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1|Endocrine Pharmacology
to-
Reproduction
Homeostasis
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
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.
2|Endocrine Pharmacology
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 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.
3|Endocrine Pharmacology
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:
PROLACTIN (PRL)
4|Endocrine Pharmacology
ANTI-DIURETIC HORMONE
Regulates water reabsorption in the collecting tubules (and the distal parts of the distal
convoluted tubules) of the kidneys
OXYTOCIN
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. Dopamines effect 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.
5|Endocrine Pharmacology
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. Turners syndrome, Prader-Willi syndrome). It may be administered 37 times per week. Peak levels occur in 24
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)
Hypothyroidism
Pancreatitis
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)
6|Endocrine Pharmacology
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
Pain at the site of injection is common, especially with the long-acting octreotide suspension.
The gonadotrophs (cells in the pituitary gland) produce the gonadotropins FSH and LH.
LH = LUTEINIZING 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.
7|Endocrine Pharmacology
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.
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
approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women
with profound LH deficiency.
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
multiple pregnancies
Gynecomastia (male)
8|Endocrine Pharmacology
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
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 36 months with a GnRH agonist reduces fibroid size and, when
combined 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
9|Endocrine Pharmacology
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
Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur.
ovarian cysts
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
Adverse effects:
o
allergy
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.
10 | E n d o c r i n e P h a r m a c o l o g y
Dopamine agonists can cause nausea, headache, light-headedness, insomnia, orthostatic hypotension, and
fatigue.
Psychiatric manifestations occasionally occur, even at lower doses, and may take months to resolve.
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.
11 | E n d o c r i n e P h a r m a c o l o g y
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.
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.
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.
Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with
coronary artery disease.
12 | E n d o c r i n e P h a r m a c o l o g y
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 hormonestriiodothyronine (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. Im 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.
13 | E n d o c r i n e P h a r m a c o l o g y
14 | E n d o c r i n e P h a r m a c o l o g y
15 | E n d o c r i n e P h a r m a c o l o g y
16 | E n d o c r i n e P h a r m a c o l o g y
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 are
observed to be opposites of each other). These are mediated by the intracellular effects on the thyroid hormones. (see diagram
below.)
17 | E n d o c r i n e P h a r m a c o l o g y
T4 and T3 can enter the cell BUT ONLY T3 IS CAPABLE OF BINDING TO THE THYROID HORMONE RECEPTOR IN THE
NUCLEUS.
18 | E n d o c r i n e P h a r m a c o l o g y
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.
THIOAMIDES
methimazole in vivo
The thioamides act by multiple mechanisms. The major action is to
prevent hormone synthesis by inhibiting the thyroid peroxidasecatalyzed 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
19 | E n d o c r i n e P h a r m a c o l o g y
The most common adverse effect is a maculopapular pruritic rash (46%), at times accompanied by
systemic signs such as fever.
Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy,
hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia.
Hepatitis (more common with propylthiouracil) and cholestatic jaundice (more common with
methimazole) can be fatal.
The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm ), an
infrequent but potentially fatal adverse reaction.
B.
IODIDES
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
131
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
Adverse effect
o Hypothyroidism
o Sialitis, sorethroat
20 | E n d o c r i n e P h a r m a c o l o g y
DILTIAZEM
Diltiazem, 90120 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 T 4
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
MEDULLA
o Epinephrine
21 | E n d o c r i n e P h a r m a c o l o g y
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 Maam 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! Im soooo
willing to read! (haha asa pa. Kung iniisip mo to, naku. Mag-FB/ twitter ka muna. Kailangan mo nang magpahinga.)
22 | E n d o c r i n e P h a r m a c o l o g y
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 the
production 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.
1. CORTISOL
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.
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
23 | E n d o c r i n e P h a r m a c o l o g y
viii.
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.
24 | E n d o c r i n e P h a r m a c o l o g y
GLUCOCORTICOIDS
DURATION OF ACTION
SHORT to MEDIUM
AGENT
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)
TRIAMCINOLONE
PARAMETHASONE best anti-inflammatory agent
among the group
FLUPREDNISOLONE
INTERMEDIATE
LONG
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:
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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Diabetes Mellitus
Psychosis
Osteoporosis
26 | E n d o c r i n e P h a r m a c o l o g y
2. ALDOSTERONE
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 391) and causes a
reduction in the synthesis of all hormonally active steroids
INDICATIONS:
27 | E n d o c r i n e P h a r m a c o l o g y
can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with
Cushing's syndrome
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.
3.
4.
METYRAPONE
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
TRILOSTANE
Trilostane is a 3B-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and
gonadal hormones and is comparable to aminoglutethimide.
MINERALOCORTICOID ANTAGONISTS
SPIRONOLACTONE
Its onset of action is slow, and the effects last for 23 days after the drug is discontinued.
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
more selective than spironolactone and has no reported effects on androgen receptors.
28 | E n d o c r i n e P h a r m a c o l o g y
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.
29 | E n d o c r i n e P h a r m a c o l o g y
The Estrogens
The major estrogens produced by women are estradiol (estradiol-17B, E2), estrone (E1), and estriol (E3)
30 | E n d o c r i n e P h a r m a c o l o g y
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.
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.
growth of axillary and pubic hair and alter the distribution of body fat to produce typical female body
contours.
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
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.
31 | E n d o c r i n e P h a r m a c o l o g y
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 atrophythere are longerlasting 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.
32 | E n d o c r i n e P h a r m a c o l o g y
decrease in Na reabsorption.
33 | E n d o c r i n e P h a r m a c o l o g y
ENDOCRINE
These preparations cause alterations in the renin-angiotensinaldosterone system. Plasma renin activity has been found to
34 | E n d o c r i n e P h a r m a c o l o g y
LIVER
Cholestatic jaundice
2.
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 occurmost often with combination preparationsand may cause
confusion with regard to pregnancy.
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.
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.
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.
35 | E n d o c r i n e P h a r m a c o l o g y
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. THATS 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.
subarachnoid hemorrhages have been found to be increased among both current and past users and may
increase with time.
4.
GASTROINTESTINAL DISORDERS
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.
DEPRESSION
Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with
some preparations.
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.
5.
6.
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
given orally
36 | E n d o c r i n e P h a r m a c o l o g y
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;
INDICATIONS:
o
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
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
INDICATIONS:
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
37 | E n d o c r i n e P h a r m a c o l o g y
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 become
resistant to tamoxifen is similar.
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.
GENITALS
SKIN
LARYNX
BONES
EFFECTS OF TESTOSTERONE
penile and scrotal growth.
appearance of pubic, axillary, and beard hair.
sebaceous glands become more active
skin tends to become thicker and oilier
larynx grows and the vocal cords become thicker, leading to a lower-pitched voice.
Skeletal growth is stimulated and epiphysial closure accelerated
stimulating and maintaining sexual function in men
MUSCLES
BLOOD
38 | E n d o c r i n e P h a r m a c o l o g y
OTHERS
Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men.
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)
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 of
endometriosis, treatment of hirsutism in women and early male pattern baldness in men.
The testosterone antagonists may either be:
A.
B.
39 | E n d o c r i n e P h a r m a c o l o g y
KETOCONAZOLE
B.
ABIRATERONE
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.
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.
B.
Used in women to treat hirsutism and in men to decrease excessive sexual drive
Adverse reaction:
1.
2.
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)
40 | E n d o c r i n e P h a r m a c o l o g y
The pancreas is a retroperitoneal organ located in the epigastric area of the abdomen. It is both an endocrine and exocrine
gland. 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
20
Glucagon, proglucagon
75
35
Somatostatin
G cell
Gastrin
HORMONES PRODUCED
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.
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 lifethreatening condition called nonketotic hyperosmolar coma.
o
In this condition, the blood glucose may rise to 620 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
41 | E n d o c r i n e P h a r m a c o l o g y
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
INSULIN RELEASE
INCREASED
GLUCOSE
LEVELS
INCREASED
ATP
PRODUCTION
42 | E n d o c r i n e P h a r m a c o l o g y
CLOSURE OF
ATPDEPENDENT
POTASSIUM
CHANNELS
CELL
DEPOLARIZATION
EXOCYTOSIS
OF INSULIN
FROM THE
BETA CELL
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)
43 | E n d o c r i n e P h a r m a c o l o g y
Preparation
Onset
Peak
Duration
Regular
0.5-1 hr
2-4 hr
6-8 hr
Lispro
15 min
1 hr
3-4 hr
Aspart
15 min
1 hr
3-4 hr
NPH
1-3 hr
6-8 hr
12-16 hr
Lente
1-4 hr
6-10 hr
14-18 hr
Ultralente
2-4 hr
8-10 hr
16-24 hr
Glargine
6 hr
No peak
24 hrs
Rapid acting
Intermediate
Long Acting
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.
44 | E n d o c r i n e P h a r m a c o l o g y
HYPOGLYCEMIA
INSULIN ALLERGY
LIPODYSTROPHY
o
Six categories of oral antidiabetic agents are now available in the USA for the treatment of persons with type 2 diabetes:
1.
2.
biguanides
3.
thiazolidinediones
4.
Alpha-glucosidase inhibitors
5.
incretin-based therapies
6.
amylin analog
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
Because of its short half-life, it is the safest sulfonylurea for elderly diabetics.
CHLORPROPAMIDE
o
TOLAZAMIDE
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.
45 | E n d o c r i n e P h a r m a c o l o g y
These potent sulfonylurea compoundsGLYBURIDE, GLIPIZIDE, AND GLIMEPIRIDEshould be used with caution
in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.
.
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.
Biguanides
METFORMIN
Mechanisms of Action
o
Reduction of hepatic glucose production through activation of the enzyme AMP-activated protein kinase
(AMPK).
The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort,
and diarrhea)
Biguanide drugs are contraindicated in patients with renal disease, alcoholism, hepatic disease, or
conditions predisposing to tissue anoxia
Thiazolidinediones
PIOGLITAZONE, ROSIGLITAZONE
These PPAR receptors are found in muscle, fat, and liver. PPAR- receptors modulate the expression of the
genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue
differentiation
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
46 | E n d o c r i n e P h a r m a c o l o g y
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.
PRAMLINTIDE
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 the first incretin therapy to become
available for the treatment of diabetes.
They alo promote potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release.
SITAGLIPTIN
Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1like molecules. Its major action is to increase circulating levels of GLP-1 and GIP. This ultimately decreases
postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels.
Glucagon is synthesized in the alpha cells of the pancreatic islets of Langerhans. Glucagon is a peptideidentical in all
mammalsconsisting of a single chain of 29 amino acid.
SEVERE HYPOGLYCEMIA
O The major use of glucagon is for emergency treatment of severe hypoglycemic reactions in patients with
type 1 diabetes when unconsciousness precludes oral feedings and intravenous glucose treatment is not
possible
O Transient nausea and occasional vomiting can result from glucagon administration
47 | E n d o c r i n e P h a r m a c o l o g y
Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general
cellular function.
Approximately 98% of the 12 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone.
Biruin mo yun?
Therefore, abnormalities in bone mineral homeostasis can lead not only to a wide variety of cellular dysfunctions (eg, tetany,
coma, muscle weakness) but also to disturbances in structural support of the body (eg, osteoporosis with fractures) and loss of
hematopoietic capacity (eg, infantile osteopetrosis).
Calcium and phosphate enter the body from the intestine. In the steady state, renal excretion of calcium and phosphate
balances intestinal absorption. This maintains normal calcium and phosphate balance in the body.
Three hormones serve as the principal regulators of calcium and phosphate homeostasis:
parathyroid hormone (PTH),
fibroblast growth factor 23 (FGF23),
and the steroid vitamin D.
Other hormonescalcitonin, prolactin, growth hormone, insulin, thyroid hormone, glucocorticoids, and sex steroidsinfluence
calcium and phosphate homeostasis under certain physiologic circumstances and can be considered secondary regulators.
PARATHYROID HORMONE
Parathyroid hormone (PTH) is a single-chain peptide hormone composed of 84 amino acids. It is produced in the parathyroid
gland.
In bone, PTH increases the activity and number of osteoclasts, the cells responsible for bone resorption. PTH also stimulate
osteoblasts (for bone formation and remodelling). Although both bone resorption and bone formation are enhanced by PTH,
the net effect of excess PTH is to increase bone resorption.
In the kidney, PTH increases the ability of the nephron to reabsorb calcium and magnesium but reduces its ability to
reabsorb phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate. Another important action of PTH on the
kidney is its stimulation of 1,25-dihydroxyvitamin D (1,25[OH]2D) production.
Bone resorption leads to INCREASED SERUM CALCIUM.
Decreased phosphate reabsorption in the kidneys leads to DECREASED SERUM PHOSPHATE
ISA PA.
48 | E n d o c r i n e P h a r m a c o l o g y
OK NA?
VITAMIN D
Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet radiation.
Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH] cholecalciferol). This metabolite is further
converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxy cholecalciferol. 1,25DIHYDROXYCHOLECALCIFEROL (CALCITRIOL) IS AN ACTIVE FOR OF VITAMIN D.
3 ORGANS NECESSARY FOR VITAMIN D SYNTHESIS: SKIN LIVER KIDNEYS
EFFECTS OF VITAMIN D
49 | E n d o c r i n e P h a r m a c o l o g y
The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain peptide hormone
Calcitonin inhibits osteoclastic bone resorption therefore, calcium is maintained in the compact bone.
GLUCOCORTICOIDS
useful in reversing the hypercalcemia associated with lymphomas and granulomatous diseases such as sarcoidosis.
ESTROGENS
Given as hormone replacement therapy for menopausal women (as discussed earlier)
50 | E n d o c r i n e P h a r m a c o l o g y
useful for the treatment of hypercalcemia associated with malignancy, for Paget's disease, and for osteoporosis
The most notable adverse effect seen in this group is ESOPHAGEAL IRRITTION. This is the reason why patients are
advised to take these drugs while in an upright sitting position with a full glass of water.
PLICAMYCIN (MITHRAMYCIN)
used clinically for two disorders of bone mineral metabolism: Paget's disease and hypercalcemia.
The cytotoxic properties of the drug appear to involve its binding to DNA and interruption of DNA directed RNA
synthesis.
o
The reasons for its usefulness in the treatment of Paget's disease and hypercalcemia are unclear but may
relate to the need for protein synthesis to sustain bone resorption.
THIAZIDES
The principal application of thiazides in the treatment of bone mineral disorders is in reducing renal calcium
excretion.
o
In the distal tubule, thiazides block sodium reabsorption at the luminal surface, increasing the calciumsodium exchange at the basolateral membrane and thus enhancing calcium reabsorption into the blood at
this site.
SALINE DIURESIS
In hypercalcemia of sufficient severity to produce symptoms, rapid reduction of serum calcium is required.
The first steps include rehydration with saline and diuresis with furosemide, although the efficacy of Furosemide in
this setting has not been proven and the drug appears to be falling out of favor.
PHOSPHATE
Giving intravenous phosphate is probably the fastest and surest way to reduce serum calcium, but it is a hazardous
procedure if not done properly. Intravenous phosphate should be used only after other methods of treatment
(bisphosphonates, calcitonin, and saline diuresis) have failed to control symptomatic hypercalcemia.
HYPOCALCEMIA
The main features of hypocalcemia are neuromusculartetany, paresthesias, laryngospasm, muscle cramps, and convulsions.
The major causes of hypocalcemia in the adult are hypoparathyroidism, vitamin D deficiency, chronic kidney disease, and
malabsorption
CALCIUM
51 | E n d o c r i n e P h a r m a c o l o g y
VITAMIN D
When rapidity of action is required, 1,25(OH)2D3 (calcitriol), 0.251 mcg daily, is the vitamin D metabolite of choice, because it
is capable of raising serum calcium within 2448 hours. Calcitriol also raises serum phosphate, although this action is
usually not observed early in treatment
In summary,
Biphosphonates
Saline diuresis (Furosemide)
Calcitonin
Plicamycin
Phosphate
Glucocorticoids
Calcium supplementation
Vitamin D
END
th
Reference: Katzung, Masters and Trevor BASIC AND CLINICAL PHARMACOLOGY 12 EDITION
th
52 | E n d o c r i n e P h a r m a c o l o g y