Chapter 10 Pharmacology and the midwife
Few women go through pregnancy, childbirth and the puerperium without receiving some form of medication. Ideally, all medication administration, management and monitoring would be based on the results of adequately sized randomized controlled trials with high response rates, supported by large pharmacovigilance follow-up databases and service users’ views (Jordan 2008). In practice, this ‘gold standard’ is rarely achieved in any discipline, and in midwifery there are additional ethical and practical difficulties, which are compounded when investigating the adverse reactions of medication (Jordan 2010, 2007). Therefore, medication administration may be based on biological theories, observations, case reports or even ‘custom and practice’.
Therapeutics in childbirth
Not all treatments are effective, and patients need to be monitored to detect non-response, particularly when antihypertensives, anticoagulants, antiemetics or analgesics are administered. Sometimes, underlying physiological problems may worsen, rendering a previously effective regimen useless; for example, as labour progresses, more analgesia may be required. More predictably, therapeutic failure may be induced by drug interactions – for example, if a patient with hypertension self-medicates with ibuprofen or another non-steroidal anti-inflammatory drug (NSAID). Clinical response shows considerable individual variation, which is not always predictable, and idiosyncratic reactions can occur; for example, some women are unduly sensitive to oxytocin, and therefore infusions are commenced using very low doses.
Adverse reactions
An adverse drug reaction is any untoward and unintended response in a patient or investigational subject to a medicinal product which is related to any dose administered (ICH 1996). Adverse drug reactions can be broadly divided into:
Dose-dependent adverse reactions
These are often the drug’s main adverse effects. Since these are often significant and predictable, they are monitored. For example, without adequate monitoring, anticoagulants can cause bleeding, and insulin can cause hypoglycaemia.
Many drugs have more than one action, potentially causing diverse adverse reactions. For example, oxytocin acts on the oxytocic receptors of the uterus, but it also acts on the antidiuretic hormone (ADH) receptors in the nephrons and can cause water retention and fluid overload.
Adverse reactions unrelated to dose: hypersensitivity responses
Some of the most serious adverse events are unpredictable, idiosyncratic, allergic or hypersensitivity responses, which may occur in any situation with any drug at any dose: common offenders include antimicrobials (particularly intravenous), hormone preparations, dextrans, heparin, vaccines, blood products, iron injections, and local anaesthetics. These adverse events are not related to known physiological actions of the drug, but are initiated when drugs trigger the immune system of susceptible people. They include: anaphylaxis, drug rashes, bone marrow dysfunction, and organ damage.
A mild hypersensitivity reaction is usually a rash. Once this has occurred, and particularly if any itching was associated, the individual is likely to be sensitized and more likely to have an anaphylactic reaction at the next exposure. Where drugs have similar chemical structures, cross-allergies occur: for example, up to 10% of people allergic to penicillins will also be allergic to cephalosporins.
Drugs in pregnancy
No drugs have been subjected to randomized controlled clinical trials for teratogenicity in human pregnancy; evidence is largely derived from observational studies, case reports of incidental exposure, and animal studies, and, therefore, no drug has been demonstrated as ‘safe’.
Approximately 4.8% of births and 4.0% of live births in Wales in 1998–2003 were associated with a congenital anomaly (CARIS 2007). The causes of about two-thirds of congenital anomalies remain unknown, and fewer than 1% are attributable to prescribed drugs (Ruggiero 2006). Exposure of either parent to a medicinal product at any time during conception or pregnancy should be reported in association with congenital anomalies (ICH 1996).
Relatively few drugs are known to cause fetal malformations, but only drugs that have been used for many years in thousands of women with no evidence of harm can be designated ‘generally regarded as safe’. No teratogenic drugs are harmful to the developing fetus in all cases. Estimates vary as to the incidence of congenital malformations: up to 30% with warfarin, up to 16% with sodium valproate (Aronson 2006). However, drugs may affect fetal growth, birthweight, preterm delivery, childbirth, neonatal health and childhood development.
Fetus vulnerability (see website also) is usually considered in stages:
Drug administration during pregnancy and breastfeeding is based on assessment of risks and benefits. Prescribing is likely to be restricted if drug exposure is known to result in a consistent pattern of similar anomalies or the incidence of congenital anomalies is above the rate in the population of 4%. The risks of fetal damage depend on several factors as well as the chemical composition of the drug:
This is complicated by epidemiological work linking congenital malformations, particularly cleft lip, cleft palate and congenital heart malformations, with adverse life events associated with severe maternal stress during the first trimester (Hansen et al 2000), and stillbirth with high levels of psychological stress (Wisborg et al 2008).
Drugs in childbirth
Drugs given during childbirth may have long-term effects. Antibiotics may alter the micro-organisms in the neonate’s colon, which, in turn, might affect the regulation of the immune system, allowing development of allergy (Jordan et al 2008, Russell & Murch 2006). Also, drugs administered in labour may reduce the chances of breastfeeding (see opioids, below).
Pharmacology in pregnancy and lactation
The actions and adverse reactions of any drug depend on the drug and its interactions with the body (pharmacodynamics) and on the concentration of the drug in the tissues, which is affected by how the drug is administered, absorbed, distributed and eliminated (pharmacokinetics). Following administration, drugs are absorbed, and distributed to their sites of action before being removed from the body: if elimination is compromised, there is a risk of drug accumulation and toxicity in either the woman or the fetus/neonate.
Breastfed infants
Most drugs pass into breast milk, but the concentrations are often too small to be harmful. Drugs that can be administered to neonates are usually suitable for nursing mothers, for example paracetamol. For a few drugs, such as lithium or clozapine, there are reports of serious adverse reactions in infants (Lawrence & Schaefer 2007).
Drug administration and absorption
Absorption makes the drug available for distribution. The extent to which a drug reaches its destination is its ‘bioavailability’ (Wilkinson 2001:5), and depends on formulation and route of administration.
The formulation of a medicine refers to its physical and chemical composition and includes active ingredients and other chemicals present, the excipients or ‘packing chemicals’. Excipients:
Routes of administration
Presence of food, antacids or bulk laxatives in the stomach can affect drug absorption for up to 2 hours – for example, amoxicillin, iron tablets. Following intrathecal administration, drug diffuses into the epidural space before circulating (Eltzschig et al 2003). Appreciable quantities are absorbed into the epidural venous plexus and pass to the general circulation, the brain and the fetus. Headache, pruritus and fetal bradycardia may occur more commonly with intrathecal than epidural analgesia (Collis et al 2008). Technical problems include: failure to flex the spine; kinking of lines; accidental removal of lines; dural puncture; need for re-insertion (Paech 1998). Complications include: puncture site tenderness for up to 7 days; dural puncture headache; intravascular injection; infection; epidural haematoma; abscess formation; accidental total spinal anaesthesia. Around 4 per million women suffer persistent neurological complications (Ruppen et al 2006).Therapeutic range
Every drug has a therapeutic range for the concentration of drug in plasma and tissues: above this, toxic effects are more likely; below it, the drug is less likely to have the desired effect. For some drugs, the range is narrow, and the therapeutic concentration is close to the concentration at which side-effects appear; for example, antiepileptic drugs, warfarin, insulin, opioids. For others, the therapeutic range is wide in most individuals, and there is a larger ‘safety margin’ between therapeutic and toxic dose. For example, in people not suffering from epilepsy, penicillins and folic acid are relatively safe, even in overdose.
For a medicine with a narrow therapeutic range, dose administration intervals are calculated to prevent more than twofold fluctuations in plasma concentrations. If strict adherence to dose intervals fails, both toxicity and therapeutic failure are likely. For example, where these drugs require administration twice each day, they should be given 12 hours apart (Wilkinson 2001). Where medicines must be given four times a day – that is, every 6 hours – this may involve disturbing sleep.
Drug distribution
Movement of drugs around the body is affected by drug properties (lipid solubility and binding), state of the circulation and other organs, pregnancy, breastfeeding, and infancy. Highly lipid-soluble drugs rapidly pass into the brain, fetus and breast milk. For example, diamorphine and fentanyl are distributed more rapidly than morphine – advantageous during emergency caesarean deliveries.
Pregnancy
Most drugs are lipid soluble and cross the placenta during pregnancy, to varying extents, but not all are harmful.
Childbirth
The placenta is an ineffective barrier to the passage of drugs, and the blood–brain barrier is underdeveloped in the fetus. Permeability may be further increased during stress, labour and hypoxia. Drugs administered in labour may enter the fetus, and may cause adverse reactions in the neonate; for example, opioids, local anaesthetics or magnesium can induce respiratory depression.
Lactation
Most drugs pass into breast milk (though concentrations may be too small to be harmful): the amount varies between women, during feeds, with the age of the infant and with use of a breast pump. The relative dose as a proportion of body weight received by the infant depends on the drug administered (for example, the dose of lithium is 80% of maternal dose), and the maturity of the infant’s liver and kidneys (Lawrence & Schaefer 2007).
Neonates
The body of the neonate contains a relatively high proportion of water and a low proportion of fat. Any lipid-soluble drugs are therefore distributed into a small volume. Thus, neonates, particularly premature babies, receive different drug doses from adults, even when body weight is taken into consideration.
Elimination or clearance of drugs
Route of elimination varies with individual drugs, but most are:
A few drugs (such as magnesium, lithium) are eliminated unchanged, whereas others are extensively metabolized. Some metabolites are active, for example those of carbamazepine and opioids, while others may cause adverse reactions, such as pethidine. Most drugs are excreted via the kidneys, although bile is also an important route of excretion, for example for oestrogens and corticosteroids.
Drug metabolism
Most metabolism takes place in the liver, though the gastrointestinal tract and the central nervous system contain enzymes responsible for the metabolism of some drugs. Metabolism deals with and detoxifies foreign substances. Metabolism varies with:
Drug excretion
Most drugs depend on the kidneys for excretion. Glomerular filtration rate (GFR), usually considered the best overall measure of the kidneys’ ability to eliminate drugs in health and disease (Levey et al 1999), is the volume of fluid filtered into the nephrons every minute, that is, the sum of the volume of filtrate formed each minute in all the functioning nephrons in the kidneys. This represents about 20% of the plasma flowing through the kidneys. In normal pregnancy, the circulating volume expands by some 8 litres, and renal plasma flow and GFR rises by 30–50% in the second trimester and declines towards term. This increases the elimination of certain drugs (Loebstein et al 1997). Therefore, doses of ongoing therapeutic regimens may need to be increased, particularly antiepileptic drugs and low molecular weight heparins. By the fourth week of pregnancy, GFR has risen 20%; therefore, increased drug elimination and decreased drug effects may occur before the woman realizes she is pregnant (Perrone et al 1992).
If GFR falls, elimination of most drugs is impaired, causing accumulation and even toxicity. If GFR is below normal, as occurs in pre-eclampsia, most drugs are administered in reduced doses or at prolonged intervals. In seriously ill women, rapidly changing GFR may complicate administration of magnesium sulphate.
The kidneys of the fetus eliminate drugs slowly into the amniotic fluid, which is then ingested through the mouth, further reducing clearance. The GFR of the neonate is only 30–40% of adult values. Therefore, some drugs, such as magnesium, may accumulate following maternal administration. These neonates should be observed for signs of muscle weakness, including respiratory depression, for 48 hours after delivery. Some drugs, such as lithium, may accumulate during breastfeeding.
Pharmacodynamics
Most drugs work as a result of the physiochemical interactions between drug molecules and the recipient’s molecules: cell receptors, ion channels or enzymes. These chemical reactions may alter the way the cells are functioning, which in turn may lead to changes in the behaviour of tissues, organs and systems.
An agonist will bind to a receptor and alter its functioning. For example salbutamol, prescribed for asthma or tocolysis, is a beta2-agonist, pethidine is an opioid agonist. Agonists usually augment the normal function of the receptors to which they bind. For example, pethidine stimulates the opioid receptors, increasing analgesia, sedation and constipation. Likewise, beta-agonists mimic some of the actions of the sympathetic nervous system, increasing heart rate, dilating bronchioles and relaxing the uterus.
An antagonist will bind to a receptor, blocking it and preventing the agonist reaching its site of action. For example, naloxone (Narcan) blocks the opioid receptors and reverses the actions of pethidine, reducing respiratory depression and sedation, but causing return of pain. Similarly, the beta-blockers (propranolol, atenolol, labetalol) block the actions of the sympathetic nervous system, slow and stabilize the heart rate and induce bronchoconstriction: they are contraindicated for people who suffer from asthma, due to the risk of life-threatening narrowing of the airways (BNF 2009:86).
Most drugs act on more than one type of cell, and therefore have multiple effects on the body. For example, nicotine acts on the central nervous system to ‘calm the nerves’, on the blood vessels to raise blood pressure, and on the respiratory epithelium to cause irritation. Other drugs are relatively specific; for example, penicillins act almost exclusively on bacterial cell walls.
Where drugs act on the same or similar receptors, ion channels or enzymes or have similar actions or adverse reactions, their actions are intensified if they are co-administered. For example, co-administration of two or more sedatives can cause respiratory depression.
The cells’ receptors are continually being renewed by their protein-synthesizing machinery. When a drug is administered over a period of time, the cells or their receptors may adapt: the number of receptors available on the cell surface may change in response to the presence of drugs.
Tolerance or desensitization
The continued presence of an agonist may reduce the number of relevant receptors available. This desensitization or downregulation of receptors is believed to be responsible for the loss of response seen with continued use of opiates, oxytocin or beta2-agonists (bronchodilators). For example, prolonged administration of oxytocin may render the uterine muscle unresponsive, leading to the uterus not contracting following delivery, increasing the risk of postpartum haemorrhage. In these circumstances, the uterus will not respond to oxytocin and other agents (for example, prostaglandins, ergometrine) will be needed to combat the haemorrhage (Robinson et al 2003).
Supersensitivity
Conversely, the continued presence of an antagonist or blocking drug may increase the number of receptors. Therefore, if an antagonist is abruptly discontinued, the tissues may be unduly sensitive. For example, abrupt withdrawal of beta-blockers makes the myocardium unduly responsive to stress, which increases the risk of a heart attack.
Drugs in labour
Analgesics
Many women request pharmacological pain relief in labour, and all drugs have advantages and disadvantages.
Inhalational analgesia: nitrous oxide with oxygen (Entonox)
Widespread use of nitrous oxide for over a hundred years has established its relative safety. Nevertheless, the administration requires close supervision. There is no indication that Entonox affects the progress of labour or breastfeeding. Other methods of analgesia are more effective, but are associated with more adverse reactions, both short and long term.
Inhalation analgesia is achieved by the use of an anaesthetic gas, nitrous oxide, in sub-anaesthetic concentrations. Concentrations of 50% nitrous oxide are needed for effective analgesia. If administered with air, rather than oxygen, hypoxia would ensue. Nitrous oxide is now administered as Entonox, using pre-mixed cylinders of 50% nitrous oxide in 50% oxygen as a homogenous gas (BOC 2004).
Nitrous oxide rapidly passes from the lungs to the circulation and brain. Analgesic effects of nitrous oxide are experienced some 25–35 seconds after administration, persisting for about 60 seconds after inhalation ceases. Therefore, women are advised to inhale on palpation of a contraction, rather than wait for the pain to reach a crescendo.
Being lipid soluble, inhalation agents cross the placenta and enter adipose tissue. The concentration of nitrous oxide in the fetus reaches 80% of maternal values within 3 minutes of administration. Like all anaesthetic gases, it is rapidly eliminated through the lungs after delivery. This is an advantage over other analgesics, which depend on the immature liver and kidneys for removal. In both mother and neonate it is estimated that the effects of Entonox have worn off after 2 to 3 minutes, although removal from tissues with low blood flow, such as fat, takes longer (Kennedy & Longnecker 1996).
When Entonox is inhaled, the women may overbreathe to maximize analgesia, risking the exhalation of too much carbon dioxide, lowering the concentration in the blood, causing:
Therefore, women’s respirations are closely supervised during administration of Entonox.
Actions and adverse reactions
Anaesthetic gases gradually suppress the reticular activating system in the brainstem, producing four stages, or depths, of anaesthesia:
When Entonox is administered, the aim is to achieve analgesia – excessive administration may give the second stage of anaesthesia, characterized by ‘lightheadedness’, dizziness, nausea or ‘laughing’. Sedation or confusion may occur, though nitrous oxide is insufficiently powerful to produce surgical anaesthesia when used alone. Prolonged exposure to nitrous oxide can inactivate vitamin B12 and may also affect pregnancy.
Interactions
The respiratory depressant action of opioids may be compounded by nitrous oxide, causing transient maternal hypoxia (Clyburn & Rosen 1993).
Cautions
Nitrous oxide is contraindicated where abnormal quantities of gas are trapped within the body, for example in women with middle ear occlusion or sinus infections (BOC 2004). Nitrous oxide may also diffuse into air bubbles formed by epidural or intrathecal analgesia, hindering the spread of local anaesthetic (Sweetman et al 2007).
Nitrous oxide should not be administered to women whose level of consciousness is already impaired.
To reduce the risk of cross-infection, including hepatitis C, appropriate microbiological filters should be placed between the patient and the breathing system; supplying clean masks and mouthpieces may not be sufficient (AAGBI 1996, Chilvers & Weisz 2000).
Opioids
The term ‘opioid’ is used to describe any preparation acting on the body’s opioid receptors, which normally respond to endorphins and enkephalins, the body’s natural mood changers and analgesics. Thus, morphine, diamorphine, pethidine, meptazinol, codeine, buprenorphine (Temgesic), pentazocine (Fortral), fentanyl and its derivatives, and the ‘morphine antagonists’ such as naloxone (Narcan) are all opioids.
Opioids are used in labour, preoperatively, intraoperatively, postoperatively and in intensive care, for analgesia, sedation and reduction of anxiety. Administration may be intramuscular, intravenous, epidural, intrathecal, oral, transdermal or buccal.
Opioids are rapidly transferred across the blood–brain barrier, the placenta and into colostrum. Transfer is more rapid and complete for the more lipophilic compounds, such as diamorphine, fentanyl and fentanyl derivatives. The fetus and neonate excrete opioids more slowly than adults, due to the immaturity of their liver enzymes. The concentration of opioids will always be higher in the fetus than in the woman, in proportion to the dose administered. This delayed clearance allows accumulation in the central nervous system, which could be sufficient to produce subtle behavioural changes, such as depression of feeding reflexes (Jordan et al 2005).
Following a single intramuscular dose of pethidine to the mother, the fetus receives maximum exposure 2 to 3 hours later; therefore, respiratory depression in the neonate is most likely in babies born at this time. If delivery occurs within 1 hour of pethidine administration, very little drug is transferred to the fetus. Should delivery occur more than 6 hours after administration, much of the pethidine will have been transferred back to the mother, although the active metabolite, normeperidine, will remain in the neonatal tissues, and is gradually excreted over several days. During this time the neonate’s behaviour will be suboptimal (irritable and difficult to feed) (Crowell et al 1994). Pethidine passes into breast milk, which compounds early difficulties with feeding.
Epidural and intrathecal opioids and local anaesthetics
Epidural administration entails injection into the fat in the narrow space between the dura mater and the bony canal. Intrathecal administration involves placing the drug in the cerebrospinal fluid (CSF) by passing a very thin needle through the dura mater.
Opioids and local anaesthetics may be administered epidurally or intrathecally or in combination as combined spinal-epidural (CSE) analgesia. These are the most effective strategies for pain relief. Epidural or CSE analgesia is usually achieved and maintained with bupivacaine and fentanyl, with diamorphine reserved for urgent situations (NCC 2004).
Following epidural administration, drugs diffuse through the dura, where they act on the receptors in the spinal cord. Absorption is increased at delivery when the mother is spontaneously pushing, and ‘top up’ injections are usually avoided at this time.
Actions
Opioid receptor binding triggers changes within nerve or smooth muscle cells, usually inhibiting their activity and neurotransmitter release. Several classes of opioid receptors exist and different opioids act selectively.
In general, opioids (endogenous and pharmacological) depress the activity of target tissues and have a calming effect. They inhibit the hypothalamus and ‘damp down’ the level of activity in the autonomic nervous system, partly by reducing the stress response attributable to noradrenaline (norepinephrine). Sometimes, sedation, mental detachment or euphoria are the predominant effects, and the woman may be able to tolerate pain, while still perceiving sensations.
Opioids regulate endocrine, gastrointestinal, autonomic and immune systems, and may trigger histamine release. They also act directly on the chemoreceptor trigger zone, which activates the vomiting centre, and interact with dopamine in the areas of the brain associated with ‘reward’.
Adverse reactions
Opioids produce drowsiness, mental clouding and sometimes euphoria. They inhibit the vital centres in the brainstem of mother and neonate. Sedation is intensified with higher doses and intravenous administration. Epidural administration of >100 micrograms fentanyl or equivalent may sedate and depress the respirations of infants (NCC 2007).
Respiratory depression
Opioids act directly on the respiratory centre to depress respiration, reducing the sensitivity of the respiratory centre to carbon dioxide, thereby depressing the normal drive to respiration. Therefore, respiration fails to increase to meet the high metabolic demands of labour. Rate, depth and regularity of respirations are decreased, reducing alveolar ventilation and oxygenation. This effect is intensified if the woman becomes so sedated that she falls asleep. If the circulation is adequate, respiratory depression is maximal within 90 minutes of intramuscular administration. Following administration of normal doses of intrathecal or epidural opioids, maternal respiratory depression, apnoea and sedation may occur 30 minutes later or be delayed up to 16 hours (Clyburn & Rosen 1993).
Respiratory depression during labour may lead to:
In the neonate, measurements with fetal scalp electrodes indicate that transcutaneous oxygen tensions fall to 37% of baseline values 7 minutes after the intramuscular administration of 50 mg pethidine but recover within 15 minutes (Clyburn & Rosen 1993). Depression of the central nervous system reduces the neonate’s reflexes, including the respiratory reflexes needed to cope with hypoxia and birth (Wagner 1993). Neonatal respiratory depression is occasionally sufficiently severe to warrant rapid reversal with naloxone.
Bradycardia
Opioids reduce the heart rate, by direct action on the cardiovascular centres in the medulla, by decreasing the activity of the sympathetic nervous system and by reducing anxiety. In labour, this may contribute to a fall in blood pressure and a reduction in placental perfusion. The subsequent depression of the fetal heart rate and loss of fetal heart baseline variability may be interpreted as fetal distress, triggering medical interventions.
Some fetal bradycardia on administration of opioid analgesia by any route is normal, attributed to the transient release of oxytocin, causing a brief tetanic contraction of the uterus (Eberle & Norris 1996). Bradycardia lasting beyond 5 to 8 minutes may be a sign of metabolic stress (Arkoosh 1991).
Hypotension
Opioids act on the cardiovascular centres, blood vessels and sympathetic nervous system to produce a fall in blood pressure, exaggerated on standing or sitting up, partly due to inhibition of the baroreceptor reflex. Any hypotension is likely to be exaggerated by the fetus compressing the maternal aorta and vena cava if the mother adopts the supine position.
When opioids are administered epidurally or intrathecally, hypotension is likely to occur within 30 minutes of administration. This may be accompanied by severe fetal bradycardia (Richardson 2000).
Thermoregulation
Opioids impair thermoregulation. Extra care is taken to ensure that the neonate is kept warm.
Breastfeeding
Opioids administered in labour transfer into the fetus, impairing coordination and suckling post birth (Jordan et al 2005). Women who have received high doses of analgesics in labour may need extra support over the first 1–3 days to establish breastfeeding (Jordan 2006).
Prolonged labour
The initial brief tetanic uterine contraction (Eberle & Norris 1996) is superseded by reduced contractility of uterine smooth muscle due to decreased release of oxytocin (Carter 2003). Opioids reduce both the uterine response to oxytocin and the oxytocin release from the posterior pituitary (Thompson & Hillier 1994), diminishing uterine contractions (Carter 2003).
Retention of urine and dysuria
Opioids inhibit the smooth muscle of the bladder and the voiding reflex – a full bladder may inhibit uterine contractions both during labour and post partum.
Gastrointestinal effects
Opioids inhibit the propulsive, peristaltic actions of the gut, while increasing segmental, non-propulsive contractions, particularly in the pyloric region of the stomach, the first part of the duodenum and the colon. Gastric stasis may cause nausea, vomiting, and oesophageal reflux. Opioids contribute to the constipation which commonly follows delivery and decrease gastrointestinal secretions, causing a dry mouth. Spasm of the biliary tract, producing pain on the right side of the abdomen, and gastrointestinal obstruction are rare adverse reactions.
Pruritus
Inhibition of peripheral nerves and histamine release may cause flushing, itching, ‘nettle rash’ and sweating, particularly following intrathecal administration (Simmons et al 2007).
Cautions and contraindications
Interactions
Hypotension, sedation and respiratory depression may be intensified by: alcohol, antihistamines, barbiturates, anaesthetics (nitrous oxide), benzodiazepines, metoclopramide, phenothiazines, tricyclic antidepressants, and other non-opioid sedatives. Protease inhibitors, cimetidine and, occasionally, ranitidine may have this effect.
Central nervous system toxicity may occur if pethidine (possibly also fentanyl) is administered within 2 weeks of any monoamine oxidase inhibitors (MAOIs; including moclobemide and, possibly, linezolid) or selegiline or rasagiline (for Parkinson’s).
Myoclonus is more likely with co-administration of: chlorpromazine, haloperidol, amitriptyline and some NSAIDs (but not diclofenac).
Drying of secretions, and therefore need for mouth care, is intensified by co-administration of hyoscine, cyclizine or related drugs (see antiemetics).
Uterotonics (for more information, see the website)
Uterotonics or oxytocics are used for induction and augmentation of labour, prevention and treatment of postpartum haemorrhage, and control of bleeding due to incomplete abortion. Uterotonics used in the UK are:
Prostaglandins
These are ‘local hormones’ and are commonly used to stimulate uterine contractions.
Actions and adverse reactions
Prostaglandins act on distinct prostaglandin receptors, affect many systems, and can occasionally cause adverse effects, including hypotension, bronchospasm, pyrexia, sensitization to pain, inflammation, glaucoma, tremor and diuresis. Hypertension may complicate administration of carboprost.
Following vaginal administration, the most important adverse reaction is uterine hyperstimulation. Uterine contractions may become abnormal and too intense, leading to pain, fetal compromise or even rupture of the uterus or cervix, with or without previous caesarean delivery. Lower doses and, possibly, gel formulations of dinoprostone present less risk (NCC 2008).
Oxytocin
Oxytocin (Syntocinon®) is manufactured to reproduce the structure and actions of the natural hormone. These actions include:
High-dose oxytocin can shorten prolonged labours (Blanch et al 1998, Sadler et al 2000), while increasing the risk of uterine hyperstimulation (NCC 2007). Failure of induction necessitating emergency caesarean is more likely if the woman has a high body mass index or the baby is heavy (McEwan 2007).
slow intravenous injection or intravenous infusion for high-risk women or following caesarean delivery (CEMACH 2005)Oxytocin acts within 1–4 minutes of intravenous administration; increased uterine contractions begin almost immediately, stabilize within 15–60 minutes of commencing intravenous infusion and last for 20 minutes after discontinuation. Oxytocin is removed by enzymes in the liver, spleen, ovaries and placenta. Estimates of half-life range from 1 to 20 minutes, although pharmacological data indicate a value of 15 minutes (Gonser 1995).
Adverse reactions
Overstimulation of the uterus
When oxytocin is administered, frequency and force of smooth muscle contractions are increased, intensifying the labour pain, more so than with prostaglandins (NCC 2008). Women report that oxytocin-induced contractions are more painful than those of spontaneous labour. Augmentation of labour with oxytocin carries an inherent risk of uterine hyperstimulation: since some individuals are hypersensitive to oxytocin, infusion always entails risk of tetanic or spasmodic uterine contractions, however low the dose.
During uterine contraction, blood vessels are compressed, impairing delivery of oxygen to the uterus, placenta and fetus. Normally, oxygenation is restored during relaxation, preventing the accumulation of lactic acid. However, if the uterus is overstimulated and relaxation is too brief, fetal hypoxia and acidosis will follow. Uterine tetany or spasm may reduce uterine blood flow to a point where the fetus is asphyxiated.
Fluid retention
Oxytocin, particularly in high doses, mimics the actions of antidiuretic hormone, and without careful monitoring may produce dangerous fluid retention. Any water retained passes, by osmosis, from plasma into tissue fluids, and thence into the cells, which swell. This causes confusion and disorientation, progressing to convulsions with or without oedema, raised jugular venous pressure and pulmonary oedema, which impairs breathing and oxygenation. The danger is greatest with administration of prolonged high doses of oxytocin, accompanied by infusions of large volumes of electrolyte-free or hypotonic fluids such as 5% glucose (BNF 2009). In reported cases of water intoxication, more than 3.5 litres of fluid had been infused (Sweetman et al 2007).
Changes in blood pressure
In conjunction with its antidiuretic actions, oxytocin may induce vasoconstriction and hypertension, particularly in women with pre-eclampsia. In contrast, administration of large amounts of oxytocin may cause vasodilatation and a sudden profound fall in blood pressure. Vasodilatation complicates haemorrhage.
Postpartum haemorrhage
Protracted administration, particularly at high doses, may exhaust and desensitize the uterine muscle, leaving it unable to contract and respond to oxytocin, increasing postpartum haemorrhage risk. Observational studies have linked induction of labour with increased incidence of postpartum haemorrhage (Magann et al 2005).
Other adverse effects of oxytocin include: nausea, hypersensitivity responses, and, possibly, reduced chances of breastfeeding (Jordan et al 2009, Ounsted et al 1978, Out et al 1988, Rajan 1994, Wiklund et al 2009).
Cautions and contraindications
Oxytocin is contraindicated in the following situations:
Cautions
Interactions
Ergometrine
Ergometrine, used alone, remains important in the management of acute postpartum or post-abortion haemorrhage. With oxytocin in Syntometrine®, it is widely used prophylactically for the active management of the third stage of labour.
When Syntometrine® is administered:
Onset of action is within 1 minute with intravenous administration, and within 3 to 7 minutes with intramuscular administration. Duration of action is 3 to 8 hours. Excretion is via the kidneys.
Actions and adverse reactions
Actions on alpha1 and serotonin receptors underlie the uterine and gut contractility brought about by ergometrine.
Contraction of the uterus
Ergometrine has a rapid stimulant effect on the uterus, particularly at term. There is a danger that the uterus will fail to relax between contractions and ergometrine is never administered before the delivery of all fetuses. Retention of placental fragments may account for the reported association with increased problems with bleeding in the first 6 weeks post partum (Begley 1990).
Vomiting and diarrhoea
Ergometrine mimics the actions of dopamine, and Syntometrine® is more likely to cause nausea or vomiting than is oxytocin alone (McDonald et al 2004). Mild or moderate diarrhoea may result from increased contractility of the gastrointestinal tract.
Vasoconstriction
Ergometrine acts on alpha1 (noradrenergic) receptors in arterioles and veins to bring about vasoconstriction and venoconstriction. This raises total peripheral resistance, and may lead to:
Breastfeeding
Ergot alkaloids act on dopamine receptors to suppress prolactin production. One drug in this group, bromocriptine, is prescribed to manage galactorrhoea and, occasionally, to suppress lactation post partum (Jordan et al 2009).
Cautions and contraindications
The vasoconstrictor properties of ergometrine make it unsuitable for women with pre-existing pulmonary, cardiac or vascular disorders – including pre-eclampsia, eclampsia, migraine and Raynaud’s phenomenon – or multiple pregnancy. If sepsis, renal or hepatic failure is present, sensitivity to ergometrine is increased. Ergometrine is contraindicated in the first and second stages of labour (BNF 2009).
Reflective activity 10.1
Get access to a computer – either at the university, Trust/hospital library or at home.
Go to the BNF site: http://www.bnf.org/bnf/bnf/current/index.htm.
Drugs for third stage
Due to the differences in the side-effect profiles of the drugs, current guidelines (NCC 2007) suggest that oxytocin (10 units) is the prophylactic drug of choice for the prevention of postpartum haemorrhage, and ergometrine should be used only if this is found to be ineffective, or in high-risk cases. Oxytocin is not currently licensed for intramuscular administration (BNF 2009) and intravenous access may be inaccessible. Therefore, the BNF (2009) recommends Syntometrine® (comprising ergometrine 500 micrograms plus 5 units oxytocin) by intramuscular injection for the routine management of the third stage. Use of this regimen necessitates the careful exclusion of women who should not receive ergometrine, for example those with pre-eclampsia. In view of the possible disruption to the delicate homeostatic balance at the sensitive transition period of parturition, the impact of exogenous oxytocin needs further research (Jordan et al 2009).
Legal aspects
The principal statute regulating the use of medicines is the Medicines Act 1968, which controls the sale and supply of medicines. Before a drug can be marketed, it must have a Marketing Authorization issued by the Secretary of State for Health. Drugs that have a manufacturing authorization are categorized into three types for the purpose of supply to the general public: prescription only, pharmacy only and general sale. Controlled drugs are prescription-only medicines that are further regulated by the Misuse of Drugs Act 1971. In health contexts, Misuse of Drugs Regulations 2001 categorizes controlled drugs into five numbered schedules, according to perceived risk of abuse (Griffith & Tengnah 2008).
Registered midwives may supply and administer, on their own initiative, any of the substances that are specified in medicines legislation under midwives exemptions, provided it is in the course of their professional midwifery practice. They may do so without the need for a prescription or patient-specific direction (PSD) from a medical practitioner (NMC 2010).
It is essential that midwives are aware of their statutory obligations around drug administration, and are conversant with legislation governing drugs and medications. In administering medications, midwives must be knowledgeable regarding the storage, use, dosage, effect and methods of administration of any drug used. This includes consideration that any equipment used is correct and properly maintained. Should the midwife be required to administer new drugs or use new equipment to administer medications, this must be under the direction of a medical practitioner (NMC 2004, 2008).
Midwives and controlled drugs
The legislation governing midwives and controlled drugs includes that the registered midwife can ‘possess diamorphine, morphine, pethidine and pentazocine in her own right so far as is necessary for the practice of her profession’ (NMC 2008). Supplies of these drugs can be made on the authority of a midwife’s supply order signed by the Supervisor of Midwives, or other Appropriate Medical Officer (a doctor authorized in writing by the local supervising authority). The Supervisor of Midwives or other Appropriate Medical Officer should be satisfied that locally agreed procedure is being followed before signing the supply order (that is that the amount being requested is appropriate etc.). Midwife prescribing may be undertaken subject to the requirements set down by the NMC (2006, 2008, 2010).
Once medicines are received – by midwives working in the community or independent midwives – they become the responsibility of the midwife, and should be stored safely and securely, and if no longer required, should be returned to the pharmacy or destroyed following set regulations (NMC 2004, 2008). Where it is necessary for midwives to keep medicines in their homes, the medicines should be placed in a secure, locked receptacle. If necessary, this should be provided by the employing body (NMC 2008).
Conclusion
Drug administration may involve difficult decisions. These problems could be ameliorated by further research into the physiological changes associated with pregnancy, labour and the puerperium that may be responsible for either therapeutic failure or adverse drug reactions, including easily overlooked events, such as failure to breastfeed.