Local Anesthetics: Uses and Objectives

• Local anesthetics are drugs that produce a loss of sensation in a localized part of the body upon direct application to nerve tissue or mucous membranes
• Spinothalamic activation produces a sensation of pain

Desirable Characteristics of Local Anesthetics

• Fast onset of action
• Brief and reversible blockade of nerve conduction
• Effectiveness on all parts of the nervous system including all nerve fiber types
• Low systemic toxicity
• Water-soluble; stable in solution

Uses of Local Anesthetics

• Skin trauma/surgery interventions
• ENT operations
• Podiatry
• Labor pain management
• Postoperative pain management
• Dentistry

Objectives of Local Anesthetic Use

• Describe the effects produced by local anesthetics on peripheral nerves, muscle, the central nervous system, and the cardiovascular system
• Contrast cocaine with common local anesthetics regarding CNS and vascular effects
• Outline various clinical applications and situations that may limit their use
• Compare the action onset and duration, chemical structure (amide or ester), and lipid solubility

Mechanism of Action for Local Anesthetics

• Blocks voltage-gated Na+ channels by binding near the intracellular end
• Drugs must cross the neuronal membrane that triggers this action
• Use-dependent block preferentially affects neurons firing at higher rates, like cardiac cells
• Higher affinity for open and inactivated Na+ channels increases the refractory period
• The Na⁺ channel has two gates: an activation gate ("voltage sensor") and an inactivation gate

Differential Sensitivity of Neurons

• Smallest nerve fibers are most sensitive because of a smaller length constant
• Myelinated fibers are blocked more rapidly than unmyelinated fibers of the same size
• Sensitivity from highest to lowest goes in this descending order: Type C and B, type A delta, type A beta and gamma, type A alpha
• Modality from highest to lowest sensation goes in this descending order: sympathetic, polymodal pain, sharp pain, temperature, light touch, motor
• Recovery occurs in the reverse direction
• Differential effects are possibly lost at high local anesthetic concentrations

The Impact of Lipid Solubility

• The rate of onset and duration positively correlates with lipid solubility
• Increased lipid solubility relates to increased potency
• Time to penetrate the nerve sheath and permeate the nerve cell membrane limits the production of local anesthesia

The Impact of pH

• Most anesthetics are tertiary amines and weak bases with a pKa of 8-9 Often supplied as HCl salts for solubility.
• In tissues, the anesthetic is mostly (90%) in ionized form
• Only the non-ionized form penetrates into neurons
• Increased extracellular acidity (due to infection or repeated injection of local aesthetic salts) delays blockage
• Bicarbonate is mixed with the anesthetic to maintain the drug in non-ionized form for faster onset and to reduce burning from an acidic drug solution

Pharmacokinetics of Local Anesthetics

• Poorly absorbed from the GI tract
• Well absorbed from mucous membranes or intradermal injection sites
• Systemic absorption effectively terminates the local action
• Peak plasma levels impacted by the injection site, total dose, and drug
• Distribution to all parts of the body, including the brain and placenta
• Distribution terminates the drug's local action
• Metabolites are excreted in the urine
• Ester-type anesthetics have low toxicity due to rapid hydrolysis by pseudocholinesterases in plasma and the liver, but are short acting Amide-type anesthetics have longer action due to hydrolysis by specific liver microsomal enzymes.

Ester vs Amide

• Cross-sensitivity/allergy occurs with drugs in the same chemical class
• Its incidence is much less with amide linkage drugs
• Esters are primarily metabolized in plasma by pseudocholinesterase, leading to a shorter action duration
• Amides are primarily metabolized by liver microsomal cytochrome P450; caution with hepatic diseases

Combined with Epinephrine/Clonidine

• Local anesthetics can be use in combination with epinephrine (vasoconstrictor, hemostasis) or clonidine
• Combining a local anesthetic with epinephrine decreases the rate of systemic absorption, which in turn decreases systemic toxicity
• Epinephrine also increases local drug concentrations, which increase neuronal uptake and duration of action
• Using the combination in areas of limited vascular supply (toes, fingers, ear lobes, penis) can produce tissue necrosis
• Epinephrine may exert direct analgesic effects via postsynaptic α2 adrenoceptors in the spinal cord, which inhibits pain transmission
• Clonidine is used clinically as a local anesthetic adjuvant for spinal anesthesia

Epidural vs. Spinal Anesthesia

• Epidural anesthesia involves a larger drug dose and longer onset time versus spinal anesthesia
• Epidural anesthesia can be performed anywhere along the vertebral column while spinal anesthesia is limited to the lumbar
• Epidural anesthesia is considered a lower quality than spinal anesthesia
• Spinal analgesia is one-shot injection while the effects of epidural anesthesia can be maintained through continued redosing postoperatively via a catheter
• Spinal anesthesia has a shorter duration of action (brief, usually 2-4 hours) than epidural (adjustable and prolonged)

Systemic Effects of Local Anesthetics

• Inadvertent intravascular injections can induce the same dose-related effects as general anesthesia
• Stage I Analgesia: Dizziness, drowsiness, sensory impairment, tongue numbness, restlessness.
• Stage II Excitement: Nystagmus, tremor, and convulsions, selective block of inhibitory neurons that fire at higher rates than excitatory neurons.
• Stage III Surgical Anesthesia: Unconsciousness, inhibition of brainstem RAS.
• Stage IV Medullary Depression: CNS and respiratory depression ending in death.

Treatment of Local Anesthetic-Induced Seizures

• Administer Benzodiazepines (e.g., midazolam) as the first-line due to their hemodynamic stability
• Administer Low dose Propofol as a fast alternative

Cardiovascular Effects of Anesthetics

• May result in hypotension (except with cocaine) which treated with ephedrine or phenylephrine
• Anesthetics can promote vasodilation, which decreases cardiac output, by inhibiting sympathetic nerves that increase heart rate and contractility
• They can cause arrhythmias by directly blocking cardiac Na+ channels, which decreases cardioexcitability/contractility as well as conduction rate, and increases refractory period
• Bupivacaine at higher doses is more cardiotoxic than other local anesthetics because slower dissociation from Na channels triggers arrhythmias
• Resuscitation is performed with intravenous lipid emulsion, which extracts lipophilic drugs from the aqueous plasma

Cocaine Use

• Topical application for corneal or nasopharyngeal anesthesia; too toxic outside of those applications
• Direct cortical stimulation can produce drug dependence, abuse potential, tolerance
• Euphoria and CNS excitation result from blocked catecholamine uptake.
• There is direct cortical stimulation that can produce euphoria, delirium and convulsions, central/respiratory depression, cardiac arrest
• Cocaine should not be combined with epinephrine because it blocks norepinephrine reuptake; this enhances vasoconstriction, leading to necrosis
• The blockade of catecholamine reuptake stimulates central and peripheral sympathetic activity and leads to vasoconstriction, hypertension, tachycardia, and arrhythmias

Allergic Reactions

• More common with Ester-type anesthetics (procaine, tetracaine).
• Metabolized into PABA (p-aminobenzoic acid) derivatives.
• Presents as cross-hypersensitive reactions within the same chemical class
• Preservatives in preparations convert to PABA-like compounds.

Local Neurotoxicity at Injection Site

• Chloroprocaine and lidocaine are more neurotoxic
• Results in transient neuropathic conditions
• An unclear mechanism involving possible: independence Na+ blockage or interference with axonal transport and calcium homeostasis

Transient Neurologic Symptoms (TNS)

• Syndrome of transient pain, dysesthesia, or both
• 1/3 of spinal anesthesia patients report receiving lidocaine for indications
• Symptoms are isolated sensory and motor deficits
• Not associated with sensory loss, motor weakness, or bowel or bladder dysfunction

Methemoglobinemia

• Benzocaine and prilocaine can cause this condition
• Prilocaine metabolizes to ortho-toluidine, which oxidizes hemoglobin to methemoglobin
• In prone patients it can cause serious cardiopulmonary and respiratory problems
• Identified via cyanosis (bluish skin), shortness of breath, and fatigue

Local Anesthetic Toxicity

• Develops 1-5 minutes after injection, with a possible range of 30-60 seconds
• Cardiac toxicity is not possible without previous CNS toxicity
• Initial manifestations can vary such as circumoral/tongue numbness, metallic taste, lightheadedness, dizziness, altered auditory/visual processing, disorientation, and drowsiness

Specific Pharmacological Properties of Some Local Anesthetics

• Procaine (Novocain) is widely combined with epinephrine due to its Short duration, Ineffective surface, infiltration, and nerve block anesthesia
• Low toxicity from rapid destruction by plasma cholinesterase
• Tetracaine (Pontocaine) has a long duration and toxicity, making it 10x more potent than procaine
• Lidocaine (Xylocaine) is the most widely selected local anesthetic, with a fast onset, use as IB antiarrhythmic, and ability to perform surface, infiltration, and nerve block
• It has CNS excitation at a high dose, four times more potency than procaine, and equal toxicity
• There's neurotoxicity as a spinal anesthetic
• Bupivacaine (Marcaine) is more useful for labor/postoperative analgesia with a longer duration than lidocaine, and lower incidence of neurotoxicity during obstetric use
• It is more cardiotoxic
• Ropivacaine (Naropin), S(-) enantiomer, has less affinity for cardiac sodium channels, with a low potential for cardiovascular toxicity
• Levobupivacaine (Chirocaine) similar Ropivacaine, however it has less affinity for cardiac sodium channels
• Mepivacaine (Carbocaine) is used for infiltration, spinal and regional nerve block; it is rapidly metabolized in the liver with a long duration
• Benzocaine (Americaine) is insoluble, used as an ointment for surface anesthesia, it can produce sustained anesthesia by penetration of hyperemic skin and normal tissue