Hormonal pharmacotherapy

Ján Mojžiš

GLUCOCORTICOIDS AND MINERALOCORTICOIDS

2

Glucocorticoids



well absorbed in GIT (i.v.; i.m.; locally)



90% of hydrocortisone is bound to albumin and



transcortin (specific corticosteroid binding globulin) 70% of cortisole – metabolised in liver by

 

microsomal enzymes to hydrocortisone synthetic corticoids – the same fate prednisone and methylprednisone (prodrugs) – prednisolone and methylprednisolone



excretion by the kidney as gluco- or sulfoconjugates

3

Mechanism of action

4

Glucocorticoids actions



glycogenolysis and gluconeogenesis



protein catabolism and



protein synthesis



lipolysis; redistribution of body fat



intestinal calcium absorption; decreased osteoblast formation and activity



secretion of gastric acid and pepsin CVS – restrict capillary permeability, maintain tone of arterioles and myocardial contractility

5

Glucocorticoids actions –

cont.

 

CNS – euphoria, insomnia, anxiety, motor activity; high dose –proepileptic effects blood cells -



of eosinophils, basophils, monocytes, lymphocytes;



in circulating phagocytes -



ability of the body to fight infections



suppression of all types of hypersensitivity

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Glucocorticoids actions –

cont.



inflammatory responses (basis of the most of their clinical uses); nonspecific action, covers all stages and components of inflammation such as:



increased capillary permeability



local exudation



cellular infiltration



phagocytic activity



collagen deposition



fibroblastic activity



scar formation

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Indications

A: Replacement therapy 1. acute adrenal insufficieny 2. chronic adrenal insufficieny (Addison ´s disease) - hydrocortisone is givent to correct the defficiency; 2/3 morning , 1/3 afternoon; failure of therapy - death

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Indications –

cont.

B: Pharmacotherapy of non-endocrinne diseases 1. Arthritis rheumatoid arthritis, osteoarthritis; rheumatic fever, gout (NSAID are trefered) 2. Collagen disease systemic lupus erythematosus, dermatomyositis, glomerulonephritis (therapy started with high dose) 3. Severe allergic reactions for short period in anaphylaxis, urticaria, angioedema

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Indications –

cont.

4. Autoimmune diseases haemolytic anemia, trombocytopenia 5. Respiratory tract bronchial asthma, aspiration pneumonia, pulmonary edema 6. Eye large number of inflammatory ocular diseases topically allergic conjuctivitis, iritis, keratitis etc.

should not be used in infective conditions 7. Skin topicaly – eczematous skin diseases systemicaly – pemfigus vulgaric, exfoliative dermatitis

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Indications –

cont.

8. GIT ulcerative colitis, Crohn ´s disease corticosteroid are indicated in acute exacerbation 9. CNS cerebral edema due to tumor, meningitis, cerebral/spinal injury 10. malignancies essential in acute lymphatic leukemia Hodgkin ´s disease and other lymphomas 11. organ transplantation

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Side effects



suppression of immune system (rendering the patient vulnerable to common infections)



osteoporosis (rendering the patient vulnerable to fractures)



peptic ulcer



suppression of growth in children



reproductive problems



edema, hypertension

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Side effects

– cont.



fragile skin



diabetes mellitus



muscular weakness



delayed healing of wounds and surgical incisions



psychiatric disturbancies



development of cushingoid habitus

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Cushing syndrome

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SEX HORMONES

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sex hormones are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty

17

Female sex hormones

Estrogens



major estrogens estradiol , estrone , and estriol



at puberty cause growth of breast, accumulation of fat, pubic and auxillary hair growth, femine body contours and behaviour are affected



estrogens are anabolic, maintain bone mass

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Actions of estrogens

ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy uterus : endometrial growth vagina : cornification of epithelial cells with thickening and stratification of epithelium cervix : increase of cervical mucous with a lowered viscosity (favoring sperm access)

19

Actions of estrogens

skin : increase in vascularization, development of soft, textured and smooth skin bone : increase osteoblastic activity electrolytes : retention of Na + , Cl and water by the kidney cholesterol : hypocholesterolemic effect

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Receptor Actions in Cells E Estrogen Growth Factors GF Peptides and Neurotransmitters E R Signaling E Second Messengers and Protein Kinase Cascades E EREs R E R E Receptor Co-Regulators TAFs A B TBP TATA F pol II Transcription (B. Katzenellenbogen et al.

Recent Prog. Horm. Res

.,2000)

22

Therapeutic uses of estrogens

a) for replacement therapy in deficient patients b) for contraception c) therapy of prostatic cancer and some brest cancer d) menstrual disorders e) suppression of lactation

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Postmenopausal hormone therapy



estrogen therapy is used in women experiencing „hot flashes“, „atrophic vaginitis“ and in women who wish to reduce risk of osteoporosis



the doses of estrogens are approximately 1/5 of doses used in oral contraception



less risk of adverse reactions

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FDA

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Primary hypogonadism



estrogen therapy (in combination with progestin) stimulates development of secondary sex characteristic in young women (11-13 years of age) with hypogonadism

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Estrogens: direct effects on the vascular wall

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Treatment of metastatic breast cancer



if estrogen receptors can be demonstrated in the neoplastic tissue - administration of large doses of estrogens may lead to arrest or regression of breast tumor growth

29

Pharmacology



naturally occuring estrogens and their derivates - well absorbed from GIT, skin, mucous membranes, and also if given intramusculary



significant first-pass effect



synthetic estrogens (ethinyl estradiol, mestranole) -well absorbed, metabolized more slowly



inactive metabolits are eliminated in urine

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Adverse reactions



nausea and vomiting



breast tenderness, endometrial hyperplasia, postmenopausal bleeding



hyperpigmentation, hypertension, migraine headache



edema - sodium and water retention



decreased bile flow - cholestasis and gallbladder diesease

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Contraindications



estrogen-dependent neoplasia



thromboembolic disease



liver disease



coronary or cerebral arterial diesease

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Antiestrogens



modify or oppose the action of estrogens



tamoxifen, clomiphene



they have been used to treat infertility



tamoxifen is currently used in the treatment of breast cancer in postmenopausal women



side effect - ovarian enlargement

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Female sex hormones

Progestins



most important progestin -

progesterone



mechanism of action - similar to estrogen



therapeutic uses



major clinical use – contraception



other - control of uterine bleeding, endometrial carcinomas

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PROGESTERONE

CH 3 C O Natural hormone secreted by the corpus luteum and the placenta H O H H PROGESTERONE it is also an important intermediate in steroid biogenesis in all tissues that produce steroids (testes, adrenal cortex) Intestinal absorption is quite erratic; must be micronized for most effective absoption

Pharmacology



rapid absorption after administration by any route



short half-life - rapidly metabolized



synthetic progestins (medroxyprogesterone, norethindrone) are less rapidly metabolized

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Adverse reactions



weight gain



edema



depression



rare thrombophlebitis and pulmonary embolism

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Antiprogestin



mifepristone - progestin antagonist



in early pregnancy - abortus of the fetus



side effect - uterine bleeding

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Ligands for Progesterone Receptor H 3 C O O Progesterone [natural] Progestins OH H O Norethindrone [oral contraceptives] Et O Et H H 3 C O OAc O O CH 3 Medroxyprogesterone Acetate (MPA) [HRT] R5020 (Promegestone) H 3 C O H Et O ORG2058 Antiprogestins H 3 C N CH 3 OH CH 3 O RU486 (Mifepristone) H 3 C N CH 3 OH OH O ZK98299 (Onapristone)

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Oral contraceptives

– cont.

Combination pills



products containing estrogen + progestin most common oral contraceptives



the pills are taken for 21 days followed by a 7 days withdrawal period to induce menses

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Oral contraceptives

– cont.

Progestin pills



only progestin is present (norethindrone, norgestrel)



less effective than combination pills



may produce irregular menstrual cycle Progestin implants



subdermal capsules (levonorgestrel) - long term



contraception six capsules are placed subcutaneously in upper arm - progestin is slowly released - contraceptive protection approximately 5 years

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Oral contraceptives

– cont.

Postcoital contraception



high doses of estrogen (diethylstilbestrole) is administered within 72 hours of coitus and continued twice daily for 5 days



should be reserved for unexpected or accidental exposure only (rape, condom rupture) – higher failure rate and side effects

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Adverse effects

Major adverse effects



breast fullness, depression, dizziness, edema, headache, nausea, vomiting Cardiovascular

 

in women who smoke and over 35 years of age thromboembolism, thrombophlebitis, hypertension, myocardial infarction, coronary thrombosis Metabolic



decreased dietary carbohydrate absorption

 

abnormal glucose tolerance test progestin causes increase LDL and decrease HDL - estrogen has the opposite effect

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Male sex hormones



Androgens prototype is testosterone (produced by interstitial cells of testis)



main function: development and maintenance of primary and secondary sex characteristics in males (androgenic)



protein retention (anabolic action)



other naturally occuring androgens: androsterone, isoandrosterone, dehydroandrosterone, dehydroisoandrosterone

Physiological effects of testosterone



enlargement of testes, penis and scrotum



pubic and axillary hair



bone growth



red cell mass increase



skeletal muscle mass increase



larynx enlarges - deepening of the voice



increase in sebaceous glands - often cause of acne



beard development

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Uses for androgens



replacement therapy in hypogonadism



delayed puberty



cryptorchidism



metastatic breast cancer in women



postpartum breast pain/engorgement



male climacteric

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Pharmacology



testosterone cannot be given orally - first pass effect



inactive metabolits are excreted in urine



testosterone is administered intramuscularly



testosterone derivate (fluoxymesterone) has longer half-life



it may be given orally

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Adverse effects

in females



masculinization



growth of facial hair



deepening of the voice



acne



excessive muscle development



menstrual irregularity



contraindicated in pregnancy - virilization of female fetus

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Adverse effects –

cont .

in males



gynecomastia (conversion testosterone to estradiol in patints vith liver disease)



decreased spermatogenesis



painful erection at the beginig of the therapy in children



growth disturbances



abnormal sexual maturation

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Adverse effects –

cont .



androgens increase serum LDL and lower HDL levels



they can cause fluid retention - edema



use of anabolic steroids by athletes - premature closing of the epiphysis of the long bone

 

hepatic abnormalities, jaundice hepatic carcinoma – longterm therapy with methyltestosterone



increased agression

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Antiandrogens

cyproterone, flutamide



they inhibit action of the androgens at the target cell



they are used to treat hirsutism in females and prostatic carcinoma in males

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THYROID HORMONES

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Introduction

the thyroid gland facilitates normal growth and maturation by maintaining of metabolism major thyroid hormones - T3 - triiodotyronine T4 - thyroxine

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T3 and T4 actions

1. Growth and development



essential for normal growth and development 2. Intermediary metabolism



indirectly enhanced lipolysis (potentiating of catecholamines)



stimulation of lipogenesis (conversion of chol. to bile acids)



stimulation of carbohydrate metabolism



catabolism of proteins (T4)

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T3 and T4 actions

– cont .

3. Calorigenesis - increased basal metabolic rate by stimulation of cellular metabolism 4. CVS - stimulation of heart 5. GIT 6. CNS – constipation (hypo), diarrhea (hyper) – mental retardation (hypothyr.), nervousness, excitability, tremor (hyperthyr.) 6. Haemopoesis – T4 simulates erythropoesis 7. Reproduction – impaired feritility (hypo)

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Thyroid gland is not essential for life, but…..

hypothyroidsm



low metabolic rate



slow speach



deep hoarse voice



lethargy



bradycardia



poor resistance to cold



during development - cretinism



mental deficiency



retardation of growth

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hyperthyroidism



tachycardia and cardiac arrhytmias



nervousnes



tremor



excess heat production



increased appetite associated wit loss of weight several drugs may depress thyroid function NSAID, glucocorticoides, X-ray contrast agents,



- and



-antagonists, sulphonylurea

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Treatment of hyperthyreoidism

(Thyreotoxicosis) goal of therapy - decrease synthesis and/or release hormone a) removal part or all of the thyroid gland b) inhibition of synthesis of the hormone c) blocking release of the hormones from the follicle

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Removal part or all of the thyroid gland

either surgically or by destruction of the gland by radioactive iodine ( 131 I)

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Inhibition of synthesis of the hormone

thioamides (carbimazole, propylthiouracil, methimazole) inhibit synthesis of hormones (

inhibit thyroid peroxidase) 

they have no effect on the thyreoglobulin alredy stored in the gland - clinical response may take several weeks or even month



they may be used as the main treatment of diffuse goitre or before surgery

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Adverse effects



skin (exanthema, erythema, urtica)



GIT (pain, nausea, vomiting, cholestatic hepatitis)



blood (leuko- and thrombocytopenia, aplastic a.



most severe complication



agranulocytosis



Lyell ´s syndrome (drug-induced skin toxic reaction - 50% lethality) Lyell ´s syndrome

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PROPYLTHIOURACIL dose to dose less potent highly plasma protein bound transfer to placenta, milk



plasma t 1/2 1-2 hours single dose acts for 4-8 hours no active metabolites 2-3 daily doses needed CARBIMAZOLE about 3x more potent less boud transfer to placenta, milk



6-10 hours 12-24 hours active metabolite - methimazole single daily dose

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Blockage of hormone release

iodide inhibits release of thyroid hormone mechanism not clear



it is rarely used as monotherapy



main use of iodine - preparation of hyperthyreoid subject for surgery



treatment of severe thyreotoxic crisis



iodide is not useful for long-term therapy

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Iodide

–

cont.



it is administerd orally



adverse effects - minor



sore mouth



metallic taste in the mouth



ulceration of mucous membranes



oversalivation



acne



alergy

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Drugs used in hypothyroidism

     

thyroid hormones are used

thyroxine

and

triiodothyronine

are given orally thyroxine - peak action is in 9 days triiodothyronine - peak action is in 1-2 d.

thyroxine is a drug of choice side effects - similar to those of hyperthyroidism

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Maine indications

1. Cretenism



thyroxine 6-8



g/kg – ASAP, because mental



retardation is only partially reversible dramatic response – growth and development are restored 2. Adult hypothyroidism



thyroxine, 50



g daily

 

g/day after 2-3 weeks 100-200 3. Nontoxic goiter



may be endemic (iodine deficiency) or sporadic (defect in hormone synthesis); T4 is used

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