Drugs for reproductive system Flashcards
What hormone are involved in reproductive pharmacology?
GnRH = released by hypothalamus (pulsatile)
LH, FSH = released by anterior pituitary
Inhibin = inhibits anterior pituitary
Oestrogen
Progesterone
Testosterone
DHT
Explain the role/mechanism of hypothalamic pituitary gonadal axis in women (how eostrogen/proge produced)
Hypothalamus —> GnRH –> Ant pit –> FSH + LH –> ovary –> follicle releases oestrogen, corpus luteum releases progesterone –> inhibit ant pit (both), hypothalamus (progesterone only)
Explain the role/mechanism of hypothalamic pituitary gonadal axis in men(how testosterone produced)
Hypothalamus –> GnRH –> Ant Pit –> FSH and ICSH –> stimulate sertoli cells (FSH) and interstitial cells (ICSH) –> interstitial cells produce testosterone –> testosterone stimulates sertoli cells or becomes dihydrotestosterone
What are the physiological effects of oestrogen?
Growth of vaginal epithelium
Growth of endometrium
Lowers plasma cholesterol
behavioural effects
Liver synthesis of transport proteins
inc blood coagulability
Maintains skin structure
reduces bowel motility
Dec rate of bone resorption
Ovarian follicle
mammary gland
What does pulsatile (low dose) GnRH stimulation do to FSH and LH?
Inc FSH and LH release
What does continuous (high dose) GnRH stimulation do to FSH and LH?
Dec FSH and LH release
List the relevant GnRH agonists used in reproductive pharmacology
- end in -relin
Goserelin
Leuprorelin
Nafarelin
Triptorelin
What is the MOA of GnRH agonists?
GnRH causes initial stimulation of FSH and LH
Continuous administration –> negative feedback –> dec FSH and LH and ICSH —> dec oestrogen, dec testosterone
What are the indications for GnRH agonists?
Precocious puberty in boys/girls
Prostate cancer, breast cancer, endometriosis
uterine fibrosis
What are the endogenous oestrogens?
Oestrone
Oestradiol
Oestriol
Not typically active
What are the synthetic steroid oestrogens?
Ethinyloestradiol
Mestranol
Tibolone
What are the synthetic non steroidal oestrogens?
Diethystilbosterol
Hexestrol
Dienestrol
What is the MOA of oestrogen?
Oestrogen –> binds oestrogen receptor (ERalpha and ERbeta)–> forms GR dimer –> crosses into lipid membrane –> binds to response element –> enters nucleus –> gene transcription and translation
What are the differences between oestradiol, oestrone, and oestriol?
oestradiol = principle oestrogenic hormone
Oestrone - metabolite of oestradiol, 1/3rd as active as oestradiol
- primarily present after menopause
- generated from androstenedione in peripheral tissue
oestriol - oestradiol metabolite
- sig less potent than oestradiol
Outline some of the pharmacokinetic properties of oestrogens?
Natural oestrogens –> inactive orally due to hepatic metabolism (need esterification or conjugation)
In circulation –> bound to sec steroid binding globulin, distributed and concentrated in fat
Undergo enterohepatic cycling = conjugated metabolites –> excreted in bile –> converted to free oestrogens by intestinal bacteria
Conjugated equine oestrogen = undergo little 1st pass metabolism, converted hepatically to sulfate and glucuronide conjugates
What is the most common oestrogen used in HRT?
estradiol
What are some ADRs of oestrogens?
Nausea (dose dependent)
For males in prostate cancer = suppression of libido, gynaecomastia, feminisation
Cholestatic jaundice, Thromboembolism, Hypertension, Migraine headache
Vaginal and cervical carcinoma
What are the C/I and Cautions for oestrogen use? (think diff than PPP)
C/I = preg, uterine fibroids
Caution = hepatic disorders, endometriosis, thromboembolic disease, hypercalcaemia
What drugs belong to the class of selective oestrogen receptor modulators (SERMs)?
Clomiphene
Tamoxifen
Raloxifene
Tibolone, bazedoxifene
What is the MOA of clomifene?
Moderate antagonist, weak agonist
Binds to the oestrogen receptors on hypothalamus and pituitary —> inhibits oestrogen mediated negative feedback of HPA —> stimulate release of LH and FSH
When is clomiphene primarily used?
Anovulatory infertility
Also effective in fertility associated with PCOS
Tx typically started at around day 5 of the cycle
What are the ADRs of clomifene?
polycystic overaies
Multiple pregnancies
Hot flushes
Gastric upset
Inc risk of ovarian cancer
What is tamoxifen and how does it work?
Both oestrogenic and antioestrogenic
MOA = competes w/ oestrogen for binding to ER in breast tissue
- potent oestrogen receptor antagonist in breast carcinoma cells, blood vessels, peripheral tissues
Partial agonist in uterus, bone, liver, pituitary
- action = stimulation of endometrial proliferation, lower Gn and prolactin levels in postmenopausal women, improve bone density –> weak oestrogenic effect
What is the primary use of tamoxifen?
Prevent or treat breast cancer in patients w/ ER positive tumour cells
- adjuvant to surgery or other chemo
- alone in advanced stages for palliative care
What are some pk properties of tamoxifen? (metabolism? enzyme genetic mutations?)
Orally active, extensively metabolically metabolised by CYP
Metabolised by CYP3A4 and CYP2D6
Active metabolite 4-OH tamoxifen
Less active in women lack CYP2D6 enzymes
- 6-10% caucasians (underexpressed); 1-2% asians (overexpressed)
What effect does raloxifene have on oestrogen?
Oestrogen agonist - bone mass and lipids
Oestrogen antagonist - breast and endometrium
Dec bone resorption, bone turnover = inc bone density and dec vertebral fractures
What are some ADRs associated with tamoxifen?
Hot flushes, sweating, vomiting
Vaginal bleeding, menstrual irregularities
Inc risk of endometrial cancer
What is raloxifene mainly used for?
Prevention and treatment of postmenopausal osteoporosis
Prevention of invasive breast cancer in high risk postmenopausal women
What are the ADRs associated with raloxifene?
Inc stroke risk, pulmonary embolism, DVT
What is tibolone? Where/how does it work? (oestrogenic, progestogenic, androgenic effects?)
Combined oestrogenic, progestogenic, androgenic properties
Acts as oestrogen in: vagina, bone, thermoreg centres of brain
Breast and endometrium = progestogenic and antiestrogenic
Androgenic effects = dec HDL, TG, lipoproteins
What are the main uses and ADRs of tibolone?
Main use = menopausal sx and prevention of osteoporosis
ADRs = vaginal bleeding, spotting, discharge and itching, breast and abdominal pain, weight gain
What are the effects of bazedoxifene w/ conjugated oestrogens?
Oestrogenic on bone
Anti-oestrogenic on breast, uterine tissue
Reduces risk = endometrial cancers associated w/ unopposed oestrogen
What progestin agents are similar to progesterone?
Progesterone
Medroxyprogesterone acetate
(they are the endogenous kinds)
What progestin agents are similar to 19-Nortestosterone?
19-nortesterone
Norethidrone (norethisterone)
What progestin agents are similar to 19-Norgestrel?
Norgestrel
Norgestimate
etonogestrel
levonorgestrel
What are some other progestins?
Dienogest, drospirenone
Gestodene, cyproterone
What are the ADRs of progesterone/progestogen use?
Breast engorgement, headache, rise in body temp, oedema, mood swings
Irregular bleeding or amenorrhoea
19-norethisterone derivates = inc LDL –> promote atherogenesis
Inc blood sugar, precipitates diabetes
Masculinization of female foetus or congenital abnormalities
What are the main uses for progesterones/progestins?
As contraceptive
HRT
Dysfunctional uterine bleeding
Endometriosis
What is mifepristone? How/when give? What do?
19-norsteroid with potent competitive antiprogestational and significant antiglucocorticoid, antiandrogenic activity
Given/MOA during follicular phase –> attenuates midcycle surge of GnRH –> slow follicular development –> failure to ovulate
Given/MOA for luteal phase = prevents secretory changes brought about by progesterone
Given/MOA later in cycle = blocks progesterone support to the endometrium –> unrestrains PG release –> stimulate uterine contraction
What are the uses of mifepristone?
Medical termination of preg
Cervical ripening
Cushing’s syndrome
What is the MOA of hormonal contraceptive pill?
Oestrogen inhibits FSH sec –> suppress development of ovarian cycle
Progest inhibits LH sec –> prevents ovulation and makes cervical mucus less suitable for sperm
Combined = alter endometrium to discourage implantation
What progestogens are in the progesterone only pill?
Levonorgestrel
Progesterone
Dienogest
Drospirenone
Etonogesterel
Medroxyprogesterone
Norethisterone
What are the ADRs associated w/ progesterone only pill?
Menstrual disturbances
Prolonged bleeding
amenorrhea, breast tenderness
depression
acne
What is the main effect of androgens on the male sex organ, bone, kidney, muscle?
Muscle = inc strength and vol
Male sex organ = penil growth, spermatogenesis, prostate growth + func
Bone = accelerated linear growth, closure of epiphyses
Kidney = stimulation of erythropoietin production
What is the role of testosterone on different tissue?
Active ligand that binds in muscle and liver
Other tissues –> its metabolite DHT binds to receptors (prostate, seminal vesicles, epididymis, skin)
Brain, liver, adipose tissue = biotransformed to oestradiol by CYP450 aromatase –> hormone receptor complex binds to DNA —> synthesis of specific RNAs and proteins
Explain some key pk properties of testosterone
Ineffective orally –> inactivated by 1st pass metabolism
What are the intramuscular testosterones?
enanthate
propionate
cypionate
isocaproate
phenylpropionate
Outline the uses for testosterone (anabolic, endometriosis)
Danazol used in endo
Anabolic effects = senile osteoporosis, chronic wasting due to HIV or cancer, burns
What are some ADRs associated w/ testosterones/androgens?
Virilisation and menstrual irregularities in women
Acne in males and females
Freq, sustained, painful erection
Oligozoospermia
Growth retardation, epiphysial closure
Cholestatic jaundice
Hepatic carcinoma
gyno
What class does finasteride and dutasteride belong to? Explain their MOA/what do
5-alpha reductase inhibitors
MOA = inhibit the conversion of testosterone to potent DHT —> dec prostate size, growth
ADRs impotence, dec libido, ejac disorders, breast tendeness
What testosterones are competitive androgen receptor antagonists? Where are they used?
Flutamide, bicalutamide, apalutamide, darolutamide, enzalutamide
MOA = inhibit activation complexing of AR and DHT
What does Danazol do? (MOA, what is, ADRs)
Synthetic steroid
MOA = supresses Gn secretion from pituitary both in men and women –> inhibit test/ovary function
- antioestrogenic and weak androgenic
- suppress gonadal funct
ADRs = acne, oily skin, weight gain, hirsutism, voice change, amenorrhoea
What is danazol used to treat?
Endometriosis
HMB
Prevention of attacks of hereditary angioedema - C1 esterase inhibitor
Benign fibrocystic breast disease
