Pharmacology and Therapy

Sex Hormone, Contraception,

and Uterotonic

Dr. Endang Isbandiati Soediono , dr, MS, SpFK

Dept.Pharmacology &Therapy,
Medical Faculty, AIRLANGGA UNIVERSITY
SURABAYA

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 1
Component
 Estrogen (E) in oral contraceptives (OC):
. Ethinyl estradiol (EE)
. Mestranol

 Progestin (P) in OC :
. Ethynodiol diacetate, Desogestrel, Gestodene,
Norgestimate, Norethindrone (- acetate),
Norethynodrel, Norgestrel, and Levonorgestrel
. P vary in progestational activity and inherent
estrogenic, antiestrogenic, and androgenic
effects.
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 2
Estrogen
Pharmacologic actions
. Neuroendocrine control of the menstrual cycle
. Developmental actions

Metabolic effects
bone, vascular endothelium, liver, CNS, and heart ; mineral,
lipid, carbohydrate, and protein metabolism
HDL >; LDL and Lp(a) <
. Serum protein > : CBG, TBG, SBG
. Hi. Concent. : antioxidant activity
. Long-term administration :
plasma renin , ACE, and endothelin-1 <
decrease angiotensin – R1
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 3
Progestin
 Pharmacological actions
. Reproductive : secretory endometrium
. Mammary gland : acini proliferation
. CNS : increase body temperature
increase ventilatory resp. to CO2
depressant and hypnotic effect
. Metabolic : increase basal insulin
long-term use : glucose intolerance (Norgestrel)
stimulate LL activity : LDL > ; HDL <
(19-Norprogestin > plasma lipid : androgenic)
aldosterone effect < : decrease Na+ reabsorption;
mineralocorticoid secretion >
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 4
Oral Contraception
 Hi. Do. Formulation :
Vascular and embolic events, cancers, others SE
 Lo-Do combination (E+P <) :
Fewer complication
 Monophasic : E+P 21Ds followed by 7Ds placebo

 Biphasic, Triphasic : 21Ds E+P followed by 7Ds pl.

. Combination multiphasic form. : lowered total
monthly ho. do.
. Mono-,Bi-, Triphasic –OC : reduce breakthrough bl.

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 5
Oral Contraception (cont.)
 Extended-cycle pill and continuous - OC :
. E+P : 84Ds followed by 7Ds pl.; 4 cycles/y
. Continuous combination regimen : E+P for 21Ds, followed
by very low do. E+P for 4 to 7Ds
. SE <

 Newer Progestin : Desogestrel, Drospirenone, Gestodene,

Norgestimate (third generation OC)
. No estrogenic effects; less androgenic compared to
Levonorgestrel : acne <
. Drospirenone : antimineralocorticoid, antialdosterone: less
weight gain
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 6
Oral Contraception (cont.2)

 Progestrin-only “minipill”: 28Ds active

ho.
. Less effective than combination-OC
. Assc. w. irregular, unpredict. menst. bl.
. Has to be taken ED at approximately the
same time; if late more than 3 Hs. pts.
should use a backup methode for 48Hs
. May not block ovulation : risk of ectopic
pregnancy FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 7
Choice of OC
 Based on : Ho. Content, dose, pattern of
pill, and coexisting medical conditions.
 Recommended in N women : EE ≤ 35 mcg and <
0,5 of Norethindrone
 Adolescents, BW< 50kg, age > 35Ys,
perimenopausal : OC , EE 20 – 25 mcg
 BW > 72,7kg : failure rate > w. Lo.do. EE
 Heavy menses : EE 50mcg
 Regular light menses : started on EE 20 mcg
 Oily skin, acne, hirsutism : low androgenic OC
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 8
Choice of OC (continued)

 Monophasic : easier to take, managed,

identified SEs
 Extended-OC: assoc. less dysmenorrhea,

migraines
 Bicycling, Tricycling : skipped the 7Ds placebo

of monophasic 28Ds .
 Shortened pill-free interval : 2Ds – to 4Ds

. Beneficial for pts. w. dysmenorrhea, menstrual

migraine

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 9
Choice of OC (continued 2)

 Candidates for Progestin-only methods :

. Migraine headaches, history of TED, HD, CVD,
SLE w. VD, hyperTG
 Age > : 35Ys who are smokers or obese, or w.

HT or V d should use progesterone-only

methods

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 10
Initiating an OC
 Quick start OC : after a negative urine test, the
first pill
 First-day start method : first pill on the first

day of next menstrual cycle

 Post partum phase The WHO precaution :

Mother hypercoagulability and effects on

lactation (21 Ds pp the risk of thrombosis is
higher ) AVOID E-containing ho. Contrac.
. Progestin-only pill do not adversely affect milk
production ; can be used after 6-weeks pp.
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 11
Hormonal contraception
 Long-acting injectable and implantation contraceptive
(P): breast-feeding women or E intolerant

 Injectable P : DMPA, deep im injection within 5Ds of

onset of menstrual bleeding, inhibit ovulation in 3 Ms
. Good candidate for women w. :
Sickle cell an. , seizure, sc for endometriosis pain
. Incidence < compared to women not using DMPA :
candida vulvovaginitis, ectopic pregnancy, PID,
endometrian and ovarian Ca
. Severe bl.: short course of E
( 7Ds 2mg Estradiol or 1,25 mg conjugated E po)
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 12
Hormonal contraception
(cont.)
 Subdermal Progestin implants
. Norplant, 6 implantable soft silicone rubber cap.,
36 mg Levonorgestrel (for up 5Ys)

 Intrauterine devices
. Intrauterine inflammation, increase PG formation,
endometrium suppression, PG spermicide,
impairment of implantation.
. Levonorgestrel IUD : increase spotting in the first
6Ms, will decline gradually over time.
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 13
 Hormonal Contraception
(cont.)
 Post- OC anmenorrhea : (rarely) last 6Ms
 Transdermal contraception : > E
 Vaginal ring

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 14
 Emergency Contraception
... to prevent unwanted pregnancy after unprotected sexual
intercourse

. Hi. Do. Combined E+ P

. P- only
. ( copper IUD)

MOA :
. prevent fertilized egg from implanting into the endometrium
. impaired sperm transport and corpus luteum function
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 15
 Emergency Contraception
(continued)
 Plan B
0,75 mg Levonorgestrel ( Do.I : within 72
Hs of unprotected intercourse ; Do. II : 12
Hs later)
 1,5 mg Levonorgestrel (2 tab.): single do.
 (FDA 2006 : > 18 ys as OTC)
 P- only : 20 tablets after unprotected s.i.
and to repeat the dose in 12 hs
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 16
 Consideration with CHC
 Medical hist., BP, benefit, SE, and risk
 > 35 ys . Breast Ca
 Smoking . thromboembolism
 Hypertension . obesity
 Dyslipidemia . SLE
 Diabetes . Sickle cell disease
 Migrain headache

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 17
Managing oral Contraceptive SE
 Immediately discontinue CHC if they experience warning
signs :
ACHES

Abdominal pain
Chest pain
Headaches
Eye problems
Severe leg pain
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 18
 Managing OC Side Effects
 Instructed to use an alternative method of
contraception if thereis a possibility of a drug
interacting altering the efficacy of the OC

. Rifampin
. Tetracycline
. Penicillin
. Anticonvulsant (Phenobarbital,
Carbamazepine, Phenytoin)
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 19
 PHARMACOLOGY OF
UTEROTONICS

DR.Dr. Endang Isbandiati Soediono, MS, SpFk

DR.Dr. Endang Isbandiati Soediono, MS, SpFk
Dept.Pharmacology&Therapy, Medical Faculty,Airlangga University
Dept.Pharmacology&Therapy,
Dept.Clinical Pharmacology,Medical Faculty,Airlangga
Dr.Soetomo-Teaching University
Hospital
Dept.Clinical Pharmacology, Dr.Soetomo-Teaching Hospital
SURABAYA
SURABAYA
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 20
 OXYTOCIC UTEROTONICS
UTEROTONICS
. Oxytocin
. Prostaglandins
. Ergot alkaloid
. Progesterone antagonist

TOCOLYTICS
. Oxytocin antagonist
. β - adrenergic agonists
. Ca2+-channel blockers
. PG-synthase inhibitor
. Magnesium sulfate
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 . Ethanol EIS11 21
 Oxytocin
 Biosynthesis
cyclic nonpeptide

larger precursor molecule

active hormone

secretory granules

Posterior pituitary
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 22
 Physiological roles
 Uterus
. Stimulate contraction : frequensi & force

Highly dependent on E

immature uterus : resistance

 Breast
. Milk ejection

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 23
Pharmacokinetics
 Absorption :
iv
initiation & augmentation of labor
im
control of postpartum bleeding

 PB : none

 Excretion : kidney

 HL : 5 menit FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 24
Pharmacodynamics
 G protein-coupled
contract uterine smooth muscle
 PG and Leukotrienes
augment uterine contraction
 Small dose :
frequency and force of uterine contraction
 High dose :
sustained contraction
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 25
Clinical Pharmacology
 Induction of Labor
early vaginal delivery

. PRM
. isoimmunization
. intrauterine growth retardation
. placental insufficiency
. maternal diabetes
. preeclampsia
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 26
Clinical Pharmacology (continued)

 Augmentation of abnormal labor

 Third stage of labor and puerperium

 Second trimester abortion

 Oxytocin challenge test

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 27
Toxicity & Contraindication
 Excessive stimulation of uterine contraction before deliver
fetal distress, placental abruption, or uterine rupture

 Hi.Do. : activation of vasopressin-R

fluid retention, or water intoxication
hyponatremia, heart failure, seizures, and death

 Bolus injection : hypotension

 Contraindication :
fetal distress, prematurity, CPD, predisposition for
uterine rupture
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 28
 EICOSANOIDS

Inhibitors of Eicosanoid biosynthesis

. calcium reducers
. glucocorticoids
. NSAIDs
. Analogs of the natural fatty acid
precursors

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 29
 membrane

phospholipids

corticosteroid phospholipase

Arachidonic acid

Lipoxygenase inhibitor lipoxygenase Cyclo-oxygenase NSAID, ASA

leukotriene
prostaglandin thromboxane prostacyclin
LTB LTC4/D4/E4
Leukocyte modulation
Phagocyte
Bronchospasm
attraction,
Congestion
activation inflammation
Mucous plugging
colchicine
inflammation FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 30
 AA
cox-1
cox-2
PGG2
cox-1
cox-2
PGH2

PGI2
TXA2

PGE2 PGD2

PGF2

Prostanoid Biosynthesis

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 31
 Basic Pharmacology
 Effects of Prostaglandins
. Smooth muscle
. Platelet
. Kidney
. Reproductive organs
. CNS & PNS
. Neuroendocrine
. Bone metabolism
. Eye
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 32
Female reproductive system

 PGF2 α

luteolysis

Tx : delayed parturition
(+) oxytocin : onset of labour

 PGE2 : oxytocic effect

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 33
Therapeutic Uses
Female Reproductive System
. Abortion
terminate pregnancy at any stage
Dinoprostone (PGE2) :
induction of labor, abortifacient, Cx softening
Misoprostol (po) + Mifepristone (RU486) :
early abortion
Carboprost tromethamine (PGF2α) :
induce 2nd T abortion &
control postpartum hemorrhage
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 34
Therapeutic Uses (continued)

. Facilitation of labor :
PGE2 & PGF2α
initiate & stimulate labor (pre &-eclampsia)
. Dysmenorrhea

Male Reproductie System : ED

Alprostadil /(+)Papaverine/ Phentolamine
Respiratory System : PGE2
Gastric cytoprotection
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 35
Therapeutic Uses (continued)

Pulmonary HT, PVD, Maintenance

of PDA
Immune System : PGE2 & PGI2
a) Organ trasplantation
b) Inflammation
c) Rheumatoid arthritis
d) Infection
Glaucoma
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 36
 ERGOT ALKALOID
Pharmacokinetics :
. Absorption : variably from GIT
. Ergotamine po 10x > im dose

Pharmacodynamic :
MOA :
. agonist
. partial agonist α-adrenoceptor
& serotonin receptor
. antagonist
Agonist & partial agonist : at Dopamine – R
Uterus : agonist/ partial agonist at 5-HT2R
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 37
 Organ System Effects
1. CNS
. Agonists : pre & postjunctional CNS 5-HT 2-R
. Bromocriptine, Carbegoline, Pergolide : pituit. D-R
 2. Vascular smooth muscle

Ergotamine : “ epinephrine reversal “ and

blockade of the response to α- agonists
 3. Uterine smooth muscle

Stimulant actions : α-agonist, serotonin, others

 4. Other smooth muscle organ

Bronchiolar, urinary : <<<

GIT : >>>
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 38
Clinical Uses :

 Migraine
 Hyperprolactinemia
 Postpartum hemorrhage
 Diagnosis of Variant Angina
 Senile cerebral insufficiency

Ergonovine : more uterus selective

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 39
  Toxicity :
. GIT
. medullary vomiting centre
. prolong vasospasm
. fibroblastic changes

 Contraindication :
. Obstructive vascular diseases
. Collagen diseases
. pregnancy

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 40
 Antiprogestins
 Mifepristone (RU486)
derv. 19-norprogestin norethindrone
competitive antagonists of :
. glucocorticoid
. progesterone

. Pharmacological action :
antagonist progesterone R-A & -B
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 41
 MOA (Mifepristone)

early
earlystage
stageof
ofpregnancy
pregnancy

decidual
decidualbreakdown
breakdown

detachment
detachmentof
ofthe
theblastocyst
blastocyst

hCG
hCG

progesterone
progesterone

prostaglandin
prostaglandin

contraction
contraction
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 42
 Pharmacokinetics

 PO : active; good bioavailability

 Peak plasma : several hours
 HL : 20 -40 hours
 PB : α1-acid glycoprotein
 Liver metabolism & enterohepatic circulation
 Excretion : feces

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 43
 Therapeutic Uses

 Mifepristone
(+) termination early pregnancy
Misoprostol

 Mifepristone (48hours)
(+) medical abortion TI
prostaglandin

 Postcoital contraceptive

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 44
 TOCOLYTICS
treatment of preterm labor

bedrest
hydration
sedation
(+)
tocolytics

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 45
 Tocolytic Therapy
 ... is to postpone delivery long enough to allow for
administration of antenatal

. corticosteroid
. transportation of the mother ...

 Less effective when Cx. dilation > 3cm

 Should not be used :

Intrauterine infection, fetal distress, severe

preeclampsia, vaginal bleeding, or maternal
9/18/19
hemodynamic instability
FKUNAIRPharmacolTheSexHoUteroto
EIS11 46
 Classes of Tocolytics
 Oxytocin Antagonist
 β - adrenergic agents
 Magnesium
 Calcium Channel Blockers
 NSAIDs
 Ethanol
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 47
Oxytocin Antagonist
 Atosiban : iv infusion for 2 - 48 hours
 Uncomplicated premature labor : 24 – 33 weeks
 Monitor blood loss; intrauterine growth restriction;
abnormal placental site; hepar / renal impairment
 Contraindication :
eclampsia, intrauterine infection / death, antep.
haemorrhge, plac. previa, abruptio placenta, prm
 SE : n, v, tachycardia, hypoT, hyperglycemia,
headache, hot flushes
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 48
 β2-Adrenergic Agonists
 Selective β2-adrenergic agonist relax the pregnant
uterus :
Ritodrine, Terbutaline

suppress prematur labor

Delay
Delaylabor
laborfor
forseveral
severaldays
days
FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 49
 β2-Adrenergic Agonists
(continued)
 Ritodrine
is a selective β2 agonist
As a uterine relaxant

 SE :
Relative higher incidence of maternal SE
hyperkalemia, arrhythmias, hyperglycemia,
hypotension, and pulmonary edema

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 50
 Calcium Channel Blocker
 Verapamil , Nifedipine
 Prolong preterm labor
 Nifedipine :
. decreasing uterine contraction
. severe dysmenorrhea
. PG - induced abortion

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 51
 Magnesium Sulfate
 Inhibiting premature labor

Antagonizes Ca2+
 Agent of choice in diabetic pts.
 Crosses placenta ⁄⁄ maternal level
 Respiratory depression in the mother :

10 ml of 10% calcium gluconate

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 52
 Ethanol
 Inhibit preterm labor
 Carbohydrate metabolism

more serious in diabetic

 Crosses placenta

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 53
 Prostaglandin Synthase
Inhibitor
 Inhibit labor

Oral / rectal Indomethacin

effective in the treatment of preterm labor

 Serious potential ADR in the fetoes

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 54
 NSAIDs
 Indomethacin
administration : po/ iv

Other methods for Preterm Labor

Prevention
Tx . Infection : (+) AB

FKUNAIRPharmacolTheSexHoUteroto
9/18/19 EIS11 55
Selamat Belajar
9/18/19
FKUNAIRPharmacolTheSexHoUteroto
EIS11 56