Farmacologia sistemului endocrin

Hormonii sexuali

Estrogeni

Estrogeni - biosinteza

Estrogeni biosinteza

• Aromataza (CYP19) + NADPH + O2• NADPH – citocrom P450 reductaza• Localizare: RE celule granulosa ovar, Sertoli si

Leydig testiculare, stroma t. adipos, sincititrofoblast placenta, os, creier, etc…

• Ovar – pricipala sursa pre-menopauza – estradiol (Gonadotropine – cAMP – aromataza/ Scc)

• Stroma t. adipos – postmenopauza – estrona (din DHEA suprarenal)

Efecte fiziologice si farmacologice

• Dezvoltare– Modificari pubertate – caractere sexuale

secundare– Crestere oase lungi, inchidere epifize

• Metabolic– Os: osteoblast – sinteza colagen I, osteocalcin,

osteopontin, osteonectin• Inhiba osteoclaste (citokine osteoblast)

– Lipidic: colesterol total, HDL, LDL, LPA, TG

Receptori estrogeni - ,

PK• Oral

– Estradiol, estrogeni conjugati, esteri estrona, ethinyl estradiol (+progestin)

– Micronizare – suprafata marita pt absorbtie rapida – OTC – flavonoizi – genisteina

• Patch transdermic – eliberare prelungita– Emulsie topica (estradiol) – minimizare efecte hepatice– I.M – solvent – ulei – estradiol valerat/ cipionat – eliberare lenta – Crème vaginale

• Legare plasmatica – SHBG/ albumina• Biotransformare hepatica – estriol – urina• Recirculare enterohepatica• Etinil estradiol – clearance lung (t1/2 = 13-27h)

EA

• Carcinogenicitate– Endometru (+ progestin)– San

• Metabolic si cardiovascular– Efect general favorabil (desi TG) – Creste colesterol bila – Efect incert de protectie cardiovasculara (postmenopauza)– Cresc risc tromboembolic

• Cognitie – incert• Alte efecte: greata, inflamatie/ edem san, migrena

Utilizare terapeutica

• Terapie substitutie hormonala – menopauza• Estrogeni conjugati (istoric) – ethinyl estradiol

(curent)– Simptome vasomotorii– Osteoporoza – preventie– Vaginita atrofica

• Terapia substitutie – asociere progestagen (preventie efect endometru)

Modulatori selectivi si antagonisti ai receptorilor de estrogen

• Model complex de interactiune – 2 receptori, seturi diferite de co-activatori/ co-represori

• SERMs – Tamoxifen, Raloxifen, Toremifen– Actiuni tisulare specifice• Efecte estrogenice – os, creier, ficat• Efecte antiestrogenice – san, edometru

• Tamoxifen, toremifen – chimioterapie cancer san

• Raloxifen – preventie/ tratament osteoporoza

Antiestrogeni

• Clomifen, Fulvestrant• Antagonisti puri in toate tesuturile• Clomifen – tratament infertilitate (anovulatie)– Creste amplitudinea pulsurilor LH, FSH (nu

modifica frecventa)• Fulvestrant – cancer de san rezistent la

tamoxifen– Afinitate ER , - reprima transactivarea• Cresc degradarea proteolitica ER alpha

Inhibitori sinteza estrogeni

• Agonisti GnRH – blocheaza biosinteza ovariana, dar nu cea periferica din androgeni suprarenali

• Aminoglutetimida – inhibitor aromataza • Alti inhibitori ai aromatazei– Steroizi: formestane, exemestane

• Analogi substrat – inhibitori suicid

– Non-steroidici: anastrozole, letrozole, vorozole• Inhibitori reversibili grup hem – CYP

– Utilitate: adjuvanti sau prima linie – cancer de san

Progestine

Efecte fiziologice si farmacologice• Neuroendocrin

– Produs in faza luteala – scade frecventa pulsurilor GnRH – tranzitie luteal – folicular (mecanism contraceptiv)

• Reproductiv– Endometru secretor

• Glande mamare– Impreuna cu estrogeni – proliferare acini

• SNC– Crestere temperatura ovulatie (0,6 C)– Depresie centrala, hipnotic

• Metabolic– Creste insulina– Creste depunerea de grasime (lipoprotein lipaza)– Creste LDL

MA, PK, utilizare• 2 receptori – PR-A si PR-B

– PR-B – efecte stimulatoare progesteron– PR-A – inhibitor efecte PR-B si alti steroizi

• PK– Progesteron – prim pasaj

• Micronizare (doze mari)• Solutii uleioase injectabil, gel vaginal, dispozitiv intravaginal

– Esteri (MPA, megestrol acetat) – oral – Legare - albumina, CBG (nu SHBG)– T1/2 – progesteron 5 min; sintetici 7- 20 h

• Utilizare terapeutica– Contraceptive (unic sau in combinatie cu estrogeni)– Terapie hormonala postmenopauza– Aplicatie intrauterina – hiperplazie endometriala– Contraceptie de urgenta – 72h

Anti-progestine si modulatori ai receptorilor

• Mifepristone (RU-486)– Antagonist competitiv ambii receptori (+glucocorticoizi,

androgeni)– Activitate agonist in anumite situatii– Onapristone – antagonist pur– Terminarea precoce a sarcinii – degradare deciduala – detasare

blastocist – scadere hCG• Ulipristal– Modulator selectiv al receptorilor progesteron– Inhibare ovulatie (LH)– Contraceptie de urgenta (72h)

Contraceptia orala• Combinatie

– Estrogen + progestin– Mono, bi, trifazic – 21 + 7– Modern = low dose

• < 35 microg estrogen

• Progestageni unici– Norethindrone – zilnic – MPA – suspensie cristalina – i.m – 3 luni

• MA– Combinatie – preventie ovulatie

• Supresie FSH, LH; abolire peak LH • Efect sinergic

– Progestine• Blocheaza ovulatia in 60-80% cicluri• Ingrosare mucus cervical, modificari endometriale - implantare

Efecte adverse• Cardiovascular

– IM, AVC – risc 0 pentru nefumatori, fara f. risc (HT, DZ)– Tromboembolism venos – Hipertensiune

• Cancer– In general, preparatele noi nu sunt asociate– Cervical (X2, termen lung, > 5 ani)– Hepatic (adenom, adenocarcinom)– San – foarte scazut– Endometrial – risc scazut cu 50%

• Metabolic si endocrin– Intoleranta glucoza, dislipidemii – minor– Proteine carrier ficat – h. tiroidieni– Proteine coagulare

• Altele: greata, edem, cefalee, migrene

Contraindicatii

• Absolute:– Boala tromboembolica (+ istoric)– Boala cerebrovasculara– IM– Boala coronariana– Hiperlipidemie congenitala– Cancer san (+suspectie) sau tract reproductiv– Sarcina

• Risc crescut: femei >35 ani, fumatoare (>15)• Relative: migrena, hipertensiune, DZ, b. biliara

Androgeni

Metabolism testosteron

• 5 - reductaza – DHT• Tisular – DHT

afinitate > testo• Aromataza – ficat,

tesut adipos

Efecte biologice

Preparate terapeutice testosteron

• Inactiv oral – pasaj hepatic• Esteri de testosteron– Creste liposolubilitatea– Enantat, Cypionat, Undecanoat– Solvent – ulei – i.m. – la 2-4 sapt. (hipogonadism)

• Testosteron alchilat– Intarziere catabolism hepatic– Metiltestosteron, oxandrolone, stanozolol, danazol

• Transdermic – excipienti – patch, gel• Androgeni alchilati cu efect selectiv anabolic

Utilizare terapeutica• Hipogonadism masculin• Senescenta masculina• Hipogonadism feminin• Cresterea performantei atletice– DHEA, androstenedione, tetrahidrogestrinone (THG)– EA: supresie gonadotropine – infertilitate

• Conversie estrogeni• Hepatotoxicitate• Dislipidemie • Virilizare (femei, copii)

• Contraceptie masculina• Stari catabolice• Eritropoietic

Antiandrogeni

• Inhibitori ai secretiei– Analogi GnRH – inhiba LH– Utilitate – cancer prostata– Ketoconazol (antifungic) – inhibitori CYP – testosteron,

cortizol• Antagonisti receptori– Flutamida, Bicalutamida, Nilutamida– In conjunctie cu analog GnRH (stimulare feedback)– Spironolactona– Ciproteron acetat– Utilitate: cancer prostata, hirsutism

Antiandrogeni

• Inhibitori 5 reductaza– Finasteride, dutasteride – Tratament hiperplazie prostatica benigna– Finasteride – alopecie masculina