Drugs and pregnancy



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DRUGS and PREGNANCY

  • INTRODUCTION

    • Uterus important organ for child birth—houses the developing egg, embryo and fetus and interfaces with the placenta

    • Uterus wall composed of smooth muscle

    • Uterine smooth muscle plays important and complex roles in the birth process

      • Effacement-- opening up and becoming more elastic

      • Contractions of wall—important in pushing baby out

      • Involution-- must return to its original state so it can start the process all over again

    • In some patients it is necessary to induce labor and in other patients to delay labor

UTERINE STIMULANTS (OXYTOCICS)

  • Drugs that contract uterine smooth muscle

    • Increase motility and contraction of the uterus

  • PROSTAGLANDINS

    • Autacoids produced in many tissues

      • Key enzyme is cyclooxygenase (types 1 and 2)

      • Blocked by NSAIDs

      • Short plasma half-life ~ 2.5-5 min—so they have local effects

    • PGE2 and PGF2alpha induce contraction of uterine SM during pregnancy

      • Synthesis by uterus increases at term

        • Especially during the end of the pregnancy

      • Levels in maternal blood, umbilical blood and amniotic fluid increase at term and during labor

      • Synthesis and effects inhibited by progesterone (inhibits the production)

    • CERVICAL RIPENING prior to labor induction

      • PROSTAGLANDIN E2 (PGE2)

        • In cervix: Relaxes SM and stimulates release of collagenase, which breaks down the collagen that makes cervix rigid—so it breaks down the collagen which makes the cervix more soft and elastic—CERVICAL RIPENING

        • In uterine wall: Induces contractions

          • Augments oxytocin effects, therefore, therapy should be stopped prior to administration of oxytocin

        • Shortens time to onset of labor and delivery time

      • SIDE EFFECTS

        • Increases GI motility ® nausea, vomiting, diarrhea

          • Same side effects as all of the other prostaglandins

        • Hyperstimulation of uterus SM—which is undesirable

      • PREPARATIONS FOR CERVICAL RIPENING

        • DINOPROSTONE (PGE2)—cervical ripening and induces contractions

          • Prepidil® (1992), endocervical gel, 0.5 mg PGE2

            • Administered via cervical catheter and syringe

              • Length of catheter depends on the amount of effacement that has occurred once it is in there you cant get it out so it can have a prolonged effect (can last up to 12 hours)

            • 20 mm or 10 mm catheter with 0 or 50% effacement

            • Often requires 2 doses, 6 hours apart

            • Oxytocin may be administered 6-12 hr after last dose

          • Cervidil® (1995), retrievable, vaginal insert w/ string to remove it

            • Contains 10 mg PGE2 released at 0.3 mg/hr for 12 h

            • Oxytocin may be administered 30 min after removal

              • Once you remove it you remove it's effects so you can stimulates labor

            • Remove if active labor begins

            • Remove if hyperstimulation (5%) or fetal distress

              • The string allows quick removal if you have these side effects




        • MISOPROSTOL (Cytotec®, 1988)—cheaper than dinoprostone

          • A tablet that can provide prostaglandins to help the stomach protected from acids and also cervical ripening

            • Help counteract the adverse effects of NSAIDs on the GI tract.

          • PGE1 derivative, alternative to dinoprostone, but not FDA approved – “off-label” use

          • ¼ 100 mg tablet inserted vaginally every 4 h

            • If you cut it up and insert it vaginally then you get the same effects as dinoprostone

          • ADVANTAGES

            • More effective, works faster, less need for oxytocin

            • More convenient, stored at room temp because they are dry tablets

            • Much less expensive $1 versus $175 for Cervidil® and potentially 3x $150 for Prepidil®

          • DISADVANTAGES

            • Higher incidence of uterine hyperstimulation

    • INHIBITION of POST-PARTUM BLEEDING (placental delivery)-- post partum blood loss

      • CARBOPROST (15-Me-PGF2a, Hemabate®, ’79)

        • PGF2 derivative

        • Used when oxytocin or methylergonovine fail to work—It is a third line drug

          • Single IM dose (250 mg) usually sufficient (max dose 2 mg)

            • injected IM so you have more systemic effects and side effects

        • MECHANISM:

          • Contraction of uterine SM most important (will compress the BV’s in its wall), but

          • Also causes vasoconstriction (PGF2a) so will decrease the blood loss

        • ADVERSE EFFECTS

          • GI effects, nausea, vomiting, diarrhea 60% patients-- especially since it's a systemic drug

            • Can pretreat with antiemetic and antidiarrheal

          • Fever is common-- when it gets to the brain

          • Systemic Vasoconstriction can ® BP­, bronchoconstriction (PGF2a)

    • TERMINATION OF PREGNANCY: PROSTAGLANDINS –b/c induce contraction of uterine SM

      • For abortion of early pregnancy

        • MISOPROSTOL (PGE1 analog) (oral)

          • Approved for use with the antiprogestin MIFEPRISTONE (RU486, Mifeprex®), to induce abortion up to 49th day of gestation (3x200 mg RU486 + 2x200 mg oral PG)

            • Mifepristone blocks the progesterone and embryo becomes detached and misoprostol induces contractions to expel the embryo

              • Misoprostol can be used 2-3 days later for SM contractions

      • For 2nd trimester abortion (wks 12/13-20)

        • DINOPROSTONE (PGE2, Prostin E2® 1977)

        • CARBOPROST (15-Me-PGF2a) (Hemabate®, 1979)

          • IM injection, 250 mg every 1.5-3.5 h as needed

        • Mean time to abortion is 17 hr, but 25% incomplete

  • OXYTOCIN

    • Natural peptide hormone

    • Principle use - induction of labor

    • POSTERIOR PITUITARY HORMONES

      • Posterior pituitary secretes two peptide hormones-- peptide hormones with disulfide bridges

        • Vasopressin (antidiuretic hormone)

        • Oxytocin

      • Synthesized in neurons in hypothalamus

      • Stored in secretory granules in nerve endings in posterior pituitary until released into circulation

    • OXYTOCIN (Pitocin®, 1980)

      • MECHANISM in UTERUS

        • G protein-linked memberane receptors (similar to V1 for vasopressin) linked to elevation of Ca2+ in uterine smooth muscle and causes contraction

        • Increases local uterine prostaglandin production towards the end of gestation especially

      • ADMINISTRATION

        • IV, IM or nasal spray

        • Inactive if given orally

      • Plasma half-life short ~12-15 min—Vasopressin also has short half life. The short half life allows the effect to go away quickly and allows you to adjust rate of infusion when it is given IV

        • Metabolized in liver and kidney

      • ACTIONS

        • Increases force, frequency and duration of uterine SM contraction, with normal relaxation

          • Sensitivity starts low, but increases throughout pregnancy

            • During pregnancy, number of receptors increases 30x

              • Not essential for delivery but it seems it is very useful

            • Just before term, there is an abrupt large increase

          • Physiological role in delivery uncertain - it is not essential

        • Contracts myoepithelial cells surrounding mammary alveoli in the breast, needed to eject milk into the sinuses

          • Reflex arch--Suckling induces a neuronal reflex that releases oxytocin

        • Has weak antidiuretic and vasopressor activity

          • Acts at vasopressin (ADH) V2 and V1 receptors in the collecting duct of the kidney and causes water retention and hyponatremia

      • OXYTOCIN: USES

        • INDUCTION OF LABOR (~20% of deliveries involve induction of labor) – when do you induce laboor?

          • Pregnancy has continued beyond term - 42 weeks

            • 40 weeks is the standard term for pregnancy

          • When early vaginal delivery will decrease mortality or morbidity for mother or baby, i.e. when continued pregnancy is a greater risk than the induction

            • Premature rupture of amniotic membranes - most common reason

              • Decreases the risk of infections

            • Severe maternal infection

            • Diabetes mellitus

            • Placental insufficiency

            • Renal insufficiency

            • Anemia

            • Pre-eclampsia (at or near term, discussed later)

          • Induction simply for convenience is controversial (2/3)-- 2/3 of deliveries are done for convenience not necessity

        • Oxytocin use for induction of labor is contraindicated (use a caesarian section in these situations!)

          • Cephalopelvic disproportion—when the head is bigger than the gap in the pelvis for the baby to fit through

          • Placental abnormality

          • Abnormal fetal presentation

          • Umbilical prolapse

          • Previous uterine surgery

          • Fetal distress

          • Improper use of oxytocin can lead to rupture of uterus and death of mother and/or fetus

      • PREINDUCTION

        • Before induction is begun, fetal lungs must be sufficiently mature and the cervix ripe (cervix must be ripened!!!!)

          • Glucocorticoids

          • Prostaglandins

      • INDUCTION – Oxytocin ADMINISTRATION

        • Dilute solution (10 mU/ml) via IV infusion pump (continuous)

        • Rate increased slowly from 6 mU/min until physiol. contraction pattern is established - max 40 mU/min

        • Maternal Monitoring: BP, HR and uterine contraction

          • Stop infusion if resting uterine pressure > 15-20 mmHg

            • If it goes above this then slow down infusion

          • Stop infusion if contraction duration > 1 min

            • The baby doesn't receive blood flow with each contraction so these must be short

          • Stop infusion if contraction frequency > 1 per 2-3 min

        • Fetal Monitoring: HR and rhythm

          • Stop infusion if heart rate or rhythm become abnormal

        • Response to change in infusion rate is rapid - why? B/c oxytocin has such a short half life

      • OTHER USES

        • Augmentation of dysfunctional labor

        • Control of post-partum uterine hemorrhage

          • After delivery of placenta, 10 U IM, or

          • 10-40U in 1 L of 5% dextrose infused 10 ml/min

        • Promotion of milk ejection--effects on the myoepithelial cells in the breast they can inhale it into the nose before feeding and it can help promote milk ejection

        • Oxytocin Challenge Test – Uterine contractions stop the flow of blood through the placenta and limits the blood supply to the fetus and this is a stress on the fetus and maybe the placenta isn’t working well enough to maintain supply of oxygen to the fetus.

          • Administered IV oxytocin near term to produce uterine contractions (3 contractions in 10 minutes) that temporarily cause the fetal blood supply ¯

          • If fetus healthy, no change in heart rate

          • If fetus not healthy, oxygen deficiency ® fetal HR ¯--might want to perform a C-section instead of a normal delivery

      • OXYTOCIN: TOXICITY

        • Serious toxicity is rare, but includes

        • Uterine rupture—can occur from excessive contractions

          • Maternal and/or fetal death

        • Water intoxication, rare - ADH effect (can activate the ADH receptors V1)

          • Most likely when oxytocin is administered in a large volume—can lead to  water retention

          • Can cause convulsions (caused by hyponatremia), coma and even death

  • ERGOT ALKALOIDS-- older drugs used for hundreds or thousands of years

    • A fascinating group of drugs produced by Claviceps purpurea, a fungus that grows on grains, especially rye

    • Like LSD are derivatives of LYSERGIC ACID

    • Ergotism: effects of ergot poisoning

    • ERGOT POISONING

      • Consumption of contaminated grain leads to ergotism or “St. Anthony’s Fire”-- back in the middle ages

        • Dementia with florid hallucinations--LSD like effects

        • VERY Prolonged vasospasm/vasoconstriction ® ischemic pain/“fire” and gangrene of feet, legs, hands and arms

          • Turned black and dropped off and looked like it burned from St. Anthony's fire

          • The reason for prolonged effects is very tight binding of the compound to the receptor

        • Uterine smooth muscle contraction ® spontaneous abortion

      • MECHANISM: Contains 20 different ergot compounds including agonists, partial agonists and antagonists at

        • -adrenergic receptors

        • Dopamine receptors

        • Serotonin (5-HT) receptors (5-HT1A, 5-HT1D, 5-HT2)

    • Ergot compounds are divided into 2 groups

      • Amine ergot alkaloids, e.g. ERGONOVINE first purified in 1932

        • Important for effects on uterus

        • Rapid GI absorption and rapid metabolism

      • Peptide ergot alkaloids, e.g. ERGOTAMINE first purified in 1920

        • Important in treatment of hyperprolactinemia and also migraine

        • Poor GI absorption, bioavailability <1%, slower metabolism, - longer duration of action

    • AMINE ERGOT ALKALOIDS

      • Ergonovine, methylergonovine and lysergic acid diethylamide (LSD)

      • Rapid GI absorption and metabolism—good bioavailability

      • ERGONOVINE, (Ergotrate®, ?) METHYLERGONOVINE (Methergine®, 1946)

        • MECHANISM

          • Partial -adrenergic agonist on SM

          • Partial 5-HT2 agonist on SM

            • Causes contraction of the uterus via these 2 receptors

            • Difference between oxytocin is that amine ergot alkaloids are less physiological

              • During a normal contraction you have it followed by relaxation but with these drugs you can get the normal pattern of contraction at low doses but at high doses you end up with a continuous contraction (not good for fetus)

        • ACTIONS on UTERUS

          • Contraction strong and prolonged--a continuous contraction and not a relaxed period in between (*bad)

          • Sensitivity increases as pregnancy progresses

          • Low doses increase force and frequency of contractions with normal relaxation, also vasoconstriction

          • As dose is raised, force increases and resting tone increases, sustained contraction can result

        • USES/INDICATIONS

          • In 18th century, Ergot was used to accelerate labor, but led to increased maternal and fetal mortality (1824)

          • Second stage of labor - following delivery of anterior shoulder - but, only with full obstetric supervision

          • Primarily used postpartum now, METHYLERGONOVINE

            • Routinely used to assist involution and decrease hemorrhage

              • Uterus shrinking back to its original size

            • Treatment of subinvolution of uterus and atony

            • Treatment of postpartum hemorrhage--NUMBER 1 REASON!!

        • ADMINISTRATION

          • Usually administered after placenta delivered

            • Oral tablet - effects seen in 5-10 min, peak plasma conc ~ 1 hr

            • IM injection - effects seen in 2-5 min

            • IV injection - effects immediate, but… (not recommended – due to BP­)--must give it slowly bc it causes the vasoconstriction and the BP just goes up

            • Use is limited to a maximum of 1 week – why? B/c they have a very long effect and the vasoconstriction accumulates

        • BIOAVAILABILITY – contrast ergotamine

          • Methylergonovine oral ~60%, IM ~80%

        • ADVERSE EFFECTS – rare with IM or oral

          • Amine ergot alkaloids less toxic than peptide alkaloids

          • Hypertension – most common, frequent when IV

            • In some cases, associated with seizure and/or headache

            • Do not use in hypertensive patients

          • Nausea and vomiting (CTZ, GI) – 10%

            • D2 agonists causes vomiting!!

          • Numbness, tingling of fingers and toes-- excessive vasoconstriction

          • Overdose/prolonged use can lead to “ergotism”

            • Above symptoms, plus: respiratory depression, hypothermia, convulsions, coma-- so much vasoconstriction!!!

            • Prolonged vasospasm, which may lead to gangrene and require limb amputation



KEY DRUGS FOR MIGRAINES

  • PEPTIDE ERGOT ALKALOIDS ERGOTAMINE/DIHYDROERGOTAMINE Only difference between these 2 drugs is that Dihydro has the double bond reduced

    • Similar in structure to the AMINE ERGOT ALKALOIDS except that it has amino acids stuck on the end and they are less lipophillic and are not absorbed as readily

    • ERGOTAMINE (purified in 1920), DHE and BROMOCRIPTINE

    • Poor GI absorption and low oral bioavailability

    • TREATMENT of MIGRAINE-- ERGOTAMINE/DIHYDROERGOTAMINE (DHE)

      • Only difference between these 2 drugs is that DHE has the double bond reduced

      • Used for acute treatment of migraine headaches (with or without aura – visual effects) and cluster headaches

      • Most useful if given during the “prodrome”

      • ACTIONS/MECHANISM (?)

        • Partial a-adrenergic agonist (Ca2+­)

        • Partial 5-HT2A, 5-HT2C agonist vascular s.m. (Ca2+­)

        • Also D2 and D3-dopaminergic agonist (cAMP¯)

        • Agonist at presynaptic 5-HT1D receptors (cAMP¯) on trigeminal nerves innervating cranial blood vessels

          • Inhibits release of inflammatory/vasodilator peptides, e.g. CGRP (calcitonin gene related peptide), substance P

        • Agonist at cranial vascular s.m. 5-HT1D receptors, e.g. on arterio-venous anastomoses

        • Should not be used prophylactically or prevention JUST DURING ACUTE ATTACK or when they have a prodrome and feel a migraine coming on.

        • MECHANISM: Dihydroergotamine

          • This is blood flow to the brain—the brain gets the blood and uses the O2 and then it drains off on the venous side. So you have these anastomosis that are kind of short circuits that allows some of the blood to go into the venous circulation before it gets into the brain. Then there are these neurons that release things like calcitonin gene related peptide (CGRP) and sub P and these cause vasodilation of the anastomoses and they trigger inflammation which may trigger more stimulation and more release. When you have dilation of the short circuit you get ischemia (in the area on the R in the picture above), which leads to pain. So to prevent this you need to constrict the anastomosis to promote blood flow in the area on the R. And we do this by using DHE binding to the 5-HT1D receptors which are coupled to a Gi protein which  cAMP and when you  cAMP in vascular SM you cause constriction. There are also presynaptic 5-HT1D receptors and if you remember when there is an  cAMP in the nerve terminal it stimulates release of neurotransmitter and when  cAMP you inhibit it—so here we are inhibiting the release of the substances that are causing vasodilation (CGRP, Sub P) macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 4.47.44 pm.png

      • BIOAVAILABILITY very low – first pass metabolism

        • Often combined with caffeine (vasoconstrictor in the brain) said to increase rate and extent GI absorption, but bioavailability still ~ 1%

        • Administered oral, sublingual, rectal, nasal, IV, IM
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