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Resident: B.Ankhzaya (MNUMS)
Local Anesthetics and Additives
1. Mechanism of action of LA
2. Structure and Function
3. Pharmacokinetics of LA
4. Pharmacodynamics of LA
5. Effects of organ systems
6. Clinical profile of LA
7. Additives of LA
8. Toxicity of LA
Local and regional anesthesia and analgesia techniques depend on a
group of drugs—local anesthetics—that transiently inhibit sensory, motor,
or autonomic nerve function, or a combination of these functions, when
the drugs are injected or applied near neural tissue.
Mechanism of action of LA
CLASSIFICATION OF NERVE FIBERS
Classification Diameter(µ) Myelin Conduction(m/sec) Location Function
A-α 6–22 + 30–120 Afferents/
A- α 6–22 + 30–120 Proprioception
A-β 5-12 + 30-70 Touch , pressure
A-γ 3–6 + 15–35 Efferent to muscle spindle Muscle tone
A-δ 1–4 + 5–25 Afferent sensory nerve Pain, touch,
B <3 +/- 3–15 Preganglionic sympathetic Autonomic
C /sympathetic/ 0.3–1.3 – 0.7–1.3 Postgang lionicsympathetic
Afferent sensory nerve
C/dorsal root/ 0.4-1.2 - 0.5-2 Pain,temperature
• LAs disrupt conduction of
impulses along nerve axons
by inhibiting the action of
sodium channels required for
• In addition, LAs interact
with other ionopores and G
protein regulated channels
suggesting a more complex
mechanism of action
1. Sodium (Na+) enters cell via sodium channels.
2. Unionized local anaesthetic (LA) crosses lipid bilayer to enter the cell where it is promptly ionized.
3. Ionized LA blocks the sodium channel from the internal surface, preventing sodium entry and depolarization. LA also inhibits
conduction by acting on potassium and calcium channels and G protein-mediated receptors.
Structure and Function
• LAs have a common structure consisting of:
• a lipophilic- aromatic ring
• a hydrophilic-amine
• a ‘link’ molecule which is either an ester or amide bond.
• Most LAs are weak bases and are presented in an acidic solution (usually their hydrochloride salt) and the
LA molecules are therefore ionized, water-soluble, and stable in solution.
• The minimum concentration of local anesthetic that will block nerve impulse conduction is affected by
several factors, including fiber size, type, and myelination; pH (acidic pH antagonizes block); frequency of
nerve stimulation; and electrolyte concentrations (hypokalemia and hypercalcemia antagonize blockade).
Factors that increase the uptake of LA into the plasma include:
• cardiac output (determines perfusion of organs)
• hepatic function (aﬀects protein binding and metabolism).
• low protein binding
• vasodilatory eﬀects: prilocaine > lidocaine > bupivacaine> ropivacaine > cocaine
• intercostal > epidural > plexus/nerve > subcutaneous.
Pharmacokinetics of LA
• Highly perfused organs (heart &brain)
Metabolism & Excretion
Esters- are metabolized in the body by plasma cholinesterase and other nonspecifc esterases, except cocaine which is
metabolized in the liver by ester hydrolysis and demethylation.
• Metabolites of ester LAs are excreted by the kidneys.
• A breakdown product of ester LAs is para-amino benzoic acid (PABA), which is implicated in the high incidence of allergic
reactions to these agents
Amides- undergo phase I and II metabolism in the liver via the cytochrome p450 system.
• Allergic responses are rarely associated with these agents.
• Metabolism of amides is slower than esters, leading to a longer half-life and greater potential to accumulate if given as an
infusion or repeated doses.
• The amide bond is stronger than the ester, allowing amide LAs to be stored for longer and even withstand autoclaving.
• Prilocaine (an amide) is further metabolized in the lungs to produce o-toluidine which in high doses can induce
Pharmacokinetics of LA
Onset of Action
• The onset of action is dependent on the relative concentrations of unionized (lipophilic) and ionized
(hydrophilic) LA molecules.
Onset time is quicker in LAs where the proportion of unionized molecules is greater. (e.g For example, let us
compare bupivacaine to lidocaine. Bupivacaine has a higher pKa than lidocaine; and is therefore a stronger base and more highly ionized
at body pH. 85% of bupivacaine molecules are ionized at pH 7.4 compared to 72% of lidocaine, thus explaining the faster onset of action
Duration of Action
• The duration of action of LAs is directly related to protein binding, agents which exhibit greater protein
binding have a longer duration of action, e.g. bupivacaine.
• Vascularity of the site of injection and the vasodilatory properties of the LA also inﬂuence duration of
action. For example, lidocaine causes localized vasodilatation which leads to i uptake of the drug away
from the site reducing the duration of action.
• The potency of LAs in vitro is determined by lipid solubility. Highly lipid-soluble LAs can enter the cell
easily to act on sodium channels, and therefore a smaller quantity of drug is required.
• However, other factors inﬂuence this relationship in vivo, e.g. vascularity of the area and the vasodilatory
properties of the drug.
Bupivacaine is more potent than lidocaine,because it is more lipophilic.
Pharmacodynamics of LA
Effects of organ system(CNS)
• Local anesthetics readily cross the blood–brain barrier, and generalized CNS toxicity may occur from
systemic absorption or direct vascular injection.
• Early symptoms include circumoral numbness, tongue paresthesia, dizziness, tinnitus, and blurred vision.
• Excitatory signs include restlessness, agitation, nervousness, garrulousness, and a feeling of “impending
• Central nervous system depression (eg, coma and respiratory arrest)
• Tonic–clonic seizures
• Potent, highly lipid-soluble local anesthetics produce seizures at lower blood concentrations than less potent
• local anesthetics such as lidocaine (1.5 mg/kg) can decrease cerebral blood ﬂow and attenuate the rise in
• Cocaine- euphoria (overdose is heralded by restlessness, emesis, tremors, convulsions, arrhythmias,
respiratory failure, and cardiac arrest )
• Transient neurological symptoms, which consist of dysesthesia, burning pain, and aching in the lower
extremities and buttocks, have been reported following spinal anesthesia with a variety of local anesthetic
agents, most commonly after use of lidocaine for outpatient spinal anesthesia in men undergoing surgery in
the lithotomy position.
• Lidocaine-Infusions of lidocaine and procaine have been used to supplement general anesthetic techniques,
as they are capable of reducing the MAC of volatile anestheticsby up to 40%. Infusions of lidocaine
inhibit inﬂammation and reduce postoperative pain. Infused lidocaine reduces postoperative opioid
requirements sufficiently to reduce length of stay after colorectal or open prostate surgery.
• Bupivacain -one of the toxic eﬀects on the heart of bupivacaine (in particular) is to inhibit the transportation
of lipid substrates (for metabolism) into the cardiac myocytes.
• Ropivacaine- Ropivacaine shares many physicochemical properties with bupivacaine.
Onset time and duration of action are similar, but ropivacaine produces less motor block when injected at
the same volume and concentration as bupivacaine (which may reflect an overall lower potency as
compared with bupivacaine).
• Levobupivacaine, the S(-) isomer of bupivacaine, which is no longer available in the United States, was
reported to have fewer cardiovascular and cerebral side effects than the racemic mixture; studies suggest its
cardiovascular effects may approximate those of ropivacaine.
• Cocaine- Cocaine’s cardiovascular reactions are unlike those of any other local anesthetic. Adrenergic
nerve terminals normally reabsorb norepinephrine afer its release. Cocaine inhibits this reuptake, thereby
potentiating the eﬀects of adrenergic stimulation. Cardiovascular responses to cocaine include hypertension
and ventricular ectopy.
Special of Drugs
• Apnea- can result from phrenic and intercostal nerve paralysis or depression of the medullary
respiratory center (as may occur after retrobulbar blocks )
• Relax bronchial smooth muscle (Intravenous lidocaine (1.5 mg/kg) may be effective in
blocking the reflex bronchoconstriction sometimes associated with intubation )
• Lidocaine (or any other inhaled agent) administered as an aerosol can
lead to bronchospasm in some patients with reactive airway disease
Effects of organ system (Respiratory)
Effects of organ system (CVS)
• All local anesthetics except cocaine produce smooth muscle relaxation at higher concentrations,
which may cause some degree of arteriolar vasodilation.
• Myocardial contractility and conduction velocity are also depressed at higher concentrations.
• At increased blood concentrations the combination of arrhythmias, heart block, depression of
ventricular contractility, and hypotension may culminate in cardiac arrest.
• Myocardial contractility and arterial blood pressure are generally unaﬀected by the usual
• Lidocaine mildly depresses normal blood coagulation (reduced thrombosis
and decreased platelet aggregation).
Effects of organ system (Hematological)
Unintentional intravascular injection of bupivacaine during regional anesthesia
may produce severe cardiovascular toxicity, including left ventricular
depression, atrioventricular heart block, and life-threatening arrhythmias such
as ventricular tachycardia and fibrillation.
Pregnancy, hypoxemia, and respiratory acidosis are predisposing risk factors.
Young children may also be at increased risk of toxicity.
• Esters appear more likely to induce a true allergic reaction (due to IgG or IgE antibodies)
especially if they are derivatives (eg, procaine or benzocaine) of p-aminobenzoic acid, a
• Commercial multidose preparations of amides often contain methylparaben, which has a
chemical structure vaguely similar to that of PABA.
Effects of organ system (Immunological)
Effects of organ system (Musculoskeletal)
• When directly injected into skeletal muscle (eg, trigger-point injection treatment of
myofascial pain), local anesthetics are mildly myotoxic.
• Regeneration usually occurs 3–4 weeks after local anesthetic injection into muscle.
Concomitant steroid or epinephrine injection worsens the myonecrosis.
Clinical profile of LA
• Vasoconstrictors (Epinephrine)-Never add vasoconstrictors to LA when
injecting near to an end artery, e.g. digits or penis, as this may cause
irreversible, ischaemic damage. Many practitioners will also avoid
vasoconstrictor containing LA solutions around the sciatic nerve due to a
perceived poor blood supply.
Typically, epinephrine is added in a concentration of 1:200,000 or 5
micrograms per mL, up to a maximum absolute dose of 200 micrograms (total
of 40 mL 1:200,000 solution delivered). To prepare this concentration, use a
1mL syringe to draw up an ampoule of 1:1000 epinephrine (i.e. 1mg/mL
epinephrine). Add 0.1 mL epinephrine to each 20mL LA.
• Clonidine -Clonidine is primarily an α2-agonist; a dose of 1–2 micrograms/kg
intensifies and prolongs sensory and motor blockade in both central and
peripheral nerve blocks. Side eﬀects include sedation and hypotension.
• Glucose -Glucose (usually 80mg/mL) is added to LAs to produce a hyperbaric
solution for spinal anaesthesia. Together with patient positioning, this provides
more reliable spread of LA in the intrathecal space compared with isobaric
Additives of LA
• Opioids (especially buprenorphine)-added to the local anesthetic solution
placed into the epidural or subarachnoid space result in synergistic
analgesia and anesthesia without increasing the risk of toxicity
• Sodium bicarbonate
Addition of sodium bicarbonate increases the pH of the solution thereby
increasing the proportion of unionized LA molecules, which hastens the
onset of action. Excessive bicarbonate can lead to precipitation of the
unionized insoluble LA.
• Steroids. Combined with intermediate- to long-acting local anesthetics,
dexamethasone extends the duration of analgesia by approximately 50%
after utilization of the supraclavicular or interscalene approach for brachial
Additives of LA
• Tonicaine -s a charged derivative of lidocaine and has shown a prolonged
duration of action after subcutaneous infltration in animals
• Sameridine-is a LA which is also an opioid receptors agonist and may
provide additional postoperative analgesia.
• Butyl amino-benzoate -was originally discovered in 1923, but a new
formulation has produced a poorly soluble agent with a low pKa which
appears selective for Aδ and C nerve fbres.
• Toxicity is estimated to occur 1 in 1000-10000 blocks.
o Drug overdose (exceeding maximum doses).
o Inadvertent intravascular injection:
• needle tip in blood vessel
• epidural vein cannulation
• connection of LA infusions to IV cannula.
o Rapid absorption of bolus dose.
o Cumulative eﬀect of infusions or repeated doses.
o Susceptible patients (metabolic mitochondrial defects, pre-existing
cardiac conduction blocks) may be at higher risk of toxicity.
Toxicity of LA
• In fact, widely used LAs are all amphipathic (they have hydrophobic and
hydrophilic moieties) so they are apt to bind both hydrophilic proteins (dissolved in
cytosol) and hydrophobic proteins (dissolved in the lipid bilayer of the cell or
• More specifcally, LAs have been shown to bind voltage-gated potassium and
calcium channels as well as sodium channels and also inhibit intracellular signal
transduction after G protein activation.
• Inhibition of voltage-gated
calcium channels slows cardiac
automaticity (bradycardia) and
conduction (conduction block).
• Inhibition of voltage-gated
sodium and potassium channels
slows action potential propagation
and repolarization, promoting re-
entrant tachycardia before
• local anaesthetic systemic toxicity (LAST)
Timing of lipid emulsion
• Other clinicians have reported using
lipid treatment successfully in cardiac
collapse before frank cardiac arrest.
• So the threshold for treatment with
lipid is currently unclear,
but it is sensible not to wait for full
circulatory arrest to occur before
giving lipid emulsion.
• If, alternatively, the lipid has some
metabolic eﬀect, then adding an
infusion would be rational. However,
to date, patients that have received
large doses of lipid emulsion have not
reported any side eﬀects
Mechanism of Lipid emulsion
Lipid emulsion may act
as a ‘lipid sink’, binding
free LA molecules and
thus reducing plasma
concentration below toxic