Local Anesthetics: Types and Uses

Local Anesthetics Definition

• Drugs that cause loss of sensation in a localized area when directly applied to nerve tissue or mucous membranes.

Desirable Characteristics

• Fast onset of action is needed
• Should provide brief, reversible blockade of nerve conduction
• Needs to be effective on all parts of the nervous system and all nerve fibers
• Should have a low degree of systemic toxicity
• Soluble in water and chemically stable in solution

Uses of Local Anesthetics

• Treatment of skin trauma and surgical procedures
• Ear, Nose, and Throat (ENT) operations
• Podiatry
• Management of labor pain
• Management of postoperative pain
• Dentistry

Chemical Structures

• Local anesthetics' chemical structures are typically categorized as either ester-type or amide-type drugs.
• Examples of ester-type drugs include Procaine, Benzocaine, and Cocaine.
• Examples of amide-type drugs include Lidocaine, Bupivacaine and Prilocaine.
• Amide-type local anesthetics have two "i"s in the generic name

Ester vs. Amide: Clinical Significance

• Cross-sensitivity (allergy) is more common within the same chemical class.
• Amide linkage class has much less incidence of allergies.
• Esters are metabolized in plasma by pseudocholinesterase, thus has a shorter duration of action.
• Amides are metabolized by liver microsomal cytochrome P450, caution is advised in patients with hepatic diseases.

Mechanism of Action

• Local anesthetics block voltage-gated Na+ channels, leading to anesthesia
• The binding site is located near the intracellular end of the Na+ channel.
• Local anesthetics must cross the neuronal membrane to reach their site of action within the channel.

Use-Dependent Block

• Local anesthetics preferentially affect neurons (cardiac cells) firing at higher rates.
• They have a higher affinity for open and inactivated Na+ channels.
• This action increases the refractory period.

Sodium Channel States

• The sodium channel has two gates: an activation gate and an inactivation gate.
• The activation gate is also known as the voltage sensor.

Differential Sensitivity of Neurons

• Smaller nerve fibers are more sensitive due to smaller length constant.
• Myelinated fibers are more rapidly blocked than unmyelinated fibers of the same size.
• Order of blocking: Type C & B > type A delta > type A beta and gamma > type A alpha
• Modality of sensation blocking occurs successively in this order: sympathetic = polymodal pain > sharp pain = temperature > light touch > motor
• Recovery occurs in the reverse direction.
• Differential effects may be lost with high local anesthetic concentrations.

Factors Influencing Local Anesthetic Action: Lipid Solubility

• The rate of onset and duration of action are positively correlated with lipid solubility.
• Increased lipid solubility results in increased potency.
• The time needed to penetrate the nerve sheath and permeate the nerve cell membrane is a limiting factor.

Factors Influencing Local Anesthetic Action: pH

• Local anesthetics are tertiary amines and weak bases with a pKa around 8-9.
• They often come as HCl salts in solution.
• At tissue pH, 90% of the drug exists in the ionized form.
• Only the Non-ionized form penetrates into the neuron.
• Increased extracellular acidity delays onset of action.
• Bicarbonate is often mixed with anesthetics, this maintains the drug in non-ionized form to accelerate the onset of anesthesia and reduces burning from acidic drug solutions.

Pharmacokinetics

• Poorly absorbed from the gastrointestinal tract
• Good absorption when applied to mucous membranes and intradermal injection sites.
• Systemic absorption terminates local action.
• Factors influencing peak plasma levels: site of injection, total dose, and the particular drug used.

Epidural vs. Spinal Anesthesia

• Epidural anesthesia involves a larger drug dose with a slower onset (25-30 minutes).
• Epidural is administered anywhere along the vertebral column, offering adjustable and prolonged block duration.
• Spinal anesthesia uses a smaller drug dose with a faster onset (approximately 5 minutes).
• Spinal is limited to the lumbar region, providing high-quality anesthesia with a single-shot injection and a brief block duration (2-4 hours).

Use with Epinephrine (vasoconstrictor; hemostasis)

• Adding epinephrine decreases the rate of systemic absorption, which results in decreased systemic toxicity
• Increasing local drug concentration, thereby enhancing neuronal uptake of the drug
• Extending the duration of action
• This combination should NOT be used in areas with limited vascular supply to avoid tissue damage or necrosis

Combined with α2 Adrenergic Receptor Agonist Clonidine

• Clonidine is used as a local anesthetic adjuvant for spinal anesthesia.
• Clonidine exerts a direct analgesic effect by activating postsynaptic α2 adrenoceptors in the spinal cord, which hyperpolarize and inhibit pain transmission.

Pharmacokinetics: Distribution, Metabolism and Excretion

• Distribution occurs widely to all parts of the body, including the brain; also crosses the placenta.
• Distribution terminates local drug action.
• Ester-type local anesthetics undergo rapid hydrolysis by pseudocholinesterases in plasma and the liver, resulting in short-acting and low-toxicity metabolites.
• Amide-type local anesthetics are hydrolyzed by liver microsomal enzymes and results in longer acting metabolites.
• The metabolites are excreted in the urine.

Systemic Effects of Local Anesthetics: Inadvertent Intravascular Injection

• CNS: All local anesthetics can induce the same dose-related effects as general anesthesia.
• Stage 1 Analgesia: Dizziness, drowsiness, sensory impairment, tongue numbness, restlessness
• Stage 2 Excitement: nystagmus, tremor, and convulsions (selective block of inhibitory neurons which fire at higher rates than excitatory neurons)
• Stage 3 Surgical Anesthesia: unconsciousness (inhibition of brainstem RAS)
• Stage 4 Medullary Depression: CNS depression, respiratory depression and death.

Treatment of Local Anesthetic-Induced Seizures

• First-line drugs are benzodiazepines (e.g., midazolam) due to their hemodynamic stability.
• Low-dose propofol is an alternative option that is more immediately available.

Cardiovascular Effects

• Hypotension (except with cocaine use) can be managed with ephedrine or phenylephrine.
• It decreases total peripheral resistance (vasodilation) by inhibiting sympathetic nerves.
• It also decreases cardiac output (decreases heart rate and contractility) by inhibiting cardiac Na+ channels.

Cardiovascular Effects: Arrhythmias

• Arrhythmias result from the direct block of cardiac Na+ channels and reduces cardioexcitability and contractility.
• Can reduce conductivity
• Can increase refractory period

Cardiovascular Effects

• Bupivacaine is more cardiotoxic than other local anesthetics.
• It causes broad QRS complexes (slower dissociation from Na+ channels), which triggers arrhythmias via creation of re-entry pathways.
• Resuscitation is extremely difficult in these cases.
• Intravenous lipid emulsion (ILE) is used for resuscitation to extract lipophilic drugs from aqueous plasma.

Cocaine

• Causes euphoria and CNS excitation due to direct cortical stimulation from blocked uptake of catecholamines.
• Prevents catecholamine reuptake, which stimulates central and peripheral sympathetic activity, leading to vasoconstriction, hypertension, tachycardia, and arrhythmias.

Allergic Reactions

• Allergic reactions are more common with ester-type anesthetics (e.g., procaine, tetracaine).
• Esters are metabolized to p-aminobenzoic acid (PABA) derivatives.
• Cross-hypersensitive reactions are found within the same chemical class.
• Preservatives in preparations can be converted to PABA-like compounds.

Local Neurotoxicity at Injection Site

• Chloroprocaine and lidocaine are more neurotoxic.
• Can cause transient neuropathic symptoms
• Unclear mechanism, may be caused independently from Na+ channel block, and/ or interference with axonal transport and calcium homeostasis

Transient Neurologic Symptoms (TNS)

• It is a syndrome of pain or dysesthesia.
• Occurs in roughly a third of patients receiving lidocaine for spinal anesthesia.
• Not associated with sensory loss, motor weakness, or bowel and bladder dysfunction.
• Causes severe pain, often exceeding surgical procedure pain.

Methemoglobinemia

• Benzocaine causes methemoglobinemia.
• Prilocaine is metabolized to ortho-toluidine, which oxidizes hemoglobin to methemoglobin.
• Moderate methemoglobinemia can cause issues in patients with cardiac or pulmonary disease, cyanosis, shortness of breath and fatigue.

Local Anesthetic Toxicity

• Typically occurs 1-5 minutes after the injection, ranging from 30 seconds to 60 minutes.
• Initial manifestations vary widely.
• Classical symptoms of CNS excitement include circumoral numbness, tongue numbness, metallic taste, lightheadedness, dizziness, visual/auditory disturbances (difficulty focusing, tinnitus), disorientation, and drowsiness.
• Cardiac toxicity classically does not occur without preceding CNS toxicity.

Cocaine: Specific Properties

• Used topically for corneal or nasopharyngeal anesthesia due to toxicity limiting parenteral use.
• It should not be combined with epinephrine because cocaine is a vasoconstrictor that inhibits norepinephrine reuptake, enhancing vasoconstriction and potentially leading to necrosis.
• Direct cortical stimulation may produce euphoria, restlessness, and in toxic doses, delirium/convulsions followed by central depression/respiratory and cardiac arrest.
• Causes Euphoric experience, which can produces drug dependence, abuse potential, tolerance, and withdrawal symptoms.

Benzocaine (Americaine): Specific Properties

• Insoluble and used as ointments for surface anesthesia only.
• It can penetrate hyperemic skin and normal mucosa to produce sustained anesthesia.

Procaine (Novocain): Specific Properties

• Topically ineffective
• Widely used for infiltration, subcutaneous and nerve block anesthesia.
• Rapidly destroyed by plasma cholinesterase into non-toxic metabolites thus has a low degree of toxicity.
• Short duration of action that is generally combined with epinephrine.

Tetracaine (Pontocaine): Specific Properties

• Used topically or by injection for infiltration and spinal anesthesia.
• Exhibits very slow onset and a prolonged duration of action.
• Has a 10-fold greater toxicity and potency than procaine.
• Allergic reactions are common with this drug.

Lidocaine (Xylocaine): Specific Properties

• Most widely used local anesthetic, also an IB antiarrhythmic.
• Effective for surface, infiltration, and nerve block anesthesia.
• Exhibits the fastest onset and a rather long acting effect.
• Is four times as potent as procaine but has about equal toxicity.
• More sedative than other local anesthetics.
• Can cause CNS Excitation at high doses.
• It can be associated with neurotoxicity and transient neurologic symptoms (TNS) when used for spinal anesthesia.

Bupivacaine (Marcaine): Specific Properties

• Used for postoperative analgesia and during labor.
• Offers a longer duration of action than lidocaine.
• This has a wider margin of safety during obstetric use compared to procaine or mepivacaine.
• Has a low incidence of neurotoxicity and TNS symptoms when used as a spinal anesthetic.
• More cardiotoxic than other LAs.

Ropivacaine (Naropin): Specific Properties

• S(–) enantiomer of bupivacaine
• Has less affinity for cardiac sodium channels than its R(+) counterpart.
• Has less potential for cardiovascular toxicity than other local anesthetics.

Levobupivacaine (Chirocaine): Specific Properties

• S(–) enantiomer of bupivacaine
• Has less affinity for cardiac sodium channels than its R(+) counterpart.
• Has less potential for cardiovascular toxicity.

Mepivacaine (Carbocaine): Specific Properties

• Used for infiltration, spinal and regional nerve block.
• Exhibits rapid onset and a long duration.
• Metabolism occurs through glucuronidation in the liver.