Pharmacology
Vol. 16 No 2 | Winter 2014
Feature
Anaesthetics
Dr Martin Steynor
MBChB, FRCA
Dr Kerry Holmes
BHB, MBChB


This article is 8 years old and may no longer reflect current clinical practice.

An outline of some of the more commonly used drugs in current obstetric anaesthetic practice.

This article is intended to outline some of the commonly used drugs in current obstetric anaesthetic practice. It is not comprehensive, but will hopefully give the non-anaesthetist some insight into why particular drugs are used, their pharmacology and potential unwanted effects. Most drugs are not licensed for use in pregnancy and anaesthetic agents are no exception. Obstetric anaesthetists have historically tended to eschew newer agents and use drugs that have been around for a long time and therefore have a well established safety profile for use in pregnancy.

Induction agents

As their name suggests, these drugs are used to rapidly induce anaesthesia when given by intravenous injection. Unlike anaesthetic gases, which act relatively slowly and are sometimes poorly tolerated by patients, they generally cause unconsciousness in one arm-brain circulation time (20–40 seconds).

Propofol

Seeing an anaesthetist holding a 20ml syringe of white liquid will be a familiar sight to many and with good reason; introduced into clinical practice in the late 1980s, propofol has become the dominant induction agent used today. The drug is water insoluble and hence has to be mixed with soya bean oil and given as an emulsion, giving its trademark appearance.

It induces anaesthesia by enhancing inhibitory neuronal transmission. Its popularity rests on its rapid redistribution and therefore quick offset of action, which results in brisk wake up with minimal ‘hangover’; its suppression of airway reflexes, which facilitates airway manipulation; and significant antiemetic properties. Downsides include myocardial depression and vasodilatation (common to most anaesthetic agents), pain on injection and prolonged infusions can precipitate a progressive, sometimes fatal, metabolic acidosis. Transfer across the placenta is fast and some studies have shown poorer Apgar scores compared with thiopentone.1,2 However, other studies have shown no difference in neonatal outcomes.3,4

Thiopentone

This barbiturate used to be the standard choice of induction agent for the obstetric anaesthetist, but its use has declined in recent years. It is a very old drug, having been developed in the 1930s, and has a long established safety profile in obstetrics. It is a potent anaesthetic and anticonvulsant and works by enhancing inhibitory GABAergic neuronal transmission. It is unstable in solution and thus has to be dissolved in water before use, which has cost, time and safety implications. Problems with its manufacture have resulted in a recent difficulty securing supplies. Like propofol, it is a myocardial depressant and vasodilator and will reduce cardiac output in a dose dependent manner. It is highly irritant and accidental intraarterial injection can cause necrosis. Anaphylactic reactions are rare, but severe when they do occur. Thiopentone readily crosses the placenta, however, plasma levels in the fetus are rarely enough to cause neonatal depression.

Ketamine

Ketamine finds occasional use on the delivery unit when inducing anaesthesia in the profoundly shocked patient. Structurally related to phenylcyclidine (‘angel dust’), it works as an antagonist at NMDA receptors and has both anaesthetic and analgesic actions. Although still a myocardial depressant, it stimulates the sympathetic nervous system, causing an increase in circulating catecholamines that maintains cardiac output and blood pressure when given. Its side effects of hallucinations and nausea limit its more widespread use. When given epidurally it prolongs the effect of local anaesthetics by three-to-four times.

Volatile anaesthetics

These gases (technically vapours) are usually used to maintain anaesthesia once the patient has been put to sleep with an intravenous drug. The most commonly used agents are sevoflurane, isoflurane and desflurane. The concentration of the gases breathed out by the patient is used to gauge the depth of anaesthesia as it is assumed to be in equilibrium with the concentration of the agent in the brain. This offers a distinct advantage over an intravenous agent, the concentration of which cannot currently be measured directly. Lower amounts of the volatile anaesthetics are needed in the pregnant patient, probably a central effect of progesterone. Their precise mechanism of action remains elusive despite intense interest in this area. It seems likely that multiple mechanisms are at play. They all tend to reduce arterial blood pressure and uterine tone in a dose dependent fashion. They readily cross the placenta and neonatal depression can occur. This is not usually a problem as most instances of their use is during emergency lower segment caesarean section and delivery occurs before a significant amount of drug is able to reach the fetus.

Nitrous oxide

Nitrous oxide (N2O) is the single most commonly used anaesthetic in obstetric practice, though to give a general anaesthetic with N2O would require it to make up 104 per cent of the inspired gas! N2O has the important attribute of providing analgesia as well as sedation. While N2O is known to inhibit methionine synthetase (an important component in the synthesis of DNA) there is no evidence that short-term use in clinically relevant concentrations has any adverse impact on mother or fetus. Prolonged exposure to concentrations >50 per cent has been shown to be teratogenic during early pregnancy in animals.

N2O has fallen from favour in anaesthesia for several reasons including an increased risk of nausea and vomiting, environmental concerns (it has a greenhouse gas effect 300-times that of carbon dioxide) and an increased incidence of myocardial infarction when used in general anaesthesia.5 Despite this, it still has a definite role in obstetrics and is often still used in caesareans performed under general anaesthesia. It has the dual benefit in this situation of providing analgesia, and thereby limiting the opioid exposure to the fetus, while having no effect on uterine tone.

Vasopressors

Hypotension is a relatively common feature of anaesthesia and is usually owing to vasodilation. During neuraxial block for caesarean it is nearly universal owing to vasodilation and sympathetic block and women will invariably need blood pressure support through the procedure. This can be effected by stimulation of either α1 receptors, causing vasoconstriction, or β1 receptors, producing an increase in heart rate. Phenylephrine is a pure α1 agonist and produces vasoconstriction, directly opposing the vasodilation seen after a spinal or epidural anaesthetic. This rise in blood pressure, owing to constriction of arterioles and veins, produces a reflex drop in heart rate. Ephedrine has both α1 effects and β1 effects so no bradycardia is seen. There is evidence that the use of phenylephrine results in a slightly higher fetal pH than ephedrine; however, this is not associated with any Apgar changes.

Muscle relaxants

Neuromuscular blocking drugs (NMBDs) do not generally cross the placenta as they are very ionised, and so do not cross membranes easily. They can be divided into depolarising, those that cause muscle contraction before paralysis, and nondepolarising. Suxamethonium is still the only depolarising NMBD in widespread clinical use. It has rapid onset, is used for rapid sequence induction and is rapidly metabolised over several minutes by plasma cholinesterases.

Non-depolarising muscle relaxants do not cause muscle contractions and include vecuronium, rocuronium (rapid onset vecuronium) and atracurium. These drugs generally have a slower onset, though high doses of rocuronium have comparable onset times to suxamethonium. This was traditionally associated with a very prolonged block time, but a new drug, sugammadex, binds up rocuronium specifically and can be used to essentially ‘turn off’ the block seen with rocuronium.

All NMDBs act by binding to the acetylcholine receptor at the neuromuscular junction of skeletal muscle and preventing its activation by the body’s own acetylcholine, which would normally result in muscle contraction. Non-depolarising NMBDs can be reversed through the use of neostigmine, which decreases the metabolism of the body’s acetylcholine thereby increasing its levels. As acetylcholine levels rise, the NMDBs are displaced from the receptors and skeletal muscle contraction returns.

Opioids

As well as analgesia, opiates are used in anaesthesia to blunt the profound increase in blood pressure and heart rate seen in response to endotracheal intubation. Opiates work on a variety of opiate receptors centrally, but are distinguished clinically more by their variable pharmacokinetic profiles.

Morphine is the prototypical opiate and still the most commonly used for intraoperative and postoperative analgesia. It is metabolised to an active metabolite that is then cleared renally. In renal failure this metabolite can accumulate and cause sedation. Morphine also increases the tone of the bladder sphincter and can cause urinary retention.

Pethidine has fewer emetogenic effects and more euphoric effects than morphine and is one-tenth as potent, so 10mg of pethidine is equivalent to 1mg morphine. The main metabolite is norpethidine, which can also accumulate in renal failure and lower the seizure threshold. Pethidine has interesting effects including an increase in uterine contraction amplitude and a mild anti-cholinergic effect that can increase the heart rate.6

Fentanyl is a potent mu opioid receptor agonist 50–100 times more potent than morphine. It is notable for its rapid onset and offset compared to other opiates. This is owing to a high lipid solubility causing it to pass across the blood-brain barrier quickly, it then rapidly redistributes throughout the body, which reduces the concentration of the drug at the receptors. However, at high doses or with prolonged infusions it will accumulate within the body. Remifentanil has gained increasing use as an analgesic in labour in place of epidurals if these are not available or are contraindicated. The reason for remifentanil’s popularity is its extremely rapid onset and its consistency in offset time regardless of duration of use.

Remifentanil’s remarkable consistency is owing to it being broken down in the plasma itself by non-specific plasma and tissue esterases, and not relying on a saturable system such as a particular organ. In theory this provides for a drug with rapid onset, but which should breakdown and not accumulate between contractions. The reality is that the effect is not perfectly matched to contraction time and there appears to be a degree of maternal sedation and desaturation.

References

  1. Copogna G et al. Propofol and thiopentone for caesarean section revisited: maternal effects and neonatal outcome. IJOA 1991; 1: 19-23.
  2. Celleno D, Capogna G, Tomassetti M, Costantino P, Di Feo G, Nisini R. Neurobehavioural effects of propofol on the neonate following elective Caesarean section. Br J Anaesth 1989; 62: 649–54.
  3. A Holdcroft and M Morgan. Intravenous induction agents for Caesarean section. Anaesthesia 1989; 44:719-720.
  4. Valtonem M, Kanto J and Rosenberg P. Comparison of propofol and thiopentone for induction of anaesthesia for elective Caesarean section. Anaesthesia 1989; 44:758-762.
  5. Leslie K, Myles P, Chan M et al. Nitrous Oxide and Long-Term Morbidity and Mortality in the ENIGMA Trial. Anesth Analg 2011; 112(2): 387-393.
  6. Sasada M and Smith S. Drugs in Anaesthesia and Intensive Care 3rd Ed. Oxford University Press 2003.

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