Local Anesthetics

By

M.H.Farjoo M.D, Ph.D

Shahid Beheshti University of Medical Science

Local Anesthetics

Introduction Classification Mechanism of action Henderson-Hasselbalch equation Modifying Factors Pharmacokinetic Toxicity Clinical Uses Drug Pictures

Of one Essence is the human race

thus has Creation put the base

One Limb impacted is sufficient

For all Others to feel the Mace

Introduction

The first LA, cocaine, was isolated in 1860. Cocaine introduced into practice in 1884 as a topical

ophthalmic anesthetic. Despite its addictive property, cocaine was used for

30 years. In 1905 procaine was synthesized, which became the

dominant LA for the next 50 years. Lidocaine, which is still a widely used LA, was

synthesized in 1943

Ester:

Amide:

Procaine

Lidocaine

Classification Ester

Cocaine Procaine (Novocaine) Tetracaine (Pontocaine) Benzocaine

Amide Lidocaine (Xylocaine) Bupivocaine (Marcaine) Prilocaine (Citanest) Articaine

Transdermal

A multivesicular liposomal formulation, effective for 72 hrs

 Esters Potency (Procaine = 1)Duration of

Action

Cocaine 2 Medium

Procaine (Novocain) 1 Short

Tetracaine (Pontocaine) 16 Long

Benzocaine Surface use only

Amides  Potency (Procaine = 1)Duration of

Action

Lidocaine (Xylocaine) 4 Medium

Mepivacaine (Carbocaine, Isocaine)

2 Medium

Bupivacaine (Marcaine), Levobupivacaine (Chirocaine)

16 Long

Articaine No data Medium

Mechanism of Action

Pain awareness, (nociception), is transmitted to the CNS by primary afferent fibers and relayed by secondary afferent fibers to the brain.

Transmission can be prevented by blocking the Na+

channels in the axons which reside: Outside the spinal cord (regional anesthesia) Inside the spinal cord (spinal anesthesia)

These drugs block conduction in all the cells that use Na+ channels for action potential.

Mechanism of Action

LAs block voltage-gated sodium channels in neurons. These Na+ fluxes are similar to those in heart muscle,

and LAs have similar effects in both tissues. Biologic toxins (scorpion venoms) bind to receptors

within the channel and prevent inactivation. LAs bind near the intracellular end of the sodium

channel.

Mechanism of Action

LAs block the channel in a time- and voltage-dependent fashion.

Channels in the rested state, have a much lower affinity for LAs than activated and inactivated channels.

So, the effect of a drug is more marked in rapidly firing axons than in resting fibers.

If the sodium current is blocked over a critical length of the nerve, impulse is blocked.

In myelinated nerves, the critical length is two to three nodes of Ranvier.

Zero

Henderson-Hasselbalch equation

Mode of entrance of LA

The pKa of most LAs is 8.0–9.0, so in the body exist as cations.

The cationic form is the most active form at the receptor site because it cannot readily exit from closed channels.

LAs are less effective when injected into infected (acidic) tissues.

Modifying Factors

Nerve fibers differ in their sensitivity to LA blockade. The smaller B and C fibers are blocked first, then other

sensory axons, and motor function is the last. Between successive action potentials, a portion of the

sodium channels will recover from the LA block. The recovery from drug-induced block is 10 to 1000

times slower than normal inactivation. So, the refractory period is lengthened and the nerve

conducts fewer electrical impulses.

Relative size and susceptibility of different types of nerve fibers to LAs.

  Fiber Type Function Diameter Myelination Conduction Velocity (m/s)

Sensitivity to Block

Type A          

  Alpha Proprioception, motor 12-20 Heavy 70-120 +

  Beta Touch, pressure 5-12 Heavy 30-70 ++

  Gamma Muscle spindles 3-6 Heavy 15-30 ++

  Delta Pain, temperature 2-5 Heavy 12-30 +++

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 None 0.7-2.3 ++++

Practicallyinfinite

Modifying Factors

Blockade by these drugs is more marked at higher frequencies of depolarization.

Sensory (pain) fibers have a high firing rate and a relatively long action potential duration.

Motor fibers fire at a slower rate and have a shorter action potential duration.

In the extremities, proximal sensory fibers are located superficially, whereas the distal ones are located deeply.

Thus, in large nerves, sensory analgesia develops proximally and then spreads distally.

Modifying Factors

Acidification of urine leads to more rapid elimination. The onset of LA can be accelerated by sodium bicarbonate

(1–2 mL) to the LA solution. This maximizes the amount of drug in the more lipid-soluble

(unionized) form. Hypercalcemia antagonizes the action of LAs by increasing

the surface potential of membrane (low-affinity rested state). Hyperkalemia enhances the effect of LAs by depolarizing

the membrane potential (inactivated high-affinity state).

Modifying Factors

LAs are marketed as hydrochloride salts (pH 4.0–6.0) to maximize aqueous solubility.

the salts are buffered in the body providing sufficient free base for their effect.

repeated injections can deplete the buffering capacity and the ensuing acidosis results in tachyphylaxis.

Tachyphylaxis to LAs is common in CSF (limited buffer capacity).

Pharmacokinetic

The LAs are metabolized in the liver (amide type) or in plasma (ester type)

The half-life of lidocaine (amide LA) is 1.6 hrs in normal patients but > 6 hours in severe liver disease.

Ester-type LAs are hydrolyzed rapidly in the blood by butyrylcholinesterase (pseudocholinesterase).

So, Ester LAs have an elimination half-life less than 1 min (procaine).

Pharmacokinetic

The smaller and more lipophilic LAs have a faster rate of interaction with the sodium channel.

Potency is correlated with lipid solubility as long as the LA retains sufficient water solubility to diffuse to its site of action.

Pharmacokinetic

LAs are often injected, so absorption and distribution are not that important in the onset of effect.

But, they are crucial in the rate of offset of their effect and CNS and cardiac toxicity.

Injection to a vascular area (intercostal nerves) results in more rapid absorption and higher blood levels.

The reverse is true about poorly perfused tissue (tendon, dermis, fat).

Pharmacokinetic

Blood levels of LAs after injection is: intercostal (highest) > caudal > epidural > brachial plexus > sciatic nerve (lowest).

Vasoconstriction by epinephrine or phenylephrine reduces absorption of LAs and decreases toxicity.

This will enhance localized neuronal uptake and increase duration of action.

This is important for drugs with intermediate or short durations of action (lidocaine).

Pharmacokinetic

Alpha2 adrenoceptors, inhibits release of substance P (neurokinin-1) in spinal cord and reduce sensory neuron firing.

This led to the use of clonidine to prolong the LA effect.

The combination of reduced systemic absorption, and alpha2 activation by epinephrine prolongs the LA effect by 50%.

Toxicity

The side effects of LAs represent extensions of their therapeutic effects (their toxicity is difficult to reduce).

An early symptom of LA toxicity is circumoral and tongue numbness and a metallic taste.

At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions.

LAs may cause depression of cortical inhibitory pathways.

This transitional stage of unbalanced excitation (seizure) is then followed by generalized CNS depression.

Toxicity

When large doses of a LA are required, pretreatment with IV diazepam or midazolam prevents CNS toxicity.

In spinal anesthesia, motor paralysis may impair respiration, and autonomic blockade can cause hypotension.

Autonomic blockade also interferes with bladder function which needs bladder catheterization.

High concentrations of LA in the subarachnoid space interferes with intra-axonal transport and calcium homeostasis => spinal toxicity.

Toxicity

Bupivacaine can cause lethal arrhythmias if high plasma concentrations are achieved.

Bupivacaine may be more cardiotoxic than other LAs.

The ECG finding is a slow idioventricular rhythm and eventually electromechanical dissociation.

Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult, though propofol can be useful.

Toxicity

The ester-type LAs are metabolized to Para amino benzoic acid derivatives.

These metabolites are responsible for allergic reactions in a small percentage of the patients.

Amides are not allergic.

Toxicity

The administration of large doses of prilocaine may lead to accumulation of o-toluidine.

It is an oxidizing agent converting hemoglobin to methemoglobin.

When sufficient methemoglobin is present, the patient may appear cyanotic and the blood "chocolate-colored."

Methemoglobinemia may cause decompensation in patients with cardiac or pulmonary disease.

The treatment is IV injection of a reducing agent (methylene blue or ascorbic acid), which rapidly converts methemoglobin to hemoglobin.

Clinical Uses

IV regional anesthesia (Bier block) is used for procedures < 60 min. involving the extremities.

LA is injected into a distal vein while the circulation of the limb is isolated with a proximally placed tourniquet.

Block of sympathetic fibers is also used to evaluate the role of sympathetic tone in peripheral vasospastic disorders.

Lidocaine is used also for arrhythmia at concentrations lower than those required for nerve block.

Clinical Uses

Systemic LAs may be used as adjuvants to the combination of a TCA (amitriptyline) and an anticonvulsant (carbamazepine) in chronic pain.

A period of 1–3 weeks may be required to observe a therapeutic in neuropathic pain.

LAs have poorly understood anti-inflammatory effects, which contributes to pain control in chronic pain.

Subclass EffectsClinical

ApplicationsPharmacokinetics,

Toxicities

Amides 

Lidocaine Slows, then blocks action potential propagation

Short-duration procedures epidural, spinal anesthesia

Parenteral duration 30–60 min 2–6 h with epinephrine Toxicity: CNS excitation

Bupivacaine Same as lidocaine

Longer-duration procedures

Parenteral duration 2–4 h Toxicity: CNS excitation cardiovascular collapse 

 Prilocaine, ropivacaine, mepivacaine, levobupivacaine: Like bupivacaine 

Subclass Effects Clinical ApplicationsPharmacokinetics,

Toxicities

Esters 

Procaine Like lidocaine Very short procedures Parenteral duration 15–30 min 30–90 min with epinephrine Toxicity: Like lidocaine

Cocaine Same as above Procedures requiring high surface activity and vasoconstriction

Topical or parenteral duration 1–2 h Toxicity: CNS excitation, convulsions, cardiac arrhythmias, hypertension, stroke

Tetracaine: Used for spinal, epidural anesthesia; duration 2–3 h 

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