Pharmacology of Local Anesthetics

History and Introduction of Local Anesthetics

Who is credited with introducing the first local anesthetic agent, cocaine?

Carl Koller, an ophthalmologist in Vienna, Austria, is given the credit for introducing cocaine as a local anesthetic.
He was the first person to start regional anesthesia. He was in search of an anesthetic that could act locally on the eye to avoid the post-operative nausea and vomiting and increased intraocular pressures caused by inhalation agents like ether and chloroform.

What role did Sigmund Freud play in the discovery of local anesthesia?

Sigmund Freud, a psychiatrist (father of psychiatry) and a close friend of Carl Koller in the same Vienna hospital, gave Koller the idea that cocaine could be used as a local anesthetic.
Freud was using cocaine himself and noticed that it produced numbness on his tongue, leading him to suggest its potential for local numbness to Koller.

How did Carl Koller first demonstrate the local anesthetic effect of cocaine?

Koller diluted cocaine powder, placed drops into his own eyes, and then touched his cornea with a sharp pin. He felt no pain, confirming its local anesthetic effect.

Who first introduced cocaine intrathecally, and who used it for the first spinal anesthesia?

William Corning, a physician, first introduced the concept of intrathecal use of cocaine. However, August Bier, a German surgeon, is credited with performing the first spinal anesthesia using cocaine in 1898.

What was the outcome for August Bier and his assistant after the first spinal anesthesia?

Both Bier and his assistant, Hildebrand, developed severe post-dural puncture headaches (PDPH) due to the large-bore, reusable needles used at the time, preventing them from celebrating the next day.

When were other key local anesthetics introduced?

Procaine: Introduced in 1903.
Chloroprocaine: Introduced in the 1930s.
Lidocaine (Lignocaine): Introduced in 1943 by Lofgren and Lundquist. It was the first amide local anesthetic.
Bupivacaine: Introduced in 1963 by Ekenstam.
Ropivacaine: Introduced in 1993.
Levobupivacaine: Introduced between 1997 and 1999.

Classification, Structure, and Chemistry of Local Anesthetics

What is the basic structure of a local anesthetic molecule?

A local anesthetic molecule consists of three parts: an aromatic ring (lipophilic/hydrophobic), an amine group (hydrophilic), and an intermediate link or chain connecting them.

How are local anesthetics classified based on their chemical structure?

They are classified into esters and amides based on the type of bond in the intermediate link.

Esters: Have an ester link (e.g., Cocaine, Procaine, Chloroprocaine, Tetracaine).
Amides: Have an amide link (e.g., Lidocaine, Bupivacaine, Ropivacaine, Levobupivacaine).

A simple way to distinguish them is by the number of 'i's in the name: esters typically have one 'i' (e.g., procaine), while amides have two 'i's (e.g., lidocaine).

How are local anesthetics classified based on their potency and duration of action?

Classification by Potency

Least Potent: Procaine, Chloroprocaine, Cocaine.
Intermediate Potency: Lidocaine, Prilocaine.
Highly Potent: Bupivacaine, Levobupivacaine, Ropivacaine, Tetracaine.

Classification by Duration of Action

Short-Acting: Procaine, Chloroprocaine.
Intermediate-Acting: Lidocaine.
Long-Acting: Bupivacaine, Levobupivacaine, Ropivacaine, Tetracaine.

What is the difference between bupivacaine and levobupivacaine?

Bupivacaine is a racemic mixture containing both dextro (R) and levo (S) enantiomers. Levobupivacaine is the pure S-enantiomer of bupivacaine.
The levo (S) isomer is associated with less cardiotoxicity than the dextro (R) isomer.

What is ropivacaine?

Ropivacaine is the pure S-enantiomer, making it a single isomer agent. This also contributes to its lower cardiotoxicity profile compared to racemic bupivacaine.

Mechanism of Action and Site of Action

Where do local anesthetics act on a nerve fiber?

Local anesthetics act primarily on the voltage-gated sodium channels located in the nerve cell membrane.

In myelinated fibers, these channels are highly concentrated at the Nodes of Ranvier.
In non-myelinated fibers, the channels are distributed continuously along the axon.

Where is the local anesthetic receptor located on the sodium channel, and why is this important?

The receptor for local anesthetics is located on the intracellular portion of the voltage-gated sodium channel.
This is important because it means the local anesthetic molecule must enter the axon (cross the membrane) to reach its site of action and produce a block.

Which form of a local anesthetic molecule can enter the axon, and which form actually causes the block?

The unionized (lipophilic) form of the molecule can cross the axonal membrane to enter the cell.
Once inside, the molecule often becomes ionized (hydrophilic), and it is this ionized form that binds to the receptor inside the sodium channel to produce the blockade.

Explain the different states of the voltage-gated sodium channel and how they relate to local anesthetic action.

The sodium channel has two gates: an outer M gate and an inner H gate. It exists in four states:

Resting State: M gate closed, H gate open. Sodium cannot enter. Unionized local anesthetics can still cross the membrane slowly.
Active/Open State: M gate opens, H gate is open. Sodium enters, causing depolarization. In this state, even ionized molecules can enter through the open channel.
Inactivated State: M gate open, H gate closed. Sodium entry stops, repolarization begins.
Deactivated State: M gate closed, H gate closed.

Local anesthetics have a higher affinity for the open and inactivated states, leading to a phenomenon called "use-dependent" or "phasic" block.

What is use-dependent (phasic) block?

Use-dependent block refers to the phenomenon where a local anesthetic's effect is enhanced when the nerve is frequently stimulated.
This is because stimulation causes sodium channels to spend more time in the open and inactivated states, where the anesthetic has a higher affinity for its receptor, allowing even ionized molecules to enter and block the channel more effectively.

Pharmacokinetics: Onset, Duration, and Potency

What is pKa and how does it affect the onset of action of a local anesthetic?

pKa is the pH at which 50% of the drug is in its ionized form and 50% is in its unionized form. The onset of action is faster when a larger percentage of the drug is in the unionized form at body pH (7.4), as this form can cross the nerve membrane.
The closer a drug's pKa is to 7.4, the more unionized molecules are available, leading to a faster onset. For example, Lidocaine (pKa 7.8) has a faster onset than Bupivacaine (pKa 8.1).

List the factors that influence the onset of action of local anesthetics.

pKa: The most important factor. A lower pKa closer to body pH results in a faster onset.
Concentration: Higher concentrations provide more molecules for diffusion, leading to a faster onset.
Additives/Preservatives: Agents that alter the pH of the solution can affect onset. Adrenaline (with sodium metabisulfite) lowers the pH, delaying onset. Adding sodium bicarbonate raises the pH, hastening onset.

How does the addition of adrenaline to a local anesthetic affect its onset and duration of action?

Onset: Adding adrenaline (which contains sodium metabisulfite as a preservative) makes the solution more acidic, lowering the pH. This decreases the proportion of unionized drug, leading to a delayed onset of action.
Duration: Adrenaline causes vasoconstriction at the injection site, which reduces vascular absorption of the local anesthetic. This keeps the drug localized longer, thereby prolonging its duration of action and reducing systemic toxicity.

How does adding sodium bicarbonate hasten the onset of a local anesthetic like lidocaine with adrenaline?

Adding sodium bicarbonate has multiple effects:

Increases pH: It raises the pH of the acidic local anesthetic solution (e.g., from 4.4 to near 7.4), increasing the proportion of unionized molecules available to penetrate the nerve membrane.
Ion Trapping: The bicarbonate converts to CO2, which easily diffuses into the axon. Inside the axon, it reforms carbonic acid, lowering the intracellular pH. This causes the local anesthetic molecules that entered (in unionized form) to become ionized and "trapped" inside, where they can bind to the receptor.

How is the correct amount of sodium bicarbonate to add to lidocaine calculated?

For 8.4% sodium bicarbonate, 1 ml contains 1 milliequivalent. To hasten the onset of lidocaine with adrenaline, you add 1 mEq (1 ml of 8.4% sodium bicarbonate) for every 10 ml of lidocaine.

What factors determine the duration of action of a local anesthetic?

Protein Binding: The most important factor. Higher protein binding (e.g., Bupivacaine 95%) leads to a longer duration of action, as the drug binds to proteins in the nerve membrane and tissues, creating a local depot.
Concentration Used: Higher concentrations generally result in a longer duration.
Vascularity of the Injection Site: More vascular sites (like intercostal spaces) lead to faster absorption into the bloodstream, shortening the duration of action. Less vascular sites (like subcutaneous tissue) result in a longer duration.

What is the mnemonic "BICEPS" used for, in relation to local anesthetics?

"BICEPS" is a mnemonic to remember the vascularity of different injection sites, which influences the rate of absorption and hence the duration of action and potential for toxicity.

B - Blood (IV) / endotracheal
I - Intercostal / Intrapleural
C - Caudal
E - Epidural
P - Peripheral (e.g., Brachial Plexus)
S - Sciatic / Femoral
S - Subcutaneous

The risk of toxicity is highest and duration shortest at the top of the list (Blood), and lowest and longest at the bottom (Subcutaneous).

What determines the potency of a local anesthetic?

Potency is primarily determined by lipid solubility. The more lipophilic a drug is, the more potent it tends to be. Lipid solubility numbers: Lidocaine (360), Ropivacaine (760), Bupivacaine (3620).

Clinical Pharmacology: Nerve Fiber Selectivity

How are nerve fibers classified, and what is the significance for local anesthetic action?

Nerve fibers are classified into A, B, and C fibers.

A fibers: Myelinated. Subdivided into A-alpha (motor, proprioception), A-beta (touch, pressure), A-gamma (muscle spindles), and A-delta (fast pain, cold temperature).
B fibers: Myelinated, preganglionic sympathetic fibers.
C fibers: Unmyelinated, responsible for slow visceral pain, warmth temperature, and ischemic pain.

Myelinated fibers (A and B) are generally more sensitive to local anesthetic block than unmyelinated fibers (C), which are relatively resistant.

What is the typical order of block for nerve fibers during spinal anesthesia?

The order of block, from first to last, is:

B fibers (Sympathetic): Blocked first, leading to vasodilation and potential hypotension.
A-delta fibers (Fast pain, Cold): Blocked next, leading to loss of cold sensation and sharp pain. This unmasks the sensation of warmth carried by unblocked C fibers.
A-gamma fibers (Muscle spindle tone)
A-beta fibers (Touch, Pressure, Proprioception)
A-alpha fibers (Motor): Blocked last.
C fibers (Slow pain, Warmth): Most resistant, blocked last, if at all.

What is the clinical significance of C fibers being resistant to local anesthetics?

C fibers carry visceral pain (e.g., from surgical stretching of organs) and are resistant to local anesthetics. This explains why a patient under spinal anesthesia might still feel a vague, sickening sensation or pain during visceral manipulation, even with good somatic block.

What class of drugs is highly effective at blocking C fibers?

Opioids are very effective at blocking the sensation carried by C fibers. This is the basis for combining opioids (like fentanyl) with local anesthetics in neuraxial anesthesia to improve the quality of the block, especially for visceral pain, and allows for the use of lower local anesthetic concentrations.

What is the order of recovery from a local anesthetic block, and why is it clinically important?

Recovery occurs in the reverse order of blockade. C fibers recover first, followed by motor fibers (A-alpha), then touch, and finally sympathetic fibers (B fibers) recover last. This is clinically important because even after a patient has regained motor function and can feel pain, a significant sympathetic block may still be present.
Moving the patient at this stage can cause a severe, sudden fall in blood pressure due to residual vasodilation.

Metabolism, Excretion, and Toxicity Considerations

How are ester and amide local anesthetics metabolized?

Esters (except Cocaine): Metabolized by pseudocholinesterase in the plasma.
Amides (except Articaine): Metabolized in the liver by phase 1 and phase 2 reactions.
Cocaine: An ester metabolized in the liver.
Articaine: An amide metabolized in the plasma.

Why are ester local anesthetics more likely to cause allergic reactions than amides?

The primary metabolite of ester local anesthetics is para-aminobenzoic acid (PABA). PABA is known to be a potential allergen and can cause allergic or anaphylactic reactions. True allergic reactions to amide local anesthetics are rare and are often caused by preservatives like methylparaben or propylparaben, which are chemically similar to PABA.

What is the role of alpha-1 acid glycoprotein in local anesthetic action?

Alpha-1 acid glycoprotein is the primary plasma protein that binds to local anesthetics. The degree of protein binding affects the drug's duration and the amount of free, active drug. Conditions that alter levels of this protein can affect drug toxicity. For example:

Neonates/infants: Lower levels, leading to more free drug and higher risk of toxicity.
Liver disease: Lower synthesis, leading to more free drug and higher risk of toxicity.
Pregnancy: Dilutional effect, leading to more free drug.
Burn patients: Higher levels, potentially reducing free drug.

Why is 5% hyperbaric lidocaine no longer commonly used for spinal anesthesia?

5% lidocaine was associated with a higher incidence of transient neurological symptoms (TNS), a form of direct nerve root toxicity. Due to these concerns, its use for spinal anesthesia has been largely abandoned since the early 2000s.

Preparations and Clinical Uses of Lidocaine

Why are there different concentrations of lidocaine for different clinical uses?

Different concentrations are used to achieve specific clinical effects for different routes of administration and tissue types. For example, a lower concentration is sufficient for infiltration, while a higher concentration is needed for topical application to penetrate mucous membranes.

List the various preparations and concentrations of lidocaine available.

Infiltration: 0.5%, 1%, 2% solutions.
Peripheral Nerve Blocks/Epidural: 1%, 2% solutions (often with adrenaline 1:200,000).
Topical (Spray): 10% solution.
Topical (Ointment): 5% ointment.
Topical (Jelly): 2% jelly (e.g., for urethral lubrication).
Topical (Patch): 5% patch.
Viscous (Oral): 2% viscous solution.
Intrathecal (Spinal): 5% hyperbaric solution with 7.5% dextrose (now rarely used due to TNS).
Intravenous: 2% preservative-free solution (for IV regional anesthesia or as an antiarrhythmic).
Dental: 2% with 1:80,000 adrenaline for enhanced vasoconstriction in the highly vascular oral mucosa.

Sympathetic Nervous System and Spinal Anesthesia

Sympathetic Outflow

What is the sympathetic outflow from the spinal cord?

The sympathetic nervous system is also known as the thoracolumbar outflow. It extends from the T1 segment to the L2 segment of the spinal cord.
Sympathetic fibers emerge from the anterolateral part of the spinal cord.
They move up to form ganglia like the stellate ganglion,
middle cervical sympathetic ganglion, and superior cervical sympathetic ganglion, supplying areas like the face.

What is the difference between sympathetic and parasympathetic outflow?

Sympathetic outflow is thoracolumbar (T1 to L2).
Parasympathetic outflow is craniosacral: cranial (via the vagus nerve) and sacral (S2, S3).

Horner's Syndrome and Sympathetic Block

What is Horner's syndrome?

Horner's syndrome is caused by a sympathetic block.
Symptoms include anhydrosis (loss of sweating), flushing, and warmth on the affected side of the face.

Why don't we typically see Horner's syndrome after a spinal block for a Cesarean section, even though a T4 block causes a total sympathectomy?

In a spinal block, the sympathetic block can extend up to T1, causing a total sympathetic block.
Horner's syndrome is usually not observed because the block is bilateral.
Since it occurs on both sides simultaneously, there is no contralateral side to compare it to, making the signs difficult to detect.

Lidocaine: Preparations and Concentrations

Why are there different concentrations of lidocaine for different routes of administration?

The concentration varies based on the route of administration and the required tissue penetration.
Higher concentrations are needed for routes with unreliable absorption, such as on mucosa, to ensure an effective dose reaches the nerve endings.

What are the concentrations of various lidocaine preparations and their uses?

10% Spray: Used for topical anesthesia of mucosa. One puff delivers 0.1 ml, containing 10 mg of lidocaine.
4% Topical: For application on mucosa.
2% Jelly: Used by urologists for urethral anesthesia. The lower concentration (2%) ensures safety even if a large volume is absorbed from the inflamed urethra.
5% Ointment: Used for anal fissures. A higher concentration is needed for penetration through mucosa and possible fecal matter.
5% Hyperbaric (Intrathecal): For spinal anesthesia. A high concentration allows for a small volume (1.5-2 ml) to deliver the required mass of drug (75-100 mg) without increasing intrathecal volume.
2% (with adrenaline): Used as a test dose for epidurals to rule out intrathecal placement.
1% or 2%: For infiltrative anesthesia and nerve blocks like brachial plexus blocks.
Viscous 2%: Used for oral cavity anesthesia, swished and spit out to anesthetize the anterior tongue and oral cavity.
4%: For airway blocks like transtracheal block.
1% (with adrenaline): For individual nerve blocks like superior laryngeal or glossopharyngeal nerve blocks.
5% Patch: For local anesthesia, requiring a high concentration to penetrate the skin.
0.5%: For Intravenous Regional Anesthesia (IVRA or Bier's block).

How do you calculate the drug amount from a percentage concentration?

1% means 1 gram in 100 ml.
10% means 10 grams in 100 ml.
10 grams = 10,000 mg in 100 ml, so 1 ml of a 10% solution contains 100 mg (10,000 mg / 100 ml).
Therefore, 5% lidocaine means 50 mg in 1 ml. To give 100 mg, you would administer 2 ml.
2% lidocaine means 20 mg in 1 ml. To give a 60 mg test dose, you administer 3 ml.

Why is a 5% concentration used for spinal anesthesia instead of a lower percentage like 1%?

The goal in spinal anesthesia is the mass of the drug (e.g., 75-100 mg of lidocaine), not the volume.
Using a 5% solution allows this mass to be delivered in a small volume (1.5-2 ml).
If a 1% solution were used, 10 ml would be needed to deliver the same 100 mg, which would unnecessarily increase the intrathecal volume.

Lidocaine: Clinical Applications and Dosing

What is a test dose in epidural anesthesia and why is it used?

A test dose is used to rule out accidental intrathecal or intravascular placement of an epidural catheter.
For non-pregnant patients, 3 ml of 2% lidocaine with adrenaline (60 mg) is used.
If injected intrathecally, this dose is sufficient to produce a motor block, indicating malposition.

How does the test dose for an epidural differ in pregnant patients?

In pregnant patients, the dose required to produce a motor block is lower (45 mg) due to factors like increased progesterone levels, higher neuronal sensitivity, and reduced CSF volume.
Therefore, a test dose of 3 ml of 1.5% lidocaine with adrenaline is used.

What are the non-local anesthetic uses of lidocaine?

Lidocaine has several other important uses:

Anti-arrhythmic (Class 1B): It is a sodium channel blocker used to treat ventricular ectopics (VPCs) to prevent ventricular tachycardia/fibrillation.
Bronchodilator: For resistant bronchospasm, given intravenously for its membrane-stabilizing effect on bronchial smooth muscle.
Pre-induction agent: To suppress the sympathetic response to laryngoscopy and intubation, and to reduce the pain of propofol injection.
Component of Opioid-Free Anesthesia (OFA): Used as an IV infusion for its analgesic properties, both intraoperatively and postoperatively.
Chronic Pain Management: As IV infusions or 5% patches for conditions like post-herpetic neuralgia.
Test for Hepatic Blood Flow: By measuring the metabolite MEGX after lidocaine injection.

What is the role of lidocaine in Opioid-Free Anesthesia (OFA)?

In opioid-free anesthesia, lidocaine is used to provide analgesia.
It is given as a loading dose of 1-1.5 mg/kg before intubation, followed by a continuous infusion (e.g., 15-20 mcg/kg/min or 1 mg/kg/hr), often continued into the postoperative period for pain management.

What is the dosage regimen for lidocaine as an anti-arrhythmic agent?

Loading dose: 1-1.5 mg/kg IV bolus (given slowly).
Infusion: To maintain a therapeutic plasma concentration of 2-3 mcg/ml, a specific tapering infusion is used:
- First 20 minutes: 60 mcg/kg/min
- Next 2 hours: 30 mcg/kg/min
- Subsequently: 15 mcg/kg/min
This is often continued for 12-18 hours while the underlying cause is addressed.

What is the maximum safe dose of lidocaine?

Adults:
- Plain: 3 mg/kg
- With Adrenaline: 7 mg/kg
Children:
- Plain: 5 mg/kg
- With Adrenaline: 10 mg/kg

Higher doses can be used in specific techniques like tumescent anesthesia due to the low concentration and vasoconstriction.

What is tumescent anesthesia and why can such a high dose of lidocaine be used?

Tumescent anesthesia is used in procedures like liposuction.
Large volumes of a very low concentration of lidocaine (0.05%) with epinephrine are injected subcutaneously.
The large volume compresses blood vessels, and the epinephrine causes vasoconstriction, which together dramatically slow systemic absorption, preventing toxic plasma levels even with total doses of 35-50 mg/kg.

Lidocaine: Metabolism and EMLA Cream

What is the primary metabolite of lidocaine and why is it important?

The primary metabolite is Monoethylglycinexylidide (MEGX).
It is important because:

80% of lidocaine's antiarrhythmic effect is attributed to MEGX.
Measuring MEGX levels after a lidocaine bolus can be used as a test to assess hepatic blood flow, as lidocaine is rapidly metabolized in the liver (first-order kinetics).

What is EMLA cream and how does it work?

EMLA stands for Eutectic Mixture of Local Anesthetics.
It is a 1:1 mixture of 2.5% lidocaine and 2.5% prilocaine.
When mixed, they form a eutectic mixture with a melting point of 18°C, which is below room temperature.
This allows both drugs to be in a liquid state and easily mixed to form a cream.
It is applied under an occlusive dressing for 45-60 minutes to anesthetize the skin to a depth of about 5 mm.

Does EMLA cream cause vasoconstriction or vasodilation?

EMLA cream initially causes local vasoconstriction.
However, after about one hour of application, it produces vasodilation.
Therefore, it is recommended to apply it for a full hour and then remove it before cannulation to benefit from the vasodilation.

Long-Acting Local Anesthetics: Bupivacaine, Ropivacaine, and Levobupivacaine

What are the common preparations of Bupivacaine, Ropivacaine, and Levobupivacaine?

Bupivacaine: Available as 0.25%, 0.5%, and heavy 0.5% with 8% dextrose for intrathecal use.
Ropivacaine: Available as 0.2%, 0.5%, 0.75%, and 1%. For intrathecal use, it is available as 0.5% and 0.75%. It is 1.5 times less potent than bupivacaine.
Levobupivacaine: Available as 0.25%, 0.5% for infiltration, and 0.5% isobaric or 0.5% heavy with 8% dextrose for intrathecal use. It is equipotent to bupivacaine.

What are the advantages of Ropivacaine over Bupivacaine?

Less Motor Block: Due to its lower lipophilicity, it provides better sensory blockade with less motor blockade, making it ideal for labor analgesia.
Reduced Cardiotoxicity: It is the S-enantiomer, which is associated with significantly less cardiotoxicity than the racemic mixture (bupivacaine).

When is isobaric Levobupivacaine particularly useful?

Isobaric levobupivacaine is useful for lower limb and orthopedic surgeries.
Because it is isobaric, it does not move significantly within the CSF, remaining near the injection site.
This results in a lower level of block (e.g., up to T10) and a prolonged duration of anesthesia, which is beneficial for longer procedures.

What are the maximum safe doses for long-acting local anesthetics?

Bupivacaine: 2 mg/kg
Levobupivacaine: 3 mg/kg
Ropivacaine: 3 mg/kg

Adrenaline as an Adjuvant

What are the advantages of adding adrenaline to a local anesthetic?

There are five key advantages:

Prolongs Duration of Block: By causing local vasoconstriction, it reduces the systemic absorption of the local anesthetic, keeping it at the nerve site longer.
Reduces Surgical Bleeding: Local vasoconstriction decreases blood loss in the surgical field.
Decreases Systemic Toxicity: Slower absorption means lower peak plasma concentrations, allowing for the use of higher, safer total doses.
Enhances Blockade: Adrenaline's alpha-2 agonistic property can produce direct analgesia and enhance the nerve block by acting on C-fibers.
Serves as a Marker for Intravascular Injection: If accidentally injected into a blood vessel, the adrenaline causes a rapid increase in heart rate and blood pressure, alerting the clinician.

Adjuvants in Neuraxial and Regional Anesthesia

What are common adjuvants used with local anesthetics besides adrenaline?

Opioids: Morphine is the gold standard for neuraxial use due to its hydrophilicity, providing prolonged analgesia. Fentanyl is a shorter-acting option.
Alpha-2 Agonists (Clonidine, Dexmedetomidine): Enhance analgesia and prolong block duration.
Dexamethasone: Used particularly in peripheral nerve blocks (e.g., brachial plexus) to significantly prolong the duration of both motor and sensory blockade, sometimes up to 24 hours.

What are the typical neuraxial doses for common adjuvants?

Intrathecal Morphine: 100 mcg (for the Indian population, due to higher sensitivity to respiratory depression).
Epidural Morphine: 2-4 mg bolus.
Intrathecal Fentanyl: 15-25 mcg.
Intrathecal Clonidine: 30 mcg.
Epidural Clonidine (e.g., caudal): 3 mcg/kg.
Intrathecal Dexmedetomidine: 5-10 mcg.
Epidural Dexamethasone: 4-8 mg.

Local Anesthetic Systemic Toxicity (LAST)

What is the CC/CNS ratio and why is it important?

The CC/CNS ratio is the ratio of the plasma concentration of a local anesthetic that causes cardiovascular collapse to the concentration that causes CNS toxicity.
A higher ratio indicates a greater margin of safety, as CNS symptoms (which serve as an early warning) will appear well before life-threatening cardiac toxicity.

Lidocaine: Ratio of ~7 (high safety margin).
Bupivacaine: Ratio of 2-3 (narrow safety margin, highly cardiotoxic).
Ropivacaine/Levobupivacaine: Ratio of ~5 (intermediate safety).

Why is bupivacaine more cardiotoxic than lidocaine?

This is explained by the "fast-in, fast-out" vs. "fast-in, slow-out" theory on cardiac sodium channels.
Lidocaine blocks the channel but rapidly dissociates during diastole ("fast-out").
Bupivacaine blocks the channel but dissociates very slowly ("slow-out"), leading to a prolonged and profound block of cardiac conduction.
This effect is exaggerated during tachycardia because the shorter diastole allows even less time for the drug to dissociate.

What patient factors increase the risk of LAST?

Extremes of age (neonates and elderly):
- Neonates: Low levels of alpha-1 acid glycoprotein, immature liver enzymes, low muscle mass for sequestration, and high cardiac output.
- Elderly: Reduced liver function (homeostenosis) and sarcopenia (decreased muscle mass).
Pregnancy: Low alpha-1 acid glycoprotein, increased cardiac output, and increased progesterone (which sensitizes sodium channels).
Liver disease: Impaired metabolism of amide local anesthetics.
Acidosis:
Burn patients:

Besides patient factors and drug type, what other factors influence the risk of LAST?

Route of administration: The BIER (Biceps-Intercostal-Epidural-Rectus sheath) mnemonic highlights highly vascular areas with rapid absorption:
- Blood (Intercostal/Interpleural)
- Intercostal
- Epidural (Caudal)
- Rectus sheath/Paravertebral/Sciatic/Femoral
Rate of administration: Rapid injection can lead to a sudden, high peak plasma concentration.
Site of injection: Highly vascular areas lead to rapid absorption.
Method of administration: Continuous infusions can lead to cumulative toxicity over time.
Accidental intravascular injection: Even a small dose can be immediately toxic.

Local Anesthetic Pharmacology: Nerve Blockade, Toxicity, and Clinical Application

Nerve Fiber Blockade by Local Anesthetics

What determines the onset of a nerve block?

The onset of a block depends on which nerve fibers are first involved.
Usually, the first fibers involved are the myelinated fibers,
specifically the B fibers and A delta fibers. They have the same thickness
and conduction velocity. Because of this, the first effects seen are
hypotension and fine pain.

What is the typical order in which different nerve fiber functions are blocked?

The order of block is:

First (Blocked): B fibers and A delta fibers - resulting in hypotension and fine pain sensation loss.
Next: Beta fibers - leading to loss of touch sensation and proprioception.
Then: A alpha fibers - causing motor paralysis.
Last (Blocked): C fibers - which carry visceral and ischemic pain sensations.

Why are C fibers blocked last by local anesthetics?

C fibers are non-myelinated. For a non-myelinated fiber to be blocked,
a sufficient length of the fiber must be exposed to the local anesthetic.
In contrast, for myelinated fibers, blocking only two or three Nodes of Ranvier
is enough to stop impulse conduction. This is the reason C fibers
are the most resistant and are blocked last.

What is the clinical significance of C fibers being blocked last?

C fibers carry visceral sensation (vague pain from organs like in appendicitis)
and ischemic pain. Because they are resistant to local anesthetics,
a patient under regional anesthesia might still feel pain from deep visceral structures,
which is a phenomenon known as "epidural sieve" or "spinal sieve."

What is the order of recovery from a local anesthetic block?

Recovery occurs in the reverse order of blockade:

First to recover: C fibers (visceral sensation).
Next: Motor fibers (A alpha).
Then: Touch and proprioception (A beta).
Last to recover: A delta and B fibers.

Does the order of fiber blockade differ between spinal, epidural, or peripheral nerve blocks?

No, there is not much of a difference. The order in which fibers are blocked
is generally the same regardless of whether you administer spinal anesthesia,
epidural anesthesia, or peripheral nerve blocks.

The "Epidural Sieve" Phenomenon

What is "epidural sieve" or "spinal sieve"?

Epidural or spinal sieve refers to a clinical situation where,
despite an effective regional block, a patient can still feel visceral pain.
This is because local anesthetics are not very effective at blocking C fibers
unless enough opioids are also given. This allows visceral pain signals
to "pass through" the block.

Can you provide a clinical example of epidural sieve?

Consider a patient under labor epidural analgesia who develops a rupture of the uterus,
or a patient under spinal anesthesia for a TURP who experiences a bladder perforation.
In both cases, everything was fine with good analgesia.
Suddenly, the patient develops very severe pain, and in the case of bladder perforation,
may also feel shoulder pain due to diaphragmatic irritation.
This sudden increase in pain is a warning sign that a visceral structure
may have been compromised, and the sensation is breaking through the anesthetic block.

Local Anesthetic Systemic Toxicity (LAST)

What is the incidence of Local Anesthetic Systemic Toxicity (LAST)?

When ultrasound is not used, the incidence is about 1 in 1,000 anesthetics.
Even with the use of ultrasound, the risk is still present at about 1 in 1,600,
as it can be difficult to always know the exact location of the needle tip.

Why is bupivacaine more cardiotoxic than lidocaine?

Both drugs block voltage-gated sodium channels in the heart's conduction system.
The key difference is their binding kinetics.
Bupivacaine is described as "fast in, slow out" – it rapidly blocks the channels
but dissociates very slowly.
Lidocaine is "fast in, fast out" – it rapidly associates and rapidly dissociates.
Bupivacaine's prolonged channel blockade can lead to conduction blockade and re-entry phenomena,
which can cause life-threatening ventricular arrhythmias like tachycardia and fibrillation.

Why is levobupivacaine less cardiotoxic than bupivacaine?

Bupivacaine is a racemic mixture of both dextrorotatory and levorotatory isomers.
The dextro isomer is the one responsible for the cardiotoxic effects (the "fast in, slow out" phenomenon).
Levobupivacaine and ropivacaine consist only of the levorotatory isomer,
making them less cardiotoxic than bupivacaine. However, they are still more cardiotoxic than lidocaine.

What does the term "CCNS ratio" mean?

CCNS ratio stands for the ratio of the drug concentration that causes
Cardiovascular Collapse (CC) to the concentration that causes Central Nervous System (CNS) toxicity.
A wide ratio means the drug is safer, as a much higher dose is needed for cardiac effects
compared to CNS effects. A narrow ratio indicates a more dangerous drug.

What are the CCNS ratios for lidocaine, bupivacaine, and ropivacaine?

Lidocaine: 7 (widest, safest).
Ropivacaine: 5 (intermediate).
Bupivacaine: 3 (narrowest, most dangerous).

What are the maximum safe doses for common local anesthetics in adults?

Lidocaine: 3 mg/kg without adrenaline, 7 mg/kg with adrenaline.
Bupivacaine, Levobupivacaine, Ropivacaine: 2-3 mg/kg. It is safer to be on the lower side (2 mg/kg). The dose is the same with or without adrenaline.

Why is adrenaline not routinely added to long-acting local anesthetics like bupivacaine?

Adrenaline is added to lidocaine (an intermediate-acting agent) to prolong its duration of action.
Long-acting drugs like bupivacaine are already long-acting, so adding adrenaline does not further prolong the block.
In some cases, like in pediatric caudal epidurals, adrenaline (1 in 200,000)
may be added to bupivacaine not to prolong the block, but to reduce the rate of absorption and thus decrease systemic toxicity.

If you mix two local anesthetics, how should you calculate the maximum safe dose?

The toxicity of local anesthetics is additive. Therefore, when combining two drugs,
you cannot use the maximum safe dose of each. You should reduce the maximum safe dose of each drug by 50%.
For example, if combining lidocaine and bupivacaine, you would calculate a maximum of
3.5 mg/kg for lidocaine and 1 mg/kg for bupivacaine.

Is it better to mix two local anesthetics in the same syringe or give them separately?

It is better to give them separately. Mixing them in the same syringe or galley pot
has been shown to delay the onset of action and shorten the duration of the block,
which defeats the purpose of combining a fast-onset drug with a long-acting drug.
There may also be unknown physical or chemical reactions when mixing.

Why is the rate and method of injection important in preventing LAST?

Injecting rapidly increases the risk of LAST for two main reasons:

It can lead to faster absorption of the drug into the bloodstream.
If the needle tip is inadvertently in a blood vessel, a rapid injection will deliver a large, toxic dose directly into the circulation.

Therefore, local anesthetics should always be injected slowly and in incremental doses.

Which patient groups are at a higher risk for LAST?

Several patient groups are at increased risk:

Neonates/Pediatrics: Due to lower levels of alpha-1 acid glycoprotein (the main binding protein), smaller muscle mass for drug sequestration, higher cardiac output, and faster heart rates (shorter diastole for drug dissociation from cardiac channels).
Elderly: Due to sarcopenia (reduced muscle mass for storage), lower alpha-1 acid glycoprotein levels (homeostenosis), and decreased hepatic metabolism.
Pregnant Women: Due to increased neuronal sensitivity from progesterone, a 50% increase in cardiac output (leading to faster absorption), and a dilutional decrease in alpha-1 acid glycoprotein. A 30% dose reduction is recommended.
Liver Disease: Impaired metabolism of amide local anesthetics.
Cardiac Disease: Patients are already more prone to arrhythmias.
Renal Disease: Metabolic acidosis, common in renal failure, decreases protein binding of local anesthetics, increasing the free fraction.

What is the safe dose for lidocaine in tumescent anesthesia?

In tumescent anesthesia, much higher doses of lidocaine (30 to 50 mg/kg) can be used safely.
This is because the lidocaine is highly diluted (e.g., 0.05%), used with epinephrine,
and injected into the subcutaneous plane where the large volume constricts vessels,
minimizing absorption and keeping blood concentrations very low (1-2 mcg/ml).

What are the symptoms of Local Anesthetic Systemic Toxicity (LAST) as plasma concentration rises?

As the plasma concentration of lidocaine increases, the symptoms progress:

2-3 mcg/ml: Therapeutic/antiarrhythmic concentration.
>5 mcg/ml (CNS Toxicity - Excitatory Phase): Anxiety, restlessness, disorientation, circumoral numbness, muscle twitching, and tremors.
>10 mcg/ml (CNS Toxicity - Depressive Phase): Generalized tonic-clonic convulsions.
>15 mcg/ml (Cardiac Toxicity): Arrhythmias, which can be followed by unconsciousness and coma.

Why does the excitatory phase of CNS toxicity occur first?

Local anesthetics block inhibitory pathways in the brain first.
The higher cortical centers normally exert a controlling influence over lower excitatory centers.
When these higher centers are selectively depressed by a low concentration of local anesthetic,
this control is lost, and the lower excitatory centers become unopposed,
leading to excitatory symptoms. As the concentration increases further,
the excitatory centers themselves become depressed, leading to the depressive phase.

Local Anesthetic Systemic Toxicity (LAST)

Phases and Symptoms of LAST

What are the three phases of local anesthetic systemic toxicity?

The toxicity can be described in three phases: early phase, intermediate phase, and terminal phase.

In the early phase, immediately the patient may develop some amount of hypotension and tachycardia,
or sometimes even hypertension and tachycardia because of the excitatory CNS phase.
The intermediate phase involves hypotension and bradycardia.
The terminal phase includes all kinds of dysrhythmias, including myocardial depression, severe hypotension,
and fatal dysrhythmias, and the patient can develop cardiac arrest.

How can the progressive toxicity of lidocaine be remembered?

It is usually remembered as: 5-10 micrograms for CNS effects, 15 micrograms for respiratory arrest
(because all the muscles will paralyze), and 25 micrograms for cardiac arrest.
However, this same pattern may not occur with bupivacaine, which can have very rapid cardiac toxicity.

What is the typical order of symptom presentation in LAST?

It is always the CNS symptoms and signs that will be the first to appear.
This allows you to immediately stop injecting the drug.
If you are injecting and suddenly the patient has a convulsion, you can stop the drug to prevent the cardiac toxicity.
Later, cardiac toxicity and even cardiac arrest can occur.

Prevention of LAST

What are the pre-procedural methods to prevent LAST?

Patient Evaluation: Examine the patient to see if they have cardiac, hepatic, or renal disease.
Patients with renal disease may have metabolic acidosis and hyperkalemia, which can cause them to develop dysrhythmias and cardiac toxicity very early.
IV Line: Always have a proper IV line so that if a loss occurs, you can give drugs and manage the patient.
Monitoring: Continuous cardiac monitoring is very important to recognize prolongation of PR, QT, and QRS intervals, as well as any tachycardia that occurs.
Resuscitative Equipment: Keep all resuscitative equipment ready, including a defibrillator, lipid emulsion 20%, anti-arrhythmic drugs, and drugs to manage hypotension and convulsions.
You must be ready to intubate and ventilate the patient.

What are the intra-procedural methods to prevent LAST?

Dosage: Calculate the maximum dose and do not give more than that.
Aspiration: Keep aspirating every 2 to 3 minutes (every 3-4 ml) to ensure you are not inside a blood vessel.
Slow Injection: Inject slowly.
Incremental Injection: Especially for epidurals, do not use more than 5 ml increments.
Do not keep a 10 ml syringe on your tray for injecting the drug; use a 5 ml syringe and give 5 ml increments.
This allows you to observe the patient between doses.
Continuous Monitoring/Observation: Constantly observe and communicate with the patient.
If you suddenly lose communication, it may indicate LAST.
Test Dose: Use a test dose (e.g., 3 ml of lidocaine with adrenaline) and monitor for tachycardia (or blood pressure response in patients on beta-blockers) to rule out intravascular placement.

Why is it important to give local anesthetics in incremental doses?

Incremental injection is very important to prevent LAST.
For example, if your catheter is intravascular and you give a 5 ml increment, you will know immediately if the patient reacts.
If you had injected 10 ml all at once, the patient might have more severe CNS toxic symptoms or even go straight into convulsions.

Why might a test dose of lidocaine with adrenaline not cause tachycardia?

If the patient is on a beta-blocker, the adrenaline (15 micrograms) will not produce a tachycardia response.
In such patients, you must look for a blood pressure response instead.
With beta-blockade, the alpha effect of adrenaline predominates, causing peripheral vasoconstriction and a 10-15 mmHg increase in systolic pressure.

What are post-procedural preventive measures?

Post-procedure monitoring is very important.
Even if the initial injection was in the correct location, continuous absorption can gradually lead to a toxic concentration.
If using a continuous catheter infusion, your job is not over once the surgery is over.
Continuous monitoring of the patient in the post-operative period is essential.

What is the disadvantage of giving a benzodiazepine like midazolam before a block?

While midazolam can reduce patient anxiety and may prevent seizures (CNS toxicity), the disadvantage is that it increases the seizure threshold.
In case of severe toxicity, you might not see any CNS symptoms, and the patient could directly progress to cardiac toxicity.

Management of LAST

What are the immediate steps once LAST occurs?

Call for help.
Stop injecting the local anesthetic.
Manage the airway and breathing: secure the airway and oxygenate the patient with 100% oxygen.
This is crucial to prevent hypoxia, hypercarbia, and acidosis, which increase the free concentration of the local anesthetic.
Support circulation.

Why is it important to secure the airway and ventilate a patient having seizures from LAST?

During convulsions, oxygen demand increases tremendously, but the patient may have laryngospasm, preventing adequate breathing.
This leads to hypoxia and hypercarbia, which decrease the association between local anesthetic molecules and alpha-1 acid glycoprotein.
This increases the free concentration of the drug, worsening toxicity.
Acidosis (both respiratory and metabolic) also releases more free molecules.
Ventilation prevents these issues.

How should convulsions from LAST be managed?

Benzodiazepine: Midazolam is the drug of choice as it is cardioprotective or has minimal cardiac depressant effects.
Thiopentone (1 mg/kg) can also be used.
Propofol should be avoided because it can cause further cardiac depression in a situation where cardiac toxicity is already occurring.
Muscle Relaxant: If the patient is convulsing and you cannot intubate due to laryngospasm, a fast-acting muscle relaxant like succinylcholine (1 mg/kg) can be given rapidly to stop convulsions and allow for intubation and ventilation.

What is the specific treatment for bupivacaine-induced LAST?

Lipid emulsion (20%) is the specific treatment.
It should be readily available in every OT and labor room where local anesthetics are used.

What is the dose and administration method for lipid emulsion?

Bolus: 1.5 ml/kg (e.g., about 100 ml for a 70 kg patient) pushed rapidly over 2-5 minutes.
Infusion: Followed by an infusion of 0.25 ml/kg/min for 10 minutes.
Repeat: If there is no improvement, you can give another bolus of 1.5 ml/kg and then continue or increase the infusion (0.5 ml/kg/min).
Maximum Dose: Do not exceed 12-15 ml/kg.

How does lipid emulsion work in treating LAST?

It works through several mechanisms:

Lipid Sink Theory: The lipid emulsion acts as a "sink" in the blood.
Local anesthetic molecules bind to the lipid, drastically decreasing the free concentration in the blood.
This creates a concentration gradient, pulling the molecules away from the heart (where they are bound to sodium channels) and into the plasma, where they are sequestered by the lipid.
Metabolic Support: LAST, especially with bupivacaine, inhibits mitochondrial function and fatty acid metabolism within cells.
Supplying extra lipids improves mitochondrial activity and intracellular lipid metabolism.

What is the required monitoring after successful treatment of LAST?

Continuous monitoring is required for a minimum of 12 to 18 hours after the patient has come out of toxicity.

Allergic Reactions to Local Anesthetics

Which local anesthetics are more prone to cause anaphylaxis?

Ester local anesthetics (like cocaine and procaine) are more prone to cause anaphylaxis because they metabolize to PABA (para-aminobenzoic acid).
Amides are very rare causes of true anaphylaxis.
However, many amide preparations contain preservatives like methylparaben and propylparaben, which are converted to PABA and can cause reactions.
If an amide allergy is suspected, a preservative-free amide local anesthetic should be used.

How is an allergy test for local anesthetics performed?

Dose: 0.1 ml of 1% lidocaine or 0.05 ml of 2% lidocaine.
Route: It should be given intradermally to raise a wheal.
Observation: Wait for 15-20 minutes.
Positive Reaction: A positive reaction is a wheal with a perimeter of erythema more than 5 mm in width around the existing wheal.

Methemoglobinemia

Which local anesthetics are notorious for causing methemoglobinemia?

Prilocaine and benzocaine are notorious for causing methemoglobinemia.
Benzocaine has a very low pKa (3.5), meaning most of the drug is unionized and rapidly enters the mucosa, but it can cause severe methemoglobinemia, which limits its use.

What is the difference between hemoglobin and methemoglobin?

The difference is in the state of the iron.
In normal hemoglobin, the iron is in the ferrous state (Fe2+).
In methemoglobin, the iron is oxidized to the ferric state (Fe3+), which cannot bind to oxygen.

How does methemoglobinemia affect a pulse oximeter reading?

Methemoglobin absorbs equal amounts of red (660 nm) and infrared (940 nm) light.
A standard pulse oximeter measures the ratio of absorption of these two wavelengths.
When the ratio is 1 (equal absorption), the oximeter displays a saturation fixed at around 85%, regardless of the true severity of the methemoglobinemia.
To accurately measure methemoglobin levels, a co-oximeter (multi-wavelength pulse oximeter) is required.

How is methemoglobinemia treated?

If methemoglobin levels are above 10-15%, it is treated with methylene blue.
The dose is 1 mg/kg.
Methylene blue is typically available as a 1% solution, meaning each ml contains 10 mg.
For a 60 kg patient requiring 60 mg, you would administer 6 ml of the 1% solution.

Total Spinal Anesthesia

What is total spinal anesthesia and why does it happen?

Total spinal anesthesia occurs when a large dose of local anesthetic, intended for the epidural space, is inadvertently injected into the intrathecal space.
Because the subarachnoid space is in continuation with the brain, the large volume of drug can reach the brainstem, causing loss of consciousness, total muscle relaxation, respiratory arrest, and severe hypotension.
This does not happen with epidural injection because the epidural space does not continue into the cranium.

How is total spinal anesthesia managed?

Management follows the ABCs:

Secure the airway and intubate the patient.
Connect the patient to mechanical ventilation.
Manage hypotension with IV fluids and vasopressors.
Treat bradycardia if it occurs.

The patient will remain anesthetized until the drug effect wears off, and must be ventilated until then.

What is a subdural block and how does it differ from a total spinal?

A subdural block occurs when the catheter is placed in the potential space between the dura mater and the arachnoid mater.
The subdural space is in continuation with the cranial subdural space.
Unlike an immediate total spinal from intrathecal injection, a subdural placement can produce a "slow" total spinal, with symptoms appearing after about 20-25 minutes as the drug slowly reaches the brain.

Other Local Anesthetic-Related Syndromes

What is Cauda Equina Syndrome?

Cauda Equina Syndrome is a rare complication associated with continuous spinal anesthesia, especially with the use of lidocaine.
It involves damage to the lumbar and sacral nerve roots, leading to paraplegia and loss of bladder and bowel control.

What is Anterior Spinal Artery Syndrome?

Anterior Spinal Artery Syndrome is caused by compromised blood flow in the anterior spinal artery, which supplies the anterior two-thirds of the spinal cord.
It can be caused by severe intraoperative hypotension or by the use of vasoconstrictors like epinephrine intrathecally.
Patients present with paraplegia and loss of pain and temperature sensation, but with preservation of proprioception and touch (dorsal column function).