation of uterine contractions before delivery can cause fetal distress, placental abruption, or

uterine rupture.

o Injections of oxytocin can cause hypotension.

VASOPRESSIN is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood

pressure. A deficiency of this hormone results in diabetes insipidus.

Vasopressin is a nonapeptide with a 6-amino-acid ring and a 3-amino-acid side chain. Vasopressin is administered by

intravenous or intramuscular injection. The half-life of circulating vasopressin is approximately 15 minutes.

Vasopressin activates two subtypes of G protein-coupled receptors.

V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction.

V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water

resorption in the collecting tubules.

DESMOPRESSIN is a structurally modified version of vasopressin. It may be given intranasally and orally. It is more selective for

V2 than for V1 receptors. It has a longer duration and better potency than vasopressin.

Adverse reactions:

o Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Overdosage can result in

hyponatremia and seizures.

o

Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with

coronary artery disease.


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Alam kong naghihingalo ka na. Kaya okay. Sige. Fine. Mag-break ka muna. Kumain. Kumanta. Sumayaw. Tawagan ang

boyfriend/ girlfriend mo (kung wala, kumain ka na lang. Wala na tayong magagawa dyan.)

Okay na?

GAME!

The normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3) and

tetraiodothyronine (T4, thyroxine)—to normalize growth and development, body temperature, and energy levels.

T3 = 3 iodine molecules present in the hormone

T4 = 4 iodine molecules present in the hormone

Aside from T3 and T4, the thyroid also produces CALCITONIN – a hormone necessary for regulation of calcium metabolism.

Calcitonin is produced by the parafollicular cells of the thyroid gland.

The cells of the thyroid gland are arranged in FOLLICLES filled with a secretory substance called COLLOID and lined with

cuboidal epithelial cells that secrete into the interior of the follicles. (the apical surface of the cells face the colloid. The basal

surface of the cell are in close apposition with the blood vessels. See the figure below)

O. Kung dumugo ng konti ang brain cells, isa pa, SLOWLY: Theeeeeeeeeeee ceeeeeeeellllssss offff theee thyroid glanddddd are

arraaaaaaaaaanged in FOOOO-LLI-CLESSSSS fiiiiiilled wiiiiiiith a se….cre….tory substance caaaaaaaaaalled COOOOO---

LLOIDDDDD and lined with cuboidal epithelial cells…. Hihi. I’m just kidding. ^_^ Basahin mo na lang ulit yung paragraph sa

taas tapos tingnan mo nang mabuti yung picture sa baba.

The major constituent of colloid is the large

glycoprotein THYROGLOBULIN, which contains the

thyroid hormones within its molecule. Once the

secretion has entered the follicles, it must be absorbed

back through the follicular epithelium into the blood

before it can function in the body.

THYROID HORMONE SYNTHESIS

For T3 and T4 to be produced, it is crucial that there is

adequate IODIDE intake. Iodide, ingested from food,

water, or medication, is rapidly absorbed. The thyroid

gland removes about 75 mcg a day from this pool for

hormone synthesis, and the balance is excreted in the

urine.


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THERE ARE FOUR IMPORTANT STEPS IN THYROID HORMONE SYNTHESIS: E – P – O – C

Repeat after me. E – P – O – C

E – ENTRY

P – PEROXIDATION

O – ORGANIFICATION

C – COUPLING

E – P – O – C

E – P – O – C

STEP NO. 1: ENTRY

The first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the

sodium/iodide symporter (NIS).

STEP NO. 2: PEROXIDATION (iodide to iodine conversion)

At the apical cell membrane, iodide is oxidized by thyroidal peroxidase to iodine.


15/52


STEP NO. 3: ORGANIFICATION – The formation of MIT and DIT

After the formation of the elemental iodine, it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form

monoiodotyrosine (MIT) and diiodotyrosine (DIT).

STEP NO. 4: COUPLING

Two molecules of DIT combine within the thyroglobulin molecule to form L-thyroxine (T4 ).

2 + 2 = 4

One molecule of MIT and one molecule of DIT combine to form T3.

1 + 2 = 3

Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid

border. T3 and T4 are then released into the blood stream. The MIT and the DIT may be used for another synthesis of thyroid

hormones.


16/52


CONTROL OF THYROID PRODUCTION

Hypothalamic cells secrete thyrotropin-releasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal

venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyrotropin (thyroid-stimulating

hormone; TSH). TSH in turn stimulates an adenylyl cyclase–mediated mechanism in the thyroid cell to increase the synthesis

and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TSH

and in the hypothalamus to inhibit the synthesis and secretion of TRH.

TRANSPORT OF THYROID HORMONES

T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Protein bound thyroid

hormone is inactive. Only the free hormone will exert an effect.

METABOLISM OF THYROID HORMONES

The primary pathway for the peripheral metabolism of thyroxine is deiodination.

DEIODINATION OF T4 PRODUCES T3.

4 – 1 = 3

The product may either be T3 (active) and rT3 (inactive).

The thyroid hormones are very crucial for central nervous system (CNS) function, cardiovascular function and metabolism. T3

and T4 exert their effect by entering the cell and binding to nuclear receptors. The activation of the receptor leads to alteration

of gene transcription and translation.


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MY DEAR STUDENT, PLEASE MEMORIZE THE TABLE ABOVE. MADALI LANG NAMAN. Halos baliktad lang sila lahat.

It is important to take note of the signs and symptoms of hypo- and hyperthyroidism.

* My dear student, this will be crucial in predicting the adverse effects and therapeutic response of your patient.

The manifestations of thyroid excess (hyperthyroidism/ thyrotoxicosis) and thyroid deficiency are very distinct (since they a re

observed to be opposites of each other). These are mediated by the intracellular effects on the thyroid hormones. (see diagram

below.)


18/52


T4 and T3 can enter the cell BUT ONLY T3 IS CAPABLE OF BINDING TO THE THYROID HORMONE RECEPTOR IN THE

NUCLEUS.

As mentioned earlier, the core concept of endocrine pharmacology:

Kapag sobra, bawasan.

Kung kulang, dagdagan.

In the event of hypothyroidism, administration of thyroid preparations to patients will

improve their symptoms. The most satisfactory preparation is levothyroxine.

SYNTHETIC LEVOTHYROXINE [T4]: the preparation of choice for replacement &

suppression therapy because of its stability, uniform content, low cost, long half-life (7

days), and conversion to produce both T3 & T4.

DESICCATED THYROID, from animal source, though inexpensive, is not recommended


19/52


for replacement therapy because of its antigenicity, instability, and variable hormone content.

LIOTHYRONINE, [T3] 3-4 times more active than levothyroxine. It is not recommended for routine replacement therapy

because of its higher cost, shorter half-life (24 hours), and greater potential for cardiotoxicity.

LIOTRIX, a 4:1 combination of synthetic T4 and T3, also expensive with the same disadvantages as liothyronine

Levothyroxine is orally administered. The adverse effects to be anticipated in the administration of the thyroid preparation

would be the manifestations of HYPERTHYROIDISM. In children, restlessness, insomnia, and accelerated bone maturation

and growth may be signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and

tachycardia, or unexplained weight loss may be the presenting symptoms. If these symptoms are present, it is important to

monitor serum TSH.

Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that

results when tissues are exposed to high levels of thyroid hormone.The most common form of hyperthyroidism is Graves' disease, or

diffuse toxic goiter.

DRUGS FOR THE TREATMENT OF HYPERTHYROIDISM

A.

THIOAMIDES

METHIMAZOLE and PROPYLTHIOURACIL are

major drugs for treatment of thyrotoxicosis

CARBIMAZOLE, is a prodrug that is converted to

methimazole in vivo

The thioamides act by multiple mechanisms. The major action is to

prevent hormone synthesis by inhibiting the thyroid peroxidase-

catalyzed reactions and blocking iodine organification. In

addition, they block coupling of the iodotyrosines. THEY BLOCK

P.O.C. OF E.P.O.C.

They do not block uptake of iodide by the gland. Propylthiouracil and

(to a much lesser extent) methimazole inhibit the peripheral

deiodination of T4 and T3.

METHIMAZOLE

o

completely absorbed

o Excretion is slower than with propylthiouracil

PROPYLTHIOURACIL

o

rapidly absorbed, reaching peak serum levels after 1 hour

o

large first-pass effect in the liver

o may be used in pregnant women

Adverse drug reactions:

o

nausea and gastrointestinal distress


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o

altered sense of taste or smell may occur with methimazole.

o The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied by

systemic signs such as fever.

o

Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy,

hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia.

o Hepatitis (more common with propylthiouracil) and cholestatic jaundice (more common with

methimazole) can be fatal.

o

The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3), an

infrequent but potentially fatal adverse reaction.

B.

IODIDES

POTASSIUM IODIDE/ LUGOL’S SOLUTION

today they are rarely used as sole therapy.

the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin

proteolysis. decreased thyroid hormone levels (?) Wolf-Chaikoff Phenomenon

iodides decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as

preoperative preparation for surgery.

Adverse reactions

o acneiform rash (similar to that of bromism),

o

swollen salivary glands

o mucous membrane ulcerations,

o conjunctivitis, rhinorrhea, drug fever,

o metallic taste, bleeding disorders

o

rarely, anaphylactoid reactions

o

iodides can induce hyperthyroidism (Jod-Basedow phenomenon)

C.

ANION INHIBITORS

Monovalent anions such as PERCHLORATE (ClO4–), PERTECHNETATE (TcO4

–), and THIOCYANATE (SCN

–)

can block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism.

However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia.

D.

RADIOACTIVE IODINE

131I is the only isotope used for treatment of thyrotoxicosis.

rapidly absorbed, concentrated by the thyroid, and incorporated into storage follicles.

MECHANISM of ACTION: destruction of the thyroid parenchyma that is evidenced by epithelial swelling and

necrosis, follicular disruption, edema, and leukocyte infiltration

Adverse effect

o Hypothyroidism

o Sialitis, sorethroat

Contraindicated in pregnant patients

ADJUNCTS TO ANTITHYROID THERAPY

PROPRANOLOL

During the acute phase of thyrotoxicosis, beta-adrenoceptor blocking agents without intrinsic sympathomimetic activity are

extremely helpful. Propranolol, 20–40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation.

Propranolol is gradually withdrawn as serum thyroxine levels return to normal.


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DILTIAZEM

Diltiazem, 90–120 mg three or four times daily, can be used to control tachycardia in patients in whom blockers are

contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem.

BARBITURATES

Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4

levels.

CHOLESTYRAMINE

Bile acid sequestrants (eg, cholestyramine) can also rapidly lower T4 levels by increasing the fecal excretion of T4.

The adrenal glands are two triangular masses on the superior poles of the kidneys. (Parang party hats ng dalawang kidneys na

nagpa-party)

The adrenal gland parenchyma is divided into the superficial CORTEX and the deeper MEDULLA. The hormones of the cortex

are LIPOPHILIC/ STEROIDAL, i.e. they are all derived from CHOLESTEROL.

CORTEX

o

Mineralocorticoid: ALDOSTERONE

o Bind to its receptor and promotes SODIUM

REABSORPTION IN THE COLLECTING TUBULE and the

distal part of the distal convoluted tubule.

o

Produced by the Zona glomerulosa

o RENIN-ANGIOTENSIN-ALDOSTERONE SYNTHESIS

o

The production of aldosterone by the adrenals is under

the influence of angiotensin, i.e. angiotensin promotes

aldosterone production.

o

Glucocorticoid: CORTISOL

o Increases serum glucose

o Immune modulating effects

decreases WBC

Inhibits PHOSPHOLIPASE A2

o

Promotes fetal lung surfactant

o

Sex Hormone: DEHYDROEPIANDROSTERONE

MEDULLA

o Epinephrine


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My dear student, as I imagine you looking at the diagram below, I feel that (multiple choice. Choose the best answer)

a. You want to vomit.

b. You are now having petit mal seizures (Kung oo, at nanumbalik na ang consciousness mo, mag-FB/ twitter ka

muna. Kailangan mo nang magpahinga)

c. You want to rip the paper into a thousand pieces. (Huwag naman sana. 22 pages na at wala pa tayo sa kalahati.

Huwag ka muna mawalan ng pag-asa at katinuan)

d. Or MAYBE…. JUST MAYBE you are one of the chosen few who at this point says “Ma’am Carigma, graaaabe. This

lecture is so enriching for my mind, my heart and my soul…. May part two pa ba ang lecture? 110 pages pa! I’m soooo

willing to read!” (haha asa pa. Kung iniisip mo to, naku. Mag-FB/ twitter ka muna. Kailangan mo nang magpahinga.)

I was just kidding. I’m just checking if you’re still alive.


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GAME! BACK TO REALITY!

Natitigan mo na ba ang diagram ng chemical reactions?

OO. Gusto kona titigan mo sya.

Hindi ako nagbibiro. Seryoso ako. Balikan mo sya ulit kung dinaanan mo lang yung diagram.

Here are the few important things that I want you to remember:

THE ADRENOCORICOSTEROIDS (All the hormones produced by the adrenal cortex – aldosterone, cortisol and

dehydroepiandrosterone) are DERIVATIVES OF CHOLESTEROL.

The adrenocorticosteroids are STRUCTURALLY RELATED. THEREFORE, THERE IS A CHANCE THAT ONE HORMONE

WILL ACTIVATE A RECEPTOR FOR ANOTHER – by virtue of the structure activity relationship (Lock-and-key

mechanism between receptors and ligands). Example: Cortisol may activate the aldosterone receptor and cause

sodium reabsorption in the kidneys.

Enzymes that mediate hydroxylation reactions (these are actually CYP enzymes) are responsible for theproduction of the adrenocorticosteroid hormones. Any agent that may impair enzyme activity will impair hormone

production.

See? May sense naman yung diagram talaga. If you understood the diagram and the rationale of the observations I had just

mentioned, MY DEAR STUDENT, YOU JUST MADE MY DAY.

Now, let us discuss each major adrenocorticosteroid hormone extensively.

1. CORTISOL

Also known as COMPOUND F/ HYDROCORTISONE The production of cortisol is promoted by the ACTH (adrenocorticotropic hormone) in the pituitary. Cortisol

is released by CIRCADIAN RHYTHM (because ACTH is highest in the early morning and after meals.)

Cortisol when released into the bloodstream is BOUND TO PLASMA PROTEIN- CORTISOL BINDING

PROTEIN (CBG) and to a small extent ALBUMIN.

It has a short half life (60-90 minutes). Most of the cortisol produced are metabolised by the LIVER.

EFFECTS OF CORTISOL

i. Gluconeogenesis and glycogen synthesis (in the fasting state)

Inhibition of glucose uptake by the muscles/ muscle catabolism (breakdown)

Increased lipolysis

THE SUMMATIVE EFFECT: INCREASED SERUM GLUCOSE

ii.

Thinning of the skin

iii.

OSTEOPOROSIS

This is due to increased osteoclast activity (bone resorption.

iv.

DECREASED FUNCTION AND DISTRIBUTION OF THE LEUKOCYTES (WBC)

DECREASED CHEMOKINE AND CYTOKINE PRODUCTION


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INHIBITION OF PHOSPHOLIPASE A2 (the enzyme that converts cholesterol to arachidonic acid –

the source of prostaglandins)

THESE ARE ACTUALLY THE MECHANISMS OF ACTION OF CORTISOL AND DRUGS RELATED

TO CORTISOL AS ANTI-INFLAMMATORY DRUGS.

v.

INCREASED RBC AND PLATELET COUNT.

vi.

In the central nervous system: INSOMNIA, DEPRESSION

vii. INCREASED INCIDENCE OF GASTRIC MUCOSAL ULCER .

viii. INCREASED PRODUCTION OF FETAL LUNG SURFACTANT

MECHANISM OF ACTION

Glucocorticoids (S) exert their effect by entering the cell by passive diffusion (since they are very lipid soluble). Once

inside the cell, (S) is joined by a chaperone molecule (HSP – Heat shock protein) until it meets the receptor (R). Before

binding with the (R), (S) will dissociate from the HSP. The activation of the receptor leads to alteration of DNA

transcription and translation leading to the response to glucocorticoids.


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GLUCOCORTICOIDS

DURATION OF ACTION AGENT

SHORT to MEDIUM HYDROCORTISONE

PREDNISONE (prodrug)

PREDNISOLONE *

METHYLPREDNISOLONE *MEPREDNISONE *

*exhibits greater anti-inflammatory effect than hydrocortisone

The members of this group have salt retaining properties (much like

aldosterone, although minimal)

INTERMEDIATE TRIAMCINOLONE

PARAMETHASONE – best anti-inflammatory agent

among the group

FLUPREDNISOLONE

(NO salt retaining properties)

LONG DEXAMETHASONE

BETAMETHASONE

(NO salt retaining properties)

Drugs that share the effects of cortisol are useful for many indications. Administration of these agents is proven to be

beneficial for patients with deficiency states of cortisol such as:

ADDISON’s DISEASE (chronic adrenocortical insufficiency)

Acute adrenocortical insufficiency

Congenital adrenal hyperplasia

Dexamathasone Suppression Test is used for the diagnosis of Cushing's syndrome. As a screening test, 1 mg

dexamethasone is given orally at 11 PM, and a plasma sample is obtained the following morning. In normal

individuals, the morning cortisol concentration is usually less than 3 mcg/dL, whereas in Cushing's syndrome the level

is usually greater than 5 mcg/dL.

To distinguish between hypercortisolism due to anxiety, depression, and alcoholism (pseudo-Cushing syndrome) and

bona fide Cushing's syndrome, a combined test is carried out, consisting of dexamethasone (0.5 mg orally every 6

hours for 2 days) followed by a standard corticotropin-releasing hormone (CRH) test (1 mg/kg given as a bolus

intravenous infusion 2 hours after the last dose of dexamethasone).


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Adverse effects of the glucocorticoids

ACUTE (2 weeks) IMMUNO SUPPRESSION

CUSHING’S SYNDROME MYOPATHY

PSYCHOSIS/ HYPOMANIA

INCREASED INTRACRANIAL PRESSURE

ADRENAL SUPPRESSION

OSTEOPOROSIS

REBOUND OCCURRENCE OF SYMPTOMS if the dose is not tapered before

discontinuation

That’s why the glucorticoids are CONTRAINDICATED in patients with

Diabetes Mellitus

Peptic ulcer disease

Cardiovascular disease, hypertension

Severe systemic infection

Psychosis

Osteoporosis


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2. ALDOSTERONE The major MINERALOCORTICOID produced in the zona glomerulosa of the cortex

The production of aldosterone is mildly affected by ACTH. Its regulation depends on ANGIOTENSIN that is

produced by the RAAS (Renin-angiotensin-aldosterone system)

Promotes SODIUM REABSORPTION IN THE COLLECTING TUBULE and the distal part of the DISTAL

CONVOLUTED TUBULE.

The half-life of aldosterone is 15-20 minutes. It is excreted renally.

Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells,

especially principal cells of the distal convoluted and collecting tubules of the kidney. The drug-receptor

complex activates a series of events similar to those described above for the glucocorticoids.

FLUDROCORTISONE, a potent steroid with both glucocorticoid and mineralocorticoid activity, is the most widely

used mineralocorticoid. Oral doses of 0.1 mg two to seven times weekly have potent salt-retaining activity and are

used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency.

3. DEHYDROEPIANDROSTERONE A weak androgen

Converted peripherally to more potent androgens or to estrogens and interaction with androgen and

estrogen receptors, respectively

GLUCOCORTICOID ANTAGONISTS

1. AMINOGLUTETHIMIDE

Aminoglutethimide blocks the conversion of cholesterol to pregnenolone (see Figure 39–1) and causes a

reduction in the synthesis of all hormonally active steroids

INDICATIONS:


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o eliminate estrogen production in patients with carcinoma of the breast

o

can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with

Cushing's syndrome

Adverse reactions: lethargy and skin rash

2. KETOCONAZOLE

an antifungal imidazole derivative is a potent and rather nonselective inhibitor of adrenal and gonadal steroid

synthesis.

inhibits the cholesterol side-chain cleavage, P450c17, C17,20-lyase, 3-hydroxysteroid dehydrogenase, and

P450c11 enzymes required for steroid hormone synthesis.

used for the treatment of patients with Cushing's syndrome.

Adverser reactions: Gastrointestinal disturbance

3. METYRAPONE

inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesis. \

can reduce cortisol production to normal levels in some patients with endogenous Cushing's syndrome

major adverse effects observed are salt and water retention and hirsutism

4. TRILOSTANE

Trilostane is a 3B-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and

gonadal hormones and is comparable to aminoglutethimide.

Adverse effects are predominantly gastrointestinal.

MINERALOCORTICOID ANTAGONISTS

SPIRONOLACTONE

7-acetylthiospironolactone that competitively antagonizes aldosterone for receptor occupancy. Its onset of action is slow, and the effects last for 2–3 days after the drug is discontinued.

used in the treatment of primary aldosteronism and as a potassium sparing diuretic

Spironolactone is also an androgen antagonist and as such is sometimes used in the treatment of hirsutism in women.

Adverse effects reported for spironolactone include hyperkalemia, cardiac arrhythmia, menstrual abnormalities,

gynecomastia, sedation, headache, gastrointestinal disturbances, and skin rashes.

EPLERENONE

another aldosterone antagonist, is approved for the treatment of hypertension

more selective than spironolactone and has no reported effects on androgen receptors.

The standard dosage in hypertension is 50–100 mg/d.

The most common toxicity is hyperkalemia but this is usually mild.


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THE HPO AXIS OF REPRODUCTION

Gonadotropin-releasing hormone (GnRH) in pulses with the appropriate amplitude, which stimulates the release of follicle-

stimulating hormone (FSH) and luteinizing hormone (LH).

At the beginning of each cycle, a variable number of follicles (vesicular follicles), each containing an ovum, begin to enlarge in

response to FSH. After 5 or 6 days, one follicle, called the dominant follicle, begins to develop more rapidly. The outer theca

and inner granulosa cells of this follicle multiply and, under the influence of LH, synthesize and release ESTROGEN at an

increasing rate. (as you will see in the diagram below)

The estrogen secretion reaches a peak just before midcycle, and the granulosa cells begin to secrete PROGESTERONE . These

changes stimulate the brief surge in LH and FSH release that precedes and causes OVULATION. This surge is thought to

be a positive feedback of estrogen to LH production by the pituitary. When the follicle ruptures, the ovum is released into the

abdominal cavity near the opening of the uterine tube.

The endometrium, in the presence of estrogen, becomes thicker. Progesterone maintains the stability of the

endometrium. In the event of fertilization, the zygote formed by the union of the sperm and the egg cell will implant in this

thickened endometrium.

Following the above events, the cavity of the ruptured follicle fills with blood (corpus hemorrhagicum), and the luteinized theca

and granulosa cells proliferate and replace the blood to form the CORPUS LUTEUM. The cells of this structure produce

estrogens and progesterone for the remainder of the cycle, or longer if pregnancy occurs.

If pregnancy does not occur, the corpus luteum begins to degenerate and ceases hormone production, eventually becoming a

corpus albicans. The endometrium, which proliferated during the follicular phase and developed its glandular function during

the luteal phase, is shed in the process of menstruation in the absence of the hormones that support the endometrium.


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The Estrogens

The major estrogens produced by women are estradiol (estradiol-17B, E2), estrone (E1), and estriol (E3)


31/52


When released into the circulation, ESTRADIOL binds strongly to an alpha2 globulin (sex hormone-binding globulin [SHBG])

and with lower affinity to albumin. Bound estrogen is relatively unavailable for diffusion into cells, and it is the free fraction

that is physiologically active.

ESTRADIOL IS THE MOST ACTIVE AMONG THE THREE ESTROGENS. Estrone and estriol have low affinity for the estrogen

receptor. Estradiol is converted by the liver and other tissues to estrone and estriol

FUNCTION OF THE ESTROGENS

Estrogens are required for the normal sexual maturation and growth of the female.

o Stimulation of the development of the vagina, uterus, and uterine tubes as well as the secondary sex

characteristics.

o

Stimulation of the stromal development and ductal growth in the breast and are responsible for the

accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty.

o growth of axillary and pubic hair and alter the distribution of body fat to produce typical female body

contours.

Estrogen plays an important role in the development of the endometrial lining.

o When estrogen production is properly coordinated with the production of progesterone during the normal

human menstrual cycle, regular periodic bleeding and shedding of the endometrial lining occur.

Estrogen decrease the rate of resorption of bone by promoting the apoptosis of osteoclasts and by antagonizing

the osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin-6.

o

THIS IS WHY POST MENOPAUSAL WOMEN ARE AT RISK FOR FRACTURES.

Estrogens increase in the high-density lipoproteins (HDL), a slight reduction in the low-density lipoproteins

(LDL), and a reduction in total plasma cholesterol levels. Plasma triglyceride levels are increased.

o

THISIS WHY WOMEN HAVE A LESSER INCIDENCE OF CARDIOVASCULAR DISEASES (MI AND STROKE)

COMPARED TO MEN. The estrogens are protective by promoting lipid balance.

MECHANISM OF ACTION.

Estrogen works similarly like the other lipophilic hormones. Estrogen (S) exerts it effect by entering the cell by passive diffusion

(since they are very lipid soluble). Once inside the cell, (S) is joined by a chaperone molecule (HSP – Heat shock protein) until it

meets the receptor (R). Before binding with the (R), (S) will dissociate from the HSP. The activation of the receptor leads to

alteration of DNA transcription and translation.


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Clinical Uses

PRIMARY HYPOGONADISM

POSTMENOPAUSAL HORMONAL THERAPY

O In addition to the signs and symptoms that follow closely upon the cessation of normal ovarian function—

such as loss of periods, vasomotor symptoms, sleep disturbances, and genital atrophy—there are longer-

lasting changes that influence the health and well-being of postmenopausal women. These include an

acceleration of bone loss, which in susceptible women may lead to vertebral, hip, and wrist fractures; and

lipid changes, which may contribute to the acceleration of atherosclerotic cardiovascular disease noted in

postmenopausal women.

O Administration of estrogens reverse the manifestations seen in menopause.

HORMONAL CONTRACEPTION (SEE DISCUSSION BELOW)

The Progestins

Natural Progestins: Progesterone

Progesterone is the most important progestin in humans. In addition to having important hormonal effects, it serves as a

precursor to the estrogens, androgens, and adrenocortical steroids. It is synthesized in the ovary, testis, and adrenal from

circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy.

In the ovary, progesterone is produced primarily by the corpus luteum.


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The mechanism of action of progesterone—described in

more detail above—is similar to that of other steroid

hormones. Progestins enter the cell and bind to

progesterone receptors that are distributed between the

nucleus and the cytoplasm. The ligand-receptor complex

binds to a progesterone response element (PRE) to activate

gene transcription.

EFFECTS OF THE PROGESTINS

Progesterone increases basal insulin levels and

the insulin response to glucose.

Progesterone can compete with aldosterone for

the mineralocorticoid receptor of the renal tubule, causing a

decrease in Na+ reabsorption.

promotes glycogen storage, stimulates lipoproteinlipase activity and seems to favor fat deposition

Progesterone is responsible for the alveolobular

development of the secretory apparatus in the breast. It

also participates in the preovulatory LH surge and causes

the maturation and secretory changes in the endometrium

that are seen following ovulation

Progesterone is rapidly absorbed following administration

by any route. Its half-life in the plasma is approximately 5

minutes. In the liver, progesterone is metabolized to

pregnanediol and conjugated with glucuronic acid. It is

excreted into the urine as pregnanediol glucuronide.

INDICATIONS FOR PROGESTIN USE:

hormone replacement therapy

treatment of premenstrual syndrome (PMS)

hormonal contraception (SEE DISCUSSION BELOW)


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Hormonal Contraception (Oral, Parenteral, & Implanted Contraceptives)

MECHANISM OF CONTRACEPTION

The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of

pituitary function that results in inhibition of ovulation. The combination agents also produce a change in the cervical

mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease the

likelihood of conception and implantation.

SYSTEMIC EFFECTS OF THE ORAL CONTRACEPTIVE AGENTS

UTERUS cervix may show some hypertrophy and polyp formation

CENTRAL NERVOUS SYSTEM Estrogens tend to increase excitability in the brain, whereasprogesterone tends to decrease it. The thermogenic action

(INCREASE IN BASAL BODY TEMPERATURE) of progesterone

and some of the synthetic progestins is also thought to occur

in the central nervous system.

ENDOCRINE These preparations cause alterations in the renin-angiotensin-

aldosterone system. Plasma renin activity has been found to


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increase, and there is an increase in aldosterone secretion

INCREASED SODIUM REABSORPTION

Progesterone increases the basal insulin level and the rise in

insulin induced by carbohydrate ingestion.

BLOOD increase in factors VII, VIII, IX, and X and a decrease inantithrombin III increased coagulative state

THROMBOEMBOLIC EVENT

LIVER Cholestatic jaundice

Adverse Effects of oral contraceptives

MILD ADVERSE EFFECTS

1.

Nausea, mastalgia, breakthrough bleeding, and edema

2.

Changes in serum proteins and other effects on endocrine function.

3. Headache is mild and often transient. However, migraine is often made worse and has been reported to be

associated with an increased frequency of cerebrovascular accidents. When this occurs or when migraine has its onset

during therapy with these agents, treatment should be discontinued.

4. Withdrawal bleeding sometimes fails to occur—most often with combination preparations—and may cause

confusion with regard to pregnancy.

MODERATE ADVERSE EFFECTS

Any of the following may require discontinuance of oral contraceptives :

1.

Breakthrough bleeding is the most common problem in using progestational agents alone for contraception.

2. Weight gain is more common with the combination agents containing androgen-like progestins.

3. Increased skin pigmentation may occur, especially in dark-skinned women.

4.

Acne may be exacerbated by agents containing androgen-like progestins, whereas agents containing large amounts

of estrogen usually cause marked improvement in acne.

5.

Hirsutism may also be aggravated by the "19-nortestosterone" derivatives, and combinations containing

nonandrogenic progestins are preferred in these patients.

6. Ureteral dilation similar to that observed in pregnancy has been reported, and bacteriuria is more frequent.

7.

Vaginal infections are more common and more difficult to treat in patients who are receiving oral contraceptives.

8.

Amenorrhea occurs in some patients.

Following cessation of administration of oral contraceptives, 95% of patients with normal menstrual histories

resume normal periods and all but a few resume normal cycles during the next few months. However, some

patients remain amenorrheic for several years.


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SEVERE ADVERSE EFFECTS

1.

VENOUS THROMBOEMBOLIC DISEASE

The overall incidence of these disorders in patients taking low-dose oral contraceptives is about three-fold

higher.

The risk of venous thrombosis or pulmonary embolism is increased among women with predisposing

conditions such as stasis, altered clotting factors such as antithrombin III, increased levels of homocysteine,

or injury.

The incidence of venous thromboembolism appears to be related to the estrogen but not the progestin

content of oral contraceptives

2. MYOCARDIAL INFARCTION

slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or

hypertension, or have hyperlipoproteinemia or diabetes .

There is a much higher risk in women who smoke. THAT’S WHY A WOMAN WHO SMOKES SHOULD

NOT BE TAKING ORAL CONTRACEPTIVES THAT CONTAIN ESTROGEN.\

The association with myocardial infarction is thought to involve acceleration of atherogenesis because of

decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet

aggregation.

3.

CEREBROVASCULAR DISEASE/ STROKE

subarachnoid hemorrhages have been found to be increased among both current and past users and may

increase with time.

4. GASTROINTESTINAL DISORDERS

Cholestatic jaundice have been reported in patients taking progestin-containing drugs.

These agents have also been found to increase the incidence of symptomatic gallbladder disease, including

cholecystitis and cholangitis.

It also appears that the incidence of hepatic adenomas is increased in women taking oral contraceptives.

Ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries

and veins has also been reported in women using these drugs.

5.

DEPRESSION

Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with

some preparations.

6.

CANCER

The occurrence of malignant tumors in patients taking oral contraceptives has been studied extensively. It is

now clear that these compounds reduce the risk of endometrial and ovarian cancer. The lifetime risk of

breast cancer in the population as a whole does not seem to be affected by oral contraceptive use. Some

studies have shown an increased risk in younger women, and it is possible that tumors that develop in

younger women become clinically apparent sooner.

The following agents are ESTROGEN RECEPTOR AGONISTS. These drugs are useful for the treatment of patients with

estrogen-responsive breast cancer or patients with endometriosis.

TAMOXIFEN

Tamoxifen, a competitive partial agonist inhibitor of estradiol at the estrogen receptor

used in the palliative treatment of breast cancer

given orally

Adverse reactions include: Hot flushes and nausea and vomiting


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TOREMIFENE

Structurally similar to Tamoxifen with very similar properties, indications, and toxicities.

RALOXIFENE

another partial estrogen agonist-antagonist (SERM) at some but not all target tissues.

has similar effects on lipids and bone but appears not to stimulate the endometrium or breast.

has a very large volume of distribution and a long half-life (> 24 hours), so it can be taken once a day

approved in the USA for the prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in

women with risk factors.

CLOMIPHENE

an older partial agonist, a weak estrogen that also acts as a competitive inhibitor of endogenous estrogens;

well absorbed when taken orally.

INDICATIONS:

o treatment of disorders of ovulation in patients who wish to become pregnant.

When clomiphene is administered in doses of 100 mg/d for 5 days, a rise in plasma LH and FSH is

observed after several days. In patients who ovulate, the initial rise is followed by a second rise of

gonadotropin levels just prior to ovulation.

Adverse effects:

o hot flushes, which resemble those experienced by menopausal patients.

o

stimulation of the ovaries and usually with ovarian enlargement; multiple pregnancy

FULVESTRANT is an investigational pure estrogen receptor antagonist that has been somewhat more effective than those with

partial agonist effects in some patients who have become resistant to tamoxifen.

MIFEPRISTONE

Mifepristone is a "19-norsteroid" that binds strongly to the progesterone receptor and inhibits the activity of

progesterone.

DANAZOL

Danazol, an isoxazole derivative of ethisterone (17 -ethinyltestosterone) with weak progestational, androgenic, and

glucocorticoid activities

used to suppress ovarian function.

INDICATIONS:

o

used in the treatment of endometriosis

o treatment of fibrocystic disease of the breast and hematologic or allergic disorders,

Adverse reactions:

o weight gain, edema, decreased breast size, acne and oily skin, increased hair growth, deepening of the voice,

headache, hot flushes, changes in libido, and muscle cramps

o mild to moderate hepatocellular damage


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Another means to supress estrogen effect aside from antagonizing the estrogen receptor IS TO PREVENT THE PRODUCTION

OF ESTROGEN. As discussed in adrenocorticosteroid section above, TESTOSTERONE MAY BE CONVERTED TO ESTROGEN, and

this is mediated by the AROMATASE enzyme (found in fats and other tissue).

ANASTROZOLE, LETROZOLE, EXEMESTANE

selective non-steroidal inhibitors of aromatase is effective in some women whose breast tumors have becomeresistant to tamoxifen is similar.

Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase.

Several other aromatase inhibitors are undergoing clinical trials in patients with breast cancer.

o FADROZOLE is an oral nonsteroidal (triazole) inhibitor of aromatase activity. These compounds appear to be

as effective as tamoxifen. In addition to their use in breast cancer, aromatase inhibitors have been

successfully employed as adjuncts to androgen antagonists in the treatment of precocious puberty and as

primary treatment in the excessive aromatase syndrome.

In humans, the most important androgen secreted by the testis is TESTOSTERONE. About 95% is produced by the Leydig cells

and only 5% by the adrenals.

About 65% of circulating testosterone is bound to sex hormone-binding globulin. SHBG is increased in plasma by estrogen,

by thyroid hormone, and in patients with cirrhosis of the liver. of the remaining testosterone is bound to albumin.

In many target tissues, testosterone is converted to dihydrotestosterone by 5-alpha-reductase. In these tissues,

dihydrotestosterone is the major active androgen. Again, TESTOSTERONE MAY BE CONVERTED TO ESTROGEN. The

conversion of testosterone to estradiol by P450 aromatase also occurs in some tissues, including adipose tissue, liver, and the

hypothalamus, where it may be of importance in regulating gonadal function.

EFFECTS OF TESTOSTERONE

GENITALS penile and scrotal growth.

SKIN appearance of pubic, axillary, and beard hair.

sebaceous glands become more active

skin tends to become thicker and oilier

LARYNX larynx grows and the vocal cords become thicker, leading to a lower-pitched voice.

BONES Skeletal growth is stimulated and epiphysial closure accelerated

stimulating and maintaining sexual function in men

MUSCLES increase lean body mass

BLOOD reduction of hormone binding and other carrier proteins and increased liver

synthesis of clotting factors, triglyceride lipase, 1-antitrypsin, haptoglobin, and sialic

acid


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OTHERS stimulate renal erythropoietin secretion and decrease HDL levels

INDICATIONS OF ANDROGEN THERAPY:

Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men.

Treatment of endometriosis in the female

Chemotherapy of breast tumors in premenopausal women.

Adverse Effects

The adverse effects of these compounds are the exaggeration of their physiologic action. The manifestations are due largely

to their masculinizing effects and are most noticeable in women and prepubertal children. hirsutism, acne, amenorrhea, clitoral enlargement (remember my dear student that the clitoris in the female is

analogous to the glans penis) , and deepening of the voice.

alteration of serum lipids and could conceivably increase susceptibility to atherosclerotic disease in women.

Hepatic dysfunction - bilirubin levels may increase until clinical jaundice is apparent. The cholestatic jaundice is

reversible upon cessation of therapy. (RECALL: Estrogen also produces this effect – CHOLESTATIC JAUNDICE)

prostatic hyperplasia may develop, causing urinary retention.

The drugs that are used to supress the effects of testosterone are very useful for the management of male patients with

prostate carcinoma which is responsive to androgen stimulation. These drugs have also been used for the management ofendometriosis, treatment of hirsutism in women and early male pattern baldness in men.

The testosterone antagonists may either be:

A.

STEROID SYNTHESIS INHIBITORS less androgen produced

B.

ANDROGEN RECEPTOR INHIBITORS receptor antagonism less androgen effect


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Steroid Synthesis Inhibitors

A. KETOCONAZOLE

Inhibitor of hydroxylases (CYP enzymes) for steroidogenesis

B.

ABIRATERONE

Inhibitor of 17-hydroxylase and 17,20-lyase

C.

Inhibitors of 5 alpha-reductase

FINASTERIDE a steroid-like inhibitor of this enzyme, is orally active and causes a reduction in

dihydrotestosterone levels

DUTASTERIDE is a similar orally active steroid derivative with a slow onset of action and a much longer

half-life than finasteride.

Receptor Inhibitors

A. CYPROTERONE and CYPROTERONE ACETATE

effective antiandrogens that inhibit the action of androgens at the target organ.

The acetate form has a marked progestational effect that suppresses the feedback enhancement of LH and

FSH, leading to a more effective antiandrogen effect.

Used in women to treat hirsutism and in men to decrease excessive sexual drive

Also used as a contraceptive agent

B.

FLUTAMIDE, BICALUTAMIDE, NILUTAMIDE

potent anti-androgen used in the treatment of prostatic carcinoma

Adverse reaction:

1.

mild gynecomastia (probably by increasing testicular estrogen production)

2. occasionally causes mild reversible hepatic toxicity

Feeling ko, kung sineryoso mo ang pagbabasa ng notes na ito, may 1203.0 kcal ka nang na-burn sa kakaisip.

YEY!!! TUMBLING MUNAAAAA

\o> \ / \

/> ___________________________ /o\ _______________________ / \

(how I wish puwede ka nga talagang pumayat sa pag-iisip. That would have been DELIGHTFUL! :D)


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The pancreas is a retroperitoneal organ located in the epigastric area of the abdomen. It is both an endocrine and exocrinegland. The pancreas plays an important role in lipid and carbohydrate digestion (production of amylase and lipase) and

bicarbonate production into the small intestine for digestion.

ENDOCRINE FUNCTION OF THE PANCREAS

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout

the pancreatic gland. Within the islets, at least four hormone-producing cells are present.

CELL TYPE % HORMONES PRODUCED

Alpha (A) cell 20 Glucagon, proglucagon

Beta (B) cell 75 Insulin, C-peptide, proinsulin, amylin

Delta (D) cell 3–5 Somatostatin

G cell 1 Gastrin

F cell (PP cell)1 1 Pancreatic polypeptide (PP)

DIABETES MELLITUS

Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion,

with or without concurrent impairment of insulin action.

The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories:

Type 1, insulin-dependent diabetes

selective beta cell (B cell) destruction and severe or absolute insulin deficiency

Interruption of the insulin replacement therapy can be life-threatening and can result in diabetic

ketoacidosis or death.

o

Diabetic ketoacidosis is caused by insufficient or absent insulin and results from excess release of

fatty acids and subsequent formation of toxic levels of ketoacids.

Type 2, non – insulin-dependent diabetes

characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin

secretion

Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-

threatening condition called nonketotic hyperosmolar coma.

o

In this condition, the blood glucose may rise to 6–20 times the normal range and an altered mental

state develops or the person loses consciousness. Urgent medical care and rehydration is required.

Type 3, other

Type 4, gestational diabetes mellitus


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contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges

Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged

into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of

four amino acids.

Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a

variety of stimuli (post-prandial insulin production)

o glucose

o

other sugars (eg, mannose)

o certain amino acids (eg, leucine, arginine)

** Inhibitory signals include somatostatin, leptin, and chronically elevated glucose and fatty acid levels.

INSULIN RELEASE

INCREASEDGLUCOSE

LEVELS

INCREASEDATP

PRODUCTION

CLOSURE OFATP-

DEPENDENTPOTASSIUMCHANNELS

CELLDEPOLARIZA-

TION

EXOCYTOSISOF INSULINFROM THEBETA CELL


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The liver and kidney are the two main organs that remove insulin from the circulation.

After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the

membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the

primary target tissues, ie, liver, muscle, and adipose tissue.

Insulin exerts its effect by binding to the insulin receptor on the cell membrane surface. This receptor contains TYROSINE

KINASE. Activation of this receptor leads to phosphorylation reactions that would eventually TRANSLOCATE THE GLUCOSE

TRANSPORTER (GLUT) on to the cell membrane surface.

Simply putting it, INSULIN WOULD BRING GLUCOSE INTO THE CELL. Without insulin, the glucose present in the blood

circulation will remain in the blood, therefore, you get HYPERGLYCEMIA.

Patients are diagnosed to have diabetes mellitus if hyperglycemia exists chronically (by testing for fasting blood

glucose (FBG), random blood glucose (RBG) and oral glucose tolerance test (OGTT).

The table below summarizes the effect of insulin (as well as glucagon)


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Four principal types of injected insulins are available:

(1) rapid-acting, with very fast onset and short duration;

(2) short-acting, with rapid onset of action;

(3) intermediate-acting; and(4) long-acting, with slow onset of action

Preparation Onset Peak Duration

Rapid acting

Regular

Lispro

Aspart

0.5-1 hr

15 min

15 min

2-4 hr

1 hr

1 hr

6-8 hr

3-4 hr

3-4 hr

Intermediate

NPH

Lente

1-3 hr

1-4 hr

6-8 hr

6-10 hr

12-16 hr

14-18 hr

Long Acting

Ultralente

Glargine

2-4 hr

6 hr

8-10 hr

No peak

16-24 hr

24 hrs

Administration of insulin is used in the treatment of type 1 DM. The goal of subcutaneous insulin therapy is to replicate normal

physiologic insulin secretion and replace the background or basal overnight, fasting, and between meal) as well as bolus or

prandial (mealtime) insulin.


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Insulin is preferably administered SUBCUTANEOUSLY.

The adverse effects noted on insulin therapy include:

HYPOGLYCEMIA

INSULIN ALLERGY

LIPODYSTROPHY

o

Atrophy of adipose tissue at the site of injection

Six categories of oral antidiabetic agents are now available in the USA for the treatment of persons with type 2 diabetes:

1. insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)

2. biguanides

3.

thiazolidinediones

4. Alpha-glucosidase inhibitors

5.

incretin-based therapies6.

amylin analog

Insulin Secretagogues: Sulfonylureas

The major action of sulfonylureas is to increase insulin release from the pancreas. They are potassium channel

blockers.

Blockade of K channels cell depolarization insulin release

Long-term administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to

the hypoglycemic effect of the drugs

FIRST-GENERATION SULFONYLUREAS (more likely to cause hypoglycemia as an adverse effect)

TOLBUTAMIDE

o

Because of its short half-life, it is the safest sulfonylurea for elderly diabetics.

CHLORPROPAMIDE

o

has a long half-life.

o It is contraindicated in patients with hepatic or renal insufficiency.

o Prolonged hypoglycemic reactions are more common in elderly patients

TOLAZAMIDE

is comparable to chlorpropamide in potency but has a shorter duration of action.

SECOND-GENERATION SULFONYLUREAS

The second-generation sulfonylureas are prescribed more frequently in the USA than are the first-generation agents

because they have fewer adverse effects and drug interactions.


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These potent sulfonylurea compounds—GLYBURIDE, GLIPIZIDE, AND GLIMEPIRIDE—should be used with caution

in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.

.

Insulin Secretagogue: Meglitinide

REPAGLINIDE, NATEGLINIDE

These drugs modulate beta-cell insulin release by regulating potassium efflux through the potassium channels

(similar to the sulfonylureas.

Less hypoglycaemia noted as adverse effects. Other adverse effects include GI disturbances.

Like the sulfonylureas, these agents should be taken before meals.

Biguanides

METFORMIN

Mechanisms of Actiono Reduction of hepatic glucose production through activation of the enzyme AMP-activated protein kinase

(AMPK).

o

Impairment of renal gluconeogenesis,

o

Slowing of glucose absorption from the gastrointestinal tract

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort,

and diarrhea)

Other adverse effects:

o Absorption of vitamin B12 appears to be reduced during long-term metformin

o Biguanide drugs are contraindicated in patients with renal disease, alcoholism, hepatic disease, or

conditions predisposing to tissue anoxia

Thiazolidinediones

PIOGLITAZONE, ROSIGLITAZONE

decrease insulin resistance.

They are ligands of peroxisome proliferator-activated receptor-gamma (PPAR- ɣ),

o These PPAR receptors are found in muscle, fat, and liver. PPAR-ɣ receptors modulate the expression of the

genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue

differentiation

Thiazolidinediones have benefit in the prevention of type 2 diabetes

An adverse effect common to both agents is fluid retention, which presents as a mild anemia and peripheral edema.

Alpha-Glucosidase Inhibitors

ACARBOSE, MIGLITOL

are competitive inhibitors of the intestinal alpha-glucosidases (enzymes found in the small intestineal lumen)

They reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides

o

Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into

the bloodstream. Complex starches, oligosaccharides, and disaccharides must be broken down into


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individual monosaccharides (by glucosidase) before being absorbed in the duodenum and upper jejunum.

WITHOUT GLUCOSIDASE, THERE WOULD BE NO ABSORPTION OF CARBIOHYDRATES.

Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of

undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas.

NEWER DRUGS FOR THE TREATMENT OF DM

PRAMLINTIDE

Pramlintide, a synthetic analog of amylin, is an injectable antihyperglycemic agent

Like amylin, it suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central

nervous system-mediated anorectic effects.

The major adverse effects of pramlintide are hypoglycemia and gastrointestinal symptoms including nausea, vomiting,

and anorexia.

EXENATIDE

As a synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is t

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