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