Local Anaesthetics:
Local anaesthetics act by producing a reversible blockade of sodium channels in nervous tissue preventing the transmission of the electrical impulses (Chapter 95, Chapter 53). The action is relatively non-selective producing a variable degree of block of sensory, motor and autonomic pathways (Chapter 88).
Following epidural injection, local anaesthetics rapidly gain access to the cerebrospinal fluid (CSF) with a peak concentrations recorded between 10 and 20 minutes. The most important route of entry is by diffusion at the dural cuff region, where arachnoid granulations protrude into the epidural space (Figure 86.1). There is, in addition, direct diffusion across the dura and direct uptake into blood vessels supplying the cord. The onset of a local anaesthetic block is segmental reflecting the rapid block of spinal nerve roots. By 30 minutes, access has also been gained to the peripheral cord and spinal nerves in the paravertebral space, the latter resulting from loss of local anaesthetic through intervertebral foramina (1).
With repeated injections of the more fat-soluble local anaesthetics such as bupivacaine, the epidural fat acts as a reservoir for the drug and so systemic blood levels do not rise providing appropriate doses are used. However, less lipid soluble agents such as lignocaine do not tend to accumulate in the epidural fat and blood levels may rise after multiple dosing.
Regression of epidural block is more circumferential unlike the segmental onset. This is caused by the continued action of local anaesthetics in the peripheral regions of the spinal cord.
Epidural opioids:
Epidural opioids have their major site of action on pre- and post-synaptic receptors in the substantia gelatinosa of the dorsal horn producing selective block of nociceptive pathways (2) (Figure 86.2). Following epidural injection, opioid drugs cross the dura to enter the CSF at a rate which is dependent on physico-chemical properties such as their molecular weight, pKa and relative oil-water solubility. There is also evidence of diffusion at the dural cuff region and direct transport via the spinal cord blood supply. The speed of uptake form the CSF into the cord substantia gelatinosa is again related to lipid solubility.
Lipid soluble opioids such as fentanyl and sufentanil, cross the dura and penetrate the cord quickly producing a rapid onset of action. The onset of analgesia corresponds to a high CSF concentration which occurs before the blood level is sufficiently high to be analgesic. More water-soluble opioids such as morphine, have a slower onset of analgesia but a more prolonged duration of action.
Drug elimination by vascular uptake is also related to lipid solubility. Thus, despite their rapid onset, the duration of action of fentanyl and sufentanil is short.
Nausea, vomiting, pruritus, urinary retention and respiratory depression may follow the use of epidural opioids. Early respiratory depression may occur within an hour of administration of larger doses of lipophilic epidural opioids. However, respiratory depression may not arise until 12 hours after an epidural dose of morphine as slow penetration of the spinal cord increases the potential for cephalad spread within the CSF (3) (Chapter 90).
Alpha-adrenergic receptor agonists:
When injected into the epidural space, alpha-adrenergic receptor agonists adrenaline and clonidine supplement analgesia produced by other drugs. The alpha-1 action of adrenaline produces vasoconstriction of the epidural vessels and prolongs the action of other agents by slowing vascular uptake. Stimulation of alpha-2 adrenergic receptors present in the dorsal horn modifies the transmission of noxious sensory information by mimicking the activation of descending noradrenergic pathways and inhibiting neurotransmitter release (4). Clonidine, a more selective alpha-2 agonist than adrenaline, has been used in combination with epidural opioids and local anaesthetics to treat both labour (5) and post-caesarean section pain (6). There are, however, concerns over sedation and cardiovascular depression associated with larger doses of epidural clonidine, both of which are undesirable in labour (7).
Anticholinesterases:
Intrathecal administration of the anticholinesterase neostigmine has been demonstrated to produce analgesia in animals. Interaction between cholinergic and alpha-2 adrenergic systems have been investigated with spinal clonidine/neostigmine combinations. By increasing spinal preganglionic sympathetic activity, neostigmine counteracts hypotension and bradycardia produced by spinal clonidine. However, due to its poor lipid solubility, it needs to be administered well before clonidine. The more lipophilic physostigmine may prove to be a more suitable alternative.
References:
1. Bromage PR. Mechanisms of action of extradural analgesia. Br J Anaesth 1975; 47: 199-211.
2. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61: 276-310.
3. Bromage PR, Camporesi EM, Durant PAC, Nielson CH. Rostral spread of epidural morphine. Anesthesiol 1982; 56:431-436
4. Eisenach J, Detweiler D, Hood D. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology 1993; 78: 277-287.
5. O'Meara ME, Gin T. Comparison of 0.125% bupivacaine with 0.125% bupivacaine and clonidine as extradural analgesia in the first stage of labour. Br J Anaesth 1993; 71: 651-656.
6. Eisenach JC, D'Angelo R, Taylor C, Hood DD. An isobolographic study of epidural clonidine and fentanyl after cesarean section. Anesth Analg 1994; 79: 285-290.
7. MacDonald R. Extradural clonidine - the need for well designed controlled trials. Br J Anaesth 1994; 72: 255-257.