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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
Crme 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