V. GeršlV. Geršl
- 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: Lippincott’s Illustrated Reviews: Pharmacology,3rd ed.
- B.G.Katzung: Basic and clinical pharmacology, 10th ed.
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.
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.,
Adrenal glucocorticoids serve as feedback inhibitors of ACTH and CRF
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-releasing hormone (CRH = CRF
Glucocorticoids - feedback inhibitors of ACTH and CRH.
- replacement therapy;
- treatment of asthma and other inflammatory diseases (e.g., rheumatoid
- treatment of severe allergic reactions;
- treatment of some cancers.
Regulation of corticosteroidRegulation of corticosteroid
Zona glomerulosaZona glomerulosa
Zona fasciculataZona fasciculata
Zona reticularisZona reticularis
Lippincott´s Pharmacology, 2006
Anterior pituitaryAnterior pituitary
Exogenous glucocorticoidsExogenous glucocorticoids
(e.g. prednisolone)(e.g. prednisolone)
Exogenous mineralocorticoidsExogenous mineralocorticoids
(e.g. fludrocortisone)(e.g. fludrocortisone)
Peripheral actions (metabolic,Peripheral actions (metabolic,
anti-inflammatory, immunosuppressive)anti-inflammatory, immunosuppressive)
Peripheral actions on saltPeripheral actions on salt
and water metabolismand water metabolism
Short negativeShort negative
feedback loopfeedback loop
Long negativeLong negative
feedback loopfeedback loop
secretion of adrenal
Summary of adrenalSummary of adrenal
ADRENAL CORTICOSTEROIDSADRENAL CORTICOSTEROIDS
INHIBITORS OF ADRENOCORTICOIDINHIBITORS OF ADRENOCORTICOID
BIOSYNTHESIS OR FUNCTIONBIOSYNTHESIS OR FUNCTION
(according to(according to
Lippincott´s Pharmacology, 2006Lippincott´s Pharmacology, 2006
Bind to specific intracellular cytoplasmic receptors in target tissues.
Glucocorticoid receptor - widely distributed in the body;
Mineralocorticoid receptor - excretory organs (kidney, colon, salivary and
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
Other glucocorticoid effects (e.g., interaction with catecholamines to
mediate dilation of vascular and bronchial musculature or Ijpolysis) -
effects are immediate.
(according to Lippincott´s
Receptor forms a
Changes in amounts of specific proteins
A lipid-soluble steroid
diffuses across the cell
membrane, and binds to a
Binding to a glucocorticoid
response element stimulates
or inhibits the activity of an
adjacent promoter, which
initiates or inhibits
transcription of a gene.
Gene regulation by 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:
1. Promote normal intermediary metabolism:
a. 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 !
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
Cushing´s 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
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 !!
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
Note: The decrease in circulating lymphocytes and macrophages ⇒
a decreased ability of the body to fight infections !!
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
osteoblasts ⇒ reduced healing and repair.
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.
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
(Addison´s 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.
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 Cushing´s 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 Cushing´s 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 patient´s hormone levels.
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.
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
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
⇒ Beclomethasone administered i.m. to the mother 48 hours prior to
birth followed by a second dose 24 hours before delivery.
Some therapeutic indications for the use of glucocorticoids in nonadrenal
Allergic reactions Angioneurotic edema, asthma, bee stings, contact
dermatitis, drug reactions, allergic rhinitis, serum sickness,
Collagen-vascular disorders Giant cell arteritis, lupus erythematosus, mixed connective
tissue syndromes, polymyositis, polymyalgia rheumatica,
rheumatoid arthritis, temporal arteritis
Eye diseases Acute uveitis, allergic conjunctivitis, choroiditis, optic
Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute
Hematologic disorders Acquired hemolytic anemia, acute allergic purpura,
leukemia, autoimmune hemolytic anemia, idiopathic
thrombocytopenic purpura, multiple myeloma
Systemic inflammation Acute respiratory distress syndrome (sustained therapy
with moderate dosage accelerates recovery and decreases
(according to Katzung BG: Basic and clinical pharmacology, 2007)
Infections Acute respiratory distress syndrome, sepsis, systemic
Inflammatory conditions of
bones and joints
Arthritis, bursitis, tenosynovitis
Neurologic disorders Cerebral edema (large doses of dexamethasone are given
to patients following brain surgery to minimize cerebral
edema in the postoperative period), multiple sclerosis
Organ transplants Prevention and treatment of rejection (immunosuppresion)
Pulmonary diseases Aspiration pneumonia, bronchial asthma, prevention of
infant respiratory distress syndrome, sarcoidosis
Renal disorders Nephrotic syndrome
Skin diseases Atopic dermatitis, dermatoses, lichen simplex chronicus
(localized neurodermatitis), mycosis fungoides,
pemphigus, seborrheic dermatitis, xerosis
Thyroid diseases Malignant exophthalmos, subacute thyroiditis
Miscellaneous Hypercalcemia, mountain sickness
(according to Katzung BG: Basic and clinical pharmacology, 2007)
Naturally occurring adrenal corticosteroids and derivates - readily
sorbed from GIT. Selected compounds can also be administered
., i.m., or topically. Bound to plasma proteins: most to corticosteroid-
nding globulin (the remainder to albumin). Metabolized by the liver
crosomal oxidizing enzymes. Conjugated to glucuronic acid or sulfate;
creted by the kidney.
ote: The half-life may increase dramatically in hepatic dysfunction.
In determining the dosage of adrenocortical steroids, many factors need
be taken into consideration, incl. activity, duration of action, type
hen large doses of the hormone are required over an extended period of
me (more than 2 weeks), suppression of the hypothalamic-pituitary-
renal (HPA) axis occurs.
o prevent this adverse effect, a regimen of alternate-day administration
the adrenocortical steroid may be useful. This schedule allows the HPA
is to recover function on the days the hormone is not taken
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.
Routes of administration and elimination of corticosteroids
IV, IMIV, IM
(according to(according to
Lippincott´s Pharmacology, 2006Lippincott´s Pharmacology, 2006
Comparison of the main corticosteroid agents (using hydrocortisone as a standard)
Hydrocortisone 1 1 S1 1 S
Approximatelly relative potency
in clinical use:
Duration ofDuration of
action afteraction after
oral doseoral dose
Drug of choice forDrug of choice for
replacement therapyreplacement therapy
Cortisone 0.8 0.8 S0.8 0.8 S Cheap; inactive untillCheap; inactive untill
converted toconverted to
hydrocortisone; not used ashydrocortisone; not used as
anti-inflammatory becauseanti-inflammatory because
of mineralocorticoid effectsof mineralocorticoid effects
Corticosterone 0.3 15 SCorticosterone 0.3 15 S
Prednisolone 4 0,8 I4 0,8 I Drug of choice for systemic
Prednisone 4 0,8 I4 0,8 I Inactive until converted to
Methylprednisolone 5 Minimal I5 Minimal I Anti-inflammatory andAnti-inflammatory and
Triamcinolone 5 None I5 None I Relatively more toxic than
Dexamethasone 30 Minimal L30 Minimal L Anti-inflammatory and
especially where water
retention is undesirable,
e.g. cerebral oedema; drug
of choice for suppression
of ACTH production
Betamethasone 30 Negligible L30 Negligible L Anti-inflammatory and
especially where water
retention is undesirable
Beclometasone + - -+ - -
effective topically and as
Budesonide + - -+ - - Anti-inflammatory andAnti-inflammatory and
effective topically and aseffective topically and as
an aerosolan aerosol
Deoxycortone Negligible 50 -Deoxycortone Negligible 50 -
Fludrocortisone 15 150 S15 150 S Drug of choice forDrug of choice for
mineralocorticoid effectsmineralocorticoid effects
Aldosterone None 500 SAldosterone None 500 S EndogenousEndogenous
Some commonly used natural and synthetic corticosteroids for general use
SHORT-TO MEDIUM-ACTING GLUCOCORTICOIDS
Hydrocortisone (cortisol) 1 1 1 20
Cortisone 0.8 0 0.8 25
Prednisone 4 0 0.3 5
Prednisolone 5 4 0.3 5
Methylprednisolone 5 5 0 4
Meprednisone 5 0 4
Triamcinolone 5 5 0 4
Paramethasone 10 0 2
Fluprednisolone 15 7 0 1.5(according to Katzung BG: Basic and clinical pharmacology, 2007)
Some commonly used natural and synthetic corticosteroids for general use
Betamethasone 25-40 10 0 0.6
Dexamethasone 30 10 0 0.75
Fludrocortisone 10 0 250 2
0 0 20
(according to Katzung BG: Basic and clinical pharmacology, 2007)
. Adverse effects
Osteoporosis, impaired synthesis of collagen (⇒ impaired wound
ealing) and myopathy that results from protein catabolism.
ote: Impaired growth in children is probably caused by the same
Edema, hypertension, and congestive heart failure due to salt and
ater retention can occur.
The CNS effects range from euphoria to psychoses inclidung suicidal
ndencies. May cause a psychological dependency.
May cause stimulation of peptic ulcers.
Corticosteroids may cause development of iatrogenic Cushing´s
yndrome, including redistribution of body fat, puffy face, increased
ody hair growth, acne, insomnia and increased appetite.
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.
Euphoria (though sometimes depression or psychotic
symptoms and emotional lability)
Moon face, with red
of femoral head)
Thin arms and
Effects of prolonged
syndrome. Italicised effects
are particularly common.
Less frequent effects,
related to dose and
duration of therapy, are
shown in brackets.
Tendency to hyperglycaemia
Negative nitrogen balance
Increased susceptibility to
(according to Rang and Dale, Pharmacology, 2007)
Drugs used: hydrocortisone, prednisolone and dexamethasone.
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.
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-γ, 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
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
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-
Some non-genomic (rapid) effects of glucocorticoids were observed.
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
The most important are:
― suppression of response to infection
― suppression of endogenous glucocorticoid synthesis
― metabolic actions
― iatrogenic Cushing's syndrome
Inhibitors of adrenocorticoid biosynthesis
Several substances - useful inhibitors of the synthesis of adrenal steroids:
metyrapone, aminoglutethimide, ketoconazole, trilostane, spironolactone,
Mifepristone competes with glucocorticoids for the receptor.
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
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.
Water and electrolyte homeostasis: Help control the body´s
water volume and concentration of electrolytes, especially sodium and
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.
Fludrocortisone - given orally to produce a mineralocorticoid effect. It:
― increases Na+
reabsorption in distal tubules and increases K+
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.
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
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
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.
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
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.]
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.
- 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
- release of active hormones (after proteolysis of thyroglobulin) into
Biosynthesis of thyroid hormonesBiosynthesis of thyroid hormones
PLASMAPLASMA THYROID CELLTHYROID CELL COLLOIDCOLLOID
22 Synthesis ofSynthesis of
Uptake ofUptake of
iodide ioniodide ion
55 Proteolytic release ofProteolytic release of
II II II
II II II II
Triidothyronine ThyroxineTriidothyronine Thyroxine
(T(T33) (T) (T44))
Amino acidsAmino acids
Tyrosine residuesTyrosine residues
(according to Lippincott´s(according to Lippincott´s
Pharmacology, 2006Pharmacology, 2006
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.
Actions of thyroid hormones
interaction 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 ...)
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.
Enzyme induction can increase the metabolism of the thyroid hormonesEnzyme induction can increase the metabolism of the thyroid hormones
TT33 = triiodothyronine; T= triiodothyronine; T44 = thyroxine= thyroxine
(according to(according to
Pharmacology, 2006Pharmacology, 2006
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
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).
E. Treatment of hyperthyreoidism (thyrotoxicosis)
Incl. Graves´ disease, toxic adenoma, goiter, and thyroiditis.
The goal is to decrease synthesis and/or release of additional
- 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.
Inhibition of thyroid hormone synthesis
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.
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)
β-Blockers that lack sympathomimetic activity (e.g., propranolol) -
effective in blunting the widespread sympathetic stimulation that occurs in
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.
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(β or B-cells -insulin, α2
or A-cells - glucagon, and α1 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.
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).
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).
Clinical uses of glucagon
Rapidly growing incidence (135 million people worldwide are afflicted with
Type 2). In USA - 20 million people - a major cause of morbidity and
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.
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.
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 β-cell necrosis.
Loss of β-cell function - usually autoimmune-mediated processes directed
against the β-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).
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
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 β-cell function, but variable insulin secretion is
insufficient to maintain glucose homeostasis. β-cell mass may become
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
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,
β-cell function declines, and insulin therapy is often required to achieve
satisfactory serum glucose levels.
Major factors contributing
to hyperglycemia observed in
Type 2 diabetes
1 Insulin resistance in peripheral tissues
2 Inadequate insulin secreation from β cells
Comparison of Type 1 and Type 2 diabetes
Age of onset
Nutritional status at
time of onset
Defect or deficiency
Usually during childhood or
10 to 20 percent of diagnosed
β Cells are destroyed,
eliminating the production of
Frequently over age 35
Obesity usually present
80 to 90 percent of diagnosed
Inability of β cells to produce
appropriate quantities of insulin;
insulin resistance; other defects
Lippincott´s Pharmacology, 2006
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.]
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.
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 β-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
⇒ insulin exocytosis (some oral antidiabetics – sulfonylureas,
meglitinides - hypoglycemic effect due to inhibition of the K+
[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.]
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
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
- Lipodystrophy (less common with human insulin)
- Allergic reactions
- Adjust doses of insulin in diabetics with renal insufficiency.
INSULIN PREPARATIONS AND TREATMENT
To do any change in insulin treatment cautiously.
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
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.
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
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.
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
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).
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).
[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.]
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.
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,
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.
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.
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 ).
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
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.
Onset and duration of action of human insulin and insulin analogs.
0 6 12 18
Aspart insulin, lispro insulin
insulin NPH insulin
Extended zinc insulin
(according to Lippincott´s Pharmacology, 2006)
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,
During pregnancy, for gestational diabetes not controlled by diet
Emergency treatment of hyperkalaemia: insulin is given with glucose
to lower extracellular K+
via redistribution into cells.
Clinical uses of insulin
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 β-cells that
occurs due to the disease or aging.
Oral hypoglycemic agents should not be given to patients with Type 1
Insulin secretagogues (they promote insulin release from the β-cells).
1. Mechanisms of action of the sulfonylureas: 1) stimulation of insulin
release from the β-cells blocking the ATP-sensitive K+
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
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.
- disulfiram-like reactions (flushing, nausea, headache after alcohol)
- allergic reactions
- GIT disturbances
- weight gain, hyperinsulinemia, and hypoglycemia
with sulfonylurea drugs
Increased hypoglycemic action
of sulfonylurea drugs
Reduce hepatic metabolism of sulfonylureas
Monoamine oxidase inhibitors
ureas from plasma
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 β-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 effective in the early release of
insulin that occurs after a meal ⇒ categorized as postprandial glucose
Combined therapy with metformin or the glitazones - better than
monotherapy with either agent in improving glycemic control.
2. Pharmacokinetics and fate: Well absorbed orally after being taken one to
thirty minutes before meals. Metabolized to inactive products by CYP3A4
in the liver; excreted through the bile.
3. Adverse effects:
- Hypoglycemia (incidence lower than with the sulfonylureas)
- Drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole,
erythromycin, and clarithromycin) may ↑ the glucose-lowering effect of
- Drugs that increase levels of this enzyme (e.g., barbiturates,
carbamazepine, rifampin) may have the opposite effect.
- Repaglinide was reported to cause severe hypoglycemia in patients who
are also taking the lipid-Iowering drug gemfibrozil.
- Weight gain (less problem than with sulfonylureas)
- Use with caution in patients with hepatic impairment.
VI. ORAL HYPOGLYCEMIC AGENTS: INSULIN SENSITIZERS
the biguanides and thiazolidinediones -improve insulin action.
They lower blood sugar by improving target-cell response to insulin
without increasing pancreatic insulin secretion.
A. BIGUANIDES (METFORMIN [met FOR min])
Orally acting, not influencing beta-cells or affecting insulin production.
It requires insulin for its action, but differs from the sulfonylureas in
that it does not promote insulin secretion.
Hyperinsulinemia is not a problem ⇒ the risk of hypoglycemia is far
less than with sulfonylurea agents (it may occur if caloric intake is not
adequate or exercise is not compensated for calorically).
1. Mechanism of action:
Metformin reduces hepatic glucose output, largely by inhibiting hepatic
gluconeogenesis (excess glucose produced by the liver is the major source of
high blood sugar in Type 2).
It also slows intestinal absorption of sugars.
Very important - ability to modestly reduce hyperlipidemia (LDL and VLDL
cholesterol ↓, and HDL ↑). These effects may not be apparent until 4-6 weeks of
use. The patient often loses weight because of loss of appetite.
The only oral hypoglycemic agent proven to decrease cardiovascular mortality.
May be used alone or in combination with other agents, as well as with insulin.
Hypoglycemia occurred when taken in combination.
[Note: If used with insulin, the dose of the hormone must be adjusted, because
metformin decreases the production of glucose by the liver.]
2. Pharmacokinetics: Well absorbed orally; not bound to serum proteins, and
it is not metabolized. The highest concentrations are in the saliva and
intestinal wall. Excretion - via the urine.
3. Adverse effects:
Contraindicated in diabetics with renal and/or hepatic disease, cardiac or
respiratory insufficiency, a history of alcohol abuse, severe infection, or
To be discontinued in patients requiring i.v. contrast radiographic agents.
Rarely, potentially fatal lactic acidosis has occurred. [Note: Diabetics being
treated with heart-failure medications should not be given metformin because
of an increased risk in lactic acidosis.]
Long-term use may interfere with vitamin B12 absorption.
A number of drug interactions (effects of metformin may be ↑by cimetidine,
furosemide, nifedipine, and oth'er agents).
4. Other uses: Polycystic ovary disease. Its ability to ↓ insulin resistance in
these women can result in ovulation and, possibly, pregnancy.
B. Thiazolidinediones (or glitazones)
Insulin sensitizers - although insulin is required for their action, these
drugs do not promote its release from the pancreatic β cells ⇒
hyperinsulinemia does not result.
Troglitazone [TROE glit a zone] was the first,but was withdrawn after a
number of deaths due to hepatotoxicity.
Presently, two members of this class are available, pioglitazone [pye oh
GLI ta zone] and rosiglitazone [roe si GLI ta zone].
1. Mechanism of action: exact mechanism remains to be elucidated;
they are known to target the peroxisome proliferator-activated receptor-γ
(PPARγ) - a nuclear hormone receptor. Ligands for PPARγ regulate
adipocyte production and secretion of fatty acids as well as glucose
metabolism ⇒ increased insulin sensitivity in adipose tissue, liver, and
Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated
HbA1c levels are improved.
LDL levels are not affected by pioglitazone, whereas LDL levels have
increased with rosiglitazone.
HDL levels increase with both drugs.
TZDs lead to an expansion of subcutaneous fat.
Pioglitazone can be used as monotherapy or in combination with other
hypoglycemics or insulin. The dose of insulin may have to be lowered.
Rosiglitazone may also be used in combination with other hypoglycemics
but not with insulin, because edema occurs with higher frequency.
2. Pharmacokinetics: Both are absorbed well after oral administration;
extensively bound to serum albumin. Both undergo extensive metabolism
by CYP450 isozymes. Some metabolites of pioglitazone have activity. The
metabolites are primarily excreted in the urine, but the parent agent leaves
via the bile.
No dosage adjustment is required in renal impairment. It is recommended
that these agents not be used in nursing mothers.
3. Adverse effects:
- deaths from hepatotoxicity after troglitazone ⇒ liver enzyme levels be
measured initially, then every 2 months for a year, and periodically
- weight increase (possibly through the ability of TZDs to increase
subcutaneous fat or due to fluid retention - it can lead to or worsen heart
- headache and anemia
- Women taking oral contraceptives and TZDs may become pregnant,
because the TZDs reduce plasma concentrations of the estrogen-
4. Other uses: As with metformin, the relief of insulin resistance with the
TZDs can cause ovulation to resume in premenopausal women with
polycystic ovarian syndrome.
VII. ORAL HYPOGLYCEMIC AGENTS: α-GLUCOSIDASE
A. Acarbose and miglitol [AY car bose] and [MIG li tol]
orally active drugs used for the treatment of Type 2 diabetes.
1. Mechanism of action:
Taken at the beginning of meals. They act by delaying the digestion of
carbohydrates ⇒ ↓ glucose absorption. Effects by reversibly inhibiting
membrane-bound α-glucosidase in the intestinal brush border.
This enzyme is responsible for the hydrolysis of oligosaccharides to glucose
and other sugars (Acarbose also inhibits pancreatic α-amylase).
⇒ the postprandial rise of blood glucose is blunted.
They do not stimulate insulin release, nor do they increase insulin action in
target tissues ⇒ as monotherapy, they do not cause hypoglycemia. When
used in combination, hypoglycemia may develop.
[It is important that the hypoglycemic patient be treated with glucose rather
than sucrose, because sucrase is also inhibited by these drugs.]
Acarbose is poorly absorbed; metabolized primarily by intestinal bacteria,
some of the metabolites are absorbed and excreted into the urine.
Miglitol is very well absorbed but has no systemic effects. It is excreted
unchanged by the kidney.
3. Adverse effects:
- flatulence, diarrhea, and abdominal cramping.
- patients with inflammatory bowel disease, colonic ulceration, or intestinal
obstruction should not use these drugs.
- they ↓ bioavailability of metformin; avoid concurrent use
Type 2 DM, as a supplement to diet and exercise to reduce
symptoms from hyperglycaemia (e.g. thirst, excessive
urination). Tight control of blood glucose has only a small
effect on vascular complications.
Metformin is preferred for obese patients unless
contraindicated by factor(s) that predispose to lactic
acidosis (renal or liver failure, heart failure, hypoxaemia).
Acarbose (α-glucosidase inhibitor) reduces carbohydrate
absorption; it causes flatulence and diarrhoea.
Drugs that act on the sulfonylurea receptor (e.g. tolbutamide,
glibenclamide) - well tolerated but often promote weight gain.
Clinical uses of oral hypoglycaemic drugs
VIII. GASTROINTESTINAL HORMONES
Oral glucose results in a higher secretion of insulin than occurs when an
equal load of glucose is given intravenously. This effect is referred to as the
"incretin effect," and is apparently reduced in Type 2 diabetes.
⇒ important role of GI hormones-notably glucagon-like peptide-1 (GLIP-1)
and gastric inhibitory polypeptide-in the digestion and absorption of nutrients
A new drug, exenatide [EX e nah tide] - polypeptide sequence about
50 % homologous to GLIP-1. It apparently mediates its effect through the
GLIP-1 receptor, and it not only improves insulin secretion but also slows
gastric emptying time, ↓ food intake, ↑ glucose suppression of glucagon
secretion, and promotes β cell regeneration or decreased apoptosis. ⇒
weight gain, postprandial hyperglycemia, and loss of β cells are reduced, and
HbA1c levels decline.
Must be administered parenterally. Short duration of action, requiring frequent
injections. Well tolerated, with a small number of patients reporting nausea.
Research to find longer-acting agents.