Drugs and pregnancy



Download 499.08 Kb.
Page2/10
Date conversion02.12.2016
Size499.08 Kb.
1   2   3   4   5   6   7   8   9   10

ERGOTAMINE

  • Ergomar®, generic ’83, sublingual

  • Cafergot®, 1953, rectal suppositories, with 100 mg caffeine

  • Ercatab®, oral tabs, with caffeine

  • * various routes!! also given with caffeine which is also a vasoconstrictor in the brain

  • DIHYDROERGOTAMINE

    • D.H.E.45®, 1946, IV, SC or IM injection

    • Migranal®, 1997, nasal spray with caffeine

  • HALF-LIFE of DHE ~ 9-10 hr

  • ADVERSE EFFECTS - IMPORTANT

    • Nausea/vomiting (10% oral, 20% parenteral, E>DHE)—D2 receptors

      • Metoclopramide often used as adjunct - Why?

      • Try to establish maximum, sub-nauseating dose

    • Potent vasoconstrictor with prolonged action - difficult to reverse due to tight binding (E>DHE)

      • Numbness, tingling of fingers and toes

      • Hypertension

      • Coronary vasospasm

      • Cumulative vasoconstriction occurs with each dose

      • Should not be used during pregnancy because it vasoconstricts and causes contraction the uterus!!!

      • Consequence: Limit dose to 6 mg/attack or 10 mg/week

  • CONTRAINDICATIONS

    • Patients with CAD, Peripheral Artery Disease, hypertension or at risk of CAD, (i.e. if BP­, cholesterol­, diabetes, obese, post-menopausal women, men > 40 y/o, family history)

    • Pregnancy cat. X ® fetal distress, toxicity due to decreased utero-placental blood flow

    • Hemiplegic or basilar migraine

  • DRUG INTERACTIONS - CYP3A4 INHIBITORS

    • Black-Box warning: Ritonavir, erythromycin, etc. can elevate plasma DHE b/c they inhibit CYP3A4 which metabolizes DHE® serious or life-threatening cerebral or peripheral ischemia

  • TRIPTANS”—more selective for 5-HT1D receptors than ergotamine

    • First line drugs for migraine with or without aura

      • Sumatriptan (Imitrex®, 1992, SC, oral, nasal)

      • Zolmitriptan (Zomig®, 1997)

      • Naratriptan (Amerge®, 1998)

      • Rizatriptan (Maxalt®, 1998)

      • Almotriptan (Axert®, 2001)

      • Frovatriptan (Frova®, 2001)

      • Eletriptan (Relpax®, 2002)

    • SUMATRIPTAN (Imitrex®, 1992)

      • Selective agonist at 5-HT1D (and 5-HT1B) receptors on cranial vascular SM and presynaptic membranes

        • These drugs are more selective

          • They are not working at the  receptors or 5-HT2 receptors like ergotamine and DHE do

      • Little effect on arterial BP, or PVR

      • First-line therapy for ACUTE severe migraine

        • NOT for prophylactic therapy because you can't use these chronically

          • You take them when you feel a migraine coming on

        • Second dose can be taken after 2 hr (t½ ~ 2 hr)

        • Maximum oral dose limited to 200 mg in a day

      • Oral bioavailability 15% - first-pass effect

        • Metabolized by MAO-A

          • So drug interactions with MAO Inhibitors

        • SC, oral and nasal preps available

      • Half-life = 2.5 hr

      • Drug Interactions

        • MAO-Is, SSRIs (serotonin antagonists--serotonin syndrome life threatening), ergot derivatives

          • MAO inhibitors- Selegelline and Tranylcypromine

          • If you combine MAO-I w/ SSRI’s you block metabolism of serotonin (done by MAO) and you block uptake (SSRI) so you get excessive actions of serotonin

      • Pregnancy category C - avoid use

        • In rats and rabbits, produces embryolethality, fetal abnormalities, and pup mortality

          • Not shown to cause problems in women but found to in animals

      • ADVERSE EFFECTS – most are transient and mild

        • Most common (50%) – unpleasant chest symptoms - described as “heavy arms” and “chest pressure”

          • Patients should be warned and told it is not dangerous

          • Possible causes

            • Pulmonary vasoconstriction, esophageal spasm, intercostal muscle spasm, bronchoconstriction—not sure exactly what is causing these symptoms tho

        • Vasospasm of arteries (heart, brain, GI)-- not much usually involved with the peripheral but they can cause some problems

          • Biggest concern – coronary vasospasm

          • Contraindicated in patients with CAD

            • Not recommended for patients at risk of CAD, e.g. post-menopausal women, men > 40 y/o, BP­, cholesterol­

      • USE of SUMATRIPTAN vs DHE

        • Sumatriptan works faster in providing relief attacks so this is very useful because want to stop a migraine as fast as possible

          • Effects seen

            • In 15 min after SC administration

            • In 30-60 min after oral administration

          • Complete relief in 2 hr for 70-80% patients

          • But, 40% patients headache returns within 48 hr

        • DHE has lower recurrence rate

          • Effects seen in 2 hours?

          • Only 18% migraine recurrence within 24 hr

        • Both contraindicated in patients with CAD

  • LYSERGIC ACID DIETHYLAMIDE (LSD)

    • Synthetic derivative of ergot compound lysergic acid

    • Potent hallucinogen – mechanism uncertain

      • Agonist at pre- or post-junctional 5-HT2 receptors in CNS or 5-HT1A and 5-HT1C

      • Lysergic acid itself is inactive

    • Schedule 1 controlled substance

      • i.e. no approved clinical uses

    • See “Drug Abuse” notes for further information

    DRUGS USED TO TREAT INFERTILITY CAUSED BY HYPERPROLACTINEMIA

    • BROMOCRIPTINE (Parlodel®, 1978)

      • Fairly Selective D2 agonist (cAMP¯)

      • USES

        • Hyperprolactinemia - lowers plasma prolactin

          • Dopamine inhibits release of prolactin from the anterior pituitary--very effective

            • Dopamine antagonists actually cause hyperprolactinemia

        • Acromegaly – caused by  GH so this drug lowers plasma growth hormone 50% in these patients also acts in the anterior pituitary

        • Parkinson’s disease – acts in c. striatum

        • HYPERPROLACTINEMIA

          • Occurs secondary to anterior pituitary adenomas (secreting prolactin—prolactinoma)

          • PROLACTIN

            • Polypeptide hormone produced by anterior pituitary

            • Stimulates milk production after parturition

              • Different from oxytocin—which promotes milk ejection

            • Prolactin secretion

              • Normally inhibited by dopamine (D2, cAMP¯) released from neurons from hypothalamus

              • Stimulated by suckling—reflex arch

          • Effects of hyperprolactinemia

            • Women: Galactorrhea, amenorrhea, infertility (interferes with normal fertility and ovulation)- mechanism unknown

            • Men: Impotence and sometimes galactorrhea

          • Treatment of hyperprolactinemia and associated infertility

            • Bromocriptine suppresses prolactin release

              • Reinstates normal ovulatory menstrual cycles and restores fertility, takes few days - 2 months

              • Suppresses galactorrhea (excess milk production)

              • Continuous tx can induce regression of the tumor, sometimes for years

            • Therapy should be stopped as soon as patient becomes pregnant and not resumed till after delivery

              • Especially if patient has PIH (pregnancy induced hypertension) or develops pre-eclampsia

      • SIDE EFFECTS

        • Hyperprolactinemia patients

        • Nausea (50%)/vomiting (works at the chemoreceptor trigger zone) and other GI symptoms, headache (19%), dizziness (17%) sometimes orthostatic hypotension

          • Remember it's a D2 agonist

          • Antiemetics can be D2 antagonists

      • ADMINISTRATION

        • With food to minimize nausea/vomiting

          • 2.5 mg, 2-3x/day

    • Other Ergot D2 Agonists

      • PERGOLIDE (Permax®, 1988-2007)

        • USE - Parkinson’s disease - adjunct to levodopa

        • More potent than bromocriptine

        • Removed from market because heart valve damage

      • CABERGOLINE (Dostinex®, 1996)

        • USE – Hyperprolactinemia –dose lower than for Parkinsons Disease so  risk for heart valve disease

        • Long half-life = 63-69 hr, administered 2x/week

        • Side effects, nausea, constipation, headache

    UTERINE RELAXANTS (TOCOLYTICS)—ending of labor

    • Relax the uterus, unlike the others we talked about that stimulate the uterus to contract and start labor process

    • Drugs used to suppress premature labor and birth

      • Inhibit contraction of the uterus

    • PREMATURE LABOR/BIRTH

      • Premature birth defined as < 37 weeks gestation

      • In USA, 11% births are premature

      • Leading cause of infant morbidity and neonatal mortality in USA

        • Most common complication of early birth: neonatal respiratory distress syndrome – Why? Because lung development occurs later in utero

        • Respiratory system is last fetal system to mature

      • Tocolytics can suppress labor, but average delivery delay is only 48 hr – so why bother? WINDOW FOR SURFACTANT DEVELOPMENT!!!

        • Answer: Allows use of glucocorticoids to accelerate fetal lung development

    • RESPIRATORY DISTRESS SYNDROME (RDS)

      • RDS results from deficiency of lung surfactant

        • A mixture of phospholipids (PC) and apoproteins that lowers the alveolar surface tension which prevents the alveoli from collapsing

      • Without sufficient surfactant:

        • Alveolar collapse, pulmonary edema

        • Lung compliance¯, small airway epithelial damage

        • Hypoxia and ultimately respiratory failure

      • Hydrocortisone initiates surfactant/lecithin synthesis in wks 30-32, becomes adequate in wks 34-36

        • Result: delivery at 26-28 wks 60-80% RDS
          delivery at 30-32 wks only 20% RDS

      • PREVENTION

        • Glucocorticoids administered to mother are beneficial when given between weeks 24-34

        • MECHANISM

          • GCs stimulate synthesis of fibroblast pneumocyte factor, that stimulates surfactant production by type II pneumocytes and stimulates lung maturation

        • Two regimens-- work on the type II pneumocytes

          • DEXAMETHASONE (Decadron®)

            • Four 6 mg IM, 12 hours apart

          • BETAMETHASONE (Celestone®)

            • Two 12 mg IM, 24 hours apart

        • Last dose should be administered >24 hr before, but <7 day before delivery-repeat courses should be avoided

          • These drugs work on protein synthesis, they don't have immediate effects. You need delivery to occur 24 hrs 7 days after last dose of glucocorticoid was given

    • MAGNESIUM SULFATE (MgSO4)

      • Tocolytic DRUG OF CHOICE, because has lowest risk of side effects and low cost, while efficacy is similar to other tocolytics

        • So slowing down labor efficacy, low cost, low risk -good drug

      • MECHANISM - a Ca2+ antagonist? Mg pretty much competes w/Ca and we know Ca is involved in regulating almost everything especially SM contraction and NT release, heart activity, respiration, etc. It is tricky to block Ca without having significant side effects

        • Normal [Mg2+]plasma 1.5-2 mM, but at 4-7 mM inhibits ACh release at uterine neuromuscular junctions

          • Blocks Ca entering the nerve terminal to release the vesicles of NT

            • normal NT release involves Ca entering the nerve terminal and releases the vesicles

          • ACh is responsible for the contraction of uterine SM

        • Concentrations > 7 mM inhibit skeletal muscle NMJs ® weakness ® trouble w/ respiratory & cardiac arrest

          • Narrow therapeutic range

      • ELIMINATION: 100% by kidney

        • Remember 70% normally reabsorbed in the Thick Ascending Limb (TAL)

      • ADMINISTRATION - IV infusion pump

        • Bolus 4-6 g, then infusion 2-3 g/hr for 48-72 hr

          • Bolus then infusion = Loading dose = big dose given at the beginning to get the concentration up quickly. Woman is going into labor and so you don't have days to get this drug up to the level you want it at in the blood

      • ADVERSE EFFECTS

        • In therapeutic range: Usually well-tolerated

          • Initial transient HYPOTENSION (flushing, headache, dizziness, feeling of warmth), dry mouth

        • Pulmonary edema (2%), can be fatal (MAIN PROBLEM!!!)

        • Higher doses: Flushing, hypothermia, paralytic ileus

        • Toxic levels: Somnolence, hypotension, paralysis, respiratory depression, cardiac arrest

      • MONITOR - to reduce risk of adverse effects and make sure levels stay in the right range

        • Mg2+ levels every 4 hr

        • Deep tendon reflexes: loss of reflex is an early indicator that Mg2+ levels are dangerously high (at 10 mmol you have no reflexes at all—so stop infusion until reflexes return)

          • Reflex response is very sensitive response that is a good indicator of Mg.

        • Renal function and fluid balance – This is the way the body eliminates the Mg. So you need to use it to detect fluid retention which increases risk of pulmonary edema

      • CONTRAINDICATIONS

        • Myasthenia gravis-- antibodies against the nicotinic Ach receptors so you get weakness and inability of muscles to contract. So adding Mg to further reduce muscle contraction is not desirable.

        • Renal failure—this is how we get rid of the Mg

        • Hypocalcemia - intensifies effect of Mg2+

      • TREATMENT of TOXICITY

        • Calcium gluconate (oxidized form of glucose), administered IV

      • EFFECTS on NEONATE

        • Mg2+ readily crosses placenta

        • Newborn may suffer-- with too much Mg

          • Muscle weakness (hypotonia)-- signs of too much Mg—suppression of nerve function

          • Sleepiness

        • Effects may persist for several days – Why?

          • Newborn kidney function not fully developed – GFR neonate 30-40% of adult. So takes longer to get rid of the Mg

    • 2-SELECTIVE ADRENERGIC AGONISTS—were important class of drugs for asthma

      • Terbutaline (Brethine®)-- also used for asthma, etc.

      • Ritodrine (Yutopar®)-- was the only 2 agonist for inhibiting labor but it's not on the market anymore

      • TERBUTALINE (Brethine®, 1974) and RITODRINE

        • Selective for 2-receptors

        • Major Uses: FDA update 2-2011:

          • Tocolysis(?)- Delay onset of labor wks 20-36 (IV, oral)

            • Initial IV infusion for max of 48-72 hrs only in hospital setting, oral administration contraindicated-- can only use 2-3 days max to stop pregnancy

          • Prophylaxis and treatment of acute asthma attack

        • Administration

          • IV, and oral

          • Side effects: Cardiac stimulation 1 or 2 action ® death, etc.

            • This drug isn't in good shape either-- cardiac problems

            • So not being used anymore. FDA is pushing that these be avoided

    • Ca2+ CHANNEL BLOCKERS

      • NIFEDIPINE

        • Blocks Ca2+ channels in smooth muscle, including uterus, vascular system arterioles

        • Can suppress labor for at least 48 hr to allow treatment w/ glucocorticoid for fetal lung development

        • Maternal side effects from vasodilation

          • Tachycardia, hypotension, facial flushing, headache, dizziness, nausea-- all result from lowered blood pressure and vasodilation

          • Hypotension may occur in hypovolemic patients

            • May compromise uteroplacental blood flow

              • Dropping maternal blood pressure makes you worry that the fetus isn't receiving enough blood (which carries nutrients and oxygen to the fetus)

        • ADMINISTRATION

          • 5-10 mg sublingual every 15-20 min,
            then 10-20 mg oral every 4-6 hours

    • NSAIDS: INDOMETHACIN

      • Second-line tocolytic drug, used when other drugs are ineffective and if < 32 weeks (b/c it can also cause premature close of the ductus arteriosis in the fetus)

      • Blocks uterine PG synthesis

      • Administration:

        • Rectal 50-100 mg, followed by oral 25-50 mg/6h for 2-3 days

        • Short period of use to slow down labor

      • Maternal adverse effects

        • Nausea, gastric irritation

        • Interstitial nephritis

        • Increased post-partum bleeding

          • b/c platelets use thromboxane which needs COX to synthesize it to promote platelet aggregation and clotting. So when you take NSAIDS you  the ability to clot thus promoting bleeding.

      • Neonatal adverse effects- These are pretty bad effects so not a first line drug!!!

        • Renal failure

        • Broncho-pulmonary dysplasia

        • Respiratory distress syndrome

        • Premature closure of the ductus arteriosus, especially if used after 32 wks gestation

        • Necrotizing enterocolitis

        • Intracerebral hemorrhage

      • Reminder: Other uses - closure of ductus arteriosus, and acute gouty arthritis

    • HYDROXYPROGESTERONE Caproate (Makena®, 2011)

      • INDICATION

        • Reduce risk of preterm birth in women with a history of preterm birth – not for use in active labor

      • ADMINISTRATION: IM injection 1/week beginning at weeks 16-21 until week 37 (when delivery is acceptable)—thought is that by its normal action of progestin it will delay that premature birth

      • MECHANISM – unknown

        • Progesterone levels decline at labor in some species

        • Progesterone administration inhibits secretion of pro-inflammatory cytokines and delays cervical ripening

    HYPERTENSION in PREGNANCY

    • Common in pregnancy ~10% of patients who are pregnant have hypertension

      • Chronic “essential” hypertension ~5%

        • Present before pregnancy or before 20th week

        • They were treated for hypertension before they got pregnant or they develop HTN early in preg.

      • Pre-eclampsia (PIH) and eclampsia—HTN Caused by the actual pregnancy!

        • “Caused” by pregnancy – “cured” by delivery

          • BUT 20% cases of eclampsia occur > 48 hr post-partum

            • Can even develop this up to 2 days after delivery!!!

        • Definition of Pre-eclampsia:

          • Develops after 20th week of gestation

          • Elevated blood pressure >140/90 mmHg

          • Proteinuria > 300 mg/day

        • Severe pre-eclampsia can be life threatening

          • When BP >180/110 and this can be life threatening

        • Rarely, seizures develop – becomes “eclampsia

      • CHRONIC HYPERTENSION

        • Most drugs used prior to pregnancy can be used

        • ACEIs and ARBs, however, are contraindicated – adverse effects on or death of fetus

        • Avoid too aggressive therapy and too low BP

          • May compromise uteroplacental blood flow

        • METHYLDOPA (Aldomet®, 1962)

          • Traditional drug of choice for therapy begun during pregnancy (pregnancy category B) and they haven’t been treated previously for HTN

            • Little effect on uteroplacental flow or fetal hemodynamicsmacintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 10.32.32 am.png

            • Does not affect fetus or neonate

          • MECHANISM

            • Competes with DOPA in DA, NE, EPI synthesis pathway – produces Me-DA and Me-NE (methyl derivatives of agents) in brain

              • The presence of the methyl group makes it resistant to MAO metabolism
  • 1   2   3   4   5   6   7   8   9   10


    The database is protected by copyright ©dentisty.org 2016
    send message

        Main page