Bez nadpisu

1

• Hormones
• V. Gerl
• According to
• - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore
  Pharmacology, 5th ed.
• - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower
  Pharmacology, 6th ed.
• R.A.Howland, M.J.Mycek Lippincotts Illustrated
  Reviews Pharmacology,3rd ed.
• B.G.Katzung Basic and clinical pharmacology,
  10th ed.

2
H O R M O N E S The nervous system and the
endocrine system are the two mechanisms
coordinating body functions and transmitting
messages between individual cells and tissues.
The nervous system communicates by eletrical
impulses (act within milliseconds). In
contrast, the endocrine system releases hormones
into the blood stream, which carries these
chemical messengers to target cells through the
body. Much broader range of response times than
do nerve impulses, from seconds to days or
longer to cause a response that may last for
weeks or month. Systems are closely
interrelated.
3
Adrenocorticosteroid Hormones
4
OVERVIEW The adrenal gland cortex, medulla.
Medulla - secretes epinephrine Cortex -
steroid hormones - adrenocorticosteroids
glucocorticoids and mineralocorticoids, and the
adrenal androgens. Cortex 3 zones that
synthesize various steroids from cholesterol and
then secrete them. The outer (zona glomerulosa)
- mineralocorticoids (aldosterone) - responsible
for regulating salt and water metabolism.
Production is regulated by the renin-angiotensin
system. The middle (zona fasciculata) -
glucocorticoids (e.g., cortisol) The inner (zona
reticularis) - adrenal androgens (e.g.,
dehydroepiandrosterone). Adrenal glucocorticoids
serve as feedback inhibitors of ACTH and CRF
secretion.
5

• Secretion by the two inner zones and, to some
  extent, the outer zone - controlled by pituitary
  corticotropin (ACTH), which is released in
  response to the hypothalamic corticotropin-releasi
  ng hormone (CRH CRF corticotropin-releasing
  factor).
• Glucocorticoids - feedback inhibitors of ACTH and
  CRH.
• replacement therapy
• treatment of asthma and other inflammatory
  diseases (e.g., rheumatoid arthritis)
• treatment of severe allergic reactions
• treatment of some cancers.

6
Regulation of corticosteroid
Hypothalamus
Stress
Corticotropin- releasing factor
Anterior pituitary
Corticotropin (ACTH)
ADRENAL CORTEX
Zona glomerulosa
Aldosterone
Zona fasciculata
Cortisol
Androgens
Zona reticularis
(according to Lippincotts Pharmacology, 2006
ADRENAL MEDULLA
7
Hypothalamus
Regulation of synthesis and secretion of
adrenal corticosteroids
CRF
ADH
Long negative feedback loop
Short negative feedback loop
Anterior pituitary
Exogenous ACTH
ACTH
Metyrapone mitotane
Renin-angiotensin system
Adrenal cortex
Mineralocorticoids
Glucocorticoids
Exogenous mineralocorticoids (e.g.
fludrocortisone)
Exogenous glucocorticoids (e.g. prednisolone)
Peripheral actions (metabolic, anti-inflammatory,
immunosuppressive)
Peripheral actions on salt and water metabolism
8
Summary of adrenal corticosteroids
ADRENAL CORTICOSTEROIDS
CORTICOSTEROIDS
Beclomethasone Betamethasone Cortisone Desoxycorti
costerone Dexamethasone Fludrocortisone Hydrocorti
sone Methylprednisolone Paramethasone Prednisolone
Prednisone Triamcinolone
INHIBITORS OF ADRENOCORTICOID BIOSYNTHESIS OR
FUNCTION
Aminoglutethimide Eplerenone Ketoconazole Metyrapo
ne Mifepristone Spironolactone Trilostane
(according to Lippincotts Pharmacology, 2006
9
ADRENOCORTICOSTEROIDS Bind to specific
intracellular cytoplasmic receptors in target
tissues. Glucocorticoid receptor - widely
distributed in the body Mineralocorticoid
receptor - excretory organs (kidney, colon,
salivary and sweat glands). The receptor-hormone
complex translocates into the nucleus, where it
attaches to gene promoter elements, acting as a
transcription factor to turn genes on or off,
depending on the tissue. This requires time to
produce an effect. Other glucocorticoid effects
(e.g., interaction with catecholamines to mediate
dilation of vascular and bronchial musculature or
Ijpolysis) - effects are immediate.
10
A lipid-soluble steroid diffuses across the cell
membrane, and binds to a cytoplasmic receptor.
Gene regulation by glucocorticoids
Corticosteroid
TARGET CELL
Corticosteroid
Inactive receptor
CYTOSOL
Activated receptor complex
Receptor forms a dimer
NUCLEUS
Glucocorticoid response element
Promoter
Gene
DNA
Binding to a glucocorticoid response element
stimulates or inhibits the activity of an
adjacent promoter, which initiates or inhibits
transcription of a gene.
mRNA
mRNA
Changes in amounts of specific proteins
(according to Lippincotts Pharmacology, 2006)
Biologic effects
11

• A. Glucocorticoids
• Cortisol - the principal human glucocorticoid.
• Diurnal production - a peak early in the morning
  followed by a decline and then a secondary,
  smaller peak in the late afternoon.
• Factors (e.g., stress, levels of the circulating
  hormone influence secretion).
• The effects of glucocorticoids
• Promote normal intermediary metabolism
• Effects on metabolism, water and electrolyte
  balance
• - carbohydrate metabolism Stimuate
  gluconeogenesis by both ?
• amino acid uptake via the liver and kidney and
  promoting increased
• activity of gluconeogenic enzymes.
  Gluconeogenesis from AAs
• after splitting the proteins. Hyperglycaemia
  steroid diabetes !

12
b. Stimulation of protein catabolism (except in
the liver), decreased protein synthesis,
particularly in muscle (adynamy, hypodynamy)c.
Stimulation of lipolysis, redistribution of fat
characteristic for Cushings syndrome. Thus,
provide the building blocks and energy that are
needed for glucose synthesis. Note
Glucocorticoid insufficiency may result in
hypoglycemia (e.g., during stressful periods or
fasting). Lipolysis - a consequence of the
glucocorticoid augmenting the action of growth
hormone on adipocytes, causing ? in the activity
of hormone-sensitive lipase. Glucocorticoids
have some mineralocorticoids actions ( sodium
and water retention and potassium loss)
!!Decrease in calcium absorption from GIT,
increase in calcium excretion via kidney
osteoporosis !!
13

• d. Increase resistence to stress By ? plasma
  glucose levels they provide
• the body with the energy it requires to combat
  stress caused by, e.g.
• trauma, fright, infection, bleeding, or disease.
• Also cause a rise in blood pressure, by enhancing
  the vasoconstrictor
• action of adrenergic stimuli on small vessels.
• Note Individuals with adrenal insufficiency may
  also respond to severe
• stress by becoming hypotensive.
• e. Alter blood cell levels in plasma
• in eosinophils, basophils, monocytes, and
  lymphocytes.
• blood levels of hemoglobin, erythrocytes, and
  polymorphonuclear
• leukocytes.
• Note The decrease in circulating lymphocytes and
  macrophages ?
• a decreased ability of the body to fight
  infections !!

14
f. Anti-inflammatory and immunosupresssive
action The most important therapeutically -
ability to dramatically reduce the inflammatory
response and to suppress immunity. The exact
mechanism is complex and incompletely
understood- ? and inhibition of peripheral
lymphocytes and macrophages- indirect inhibition
of phospholipase A2 (due to the steroid-mediated
elevation of lipocortin 1 annexin), which
blocks the release of arachidonic acid.- COX-II
synthesis is ? ? ?availability of PGS. -
Interference in mast cell degranulation results
- ? histamine and capillary permeability.- ? in
inducible NO synthesis.The most pronounced
activity in the tissues of mesenchymal origin
i.e., ? in lymphocytes, ? activity of
fibroblasts, chondroblasts and osteoblasts ?
reduced healing and repair.
15
g. Negative feedback effects on the anterior
pituitary and hypothalamus inhibition of ACTH
and CRF ? inhibition of further glucocorticoid
synthesis and atrophy of the adrenal cortex !!!
After prolonged therapy it takes many months to
return to normal function. Also inhibition of TSH
production, whereas growth hormone production is
increased.
16
C. Therapeutic uses of the adrenal
corticosteroids Semisynthetic derivates of the
glucocorticoids - vary in their anti-inflammatory
potency, the degree to which they cause Na
retention, and the lenght of time of activity. 1.
Replacement therapy of primary adrenocortical
insufficiency (Addisons disease) caused by
adrenal cortex dysfunction. HYDROCORTISONE (hye
droe KOR ti sone - identical to the natural
cortisol) is given to correct the deficiency.
The dosage is divided so that two thirds of the
normal daily dose is given in the morning, and
one third in the afternoon. Note The goal is to
approximate the daily hormone levels resulting
from the circadian rhythm exhibited to cortisol
(plasma levels to be maximal around 8 A.M. and
then to decrease throughout the day to their
lowest level around 1 A.M !!! FLUDROCORTISONE
(floo droe KOR ti sone) - a synthetic
mineralocorticoid with some glucocorticoid
activity, may also be necessary to raise the
mineralocorticoid activity to normal levels.
17
2. Replacement therapy for secondary or tertiary
adrenocortical insufficiency Caused by a defect
either in CRF production by the hypothalamus or
ACTH production by the pituitary. Note the
adrenal synthesis of mineralocorticoids is less
impaired. The adrenal cortex responds to ACTH by
synthesizing and releasing the adrenal
corticosteroids. Hydrocortisone is also used. 3.
Diagnosis of Cushings syndrome Caused by a
hypersecretion of glucocorticoids (either
excessive release of ACTH or to an adrenal
tumor). Dexamethasone suppression test - used to
diagnose the cause. It suppresses cortisol
release in pituitary-dependent Cushings
syndrome, but it does not suppress release from
adrenal tumors. 4. Replacement therapy for
congenital adrenal hyperplasia (CAH) Resulting
from an enzyme defect in the synthesis of one or
more adrenal steroids hormones
administration of sufficient corticosteroids
necessary to normalize the patients hormone
levels.
18
5. Relief of inflammatory symptoms
Glucocorticoids dramatically reduce the
manifestations of inflammations (e.g., rheumatoid
and osteoarthritis inflammations, inflammatory
conditions of the skin), including the redness,
swelling, heat, and tenderness that are commonly
present at the inflammatory site. Decreased
production of PGS and leukotrienes - believed to
be central to the anti-inflammatory action.
Furthermore, the effect is associated with their
effects on the distribution, concentration, and
function of leukocytes. These include an ? in
the concentration of neutrophils, a ? in
lymphocytes (T and B cells), basophils,
eosinophils, and monocytes, and an inhibition of
the ability of leukocytes and macrophages to
respond to mitogens and antigens. Also their
abilities to reduce the amount of histamine
released by basophils and to inhibit the activity
of kinins and NO synthesis.Note The ability of
glucocorticoids to inhibit the immune response is
also a result of the other actions.
19
6. Treatment af allergies In the treatment of
the symptoms of drug, serum, and transfusion
allergic reactions, bronchial asthma, and
allergic rhinitis. These drugs are not, however,
curative. Note In aerosol - a significant
advance in asthma. Applied topically to the
respiratory tract through inhalation ? it
minimizes systemic effects and allows to reduce
or eliminate the use of oral steroids. 7.
Immunosupressive activity and used (prevention of
rejection of organs after transplantation) 8.
Hematological disorders (lymphatic leukaemia,
haemolytic anaemia) 9. GIT diseases (ulcerative
colitis, inflammatory bowel disease) 10.
Nephrotic syndrome and other autoimmune
diseases. 11. Topically in dermatology (ekzema
...) 12. Acceleration of lung maturation
Respiratory distress syndrome a problem in
premature infants. Fetal cortisol is a regulator
of lung maturation. ? Beclomethasone
administered i.m. to the mother 48 hours prior to
birth followed by a second dose 24 hours before
delivery.
20
Some therapeutic indications for the use of
glucocorticoids in nonadrenal disorders
(according to Katzung BG Basic and clinical
pharmacology, 2007)
21
(according to Katzung BG Basic and clinical
pharmacology, 2007)
22

• D. Pharmacology
• Naturally occurring adrenal corticosteroids and
  derivates - readily
• absorbed from GIT. Selected compounds can also be
  administered
• i.v., i.m., or topically. Bound to plasma
  proteins most to corticosteroid-
• binding globulin (the remainder to albumin).
  Metabolized by the liver
• microsomal oxidizing enzymes. Conjugated to
  glucuronic acid or sulfate
• excreted by the kidney.
• Note The half-life may increase dramatically in
  hepatic dysfunction.
• 2. In determining the dosage of adrenocortical
  steroids, many factors need
• to be taken into consideration, incl. activity,
  duration of action, type
• of preparation .
• When large doses of the hormone are required over
  an extended period of
• time (more than 2 weeks), suppression of the
  hypothalamic-pituitary-
• adrenal (HPA) axis occurs.
• To prevent this adverse effect, a regimen of
  alternate-day administration
• of the adrenocortical steroid may be useful. This
  schedule allows the HPA
• axis to recover function on the days the hormone
  is not taken

23
The only glucocorticoid that has no effect on the
fetus in pregnancy prednisone. It is a prodrug
that is not converted to the active compound,
prednisolone, in the fetal liver. Any
prednisolone formed in the mother is
biotransformed to prednisone by the fetus.
24
Routes of administration and elimination of
corticosteroids
IM Cortisone Desoxycorticosterone Triamcinolone I
V, IM Dexamethasone Hydrocortisone Methylprednisol
one Prednisolone
(according to Lippincotts Pharmacology, 2006
25
Glucocortifcoids
1
Hydrocortisone
1
0.8
Anti-inflammatory effect
Cortisone
0.8
Salt-retaining effect
4
Prednisone
0.3
5
Prednisolone
0.8
5
Methylprednisolone
0.5
5
Triamcinolone
0
35
Betamethasone
0
30
Dexamethasone
0
10
Paramethasone
0
Mineralocorticoids
10
Fludrocortisone
125
0
Deoxycorticosterone
(according to Lippincotts Pharmacology, 2006
20
26
Comparison of the main corticosteroid agents
(using hydrocortisone as a standard)
Approximatelly relative potency in clinical use
Duration of action after oral dose
Comments
Compound
Anti-inflammatory Sodium-retaining
Drug of choice for replacement therapy
Hydrocortisone 1
1 S
(cortisol)
Cheap inactive untill converted to
hydrocortisone not used as anti-inflammatory
because of mineralocorticoid effects
Cortisone 0.8
0.8
S
Corticosterone 0.3
15 S

Prednisolone 4
0,8 I

Drug of choice for systemic anti-inflammatory and
immunosuppressive effects
Inactive until converted to prednisolone
Prednisone 4
0,8
I
Anti-inflammatory and immunosuppressive
Methylprednisolone 5
Minimal I

Relatively more toxic than others
Triamcinolone 5
None I

27
Dexamethasone 30
Minimal L
Anti-inflammatory and immunosuppressive, used
especially where water retention is undesirable,
e.g. cerebral oedema drug of choice for
suppression of ACTH production
Anti-inflammatory and immunosuppressive, used
especially where water retention is undesirable
Betamethasone 30
Negligible L
Anti-inflammatory and immunosuppressive
effective topically and as an aerosol
Beclometasone
- -
diproprionate
Anti-inflammatory and immunosuppressive
effective topically and as an aerosol
Budesonide
-
-
Deoxycortone Negligible
50 -
Fludrocortisone 15
150 S

Drug of choice for mineralocorticoid effects
Endogenous mineralocorticoid
Aldosterone None
500 S

28
Some commonly used natural and synthetic
corticosteroids for general use
(according to Katzung BG Basic and clinical
pharmacology, 2007)
29
Some commonly used natural and synthetic
corticosteroids for general use
(according to Katzung BG Basic and clinical
pharmacology, 2007)
30

• E. Adverse effects
• Osteoporosis, impaired synthesis of collagen (?
  impaired wound
• healing) and myopathy that results from protein
  catabolism.
• Note Impaired growth in children is probably
  caused by the same
• action.
• 2. Edema, hypertension, and congestive heart
  failure due to salt and
• water retention can occur.
• 3. The CNS effects range from euphoria to
  psychoses inclidung suicidal
• tendencies. May cause a psychological dependency.
• 4. May cause stimulation of peptic ulcers.
• 5. Corticosteroids may cause development of
  iatrogenic Cushings
• syndrome, including redistribution of body fat,
  puffy face, increased
• body hair growth, acne, insomnia and increased
  appetite.

31
6. Withdrawal from the drugs can be a serious
problem, because hypothalamic-pituitary-adrenal
suppression. Abrupt removal - an acute adrenal
insufficiency syndrome that can be lethal. This
fact, coupled with the possibility of
psychological dependence and the fact that
withdrawal might cause an exacerbation of the
disease, means that the individual schedule for
withdrawal may be based on trial and error. The
patient must be carefully monitored. 7.
Hypercoagulability, raised intracranial pressure,
glaucoma, fever. 8. Suppression of response to
infection. 9. Suppression of endogenous
glucocorticoid synthesis.
32
Euphoria (though sometimes depression or
psychotic symptoms and emotional lability)
Effects of prolonged glucocorticoid excess
iatrogenic Cushings syndrome. Italicised effects
are particularly common. Less frequent effects,
related to dose and duration of therapy, are
shown in brackets.
(Benign intracranial hypertension)
Buffalo hump
(Cataracts)
Moon face, with red (plethoric) cheeks
(Hypertension)
Increased abdominal fat
Thinning of skin
(Avascular necrosis of femoral head)
Also Osteoporosis Tendency to
hyperglycaemia Negative nitrogen balance
Increased appetite Increased
susceptibility to
infection Obesity
Thin arms and legs muscle wasting
Easy bruising
Poor wound healing
(according to Rang and Dale, Pharmacology, 2007)
33
Glucocorticoids

• Drugs used hydrocortisone, prednisolone and
  dexamethasone.
• Metabolic actions
• On carbohydrates decreased uptake and
  utilisation of glucose and increased
  gluconeogenesis this causes a tendency to
  hyperglycaemia.
• On proteins increased catabolism, reduced
  anabolism.
• On fat a permissive effect on lipolytic
  hormones, and a redistribution of fat, as in
  Gushing's syndrome.

34

• Regulatory actions
• On hypothalamus and anterior pituitary a
  negative feedback a reduced release of
  endogenous glucocorticoids.
• On vascular events reduced vasodilatation,
  decreased fluid exudation.
• On cellular events
• ? in areas of acute inflammation decreased
  influx and activity of leucocytes
• ? in areas of chronic inflammation
  decreased activity of mononuclear cells,
• decreased proliferation of blood
  vessels, less fibrosis
• ? in lymphoid areas decreased clonal
  expansion of T and B cells and decreased
• action of cytokine- secreting T cells.
• On inflammatory and immune mediators
• ? decreased production and action of
  cytokines including many interleukins,
• tumour necrosis factor-g,
  granulocyte-macrophage colony-stimulating factor
• ? reduced generation of eicosanoids
• ? decreased generation of IgG
• ? decrease in complement components in the
  blood.
• Overall effects reduction in chronic
  inflammation and autoimmune reactions but also
  decreased healing and diminution in the
  protective aspects of the inflammatory response.

35
Mechanism of action of the glucocorticoids

• Interact with intracellular receptors the
  resuIting steroid-receptor complexes dimerise
  (form pairs) then interact with DNA to modify
  gene transcription inducing synthesis of some
  proteins and inhibiting synthesis of others.
• For metabolic actions, most mediator proteins are
  enzymes, e.g. cAMP-dependent kinase, but not all
  actions on genes are known.
• For anti-inflammatory and immunosuppressive
  actions, some actions at the level of the genes
  are known
• ? inhibition of transcription of the genes
  for COX-2, cytokines (e.g. interleukins), cell
  adhesion molecules and inducible form of NO
  synthase
• ? block of vitamin D3-mediated induction of
  the osteocalcin gene in
• osteoblasts and modification of
  transcription of the collagenase genes
• ? icreased synthesis of annexin-1 - an
  important factor in negative feedback on the
  hypothalamus and anterior pituitary and may have
  anti-
• inflammatory actions.
• Some non-genomic (rapid) effects of
  glucocorticoids were observed.

36
Pharmacokinetics and unwanted actions of the
glucocorticoids

• Administration can be oral, topical and
  parenteral. The drugs are bound to
  corticosteroid-binding globulin in the blood and
  enter cells by diffusion. They are metabolised in
  the liver.
• Unwanted effects are seen mainly with prolonged
  systemic use as anti-inflammatory or
  immunosuppressive agents (in which case all the
  metabolic actions are unwanted), but not usually
  with replacement therapy.
• The most important are
• ? suppression of response to infection
• ? suppression of endogenous glucocorticoid
  synthesis
• ? metabolic actions
• ? osteoporosis
• ? iatrogenic Cushing's syndrome

37
Inhibitors of adrenocorticoid biosynthesis
Several substances - useful inhibitors of the
synthesis of adrenal steroids metyrapone,
aminoglutethimide, ketoconazole, trilostane,
spironolactone, and eplerenone. Mifepristone
competes with glucocorticoids for the receptor.
38
1. Metyrapone me TEER ah pone - used for tests
of adrenal function and can be used for the
treatment of pregnant women with Gushing
syndrome. It interferes with corticosteroid
synthesis by blocking the final step
(11-hydroxylation) in glucocorticoid synthesis,
leading to an increase in 11-deoxycortisol as
well as adrenal androgens and the potent
mineralocorticoid 11-deoxycorticosterone. The
adverse effects include salt and water retention,
hirsutism, transient dizziness, and
gastrointestinal disturbances. 2.
Aminoglutethimide - inhibits the conversion of
cholesterol to pregnenolone --- the synthesis of
all hormonally active steroids is reduced. It
has been used therapeutically in the treatment of
breast cancer to reduce or eliminate androgen and
estrogen production. Note Tamoxifen has
largely replaced aminoglutethimide. In these
cases, it is used in conjunction with
dexamethasone. However, it increases the
clearance of dexamethasone. Aminoglutethimide
may also be useful in malignancies of the adrenal
cortex to reduce the secretion of steroids.
Recent studies indicate it is an aromatase
inhibitor.
39
3. Ketoconazole kee toe KON ah zole is an
antifungal agent that strongly inhibits all
gonadal and adrenal steroid hormone synthesis. It
is used in the treatment of patients with Gushing
syndrome. 4. Trilostane TRYE loe stane
reversibly inhibits 3-hydroxysteroid
dehydrogenase and, thus, affects aldosterone,
cortisol, and gonadal hormone synthesis. Its side
effects are gastrointestinal. 5. Mifepristone
At high doses - a potent glucocorticoid
antagonist as well as an antiprogestin. It forms
a complex with the glucocorticoid receptor, but
the rapid dissociation of the drug from the
receptor leads to a faulty translocation into the
nucleus. Its use is presently limited to
treatment of inoperable patients with ectopic
ACTH syndrome. Further substance MITOTANE -
derivative of DDT, decreases synthesis mainly by
a cytotoxic action used only in inoperable
tumours of the adrenal cortex.
40
MINERALOCORTICOIDS Water and electrolyte
homeostasis Help control the bodys water
volume and concentration of electrolytes,
especially sodium and potassium. ALDOSTERONE,
causing a reabsorption of Na, bicarbonate, and
water. Decreases reabsorption of K, which is
then lost in urine. Note Elevated aldosterone
levels may cause alkalosis and hypokalemia,
whereas retention of sodium and water leads to an
increase in blood volume and blood pressure.
41
Mineralocorticoids
Fludrocortisone - given orally to produce a
mineralocorticoid effect. It ? increases Na
reabsorption in distal tubules and increases K
and H efflux into the tubules ?
acts, like most steroids, on intracellular
receptors that modulate DNA
transcription causing synthesis of protein
mediators ? is used with a glucocorticoid in
replacement therapy.
42
Inhibitors of biosynthesis 1. Spironolactone
This antihypertensive drug competes for the
mineralocorticoid receptor ? inhibits Na
reabsorption in the kidney. It can also
antagonize aldosterone and testosterone
synthesis. It is effective against
hyperaldosteronism. Spironolactone is also
useful in the treatment of hirsutism in women,
probably due to interference at the androgen
receptor of the hair follicle. Adverse effects
hyperkalemia, gynecomastia, menstrual
irregularities, and skin rashes. 2. Eplerenone
e PLEA en one - binds to the mineralocorticoid
receptor i.e., aldosterone antagonist. This
specificity avoids the unwanted side effects of
spironolactone. It is approved as an
antihypertensive.
43
THYROID HORMONES They facilitate normal growth
and maturation - by maintaining a level of
metabolism in the tissues. Two major hormones -
triiodothyronine (T3 the most active form), and
thyroxine (T4). Inadequate secretion of the
hormone (hypothyroidism) - bradycardia, poor
resistance to cold, and mental and physical
slowing (in children, this can cause mental
retardation and dwarfism). Hyperthyroidism
tachycardia, cardiac arrhythmias, body wasting,
nervousness, tremor, and excess heat production
can occur. Thyroid gland also secretes
calcitonin - a serum Ca-lowering hormone.
44
Thyroid hormone synthesis and secretion TSH
action - mediated by cAMP ? stimulation of iodide
(I2) uptake. Oxidation to iodine (I-) by a
peroxidase - followed by iodination of tyrosines
on thyroglobulin. Antibodies to thyroid
peroxide diagnostic for Hashimoto thyroiditis.
Condensation of 2 iodotyrosine ? T4 or T3, bound
to the protein ? released following proteolytic
cleavage of the thyroglobulin. A. Synthesis -
uptake of plasma iodide by the follicle cells -
iodination of tyrosine (MIT and DIT) - two
molecules are coupled T3 and T4 - binding to
globulin colloid (thyroglobulin), the storage
form of thyroid hormone. - release of active
hormones (after proteolysis of thyroglobulin)
into blood
45
Biosynthesis of thyroid hormones
(according to Lippincotts Pharmacology, 2006
PLASMA
THYROID CELL
COLLOID
OH
CH2
OH
Tyrosine residues
Synthesis of thyroglobulin
2
Propylthiouracil Methimazole
CH2
Amino acids
Thyroglobulin
Elevated iodide
Uptake of iodide ion
1
H2O2
Peroxidase
I2
I-
I-
3
Iodination
I
OH
OH
CH2
HO
I
I
I
I
OH
I
O
O
I
I
I
I
I
4
Condensation
I
CH2
CH2
CH2
CH2
HO
Proteolytic release of hormones
5
C
H
H
NH3
NH3
C
I
O
COO-
COO-
I
I
Propylthiouracil Methimazole
Triidothyronine Thyroxine (T3)
(T4)
CH2
46
Regulation of secretion Secretion of TSH by the
anterior pituitary is stimulated by the
hypothalamic TRH. Feedback inhibition of TRH
occurs with high levels of circulating thyroid
hormone. Note At pharmacologic doses,
dopamine, somatostatin, or glucocorticoids can
also suppress TSH secretion. Most of T3 and T4
is bound to thyroxine-binding globulin in the
plasma. B. Mechanism of action T4 and T3 must
dissociate from thyroxine-binding plasma proteins
prior to entry into cells (by diffusion or by
active transport). In the cell, T4 is
enzymatically deiodinated to T3, which enters the
nucleus and attaches to specific receptors ?
activation of the receptors promotes the
formation of RNA and subsequent protein
synthesis, which is responsible for the effects
of T4.
47
Actions of thyroid hormonesinteraction
intracellulary with receptor causing DNA-directed
mRNA and protein synthesis/1/ affecting
metabolism (? in basal metabolism rate, heat
production, increase in oxygen consumption,
callorigenic action, modulation of action of
other hormones - e.g. catecholamines,
increase in cardiac rate ...)/2/ affecting
growth and development (particularly necessary
for normal growth and maturation of CNS,
skeletal development ...)
48
C. Pharmacokinetics T4 and T3 - absorbed after
oral administration. Food, Ca preparations, and
Al-containing antacids ? absorption of T4 but not
T3. T4 is converted to T3 by one of two distinct
deiodinases, depending on the tissue. The
hormones are metabolized through the microsomal
P450 system. Drugs that induce the P450 enzymes
(phenytoin, rifampin, phenobarbital) accelerate
metabolism of hormones.
49
Enzyme induction can increase the metabolism of
the thyroid hormones T3 triiodothyronine T4
thyroxine
T3 T4
P-450
Phenytoin Rifampin Phenobarbital
P-450
Enzyme induction
P-450
Metabolites
(according to Lippincotts Pharmacology, 2006
50
D. Treatment of hypothyroidism Usually results
from autoimmune destruction of the gland or the
peroidase and is diagnosed by elevated TSH. It
is treated with LEVOTHYROXINE (T4) leh vo thye
ROK sin or TRIIODOTHYRONINE (LIOTHYRONINE)The
drug is given once daily because of its long
half-life. Steady state is achieved in 6-8 weeks.
adverse effects - related to T4 levels - signs
of hyperthyroidism (risk of precipitating AP,
dysrhythmias, cardiac failure, nervousness, heart
palpitations and tachycardia, intolerance to
heat, unexplained weight loss).
51
E. Treatment of hyperthyreoidism
(thyrotoxicosis)Incl. Graves disease, toxic
adenoma, goiter, and thyroiditis. The goal is
to decrease synthesis and/or release of
additional hormone.- Removal of part or all of
the thyroid - Either surgically or by beta
particles emitted by radioactive iodine
(I131).Younger patients - treated with the
isotope without prior pretreatment with
methimazole elderly patients - the
opposite.Most patients become hypothyroid as a
result of this drug and require treatment with
levothyroxine.
52
Inhibition of thyroid hormone synthesis
Thioamides PROPYLTHIOURACIL (proe pill thye oh
ZOOR a sil), - METHIMAZOLE (meth IM a zole) and
CARBIMAZOLE Inhibition both the iodination of
tyrosyl groups and the coupling of
iodotyrosines to form T3 and T4. No effect on the
thyroglobulin. ? clinical effect of these
drugs may be delayed until thyroglobulin
stores are depleted. Well absorbed short
half-lives ? several doses required per day of
PTU a single dose of methimazole suffices .
Relatively rare adverse effects agranulocytosis,
rash, and edema. Not effective in the
treatment of thyroid storm. Relapse may occur.
53
Blockade of hormone release Pharmacological
(i.e. high) dose of IODIDE inhibits the
iodination of tyrosines, also inhibits thyroid
hormone release by mechanisms not yet
understood. Employed to treat potentially fatal
thyrotoxic crisis (thyroid storm), or it is
used prior to surgery (it decreases the
vascularity of the thyroid gland). Not useful
for long-term therapy - since the thyroid ceases
to respond to the drug after a few weeks.
Administered orally. Adverse effects are
relatively minor, sore mouth, rashes,
ulcerations and a metalic taste. Blockade of
peripheral effects of thyroid hormones Mainly
sympathetic blocking drugs (beta-blockers)
54
Thyroid storm b-Blockers that lack
sympathomimetic activity (e.g., propranolol) -
effective in blunting the widespread sympathetic
stimulation that occurs in hyperthyroidism. I.v.
administration is effective in treating thyroid
storm. An alternative in patients suffering
from severe heart failure or asthma is the
calcium channel blocker, diltiazem.
55
INSULIN AND ORAL HYPOGLYCEMIC DRUGS Pancreas -
endocrine gland (peptide hormones insulin,
glucagon, and somatostatin) and exocrine gland
(digestive enzymes). Peptide hormones - from
cells Langerhans islets(ß or B-cells -insulin, a2
or A-cells - glucagon, and a1 or D-cells -
somatostatin). Hormones play an important role
in regulating the metabolic activities of the
body, particularly the homeostasis of blood
glucose. Hyperinsulinemia (due, e.g., to an
insulinoma) ? severe hypoglycemia. More commonly
- relative or absolute lack of insulin e.g. in
diabetes mellitus ? hyperglycemia, if untreated ?
retinopathy, nephropathy, neuropathy,
cardiovascular complications.
56
Metabolic roles of insulin and glucagon High
serum glucose ? ? insulin release from beta cells
of the pancreas. Increased serum insulin ?
lower blood glucose levels by driving
carbohydrate into cells. Low serum glucose ? ?
in insulin and ? glucagon. Elevated serum
glucagon ? mobilization of energy storage forms.
Used to fuel gluconeogenesis in the liver,
producing glucose. Somatostatin - regulates (by
local, paracrine inhibitory regulation the
secretion of insulin and glucagon within the
islets).
57
Clinical uses of glucagon

• Glucagon can be administered i.m. or s.c. as well
  as i.v.
• Treatment of hypoglycaemia in unconscious
  patients (who cannot drink) unlike i.v. glucose
  it can be administered by non-medical personnel
  (e.g. spouses or ambulance crew). It is also
  useful if there is difficulty in obtaining i.v.
  access.
• Treatment of acute cardiac failure precipitated
  by injudicious use of b-adrenoceptor antagonists
  where it will increase the force of contraction
  of the heart (positive inotropic action).

58
Summary of hypoglycemic agents
HYPOGLYCEMIC DRUGS
INSULIN
Aspart insulin Extended zinc insulin Glargine
insulin Glulisine insulin Insulin zinc
suspension Lispro insulin NPH insulin
suspension Protamine zinc insulin Semilente
insulin Ultralente insulin
ORAL HYPOGLYCEMIC DRUGS
Glipizide Glimepiride Glyburide Metformin Nateglin
ide Pioglitazone Repaglinide Rosiglitazone Tolbuta
mide Troglitazone
a-GLUCOSIDASE INHIBITORS
Acarbose Miglitol
(according to Lippincotts Pharmacology, 2006
GASTROINTESTINAL HORMONES
Exenatide
59
DIABETES MELLITUS Rapidly growing incidence (135
million people worldwide are afflicted with Type
2). In USA - 20 million people - a major cause of
morbidity and mortality. Diabetes is not a
single disease - it is a heterogeneous group of
syndromes characterized by an elevation of blood
glucose caused by a relative or absolute
deficiency of insulin. Insulin-dependent
diabetes mellitus (Type 1), and
non-insulin-dependent diabetes mellitus (Type
2). Other types of diabetes have also been
identified.
60
E.g., maturity-onset diabetes of the young (MODY)
- Type 3 diabetes - heterogeneous group -
dysregulation of glucose sensing or insulin
secretion is due to mutations of particular
genes. It is inherited in an autosomally dominant
fashion, is nonketotic. Occurs before 25 years of
age patients are not obese insulin resistance
and hypertriacylglycerolemia are absent. About
1-5 of all diabetes cases. Treatment varies
with the type of MODY. Gestational diabetes -
Type 4 - glucose intolerance associated with
pregnancy. It is important to maintain tight
glycemic control close to the normal range during
pregnancy, because hyperglycemia can lead to
congenital abnormalities in the fetus. Diet,
exercise, and/or insulin administration are
effective in this condition.
61

• Type 1 diabetes (insulin-dependent diabetes
  mellitus)
• Around the puberty but can occur at any age -
  10-20 of diabetics. Absolute deficiency of
  insulin caused by massive ß-cell necrosis.
• Loss of b-cell function - usually
  autoimmune-mediated processes directed against
  the b-cell. It may be triggered by viruses or
  chemical toxins.
• pancreas fails to respond to glucose - classic
  symptoms of insulin deficiency (polydipsia,
  polyphagia, polyuria, and weight loss).
• It requires exogenous insulin to avoid the
  catabolic state - hyperglycemia and
  life-threatening ketoacidosis.
• Type 1 can neither maintain a basal secretion
  level of insulin nor respond to variations in
  circulating fuels.
• Development and progression of neuropathy,
  nephropathy, retinopathy - related to the extent
  of glycemic control (blood levels of glucose
  and/or glycosylated hemoglobin A1c).

62
Treatment Exogenous (injected) insulin to
control hyperglycemia, avoid ketoacidosis, and
maintain acceptable levels of glycosylated
hemoglobin (HbA1c). ? to maintain blood glucose
as close to normal as possible, and to avoid wide
swings in their levels (that contribute to
long-term complications). Frequent
self-monitoring and treatment by insulin.
Continuous s.c. insulin infusion (insulin pump)
- eliminates multiple daily injections
programmed to deliver the basal rate of insulin
secretion. It also allows to control delivery of
a bolus of insulin to compensate for high blood
glucose or in anticipation of postprandial needs.
Inhaled forms - in trial. Pancreas
transplantation transplantation of islet cells -
also under investigation.
63
Type 2 diabetes (non-insulin-dependent diabetes
mellitus) maturity onset - most diabetics.
Influenced by genetic factors, aging, obesity,
and peripheral insulin resistance rather than by
autoimmune processes or viruses. The metabolic
alterations observed are milder than those in
Type 1 (e.g., patients typically are not
ketotic). But long-term consequences can be
devastating (e.g., vascular complications,
subsequent infection ? amputation of the lower
limbs). Pancreas retains some ß-cell function,
but variable insulin secretion is insufficient to
maintain glucose homeostasis. ß-cell mass may
become gradually reduced. Often obese.
Frequently lack of sensitivity of target organs
to either endogenous or exogenous insulin ? the
resistance to insulin - considered to be a major
causation of this type of diabetes - sometimes
referred to as "metabolic syndrome."
64
Treatment To maintain blood glucose within
normal limits and to prevent the development of
complications. Weight reduction, exercise,
dietary modification - decrease insulin
resistance and correct the hyperglycemia in some
patients. Mostly dependent on oral hypoglycemic
agents. As the disease progresses, b-cell
function declines, and insulin therapy is often
required to achieve satisfactory serum glucose
levels.
65
1 Insulin resistance in peripheral tissues
Major factors contributing to hyperglycemia
observed in Type 2 diabetes
LIVER
Increased production of glucose
Glucose
Decreased glucose uptake
ADIPOSE TISSUE
MUSCLE
2 Inadequate insulin secreation from b cells
Insulin
(according to Lippincotts Pharmacology, 2006
PANCREAS
66
Comparison of Type 1 and Type 2 diabetes
Type 2 (Non-insulin- dependent diabetes)
Type 1 (Insulin-dependent diabetes)
Frequently over age 35 Obesity usually present
80 to 90 percent of diagnosed diabetics Very
strong Inability of b cells to produce
appropriate quantities of insulin insulin
resistance other defects
Usually during childhood or puberty Frequently
undernourished 10 to 20 percent of diagnosed
diabetics Moderate b Cells are destroyed,
eliminating the production of insulin
Age of onset Nutritional status at time of
onset Prevalence Genetic predisposition Defect
or deficiency
(according to Lippincotts Pharmacology, 2006
67
INSULIN AND ITS ANALOGS IN su lin polypeptide
hormone two peptide chains connected by
disulfide bonds. Synthesized as a precursor
(pro-insulin) ? proteolytic cleavage ? insulin
and peptide C - both are secreted by b-cells.
Note Normal individuals secrete less
pro-insulin than insulin Type 2 secrete high
levels of the prohormone. RIAs do not distinguish
between these two types ? Type 2 may have lower
levels of insulin than the assay indicates ?
measurement of circulating C peptide a better
index of insulin levels. Sources Human
insulin - replaced I. from beef or pork pancreas.
By recombinant DNA technology - special strains
of E. coli or yeast - genetically altered to
contain the gene for human insulin.
Modifications of amino acid sequence ? different
pharmacokin. properties insulins-lispro, aspart,
and glulisine - faster onset and shorter duration
of action than regular insulin (they do not
aggregate or form complexes). insulin glargine
and insulin detimir - long-acting, prolonged,
flat levels of the hormone following a single
injection.
68

• Insulin secretion
• Regulated not only by blood glucose but also by
  certain amino acids, other hormones, and
  mediators.
• Triggered by high blood glucose it is taken up
  by glucose transporter into b-cells - there
  phosphorylated by glucokinase - products of
  glucose metabolism enter the mitochondrial
  respiratory chain generation of ATP.
• in ATP ? block of K channels ? membrane
  depolarization ? influx of Ca2 ? insulin
  exocytosis (some oral antidiabetics
  sulfonylureas, meglitinides - hypoglycemic effect
  due to inhibition of the K channels).
• Note Glucose by injection - a weaker effect on
  insulin secretion than orally - orally, glucose
  stimulates production of digestive hormones by
  the gut, which in turn stimulate insulin
  secretion by the pancreas.

69
Administration Polypeptide ? degraded in GIT if
taken orally ? mostly by subcutaneous injection
(in a hyperglycemic emergency, regular insulin
intravenously - its plasma half-life 9 minutes
). Continuous s.c. infusion also - it does not
require multiple injections. Aerosol preparation
(inhaled and absorbed in the deep lung) or oral
spray (absorbed through the buccal mucosa) - in
trials Preparations vary in their onset and in
durations of activity (due to the size and
composition of the insulin crystals and AA
sequences - the less soluble the longer action).
Dose, site of injection, blood supply,
temperature, and physical activity can affect the
duration of action of the various preparations.
Inactivated by the reducing enzyme, insulinase
(mainly in the liver and kidney).
70

• Adverse reactions to insulin
• - Symptoms of hypoglycemia - the most serious and
  common adverse reactions to an overdose
• Long-term diabetics - often do not produce
  adequate amounts of the counter-regulatory
  hormones (glucagon, epinephrine, cortisol,
  growth hormone) - which normally provide an
  effective defense against hypoglycemia.
• - Lipodystrophy (less common with human insulin)
• - Allergic reactions
• - Adjust doses of insulin in diabetics with renal
  insufficiency.

71
INSULIN PREPARATIONS AND TREATMENT To do any
change in insulin treatment cautiously.
72
A. Rapid-onset and short-acting preparations
Regular insulin - short-acting, soluble,
crystalline zinc insulin. Usually s.c. (i.v. in
emergencies) rapidly ? blood sugar. Safely used
in pregnancy (use of other 3 preparations only if
clearly needed). Effect - within 30 min peaks
between 2 - 3 hours after s.c. injection lasts
5-8 hours. When administered at mealtime, the
blood glucose rises faster than the insulin with
resultant early postprandial hyperglycemia and an
increased risk of late postprandial hypoglycemia
? should be injected 30-45 or more min before the
meal to minimize the mismatching. The duration
of action and the time of onset and the intensity
of peak action increase with the size of the
dose. Clinically, this is a critical issue
because the pharmacokinetics and pharmacodynamics
of small doses of regular and NPH insulins differ
greatly from those of large doses. Particularly
useful for i.v. therapy in the management of
diabetic ketoacidosis and when the insulin
requirement is changing rapidly, e.g. after
surgery or during acute infections.
73
Rapid-acting insulin Three injected rapid-acting
insulin analogs insulin lispro, insulin aspart,
and insulin glulisine, and one inhaled form of
rapid-acting insulin, human insulin recombinant
inhaled, are commercially available. More
physiologic prandial insulin replacement (their
rapid onset and early peak action more closely
mimic normal endogenous prandial insulin
secretion than regular insulin) additional
benefit allowing insulin to be taken immediately
before the meal without sacrificing glucose
control. Duration of action is rarely more than
3-5 hours (with the exception of inhaled insulin,
which may last 6-7 hours), which decreases the
risk of late postmeal hypoglycemia. Injected
rapid-acting insulins have the lowest variability
of absorption (approximately 5) of all insulins
(compared to 25 for regular insulin and 25-50
for intermediate- and long-acting formulations).
Preferred for use in continuous s.c. insulin
infusion devices.
74
Insulin lispro LIS proe, insulin aspart AS
part, insulin glulisine gloo LYSE een rapid
onset and short duration of action -
ultrashort-acting insulins possibility of more
flexible treatment regimens and ? risk of
hypoglycemia. Lispro insulin

differs from
regular insulin in that lysine and proline at
positions 28 and 29 in the B chain are reversed ?
more rapid absorption after s.c. inj. than after
regular insulin ? acts more rapidly and has
shorter duration of activity. Usually 15 mins
prior to a meal, peak levels - 30 to 90 mins
after inj. (regular insulin 50 to 120 mins). Also
for i.v. administration. Advantage - low
propensity (in contrast to human insulin) to
self-associate in antiparallel fashion and form
dimers. Rapidly absorbed (onset of action 5-15
min peak activity 1 hour).
75
Aspart insulin and glulisine insulin -

pharmacokinetic and pharmacodynamic properties
similar to lispro Aspart insulin - by
substitution of the B28 proline with aspartic
acid ? it reduces insulin self-aggregation.
Absorption and activity profile - similar to
insulin lispro more reproducible than regular
insulin. Insulin glulisine - by substituting an
asparagine for lysine at B3 and glutamic acid for
lysine at B29. Absorption, action, immunologic
characteristics are similar to other injected
rapid-acting insulins. Administered to mimic
the prandial (mealtime) release of insulin
usually not used alone but with a longer-acting
insulin to assure glucose control (e.g.,
glulisine can be taken either 15 min before or
within 20 min after starting a meal). Administered
s.c. Note Uspro insulin - preferred for
external insulin pumps over the buffered form of
regular insulin - it does not form hexamers.
However, reports of precipitation of lispro
insulin in infusion catheters were described,
resulting in fluctuations in glucose control.
76
Inhaled human insulin - a powder form of rDNA
human insulin administered through an inhaler
device marketed for pre-prandial and blood sugar
correction use in adults with type 1 and 2
diabetes not approved for use in children,
teenagers, or adults with asthma, bronchitis,
emphysema, smokers, or those within 6 months of
quitting smoking (because of concerns about lung
safety) Although this route of administration is
well tolerated, studies have shown that less than
30 of users were able to achieve target blood
glucoses after 6 months of therapy with inhaled
human insulin.
77
B. Intermediate-acting insulin preparations 1.
Lente insulin Amorphous precipitate of insulin
with zinc ion in acetate buffer combined with 70
ultralente insulin. Onset and peak effect -
slower than in regular insulin, but are sustained
for a longer period. Not suitable for i.v. 2.
Isophane NPH insulin suspension

Neutral protamine Hagedorn (NPH) insulin (also
called isophane insulin) - suspension of
crystalline zinc insulin combined with
polypeptide, protamine. Intermediate duration of
action (due to delayed absorption of the insulin
- complex with protamine is less-soluble
complex). Onset cca 2-5 hours duration of 4-12
hours Only s.c. (never i.v.). Use in all forms of
diabetes except diabetic ketoacidosis or
emergency hyperglycemia. Usually given along with
regular lispro, aspart, or glulisine insulin.
Given 2-4 times daily in patients with type 1
diabetes. /Note A similar compound called
neutral protamine Iyspro (NPL) insulin/
78
C. Prolonged-acting insulin preparations 1.
Ultralente insulin (extended zinc insulin)
Suspension of
zinc insulin crystals in acetate buffer ? large
particles that are slow to dissolve ? slow onset
of action and long-Iasting effect 2. Insulin
glargine (GLAR geen)

Precipitation at the injection site ? longer
action. Slower onset than NPH insulin flat,
prolonged hypoglycemic effect (i.e., it has no
peak ). Slow onset of action (1-1.5 hours)
maximum effect after 4-6 hours. This maximum
activity is maintained for 11-24 hours or longer.
Must be given s.c. Insulin detemir ( deh TEE
meer) - in clinical trials, it has a fatty-acid
side chain (it associates with tissue-bound
albumin at the injection site properties similar
to insulin glargine). Has the most reproducible
effect of the intermediate- and long-acting
insulins, and its use is associated with less
hypoglycemia than NPH insulin. Dose-dependent
onset of 1-2 hours duration of action of more
than 24 hours. Given twice daily to obtain a
smooth background insulin level.
79
D. Insulin combinations Premixed combinations of
human insulins (e.g., 70 NPH insulin 30
regular insulin 50 of each of these 75 NPL
insulin 25 lispro ).
80
Standard treatment - injection of insulin twice
daily. This results in mean blood glucose in the
range of 225 to 275 mg/dL, with HbA1c of 8 9
of total hemoglobin. Intensive treatment - to
normalize blood glucose through more frequent
injections of insulin (3 or more times daily in
response to monitoring blood glucose). Mean blood
glucose levels of 150 mg/dL can be achieved with
intensive treatment, with an HbA1c of
approximately 7 of total Hb. Note Normal
mean blood glucose is approximately 110 mg/dL or
less, with an HbA1c of 6 or less. ? total
normalization of blood glucose is not achieved,
and the frequency of hypoglycemic episodes, coma,
and seizures due to excessive insulin is
particularly high with intensive treatment
regimens. Nonetheless, patients on intensive
therapy show 60 reduction in the long-term
complications of diabetes-retinopathy,
nephropathy, and neuropathy-compared to standard
care.
81
Onset and duration of action of human insulin and
insulin analogs.
Aspart insulin, lispro insulin
Glulisine insulin
Regular insulin
NPH insulin
Extended zinc insulin
Glargine insulin
Relative plasma insulin level
0 6
12
18 24
Hours
(according to Lippincotts Pharmacology, 2006)
82
Clinical uses of insulin

• Patients with type 1 DM require long-term
  maintenance treatment with insulin. An
  intermediate-acting preparation (e.g. isophane
  insulin) is often combined with a short- acting
  preparation (e.g. soluble insulin) taken before
  meals.
• Soluble insulin is used (i.v.) in emergency
  treatment of hyperglycaemic diabetic emergencies
  (e.g. diabetic ketoacidosis).
• Many patients with type 2 DM ultimately require
  insulin treatment.
• Short-term treatment of patients with type 2 DM
  or impaired glucose tolerance during intercurrent
  events (e.g. operations, infections, myocardial
  infarction).
• During pregnancy, for gestational diabetes not
  controlled by diet alone.
• Emergency treatment of hyperkalaemia insulin is
  given with glucose to lower extracellular K via
  redistribution into cells.

83
ORAL HYPOGLYCEMIC AGENTS INSULIN SECRETAGOGUES
Useful in the treatment of Type 2
(non-insulin-dependent) diabetes but cannot be
managed by diet alone. The patient most likely
to respond well to oral hypoglycemic agents is
one who develops diabetes after age 40 and has
had diabetes less than 5 years. Patients with
long-standing disease may require a combination
of hypoglycemic drugs with or without insulin to
control their hyperglycemia. The hormone is
added because of the progressive decline in
ß-cells that occurs due to the disease or aging.
Oral hypoglycemic agents should not be given to
patients with Type 1 diabetes.
84
A. Sulfonylureas Insulin secretagogues (they
promote insulin release from the b-cells). 1.
Mechanisms of action of the sulfonylureas 1)
stimulation of insulin release from the ß-cells
blocking the ATP-sensitive K channels, resulting
in depolarization and Ca2 influx 2) reduction
of serum glucagon levels and 3) increasing
binding of insulin to target tissues and
receptors. 2. Pharmacokinetics and fate Given
orally bind to serum proteins metabolized by
the liver excreted by the liver or kidney.
Tolbutamide has the shortest
duration of action (6-12 hours),whereas the
second-generation agents last about 24 hours.
1st generation TOLBUTAMIDE (tole BYOO ta
mide), CHLORPROPAMIDE (klor PROE pa mide),
TOLAZAMIDE (tole AZ a mide), ACETOHEXAMIDE (a
seat oh HEX a mide), 2nd generation
GLIBENCLAMIDE, GLYBURIDE (GLYE byoor ide)
GLIPIZIDE (GLIP i zide), GLIMEPIRIDE
85

• Administration, fate given orally, metabolized
  by the liver, and excreted by the liver or
  kidney. Contraindicated in patients with hepatic
  or renal insuficiency (delayed excretion of the
  drug may cause hypoglycemia).
• Renal impairment - particular problem in agents
  that are metabolized to active compounds (e.g.,
  glyburide and glimepiride). They traverse the
  placenta - can deplete insulin from the fetal
  pancreas ? pregnant women with Type 2 diabetes
  should be treated with insulin.
• All bind strongly to plasma albumins
  interactions with other drugs (e.g. salicylates,
  sulfonamides) which compete for binding sites
  hypoglycaemia Not used in type I diabetes.
• Adverse effects
• - hypoglycemia
• - disulfiram-like reactions (flushing, nausea,
  headache after alcohol)
• - allergic reactions
• GIT disturbances
• weight gain, hyperinsulinemia, and hypoglycemia

86
Drugs interacting with sulfonylurea drugs
Sulfonylureas
Allopurinol Probenecid Phenylbutazone Salicylates
Sulfonamides
Clofibrate Phenylbutazone Salicylates Sulfonamides
Decrease urinary excretion of sulfonylureas
or their metabolites
Displace sulfonyl- ureas from plasma protein
Increased hypoglycemic action of sulfonylurea
drugs
Reduce hepatic metabolism of sulfonylureas
Dicumarol Chloramphenicol Monoamine oxidase
inhibitors Pnehylbutazone
(according to Lippincotts Pharmacology, 2006
Sulfonylureas
87
B. Meglitinide analogs repaglinide re PAG lin
ide and nateglinide nuh TAY gli nide. Although
they are not sulfonylureas, they have common
actions. 1. Mechanism of action Action is
dependent on functioning b-cells. They bind to a
distinct site on the sulfonylurea receptor of
ATP-sensitive K channels ? series of reactions
culminating ? release of insulin. In contrast to
the sulfonylureas - they have a rapid onset and
short duration of action. They are particularly
eff