1. Local Anesthetics By S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences

2. Introduction
Schematic diagram of a primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control. The primary afferent neuron cell body is not shown. At least three nociceptors are recognized: acid, injury, and heat receptors. The nerve ending also bears opioid receptors, which can inhibit action potential generation. The axon bears sodium channels and potassium channels (not shown), which are essential for action potential propagation. Synaptic transmission involves release of substance P, a neuropeptide (NP) and glutamate and activation of their receptors on the secondary neuron. Alpha2 adrenoceptors and opioid receptors modulate the transmission process.

3. History
Cocaine, the first local anesthetic introduced into medical practice, was isolated by Niemann in 1860
Procaine was synthesized by Einhorn in 1905
Lidocaine, which is still a widely used local anesthetic, was synthesized in 1943 by Löfgren.

4. Basic Pharmacology of Local Anesthetics

5. Chemistry: Structure Ester
Cocaine
Procaine (Novocain)
Tetracaine (Pontocaine)
Benzocaine

6. Chemistry: Structure Amides
Lidocaine (Xylocaine)
Mepivacaine
Bupivacaine; Levobupivacaine
Ropivacaine (Naropin)

7. Chemistry Local anesthetics are weak bases
the pKa of most local anesthetics is in the range of 8.0–9.0
Cationic form is the most active form
The uncharged form is important for rapid penetration of biologic membranes

8. Pharmacokinetics
Local anesthetics are usually administered by injection into dermis and soft tissues around nerves
Absorption and distribution are not as important

9. Absorption
Systemic absorption of injected local anesthetic depends on:
Dosage
Site of injection
Drug-tissue binding
Local tissue blood flow
Use of vasoconstrictors (eg, epinephrine)
Physicochemical properties of the drug

10. Distribution, Metabolism and Excretion
The amide local anesthetics are widely distributed after intravenous bolus administration
The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites
Decreased hepatic elimination of local anesthetics would be anticipated in patients with reduced hepatic blood flow or hepatic diseases

11. Pharmacodynamics: Mechanism of Action
Functional and structural features of the Na+ channel that determine local anesthetic interactions. A: Cartoon of the sodium channel in an axonal membrane in the resting (m gates closed, h gate open), activated (m gates open, h gate open), and inactivated states (m gates open, h gate closed). Recovery from the inactivated, refractory state requires closure of the m gates and opening of the h gate. Local anesthetics bind to a receptor (R) within the channel and access it via the membrane phase or from the cytoplasm. B: Molecular arrangement of the six membrane-spanning peptides, four of which combine to form the channel around a central pore. The S4 segments (marked with "+" signs) are thought to constitute the voltage-sensing m gates of the channel. The linker peptide connecting the III and IV hexamers acts as the inactivation h gate. Ions travel through an open channel along a pore defined at its narrowest dimension by partial membrane penetration of the four extracellular loops of protein connecting S5 and S6 in each domain. Local anesthetic binding occurs on S6 segments and at other regions of the channel. C: Three-dimensional drawing showing the configuration of the four hexamers around the central pore in the membrane.

12. Pharmacodynamics
The function of sodium channels can be disrupted in several ways:
batrachotoxin, aconitine, veratridine
bind to receptors within the channel and prevent inactivation
tetrodotoxin (TTX) and saxitoxin
block sodium channels by binding to channel receptors near the extracellular surface
Spinal neurons can be differentiated on the basis of tetrodotoxin effect into:
TTX-sensitive
TTX-resistant neurons

13. Pharmacodynamics With increasing concentrations of a local anesthetic
The threshold for excitation increases
Impulse conduction slows
The rate of rise of the action potential declines
The action potential amplitude decreases
The ability to generate an action potential is completely abolished
These effects result from binding of the local anesthetic to more and more sodium channels
Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes.
(Modified and reproduced, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225.)

14. Effect of Extra cellurar Ions
Increase in extracellular calcium partially antagonizes the action of local anesthetics
Owing to the calcium-induced increase in the surface potential on the membrane.
Increases in extracellular potassium enhancing the effect of local anesthetics.:
Depolarize the membrane potential and favor the inactivated state.

15. Relative Size and Susceptibility of Different Types of Nerve Fibers to Local Anesthetics
Fiber Type
Function
Diameter (m)
Myelination
Conduction Velocity (m/s)
Sensitivity to Block
Type A 
  Alpha
Proprioception, motor
12–20
Heavy
70–120 +
  Beta
Touch, pressure
5–12
30–70 ++
  Gamma
Muscle spindles
3–6
15–30
  Delta
Pain, temperature
2–5
5–25
+++
Type B 
Preganglionic autonomic
< 3
Light
3–15
++++
Type C 
  Dorsal root
Pain
0.4–1.2
None
0.5–2.3
  Sympathetic
Postganglionic
0.3–1.3
0.7–2.3

16. Nerve fibers differ significantly in their susceptibility
Effect of Fiber Diameter
Effect of Firing Frequency
Effect of Fiber Position in the Nerve Bundle
Effects on Other Excitable Membranes

17. Clinical Pharmacology of Local Anesthetics

18. Clinical Pharmacology
Can provide highly effective analgesia in well- defined regions of the body
The usual routes of administration
Topical application
Injection in the vicinity of peripheral nerve endings (perineural infiltration)
Injection in the vicinity of major nerve trunks (blocks)
Injection into the epidural or subarachnoid spaces surrounding the spinal cord
Intravenous regional anesthesia (Bier block)

19. Schematic diagram of the typical sites of injection of local anesthetics in and around the spinal canal

20. The choice of local anesthetic
The choice of local anesthetic is usually based on the duration of action required
Short-acting:
Procaine and chloroprocaine
Intermediate duration :
lidocaine, mepivacaine, and prilocaine
long-acting :
tetracaine, bupivacaine, levobupivacaine, and ropivacaine

21. Some tips
The onset of local anesthesia can be accelerated by the addition of sodium bicarbonate
Repeated injections of local anesthetics can result in loss of effectiveness
Pregnancy appears to increase susceptibility to local anesthetic toxicity

22. Toxicity Central Nervous System Neurotoxicity Cardiovascular System
Lidociaine
Cardiovascular System
Bupivacaine
Hematologic Effects
Prilocaine: metabolite o-toluidine
Allergic Reactions
The ester-type local anesthetics: p-aminobenzoic acid derivatives