ENDOCRINE-AGENTS

ANTIDIABETIC DRUGS
 Definition
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 (Katzung B.G., 2009; WHO 2014)
 Pancreatic Islet Hormones

The islet of Langerhans contain four main types of

peptide-secreting cells:

A cells glucagon
B cells insulin
D cells somatostatin
PP cells pancreatic polypeptide

B cells secrete a peptide known as islet amyoid

polypeptide or amylindelay gastric emptying and
opposes insulin by stimulating glycogen breakdown in
striated muscle and c-peptide
 Classification

Type 1 diabetes
Pancreas fails to produce the insulin
which is essential for survival.
Type 2 diabetes
The body's inability to respond
properly to the action of insulin
produced by the pancreas
Environmental fc
Lifestyle changes Genetic Factors
High fat/lack of exercise
Interaction
Obesity

Insulin resistance Decreased insulin seretion

Relative insufficiency of insulin action

Development of type 2 diabetes

 Factors causing increase in visceral fat
1 Stress-related factors
-overeating, especially excessive intake of simple sugars

-smoking
-Increase in alkohol intake
-disorders of nervous and endocrine systems:increase in
cortisol, abnormality in sex hormone secretion

2 Lowered energy consumption due to a lack of

exercise
3 Genetic factors
4 Aging
 PHARMACOTHERAPY

Achieving the glucose target and hemoglobin

AIC goal
AIC 6,5% for most patients
AIC > 6,5 % if the lower target cannot achieved without AEs
In large clinical trialintensive gluc-lowering th/ (target AIC <
6% in pt with baseline AIC >8,5% was associated with
increased mortality in older and middle-aged patients with
longstanding diabetes who were at high risk CVD
In other trial : higher AIC target for intensively treated pt
no- between group diff in CVD endpoints, CV deaths, or
overall death. (Duckworth W., et al. 2009 ; Gerstein H.C., et
al. 2008)
 INSULIN
A small protein, 5808 MW
It contains 51 amino acids arranged in 2
chains (A and B), linked by disulfide bridge
Proinsulin:
a long single-chain protein molecules,
is processed within AG of beta cells and
packaged into granules
Hydrolyzed into insulin
INSULIN SYNTHESIS AND SECRETION

Insulin is synthesis as a precursor (preproinsulin) in the rough endoplasmic reticulum

Preproinsulin is transported to the Golgi apparatusproteolytic cleavage to proinsulin and then

to insulin and C-peptide

Insulin and C-peptide are stored in granules in B cells

Insulin and C-peptide are normally co-secreted by exocytosis in equimolar amounts is

released from pancreatic beta cells

The main factor controlling the synthesis and secretion is the blood gluc concentration.

Stimulants : glucose, mannose, certain AA (leucine, arginine), hormones (glucagon-like

polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon,
cholecystokinin and vagal activity.
 The Key Elements in Insulin Secretion

Glucose transport 2 (GLUT2)

Glucokinase (GK)
Mitochondria
ATP-sensitive K+ channels (K+ATPchannels)
Voltage-dependent Ca2+-channels (VDCC)
Exocytosis
INSULIN SECRETION
INSULIN SECRETION
 CIRCULATING INSULIN
Basal insulin values : 5-15 U/mL (30-90
pmol/L)
During meals :60-90 U/mL (360-540 pmol/L)
 INSULIN RECEPTOR
After insulin has entered the circulation
diffuses into tissues bound by
specialized receptors
The insulin receptor :
Consist of 2 covalently linked heterodimers
Each containing an subunit and subunit
The subunit contains a tyrosine kinase
INSULIN RECEPTOR
Binding sites

Cell
membrane

Intracellular
space

Tyrosin kinase
 INSULIN DEGRADATION
The two main organs to remove insulin
from the circulation : Liver and Kidney
The liver clears the blood : approx. 60% of
the insulin released from pancreas
The kidney removing 35-40%of the
endogenous hormone
The half-life of circulating insulin is 3-5
minutes
 Subclass drugs used for Diabetes

Insulin
Sulfonylureas
Glitinides
Biguanides
Alpha-glucosidase inhibitors
Thiazolidinediones
Incretin-based drugs
Amylin analog
 INSULIN
Rapid-acting : Lispro

Short-acting : Regular

Intermediate-acting : NPH

Long-acting : Detemir, Glargine

Mechanism of action : activate insulin receptor

Effects: reduce circulating glucose

Type 1 and 2 DM
 SULFONYLUREAS
The drugs bind to the -cell sulphonylurea receptor (SUR)-1
closes K-ATP CHANNELS)reduces cellular potassium efflux
depolarizationopening voltage-dependent Ca channels
influx of Ca release insulin

When sulphonylureas interact with SUR1release of pre-formed

insulin granules adjacent to the plasma membranc(first phase of
insulin release)

Generasi pertama: Tolbutamid, Chlorpropamide, Tolazamide

Generasi kedua* : Glypizide, glyburide, glimepiride
 GLINITIDES
Repaglinide and Nateglinide
Mechanism of action : similar to
sulfonylurea with some overlap in binding
site
Type 2 diabetes
Oral
 BIGUANIDES
Metformin

Mechanism of action :

Reduced hepatic and renal gluconeogenesis

Effects : decreased endogenous glucose production

Type 2 diabetes
 ALPHA-GLUCOSIDASE INHIBITOR

Acarbose, miglitol
Competitive and reversible inhibitors of
pancreatic a-amylase and membrane-
bound intestinal a-glucosidase hydrolase
enzymes.
Effects:
reduce conversion of starch and
disaccharides to monosaccharides
Reduce PP hyperglycaemia
 ALPHA-GLUCOSIDASE INHIBITORS

Acarbose
the first alpha-glucoside inhibitors
introduce in the early 1990s
Do not cause weight gain
Can reduce postprandial hyperglycemia
Have lowered plasma triglyceride
concentrations in some studies (Lebovitz H.E., et al.
1998)
 THIAZOLIDINEDIONES
Rosiglitazone
Regulates gene expression by binding PPAR-

Pioglitazone
Regulates gene expresion by binding PPAR-
and PPAR-

*PPAR=Peroxisome proliferator-activated receptor

 Thiazolidinediones are selective agonists of PPAR. When activated by a
ligand, such as a thiazolidinedione, PPAR binds to the 9-cis retinoic acid
receptor (RXR [retinoid X receptor]) to form a heterodimer.This binds to DNA to
regulate the genetic transcription and translation of a variety of proteins
involved in cellular differentiation and glucose and lipid metabolism
 PPARgamma agonists increase peripheral insulin sensitivity by increasing the
transcription of genes, which, in turn, increase glucose uptake, also improving insulin-
stimulated glucose disposal in muscle. PPARgamma agonists increase insulin signaling,
reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus
favoring the formation of smaller, more insulin-sensitive adipocytes.
ANTIDIURETIC DRUGS
ANTI DIURETIC HORMONE (ADH)
 Secretion of ADH to reabsorb water is
regulated by two mechanisms:
Osmoreceptors
Baroreceptors
 Osmoreceptors

located in the anterolateral hypothalamus

Changes in Posm result in cell swelling or shrinkingsignaling the release

(or prevention of the release) of ADH

At Posm below 280 mosm/kg, these cells are virtually inactive and do not
stimulate ADH secretion.

Small changes above this Posm (even of only 1%) will trigger major firing
changes in osmoreceptors

At a Posm of 290 mosm/kg, enough ADH would be secreted (5 pg/mL) to

cause a maximum retention of water, yielding Urine osm of 1250 mosm/kg

Any [ADH] above 5 pg/mL results in this same maximal antidiuresis

 Baroreceptors

Located in the carotid sinus and aortic arch

Baroreceptors must be suppressed in order to stimulate

the release of ADH

Sensory fibers from cranial nerve IX (glossopharyngeal)

and X (vagus) carry this signal from the sinus and arch
to the ADH-releasing neurons of the hypothalamus.
Baroreceptors
 The major characteristics of osmoreceptors
and baroreceptors.

Receptors Osmoreceptors Baroreceptors

anterolateral
Location carotid sinus & aortic arch
hypothalamus
Value Measured Posm circulating volume
ADH Release Stimulated
activation of receptor suppression of receptor
By
Change Required for
1% above 280 mosm/kg 10-15% decrease
Action
Resulting Amount of ADH small large
Override Other? no yes
 ACTION OF ADH
Water reabsorption:
ADH interactions with V2 receptors on the basolateral membrane
of collecting-duct principal cells.
Coupled to adenylyl cyclase by a G protien, these receptors lead to
the eventual activation of cAMP-dependent protein kinase A, which
increases water-channel insertion into the apical membrane.
The V2-receptor interactions also increase the collecting duct
permeability to urea. As a result, with ADH present, urea and
sodium ion contribute equally to the osmolality of the medullary
interstitium.

Vasoconstriction:
This action is achieved at high [ADH] and is mediated by V1
receptors on vascular smooth muscle cells
ACTION OF ADH
 Three malfunctions of the ADH
system

Central diabetes insipidus: This disease is seen when the pituitary

gland is unable to secrete ADH.

Nephrogenic diabetes insipidus: This disease is seen when the

collecting ducts are unable to respond to ADH due to a mutation in
the V2 receptor.

Syndrome of inappropriate ADH secretion (SIADH): This disease is

seen when drugs or tumors result in continued secretion of ADH or
increased action of ADH on the collecting ducts.
 ADH AGONISTS

Two peptides, ADH (Vasopressin) and

desmopressin, facilitate water reabsorption
from the collecting tubule by cAMP-
mediated insertion of water channels there.

Clinical Uses: central diabetes insipidus but

not nephrogenic diabetes insipidus.
 ADH AGONISTS
Vasopressin :
A nonpeptide with a 6-amino-acid ring and a 3-amino-acid
side chain
IV or IM
T1/2 15 minutes
Metabolism : hepar and renal
Desmopressin
A long-acting synthetic analog of vasopressin with minimal
V1 activity
IV,SC, intranasal and oral
T1/2 1,5 2,5 hours
 ADH ANTAGONIST
Hyponatremia is the most common electrolyte disorder
encountered in clinical practice, and recent data have
demonstrated that it is associated with an increase in
mortality and morbidity
The most common forms of hyponatremia encountered
in clinical practice are hypervolemic (due to congestive
heart failure or cirrhosis) and euvolemic (largely due to
the syndrome of inappropriate antidiuretic hormone
action)
 CONIVAPTAN
In 2005 the first drug that specifically antagonizes arginine
vasopressin action at the receptor level was approved (the
intravenous drug conivaptan, which antagonizes both the
vasopressin V1a and V2 receptors)

In 2009, an oral vasopressin V2 receptor antagonist, tolvaptan,

was also approved for the treatment of euvolemic and
hypervolemic hyponatremia

Both of these agents (broadly termed 'vaptans') had clinical trial data
demonstrating their efficacy in increasing serum sodium levels as well as
increasing the percentage of patients with hyponatremia who normalized their
serum sodium levels as compared with placebo ( Zeltser, et al., 2007;Schrier, et al., 2006)
Mechanism of action V2-receptor
antagonists.
The binding of arginine vasopressin to the
vasopressin V2 receptor (V2R) stimulates a
Gs-coupled protein that activates adenylyl
cyclasecausing production of cyclic
adenosine monophosphate to activate protein
kinase A.
This pathway increases the exocytosis of
vesicles containing aquaporin water channels
and inhibits endocytosis of the vesicles, both
of which result in increases in aquaporin-2
channel formation and apical membrane
insertion.
This allows an increase in the permeability of
water from the collecting duct.
Vasopressin V2 receptors block this effect,
and thus the collecting duct remains
impermeable to water and free water excretion
increases.
Conivaptan :
High affinity for both V1a and V2 receptors
Is approved by FDA : for IV adm in
hyponatremia but not in CHF
Tolvaptan :
Has a 30-fold higher affinity for V2 than
V1a receptors
THYROID AGENTS
 Thyroid Physiology

The normal thyroid gland secretes

amounts of the thyroid hormones
Triiodothyronine (T3)
Tetraiodothyronine (T4,thyroxine)
These hormon contain 59% and 65%
(respectively) of iodine
Calcitonin, the second type of thyroid
hormone
 Thyroid Physiology

The thyroid secretes about 80 micrograms of T4, but

only 5 micrograms of T3 per day.
However, T3 has a much greater biological activity
(about 10X) than T4.
An additional 25 micrograms/day of T3 is produced by
peripheral monodeiodination of T4.
Why is Iodine Important in Thyroid Hormone Production?

Thyroid hormones are unique biological molecules in that

they incorporate iodine in their structure.
Thus, adequate iodine intake (diet, water) is required for
normal thyroid hormone production.
Major sources of iodine:
- iodized salt
- iodized bread
- dairy products
Minimum requirement: 75 micrograms/day
US intake: 200 - 500 micrograms/day
 Iodine Metabolism

Dietary iodine is absorbed in the GI tract, then taken up by

the thyroid gland (or removed from the body by the
kidneys).
The transport of iodide into follicular cells is dependent
upon a sodium/iodine cotransport system.
Iodide taken up by the thyroid gland is oxidized by
peroxide in the lumen of the follicle:
peroxidase
I- I+
Oxidized iodine can then be used in
production of thyroid hormones.
 Byosynthesis of Thyroid Hormones

The thyroid hormones thyroxine (T4) and

T3 are formed within the thyroid gland
Once taken up by the thyroid gland, iodine
undergoes a series of enzymatic reactions
before it converts into active thyroid
hormones
 Thyroid Hormone Synthesis
The first step in the synthesis of thyroid
hormones is the organification of iodine
Iodide is taken up, converted to iodine, and then
condensed onto tyrosine residues which reside along the
polypeptide backbone of a protein molecule called
thyroglobulin.
This reaction results in either a mono-iodinated tyrosine
(MIT) or di-iodinated tyrosine (DIT) being incorporated
into thyroglobulin.
This newly formed iodothyroglobulin forms one of the
most important constituents of the colloid material,
present in the follicle of the thyroid unit.
Thyroid Hormone Synthesis

The other synthetic reaction, that is closely

linked to organification, is a coupling
reaction, where iodotyrosine molecules are
coupled together. If two di-iodotyrosine
molecules couple together, the result is the
formation of thyroxin (T4). If a di-
iodotyrosine and a mono-iodotyrosine are
coupled together, the result is the formation
of tri-iodothyronine (T3).
Thyroid Hormone Synthesis

The major coupling reaction is the di-

iodotyrosine coupling to produce T4. Although
T3 is more biologically active than T4, the
major production of T3 actually occurs outside
of the thyroid gland. The majority of T3 is
produced by peripheral conversion from T4 in
a deiodination reaction involving a specific
enzyme which removes one iodine from the
outer ring of T4.
 Thyroid Hormone Synthesis
The T3 and T4 released from the thyroid
by proteolysis reach the bloodstream
where they are bound to thyroid hormone
binding proteins. The major thyroid
hormone binding protein is thyroxin
binding globulin (TBG) which accounts for
about 75% of the bound hormone.
Thyroid Hormone Synthesis

In order to attain normal levels of thyroid hormone

synthesis, an adequate supply of iodine is
essential. The recommended minimum intake of
iodine is 150 micrograms a day. Intake of less
than 50 micrograms a day is associated with
goiter. High iodine levels inhibit iodide oxidation
and organification. Additionally, iodine excess
inhibits thyroglobulin proteolysis (this is the
principal mechanism for the antithyroid effect of
inorganic iodine in patients with thyrotoxicosis).
 Transport Of Thyroid Hormones

T4 and T3 in plasma are reversibly bound to

protein, primarily TBG

0,04% of total T4 and 0,4% of T3 exist in the free

form
 Anti Thyroid Agents

Antithyroid drugs were developed as derivates of thiourea

Thiourea was the first drug used in man, followed by

thiouracil (JAMA 1943)

Both compounds caused agranulocytosis in approx. 1% of

patients

PTU was found to have a lower risk of agranulocytosis,

and methimazole, introduced a few years later, in
1949,seemed to have a lower rate still
 Comparisons of PTU and
methimazole
PTU Methimazole
Serum protein binding 75% Nil
Serum half-life 75 minutes 4-6 hours
GI absorption Almost complete Almost complete
Peak serum 1 hour after ingestion 1 h after ingestion
concentration

Duration of action 12-24 h Possibly >24 h

Metabolites Glucuronide Not-well characterized
Transplancetal passage Lower Higher
Levels in breast milk lower higher
 Mechanism of Action

Inhibit iodine utilization by the thyroid Organification

(Iodine binding to Tyrosine residues in Tg)

Inhibition of Coupling of iodotyrosines . Inhibition

of T4 to T3 Conversion (PTU only) .

Possible immunosuppressive effects

Effects of Antithyroid Drugs: peripheral
Effects of Antityhroid Drugs :
intrathyroidal
 The Uses of Antithyroid Drugs

2 contexts of antithyroid drug use .

Short Term Therapy (weeks-months)
To cool down the patient prior to radioiodine.
Long-Term Therapy (1-2 years)
remission, that may or may not occur, usually
followed by radioiodine therapy
ADRENOCORTICOSTEROIDS
 Adrenocortical Hormone
Steroid molecules
Produced and released by the adrenal
cortex
Both natural and synthetic : used for the
dx and tx of disorder of adrenal function
Secretion is controlled by ACTH
 Classification of steroid
hormone
Glucocorticoids
Mineralocorticoids
In humans, the major glucocorticoid :
cortisol
the most important mineralocorticoid :
aldosterone
 Cortisol: Stress Hormone

Cortisol is a glucocorticoid hormone

synthesized from cholesterol by enzymes of the
cytochrome P450 family in the zona fasciculata,
the middle area of the adrenal cortex

cortisol is the primary hormone responsible for

the stress response
 Cortisol: Stress Hormone

Expressed at the highest levels in the early morning

Cortisols main function is to restore homeostasis following

exposure to stress

The presence of cortisol triggers the expression of enzymes critical

for gluconeogenesis, facilitating this increase in glucose
production. Conversely, it also stimulates glycogen synthesis in the
liver, which decreases net blood sugar levels
 Cortisol: Stress Hormone

Cortisol prevents cells from losing sodium

and accelerates the rate of potassium
excretion

Cortisols ability to regulate the action of

cellular sodium-potassium pumps has
even led to speculation that it originally
evolved as a sodium transporter
 Cortisol: Stress Hormone

Cortisols weakening effects on the

immune response

The hippocampus, the region of the brain

where memories are processed and
stored, contains many cortisol receptors
Mechanism of Action of Steroid
Hormones:
 Mechanism of ACTH
The hormone ACTH binds to its adrenal receptor in the zona
fasciculata, which is coupled to adenylate cyclase, thereby resulting
in phosphorylation of a cyclic adenosine monophosphate (cAMP)-
dependent protein kinase.
This protein kinase activates cholesterol ester hydroxylase, which
breaks down cholesterol esters into free fatty acids and cholesterol.
The cholesterol is transported to the mitochondria for steroid
biosynthesis. MSH also activates cholesterol ester hydroxylase, but
through a non-cAMP-dependent pathway.
Protein kinase activation also results in the synthesis of a labile
protein factor that leads to increased binding of cholesterol to
P450scc in the mitochondria.
ACTH can increase uptake of the precursor, LDL cholesterol
Mechanism of adrenocorticotropic hormone action. ( ACTH, adrenocorticotropic hormone;
cAMP, cyclic adenosine monophosphate; PK, protein kinase; CEH, cholesterol ester
hydroxylase; FFA, free fatty acids; Chol, cholesterol; CE, cholesterol esters; SCC, side chain
cleavage; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme; MSH, melanocyte-stimulating
hormone; LDL, low-density lipoprotein; AA, amino acids) (Simpson ER, Waterman MR: Steroid
hormone biosynthesis in the adrenal cortex and its regulation by adrenocorticotropin. In
DeGroot L (ed): Endocrinology, Vol 2, p 1543. Philadelphia, WB Saunders, 1989)
 Mineralocorticoids

Mineralocorticoid function (regulation of sodium and potassium levels) involves the

action of steroids that are mediated by mineralocorticoid receptors.

Aldosterone, which is secreted by the zona glomerulosa, is the primary

mineralocorticoid in humans. It is regulated by the renin-angiotensin system

other steroids also may bind to the mineralocorticoid receptors, including 11-
dedoxycortisol, corticosterone, 18-hydroxycorticosterone, and cortisol. Aldosterone
and 9-fluorocortisol (fludrocortisone), a synthetic mineralocorticoid most
commonly used for replacement purposes, have potencies approximately 3000 and
125 times greater than that of cortisol, respectively
 Mineralocorticoids

The mineralocorticoid hormone-receptor complex binds to a

chromatin-specific DNA site to produce mRNA synthesis.

The primary target for aldosterone activity is the kidney.

Mineralocorticoid excess results in excessive sodium retention,

expansion of extracellular fluid volume (weight gain), hypertension,
and hypokalemia. Mineralocorticoid deficiency results in sodium
depletion, loss of extracellular fluid, hypotension, and hyperkalemia.
 CORTICOIDS FOR ORAL &
PARENTERAL USE
Glucocorticoids: Mineralocorticoid :
Betamethasone Fludrocortisone
Betamethasone sodium acetate
phosphate (iv,im,
intralesional,intraarticular) Adrenal steroid
Cortisone inhibitors:
Dexamethasone Ketoconazole
Dexamethasone acetate Mifepristone
Hydrocortisone
Mitotane
Hydrocortisone acetate
methylprednisolone
Terimakasih