Bez nadpisu

Hormones Hormones

V. GeršlV. 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.- 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.

Adrenocorticosteroid Hormones Adrenocorticosteroid Hormones

OVERVIEW

The adrenal gland – cortex, medulla.

Medulla - secretes epinephrine;

Cortex - steroid hormones - adrenocorticosteroids = glucocorticoids and mineralocorticoids, and the adrenal androgens. Cortex – 3 zones that synthesize various steroids from cholesterol and then secrete them.

The outer (zona glomerulosa) - mineralocorticoids (aldosterone) - responsible for regulating salt and water metabolism. Production is regulated by the renin-angiotensin system.

The middle (zona fasciculata) - glucocorticoids (e.g., cortisol)

The inner (zona reticularis) - adrenal androgens (e.g., dehydroepiandrosterone).

Adrenal glucocorticoids serve as feedback inhibitors of ACTH and CRF secretion.

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 corticotropin-releasing factor).

Glucocorticoids - feedback inhibitors of ACTH and CRH.

- replacement therapy;

- treatment of asthma and other inflammatory diseases (e.g., rheumatoid arthritis);

- treatment of severe allergic reactions;

- treatment of some cancers.

Regulation of corticosteroidRegulation of corticosteroidHypothalamusHypothalamus

StressStressCorticotropin-Corticotropin-

releasingreleasingfactorfactor

AnteriorAnteriorpituitarypituitary

CorticotropinCorticotropin(ACTH)(ACTH)

ADRENALADRENALMEDULLAMEDULLA

ADRENALADRENALCORTEXCORTEX

Zona glomerulosaZona glomerulosa

Zona fasciculataZona fasciculata

Zona reticularisZona reticularis

AldosteroneAldosterone

CortisolCortisol

AndrogensAndrogens(according to Lippincott´s Pharmacology, 2006

HypothalamusHypothalamus

Anterior pituitaryAnterior pituitary

ExogenousExogenousACTHACTH

MetyraponeMetyraponemitotanemitotane

CRFCRF

Exogenous glucocorticoidsExogenous glucocorticoids(e.g. prednisolone)(e.g. prednisolone)

Exogenous mineralocorticoidsExogenous mineralocorticoids(e.g. fludrocortisone)(e.g. fludrocortisone)

GlucocorticoidsGlucocorticoids

Peripheral actions (metabolic,Peripheral actions (metabolic,anti-inflammatory, immunosuppressive)anti-inflammatory, immunosuppressive)

Peripheral actions on saltPeripheral actions on saltand water metabolismand water metabolism

MineralocorticoidsMineralocorticoids

AdrenalAdrenalcortexcortex

Renin-angiotensinRenin-angiotensinsystemsystem

Short negativeShort negativefeedback loopfeedback loop

Long negativeLong negativefeedback loopfeedback loop

ADHADH

ACTHACTH

Regulation of synthesis and secretion of adrenalcorticosteroids

Summary of adrenalSummary of adrenalcorticosteroidscorticosteroids ADRENAL CORTICOSTEROIDSADRENAL CORTICOSTEROIDS

CORTICOSTEROIDSCORTICOSTEROIDS

INHIBITORS OF ADRENOCORTICOID INHIBITORS OF ADRENOCORTICOID BIOSYNTHESIS OR FUNCTIONBIOSYNTHESIS OR FUNCTION

BeclomethasoneBeclomethasoneBetamethasoneBetamethasoneCortisoneCortisoneDesoxycorticosteroneDesoxycorticosteroneDexamethasoneDexamethasoneFludrocortisoneFludrocortisoneHydrocortisoneHydrocortisoneMethylprednisoloneMethylprednisoloneParamethasoneParamethasonePrednisolonePrednisolonePrednisonePrednisoneTriamcinoloneTriamcinolone

AminoglutethimideAminoglutethimideEplerenoneEplerenoneKetoconazoleKetoconazoleMetyraponeMetyraponeMifepristoneMifepristoneSpironolactoneSpironolactoneTrilostaneTrilostane

(according to (according to Lippincott´s Pharmacology, 2006Lippincott´s Pharmacology, 2006

ADRENOCORTICOSTEROIDS

Bind to specific intracellular cytoplasmic receptors in target tissues.

Glucocorticoid receptor - widely distributed in the body;

Mineralocorticoid receptor - excretory organs (kidney, colon, salivary and sweat glands).

The receptor-hormone complex translocates into the nucleus, where it attaches to gene promoter elements, acting as a transcription factor to turn genes on or off, depending on the tissue. This requires time to produce an effect.

Other glucocorticoid effects (e.g., interaction with catecholamines to mediate dilation of vascular and bronchial musculature or Ijpolysis) - effects are immediate.

(according to Lippincott´s Pharmacology, 2006)

Corticosteroid

CorticosteroidTARGET

CELL

Inactive receptor

CYTOSOLActivated receptor complexReceptor forms a

dimer

NUCLEUS

Glucocorticoidresponse

element

DNA

Promoter

Gene

mRNA

Changes in amounts of specific proteins

mRNA

Biologic effects

A lipid-soluble steroid diffuses across the cell

membrane, and binds to a cytoplasmic receptor.

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

A. Glucocorticoids

Cortisol - the principal human glucocorticoid.

Diurnal production - a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon.

Factors (e.g., stress, levels of the circulating hormone influence secretion).

The effects of glucocorticoids:

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 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 !!

d. Increase resistence to stress: By plasma glucose levels they provide

the body with the energy it requires to combat stress caused by, e.g.

trauma, fright, infection, bleeding, or disease.

Also cause a rise in blood pressure, by enhancing the vasoconstrictor

action of adrenergic stimuli on small vessels.

Note: Individuals with adrenal insufficiency may also respond to severe

stress by becoming hypotensive.

e. Alter blood cell levels in plasma: in eosinophils, basophils, monocytes, and lymphocytes. blood levels of hemoglobin, erythrocytes, and polymorphonuclear

leukocytes.

Note: The decrease in circulating lymphocytes and macrophages

a decreased ability of the body to fight infections !!

f. Anti-inflammatory and immunosupresssive action:

The most important therapeutically - ability to dramatically reduce the inflammatory response and to suppress immunity. The exact mechanism is complex and incompletely understood:- and inhibition of peripheral lymphocytes and macrophages- indirect inhibition of phospholipase A2 (due to the steroid-mediated elevation of lipocortin 1 = annexin), which blocks the release of arachidonic acid.- COX-II synthesis is availability of PGS. - Interference in mast cell degranulation results - histamine and capillary permeability.- in inducible NO synthesis.

The most pronounced activity in the tissues of mesenchymal origin –i.e., in lymphocytes, activity of fibroblasts, chondroblasts and osteoblasts reduced healing and repair.

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 corticosteroidsSemisynthetic 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 releasingthe 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 after transplantation)8. Hematological disorders (lymphatic leukaemia, haemolytic anaemia)9. GIT diseases (ulcerative colitis, inflammatory bowel disease)10. Nephrotic syndrome and other autoimmune diseases.11. Topically in dermatology (ekzema ...)12. Acceleration of lung maturation: Respiratory distress syndrome – a problem in premature infants. Fetal cortisol is a regulator of lung maturation. Beclomethasone administered i.m. to the mother 48 hours prior to birth followed by a second dose 24 hours before delivery.

Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders

Disorder Examples

Allergic reactions Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria

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 neuritis

Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis

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 mortality)

(according to Katzung BG: Basic and clinical pharmacology, 2007)

Disorder Examples

Infections Acute respiratory distress syndrome, sepsis, systemic inflammatory syndrome

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


D. Pharmacology1. Naturally occurring adrenal corticosteroids and derivates - readily absorbed from GIT. Selected compounds can also be administered i.v., i.m., or topically. Bound to plasma proteins: most to corticosteroid-binding globulin (the remainder to albumin). Metabolized by the liver microsomal oxidizing enzymes. Conjugated to glucuronic acid or sulfate; excreted by the kidney.Note: The half-life may increase dramatically in hepatic dysfunction.2. In determining the dosage of adrenocortical steroids, many factors need to be taken into consideration, incl. activity, duration of action, type of preparation ….When large doses of the hormone are required over an extended period of time (more than 2 weeks), suppression of the hypothalamic-pituitary-adrenal (HPA) axis occurs. To prevent this adverse effect, a regimen of alternate-day administration of the adrenocortical steroid may be useful. This schedule allows the HPA axis to recover function on the days the hormone is not taken

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

IMIMCortisoneCortisoneDesoxycorticosteroneDesoxycorticosteroneTriamcinoloneTriamcinolone

IV, IMIV, IMDexamethasoneDexamethasoneHydrocortisoneHydrocortisoneMethylprednisoloneMethylprednisolonePrednisolonePrednisolone


GlucocortifcoidsGlucocortifcoids

MineralocorticoidsMineralocorticoids

HydrocortisoneHydrocortisone

CortisoneCortisone

PrednisonePrednisone

PrednisolonePrednisolone

MethylprednisoloneMethylprednisolone

TriamcinoloneTriamcinolone

BetamethasoneBetamethasone

DexamethasoneDexamethasone

ParamethasoneParamethasone

FludrocortisoneFludrocortisone

DeoxycorticosteroneDeoxycorticosterone

Anti-inflammatory effectAnti-inflammatory effectSalt-retaining effectSalt-retaining effect

11110.80.80.80.8

440.30.3

550.80.8

550.50.5

5500

00

00

00

00

3535

3030

1010

1010

2020

125125


Comparison of the main corticosteroid agents (using hydrocortisone as a standard)

Compound CommentsComments

Hydrocortisone 1 1 S 1 1 S (cortisol)(cortisol)

Anti-inflammatory Sodium-retaining

Approximatelly relative potencyin clinical use:

Duration of Duration of action afteraction afteroral doseoral dose

Drug of choice for Drug of choice for replacement therapyreplacement therapy

Cortisone 0.8 0.8 S 0.8 0.8 S

Cheap; inactive untill Cheap; inactive untill converted to converted to hydrocortisone; not used as hydrocortisone; not used as anti-inflammatory because anti-inflammatory because of mineralocorticoid effectsof mineralocorticoid effects

Corticosterone 0.3 15 S Corticosterone 0.3 15 S Prednisolone 4 0,8 I 4 0,8 I

Drug of choice for systemic anti-inflammatory and immunosuppressive effects

Prednisone 4 0,8 I 4 0,8 I

Inactive until converted to prednisolone

Methylprednisolone 5 Minimal I 5 Minimal I

Anti-inflammatory and Anti-inflammatory and immunosuppressiveimmunosuppressive

Triamcinolone 5 None I 5 None I

Relatively more toxic than others

Dexamethasone 30 Minimal L 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

Betamethasone 30 Negligible L 30 Negligible L Anti-inflammatory and immunosuppressive, used especially where water retention is undesirable

Beclometasone + - - + - - diproprionatediproprionate

Anti-inflammatory and immunosuppressive; effective topically and as an aerosol

Budesonide + - - + - - Anti-inflammatory and Anti-inflammatory and immunosuppressive; immunosuppressive; effective topically and as effective topically and as an aerosolan aerosol

Deoxycortone Negligible 50 -Deoxycortone Negligible 50 -

Fludrocortisone 15 150 S 15 150 S

Drug of choice for Drug of choice for mineralocorticoid effectsmineralocorticoid effects

Aldosterone None 500 S Aldosterone None 500 S

Endogenous Endogenous mineralocorticoidmineralocorticoid

Some commonly used natural and synthetic corticosteroids for general use

Agent

ActivityEquivalent oral dose

(mg)Anti-

inflammatory Topical Salt-retaining

SHORT-TO MEDIUM-ACTING GLUCOCORTICOIDSHydrocortisone (cortisol) 1 1 1 20

Cortisone 0.8 0 0.8 25Prednisone 4 0 0.3 5

Prednisolone 5 4 0.3 5Methylprednisolone 5 5 0 4

Meprednisone 5 0 4

INTERMEDIATE-ACTING GLUCOCORTICOIDSTriamcinolone 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

Agent

ActivityEquivalent oral dose

(mg)Anti-

inflammatory Topical Salt-retaining

LONG-ACTING GLUCOCORTICOIDSBetamethasone 25-40 10 0 0.6Dexamethasone 30 10 0 0.75

MINERALOCORTICOIDSFludrocortisone 10 0 250 2

Desoxycorticosterone acetate 0 0 20


E. Adverse effects

1. Osteoporosis, impaired synthesis of collagen ( impaired wound

healing) and myopathy that results from protein catabolism.

Note: Impaired growth in children is probably caused by the same

action.

2. Edema, hypertension, and congestive heart failure due to salt and

water retention can occur.

3. The CNS effects range from euphoria to psychoses inclidung suicidal

tendencies. May cause a psychological dependency.

4. May cause stimulation of peptic ulcers.

5. Corticosteroids may cause development of iatrogenic Cushing´s

syndrome, including redistribution of body fat, puffy face, increased

body 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)

(Benign intracranial hypertension)

(Cataracts)

Moon face, with red (plethoric) cheeks

Buffalo hump

(Hypertension)

Increased abdominal fat(Avascular necrosis

of femoral head)

Thinning of skin

Easy bruising

Poor wound healing

Thin arms and legs: muscle wasting

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.

Also: Osteoporosis Tendency to hyperglycaemia Negative nitrogen balance Increased appetite Increased susceptibility to infection Obesity(according to Rang and Dale, Pharmacology, 2007)

Glucocorticoids

Drugs used: hydrocortisone, prednisolone and dexamethasone.

Metabolic actions

On carbohydrates: decreased uptake and utilisation of glucose and increased gluconeogenesis; this causes a tendency to hyperglycaemia.

On proteins: increased catabolism, reduced anabolism.

On fat: a permissive effect on lipolytic hormones, and a redistribution of fat, as in Gushing's syndrome.

Regulatory actions On hypothalamus and anterior pituitary: a negative feedback – a reduced release

of endogenous glucocorticoids. On vascular events: reduced vasodilatation, decreased fluid exudation. On cellular events: ― in areas of acute inflammation: decreased influx and activity of leucocytes ― in areas of chronic inflammation: decreased activity of mononuclear cells, decreased proliferation of blood vessels, less fibrosis ― in lymphoid areas: decreased clonal expansion of T and B cells and decreased action of cytokine- secreting T cells. On inflammatory and immune mediators: ― decreased production and action of cytokines including many interleukins, tumour necrosis factor-, granulocyte-macrophage colony-stimulating factor ― reduced generation of eicosanoids ― decreased generation of IgG ― decrease in complement components in the blood. Overall effects: reduction in chronic inflammation and autoimmune reactions but

also decreased healing and diminution in the protective aspects of the inflammatory response.

Mechanism of action of the glucocorticoids Interact with intracellular receptors; the resuIting steroid-receptor

complexes dimerise (form pairs) then interact with DNA to modify gene transcription: inducing synthesis of some proteins and inhibiting synthesis of others.

For metabolic actions, most mediator proteins are enzymes, e.g. cAMP-dependent kinase, but not all actions on genes are known.

For anti-inflammatory and immunosuppressive actions, some actions at the level of the genes are known:

― inhibition of transcription of the genes for COX-2, cytokines (e.g. interleukins), cell adhesion molecules and inducible form of NO synthase

― block of vitamin D3-mediated induction of the osteocalcin gene in osteoblasts and modification of transcription of the collagenase genes ― icreased synthesis of annexin-1 - an important factor in negative

feedback on the hypothalamus and anterior pituitary and may have anti- inflammatory actions. Some non-genomic (rapid) effects of glucocorticoids were observed.

Pharmacokinetics and unwanted actions of the glucocorticoids

Administration can be oral, topical and parenteral. The drugs are bound to corticosteroid-binding globulin in the blood and enter cells by diffusion. They are metabolised in the liver.

Unwanted effects are seen mainly with prolonged systemic use as anti-inflammatory or immunosuppressive agents (in which case all the metabolic actions are unwanted), but not usually with replacement therapy.

The most important are: ― suppression of response to infection ― suppression of endogenous glucocorticoid synthesis ― metabolic actions ― osteoporosis ― iatrogenic Cushing's syndrome

Inhibitors of adrenocorticoid biosynthesis

Several substances - useful inhibitors of the synthesis of adrenal steroids: metyrapone, aminoglutethimide, ketoconazole, trilostane, spironolactone, and eplerenone.

Mifepristone competes with glucocorticoids for the receptor.

1. Metyrapone: [me TEER ah pone] - used for tests of adrenal function and can be used for the treatment of pregnant women with Gushing syndrome. It interferes with corticosteroid synthesis by blocking the final step (11-hydroxylation) in glucocorticoid synthesis, leading to an increase in 11-deoxycortisol as well as adrenal androgens and the potent mineralocorticoid 11-deoxycorticosterone. The adverse effects include salt and water retention, hirsutism, transient dizziness, and gastrointestinal disturbances.

2. Aminoglutethimide: - inhibits the conversion of cholesterol to pregnenolone --- the synthesis of all hormonally active steroids is reduced.

It has been used therapeutically in the treatment of breast cancer to reduce or eliminate androgen and estrogen production.

[Note: Tamoxifen has largely replaced aminoglutethimide]. In these cases, it is used in conjunction with dexamethasone. However, it increases the clearance of dexamethasone.

Aminoglutethimide may also be useful in malignancies of the adrenal cortex to reduce the secretion of steroids. Recent studies indicate it is an aromatase inhibitor.

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.

MINERALOCORTICOIDS

Water and electrolyte homeostasis: Help control the body´s

water volume and concentration of electrolytes, especially sodium and

potassium.

ALDOSTERONE, causing a reabsorption of Na, bicarbonate, and

water. Decreases reabsorption of K, which is then lost in urine.

Note: Elevated aldosterone levels may cause alkalosis and

hypokalemia, whereas retention of sodium and water leads to an

increase in blood volume and blood pressure.

Mineralocorticoids

Fludrocortisone - given orally to produce a mineralocorticoid effect. It:

― increases Na+ reabsorption in distal tubules and increases K+ and H+ efflux into the tubules ― acts, like most steroids, on intracellular receptors that modulate DNA transcription causing synthesis of protein mediators ― is used with a glucocorticoid in replacement therapy.

Inhibitors of biosynthesis

1. Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor inhibits Na reabsorption in the kidney. It can also antagonize aldosterone and testosterone synthesis. It is effective against hyperaldosteronism.

Spironolactone is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle.

Adverse effects: hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes.

2. Eplerenone: [e PLEA en one] - binds to the mineralocorticoid receptor – i.e., aldosterone antagonist. This specificity avoids the unwanted side effects of spironolactone. It is approved as an antihypertensive.

THYROID HORMONES

They facilitate normal growth and maturation - by maintaining a level of metabolism in the tissues.

Two major hormones - triiodothyronine (T3; the most active form), and thyroxine (T4).

Inadequate secretion of the hormone (hypothyroidism) - bradycardia, poor resistance to cold, and mental and physical slowing (in children, this can cause mental retardation and dwarfism).

Hyperthyroidism – tachycardia, cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production can occur.

[Thyroid gland also secretes calcitonin - a serum Ca-lowering hormone.]

Thyroid hormone synthesis and secretion:

TSH action - mediated by cAMP stimulation of iodide (I2) uptake. Oxidation to iodine (I-) by a peroxidase - followed by iodination of tyrosines on thyroglobulin. [Antibodies to thyroid peroxide = diagnostic for Hashimoto thyroiditis.] Condensation of 2 iodotyrosine T4 or T3, bound to the protein released following proteolytic cleavage of the thyroglobulin.

A. Synthesis:

- uptake of plasma iodide by the follicle cells- iodination of tyrosine (MIT and DIT)- two molecules are coupled »»» T3 and T4- binding to globulin »»» colloid (thyroglobulin), the storage form of thyroid hormone.- release of active hormones (after proteolysis of thyroglobulin) into blood

Biosynthesis of thyroid hormonesBiosynthesis of thyroid hormones

PLASMAPLASMA THYROID CELLTHYROID CELL COLLOIDCOLLOID

2 2 Synthesis ofSynthesis ofthyroglobulinthyroglobulin

1 1 Uptake ofUptake ofiodide ioniodide ion

5 5 Proteolytic release of Proteolytic release of hormoneshormones

3 3 IodinationIodination

4 4 CondensationCondensation

OHOH OHOH

OHOH

OHOH

HOHO

HOHO

OHOH

II II II

II II II IIOO OO

CHCH22 CHCH22

HHCOOCOO--

CC NHNH33++ NHNH33

++HH CCCOOCOO--

Triidothyronine ThyroxineTriidothyronine Thyroxine (T(T33) (T) (T44))

Amino acidsAmino acids

PeroxidasePeroxidaseII-- II-- II22

CHCH22

CHCH22

ThyroglobulinThyroglobulin

Tyrosine residuesTyrosine residues

PropylthiouracilPropylthiouracilMethimazoleMethimazole

ElevatedElevatediodideiodideHH22OO22

II

II

II II

II

IIII II

CHCH22

CHCH22

CHCH22

CHCH22

OO

PropylthiouracilPropylthiouracilMethimazoleMethimazole

(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 ...)

C. Pharmacokinetics

T4 and T3 - absorbed after oral administration.

Food, Ca preparations, and Al-containing antacids absorption of T4 but not T3. T4 is converted to T3 by one of two distinct deiodinases, depending on the tissue.

The hormones are metabolized through the microsomal P450 system. Drugs that induce the P450 enzymes (phenytoin, rifampin, phenobarbital) accelerate metabolism of hormones.

Enzyme induction can increase the metabolism of the thyroid hormonesEnzyme induction can increase the metabolism of the thyroid hormonesTT33 = triiodothyronine; T = triiodothyronine; T44 = thyroxine = thyroxine

PhenytoinPhenytoinRifampinRifampinPhenobarbitalPhenobarbital

EnzymeEnzymeinductioninduction

TT33

TT44

MetabolitesMetabolites

P-450P-450

P-450P-450P-450P-450

(according to (according to Lippincott´s Lippincott´s 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 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)

Incl. Graves´ disease, toxic adenoma, goiter, and thyroiditis.

The goal is to decrease synthesis and/or release of additional hormone.

- Removal of part or all of the thyroid - Either surgically or by beta particles emitted by radioactive iodine (I131).

Younger patients - treated with the isotope without prior pretreatment with methimazole; elderly patients - the opposite.

Most patients become hypothyroid as a result of this drug and require

treatment with levothyroxine.

Inhibition of thyroid hormone synthesis

Thioamides PROPYLTHIOURACIL (proe pill thye oh ZOOR a sil), - METHIMAZOLE (meth IM a zole) and CARBIMAZOLE Inhibition both the iodination of tyrosyl groups and the coupling of

iodotyrosines to form T3 and T4. No effect on the thyroglobulin.

clinical effect of these drugs may be delayed until thyroglobulin stores are depleted.

Well absorbed; short half-lives several doses required per day of PTU; a single dose of methimazole suffices .

Relatively rare adverse effects: agranulocytosis, rash, and edema.

Not effective in the treatment of thyroid storm. Relapse may occur.

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)

Thyroid storm: -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

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

Summary of hypoglycemic agents HYPOGLYCEMIC DRUGS

INSULIN

ORAL HYPOGLYCEMIC DRUGS

-GLUCOSIDASE INHIBITORS

GASTROINTESTINALHORMONES

Aspart insulinExtended zinc insulinGlargine insulinGlulisine insulinInsulin zinc suspensionLispro insulinNPH insulin suspensionProtamine zinc insulinSemilente insulinUltralente insulin

GlipizideGlimepirideGlyburideMetforminNateglinidePioglitazoneRepaglinideRosiglitazoneTolbutamideTroglitazone

AcarboseMiglitol

Exenatide

(according to Lippincott´s Pharmacology, 2006

DIABETES MELLITUS

Rapidly growing incidence (135 million people worldwide are afflicted with Type 2). In USA - 20 million people - a major cause of morbidity and mortality.

Diabetes is not a single disease - it is a heterogeneous group of syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin.

Insulin-dependent diabetes mellitus (Type 1), and non-insulin-dependent diabetes mellitus (Type 2).

Other types of diabetes have also been identified.

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 -cell function - usually autoimmune-mediated processes directed against the -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).

Treatment:

Exogenous (injected) insulin to control hyperglycemia, avoid ketoacidosis, and maintain acceptable levels of glycosylated hemoglobin (HbA1c).

to maintain blood glucose as close to normal as possible, and to avoid wide swings in their levels (that contribute to long-term complications).

Frequent self-monitoring and treatment by insulin.

Continuous s.c. insulin infusion (insulin pump) - eliminates multiple daily injections; programmed to deliver the basal rate of insulin secretion. It also allows to control delivery of a bolus of insulin to compensate for high blood glucose or in anticipation of postprandial needs.

Inhaled forms - in trial.

Pancreas transplantation; transplantation of islet cells - also under investigation.

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 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."

Treatment:

To maintain blood glucose within normal limits and to prevent the development of complications.

Weight reduction, exercise, dietary modification - decrease insulin resistance and correct the hyperglycemia in some patients.

Mostly dependent on oral hypoglycemic agents. As the disease progresses, -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 cells

PANCREAS

Insulin

ADIPOSETISSUE

MUSCLE

Glucose

LIVER

Increased productionof glucose

Decreasedglucose uptake


Comparison of Type 1 and Type 2 diabetes

Age of onset

Nutritional status at time of onset

Prevalence

Genetic predisposition

Defect or deficiency

Type 1(Insulin-dependent

diabetes)

Type 2(Non-insulin-

dependent diabetes)

Usually during childhood or puberty

Frequently undernourished

10 to 20 percent of diagnosed diabetics

Moderate

Cells are destroyed, eliminating the production of insulin

Frequently over age 35

Obesity usually present

80 to 90 percent of diagnosed diabetics

Very strong

Inability of cells to produce appropriate quantities of insulin; insulin resistance; other defects


INSULIN AND ITS ANALOGS [IN su lin]

polypeptide hormone; two peptide chains connected by disulfide bonds. Synthesized as a precursor (pro-insulin) proteolytic cleavage insulin and peptide C - both are secreted by b-cells.

[Note: Normal individuals secrete less pro-insulin than insulin; Type 2 secrete high levels of the prohormone. RIAs do not distinguish between these two types Type 2 may have lower levels of insulin than the assay indicates measurement of circulating C peptide = a better index of insulin levels.] Sources: Human insulin - replaced I. from beef or pork pancreas. By recombinant DNA technology - special strains of E. coli or yeast - genetically altered to contain the gene for human insulin. Modifications of amino acid sequence different pharmacokin. properties:insulins-lispro, aspart, and glulisine - faster onset and shorter duration of action than regular insulin (they do not aggregate or form complexes). insulin glargine and insulin detimir - long-acting, prolonged, flat levels of the hormone following a single injection.

Insulin secretion

Regulated not only by blood glucose but also by certain amino acids, other hormones, and mediators.

Triggered by high blood glucose – it is taken up by glucose transporter into -cells - there phosphorylated by glucokinase - products of glucose metabolism enter the mitochondrial respiratory chain – generation of ATP.

in ATP block of K+ channels membrane depolarization influx of Ca2+ insulin exocytosis (some oral antidiabetics – sulfonylureas, meglitinides - hypoglycemic effect due to inhibition of the K+ channels).

[Note: Glucose by injection - a weaker effect on insulin secretion than orally - orally, glucose stimulates production of digestive hormones by the gut, which in turn stimulate insulin secretion by the pancreas.]

Administration

Polypeptide degraded in GIT if taken orally mostly by subcutaneous injection (in a hyperglycemic emergency, regular insulin intravenously - its plasma half-life ≤ 9 minutes ).

Continuous s.c. infusion also - it does not require multiple injections.

Aerosol preparation (inhaled and absorbed in the deep lung) or oral spray (absorbed through the buccal mucosa) - in trials

Preparations vary in their onset and in durations of activity (due to the size and composition of the insulin crystals and AA sequences - the less soluble the longer action).

Dose, site of injection, blood supply, temperature, and physical activity can affect the duration of action of the various preparations.

Inactivated by the reducing enzyme, insulinase (mainly in the liver and kidney).

Adverse reactions to insulin

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

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 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

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.

Insulin lispro [LIS proe], insulin aspart [AS part], insulin glulisine [gloo LYSE een]: rapid onset and short duration of action - ultrashort-acting insulins; possibility of more flexible treatment regimens and risk of hypoglycemia.

Lispro insulin: differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed more rapid absorption after s.c. inj. than after regular insulin acts more rapidly and has shorter duration of activity. Usually 15 mins prior to a meal, peak levels - 30 to 90 mins after inj. (regular insulin 50 to 120 mins). Also for i.v. administration.

Advantage - low propensity (in contrast to human insulin) to self-associate in antiparallel fashion and form dimers. Rapidly absorbed (onset of action 5-15 min; peak activity 1 hour).

Aspart insulin and glulisine insulin - pharmacokinetic and pharmacodynamic properties similar to lispro

Aspart insulin - by substitution of the B28 proline with aspartic acid it reduces insulin self-aggregation. Absorption and activity profile - similar to insulin lispro; more reproducible than regular insulin.Insulin glulisine - by substituting an asparagine for lysine at B3 and glutamic acid for lysine at B29. Absorption, action, immunologic characteristics are similar to other injected rapid-acting insulins.

Administered to mimic the prandial (mealtime) release of insulin; usually not used alone but with a longer-acting insulin to assure glucose control (e.g., glulisine can be taken either 15 min before or within 20 min after starting a meal).Administered s.c. [Note: Uspro insulin - preferred for external insulin pumps over the buffered form of regular insulin - it does not form hexamers. However, reports of precipitation of lispro insulin in infusion catheters were described, resulting in fluctuations in glucose control.]

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, protamine.

Intermediate duration of action (due to delayed absorption of the insulin - complex with protamine is less-soluble complex). Onset cca 2-5 hours; duration of 4-12 hours

Only s.c. (never i.v.).

Use in all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia. Usually given along with regular lispro, aspart, or glulisine insulin. Given 2-4 times daily in patients with type 1 diabetes. /Note: A similar compound called neutral protamine Iyspro (NPL) insulin/

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 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.

Onset and duration of action of human insulin and insulin analogs.

0 6 12 18 24 Hours

Rel

ativ

e pl

asm

a in

sulin

leve

l

Glulisine insulin

Aspart insulin, lispro insulinRegular insulin NPH insulin

Extended zinc insulin

Glargine 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, myocardial infarction).

During pregnancy, for gestational diabetes not controlled by diet alone.

Emergency treatment of hyperkalaemia: insulin is given with glucose to lower extracellular K+ via redistribution into cells.

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 diabetes.

A. Sulfonylureas

Insulin secretagogues (they promote insulin release from the -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

Administration, fate: given orally, metabolized by the liver, and excreted by the liver or kidney. Contraindicated in patients with hepatic or renal insuficiency (delayed excretion of the drug may cause hypoglycemia).

Renal impairment - particular problem in agents that are metabolized to active compounds (e.g., glyburide and glimepiride). They traverse the placenta - can deplete insulin from the fetal pancreas pregnant women with Type 2 diabetes should be treated with insulin.

All bind strongly to plasma albumins »»» interactions with other drugs (e.g. salicylates, sulfonamides) which compete for binding sites »»» hypoglycaemia Not used in type I diabetes.

Adverse effects:- hypoglycemia- disulfiram-like reactions (flushing, nausea, headache after alcohol)- allergic reactions- GIT disturbances - weight gain, hyperinsulinemia, and hypoglycemia

Drugs interacting with sulfonylurea drugs

Sulfonylureas

Sulfonylureas

Increased hypoglycemic actionof sulfonylurea drugs

Reduce hepatic metabolism of sulfonylureas

DicumarolChloramphenicol

Monoamine oxidase inhibitorsPnehylbutazone

ClofibratePhenylbutazone

SalicylatesSulfonamides

AllopurinolProbenecid

PhenylbutazoneSalicylates

Sulfonamides

Displace sulfonyl-ureas from plasma

protein

Decrease urinaryexcretion of

sulfonylureas ortheir metabolites


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 -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.

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 repaglinide

- 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:

Largely GIT.

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 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 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- (PPAR) - a nuclear hormone receptor. Ligands for PPAR 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 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 thereafter.

- weight increase (possibly through the ability of TZDs to increase subcutaneous fat or due to fluid retention - it can lead to or worsen heart failure)

- headache and anemia

- Women taking oral contraceptives and TZDs may become pregnant, because the TZDs reduce plasma concentrations of the estrogen-containing contraceptives.

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: -GLUCOSIDASE INHIBITORS

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 -glucosidase in the intestinal brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars (Acarbose also inhibits pancreatic -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.]

2. Pharmacokinetics:

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

Duration of action of some oral hypoglycemicagents

Tolbutamide

Glyburide

Glipizide

Glyburide

Nateglinide

Repaglinide

Metformin

Pioglitazone

Rosiglitazone

Acarbose

Miglitol

8 hrs

18 hrs

20 hrs

24 hrs

2 hrs

2 hrs

6 hrs

>24 hrs

>24 hrs

6 hrs

6 hrs(according to Lippincott´s Pharmacology, 2006

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 (-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 including glucose.

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 cell regeneration or decreased apoptosis. weight gain, postprandial hyperglycemia, and loss of 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.

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