Local Anesthetics Flashcards Preview

Pharmacology > Local Anesthetics > Flashcards

Flashcards in Local Anesthetics Deck (83):

Local Anesthetics

• Produce temporary conduction blockade of impulses along central &/or peripheral nerve pathways
• Spontaneous, complete return of nerve conduction as drug is cleared from site of action (No evidence of damage to nerve fibers due to drug effects)


Local Anesthetics (preparation)

• Prepared as hydrochloride salts
– Acidic solution, water‐soluble (pH 4‐7)


Local Anesthetics (ionization)

• Weak bases (pKs 7.6‐9.1)
– More non‐ionized in solutions with greater alkalinity relative to the drug
-more ionized at physiological pH


LA (ionized vs non-ionized forms)

• Lipid‐soluble (non‐ionized) form crosses the axon membrane to its intracellular site of action
• Ionized form is the active form at the sodium channel in then axon (intracellular)
– Both ionized and non‐ionized forms may attach to Na+ channel at different sites to inactivate.



• Addition of NaHCO3
– speeds onset
• Increases non‐ionized fraction
– Enhances depth of sensory and motor blockade
• More drug reaches intracellular site of action by crossing neural cell lipid membranes
– Intracellularly, the non‐ionized form equilibrates with the ionized form based on intracellular pH
– 1 mEq NaHCO3 / 10 cc (Lido or Mepiv) – 0.1 mEq NaHCO3 / 10 cc (Bupiv)


Ion Trapping

• IonTrappingmayoccurwhenthereisapHgradient across membranes because only the non‐ionized (non protein‐bound), lipid‐soluble fraction equilibrates across cell membranes
– Ex. Fetal blood pH is lower than maternal blood pH
• Administration of weak bases (i.e., opioids and LAs) to parturients results in accumulation of drug in the fetus


Structure Activity Relationship

• Lipophilic group (generally a benzene ring, such as PABA) separated by a hydrophilic group (usually a tertiary amine) by
– An aminoamide linkage – An aminoester linkage
• Classification
• The linkage is the basis for classification of LAs as – Amides vs. Esters


Potency correlates with...

lipid solubility


modification of the chemical structure alters...

pharmacologic effects:
-rate of metabolism
-duration of action



chiral drugs


Available in racemic mixtures...

-S enantiomers are less toxic than R enantiomers
(vary in pharmacokinetics, pharmacodynamics, and toxicity)


LA mechanism (ionization)

• The non‐ionized form of a LA crosses the lipid axon membrane
• The drug’s ionized and non‐ionized forms equilibrate within the cell
• The ionized form of the drug is the active form of the drug within the cell &/or the non‐ ionized form may inactivate the channel


LA (state of channel)

• LA binding to the Na+ channel (intracellularly) is dependent on the conformational state of the channel
– Activated, open
– Inactivated, closed
– Resting, closed



• LAs prevent transmission of nerve impulses by binding to (blocking) sodium channels of the axon in the inactive‐closed state intracellularly
– The ionized form of the drug binds to the inactive, closed, sodium channel
• The ionized form is the active form of the drug intracellularly
– Slows rate of depolarization so threshold cannot be reached
• No action potential is propagated
LAs do not alter threshold for propagation nor do they alter resting
transmembrane potential


Sodium Channel Blockade "frequency dependent"

• Sodium channel blockade by LAs is“frequency‐ dependent”
– Na+ channels recover between action potentials and develop additional conduction blockade each time the Na+ channel opens
• More frequent action potentialsfaster the nerve is blocked by LA • Small, unmyelinated fibers are more easily blocked
than large, myelinated fibers – Autonomic>sensory>motor


Minimal Concentration (Cm)

• Cm
– The concentration of LA required to produce conduction blockade of nerve impulses
– Motor fibers have 2x the Cm as sensory fibers
• Recall that sensory fibers are blocked at lower concentrations than motor fibers and autonomic fibers are more easily blocked (at lower concentrations) than sensory fibers


Differential Blockade in Neuraxial Anesthesia

• Increasesinconcentrationsinterruptautonomic, sensory, and motor pathways

– Autonomic blockade at lowest concentrations • “Sympathectomy”
– Sensory blockade at low to moderate conc. • Pain and temperature
– Motor blockade at higher concentrations (2x Cm)
• Variable degree of motor paralysis at concentrations used for surgical procedures depending on dose, site, agent, etc


Nerves at the ____________ are blocked prior to nerves near the ____________ of the nerve bundle.


d/t diffusion


LA (other mechanisms)

-may also block voltage-dependent K channels
-the is evidence of activity on G-protein coupled receptors as well


Differential Blockade (thickness, myelination, sensory/motor)

• Thin fibers more easily blocked than thick fibers
• Unmyelinated fibers more easily blocked than myelinated
– Need to block Na+ channels at the Nodes of Ranvier • 2‐3 Nodes of Ranvier must be blocked to produce blockade
• Possible to block pain and temperature fibers (A‐ delta and C fibers) in the absence of motor blockade using very lo [c]
– “Walking epidural”


Sequence of Blockade

– Sympathetic blockade—First (vasodilate)
• Autonomic blockade (“sympathectomy”)
• B fibers

– Pain and Temp blockade (loss of pain)
• A‐delta and C fibers

-Proprioception (Inability to determine body position/loc)
• A‐alpha (type Ia and Ib) and A‐beta (type II)

– Touch and Pressure (Often pts feel pressure/vibration)
• A‐beta

– Motor—Last
• A‐gamma fibers



• LAs are injected into tissues near their target site of action
– Rarely adm IV or arterially (intentionally)
• Absorption and circulation take the drug
away from its site of action


Determinants of toxicity and elimination

• Vascularity of the tissue
-– High plasma concentrations are undesirable due to the potential for toxic effects


Absorption (mucous membranes)

• Mucous membranes are a weak barrier to absorption of LAs (d/t vascularity)
– Easily absorbed into circulation from trachea


Absorption (skin)

• Skin requires high water content for
– Eutectic Mixture of Local Anesthetics (EMLA) cream is available for dermal analgesia
• 1:1 ratio of 5% lidocaine and 5% prilocaine emulsion
– Should not be used on mucous membranes or broken skin
EMLA 1 hour for good effect. DOA up to 2 hours. Limit to small area. 1- 2 gm/10 cm2
Caution in patients with predisposition for methemoglobinemia


Blood Flow (absorption) dependent on...

• Site of injection
• Addition of vasoconstrictor to LA (epi)
– Epi causes vasoconstriction locally
– Decreased perfusion- ↓absorption into blood
» Prolongs the action of the LA
• The LA used
– Drugs with hi affinity for tissue proteins are absorbed more slowly – Cocaine is the only LA with intrinsic vasoconstrictor properties


Distribution depends on...

-Organ Uptake
-Tissue: Blood partition Coefficient
-Tissue Mass


Organ Uptake

-central compartment responsible for rapid uptake (IV)
-after IV administration, the is significant fist pass pulmonary uptake


Tissue: Blood Partition Coefficient

- a measure of affinity of a drug for different tissues/states
-Hi tissue:blood coefficient implies a greater affinity for the tissue, the tissue will hold greater concentrations of the drug than the blood at equilibrium


Tissue Mass

muscle is often a reservoir d/t it's mass (decreased in elderly)


Esters (metabolism and excretion)

• Metabolized by pseudocholinesterase
– Rapid hydrolysis
(Systemic toxicity is indirectly proportional to the rate of hydrolysis of esters
Rate of hydrolysis)
» Chloroprocaine > procaine > tetracaine
» water‐soluble metabolites excreted in urine
– Prolonged DOA and increased potential for toxicity with atypical plasma cholinesterase, pregnancy, renal insufficiency


Procaine and benzocaine metabolized to....

PABA – Allergen


the only ester that is partially metabolized by the liver


(N‐methylation as well as hydrolysis)
– Partially excreted unchanged in the urine


Amide (metabolism and excretion)

• Metabolized by N‐dealkylation and hydroxylation by CYP450
– ↓hepatic blood flow and ↓hep fxn ↑risk for toxic effects
– Rate of metabolism is agent dependent


– Metabolites are dependent on renal clearance
• Prilocaine (and benzocaine) metabolite o‐toluidine converts hgb to methemoglobin to methemoglobinemia
– Treat with methylene blue 1‐2 mg/kg over 5 min


LA Neuro Effects

• First symptoms of LA toxicity originate in the CNS in awake patients

– Early signs
• Circumoral numbness, tongue parasthesia, dizziness,
blurred vision

– Then....
• Exitatory signs may precede CNS depression

– Restlessness, agitation, paranoia
• CNS depression

– Slurred speech, drowsiness, LOC

– And later...
• Muscle twitching, tonic clonic seizures, respiratory arrest, death


Cauda Equina Syndrome

-permanent neurologic damage of the nerves of the cauda equina
-associated with Large or repeated doses (or in fusions via catheter) of 5% lidocaine into the SA space


Transient Neurologic Symptoms

-dysesthesia, burning, aching in the lower extremities and buttocks due to radicular irritation
-sx resolve in a week typically
-increased risk in the lithotomy position and ambulatory surg


LA Respiratory Effects

-relax bronchial smooth muscle (IV lido may reduce bronchoconstriction during laryngoscopy and tracheal intubation- 1-1.5 mg/kg IV)

-1st pass pulmonary uptake
(Lido, bupiv, prilo)

(sypathectomy has been implicated in bronchoconstriction after spinal anesthesia)


LA CV effects

-depress automaticity, inotrophy, chronotrophy (class I antidysrhythmics)

-– Sodium channel blockade
– Autonomic inhibition



LA CV effects toxicity

-CV toxicity requires 2‐3 times the blood concentration required to produce CNS toxicity

-CV collapse may be the presenting sign for patients under general anesthesia
– CV stimulation (↑HR and BP) may precede collapse
• Represents blockade of inhibitory fibers


LA Immune effects

LAs rarely produce anaphylaxis
– Esters more likely to produce allergic rxn
• Derivatives of PABA
– Amides often contain methylparaben preservative
• Methylparaben is structurally similar to PABA

• LAs may decrease the inflammatory response to surgery


Musculoskeletal Effects

• Documented myotoxicity when directly injected into muscle tissue
– But used for trigger point injections commonly


Utility in Pain Management

• Lidocaine infusion decreases post operative opioid requirements and may shorten hospital stay after abdominal procedures.


LA Drug Interactions

-2 LAs, additive effects
-LAs potentiate NMDR
-situations which inhibit plasma cholinesterase slow the metabolism of ester LAs (metoclopramide, echothophate, pregnancy)


LAs Placental transfer (amides)

• Amides may cross the placenta and fetal ion trapping may occur
– Prilocaine>lidocaine>bupivicaine
• ↑tissue protein binding leads to ↓availability for placental transfer


LAs Placental Transfer (esters)

• Esters are generally not available for placental transfer due to rapid hydrolysis in the plasma
– Rate of hydrolysis: chloro>proc>tetra
– Chloroprocaine is considered by many to be the LA of choice for labor epidurals


LA DOA is proportional to...

the time the drug is in contact with the nerve fiber


LA and use of Vasoconstrictors

– Addition of epi (1:200,000) produces vasoconstriction and limits absorption away from the site of action causing ↑DOA
• Decreases risk of toxicity
• Shorter acting agents have more profound effects than longer acting
• Vasoconstrictors do not affect speed of onset

-Epi may produce cardiac irritability in the presence of volatile agents
-Epi should not be used for infiltration into tissues supplied by end-arteries (fingers, ears, nose, penis)


Systemic absorption and toxicity after administration is dependent on...

– Dose administered
– Vascularity of the injection site
– Presence of epi in the solution
– Physicochemical properties of the drug


Treatment Systemic Toxicity: Local Neuro Toxicity

– Cauda equina (SA)
• Stop drug delivery!


Treatment Systemic Toxicity: CNS

– Hyperventilation (with 100% O2)
• Decreases delivery of drug to brain
– Administer a benzodiazepine or STP


Treatment Systemic Toxicity: CV

-supportive measures (CPR, ACLS, no lido)
-bupivicaine toxicité resistant to therapy (recent research supports efficacy of treatment with lipid emulsion)


Esther (Cocaine action)

– The only LA which intrinsically produces vasoconstriction (unique) due to inhibition of norepinephrine reuptake in both peripheral and central NS (unique)
– Also inhibs dopa and other catecholamine reuptake


Esther (Cocaine uses)

used primarily for topicalization of the upper resp tract and GU tract (esp ENT surgery)


Esther (Cocaine abuse potential)

Schedule II


Esther (Cocaine metabolism)

Hepatic Metabolism (unique)


Cocaine Toxicity

SNS stimulation
-blocks presynaptic NE and dopamine reuptake

-coronary angiospasm, ischemia
-tachycardia, HTN, increased myocardial oxygen requirements
-cardiac effects can last 6 weeks after use
-hyperpyrexia leading to seizures (treat with NTG, esmolol, benzo)

Addition of Epi may sensitize the myocardium to catecholamines and exaggerate cardiac stimulating effects of cocaine


Esters (Procaine- onset, duration, potency, toxicity)

– Fast onset
– Short duration ~6% protein binding
– Low potency -3% non‐ionized at pH 7.4 (pK 8.9)
– Low toxicity


Esters (Procaine uses)

– Used for local infiltration and spinal anesthesia for very short procedures


Esters (Procaine metabolism)

– Metabolized by pseudocholinesterase to PABA


Esters (Chloroprocaine- onset, duration, potency, toxicity)

– Very rapid onset
– Short duration d/t rapid hydrolysis
– Low potency—2% non‐ionized at 7.4 pH (pK 9.1)
– Very low toxicity d/t rapid hydrolysis


Esters (Chloroprocaine- uses)

– Used for local infiltration nerve block and epidural anesthesia esp. in parturients


Esters (Chloroprocaine- metabolism)

– Metabolized by plasma cholinesterases


Esters (Tetracaine- onset, duration, potency, toxicity)

-slow onset
-very long duration
-high potency 14% non-ionized at 7.4 pH (pK 8.6)
-moderate toxicity


Esters (Tetracaine- uses)

– Used primarily for spinal anesthesia
– Produces motor and sensory blockade of similar duration and intensity


Esters (Tetracaine- metabolism)

-hydrolized by plasma esterases


Amides (Lidocaine- onset, duration, potency, toxicity)

-rapid onset
-moderate duration- 65% protein binding
-moderate potency- 24% non-ionized at 7.4 (pK 7.7)
-moderate toxicity


Amides (Lidocaine uses)

– Used for all types of regional/local/topical anesthesia
• Nebulized for upper and lower resp surface anesthesia prior to laryngoscopy or bronchoscopy


Amides (Lidocaine- metabolism)

hepatic metabolism



– Cauda equina syndrome- higher risk when hi [c] (5%) adm via catheter into SA space
– Significant first pass pulmonary uptake


Lidocaine IV uses

• For VT/VF
• To blunt the sympathetic response to tracheal intubation
• To attenuate bronchoconstriction
• As an antitussive agent
• For its sedative properties
• To reduce pain on injection of propofol or other drugs


Amides (Mepivicaine- onset, duration, potency, toxicity)

– Moderate onset
– Moderate duration
– Moderate potency—39% non‐ionized at 7.4 (pK 7.6)
– Moderate toxicity


Amides (Mepiviciane- uses)

– Used for local infiltration, peripheral blocks, and epidural anesthesia


Amides (Bupiciciane- onset, duration, potency, toxicity)

– Slow onset
– Very long duration~95% protein binding
– High potency—17% non‐ionized at 7.4 pH (pK 8.1)
– High toxicity


Amides (Bupiviciane- uses)

– Used for all types of regional anesthesia
– Sensory block is greater than motor blockade



-1st pass pulmonary uptake is dose dependent
-propranolol impairs pulmonary uptake


Bupivicaine (cardiac toxicity)

– Cardiac toxicity is resistant to treatment due to avid binding of bupiv to cardiac Na+ channels
– Hypotension, arrhythmias, AV Block,
– Risk for CV toxicity ↑with Pregnancy, β‐blockade, Ca Channel Blockers, epi, phenylephrine – R isomer is responsible for CV toxicity


Amides (Etidocaine- onset, duration, potency, toxicity)

– Rapid onset
– Very long duration
– High potency—33% non‐ionized at 7.4 (pK 7.7)
– Moderate toxicity


Amides (Priocaine- metabolism)

– First pass pulmonary uptake
– Metabolism in liver...Metabolite = o‐toluidine
– May be responsible for methemoglobinemia after prilocaine administration
-Treat methemoglobinemia with 1mg/kg methylene blue over 5 minutes


fastest metabolism

Prilocaine> lidocaine> mepivicaine> ropivicaine> bupivicaine


Amides (Ropivicaine- onset, duration, potency, toxicity)

– Slow onset
– Long duration pK 8.1
– High potency
– Moderate toxicity


Amides (Ropiviciane- uses)

– Sensory block in excess of motor blockade • Walking epidural
– Used for all types of regional anesthesia – Less cardiotoxicity than bupivicaine



L isomer of bupiv – Less cardiotoxicity