27. Drugs in pregnancy and labour 27.1 Introduction 27.2 Common complaints in pregnancy and labour and their treatments 27.2.1 Pre-eclampsia and eclampsia. 27.2.2 Suppression of early labour 27.2.3 Neonatal respiratory distress syndrome 27.2.4 Postpartum haemorrhage 27.2.5 Prolactin excess 27.2.6 Nause

Mullaney, Ian

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This is the author’s version of a work that was submitted/accepted for pub-lication in the following source:Mullaney, Ian (2012) Drugs in pregnancy and labour. In Doggrell, Sheila(Ed.) Pharmacology in One Semester.This file was downloaded from: http://eprints.qut.edu.au/54893/c© Copyright 2012 Ian MullaneyNotice: Changes introduced as a result of publishing processes such ascopy-editing and formatting may not be reflected in this document. For adefinitive version of this work, please refer to the published source:Creative Commons — Attribution-NonCommercial 3.0 Unported — CC BY-NC 3.0http://creativecommons.org/licenses/by-nc/3.0/[22/10/2012 11:53:22 AM]Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0)This is a human-readable summary of the Legal Code (the full license).DisclaimerYou are free:to Share — to copy, distribute and transmit the workto Remix — to adapt the workUnder the following conditions:Attribution — You must attribute the work in the manner specified by the author orlicensor (but not in any way that suggests that they endorse you or your use of the work).Noncommercial — You may not use this work for commercial purposes.With the understanding that:Waiver — Any of the above conditions can be waived if you get permission from the copyright holder.Public Domain — Where the work or any of its elements is in the public domain under applicablelaw, that status is in no way affected by the license.Other Rights — In no way are any of the following rights affected by the license:Your fair dealing or fair use rights, or other applicable copyright exceptions and limitations;The author's moral rights;Rights other persons may have either in the work itself or in how the work is used, such aspublicity or privacy rights.Creative Commons — Attribution-NonCommercial 3.0 Unported — CC BY-NC 3.0http://creativecommons.org/licenses/by-nc/3.0/[22/10/2012 11:53:22 AM]Use this license for your own work.This page is available in the following languages: Castellano Castellano (España) Català Dansk Deutsch English Esperanto français hrvatski Italiano Latviski Nederlands Norsk polskiPortuguês Português (BR) Suomeksi svenska Ελληνικά Русский українська 語 (台 ) Notice — For any reuse or distribution, you must make clear to others the license terms of this work.The best way to do this is with a link to this web page.Chapter 27. DRUGS IN PREGNANCY AND LABOUR Ian Mullaney School of Pharmacy, Faculty of Health Sciences, Murdoch University, Murdoch, WA6150, Australia. Phone +61 8 93601236  Fax +61 8 93601240  Email i.mullaney@murdoch.edu.au Reviewed by Sheila Doggrell, Queensland University of Technology  Key words: Pregnancy, eclampsia, pre-eclampsia, suppression of labour, tocolytics, oxytocics, neonatal respiratory distress syndrome, postpartum haemorrhage Contents 27. Drugs in pregnancy and labour  27.1 Introduction  27.2 Common complaints in pregnancy and labour and their treatments  27.2.1 Pre-eclampsia and eclampsia.   27.2.2 Suppression of early labour  27.2.3 Neonatal respiratory distress syndrome  27.2.4 Postpartum haemorrhage  27.2.5 Prolactin excess  27.2.6 Nausea  27.1 Introduction.   It is a condition of use of many drugs that extra care and attention should be used when administered to pregnant women. It is well established that some drugs can have temporary or permanent effects on the developing foetus. Drugs that have such an effect are known as teratogens, the most notorious being thalidomide which was prescribed to pregnant women as a treatment for morning sickness and resulted in a variety of serious birth defects for many thousands of babies. However, this chapter is concerned with drugs that are used to treat medical complaints arising from problems occurring in pregnancy and labour and not with adverse effects on mother or foetus as a result of drug administration. 27.2 Common complaints in pregnancy and labour and their treatments 27.2.1 Pre-eclampsia and eclampsia.  Pre-eclampsia is defined as a hypertensive state of unknown cause occurring in pregnancy. Pre-eclampsia is diagnosed when consistent systolic pressures over 140mm Hg and/or diastolic pressures over 90 mm Hg are observed. These changes are accompanied by elevated protein levels in the urine (hyperproteinuria). Pre-eclampsia can progress to eclampsia, a condition characterised by tonic clonic convulsive seizures. Treatment involves reduction of blood pressure with antihypertensives and control of seizures with anticonvulsives. If these treatments are unsuccessful, abortion or delivery of the foetus is the only effective alternative.  Most antihypertensives exert their effects by dilating blood vessels, easing constricted blood flow and reducing intravessel pressure. These drugs are used to treat a number of disease states including angina, congestive heart failure and acute myocardial infarction in which lowering of blood pressure is crucial in alleviating symptoms. Antihypertensives used in the treatment of pre-eclampsia include nifedipine, hydralazine, labetalol and methyldopa.  Nifedipine is a selective blocker of L-type voltage-sensitive calcium channels in arterial smooth muscle. Inhibition of these channels results in reduced calcium entry into these cells causing vasodilation. Adverse effects of nifedipine include headache, flushing, nausea, vomiting and peripheral oedema.  A second antihypertensive used in the treatment of pre-eclampsia is hydralazine. Although its exact mechanism of action is unclear, hydralazine degrades to nitric oxide which is a direct acting vasodilator. Hydralazine has similar adverse effects to nifedipine.  Labetalol is a mixed  adrenoceptor antagonist () which produces peripheral vasodilation by blocking the effects of sympathetic nervous system thereby reducing blood pressure. Labetalol has a number of adverse effects including postural hypotension and bronchoconstriction and as such should not be used in patients with asthma, bradycardia and second or third degree atrioventricular block.  Methyldopa is converted to its active metabolite -methylnoradrenaline in sympathetic neurons and stored in the secretory vesicles of these cells. When released, α-methylnoradrenaline acts as an agonist of presynaptic central nervous system α2-adrenergic receptors. Activation of these receptors in the brainstem appears to inhibit sympathetic nervous system output and lower blood pressure. However, it is contraindicated in patients with active liver disease and phaeochromocytoma (tumour of the adrenal gland) and use of methyldopa may exacerbate depression in sufferers. Adverse effects are those associated with sympathetic disruption and include sedation, orthostatic hypotension, dry mouth and rash. Progression of pre-eclampsia to eclampsia is characterised by the appearance of tonic clonic seizures. Magnesium sulphate is the drug of choice to prevent these convulsions.  The resultant elevated blood magnesium levels (hypermagnesaemia) depresses neuronal activity, reducing excitation and calming the uncontrolled nerve firing that can result in seizures. The magnesium competes with excitatory calcium decreasing neurotransmitter release at the synapse. This treatment is contraindicated with patients with existing elevated blood magnesium levels and those with kidney problems. Concomitant use of magnesium sulphate and nifedipine can result in hypotension and use of these drugs in combination should be monitored. Adverse effects include myasthenia gravis, muscle weakness, respiratory depression, bradycardia and thirst. When pharmacological treatment for pre-eclampsia and eclampsia fails, there is real concern for the safety of the mother. Abortion or delivery by caesarean section or labour induction is the treatment of choice. Myometrial stimulants (also known as oxytocics) are used for induction and augmentation of labour, prevention and treatment of post-partum haemorrhage, control of bleeding due to incomplete abortion, active management of the third stage of labour. The oxytocics most commonly used are oxytocin, prostaglandin E and ergometrine.  Oxytocin is a 9 amino acid produced in the posterior pituitary gland. Exogenous oxytocin, administered by means of continuous infusion by pump, stimulates the frequency and force of uterine contractions, initiating labour and parturition. Prolonged use can result in water intoxication, uterine rupture and hypotension in the mother and bradycardia, brain damage, seizures and death in the infant.  Prostaglandin E2 (dinoprostone) and prostaglandin E1 (misoprostol) are first line drugs of choice as labour inductor. These form part of the eicosanoids, a family of lipid derived hormones which have a multiplicity of different cellular functions including smooth muscle contraction.  Finally, ergometrine, an alkaloid structurally similar to LSD can also be used to facilitate delivery of the placenta and to prevent bleeding after childbirth by reducing blood flow through constriction of smooth muscle in the blood vessel walls causing vessel narrowing. It is usually combined with oxytocin as syntometrine. 27.2.2 Suppression of early labour.  A number of drugs are used as uterine relaxants. These drugs, known as tocolytics, are particularly useful in the suppression of early or premature labour affording time for further foetal development and prolonging foetal survival. Several drug classes have been shown to possess tocolytic properties. These include 2 adrenergic receptor agonists, oxytocin antagonists and calcium channel blockers.   Included in the 2 adrenoceptor agonist class are terbutaline, ritodrine, salbutamol, fenoterol and adrenaline. These drugs work by directly activating adrenergic receptors that mediate smooth muscle relaxation terminating uterine contractions. However, these drugs can have a number of adverse effects on both the mother and the foetus due to their ability to act on the respiratory and cardiovascular systems. Common maternal adverse effects include cardiac arrhythmias, altered thyroid function and tachycardia whilst tachycardia, hypoglycaemia, hypotension and myocardial ischaemia have been noted in the foetus and neonate.  Atosiban is a peptide analogue of oxytocin which antagonises the uterine contracting properties of the hormone at its receptor resulting in cessation of preterm labour. It is preferred over the 2 adrenergic agonists due to its lower incidence of adverse effects although reactions to the drug such as nausea, vomiting and hyperglycaemia have been noted.  Calcium channel blockers such as nifedipine, which has previously been discussed for its use as an antihypertensive in pre-eclampsia is also has tocolytic properties.   27.2.3 Neonatal respiratory distress syndrome.  One consequence of premature birth is impairment of lung development in the neonate. This manifests itself as neonatal respiratory distress syndrome and is characterised by a deficiency in lung surfactant which causes the integrity of the lung structure to collapse resulting in severe breathing difficulties. Intraventricular haemorrhage and death may follow. Corticosteroids such as dexamethasone and bexamethasone are used in conjunction with tocolytics as therapies to treat this syndrome. The tocolytics prevent premature birth giving the lungs extra time to develop whilst the steroids act via cell surface receptors to directly activate survival genes. Adverse reactions to these steroids include fluid and electrolyte imbalances, muscle weakness, GI disturbances and hypertension. 27.2.4 Postpartum haemorrhage.  Postpartum haemorrhage is the leading cause of maternal mortality causing approximately 140000 deaths each year.  Oxytocics, particularly oxytocin, are the preferred treatment. Problems associated with the use of oxytocin are outlined above.  27.2.5 Prolactin excess.  Prolactin is a peptide hormone secreted by lactotrophic cells in the anterior pituitary. Increases in prolactin secretion, during pregnancy, results in maturation of milk secreting duct in the mammary gland. Although not restricted to pregnant women, excess production of prolactin (hyperprolactinaemia) will result in overactive, secreting mammary tissue. Prolactin secretion is under the control of D2 dopamine receptors in the lactotrophic cells.  Dopamine, secreted from the hypothalamus, acts on these receptors to inhibit the prolactin production. Hyperprolactinaemia results when circulating levels of dopamine drop and the inhibitory processes compromised resulting in large levels of circulating prolactin in the blood. Treatment is with bromocriptine, a dopamine receptor agonist, which decreases excessive prolactin secretion. Adverse effects include nausea and vomiting, dizziness and constipation. 27.2.6 Nausea.  Nausea and vomiting during pregnancy (also known as morning sickness) is common during the early stages of pregnancy. These are multiple causes ranging from changes in circulating steroid hormones such as oestrogen and progesterone to hypoglycaemia resulting from placental transfer of glucose from the mother to the foetus. In most cases no treatment is required as the condition will normally disappear after the first trimester of pregnancy. However, severe morning sickness known as hyperemesis gravidarum (HG) affecting around one in 1,000 pregnant women can occur. The symptoms of hyperemesis gravidarum include repeated vomiting, weight loss and dehydration. Treatment usually involves hospitalisation, and the administering of intravenous liquids and nutrition. The possible complications associated with untreated hyperemesis gravidarum include electrolyte imbalances, extreme depression and anxiety and malnourishment of the foetus.   In extreme cases of morning sickness, antiemetics may be prescribed. These drugs work by blocking neurotransmitter inputs to the chemoreceptor trigger zone (CTZ), the principal vomiting control centre, of the medulla. First choice is ondansetron, a blocker of 5HT-3 receptors found in the CTZ, given orally or by injection. This drug, which is also used as an antiemetic during cancer chemotherapy, has a number of unwanted effects such as headache and GI upset. Other drugs used include promethazine (histamine H1 receptor blocker) and metoclopramide and chlorpromazine (dopamine D2 receptor blockers).   

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