Cellular sites of action

Frequency and voltage dependence

Differential sensitivity of nerve fibers

Prolongation of action by vasoconstrictors

route of adminstration

Topical

nerve block

infiltration

IV regional

spinal and epidural

Act on cell membranes to prevent the generation and conduction of nerve impulses

Block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na+

Block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Ca+

Due to direct interaction with voltage-gated Na+ channels

Due to direct interaction with voltage-gated Ca+ channels

§Rate of rise of AP declines

§The threshold for electrical excitability gradually increases

§Impulse conduction slows

§Safety factor for conduction decreases

§Frequency and voltage dependence

Different conformational states of the Na+ channel (resting, various closed, open and inactivated) bind LAs with different affinities

known as the Modulated Receptor Hypothesis)

have a higher affinity for the open and inactivated states of the Na+ channel than for the resting state

have a higher affinity for the open and inactivated states of the Ca+ channel than for the resting state

Different conformational states of the Na+ channel (resting, various closed, open and inactivated) block LAs with different affinities

binds to a site on the channels pore

NON- restriction of conformational changes that underlie activation of the channel.

Restriction of conformational changes that underlie activation of the channel.

Physical occlusion of the pore.

binds to a site on the ion channel

§G protein-coupled receptors: muscarinic, β-adrenergic, substance P

§Ion channels: K+, Ca2+, pacemaker channels, ligand-gated channels (e.g., ionotropic glutamate receptors), transient receptor potential (TRP) channels

§G protein-coupled receptors: §K+, Ca2+, pacemaker channels, ligand-gated channels (e.g., ionotropic glutamate receptors), transient receptor potential (TRP) channels

§G protein-coupled receptors: K+, Ca2+, pacemaker channels, ligand-gated channels (e.g., ionotropic glutamate receptors), transient receptor potential (TRP) channels

§How the nerve is stimulated

§Resting membrane potential

§Higher frequency of stimulation and more positive membrane potential causes a greater degree of anesthetic block.

§lowest frequency of stimulation and more positive membrane potential causes a greater degree of anesthetic block.

§Physical occlusion of the pore.

pKa

Lipid solubility

Molecular size

Binding to different channel states

Protein binding

Different nerve fibers demonstrate varying sensitivities to LAs.

Autonomic fibers, small unmyelinated C fibers (mediating pain sensation) – sensitive to blockade.

Autonomic fibers, large unmyelinated C fibers (mediating pain sensation) – sensitive to blockade.

Small myelinated Aδ fibers (mediating pain and temperature sensation) – sensitive to blockade.

Large myelinated Aδ fibers (mediating pain and temperature sensation) – sensitive to blockade.

Large myelinated Aγ, Aβ and Aα fibers (mediating postural, touch, pressure and motor information) – less sensitive to blockade

Small myelinated Aγ, Aβ and Aα fibers (mediating postural, touch, pressure and motor information) – less sensitive to blockade

Differential rate of block of fibers is of importance in the use of LAs.

Differential rate of stimuate of fibers is of importance in the use of LAs.

Duration of action of an LA is proportional to the time of contact with nerve.

Duration of action of an LA is not proportional to the time of contact with nerve.

Use of vasoconstrictors in LA preparations for anatomical regions with limited collateral circulation should be avoided.

Use of vasoconstrictors in LA preparations for anatomical regions with collateral circulation should be avoided.

Decreases the rate of absorption.

Increase the rate of absorption.

Localizes the anesthetic to the desired site.

Allow drug’s elimination to keep pace with entry into circulation (may reduce LA’s systemic toxicity).

Allow drug’s absorption to keep pace with entry into circulation (may reduce LA’s systemic toxicity).

Frequency and Voltage Dependence:

Prolongation of Action by Vasoconstrictors:

Differential Sensitivity of Nerve Fibers:

Cellular Sites of action:

Lipid solubility

CNS

CVS

Neuromuscular Junction and Ganglia:

PNS

If absorbed, LAs may cause stimulation leading to restlessness, tremor and clonic convulsions.

In general, more potent LAs readily cause convulsions

Central stimulation is followed by depression not leading to death by respiratory failure

If not absorbed, LAs may cause stimulation leading to restlessness, tremor and clonic convulsions.

Central stimulation is followed by depression leading to death by respiratory failure

If absorbed, LAs primarily action on the myocardium leading to a decrease in electrical excitability, conduction rate and force of contraction

If absorbed, LAs primarily action on the myocardium leading to a increase decrease in electrical excitability, conduction rate and force of contraction

Most LA cause arteriolar dilation.

Most LA cause arteriolar release.

§If absorbed, LAs block transmission at the neuromuscular junction and ganglia.

§Due to blockade of nicotinic receptors by high concentrations of LA

§Due to stimulation of nicotinic receptors by high concentrations of LA

§If absorbed, LAs stiumation transmission at the neuromuscular junction and ganglia.

Topical Anesthesia

Infiltration Anesthesia:

Nerve Block Anesthesia:

Intravenous Regional Anesthesia (Bier Block):

Spinal Anesthesia and Epidural Anesthesia

§Involves anesthesia of mucus membranes of the nose, eye, mouth, throat, tracheobronchial tree, esophagus and genitourinary tract.

§LAs are rapidly absorbed rapidly into the circulation following topical administration to mucus membranes or denuded skin.

§Involves injection of LA directly into tissue without taking into consideration the nerve supply.

§Duration of infiltration anesthesia can be increased by adding epinephrine to the injection solution.

lidocaine, tetracaine and bupivacaine.

lidocaine and bupivacaine.

tetracaine and lidocaine.

Involves injection of LA directly into tissue without taking into consideration the nerve supply

Infiltration anesthesia can be:

include only the skin and intra-abdominal organs

Infiltration anesthesia can be:

include only the skin

Involves injection of LA directly into tissue with taking into consideration the nerve supply

§Duration of infiltration anesthesia can be increased by adding epinephrine to the injection solution.

Advantage of infiltration anesthesia: provide satisfactory anesthesia without disruption of normal body functions

Disadvantage: relatively large amounts of drug are needed to anesthetize relatively small areas

Disadvantage: provide satisfactory anesthesia without disruption of normal body functions

Advantage of infiltration anesthesia: relatively large amounts of drug are needed to anesthetize relatively small areas

lidocaine and bupivacaine.

lidocaine, tetracaine and bupivacaine.

lidocaine

Involves injection of an LA into or about individual peripheral nerves or nerve plexuses.

Blockade of peripheral nerves or nerve plexuses also anesthetizes somatic motor nerves leading to skeletal muscle relaxation (essential for surgical procedures).

Stiumation of peripheral nerves or nerve plexuses also anesthetizes somatic motor nerves leading to skeletal muscle relaxation (essential for surgical procedures).

Areas of sensory or motor block usually start several centimeters distal to site of injection:

Areas of motor block usually start several centimeters distal to site of injection:

§Brachial plexus block: useful for procedures of upper extremity and shoulder.

§Intercostal nerve block: effective for anesthesia and relaxation of anterior abdominal wall

§Intercostal nerve block: useful for procedures of upper extremity and shoulder.

§Brachial plexus block: ueffective for anesthesia and relaxation of anterior abdominal wall

Cervical plexus block: §useful for knee surgery

Other useful nerve blocks include individual nerves of the wrist, ankle and elbow.

Sciatic and femoral nerve blocks: useful for knee surgery

Other useful nerve blocks include individual nerves of the wrist, ankle and elbow.

Cervical plexus block: used for surgery of the neck

Sciatic and femoral nerve blocks: § for surgery of the neck

Degree of ionization of the drug

Time

Concentration and volume of the drug

proximity of the injection to the nerve

lipid solubility

§Long-acting (400-450 mins): procaine

§Short-acting (20-45 mins): e.g., procaine

§Long-acting (400-450 mins): e.g., bupivacaine, ropivacaine and tetracaine

§Intermediate-acting (60-120 mins): e.g., lidocaine

§Intermediate-acting (60-120 mins): e.g., bupivacaine, ropivacaine and tetracaine

Physical characteristics of drug

§Whether epinephrine was used.

§Surface area exposed to the drug.

§Rate of blood flow to site of injection.

§Amount of drug injected.

§Relies on blood vessels to bring the LA solution to nerve trunks and endings.

§Relies on blood arteries to bring the LA solution to nerve trunks and endings.

§Used for surgery of the forearm and hand (can be adapted for foot and distal leg)

§Lidocaine is the drug of choice for this procedure.

§Iodine is the drug of choice for this procedure.

§to exsanguinate an extremity and a proximally located tourniquet to inflate BP to 100-150 mm Hg above systolic pressure.

§Esmarch bandage is removed and the LA is injected to previously cannulated vein

§Typically complete anesthesia of the limb ensues within 5-10 mins.

§Typically complete anesthesia of the limb ensues within 5-20mins.

§Esmarch bandage is added and the LA is injected to previously cannulated vein

Physiological side effects of spinal anesthesia are due to the blockade of sympathetic outflow produced by LA block of sympathetic fibers in the spinal nerve roots

Involves the injection of LA into the CSF in the lumbar space.

After termination of the spinal cord at the second lumbar vertebra, the lumbar and sacral roots are bathed in CSF until the termination of the thecal sac in the sacrum.

Involves the injection of LA into the HCFin the lumbar space.

Physiological side effects of spinal anesthesia are due to the situation of sympathetic outflow produced by LA block of sympathetic fibers in the spinal nerve roots

§Produces non- negligible plasma levels of LA.

§Ability to produce anesthesia of a considerable part of the body.

§Produces negligible plasma levels of LA.

§Ability to produce anesthesia of a considerable to a certain part of the body

lidocaine

tetracaine

bupivacaine.

Involves injecting the LA into the epidural space (bounded by ligamentum flavum posteriorly, the spinal periosteum laterally and the dura anteriorly).

Involves orally take the LA into the epidural space (bounded by ligamentum flavum posteriorly, the spinal periosteum laterally and the dura anteriorly).

Can be performed in the spinal cord (caudal anesthesia) or in the lumbar, thoracic or cervical regions of the spine.

Can be performed in the sacral hiatus (caudal anesthesia) or in the lumbar, thoracic or cervical regions of the spine.

Popularity of this route of administration is based on the development of catheters that can be placed into the epidural space to allow for continuous infusions or repeated bolus injections of LAs.

§May also act on the spinal cord and paravertebral nerves

§May also act on the spinal cord and thoracic nerves

§May also act on the only the spinal cord

lidocaine

bupivacaine.

§Causes faster, more intense, longer-lasting and more extensive anesthesia than procaine.

§Causes faster, less intense, longer-lasting and more extensive anesthesia than procaine.

§Active parenterally. Also formulated for topical, ophthalmic, mucosal and transdermal use.

§Active only parenterally.

§Used for local or regional anesthesia for infiltration and nerve block.

§Used for local anesthesia for infiltration and nerve block.

§Used for regional anesthesia for infiltration and nerve block.

§Potent LA capable of producing prolonged anesthesia.

§Potent LA capable of blocking prolonged anesthesia.

§Can provide more sensory than motor block.

§Can provide less sensory than motor block.

true

false

Used for local or regional anesthesia for infiltration and nerve block.

Used for production of local or regional anesthesia or analgesia for surgery, dental or oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures

After termination of the spinal cord at the second lumbar vertebra, the lumbar and sacral roots are bathed in CSF until the termination of the thecal sac in the sacrum

After termination of the spinal cord at the first lumbar vertebra, the lumbar and sacral roots are bathed in CSF until the termination of the thecal sac in the sacrum

After termination of the spinal cord at the second lumbar vertebra, the lumbar and sacral roots are bathed in CSF until absorption of the thecal sac in the sacrum

After termination of the spinal cord at the first lumbar vertebra, the lumbar and sacral roots are bathed in CSF until the absorption termination of the thecal sac in the sacrum