27.02.1 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 a/b adrenoceptor antagonist (a1, b1, b2) 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 a-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.