Local Anesthetics

Definition

Drugs which

–  produce a REVERSIBLE loss of sensation …

–  in a localized part of the body…..

–  when applied directly onto nerve tissues or mucous membranes

Local anesthetics are ‘local’ ONLY because of how they are administered!     (Selectivity)

Local anesthetics are the agents used to bring about local effects by targeting specific restricted areas. The effects can be easily reversed.

Administered by topical application or injection into superficial region, where they cause loss of sensations. Mostly sensory and pain sensations are lost first, followed by others. at times motor activity is also affected.

1. Effects are reversible
2. Inhibit impulse conduction
3. Sodium channels are targeted
4. Action potential generation is required.

Local anesthetics are usually designed in a way that effects are reversible and do not cause damage to underlying cells or tissue.

History

The first clinically used local anesthetic cocaine. It is a natural alkaloid from Erythroxylon coca. It was discovered in 1860 and was used till 1884. Later on it was discovered that it had high addictive potential, so labelled drug of abuse and discontinued. Others have been discovered with less abuse potential like procaine, procainamide. Lidocaine is the latest drug or lignocaine as generally known (synthetic local anesthetic considered prototype).

Prototype Drug       Lignocaine (Synthetic)

Properties Desirable in a Local Anesthetic

1. Non-irritating if applied topically or on mucous membranes

2. Does not cause permanent damage to nerve structure

3. Systemic toxicity should be low

4. Highly effective if:

a.       Injected

b.      Applied locally

5. Onset of action as quick as possible

6. Duration of action long enough to allow time for counter plated surgery

Classification According To Chemistry

Esters

·         Cocaine

·         Procaine

·         Tetracaine

·         Benzocaine

Amides

·         Lignocaine/Lidocaine

·         Bupivacaine

·           Prilocaine

·         Cinchocaine

·         Ropivacaine

According to Duration of action

Short Duration of Action

Procaine

Medium Duration of Action

Cocaine

Lidocaine

Mepivacaine

Prilocaine

Long Duration of Action

Tetracaine

Bupivacaine

Etidocaine

Ropivacaine

Classification According to Clinical Uses

Surface Anesthesia

• Tetracaine
•  Lignocaine
•  Cocaine
• Benzocaine

Infiltration Anesthesia & Field Block Anesthesia

•  Lignocaine
•  Procaine
•  Bupivacaine
• Lignocaine
•  Tetracaine
•  Bupivacaine

Nerve Block Anesthesia

·         Procaine

·          Lignocaine

·          Bupivacaine

·          Tetracaine

·          Ropivacaine

Spinal Anesthesia

Epidural Anesthesia

Lignocaine

Bupivacaine

Anesthetic Used In Ophthalmology

Proparacaine

Chemistry

Most local anesthetics consist of 3 parts:

a)      Lipophilic Aromatic group

b)      Intermediate alkyl chain

c)      Hydrophilic Amino group

Intermediate alkyl chains are either esters or amides.

Local anesthetics are Weak Bases

Two types of linkages give rise to 2 chemical classes of local anesthetics.

ESTER LINKAGE

PROCAINE

1. procaine (Novocaine)
2. tetracaine (Pontocaine)
3. benzocaine
4. cocaine

Local anesthetics which consist of ester type of side chains are:

1. rapidly metabolized by plasma esterases
2. have short duration of action
3. are less distributed
4. with rate of metabolism higher.
5. Hypersensitivity type of reactions is commonly seen because they are converted into para amino benzoic acid, having potential to produce hypersensitivity.

AMIDE LINKAGE

LIDOCAINE

a)      lidocaine (Xylocaine)

b)      mepivacaine (Carbocaine)

c)      bupivacaine (Marcaine)

d)      etidocaine (Duranest)

e)      ropivacaine (Naropin)

Local anesthetics which consist of amide type of linkage are:

1. Less rapidly metabolized
2. Have longer duration of action
3. More widely distributed
4. Mainly metabolized by cytochrome P450 enzymes in liver.
5. Mostly present bound to alpha glycoproteins, thus hypersensitivity type reactions are rare

Local anesthetics are mostly available for therapeutic application as salts, and are said to be weak bases, with pKa 8-9.

Salt form increases the stability and solubility.

To bring about the effects, they are required to penetrate through membranes, thus lipid solubility is necessary.

Non-ionized form is important to penetrate through membranes to reach exoplasm. Once reaches the exoplasm, it changes to catoinic form, which binds local anesthetic receptors.

Action depends on :

1. pKa value
2. pH of medium (if physiological, effects are easily produced)

When pH of area i slow, local anesthetic (as is weak base) cannot penetrate through membrane, hence effects are not produced.

In inflammation, local anesthetics are not recommended, as low pH is produced and ionized form of local anesthetic is produced, which cannot transverse membrane.

Mechanism of Action

· Diffusion into the nerve fiber

· Blockade of sodium channels.

Physiology of action potential generation

In neurons, excitable membranes have more Na⁺ outside in resting stage while K⁺ inside. Potential is -60 to -90 mV. Movement of ions is possible, energy for which is supplied by Na K ATPase pump.

When impulse conduction takes place, threshold is reached, opening of Na channels occurs, with movement of Na ions down the concentration gradient. With this movement, potential reaches +40 mV, known as depolarization.

Closing of Na channels and opening of K channels, leads to K efflux and beginning of repolarization.

If potential is decreased further, hyperpolarization occurs.

When action potential moves along the entire length of nerves, impulse conduction occurs.

Local anesthetics act by targeting the Na channels, which are transmembrane structures with one end towards outside (M gate or Na activation gate), other towards inside (H gate or inactivation gate).

M gate is usually closed in resting state, opens with threshold and Na ions transverse through Na channels, leading to depolarization. After a few msec close, and further movement does not occur.

If local anesthetic is given in non-ionizable, non-polar form, it transverses through membrane, within exoplasm cationic form binds local anesthetic receptor site, which is present on inner side.

Na channel blockage occurs, further opening is inhibited.

Channels are closed in inactivated state, thus action potential is slowed down, and eventually inhibited.

Progressively increasing conc. of a local anesthetic applied to a nerve fiber produce blockade of more & more Na+ channels :

1.        The threshold for excitation increases

2.        Impulse conduction slows

3.        The rate of rise of Action Potential declines

4.        The AP amplitude decreases

5.        Finally the ability to generate an Action Potential is abolished

local anesthetics are said to be more effective in neurons which are rapidly firing, in inactivated state or activated state. Resting state has low affinity for local anesthetics.

Susceptibility Of Nerve Fiber To Local Anesthetic 

1.      Size of nerve fiber

Smaller fibers are blocked first, then larger ones. Thus less time is required in smaller fibers.

2.      State of myelination

Myelinated fibers are blocked first than unmyelinated fibers.

3.      Rate of firing

Rapidly firing neurons are blocked first, as have more affinity for local anesthetics.

Order Of Blockade

1.      Autonomic

2.      pain

3.      temperature

4.      Touch

5.      deep pressure

6.      motor

Recovery  in reverse order

Usually sensory blockage occurs first, followed by motor paralysis towards end.

Exception is in mixed type of nerve trunks especially within extremities where motor fibers are present towards periphery with sensory towards inner core, thus motor are blocked first.

Pharmacokinetics

Most local anesthetics are injected within target site thus absorption and distribution has little role, but absorption and distribution may play role when applied topically on mucous membranes.

·          Absorption

Absorption of some local anesthetics depend on:

1. Type of local anesthetic being applied e.g. topical application
2. Site where applied e.g. if highly perfused area, absorption is rapid thus more effective like tracheobronchial tree (has rapid absorption), fat region slows down absorption
3. Medium in which local anesthetic is applied, for infiltration medium around, interstitial or aqueous has more solubility and wider area is affected, as compared to those having less diffusion through medium.
4. Addition of vasoconstrictor substance. When drug is administered into area, it is absorbed, distributed and systemic levels are achieved. Some undesirable effects occur as well including toxicity, CNS effects, and cardiovascular toxicity. Aim is to restrict it within local area.

To achieve this, local anesthetic is mostly combined with vasoconstrictor, most commonly adrenaline is used, epinephrine, phenyl ephrine may be used as well.

1. Vasoconstriction restricts blood flow, high blood levels are not achieved
2. Duration of action is also prolonged
3. By acting on alpha 2 receptors,  especially central alpha 2 receptors has agonist effect, which decreases release of substance P, which provides good analgesia. By acting through alpha 2 receptors, reduce sensory neuron firing.

Clonidine (central alpha 2 agonist) is being utilized in experiments for combining it with local anesthetics to augment their effects.

·         Biotransformation & Excretion

Biotransformation of most esters and amides is based on chemical structure.

1. Esters are rapidly hydrolyzed by plasma esterases, having short DOA/quicker termination and less widely distribution.
2. Amines are metabolized by cytochrome P450 in liver, having slow metabolism, longer DOA, more wider distribution. Metabolites formed are water soluble and are excreted by kidneys. As these are weak bases, so acidification of urine can enhance excretion through urine.

Plasma protein binding may be used as an indirect measure of tissue binding tendencies

Adverse Effects

Most serious, if given in low doses, most effects are avoided. Low blood levels reduce the occurrence of toxicities.

1.       CNS

Stimulation followed by depression.

Stimulation is due to inhibition of inhibitory pathways.

Later on excitatory pathways are also inhibited, leading to wider range of effects including:

1. light headedness
2. restlessness
3. sleepiness
4. auditory/visual disturbance
5. metallic taste
6. tongue numbness
7. muscle twitching
8. nystagmus
9. tonic clonic convulsions

To avoid CNS effects:

1. keep low dose of local anesthetic
2. administered to less perfused area
3. before administration, pre medication to avoid CNS effects. Benzodiazepines (sedative/hypnotics) given. If convulsions appear, then Midazolam, Thiopentone Na, propafol is administered I/V.
4. another way of managing is enhancing hyperventilation which corrects acidosis and decreases K extracellularly, producing hyperventilation and rested state, which has low affinity for local anesthetic.

2.      Local  Neurotoxicity

Within cauda equine can cause local neurotoxicity, usually between L2-L3 mostly when given by spinal anesthesia.

3.       CVS

a.       Depressant effect by acting on cardiac Na channels. Later on in high doses, Ca channels are also inhibited.

b.      Also effect autonomic system by enhancing sympathetic outflow, specifically blood vessels and heart, where vasodilatation, hypotensive effects are seen.

Cocaine is an exception as is a potent vasoconstrictor, hypertension, tachycardia and arrhythmias occur. Norepinephrine from synaptic cleft is not reuptaken and accumulates, producing cardiac stimulatory effects.

Bupivacaine is highly cardio toxic, and is selective for cardiac sodium channels. If administered, cardiac toxicity is seen.

This can be countered by giving atropine to correct heart block.

Levobupivacaine is an isomer of bupivacaine and is said to be less cardio toxic.

Another agent, rupivacaine is said to be more safer in the setting where we want to avoid cardiac toxicity or in underlying cardiac disease. They have even lesser affinity for cardiac sodium channels.

4.       ANS

ANS is highly sensitive to effects of local anesthetics, most nerves are affected in dose priority. They inhibit nerves to blood vessels and heart, producing hypotensive effects.

If severe hypotension occurs, foot ends of bed are raised and sympathomimetics are given  (ephedrine).

5.      Motor Paralysis

Motor paralysis is last to occur. Inhibition of motor activity is undesirable. It is usually seen when spinal or epidural anesthesia is administered. It is also the first to recover during recovery.

6.       Hematological Effects

Seen if given in very high doses.

Prilocaine if given in higher doses, can convert hemoglobin into met hemoglobin, producing cyanosis and chocolate brown coloured blood.

To treat, I/V reducing agent such as methylene blue, ascorbic acid should be administered, which converts met hemoglobin to hemoglobin.

This is seen due to metabolite produced by high toxic levels known as o-toluidine.

7.       Hypersensitivity reactions

Seen with ester type, as rapidly metabolized and converted into PABA, which is more prone to cause hypersensitivity reactions. Rarely seen with amide type of local anesthetics.

Prevention of Toxicity

1.      Enquire about history of allergy.

2.      Caution in presence of liver/myocardial damage.

3.      Proper site (correct knowledge of nerve course).

4.      Minimal effective dose usage (avoid I/V administration).

5.      Wait after injection.

6.      Observe the face for any twitching, excitement, and pulse for tachycardia.

7.      Observe post – op for allergic reactions.

8.      Avoid food intake at least 04 hrs. prior to anesthesia to prevent vomiting.

Cocaine

·         Medical use limited to surface or topical anesthesia

·         Avoid epinephrine because cocaine already has vasoconstrictor properties.  (EXCEPTION!!!)

·         A toxic action on heart may induce rapid and lethal cardiac failure.

·         A marked pyrexia is associated with cocaine overdose.

Benzocaine

·         pKa ~ 3,  essentially all non-ionized…. mechanism may be non-specific

·         Available in many OTC preps for relief of pain and irritation

·         for surface anesthesia (topical) only …  ointments, sprays, etc.

·         Used to produce anesthesia of mucous membranes

·         methemoglobinemia is seen as well

Selective Pharmacological Properties Of Some Amide – Type

Lidocaine (Xylocaine)

·       Most widely used Local Anesthetic

·         Effective by all routes.

·         Faster onset, more intense, longer lasting, than procaine.

·         Good alternative for those allergic to ester type

·         More potent than procaine but about equal toxicity

·          More sedative than others

Bupivacaine (Marcaine)

·         No topical effectiveness

·         Slower onset and one of the longer duration agents

·         Unique property of sensory and motor dissociation can provide sensory analgesia with minimal motor block

·         has been popular drug for analgesia during labor

·         More cardio toxic than other Local Anesthetic

Ropivacaine

·         Enantiomer of bupivacaine (S stereoisomer)

·         No topical effectiveness

·         Clinically ~ equivalent to bupivacaine

·         Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicit

Clinical Applications

1.      Surface Anesthesia (Topical)

§ Lidocaine, tetracaine

Local anesthetic is topically applied to mucous membranes or abraded skin. Mostly used in

a.       Ear

b.      Nose,

c.       mouth,

d.      throat,

e.       trachea-bronchial tree,

f.       nasopharynx, cornea and

g.       gastro-urinary tracts

Use of vasoconstrictor is not recommended when topically applied, because of vasoconstrictor agents are not absorbed through mucous membranes.

Cocaine is also used for topical application, mainly in ear, nose and mouth. It is highly vasoconstrictor (may cause ischemia). Typical vasoconstrictors have quick onset and duration of  action of 35-40 minutes. Certain preparations like EMLA cream combination having lidocaine 2.5%, prilocaine 2.5% each, are applied on skin to produce effects as deep as 5 mm. thus local anesthetic effect is produced.

2.      Infiltration Anesthesia

*    Direct injection into tissues to reach nerve branches and terminals.

*    Used in minor surgery.

*    Immediate onset with variable duration.

This type involves skin region as deep as intraabdominal tissue

§ Most Local Anesthetics are used

 3.   Nerve Block Or Field Block

*    Interruption of nerve conduction upon injection into the region of nerve plexus or trunk.

*    Used for surgery, dentistry, analgesia.

*    Less anesthetic needed than for infiltration

Given within specific nerve area such as brachial plexus, within intercostal nerves abdominal nerves are targeted, cervical plexus when neck region is targeted.

§ Most Local anesthetics are used

4.   Spinal Anesthesia

*    Injection into subarachnoid space below level of L2 vertebra (usually between L2-L3 or L3-L4) to produce effect in spinal roots and spinal cord.

*    Use two types of local anesthesias, when dissolved in water: hyperbaric or hypobaric solutions depending on area of blockade.

*    Used for

a.       surgery to abdomen, pelvis or leg

b.      when can’t use general anesthesia.

c.      Persons suffering from organic disorders, hepatic, renal or cardiovascular manifestations.

§ Lidocaine, tetracaine

5.      Epidural and Caudal Anesthesia

Usually selected when lower part of body is targeted e.g. pelvic region. Administration of local anesthetic into epidural space or near dura matter where nearly most nerves pass closely, area supplied by these nerves are targeted.

a.  Ligamentum flavum (posteriorly)

b.  Spinal periostetum  (laterally)

c.  Dura (anteriorly)

–  Injection into epidural space usually at lumbar or sacral levels.

–  Used like spinal and also painless childbirth.

–  Unwanted effects similar to that of spinal.

§ Lidocaine, bupivacaine, ropivacaine

Spinal and epidural anesthesias have complications:

1. Hematoma
2. Pain
3. Introduction of foreign particle
4. Headache usually seen –reason is seepage of CSF may take place at site of administration. This can be avoided by using small bore needle rather than wide bored.

If  headache does develop, we manage it by technique of blood patch. Patient’s own blood is applied to site of injection. Clotting takes place, seepage is inhibited or restricted, headache can be treated.

5. Hypotension may also occur as vasodilatation takes place. To correct it, raise foot ends of patient or introduce sympathomimetic
6. Cauda equina syndrome –damage to nerve roots takes place, most of motor activity of body is lost especially urinary and bowel activity.
7. Respiratory paralysis is rare, but can occur if paralysis of intercostal muscles occurs.

Esters	Amides
Ester linkage	amide linkage
Incomplete anesthesia	Complete anesthesia
Less PPB	More PPB
Less analgesia	More analgesia
Short acting	Long acting
Quickly hydrolyzed by pseudocholinesterases in plasma	Slowly hydrolyzed by cyp 450 in liver
More chances of hypersensitivity reactions	Less chances of hypersensitivity reactions
Less potent	More potent
Less distribution	Widely distributed
PABA analog	No PABA

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