Local Anesthetics

• Local anesthetics are drugs that cause loss of sensation to a localized body part when directly applied to nerve tissue or mucous membrane.

Desirable Characteristics

• Fast action
• Brief, reversible nerve conduction blockade
• Act on all parts of the nervous system and all nerve fiber types
• Low systemic toxicity
• Soluble and stable in water

Uses

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

Chemical Structures

• Amides have two "i"s in their names

Ester vs. Amide

• Cross-sensitivity (allergy) occurs in the same chemical class
• Incidence is less common with amide linkage class
• Esters are metabolized mostly in plasma by pseudocholinesterase, resulting in shorter action duration.
• Amides are metabolized mostly by liver microsomal cytochrome P450, so caution should be used for patients with hepatic diseases.

Mechanism of Action

• Block voltage-gated Na+ channels.
• Act on the intracellular end of the Na+ channel, requiring them to cross the neuronal membrane.

Use-Dependent Block

• Neurons (cardiac cells) firing at higher rates are preferentially affected
• There is a higher affinity for open and inactivated Na+ channels
• The refractory period is increased.

Na+ Channel States

• The Na⁺ channel has two gates: activation gate ("voltage sensor") and inactivation gate.

Differential Sensitivity of Neurons

• Smaller nerve fibers are more sensitive due to smaller length constant
• Myelinated fibers are more rapidly blocked compared to unmyelinated fibers of the same size.
• Type C and B fibers > type A delta > type A beta and gamma > type A alpha
• Modality of sensation sensitivity: sympathetic = polymodal pain > sharp pain = temperature > light touch > motor
• Recovery occurs in the reverse order.
• Differential effects may be lost at a high enough concentration of the local anesthetic.

Factors Influencing Local Anesthetic Action

• The rate of onset and duration is positively correlated with lipid solubility.
• Increased lipid solubility increases potency.
• The time needed to penetrate the nerve sheath and permeate the nerve cell membrane is a limiting factor in producing local anesthesia.

pH Effects

• Most local anesthetics are tertiary amines and weak bases with a pKa of 8-9
• They are often in the form of HCl salts in solution
• 90% exists in ionized form at tissue pH.
• Non-ionized forms penetrate into the neuron
• Increased extracellular acidity(infections; repeated injections of local anesthetic HCl salts) delays the onset of action
• Bicarbonate is often mixed with anesthetics to maintain the drug in non-ionized form for faster onset and to reduce burning from acidic drug solutions.

Pharmacokinetics

• Poor absorption from the GI tract.
• Good absorption from mucous membranes and intradermal injection sites.
• Systemic absorption stops local action.
• Factors influencing peak plasma level: site of injection, total dose, particular drug.
• Widely distributes to all parts of the body including the brain and crosses the placenta
• Distribution stops local drug action.
• Ester type local anesthetics have rapid hydrolysis by pseudocholinesterases in plasma and liver, resulting in short action and low toxicity.
• Amide type local anesthetics are hydrolyzed by liver microsomal enzymes resulting in longer action.
• Metabolites are excreted in the urine

Epidural vs. Spinal Anesthesia

• Epidural Anesthesia: Large dose, Approximately 25-30 minutes onset of anesthesia, Anywhere along the vertebral column spine level that can be performed, Postoperative redosing is possible via a catheter, and its block is adjustable and prolonged.
• Spinal Anesthesia: Smaller dose, Approximately 5 mn onset of anesthesia, Lumbar only is the spine level that can be performed, generally a single shot injection and its duration is brief.

Combined with Epinephrine

• Decreases the rate of systemic absorption and systemic toxicity will be less
• Local drug concentration and neuronal uptake are increased
• Duration of action is increased
• Should not be used in areas of limited vascular supply (toes, fingers, ear lobes, penis) because it may produce tissue necrosis.

Combined with α2 Adrenergic Receptor Agonist Clonidine

• Epinephrine can exert a direct analgesic effect through postsynaptic α2 adrenoceptors in the spinal cord
• Hyperpolarizes and inhibits pain transmission
• Clonidine is a local anesthetic adjuvant for spinal anesthesia

Systemic Effects of Local Anesthetics

• Inadvertent Intravascular Injection
• Effects are dose-related and induce the same 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 firing fast)
• Stage III Surgical Anesthesia: unconsciousness (inhibition of the brainstem RAS)
• Stage IV Medullary Depression: CNS & respiratory depression and death.
• Treatment for Local Anesthetic-Induced Seizures: Benzodiazepines (e.g., midazolam) are the first-line drugs due to hemodynamic stability, Low dose propofol is an alternative often immediately available.
• Hypotension can be managed with ephedrine, phenylephrine, except with Cocaine.
• Decreases TPR (vasodilation) by inhibiting sympathetic nerves.
• Decreases Cardiac Output (decreased heart rate and contractility) by inhibiting cardiac Na+ channels.
• Arrhythmias: direct block of cardiac Na+ channels, results Cardioexcitability and contractility is decreased, Decrease conduction rate and increased refractory period

Cardiovascular Effects

• Bupivacaine is more cardiotoxic than other local anesthetics
• Broad QRS complexes (slower dissociation from Na+ channels)
• Triggers arrhythmias via creation of re-entry pathways, makes resuscitation extremely difficult
• Intravenous lipid emulsion (ILE) Resuscitation extracts a lipophilic drug from the aqueous plasma.

Cocaine

• Causes Euphoria and CNS excitation through direct cortical stimulation from blocked catecholamine uptake.
• Blockade of catecholamine reuptake stimulates vasoconstriction, hypertension, tachycardia, and arrhythmias via peripheral sympathetic activity.

Allergic Reactions

• More common with Ester types (procaine, tetracaine).
• Metabolizes to p-aminobenzoic acid (PABA) derivatives.
• Cross-hypersensitive reactions are within the same chemical class
• Preservatives in preparations can be converted to PABA-like compounds.

Local Neurotoxicity at the Injection Site

• Chloroprocaine and lidocaine are more neurotoxic.
• Transient neuropathic symptoms can occur.
• Can occur independently from Na+ channel block or interference with axonal transport and calcium homeostasis
• Transient Neurologic Symptoms (TNS) are defined as a syndrome of transient pain or dysesthesia
• 1/3 of patients receiving lidocaine for spinal anesthesia get TNS
• Symptoms are not associated with sensory loss, motor weakness, or bowel and bladder dysfunction
• There is severe pain, often exceeding that induced by the surgery

Methemoglobinemia

• Benzocaine
• Prilocaine is metabolized to ortho-toluidine, which oxidizes hemoglobin to methemoglobin
• Moderate methemoglobinemia can cause issues in patients with cardiac or pulmonary disease:
• Cyanosis (bluish discoloration of the skin)
• Shortness of breath
• Fatigue

Local Anesthetic Toxicity

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

Specific Pharmacological Properties

Cocaine

• Use topically for corneal or nasopharyngeal anesthesia
• Too toxic for parenteral purposes
• Do not combine with epinephrine as cocaine is a vasoconstrictor.
• Blocks norepinephrine reuptake, enhancing vasoconstriction and leading to necrosis
• Direct cortical stimulation produces euphoria, restlessness, delirium, and convulsions
• In toxic doses can cause central depression, respiratory and cardiac arrest
• Euphoric experience causes drug dependence, abuse potential, tolerance, and withdrawal symptoms

Benzocaine (Americaine)

• Insoluble, used as ointments for surface anesthesia only
• Can penetrate hyperemic skin and normal mucosa to produce sustained anesthesia

Procaine (Novocain)

• Ineffective topically.
• Used for infiltration, subcutaneous, and nerve block anesthesia
• Low toxicity due to rapid breakdown by plasma cholinesterase to non-toxic metabolites
• Short duration, so it's combined with epinephrine

Tetracaine (Pontocaine)

• Topical or injection for infiltration and spinal anesthesia
• Very slow onset and has prolonged action
• 10-fold more toxic and more potent than procaine
• High allergy risk

Lidocaine (Xylocaine)

• Most widely used local anesthetic and is also a class IB antiarrhythmic
• Effective for surface, infiltration, and nerve block anesthesia
• Fastest onset and rather long acting
• Four times as potent as procaine, and about equal in toxicity
• More sedative than other local anesthetics
• CNS excitation at higher doses
• Causes Neurotoxicity and TNS when used as a spinal anesthetic

Bupivacaine (Marcaine)

• Useful for postoperative analgesia and during labor
• Longer duration of action than lidocaine
• Wider margin of safety for obstetric use than procaine or mepivacaine.
• Low incidence of neurotoxicity and TNS when used as a spinal anesthetic
• More cardiotoxic

Ropivacaine (Naropin)

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

Levobupivacaine (Chirocaine)

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

Mepivacaine (Carbocaine)

• Use for Infiltration, spinal, and regional nerve blocks.
• Rapid onset and long duration.
• Glucuronidation in the liver is the primary route of metabolism