Cardiac Drugs in Pregnancy (Current Cardiovascular Therapy), 2014th Ed.

Obstetric Drugs in the Management of Cardiovascular Disease

Catherine Elliott 

(1)

Department of Obstetrics and Gynaecology, Groote Schuur Hospital, Observatory, Cape Town, 7925, South Africa

Catherine Elliott

Email: elliottcath@hotmail.com

Abstract

Cardiac Disease complicates 0.6 % of pregnancies in South Africa (Sliwa et al. 2010). The term cardiac disease encompasses all possible heart disease from structural congenital lesions, to functional abnormalities and acquired valve lesions. When women suffering from cardiac disease conceive, the physiological haemodynamic changes in pregnancy as well as potential obstetric complications can result in cardiac deterioration. Medications used in the management of both routine general obstetrics and in the case of obstetric emergencies may adversely affect the heart function. Knowledge of the mechanisms of action of obstetric medications and potential side effects is vital when managing pregnant women with heart disease.

Introduction

Cardiac Disease complicates 0.6 % of pregnancies in South Africa (Sliwa et al. 2010). The term cardiac disease encompasses all possible heart disease from structural congenital lesions, to functional abnormalities and acquired valve lesions. When women suffering from cardiac disease conceive, the physiological haemodynamic changes in pregnancy as well as potential obstetric complications can result in cardiac deterioration. Medications used in the management of both routine general obstetrics and in the case of obstetric emergencies may adversely affect the heart function. Knowledge of the mechanisms of action of obstetric medications and potential side effects is vital when managing pregnant women with heart disease.

This chapter will discuss the effect of drugs used in obstetric management on the cardiovascular system.

The Physiological Changes in Pregnancy

The physiological adaptions in pregnancy, designed to support the pregnancy and placental perfusion include circulatory adaptions. These are usually well tolerated in pregnancy, but may adversely affect cardiac function in the presence of heart disease.

The central adaption is peripheral vasodilatation with a decrease in peripheral vascular resistance. Following this, the cardiac output increases by about 40–50 % mostly due to an increase in stroke volume and secondly due to an increase in the heart rate (10–20 beats/min) from about 60–80 bpm (Nelson-Piercy 2002). The blood pressure will decrease due to the drop in peripheral vascular resistance. There is a 40–50 % increase in blood volume and another 50 % increase at delivery when there is an autrotransfusion of blood from the contracting uterus into the general circulation (Powrie 2010; Elliott 2012).

These changes can occur as early as the first trimester, and usually return to baseline by 6 weeks postpartum (Powrie 2010). The normal heart can tolerate these changes well, and pregnancies remain uncomplicated, however in the case of heart disease, be it structural or functional, the circulatory system may be compromised. The stressors placed on the heart may put the mother at increased risk of a cardiac event and even death, and any decrease in cardiac output will reduce placental perfusion and result in potential fetal hypoxemia.

Medications Used in Obstetric Practice

Tocolytic Therapy

Tocolysis is the medical suppression of uterine contractions, with the aim of arresting labour in the case of preterm labour, or decreasing the intensity and frequency of contractions, in the case of fetal distress, in preparation for emergency caesarian section. Arresting labour in the case of preterm labour will allow for the administration of corticosteroids both to promote fetal lung maturity and thereby reduce the risk of respiratory distress syndrome, and to reduce the risk of intraventricular haemorrhage in the preterm neonate. Inhibiting uterine contractions allows for the transfer, in utero, of the fetus to a neonatal facility of the appropriate level of care and thereby reducing the risk of perinatal mortality. Tocolysis is therefore effective in improving perinatal outcome by prolonging pregnancy for 48 h, but is not of great value if used as maintenance therapy (Roos et al. 2013).

Commonly used tocolytics include β-agonists, calcium channel blockers, oxytocin receptor antagonists, prostaglandin synthetase inhibitors, nitric oxide donors and magnesium sulphate (used in United States of America) (Royal College of Obstetrics and Gynaecology 2011).

β-agonists

These drugs stimulate the β-receptors (predominantly β2 adrenergic receptors), which have the effect of relaxing smooth muscle in sites including the myometrium, arterioles and bronchioles. This is achieved by the drug binding to the β-receptor as it is structurally similar to that of the endogenous catecholamines (Caughey and Parer 2001). This results in the stimulation of adenylate cyclase on the uterine smooth muscle (Royal College of Obstetrics and Gynaecology 2011; Caughey and Parer 2001) and a cascade of reactions culminating in the inhibition of myosin light chain kinase and the resultant relaxation of the smooth muscle (in this case the uterine myocyte) (Caughey and Parer 2001). This class of drug includes ritodrine hydrochloride, hexoprenaline (Ipradol®), terbutaline and salbutamol. In industrialized countries ritodrine was until fairly recently the drug of choice and was widely used. Ritodrine is effective in delaying delivery for 48 h, but not any more effective than placebo in prolonging the pregnancy to term (The Canadian Preterm Labor Investigators Group 1992).

The use of these drugs as first-line tocolytic treatment has decreased in recent years due to the associated adverse effects and the introduction of newer drugs.

β-agonists are administered as an IVI infusion or as bolus injection given slowly over 10 min. The half-life is 150 min. The parenteral administration of β agonists elicits undesirable side effects, which include haemodynamic effects such as a marked tachycardia and peripheral vasodilation (Romero et al. 2000). The rise in pulse rate is the most common side effect and can increase by as much as 30 bpm (Moutquin et al. 2000).

This is disadvantageous in any condition associated with reduced left ventricular filling. Stroke volume and cardiac output depends on ventricular filling. In lesions such as a tight mitral stenosis, or atrial fibrillation, the left ventricular filling is already suboptimal, and tachyarrhythmia is particularly dangerous (Nelson-Piercy 2002).

Ritodrine crosses the placenta and fetal concentrations have been reported to be anything from 20 to 100 % (Valenzuela et al. 1995). The tachycardia elicited by β-agonists, is often also reflected by the development of a fetal tachycardia (Moutquin et al. 2000).

Additional side effects have been listed and include maternal arrhythmias, nausea, palpitations, dyspnea (Caughey and Parer 2001) hyperglycemia, tremor, hypokalemia and altered thyroid function tests (Caughey and Parer 2001; The Canadian Preterm Labor Investigators Group 1992; Moutquin et al. 2000). A rare but significant side effect includes the onset of fulminant pulmonary edema, especially when β2-agonists are used in conjunction with corticosteroids to promote fetal lung maturity or when used in the patient with heart disease (described in the setting of tight mitral stenosis) (The Canadian Preterm Labor Investigators Group 1992).

In summary, β2-agonists are very effective in delaying delivery for 48 h thereby fulfilling the criteria for effective tocolysis, but are contraindicated in patients with heart disease.

Nifedipine

Nifedipine is a dihydropyridine calcium channel blocker. It is used in South Africa as a cost effective tocolytic. It is conveniently administered orally.

The efficacy of nifedipine is comparable to other standard tocolytics such as ritodrine as well as the newer drugs such as atosiban (see below) (Royal College of Obstetrics and Gynaecology, Kashanian et al. 2005). Calcium channel blockers limit the release of calcium from the sarcoplasmic reticulum and thereby decrease the contractility of muscle. The effect can be variable in pregnancy due to differing expression of the cytochrome P450 3A substrate. This enzyme is responsible for the metabolism of nifedipine, with the genotype carried by the patient influencing the oral clearance of the drug (David 2013).

The main side effect is that of hypotension (Kashanian et al. 2005). Other listed side effects include, tachycardia, flushing, headache, syncope, dizziness, palpitations and rarely cardiac failure (Kashanian et al. 2005). The side effect profile is considered to be better than that of the β2-agonists (Royal College of Obstetrics and Gynaecology 2011) and is therefore often used in preference to the β2-agonists.

The safety of nifedipine has been well established in the general population; however in the presence of heart disease its use can have severe consequences. Myocardial infarction, congestive cardiac failure and pulmonary edema have all been described with the administration of nifedipine as a tocolytic. These complications may be directly ascribed to the drug, rather than the underlying cardiac condition. The use of this drug is contraindicated in cases where there is comorbidity in the form of sepsis, cardiac disease, thyroid disease or any degree of hypovolemia. The cardiovascular effects of hypotension and resultant tachycardia preclude its use in patients with heart disease. It has been known to cause sudden death in pregnant patients with undiagnosed heart disease and should never be administered indiscriminately.

In summary, nifedipine is an effective tocolytic. Oral administration is convenient. However, it should not be administered without full knowledge of any underlying comorbidity.

Atosiban

Atosiban is a nona-peptide oxytocin analog that acts as a competitive, selective oxytocin vasopressin receptor antagonist and inhibits oxytocin induced uterine contractions and is used as a tocolytic (Romero et al. 2000; Moutquin et al. 2000; Kashanian et al. 2005; Goodwin et al. 1995).

Atosiban is administered as an intravenous infusion. It has a half-life of 20 min and therefore plasma levels decrease rapidly after cessation of administration (Valenzuela et al. 1995; Kashanian et al. 2005).

This half-life means that a steady state is achieved fairly quickly, (within 1 h of administration) (Goodwin et al. 1995). Atosiban has been found to be effective in delaying delivery by 48 h in the case of preterm labour (Valenzuela et al. 2000).

Maintenance therapy using atosiban is also effective in maintaining uterine quiescence, and can be administered as a subcutaneous infusion. The safety profile of atosiban is at least comparable and possibly better than that of β2-agonists (Valenzuela et al. 2000), although some patients choose to discontinue the drug due to drip-site inflammation and irritation.

The efficacy of Atosiban has been found to be the same as other standard tocolytics mentioned above, namely, ritodrine and nifedipine, however the side effects are much reduced, and do not compare to those associated with the β2-agonists or calcium channel blockers (Kashanian et al. 2005; Moutquin et al. 2000). Atosiban is therefore, not contraindicated in cardiac patients (Royal College of Obstetrics and Gynaecology 2011) and the benefit of using atosiban lies - in the improved maternal side effect profile. Listed side effects include nausea, vomiting and chest pain, although the latter has not been found to occur more frequently than placebo, In particular, studies have shown there is a negligible incidence of tachycardia and chest pain and cardiovascular side-effects are substantially lower than those associated with the use of ritodrine (Moutquin et al. 2000). In fact, when compared to placebo, atosiban showed no significant differences in side-effect profile and women undergoing tocolysis do not discontinue atosiban due to side effects, as they do with ritodrine (Romero et al. 2000; Valenzuela et al. 2000).

In addition, the use of atosiban produced no cases of pulmonary edema when compared to placebo (Romero et al. 2000). Atosiban does not appear to cross the placenta and does not accumulate in the fetal circulation.

In summary, Atosiban has been recommended as the tocolytic of choice when managing preterm labour in patients with heart disease (Kashanian et al. 2005).

Non-steroidal Anti-inflammatory Drugs

Cox-2 inhibitors, inhibit the production of prostaglandins, and are used before 32 weeks gestation as a tocolytic (Gibbon 2005). Indomethacin inhibits the cyclooxygenase enzyme in the conversion of arachydonic acid to prostaglandins. Prostaglandins increase the intracellular calcium in the uterine myocyte (Vermillion and Landen 2001) and are also implicated in the cervical changes occurring at the onset of labour both at term and preterm gestations. Premature closure of the ductus arteriosus has been found in the fetus if used after this gestation, although some authors would suggest that this risk has been exaggerated (Nelson-Piercy 2002). The most commonly used drug from this class is indomethacin (Indocid®), which is usually administered orally, but may also be given per rectum (Vermillion and Landen 2001). Cox-2 inhibitors are contraindicated in the case of ischemic heart disease (IHD) and in patients who have a high risk of IHD. They cause an increase in peripheral vascular resistance (Sorensen et al. 1992), (although the blood pressure may not change) and have been associated with an increased risk of adverse cardiac events, such as myocardial infarction (Nelson-Piercy 2002; Gibbon 2005) and should be used with caution in hypertensive patients (Sorensen et al. 1992).

Magnesium Sulphate

The use of magnesium sulphate as a tocolytic is confined in most part to the United States of America. It is mentioned here to complete the list of tocolytics. The mechanism of action of magnesium sulphate as a tocolytic is not fully understood (Ramsey and Rouse 2001), and the Cochrane Collaboration disputes this indication. Those in favour of its tocolytic potential, suggest administering it as a loading dose and then as an infusion to maintain levels of 5–8 mg/dL which will allow for a therapeutic decrease in muscular contractility, including in the myocyte. Toxicity may lead to maternal respiratory failure due to intercostal muscle paralysis (Ramsey and Rouse 2001). It is excreted by the kidneys and absolute contraindications are myasthenia gravis and heart block (Ramsey and Rouse 2001). Apart from a mild drop in blood pressure, magnesium sulphate does not have any major effects on the cardiovascular system.

Oxytocic Therapy

These drugs enhance uterine contractions and are used to augment labour, induce labour or to terminate a pregnancy.

They are also used postpartum in the management of the third stage of labour and in the management of postpartum haemorrhage to facilitate uterine contraction.

These drugs include: oxytocin, ergometrine and the prostaglandins, F2alpha and misoprostol.

Oxytocin

Oxytocin is a polypeptide hormone, which has been artificially synthesized (Dyer et al. 2010). By binding to the surface of the uterine myocyte, oxytocin results in the synthesis of prostaglandin via the generation of diacylglycerol (DAG), inositol tri-phosphate and via the COX-2 pathway as well as by triggering the release of calcium from the sarcoplasmic reticulum. This results in contraction of the myometrial smooth muscle. When oxytocin is administered as a rate controlled infusion, the myometrial response is contraction followed by relaxation in a cyclical fashion (Gohil 2001) This drug is used for the induction or augmentation of labour. When used in this clinical setting, it is administered as an IVI infusion via an infusion pump and the rate is titrated against uterine contractions. This formulation of oxytocin is fast acting (within 5 min) and the effect lasts up to 1 h, however a rapid decrease in response is seen in the first 10 min after discontinuation. The half-life is 3 min (Gibbon 2005).

Oxytocin is also administered as a once off intramuscular injection directly after the delivery of the placenta to provoke uterine contraction as part of the active management of the third stage of labour. At caesarean section, it is given as a slow intravenous bolus of 5 IU for the same indication. Active management of the third stage of labour reduces the risk of post-partum haemorrhage by ensuring the early delivery of the separated placenta.

Oxytocin should be used judiciously in the induction or augmentation of labour. Complications of the administration include uterine hyperstimulation and resultant fetal distress. Careful monitoring of the effect in terms of frequency and amplitude of uterine contractions is mandatory, as is regular, if not continuous fetal heart rate monitoring.

During the administration of oxytocin, pulmonary wedge pressure is markedly increased. A rare but serious complication is hyponatraemia with cerebral edema and convulsions have been described with high doses, as oxytocin has a similar structure to that of vasopressin (Gibbon 2005; Dyer et al. 2010).

The haemodynamic effects of oxytocin are not well tolerated in patients with poor ventricular function, or in those where a decrease in peripheral vascular resistance will worsen the clinical scenario, such as in the case of stenotic heart lesions, or those who have poor ventricular function due to cardiomyopathy. This drug is used with caution in patients with cardiac disease and some authors will state that it is in fact contraindicated in patients with heart disease.

Ergometrine

This medication belongs to the class of ergot alkaloids (www.mims.com/USA/drug/info/ergometrine) and is usually administered in the management of obstetric haemorrhage caused by uterine atony.

It is administered by intravenous injection as a bolus dose; it may be administered up to four times a day for 48 h and has an immediate onset of action (Gohil 2001).

Ergometrine causes rapid contraction of the uterine muscle, which is sustained over time. In low doses, an increase in frequency and amplitude of the contractions is noted while high doses, result in an increase in uterine tone (www.mms.com/USA/drug/info/ergometrine). The mechanism of action is not fully understood. Due to these effects, ergometrine is never used prior to delivery of the fetus.

Ergometrine has a half-life of 2 h. The side effects associated with the use of ergometrine include breathing difficulties, chest pain, dizziness, headaches, palpitations, and arrhythmias, raised blood pressure, vasoconstriction, vomiting and pulmonary edema.

Although oxytocin is used as the first-line agent for treating postpartum haemorrhage, ergometrine has been found to be a very effective oxytocic drug, and in fact superior, to other oxytocics such as oxytocin (Aflaifel and Weeks 2012). Unless ergometrine is contraindicated the benefits of its use outweigh the risks in the setting of ongoing uterine atony despite oxytocin administration (Aflaifel and Weeks 2012).

Ergometrine is contraindicated in the case of cardiac disease, due to the vasoconstrictive effects. It causes vasoconstriction in the peripheral and cerebral vessels, leading to an 11 % increase in mean arterial blood pressure (Dyer et al. 2010) and a 30 % increase in pulmonary artery pressure (Dyer et al. 2010). It can also cause spasm of the renal arteries and the coronary arteries, resulting in myocardial infarction in rare cases (Dyer et al. 2010).

Syntometrine is the combination of oxytocin and ergometrine (5 IU oxytocin and 0.5 mg ergometrine) and is administered as a single IMI dose in the active management of the third stage of labour, and occasionally it is used as a single dose given to prevent postpartum haemorrhage in high-risk cases. In this combination, the oxytocin ensures a rapid onset of oxytocic action while the ergometrine ensures that the oxytocic effect lasts for several hours (Dyer et al. 2010). However, this formulation causes a marked elevation in blood pressure and commonly results in nausea and vomiting.

Prostaglandins

Prostaglandins increase the calcium concentration inside the myocyte via G-protein (Dyer et al. 2010). Prostaglandins provoke and enhance uterine contractions, and are used in the treatment of severe postpartum haemorrhage as a third line agent. PGF2α is the prostaglandin used for this indication. It is administered intramuscularly, directly into the myometrium, either under direct vision at the time of caesarean laparotomy or via the anterior abdominal wall using a long needle. Inadvertent intravascular administration of PGF2α may cause severe bronchospasm leading to hypoxemia. Marked hypertension and pulmonary hypertension are also likely consequences of intravenous injection.

Misoprostol

Misoprostol is a 16-methyl prostaglandin E1 analogue and is a relatively low cost medication. It is used off label for the induction of labour, termination of pregnancy and in the management of postpartum haemorrhage due to uterine atony. In this setting it is usually used only as a first line agent when others are unavailable, such as in the setting of a home birth. Misoprostol does not need to be kept in the fridge. It can be administered orally, sublingually, rectally and vaginally. If it is administered vaginally it has not been found to have any haemodynamic effect (Dyer et al. 2010).

Magnesium Sulphate for Neuroprotection

Magnesium sulphate is administered antenatally to a mother at risk of preterm delivery at less than 30 weeks gestation, for its beneficial effect on the fetus. It has a neuroprotective effect on the fetal brain and has been shown to decrease the risk of severe gross motor dysfunction and cerebral palsy in the preterm neonate and children up to 2 years (Doyle 2010; Crowther et al. 2003). It is administered as a loading bolus via an infusion of 6 g followed by a continuous infusion of 2 g/h (Rouse et al. 2008). Magnesium sulphate is predominantly excreted by the renal system and maternal urine output must remain at a minimum of 30 ml/h. Magnesium sulphate has not been shown to have any major effects on the maternal cardiovascular system. In its use in this setting has not demonstrated any adverse maternal complications.

Table 1

Medications used in obstetric practice and their cardiovascular effects

Medication

Example

Indication

Main adverse effects on the cardiovascular system

β-agonists

Hexoprenaline (Ipradol)®

Tocolysis

Tachycardia

Peripheral vasodilatation

Pulmonary edema

Calcium channel blocker

Nifedipine (Adalat®)

Tocolysis

Hypotension

Hypertension

Tachycardia

Oxytocin receptor antagonist

Atosiban (Antocin®)

Tocolysis

None

NSAIDs

Indomethacin (Indocid®)

Tocolysis

Vasoconstriction

MgSO4

MgSO4

Neuroprotection for the fetusTocolysis in USA

Almost none

Oxytocin

Oxytocin (Syntocinon®)

Labour augmentation or induction

Hypotension

Uterine involution

Ergot alkaloids

Ergometrine (Ergometrine®)

Postpartum haemorrhage

Vasoconstriction

Prostaglandins

 F2Alpha

Dinoprost (Prostin F2Alpha®)

Postpartum haemorrhage/TOP

Bronchospasm

 Prostaglandin E1

Misoprostol (Cytotec®)

Induction of labour/TOP

None

Postpartum haemorrhage

Conclusion

Almost all medications used in obstetric practice have cardiovascular effects. The use of drugs with potential adverse effects on the cardiovascular system may increase the likelihood of morbidity and mortality in pregnant women with heart disease. A thorough knowledge of the patient’s current and prior medical history is mandatory before administering any medication, and medications known to have haemodynamic consequences are best avoided in patients with known cardiac disease.

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