Neuraxial Agents

_____terminals are key drug targets for neuraxial anesthesia; they modulate ____release and ____influx.

Presynaptic

neurotransmitter

calcium

Primary afferent neurons release neurotransmitters, activating ____receptors on second-order projection neurons in the spinal cord

Second-order neurons in the dorsal horn express various receptors like:

Inhibitory modulation can occur with ______receptors [5]

postsynaptic

NMDA, AMPA, mGluR

opioid, GABA, serotonin, cholinergic, and alpha2-adrenergic receptors.

_______- the most widely used drugs for neuraxial analgesia

Local Anesthetics

MOA of LA

in what channel states do they preferentially bind to?

• Block voltage-gated Na+ channels, inhibiting action potentials. Local anesthetic agents act by interrupting the propagation of an impulse, thereby inhibiting the nerve conduction of a painful stimulus.

• Bind preferentially to open [active] or closed  [inactivated] channel states.

what does a non-selective blockade from LA mean

• affects sensory and motor nerves → AKA potential motor side effects.

  • local anesthetics are capable of blocking the transmission of all nerve fibers, not just A-delta and C fibers. Therefore, the potential for motor blockade, as well as sensory blockade, limits the use of these agents.

• Location of opioid receptors in CNS:

• brainstem, thalamus, fore brain, and mesencephalon.

• postsynaptic receptors located on cells originating in the dorsal horn, as well as presynaptic receptors found on the spinal terminals of primary afferent fibers

MOA of opioids intrathecal

direct inhibition of neurotransmitter release (e.g., glutamate, substance P).

MOA of opioids epidural space

• Epidural: combination of local spinal action and systemic absorption (esp. lipophilic agents like fentanyl).

• Hydrophilic opioids (e.g., ____): greater ____spread, higher risk of delayed ____, and ______risk of N&V

• morphine

• rostral

• respiratory depression

• increased

• The most frequent side effects of intrathecal morphine are _______

• constipation, sweating, urinary retention, nausea and vomiting, and disturbances of the libido

Voltage-gated calcium channels (VDCCs): critical for ____release AKA pain transmission. Found in high concentrations in the ___of the spinal cord and ____

• neurotransmitter

• dorsal horn

• dorsal root ganglia

___-type Ca channels most relevant in nociceptive transmission

N

Ziconotide

• MOA

• pros and cons

• FDA-approved N-type blocker; non-opioid analgesic for refractory chronic pain.

  • It potently blocks N-type VDCCs in vitro and inhibits wind-up.

  • No tolerance reported

  • Expensive!

  • High side effect profile AKA narrow therapeutic index (e.g., confusion, somnolence, urinary retention).

discuss wind-up

• The process of wind-up involves the activation of spinal NMDA receptors after injury, which induces a state of facilitated processing from repetitive small afferent fiber stimulation → leads to increased response to high and low threshold stimulation and enhanced receptor field size

discuss Gabapentin and pregabalin use in neuraxial anesthesia

• act on α2δ subunit; experimental for neuraxial use.

  • antihyperalgesic and anti-allodynic properties in chronic pain

discuss the MOA of GABA-a vs GABA-b

• GABAA: ionotropic → Cl⁻ influx, hyperpolarization.

• GABAB: metabotropic → ↑K⁺ efflux, ↓Ca²⁺ influx, ↓adenylate cyclase.

• Baclofen (____ agonist): FDA-approved for spasticity; fourth-line agent for chronic pain.

  • Blocks the activity of ___&___ nociceptive fibers

  • Effective for ___&____neuropathic pain.

GABAB receptor agonists administered via the intrathecal or epidural route produce ____&____, and therefore block the release of glutamate, substance P, and calcitonin gene-related peptide (CGRP) from primary afferents, and GABA from interneurons

• GABAB

• peripheral C and A-delta

• central and peripheral

• pre- and postsynaptic inhibition

SE of baclofen

• sedation, withdrawal (life-threatening), catheter complications.

  • At therapeutic doses, baclofen is associated with numerous adverse effects, including drowsiness, flaccidity, headache, confusion, hypotension, weight gain, constipation, nausea, urinary frequency, and sexual dysfunction.

  •  Intrathecal baclofen overdose can lead to respiratory depression, seizures, obtundation

concerns with versed in neuraxial anesthesia

Concerns: neurotoxicity

does Alpha 2 adrenergic receptors work on the pre or post synapse?

BOTH!

• modulate pain at spinal level.

  • Presynaptic inhibition: ↓neurotransmitter release.

  • Postsynaptic hyperpolarization: ↑K⁺ channel activity.

what is the most studied A2 adrenergic agonist for neuraxial anesthesia

discuss its MOA and which subtypes produce which responses

risks

• effective adjunct to opioids and local anesthetics.

  • Clonidine binds to pre- and post synaptic α2 receptors in the dorsal horn. Activation of these receptors depresses presynaptic C-fiber transmitter release and hyperpolarizes the postsynaptic membrane through the Gi-coupled potassium channel

  • The 2b subtype produces hemodynamic responses (primarily hypotension), whereas the 2a receptor is responsible for analgesia.

  • Risks: hypotension, bradycardia, sedation.

• Intrathecal clonidine has been reported to provide significant analgesia in combination with _____for neuropathic pain and cancer pain

  • When added to ____, clonidine can extend the duration of pain relief for labor analgesia and postoperative pain

• opioids

• opioids

T/F: dexmedetomidine prolongs local anesthetic motor and sensory blockade when compared to opioids

TRUE!

it also has similar efficacy to clonidine and fewer hemodynamic effects.

glutamatergic antagonists

Divided into the G-protein-coupled (_____) receptors (mGluR) and ion channel (____) receptors, which include NMDA, AMPA, and kainite receptors.

·       The NMDA receptors contain ion channels permeable to ____

metabotropic

ionotropic

calcium, sodium, and potassium

• ____receptors: key in “wind-up” and central sensitization [responsible for phenomena such as allodynia and hyperalgesia] .

• NMDA

• Ketamine: non-competitive ___antagonist; administered epidurally/intrathecally for acute and chronic pain.

  • ____ketamine: more viable, fewer CNS side effects.

  • Risks:_______

• ___[enantiomer] ketamine: higher affinity and potency; conflicting data on safety.

• NMDA

• Epidural

• neurotoxicity, psychomimetic effects, especially with preservative-containing formulations.

• S(+)-

• In the spinal cord, ______ acts presynaptically to increase the release of glutamate from primary afferent C fibers and postsynaptically to _____excite dorsal horn neurons.

• Both effects promote the development and maintenance of ___&____

• The intrathecal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) prevents the development of _____ and inhibits the release of ____

• prostaglandin E2 (PGE2)

• directly

• central sensitization and enhanced pain states.

• hyperalgesia

• PGE2

T/F: Ketorolac is FDA approved for neuraxial use

FALSE

• Human studies are inconsistent or negative; better evidence in cancer pain.

• Not FDA approved for neuraxial use.

• Muscarinic (__&__) receptors mediate spinal analgesia.

• Found in the_____ and superficial laminae of the _____

• M1, M3

• dorsal root ganglia; dorsal horn

use of neostigmine for neuraxial anesthesia

• Neostigmine (cholinesterase inhibitor): prolongs analgesia and dec urinary retention when combined with opioids [morphine]/local anesthetics.

• As sole agent: limited due to SEVERE nausea/vomiting.

• Promising results in pediatric caudal analgesia and combined spinal-epidural anesthesia.

neostigmine, when used in combination with an alpha-adrenergic agonist such as clonidine, might provide superior ____ analgesia while reducing the risk of side effects

labor

• The antinociceptive effects of somatostatin result from ___inhibition.

  • Epidural somatostatin has been demonstrated in several studies to provide ____pain relief for patients undergoing major surgical procedures

• presynaptic

• postoperative