Pharmacokinetics of drugs in the epidural and subarachnoid space

Question 1

Can epidural drugs extend intracranially? why?

Answer 1

No.

Superiorly, the epidural space terminates at the fusion of the spinal and periosteal layers of dura mater

The intracranial extension of epidurally infused drugs is made IMPOSSIBLE by this fixed anatomical unit

Question 2

Where does the epidural space terminate inferiorly

Answer 2

At the sacral hiatus and sacrococcygeal membrane

Question 3

Describe the posterior, anterior, lateral borders of the epidural space

Answer 3

Posterior

• Laminae
• Capsules of facet joints
• ligamentum flavum

Lateral

• pedicles of vertebral arches
• intervertebral foraminae

Anterior
- vertebral bodies, intervertebral discs and posterior longitudinal ligament

Question 4

What is the contents of the epidural space

Answer 4

Fat
Nerve roots
Blood vessels
Lymphatics
Haphazard fibrous connections to ligamentum flavum which can have an unpredictable effect on the course of an epidural catheter

Question 5

How does the epidural space communicate with the paravertebral space

Answer 5

Via intervertebral foraminae

Question 6

How do drugs introduced into the epidural space bring about anaesthetic effect

Answer 6

Local anaesthetics introduced into the epidural space:

1. Diffuse across spinal meninges and into the CSF
2. Distribute into epidural fat
3. Exit intervertebral foramina and reach the paravertebral space

Enter CSF to block spinal cord itself and cauda equina
Enter paravertebral space to block dorsal and ventral roots and SNS paravertebral chain

Question 7

Why is there a 5 - 10 fold dose difference between epidural drug administration and subarachnoid drug administration?

Answer 7

1. Distribution of drug into epidural fat
2. Many meninges must be traversed prior to reaching target site (substantia gelatinosa, lamina II in the spinal cord)
3. There is a greater distance over which the local anaesthetic must travel to reach the target site (Spinal cord)

Question 8

What influences the speed of onset of epidural adminstered local anaesthetics

Answer 8

Lipid solubility

pH of injectate (adjusted with NaHCO3) –> higher pH means more unionized and lipid soluble portion of drug

Question 9

How does CSF flow and volume influence epidural pharmacokinetics

Answer 9

Approximately 500 ml of CSF may flow over the administration site in 24 hours.
–> concentration gradient changes promote movement of drug into CSF from the epidural fat reservoir.

–> flow of csf moves local anaesthetic to target sites or to areas for potential side effects respiratory centre –> apnoea

Question 10

What factors determine the penetration of an epidurally administered local anaesthetic

Answer 10

Fickian principles

1. Concentration gradient
2. Surface area (volume LA injected)
3. Lipid solubulity (including pKa and pH)
4. Protein binding (?free fraction of drug)

Question 11

How would you describe systemic absorption of epidural anaesthetics

Answer 11

Fast initial phase

Slow late phase (due to redistribution from epidural fat)

Question 12

What is the subarachnoid space

Answer 12

It is the space, containing CSF, between the arachnoid mater and the pia mater.

Unlike the epidural space, this space communicates with the CSF spaces in the head

Question 13

What distance does the subarachnoid administered local anaesthetic travel in order to reach its target site? What is its target site?

Answer 13

2mm into the spinal cord: The substantia gelatinosa, lamina 2.

Question 14

Why is the dose 5 - 10 times smaller and the onset more rapid with subarachnoid vs epidural administration

Answer 14

Subarachnoid:

1. Rapid increase in CSF concentration –> fast
2. Minimal meninges to diffuse through
3. No distribution into epidural fat

Question 15

Is systemic anaesthetic toxicity more likely in spinal or epidural anaesthesia –> why?

Answer 15

Spinal –> much smaller doses –> lower systemic toxicity

Question 16

Is systemic absorption faster with spinal or epidural adminsitration

Answer 16

Systemic absorption is SLOWER with SPINAL (subarachnoid).

There is no rapid redistribution phase with subarachnoid anaesthetic administration (as with epidural)

Question 17

Why do intrathecal fentanyl / morphine have persisting effects versus other routes of administration

Answer 17

The perfusion of the subarachnoid space is limited, systemic drug distribution is slow. Drugs which would otherwise be rapidly metabolized or distributed (e.g. fentanyl or morphine) have persisting effects because their absorption from CSF will be slow, and there is nothing there to metabolize them.

Half life increases

Question 18

Will half life be increased for hydrophilic or hydrophobic drugs administered intrathecally

Answer 18

Hydrophilic drugs will have a longer half life as there is nothing in the CSF that metabolizes them and the perfusion to the csf and intrathecal space is limited. So these drugs linger. If they are highly lipid soluble, they tend to diffuse out of the CSF faster and their half life is less prolonged.

Question 19

What is baricity

Answer 19

This term refers to the comparative density of the spinal anaesthetic solution in comparison to CSF.

Baricity = Density of the solution
__________________
Density of CSF

Isobaric –> same density as CSF (‘level’)

Hyperbaric –> higher density than CSF (‘sink’)

Hypobaric –> No longer used (epidural instead to achieve higher levels)

Question 20

Do the meninges perform metabolic functions on epidural/intrathecal drugs ?

Answer 20

No (except they do contain COMT)

Biotransformation relies on distribution into systemic circulation into usual metabolic pathways

Question 21

List 5 non-anaesthetic intrathecal injections

Answer 21

1. Baclofen (via pump for spasticity - GABA b agonist)
2. Clonidine (analgaesia)
3. Analgaesics (palliative care / cancer pain)
4. Antineoplastic drugs (methotrexate for primary CNS lymphoma)
5. Antibiotics (ventriculitis or post neurosurgical infections)