Hormones V. Geršl 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: Lippincott ’ s Illustrated Reviews: Pharmacology,3rd ed.
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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., dehydroepiandrosterone).
Adrenal glucocorticoids serve as feedback inhibitors of ACTH and CRF secretion.
Regulation of corticosteroid outer zone
Lippincott´s Pharmacology, 2006
Hypothalamus outer zone
Regulation of synthesis and secretion of adrenal
Peripheral actions (metabolic,
Peripheral actions on salt
and water metabolism
Summary of adrenal outer zone
INHIBITORS OF ADRENOCORTICOID
BIOSYNTHESIS OR FUNCTION
Lippincott´s Pharmacology, 2006
ADRENOCORTICOSTEROIDS outer zone
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.
A lipid-soluble steroid diffuses across the cell membrane, and binds to a cytoplasmic receptor.
Gene regulation by glucocorticoids
Receptor forms a dimer
Binding to a glucocorticoid response element stimulates or inhibits the activity of an adjacent promoter, which initiates or inhibits transcription of a gene.
Changes in amounts of specific proteins
(according to Lippincott´s Pharmacology, 2006)
b. and binds to a cytoplasmic receptor. 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 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 !!
f. Anti-inflammatory and immunosupresssive action: and binds to a cytoplasmic receptor.The most important therapeutically - ability to dramatically reduce the inflammatory response and to suppress immunity. The exact mechanism iscomplex 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.
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 hypothalamus:
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: adrenocortical 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: adrenocortical 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 problemin 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.
Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders
(according to Katzung BG: Basic and clinical pharmacology, 2007)
The only glucocorticoid that has no 2007)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.
Lippincott´s Pharmacology, 2006
Lippincott´s Pharmacology, 2006
Comparison of the main corticosteroid agents (using hydrocortisone as a standard)
Approximatelly relative potency
in clinical use:
Drug of choice for replacement therapy
Hydrocortisone 1 1 S
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
Drug of choice for systemic anti-inflammatory and immunosuppressive effects
Prednisolone 4 0,8 I
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
Dexamethasone hydrocortisone as a standard) 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 + - -
Anti-inflammatory and immunosuppressive; effective topically and as an aerosol
Budesonide + - -
Deoxycortone Negligible 50 -
Fludrocortisone 15 150 S
Drug of choice for mineralocorticoid effects
Aldosterone None 500 S
(according to Katzung BG: Basic and clinical pharmacology, 2007)
(according to Katzung BG: Basic and clinical pharmacology, 2007)
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)
Effects of prolonged glucocorticoid excess: iatrogenic Cushing´s syndrome. Italicised effects are particularly common. Less frequent effects, related to dose and duration of therapy, are shown in brackets.
(Benign intracranial hypertension)
Moon face, with red (plethoric) cheeks
Increased abdominal fat
Thinning of skin
(Avascular necrosis of femoral head)
Tendency to hyperglycaemia
Negative nitrogen balance
Increased susceptibility to
Thin arms and legs: muscle wasting
Poor wound healing
(according to Rang and Dale, Pharmacology, 2007)
Glucocorticoids and emotional lability)
Mechanism of action of the glucocorticoids and emotional lability)
Pharmacokinetics and unwanted actions of the glucocorticoids and emotional lability)
― suppression of response to infection
Inhibitors of adrenocorticoid biosynthesis and emotional lability)
Several substances - useful inhibitors of the synthesis of adrenal steroids: metyrapone, aminoglutethimide, ketoconazole, trilostane, spironolactone, and eplerenone.
Mifepristone competes with glucocorticoids for the receptor.
1. Metyrapone: and emotional lability) [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 replacedaminoglutethimide]. In these cases, it is used in conjunction with dexamethasone. However, it increases the clearance of dexamethasone.
Aminoglutethimidemay also be useful in malignancies of the adrenal cortex to reduce the secretion of steroids. Recent studies indicate it is an aromatase inhibitor.
3. Ketoconazole: and emotional lability) [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.
MINERALOCORTICOIDS and emotional lability)
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.
Mineralocorticoids and emotional lability)
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.
Inhibitors of biosynthesis and emotional lability)
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.
THYROID HORMONES and emotional lability)
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.]
Thyroid hormone synthesis and secretion: and emotional lability)
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 hormones and emotional lability)
(according to Lippincott´s
Proteolytic release of
Regulation of secretion: and emotional lability) 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 T3and 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 thereceptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4.
Actions of thyroid hormones and emotional lability)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 ...)
C. Pharmacokinetics and emotional lability)
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.
T3 = triiodothyronine; T4 = thyroxine
D. Treatment of hypothyroidism hormonesUsually 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).
E. Treatment of hyperthyreoidism (thyrotoxicosis) hormonesIncl. 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 particlesemitted 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 requiretreatment with levothyroxine.
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 hormones
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)
Thyroid storm: hormones
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.
INSULIN AND ORAL HYPOGLYCEMIC DRUGS hormones
Pancreas - endocrine gland(peptide hormones insulin, glucagon, and somatostatin) andexocrine 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 mellitushyperglycemia, if untreated retinopathy, nephropathy, neuropathy, cardiovascular complications.
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).
Clinical uses of glucagon hormones
Summary of hypoglycemic agents hormones
Extended zinc insulin
Insulin zinc suspension
NPH insulin suspension
Protamine zinc insulin
DIABETES MELLITUS hormones
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.
E.g., hormonesmaturity-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.
About1-5 % 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.
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.
Type 2 diabetes hormones(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 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."
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.
1 hormonesInsulin resistance in peripheral tissues
Major factors contributing
to hyperglycemia observed in
Type 2 diabetes
2Inadequate insulin secreation from b cells
Frequently over age 35
Obesity usually present
80 to 90 percent of diagnosed diabetics
Inability of b cells to produce appropriate quantities of insulin; insulin resistance; other defects
Usually during childhood or puberty
10 to 20 percent of diagnosed diabetics
b Cells are destroyed, eliminating the production of insulin
Age of onset
Nutritional status at time of onset
Defect or deficiency
Lippincott´s Pharmacology, 2006
INSULIN AND ITS ANALOGS hormones[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.
[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.]
Polypeptidedegraded in GITif taken orally mostly by subcutaneous injection (in a hyperglycemic emergency, regular insulin intravenously - its plasma half-life ≤ 9 minutes).
Continuous s.c. infusionalso - 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).
INSULIN PREPARATIONS AND TREATMENT hormones
To do any change in insulin treatment cautiously.
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.
Rapid-acting insulin hormones
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.
I hormonesnsulinlispro [LIS proe], insulinaspart [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 reversedmore rapid absorption after s.c. inj. than after regular insulinacts 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 hormonesand 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 hormones- 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.
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 withpolypeptide, protamine.
Intermediateduration 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/
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 hormones
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 hormones- 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.
Aspart insulin, lispro insulin
Extended zinc insulin
0 6 12 18 24
(according to Lippincott´s Pharmacology, 2006)
Clinical uses of insulin analogs.
ORAL HYPOGLYCEMIC AGENTS: analogs.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 diabetes.
A. Sulfonylureas analogs.
Insulin secretagogues (they promote insulin release from the b-cells).
1. Mechanisms of action of the sulfonylureas:1) stimulation of insulin release from the β-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
Drugs interacting analogs.
with sulfonylurea drugs
ureas from plasma
Increased hypoglycemic action
of sulfonylurea drugs
Reduce hepatic metabolism of sulfonylureas
Monoamine oxidase inhibitors
B. Meglitinide analogs 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 effective in the early release of insulin that occurs after a meal categorized as postprandial glucose regulators.
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.
VI. ORAL HYPOGLYCEMIC AGENTS: analogs.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. analogs.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: analogs.
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 provento 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: analogs.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 pregnancy.
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 druginteractions (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 analogs.(or glitazones)
Insulin sensitizers -although insulin is required for their action, these drugs do not promote its release from the pancreatic b 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-g (PPARg)-a nuclear hormone receptor. Ligands for PPARg regulate adipocyte production and secretion of fatty acids as well as glucose metabolism increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.
Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated HbA1c levels are improved.
LDL levels are not affected analogs. 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.
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.]
Duration of action of analogs.
some oral hypoglycemic
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 b cell regeneration or decreased apoptosis. weight gain, postprandial hyperglycemia, and loss of b 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.