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ANTlFERTlLlTY DRUGS
Types of estrogens :
Natural estrogens :
- Estradiol (estradiol-17B , E2)
- Estrone (E1), hepatically formed from estradiol
- Estriol (E3) , hepatically formed from estradiol
Steroidal synthesic estrogens :
- Ethinyl estradiol
- Mestranol
- Quinestrol
Non steroidal synthetic estrogens :
- Diethylstilesterol
- !hlorotrianisene
Mechanism of action of oestrogens :
1 " free estro#en reacts $ith estro#en receptors (nuclear receptors)
2 " estro#en-receptor comple% promote transcription of many #enes (#enomic effects)
3 " non #enomic effects (Do not re&uire time ecause they are not thorou#h #enomic receptors) as
increased uterine lood flo$
Pharmacodynamics of estrogens :
Plasma lipid effects :
1 " increase hi#h-density lipoproteins
2 " sli#ht decrease in lo$-density lipoproteins
3 " decreased cholesterol
' " increase plasma tri#lycerides due to increased tri#lycerides synthesis
II.metabolic & CVS effects of estrogen :
- maintain normal s(in)lood *essel structure (in $oman)
- decrease rate of one resorption y promotin# apoptosis of osteoclasts , parathyroid hormone
anta#onism (We can use it in osteomalacia in post menopausal women)
- promote intestinal asorption ( decrease o$el motility)
+eptitic effects, increased increase protein synthesis increase ,
- thyro%ine-indin# #loulin (-B.)
- se% hormone-indin# #loulin (/+B.)
- renin sustrate (angiotensinogen)
- firino#en
- increase serum concentrations of thyro%in, estro#en, testosterone, iron , copper , other
compounds
strogen pharmacological actions :
- enhances lood coa#ulation , increase circulatin# factors 00, 100 , 02 , 2 (hepatic effects)
- decreased antithromin 000 3 plasmino#en concentration
) We don't give it to women with blood clotting disorders (
Maturation effects of estrogens :
- 4e&uired for normal female maturation
- stimulate the de*elopment of, *a#ina , uterus tues , se% characteristics , reast #ro$th ,
- closin# of the epiphyses of lon# ones (puerty)
- a%illary 3 puic hair , promote redistriution of ody fat
- s(in pi#mentation 5 particularly in the nipple re#ion
ndometrial effects of estrogens :
- 6romotes endometrial linin# de*elopment
- !ontinuous, e%cessi*e estro#en e%posure endometrial hyperplasia (may cause anormal
leedin#) "
Miscellaneous effects of estrogens :
- salt and $ater retention
- increase synthesis of pro#esterone receptors
Pharmaco!inetics of estrogens :
- oth natural 3 synthetic estro#en are $ell asored
- most estro#ens are readily asored from s(in 3 mucus memranes(topical) and can e #i*en
y transdermal patches , topically in *a#ina as cream or suppository "
- natural estro#en(not free) are ound to se%-steroid-indin# #loulin and to alumin "
- only free estradiol is physiolo#ically acti*e
7atural estro#ens are rapidly metaoli8ed in the li*er
- synthetic estro#ens and non-steroidal estro#ens are less rapidly de#raded
- *ariale amount of enterohepatic cyclin#
N.B
** If given orally it will give more hepatic circulation( more
st
pass effect)
** if given as transdermal patches(topically) decrease action in the liver decrease
st
pass
metabolism
** estrogen combine with antibacterial drugs (esp. broad spectrum) so bacteria will split
con!ugated estrogen to decon!ugated form decrease enterohepatic circulation decrease
"#$
- small amount in reast mil(
- hepatic concentration, undesirale actions may result ,
9 increased clottin# factor synthesis
9 increase plasma rennin sustrate
"ses of estrogens :
:lone or !omined $ith pro#estrins
- contraception
- menstrual irre#ularities (%ypogonadism)
- dysmenorrhoea(no menstruation)
- menopause, hot flushes , insomnia , s$eatin# , an%iety , o*er reathin# , *a#inal atrophy (low
dose of estrogen to avoid adverse effects
li&e caner (
** 'referred to combine estrogen ( progestine to reduce entometrial cancer N)" breast
cancer
- con;u#ated estro#en , ethinyl estradiol
- postmenopausal osteoporosis
- hypo#onadism (estro#en-deficient patients) comine $ith pro#estin
- prostatic carcinoma (anti-andro#enic effect)
e"#" diethyl stilesterol ( *a#inal carcinoma in youn# $omen $hose mothers recei*ed it early
pre#nancy terato#enic effect)
"ses of estrogen :
- postcoital use (after se*ual intercourse $ithin 2'-'< hrs)
- atrophic *a#initis ( *a#inal cream , reduce hepatic effects)
- hirsutism
#d$erse effects of estrogen ,
- nausea , headache, mi#raine
- reast tenderness and hypertrophy
- hyper-pi#mentation ( reversible slowly after stoppage)
- depression
- uterine leedin# $ith hormonal replacement therapy ( estro#en only)
- endometrial , reast , *a#inal cancer (combined will decrease the ris&)
- impair #lucose tolerance (DM)
- !1/ , thromoemolism , hypertension
- increased fre&uency of cholestasis , #all ladder disease
Contraindications of estrogen :
- reast or endometrial cancer
- se*ere li*er disease =4 #allladder disease
- un(no$n #enital leedin#
- history of thromoemolic disorders
- hea*y smo(ers
PROGESTlNS :
Types :
6ro#esterone 0M (not effective orally + severe
st
pass metabolism)
+ydro%ypro#esterone , 0M
Medro%ypro#esterone 0M 3 talets
Components of oral contracepti$es :
- >-nor#estrel , talets
- norethindrone acetate , talets
- deso#estrel , talets
"hose are called ,
rd
generation
PROGESTETONE :
- natural in o*ary , testis , adrenal #land , placenta
- precursor for estro#en , testosterone , adrenal corticosteroids
- half life , ? min
- ineffecti*e orally ( e*tensive first pass effect)
Pharmacological actions of progesterone ,
-echanism of action is similar to estrogen
- limited effect on protein metaolism
- stimulates lipoprotein lipase
- promotes fat deposition
- increase insulin le*el 3 insulin response to #lucose "
- promotes #lyco#en stora#e ( li*er )3 (eto#enesis
- competes $ith aldosterone at renal tuule, decrease 7a@ ressotion "
- increase ody temperature
- depressant )hypotonic !7/ effects
- de*elopment of the reast secretoy apparatus and endometrium
"ses of progestins :
- hormone replacement therapy
- contraception
- induction of lon#-term o*arian suppression (lar#e , medro%ypro#esterone acetate) prolon# an
o*ulation A amenorrhea used to treat ,
9 dysmenorrheal 9hirsuitism
9 leedin# disorders ($here estro#ens contraindicated)
#d$erse effects of progestins :
- increase lood pressure
- decrease in hi#h density lipoproteins (+D>)
- nausea 3 *omitin#
- headache
- menstrual irre#ularities
- $ei#ht #ain
- masculini8ation (norethindrone)
- ectopic pre#nancy
ORAL CONTRACEPTlVES :
- oral contracepti*e preparations contain ,
Estro#en , pro#estrins , estro#ens and pro#estrins (best way)
%ral administration :
- estro#en)pro#estin cominations
- pro#estin only preparations
- only one implant preparation (norplant) (yen8ere3 ta7t el ;eld ye3By lon#er duration)
- cominations of estro#ens and pro#estin (1CCD effecti*e)
- lo$ conc" of estro#en ( to avoid cancer)
- #i*en for 21 days startin# ?
th
day of the cycle
- at the same time e*eryday(to avoid hormonal disturbance and to maintain constant blood
level)
Mechanism of contraceptions :
- inhiition of o*ulation , suppress pituitary #onadotropins , E/+ , >+
- chan#e in cer*ical mucus , thic(
- renders endometrium unfa*orale for implantation
- chan#e transport time of sperm throu#h falloian tue
- anormal contraction of fallopian tues 3 uterine musculature
- pro#estrins alone does not al$ays inhiit o*ulation , i"e" other factors are si#nificant
Combined contracepti$e pills :
M=7=6+:/0! E=4MF>:-0=7, (most effective)
!onstant dosa#e of oth components durin# the cycle
B06+:/0!, dose of one component is chan#ed (progestin)
-406+:/0!, dose of t$o components are chan#ed , increase pro#estin and estro#en then
decrease estro#en only
See the ne&t table
Triphasic oral contracepti$es :
- mimic normal cycle
- possess hi#h efficacy of monophasic pills
- less rea(-throu#h leedin#
- reduce incidence of post-pill amenorrhea
"ses of oral contracepti$e :
- contraception ,
9 comination therapy is *ery effecti*e 1CCD
9 conception ris( is lo$
'actors contributing to contracepti$e failure :
- phenytoin , ariturates administration (en8yme inducers)
- antiiotic administration (ampicillin)
- missin# doses
#d$erse effects of oral contracepti$es :
Mild :
- nausea , edema , rea(throu#h leedin#
9 more common $ith pro#estational a#ent only (2?D)
9 less $ith comination , iphasic and triphasic
- chan#es in serum protein ,
9 increase sedimentation rates, secondary to increased firino#en le*els
- headache mi#raine
- reast tenderness ,enlar#ement
Moderate :
- $ei#ht #ain (pro#estin)
- acne (pro#estin)
- hirsutism (pro#estin)
- s(in pi#mentation
- amenorrhea
Se$ere :
- !1/, thromoemolic disorders (estro#en), hypertension
- myocardial infarction
- cerero*ascular disorders
- .0- disorders (#all ladder disease , cholestasis)
- depression
- cancer increase ris( of endometrial carcinoma $hen estro#en is #i*en alone
- carcino#enicity , diethystilesterol may lead to *a#inal adenocarcinoma in female offsprin#s
Contraindications to oral contracepti$e pills :
#bsolute contraindication :
- thromoemolic disorder
- cerero*ascular disorders
- coronary artery or ischemic heart disease
- (no$n or suspected reast carcinoma or estro#en-dependent neoplasia
- pre#nancy
- li*er impairment , li*er tumor
- pre*ious cholestasis durin# pre#nancy
(elati$e contraindications :
- mi#raine
- hypertension
- diaetes (estro#en)
- lactation (estrogen suppresses lactaction)
- family history of hyperlipidaemia
Progestin only pills :
- *ery lo$ dose pro#estin (mini-pills)
- pills ta(en on first day of cycle and e*eryday
)isad$antages :
- tendency for irre#ular leedin#
- failure rates are hi#h (success G7D)
#d$antages :
- reast feedin# , does not suppress lactation
) el estro#en e2ather 3ala lactation as pro#esterone may2ather (
- protection a#ainst cancer endometrium
- contraindication to estro#en use (hypertension-reast cancer-prior thromoemolism)
- smo(ers ao*e a#e of 3?
#$ailability :
=rally as talets ,
7orethinidrone , dl-nor#estrel
Medroxyprogesterone acetate :
0M preparation , 1?C m#
- e*ery 3 months
- lon# duration contraception (single dose . . , months)
- menstrual irre#ularities
- suppression of o*ulation (after stoppage/ it may reach year)
- reduction of one density
- increased ris( of atherosclerosis
Norplant :
- sudermal implant system
- release a steady dose of >-nor#estrel for lon#-term contraception
- 7orplant effecti*e for ? years(si% silastic capsule , 3B m# each)
)isad$antages :
7eeded for sur#ical insertion 3 remo*al , irre#ular leedin#
#d$antages :
>ittle effect on lipoprotein or lood pressure
Post*coital contraception +morning*after pills, :
- pre*ent pre#nancy follo$in# se%ual intercourse
- implantation of lastocyte is inhiited y hi#h doses of estro#en alone or $ith pro#estin
- not recommended for routine use
- important to e#in therapy $ithin 72 hours (GGD)
Indications :
ur#ent pre*ention of pre#nancy e"# "
- rape
- e%posure to terato#ens as cytoto%ic dru#s
- condom torn durin# intercourse
(egimens :
- hi#h dose of estro#en (ethinyl estradiol ), ?Cm#)d)? (7?D)
- ethinyl estradiol @ nor#esterel (' talets , t$o a once and after 12 h) ( 7?-<?D)
- mifepristone @ misoprostol (<?-1CCD)
MI'SP(IST%N :
- an anta#onist at pro#esterone receptors
- has luteolytic effect
- sensiti8es the uterus to the action of prosta#landins
- #i*en orally t1)2 A21 hours , ta(en once
- comined $ith misoprostol (more efficacy)
-ong acting hormonal methods :
- *a#inal rin#
- transdermal patch
- implant (norplant) pr##estin only preparation
- intrauterine de*ice ( copper)
_r fertility drugs
- _ _s _nml 4 L 5
Continuous administration in depot formulation ...
- Implant / continuous release
- Side effect mainly in continuous form because continuous form cause inhibition instead
of acti$ation to 'S0 & -0
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O => P *** mechanism of action
'S0 causes maturation of follicle & -0 is the responsible for o$ulation
9:;Q28 => RFSFT UVW28
- Tamo&ifine is used for treatment of ad$anced breast cancer in pre & post menopausal
FERTlLlTY DRUGS OR
OVULATlON lNDUClNG AGENTS
1 " :ntiestro#ens,e#"!lomiphene citrate 3 -amo%ifen
2 " Bromocriptine
3 " .onadotropin-releasin# hormone analo#s (.n4+)
9 .oserline 9leprolide
' " human #onadotropins ,
+M.- human menopausal #onadotropins
+!.- human chorionic #onadotropins
+6.- human pituitary #onadotropins
Clomiphene citrate
7onsteroidal dru# -
Hea( estro#enic acti*ity -
- : partial estro#en a#onist
Mechanism of action ,
- competes $ith estro#en at hypothalamus for its receptors leadin# to remo*al of the ne#ati*e
feedac( effect of estro#en on pituitary #land "
- an increase in #onadotropins ( E/+ 5 >+ ) secretion "
- E/+ act on the o*ary inducin# o*ulation "
- >+ causes maturation of follicles "
- on cer*i%, clomiphene reduce the &uantity and &uality of cer*ical mucus $hich hinder ascent of
sperm (antiestro#enic effect) "
- dru# of choice for o*ulation disorders in $omen due to oli#omenorrhea, amenorrhea and
o*ulatory dysfunction not due to o*arian or pituitary failure "
- #i*en as talets ( ?C 5 1CC m# )day ) for ? days startin# on ?
th
5 1Cth of the cycle "
- course of clomiphene could e repeated for further ? months "
#d$erse effects of clomiphene :
- hot flushes
- #astric upset 3 constipation
- $ei#ht #ain
- reast tenderness
- o*arian enlar#ement
- multiple irth (t$ins 1CD)
- re*ersile hair loss
- aller#ic manifestation ,
s(in rashes
- depression
- *isual disturances ( I-')
TAMOXlFEN :
- is a nonsteroidal a#ent , #i*en orally
- competiti*e partial a#onist and inhiitor of estradiol at estro#en receptors
- e%tensi*ely used as a treatment of ad*anced reast cancer in postmenopausal $omen "
99 -hese points are included in the slides ut the doctor didnIt mention them in the lecture so ;ust
read them incase they rin# them in e%am ,
- 0s e%creted mainly y the li*er "
- :#onist acti*ity is sho$n on ,
1 " Bone, pre*ent loss of one density "
2 " 6lasma lipid le*el, reduces ris( of atherosclerosis "
3 " Fterus, increase the ris( of endometrial cancer "
- Dose , 1C 5 2C m# t$ice daily
BROMOCRlPTlNE :
- semi-synthetic er#ot al(aloid , #i*en orally
- dopamine a#onist
- acts on hypothalamus to inhiit 64+
- decrease prolactin secretion from pituitary #land
- hyperprolactenemia states
- +yperprolactinaemia #alactorrhoea 3 hypo#onadismamenorrhoea infertility"
- !auses,
1"6ituitary adenoma"
2" 1)3 cases of acrome#aly ( Increase growth hormone after puberty)
3" /tress
'" Dru#s, Methyldopa"
Therapeutic uses of bromocriptine :
- 0nfertility 2ndry to hyperprolactinemia
- /uppression of lactation "
- :crome#aly "
- 6ar(insonJs disease (0ecrease 0opamine)
#d$erse effects of bromocriptine :
- 6ostural hypotension ( 1
st
dose )
- .0- K nausea , *omitin# , constipation
- 7asal con#estion
- >e# cramps
- 0n*oluntary mo*ements
- 0nsomnia
Human gonadotropins :
+M. , +uman Menopausal .onadotropins ( mi% of E/+ 3 >+)
+6. , +uman 6ituitary .onadotropins (E/+ 3 >+)
+!. , +uman !hrionic .onadotropins ( 6redominance of >+ acti*ity)
Mechanism of action :
- +!. stimulates #onadal steroid hormone production "
- 0nterstitial 3 corpus luteum cells produce pro#esterone "
- /timulates mid-cycle >+ sur#e 3 promotes o*ulation in hypo#onadotropic states "
Indications of 0MX :
* Eailure $ith clomiphene "
- Homen infertility due to pituitary insufficiency "
Schedule for 0MX :
* Daily in;ection of +M., 0M (1' days) "
* Daily measure of estrodiol le*els "
* 2 days after o*ulation (day 1B ) #i*e +!. (one in;ection) "
* :d*ice patient for intercourse that ni#ht and for ne%t 3 days "
#d$erse effects of 0MX:
- =*arian hyperstimulation "
- Multiple pre#nancy "
- +i#h ectopic rate "
- 0ncrease in rate of aortions "
Gonadotropin - Releasing Hormone Analogs (GnRH) :
- .oserline "
- >eprolide "
0nduce o*ulation in $omen $ith amenorrhea of hypothalamic ori#in $hen administered in
pulsatile form usin# pump ( 1-1C Miro#ram) 1-2 hour) "
#d$antages of Xonadotropin Y (eleasing 0ormone #nalogs :
* 7ormal follicular de*elopment "
- 0ncidence of multiple pre#nancies are less compared to +M. "
- !ontinuous administration suppresses o*arian function LDo$n-re#ulationL of receptors or
desensiti8ation "
- !ontinuous administration (#onadal suppression) used in treatment of endometriosis,
precocious puerty 3 #onadal hormone 5 dependent tumors e#" 6rostatic cancer and ad*anced
reast cancer "
Side effects of Xonadotropin* (eleasing 0ormone #nalogs :
* +ypo-estro#enism (>on# term use)
- +ot flushes "
- Decreased liido (se*ual desire)
- =steoporosis "
Xood luc!
Pharma team girls
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