Local Anesthetics

• Local anesthetics cause loss of sensation in a localized area when applied to nerve tissue or mucous membranes.

Desirable Characteristics

• Fast onset of action is ideal.
• They should provide brief and reversible nerve conduction blockade.
• Effective on all parts of the nervous system and all nerve fiber types.
• They should have a low degree of systemic toxicity.
• They should be soluble in water and stable in solution.

Common Uses

• Local anesthetics are used for skin trauma and surgery.
• They are used in ENT operations, podiatry, labor pain management, postoperative pain relief, and dentistry.

Chemical Structure

• Local anesthetics can be categorized into ester-type and amide-type drugs based on their chemical structure.
• Important examples of ester-type drugs include procaine, benzocaine, and cocaine.
• Lidocaine, bupivacaine, and prilocaine are examples of amide-type local anesthetics.
• Amides have 2 "i's" in their names.

Ester vs Amide

• Cross-sensitivity (allergy) tends to occur with drugs within the same chemical class and is less common with amides.
• Esters are mainly metabolized in plasma by pseudocholinesterase, resulting in a shorter duration of action.
• Amides are primarily metabolized by liver microsomal cytochrome P450 so caution should be used in patients with hepatic diseases.

Mechanism of Action

• Local anesthetics work by blocking voltage-gated Na+ channels.
• The site of action is at the intracellular end of the Na+ channel.
• They must cross the neuronal membrane to bind.
• Sodium channel has 2 gates; an activation gate ("voltage sensor") and an inactivation gate

Use-Dependent Block

• Local anesthetics preferentially affect neurons (cardiac cells) firing at higher rates by having a higher affinity for open/inactivated Na+ channels and increase the refractory period.

Differential Sensitivity of Neurons

• Smaller nerve fibers are more sensitive to local anesthetics due to a smaller length constant.
• Myelinated fibers are more rapidly blocked than unmyelinated ones, if fibers are the same size.
• Type C and B fibers are more sensitive than type A delta, which is more sensitive than type A beta and gamma, and lastly, type A alpha.
• Modality of sensation sensitivity: sympathetic = polymodal pain > sharp pain = temperature > light touch > motor.
• The recovery of nerve function occurs in the reverse order.
• Differential effects on nerve function may be lost at high concentrations of local anesthetic.

Factors Affecting Action

• The rate of onset and duration is positively correlated with lipid solubility.
• Increased lipid solubility leads to increased potency.
• A limiting factor in local anesthesia is the time required to penetrate the nerve sheath and permeate the nerve cell membrane.

pH Impact

• Most local anesthetics are tertiary amines and weak bases with a pKa of 8-9.
• They are often used as HCl salts in solution.
• At tissue pH, about 90% exists in an ionized form.
• The non-ionized form is what penetrates the neuron.
• Increased extracellular acidity (infections or repeated injections of local anesthetic HCl salts) delays the onset of action.
• Bicarbonate is sometimes mixed in to maintain the drug in a non-ionized form to accelerate onset and decrease burning from the acidic drug solution.

Pharmacokinetics

• Absorption, distribution, metabolism, and excretion (ADME) affect local anesthetics.
• Local anesthetics are poorly absorbed from the gastrointestinal tract.
• Good absorption occurs from mucous membranes and intradermal injection sites.
• Systemic absorption terminates the local action.
• Factors like site of injection, total dose, and particular drug influence peak plasma levels.
• Local anesthetics distribute widely throughout the body, including the brain, and cross the placenta.
• The distribution terminates the local drug action.
• Ester-type local anesthetics undergo rapid hydrolysis by pseudocholinesterases in plasma and liver, resulting in a short-acting effect and low toxicity.
• Amide-type local anesthetics are metabolized by liver microsomal enzymes and are longer acting.
• Metabolites are excreted in the urine.

Epidural vs Spinal Anesthesia

• Epidural involves administering a larger dose compared to spinal anesthesia.
• Epidural onset takes approximately 25-30 minutes, while spinal anesthesia takes about 5 minutes.
• Epidural can be done anywhere along the vertebral column; spinal is lumbar only.
• Epidural has a prolonged duration with adjustable dosing while spinal is brief as a single shot.

Combined With Epinephrine

• Combining with epinephrine (a vasoconstrictor and hemostatic agent) decreases the rate of systemic absorption and toxicity.
• Epinephrine leads to increased local drug concentration, increasing neuronal uptake and duration of action.
• These combinations should not be used in areas with limited vascular supply to avoid tissue necrosis, such as the toes, fingers, ear lobes, and penis.

Clonidine Combination

• Combining with α2 adrenergic receptor agonist clonidine may exert a direct analgesic effect via postsynaptic α2 adrenoceptors in the spinal cord.
• Clonidine hyperpolarizes and inhibits pain transmission.
• Clonidine is used clinically as a local anesthetic adjuvant for spinal anesthesia.

Systemic Effects

• All local anesthetics can induce the same dose-related CNS effects as general anesthesia, following stages:
• Stage I (Analgesia): Dizziness, drowsiness, sensory impairment, tongue numbness, and restlessness.
• Stage II (Excitement): Nystagmus, tremor, and convulsions, caused by a selective block of inhibitory neurons firing at higher rates.
• Stage III (Surgical Anesthesia): Unconsciousness due to inhibition of the brainstem reticular activating system (RAS).
• Stage IV (Medullary Depression): Causes CNS depression, respiratory depression, and death.
• Treatment of local anesthetic-induced seizures:
• Benzodiazepines (e.g., midazolam) are given as first-line drugs due to their hemodynamic stability.
• Low-dose propofol can be an alternative if benzodiazepines are not immediately available.

Cardiovascular Effects

• Hypotension (except caused by cocaine) can be managed with ephedrine or phenylephrine.
• Local anesthetics decrease total peripheral resistance (TPR) through vasodilation by inhibiting sympathetic nerves.
• Decreases cardiac output decreases heart rate and contractility by inhibiting cardiac Na+ channels.
• Arrythmias via direct block of cardiac Na+ channels.
• Decrease cardioexcitability and contractility
• Decrease conduction rate
• Increase refractory period
• Bupivacaine is more cardiotoxic than other anesthetics.
• Broad QRS complexes (slower dissociation from Na+ channels), triggers arrthymias
• Resuscitation is extremely difficult
• Intravenous Lipid Emulsion (ILE) Resuscitation is where you extract lipophilic drugs from an aqueous plasma

Cocaine's Unique Effects

• Causes euphoria and CNS excitation due to direct cortical stimulation from blocked uptake of catecholamines.
• Blockade of catecholamine reuptake stimulates central and peripheral sympathetic activity, leading to vasoconstriction, hypertension, tachycardia, and arrhythmias.
• Should never be combined with epinephrine because leads to necrosis due to vasoconstriction enhancements.
• Euphoric effects may cause dependence, abuse potential, tolerance, and withdrawal symptoms.

Allergic Reactions

• More common with ester-type local anesthetics (procaine, tetracaine) due to their metabolism into PABA derivatives.
• Cross-hypersensitive reactions can occur within the same chemical class.
• Preservatives in local anesthetic preparations could convert to PABA-like compounds.

Local Neurotoxicity

• Chloroprocaine and lidocaine are identified as being more neurotoxic.
• Leads to transient neuropathic symptoms from an unclear mechanism:
  • Independent from Na+ channel block
  • Interference with axonal transport and calcium homeostasis

Transient Neurologic Symptoms (TNS)

• Leads to a syndrome of transient pain or dysesthesia.
• 1/3 of patients that use lidocaine get it for spinal anesthesia
• Not associated with sensory loss, motor weakness, or bowel/bladder dysfunction
• Severe pain exceeding the pain induced by the surgical prodecure.

Methemoglobinemia

• Benzocaine causes it.
• Prilocaine: Metabolized to ortho-toluidine, which oxidized hemoglobin to methemoglobin
• Moderate methemoglobinemia can cause issues in patients with cardiac or pulmonary disease
• Symptoms include:
  • Cyanosis (bluish discoloration of the skin)
  • Shortness of breath
  • Fatigue

Local Anesthetic Toxicity

• Typically occurs 1-5 minutes after the injection or can be within a range of 30-60 seconds.
• Classic CNS excitement such as; Circumoral and/or tongue numbness Metallic taste Lightheadedness Dizziness Visual and auditory disturbances (difficulty focusing and tinnitus) Disorientation Drowsiness
• Cardiac toxicity does not typically occur without preceding CNS toxicity.

Drug Specific Info

• Cocaine is used topically for corneal/nasopharyngeal anesthesia only, due to toxic effects.
• Benzocaine as ointments can only be used for surface anesthesia due to it being insoluble.
• It also can penetrate hyperemic skin and normal/mucous membranes for sustained anesthesia.
• Procaine is ineffective topically but has a width range for infiltration, subcutaneous, an nerve block anesthesia.
• It has a low degree of toxicity and short duration, so typically is combined with epinephrine.
• Tetracaine can be used topically or for injection for infiltration and spinal anesthesia.
• It has a very slow onset and prolonged action, and is 10x more potent and more toxic than procaine.
• Lidocaine is antiarrythmic and used for surface level, has a fast onset and has CNS excitation.
• It's also associated with neurotoxcitiy and TNS when used for spinal anesthesia
• Bupivacaine is useful for postperative and during labor.
• It is longer durations that lidocaine and is more cardiotoxic.
• It is useful in obstetrics.
• Ropivacaine/Levobupivacaine is useful for cardiovascular reasons as they're less toxic.
• Mepivacaine involves infiltration, spinal and regional nerve block.