NEWER ABORTIFACIENTS
Dr.Rachana MenonModerator: Dr.Anuradha HV
DEPT OF PHARMACOLOGY
OUTLINE
History & problem statement
Physiology of Fertilization and Implantation
Pharmacology of Abortifacients
Newer agents
Non pharmacological treatments
Conclusions
INTRODUCTION
• Abortion - termination of pregnancy before 28 weeks of
gestation or viability
• WHO definition- termination of pregnancy before
22 weeks or when the fetus weigh 500 g or less
• Spontaneous or induced
• Abortion is important as it contributes to approximately
50% of maternal death worldwide
HISTORY
Shennong - 2700 BCE
Ancient Egypt with its Ebers Papyrus
Classical Greece-Silphium
Hippocratic Oath – Hippocratic Corpus contain
descriptions of abortive techniques.
Aristotle, in his treatise (350 BCE)
Islamic tradition and Christianity
The Soviet Union (1919), Iceland (1935) and Sweden
(1938).
In 1935 Nazi Germany, a law was passed permitting
abortions for those deemed "hereditarily ill,"
Beginning in the second half of the twentieth century,
abortion was legalized in a greater number of
countries
HISTORY (Contd.)
• 1973- Misoprostol ( Nsaid)
• 1988- Mifepristone + sulprostone ( France)
• 1994-MTX / Misoprostol
• 1997- Misoprostol for abortion
• 2000- FDA approved RU 486+ Misoprostol
PROBLEM STATEMENT 53 million abortions performed each year
Abortion is important as it contributes to approximately
50% of maternal death worldwide
Unsafe conditions, especially in developing countries.
Approximately 13% of all maternal deaths - poor access
to safe practice
Service is not available legally
Morbidity with loss of fertility and the sequelae of
chronic pelvic pain
Fertilization
ABORTION
• Medical or surgical termination of pregnancy
before the time of fetal viability.
– FIRST TRIMESTER – First 12 WEEKS
– SECOND TRIMESTER – 13-24 WEEKS OF
GESTATION
INDICATIONS
• Persistent heart disease
• Advanced hypertensive vascular disease
• Invasive carcinoma of the cervix.
• Medical and surgical disorders
• Cases of rape or incest
• Birth of a fetus with a significant anatomical or mental
deformity
• Unwanted pregnancy
• anatomical or mental deformity.
CLASSIFICATION
PROSTAGLANDIN ANALOGUES
• CARBOPROST• SULPROSTONE• DINOPROSTONE• GEMEPROST• MISOPROSTOL
ANTIPROGESTINS
• MIFEPRISTONE• LILOPRISTONE• ONAPRISTONE• ULIPRISTAL
ANTI METABOLITES
• METHOTREXATE
First Trimester
Mifepristone + PG analog
misoprostol /gemeprost
up to 63 days
of gestational age
Methotrexate + a PG
analog up to 49 days
gestation
PG analogue alone..
Vacuum aspiration
• Dilation and
curettage
• Dilatation and
evacuation
• Induction method
Second Trimester
PROSTAGLANDIN ANALOGUES
• Carboprost
• Sulprostone
• Gemeprost
• Misoprostol
• Dinoprostone
Prostaglandins – Structural Features
Prostaglandins are a class of eicosanoids
2- total number of double bonds in the side chain group
α- orientation of the OH group at 9 position of cyclopentolate ring is above the plane of that ring
Contd..
PGI2 (IP)PGD2 (DP1 and DP2) PGE2 receptors (EPs 1–4) PGF2 (FP)
EP2, EP4, IP, and DP1 activate
adenylyl cyclase Gs. cAMP
levels,
EP1, FP, and activate phosphatidylinositol metabolism
EP3, can couple to both elevation of intracellular Ca
and a inc/ decrease in cyclic
AMP
Pharmacological action on Uterus
• Nonpregnant uterus - contracted by PGF2 relaxed by PGEs.
• Sensitivity prominent before menstruation .Relaxation is
greatest at midcycle..
• Pregnant uterus –PGI2 and high conc of PGE2 - relaxation.
Low dose PGE2 / PGF2 -Contraction.
• PGE2 / PGF2 IV to produces a dose-dependent increase in
uterine tone and in the frequency and intensity of rhythmic
uterine contractions.
• Cervix- soft and makes it more yielding
CARBOPROST Carboprost tromethamine PGF2α analogue
First analogue to be tested clinically on a large scale
for the termination of second trimester pregnancy.
Intra-amniotically (viable second-trimester pregnancy)
Dose: IM 125 µg /ml
Limited value as a primary method for abortion
Post partum haemorrhage
– ADR: diarrhoea (most common)– fever chills vomiting– Cardiovascular collapse, P.HTN
HEAMORRAGIC CYSTITIS
PID
SULPROSTONE• PGE2 methyl sulphonylamide
• Used in the 1980s for the termination of second-
trimester pregnancy
• ADR: severe cardiovascular complications- MI
attributed to coronary spasm, broncho constriction
• WITHDRAWN FROM THE MARKET
• USES: PPH
GEMEPROST PGE1 analogue
USES :dilate the cervix before VA in late-first and early-
second-trimester abortion
Second trimester : Gemeprost is more efficacious when
compared with intra-amniotic PGF2α or extra-amniotic
PGE2 and dinoprostone intracervically
A vaginal pessary- 1mg 3 hrs
before the procedure
Vaginal bleeding, cramps, nausea, vomiting, diarrhea, headache, muscle weakness , backache ,chest pain
DINOPROSTONE• Synthetic derivative of PGE2
• ROUTE OF ADMINISTRATION : vaginal/ oral
• Intravaginal suppository 20mg 3-5 hrs repeated. (17hrs)
• Half life 2.5-5 mins. Excreted in urine
• Induction abortion in second trimester/ early abortion (US)
• Cervical ripening-10mg tab / 0.5 mg gel 6 hrly
• Benign hydatiform mole
• Menstrual regulation
• SIDE EFFECTS
PROLONGED VAGINAL
BLEEDINGSEVERE
MENSTRUAL CRAMPS
GI TOXICITY
Controlled release
formulation
MISOPROSTOL
Presence of a methyl ester at C-1 increase anti
secretory activity
A methyl group at C-16 and a hydroxyl group at C-16
rather than at C-15
Incease oral activty and duration of action
PHARMACOLOGICAL ACTION
Uterotonic
• Single oral dose ↑ tonus (for 1-2h)
• Repeated oral doses→regular contractions
• Single vaginal dose will produce regular
contractions (sustained plasma conc.)
• Increased tonus more rapid with oral/sublingual
(8/11min.) compared with vaginal (20 min.)
Cervical softening
• Reduces the force required for cervical dilatation
• Encouraging disintegration of total collagen content
• increase in collagen solubility an increase in
collagenolytic activity.
• an influx of inflammatory cells into the cervical stroma
• Increase matrix metalloproteinases
• leads to the degradation of collagen and cervical
softening
PHARMACOKINETICS After oral administration, rapidly absorbed from the GI tract. Rapid
first-pass metabolism
DE ESTERIFICATION-MISOPROSTOL ACID
t1/2 20-40 mins
DOSE:400 μg oral misoprostol, the plasma misoprostol level
increases rapidly and peaks at about 30 minutes declines rapidly by
120 minutes and remains low thereafter.
ROUTES OF ADMINISTRATION : Oral, vaginal, sublingual, buccal
or rectal
Mainly urinary excretion
VAGINAL BUCCAL SUBLINGUAL RECTAL
Longer time to peak plasma concentration (70-80min.)
Similar concentration profile to vaginal administration
Tablet dissolves in approx. 20 minutes
Similar concentration profile to vaginal administration
Greater overall bioavailability (AUC)
Lower bioavailability (~50%)
Shorter time to peak concentration than oral and vaginal
Lower bioavailability (~33%)
Longer duration of action(8hrs)
Highest peak concentration
Onset of action significantly slowerthan other routes
Large degree of variation in bioavailability between women
Greatest bioavailability
Mechanism for direct vagina → uterus transport of progesterone exists
No first pass metabolism in the liver
THERAPEUTIC USES
1. Medical Abortion:
600mg(RU 486) 400 µg (24-38 hrs) FDA (2000)
Moistening the tablets appears to slightly increase
plasma levels
2.Cervical Ripening Before Surgical Abortion
• 400 µg of misoprostol vaginally 3 to 4 hours
• 400 µg orally 8 to 12 hours, or 400 mcg sublingually 2 to 4
hours prior to suction curettage.
Buccal administration is widely used
SECOND TRIMESTER : D&E
• INCOMPLETE ABORTION • single dose of 600µg orally OR 800µg vaginally, or a
single dose of 400µg sublingually..
1.400 µg vaginally for 3-4 hrs
2.400 µg + 600 µg of buccal
misoprostol for at least 90 minutes
3.600 µg Buccal Misoprostol 2-4 hrs
Cervical Ripening Before Other Procedures
• The optimal dosing regimen for cervical ripening before
hysteroscopy is unclear.
• 200, 400 or 1000 µg of vaginal misoprostol or 400 µg of
oral misoprostol given at least 9 to 12 hours
preoperatively
• NSAID induced gastric ulcer and chronic heavy
smokers
• 200 µg for 4 times a day Orally
Adverse drug reaction
• Diarrhoea & abdominal pain
Headache• Nausea• Flatulence• Chills/shivering/fever• – Hyperpyrexia (>40°)- doses >600 µg• – Delerium- doses >800 µg• Uterine rupture• Uterine hyperstimulation case reports• Amniotic fluid embolism• Misoprostol is considered a teratogen!!!!
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ANTIPROGESTINS MIFEPRISTONE ONAPRISTONE ULIPRISTAL LILOPRISTONE
MIFEPRISTONE
Known as RU 486- 1981 It is insoluble in water Rapidly dissolves in the gastric ileum when ingested
orally. Remains stable after 3 years at ambient temperature
CHEMICAL STRUCTURE 19-nortestosterone-
derived compound at the 11β position
Is a beta-aryl-substituted
C11 -antiestrogens
• C11 b side chain- antagonistic properties to glucocorticosteroid and progestational hormones
p-dimethylaminophenyl group
Blockage of the progesterone receptorresults in vascular damage, decidual necrosis and bleeding
MECHANISM OF ACTION Progesterone antagonist ( PA)
CELL AND PROMOTER SPECIFIC CAPACITY
COMPETITIVEANTAGONISM
H
H Hdimerize
H HP?
hsp90H
hsp70
hsp59
Rhsp70H
HRE target gene
5’ flanking region
GeneTranscription
CONTD…
MIFEPRISTONE NCoR/SMRT
SRC-1/NcoA-2p300,CBD
Pharmacological actions• Decidual breakdown by blockade of uterine PR• Detachment of the blastocyst which decreases hCG
production• Decrease in progesterone secretion from the corpus
luteum– increase uterine PG levels – sensitizes the myometrium to their contractile actions.
• Cervical softening, which facilitates expulsion of the detached blastocyst
2-5mg/kg
Ovulation
A fall in estradiol
Inhibition of folliculogenesis
Delay or prevent ovulation depending on the
timing of administration : UNCLEAR MECHANISM
Impair secretory endometrium and produces
WITHDRAWAL BLEEDING
3 mg/kg/day
Anti glucocorticoid effect
• Exerted both on the central actions of cortisol -inhibition of feedback control of cortisol and peripheral action
• Binds to the glucocorticoid receptor in human
mononuclear leukocytes
4-6 mg/kg and above
Anti androgenic action
• Modest anti androgenic action• 30 mg/kg for anti androgenic activity
Pharmacokinetics
Orally active with good bioavailability
t1/2 of 20-40 hrs
RU 42 633,mono demethylated metabolite most widely
found in plasma
Bound by α 1-acid glycoprotein.
Hepatic metabolism and enterohepatic circulation
Metabolic products are found predominantly in the faeces
N-demethylation and terminal hydroxylationof the 17-propynyl chain. with CYP450 3A4
Drug interactions• Ketoconazole• Itraconazole • Erythromycin • Grapefruit juice
Rifampicin Dexamethasone Phenytoin phenobarbital carbamazepine
Increase serum levels of
mifepristone.
lower serum levels of mifepristone.
Therapeutic uses• Emergency postcoital contraception
600 mg of mifepristone within 72 hrs.
• Cervical ripening- 36–48 h following treatment
• First and Second trimester TOP.
• Labour induction 600mg daily for 2-3 dys
• Medical management of fetal death
• Potential use in IVF,fibroids,Endometriosis
• Cushing syndrome UNDER TRIAL
• Burns, GR depentant HTN
• Arthritis,glaucoma,HIV
Mifepristone-Misoporstol Regimens
FDA Protocol Alternate Protocol
Gestational age limit 49 days 63 days
Mifepristone dose 600 mg. oral 200 mg. oral
Misoprostol dose, route, and timing
400 µg oralOffice administration
48 hours later
800 µg vaginal or buccalHome self-administration
6 - 72 hours later (vaginal)24 - 36 hours later (buccal)
Office follow-up visit 10-15 days after mifepristone 4 - 10 days after mifepristone
Minimum office visits 3 2
Vaginal bleeding- 8-17 days Endometrial hyperplasia (5-10mg) Abdominal pain Uterine cramps Nausea Vomiting Diarrhea due to the prostaglandin Fulminant septic shock associated with
Clostridium sordellii BLACK BOX WARNING FDA!!!!
SIDE EFFECTS
ULIPRISTAL
• Derivative of 19-norprogesterone SPRM
• Acting as a partial agonist at progesterone receptors
• Dimethyl-aminophenol group at the 11 position, with an
additional acetoxy group at the C17
Pharmacological actions
• In high doses, - anti-proliferative effects in the uterus
• Inhibit ovulation…. can block ovarian rupture at or
even just after the time of the LH surge
• Ulipristal may also block endometrial implantation of
the fertilized egg
• Weak glucocorticoid antagonist
• Uses: Emergency contraceptive ( US &EU 2010)
• DOSE:30 mg orally once, given as soon as possible, but
no later than 120 hours
• Remains effective up to 120 hours (5 days) after
intercourse
• The half-life-32 hours
• Metabolism occurs predominantly by (CYP) 3A4 hepatic
isoenzyme
high plasma protein binding
• ADR:Self-limited headache and some abdominal pain
Onapristone
• pure PA and has no progesterone agonistic effects• Devoid of any progestogenic or antiproliferative effects
on the endometrium of post-menopausal women • Shorter half-life• Effective endocrine agent in experimental breast
cancer models
• Onapristone developed liver function test abnormalities, the development of this drug and recruitment to the study stopped in 1995.
Anti-metabolite Methotrexate
MTX is an antifolate belonging to the antimetabolite class of antineoplastic agent.
• MTX is a cell cycle specific chemotherapeutic agents that acts on S-phase & • thus inhibit DNA synthesis
Folic acid Tetrahydrofolic acid
Dihydrofolate reductaseCo enzy for one carbon transfer reaction
`
An essential
component of DNA
Key metabolic
event
Pharmacokinetics
Readily absorbed from the GI tract at doses of <25 mg/m2
• 7-hydroxy-methotrexate NEPHROTOXIC
• t ½ 8 hrs IM
• 50% of methotrexate binds to plasma proteins
• Up to 90% of a given dose is excreted unchanged in the
urine within 48 hours
• Retained in the form of polyglutamates for long periods
• Weeks in the kidneys and for several months in the liver
SULFONAMIDESALICYLATES
TETRACYCLINECHLORAMPHENICOL
PHENYTOIN
Methotrexate/Misoprostol Regimens
• Methotrexate: 50 mg/m2 IM or 50 mg PO
• Misoprostol: 800 µg PV 3–7 days later
• Efficacy decreases after 49 days’ gestation
• Rh immune globulin to Rh negative patients before
misoprostol
• Initial follow-up ~1 week after methotrexate
• Subsequent care based on results of
physical exam, ultrasonography
• If Bhcg has fallen by >80% over 7days,procedure was
successful
• Prior to MTX administration the following laboratory parameters should be confirmed:
Guidelines for parenteral administration of intermediate- or high-dose methotrexate (HDMTX)
WBCs > 1500/mm3 Neutrophils > 200/mm3 Platelets > 75,000/mm3
s.bilirubin<1.2mg/dlSGPT (ALT)<450 U
Normal s. Cr.Creatinine clearance>60ml/min
Previous mucositis should be healed& pleural effusions should be drained prior to MTX administration
Contraindications
• Anemia (Hgb < 10 g/dL)/ leucopenia/thrombocytoenia
• Known coagulopathy
• Active renal or liver disease
• Uncontrolled seizure disorder
• Acute inflammatory bowel disease
• Intrauterine device in situ
• High intial hcg concentration >5000mU/ml
• Ectopic pregnancy > 4cm in size as in TVS
Regimens for medical abortion and their effectiveness
Regimens Effectiveness
Use up to
Mifepristone + misoprostol or mifepristone + gemeprost
>96% 9 weeks from last menstrual period
Misoprostol alone >83% 12 weeks from last menstrual period
Methotrexate + misoprostol >90% 9 weeks from last menstrual period
SOME OLDER TECHINQUES
Older days…
Hystrecotomy (sectio parva)
Intra-amniotic injection of hypertonic
saline/hyperosmolar urea
Intra- or extra-amniotic administration of
ethacryidine lactate (Rivanol)
Parenteral/intra-amniotic / extra-amniotic
administration of prostaglandin (PG) analogues
I.V / i.m. administration of oxytocin
ETHACRIDINE LACTATE
• Ethacridine lactate/Rivanol is a yellow dye with
antiseptic properties
• MOA: Stimulates endogenous PG and thromboxane
production, promoting cervical priming and initiating
labour
• DOSE:0.1%-solution of ethacridine lactate - extra-
amniotic space through a sterile catheter at a dose of
10 mL per gestational week
• 20-40 hrs mini labour
• Maximum of 150 ml
Hypertonic Saline
One of the first described instillation methods
• When used alone, intra-amniotic hypertonic saline
has a long latent period until the onset of
contractions
• Time to abortion of 30 hours
• Addition of oxytocin to this regimen improves the
efficacy and expulsion time
Hypertonic Saline (Contd.)
Use of concentrations exceeding 20%.• Maternal hypernatremia • Coagulopathy• Hemorrhage transfusion • Cervical laceration
SIDE EFFECTS
IV OXYTOCIN First described by Winkler and associates
100 units per 500 mL of DNS, is infused over 3 hours
1 hour is allowed for diuresis to preclude water
intoxication
The dose is increased 50 units per 500 mL of DNS
until delivery is achieved
Maximum of 300 units
Mean time to delivery of 8.2 hours
UREA
• Rapidly traverses cell membranes
• Osmotic diuretic
• Has a long instillation to abortion interval when
used alone
• Intra-amniotic urea, 80 to 90 g, with intravenous
oxytocin
• Average time to expulsion of 19 to 29 hours
SIDE EFFECTS
Puncture of the intra-amniotic space
The introduction of a Foley catheter into the
extra-amniotic space
Long induction-to-abortion interval
Need for curettage after the expulsion of the
fetus
The IV infusion of oxytocin -water intoxication.
Hypertonic saline – DIC
HERBAL MEDICINES
ABORTION AND MYTH!!!!
• LAMINARIA• Angelica/Dong Quai• Black Cohosh • Blue Cohosh • Cotton Root Bark • Evening Primrose • Parsley• Pennyroyal.• Pineapple and Papaya• Vitamin C
In India…MTP Act - 1971Aims to improve the maternal health Prevent large number of unsafe abortions and
consequent high incidence of maternal mortality & morbidity
Legalizes abortion servicesPromotes access to safe abortion services to
womenDe-criminalizes the abortion seekerOffers protection to medical practitioners who
otherwise would be penalized under the Indian Penal Code (sections 315-316)
MTP Act: addressing a public health priority
• Up to 20 weeks gestation
• With the consent of the women. If the women is below
18 years or is mentally ill, then with consent of a
guardian
• Opinion of two RMPs required for termination of
pregnancy between 12 and 20 weeks
WHEN CAN PREGNANCIES
BE TERMINATED??
MEDICAL ABORTION
• MTP using Mifepristrone (RU 486) & Misoprostol
approved for up to 7 weeks termination
• Only an RMP (as defined by the MTP Act) can prescribe
the drugs
• Has to follow MTP Act, Rules & Regulations
• Can prescribe in his/her clinic, provided he/she has
access to an approved place
• Should display a certificate from owner of approved place
agreeing to provide access
Thank you