local anesthetics
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Local Anesthetics
By
M.H.Farjoo M.D, Ph.D
Shahid Beheshti University of Medical Science
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Local Anesthetics
Introduction Classification Mechanism of action Henderson-Hasselbalch equation Modifying Factors Pharmacokinetic Toxicity Clinical Uses Drug Pictures
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Of one Essence is the human race
thus has Creation put the base
One Limb impacted is sufficient
For all Others to feel the Mace
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Introduction
The first LA, cocaine, was isolated in 1860. Cocaine introduced into practice in 1884 as a topical
ophthalmic anesthetic. Despite its addictive property, cocaine was used for
30 years. In 1905 procaine was synthesized, which became the
dominant LA for the next 50 years. Lidocaine, which is still a widely used LA, was
synthesized in 1943
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Ester:
Amide:
Procaine
Lidocaine
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Classification Ester
Cocaine Procaine (Novocaine) Tetracaine (Pontocaine) Benzocaine
Amide Lidocaine (Xylocaine) Bupivocaine (Marcaine) Prilocaine (Citanest) Articaine
Transdermal
A multivesicular liposomal formulation, effective for 72 hrs
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Esters Potency (Procaine = 1)Duration of
Action
Cocaine 2 Medium
Procaine (Novocain) 1 Short
Tetracaine (Pontocaine) 16 Long
Benzocaine Surface use only
Amides Potency (Procaine = 1)Duration of
Action
Lidocaine (Xylocaine) 4 Medium
Mepivacaine (Carbocaine, Isocaine)
2 Medium
Bupivacaine (Marcaine), Levobupivacaine (Chirocaine)
16 Long
Articaine No data Medium
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Mechanism of Action
Pain awareness, (nociception), is transmitted to the CNS by primary afferent fibers and relayed by secondary afferent fibers to the brain.
Transmission can be prevented by blocking the Na+
channels in the axons which reside: Outside the spinal cord (regional anesthesia) Inside the spinal cord (spinal anesthesia)
These drugs block conduction in all the cells that use Na+ channels for action potential.
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Mechanism of Action
LAs block voltage-gated sodium channels in neurons. These Na+ fluxes are similar to those in heart muscle,
and LAs have similar effects in both tissues. Biologic toxins (scorpion venoms) bind to receptors
within the channel and prevent inactivation. LAs bind near the intracellular end of the sodium
channel.
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Mechanism of Action
LAs block the channel in a time- and voltage-dependent fashion.
Channels in the rested state, have a much lower affinity for LAs than activated and inactivated channels.
So, the effect of a drug is more marked in rapidly firing axons than in resting fibers.
If the sodium current is blocked over a critical length of the nerve, impulse is blocked.
In myelinated nerves, the critical length is two to three nodes of Ranvier.
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Zero
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Henderson-Hasselbalch equation
Mode of entrance of LA
The pKa of most LAs is 8.0–9.0, so in the body exist as cations.
The cationic form is the most active form at the receptor site because it cannot readily exit from closed channels.
LAs are less effective when injected into infected (acidic) tissues.
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Modifying Factors
Nerve fibers differ in their sensitivity to LA blockade. The smaller B and C fibers are blocked first, then other
sensory axons, and motor function is the last. Between successive action potentials, a portion of the
sodium channels will recover from the LA block. The recovery from drug-induced block is 10 to 1000
times slower than normal inactivation. So, the refractory period is lengthened and the nerve
conducts fewer electrical impulses.
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Relative size and susceptibility of different types of nerve fibers to LAs.
Fiber Type Function Diameter Myelination Conduction Velocity (m/s)
Sensitivity to Block
Type A
Alpha Proprioception, motor 12-20 Heavy 70-120 +
Beta Touch, pressure 5-12 Heavy 30-70 ++
Gamma Muscle spindles 3-6 Heavy 15-30 ++
Delta Pain, temperature 2-5 Heavy 12-30 +++
Type B Preganglionic autonomic < 3 Light 3-15 ++++
Type C
Dorsal root Pain 0.4-1.2 None 0.5-2.3 ++++
Sympathetic Postganglionic 0.3-1.3 None 0.7-2.3 ++++
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Practicallyinfinite
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Modifying Factors
Blockade by these drugs is more marked at higher frequencies of depolarization.
Sensory (pain) fibers have a high firing rate and a relatively long action potential duration.
Motor fibers fire at a slower rate and have a shorter action potential duration.
In the extremities, proximal sensory fibers are located superficially, whereas the distal ones are located deeply.
Thus, in large nerves, sensory analgesia develops proximally and then spreads distally.
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Modifying Factors
Acidification of urine leads to more rapid elimination. The onset of LA can be accelerated by sodium bicarbonate
(1–2 mL) to the LA solution. This maximizes the amount of drug in the more lipid-soluble
(unionized) form. Hypercalcemia antagonizes the action of LAs by increasing
the surface potential of membrane (low-affinity rested state). Hyperkalemia enhances the effect of LAs by depolarizing
the membrane potential (inactivated high-affinity state).
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Modifying Factors
LAs are marketed as hydrochloride salts (pH 4.0–6.0) to maximize aqueous solubility.
the salts are buffered in the body providing sufficient free base for their effect.
repeated injections can deplete the buffering capacity and the ensuing acidosis results in tachyphylaxis.
Tachyphylaxis to LAs is common in CSF (limited buffer capacity).
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Pharmacokinetic
The LAs are metabolized in the liver (amide type) or in plasma (ester type)
The half-life of lidocaine (amide LA) is 1.6 hrs in normal patients but > 6 hours in severe liver disease.
Ester-type LAs are hydrolyzed rapidly in the blood by butyrylcholinesterase (pseudocholinesterase).
So, Ester LAs have an elimination half-life less than 1 min (procaine).
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Pharmacokinetic
The smaller and more lipophilic LAs have a faster rate of interaction with the sodium channel.
Potency is correlated with lipid solubility as long as the LA retains sufficient water solubility to diffuse to its site of action.
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Pharmacokinetic
LAs are often injected, so absorption and distribution are not that important in the onset of effect.
But, they are crucial in the rate of offset of their effect and CNS and cardiac toxicity.
Injection to a vascular area (intercostal nerves) results in more rapid absorption and higher blood levels.
The reverse is true about poorly perfused tissue (tendon, dermis, fat).
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Pharmacokinetic
Blood levels of LAs after injection is: intercostal (highest) > caudal > epidural > brachial plexus > sciatic nerve (lowest).
Vasoconstriction by epinephrine or phenylephrine reduces absorption of LAs and decreases toxicity.
This will enhance localized neuronal uptake and increase duration of action.
This is important for drugs with intermediate or short durations of action (lidocaine).
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Pharmacokinetic
Alpha2 adrenoceptors, inhibits release of substance P (neurokinin-1) in spinal cord and reduce sensory neuron firing.
This led to the use of clonidine to prolong the LA effect.
The combination of reduced systemic absorption, and alpha2 activation by epinephrine prolongs the LA effect by 50%.
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Toxicity
The side effects of LAs represent extensions of their therapeutic effects (their toxicity is difficult to reduce).
An early symptom of LA toxicity is circumoral and tongue numbness and a metallic taste.
At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions.
LAs may cause depression of cortical inhibitory pathways.
This transitional stage of unbalanced excitation (seizure) is then followed by generalized CNS depression.
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Toxicity
When large doses of a LA are required, pretreatment with IV diazepam or midazolam prevents CNS toxicity.
In spinal anesthesia, motor paralysis may impair respiration, and autonomic blockade can cause hypotension.
Autonomic blockade also interferes with bladder function which needs bladder catheterization.
High concentrations of LA in the subarachnoid space interferes with intra-axonal transport and calcium homeostasis => spinal toxicity.
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Toxicity
Bupivacaine can cause lethal arrhythmias if high plasma concentrations are achieved.
Bupivacaine may be more cardiotoxic than other LAs.
The ECG finding is a slow idioventricular rhythm and eventually electromechanical dissociation.
Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult, though propofol can be useful.
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Toxicity
The ester-type LAs are metabolized to Para amino benzoic acid derivatives.
These metabolites are responsible for allergic reactions in a small percentage of the patients.
Amides are not allergic.
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Toxicity
The administration of large doses of prilocaine may lead to accumulation of o-toluidine.
It is an oxidizing agent converting hemoglobin to methemoglobin.
When sufficient methemoglobin is present, the patient may appear cyanotic and the blood "chocolate-colored."
Methemoglobinemia may cause decompensation in patients with cardiac or pulmonary disease.
The treatment is IV injection of a reducing agent (methylene blue or ascorbic acid), which rapidly converts methemoglobin to hemoglobin.
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Clinical Uses
IV regional anesthesia (Bier block) is used for procedures < 60 min. involving the extremities.
LA is injected into a distal vein while the circulation of the limb is isolated with a proximally placed tourniquet.
Block of sympathetic fibers is also used to evaluate the role of sympathetic tone in peripheral vasospastic disorders.
Lidocaine is used also for arrhythmia at concentrations lower than those required for nerve block.
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Clinical Uses
Systemic LAs may be used as adjuvants to the combination of a TCA (amitriptyline) and an anticonvulsant (carbamazepine) in chronic pain.
A period of 1–3 weeks may be required to observe a therapeutic in neuropathic pain.
LAs have poorly understood anti-inflammatory effects, which contributes to pain control in chronic pain.
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Subclass EffectsClinical
ApplicationsPharmacokinetics,
Toxicities
Amides
Lidocaine Slows, then blocks action potential propagation
Short-duration procedures epidural, spinal anesthesia
Parenteral duration 30–60 min 2–6 h with epinephrine Toxicity: CNS excitation
Bupivacaine Same as lidocaine
Longer-duration procedures
Parenteral duration 2–4 h Toxicity: CNS excitation cardiovascular collapse
Prilocaine, ropivacaine, mepivacaine, levobupivacaine: Like bupivacaine
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Subclass Effects Clinical ApplicationsPharmacokinetics,
Toxicities
Esters
Procaine Like lidocaine Very short procedures Parenteral duration 15–30 min 30–90 min with epinephrine Toxicity: Like lidocaine
Cocaine Same as above Procedures requiring high surface activity and vasoconstriction
Topical or parenteral duration 1–2 h Toxicity: CNS excitation, convulsions, cardiac arrhythmias, hypertension, stroke
Tetracaine: Used for spinal, epidural anesthesia; duration 2–3 h
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Thank youAny question?