Local Anesthetics Pharmacology

Iyad M.Abou Rabii

February , 2010
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 What are local anesthetics?

§ Local anesthetic: produce loss of sensation to pain in a specific area of

the body without the loss of consciousness

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 History

§ Genus Erythroxylum discovered in South America,

Venezuela, Bolivia, and Peru since pre-Columbian
periods
§ Coca leaves from the genus Erythroxylum contain high
concentration of alkaloid up to 0.7-1.8%
§ In 1571, Pedro Pizarro, a conquistador of Inca, observed
nobles and high rank officials of the Inca empire
consumed the coca plant.
§ After the fall of the Inca empire, coca consumption spread
widely to the population
§

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 Development of general and local
anesthesia

§ Took place in Western Europe from 1750 to 1850

§ Chemists and physicians collected sample of coca leaves
for experiments
§ Isolated active principle of coca leaf, synthesized to a drug
for patients to feel more relief of pain when taking
surgeries
§ In 1860, German chemist Albert Niemann successfully
isolate the active principle of coca leaf; he named it
cocaine

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 Development of general and local anesthesia
(cont.)

§ Niemann discovered the effect of numbness of the tongues caused by

alkaloid in 1860
§ Based on Niemann’s discovery, Russian physician Basil Von Anrep
did experiments on animals, such as rats, dogs, and cats.
§ He injected small quantity of 1% solution to his tongue; tongue
became insensitive
§ He concluded cocaine is a good drug for surgical anesthetic
§ William Steward Halsted and Richard John Hall developed the inferior
dental nerve block techniques for dentistry

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 Cocaine Addiction

§ An ophthalmologist Carl Koller realized the importance of

the alkaloid’s anesthetic effect on mucous membranes
§ In 1884, he used the first local anesthetic on a patient with
glaucoma
§ In 1898, Professor Heinrich Braun introduced procaine as
the first derivative of cocaine, also known as the first
synthetic local anesthetic drug
§ Trade name is Novocaine®


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 Procaine replaced cocaine (Problems)

§ Took too long to set (i.e. to produce the desired anesthetic

result)
§ Wore off too quickly, not nearly as potent as cocaine
§ Classified as an ester; esters have high potential to cause
allergic reactions
§ Caused high conc. of adrenaline resulted in increasing heart
rate, make people feel nervous
§ Most dentists preferred not to used any local anesthetic at all
that time; they used nitrous oxide gas.


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 Lidocaine

§ In 1940, the first modern local anesthetic

agent was lidocaine, trade name
Xylocaine®
§ It developed as a derivative of xylidine
§ Lidocaine relieves pain during the dental
surgeries
§ Belongs to the amide class, cause little
allergenic reaction; it’s hypoallergenic
§ Sets on quickly and produces a desired
anesthesia effect for several hours
§ It’s accepted broadly as the local
anesthetic in United States today

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 Cell Membrane Receptors

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Membrane potential and neurotransmission:

§ Neuron transmits information mainly by two mechanisms:

§ Information within a neuron is mainly transmitted by electrical signals.

§ Electrical signals are propagated by the mechanism called action
potential.

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neurotransmission: Resting Potential

§ Resting neurons maintain an intracellular negative membrane

potential.
§ Na+/K+ ATPase (sodium pump) transports intracellular Na+ to
extracellular in exchange of entry of K+ into cells. This creates a
concentration gradients of Na+ and K+

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neurotransmission: Resting Potential

§ The resting neuron cell membrane contains much more open K+

channels than open Na+ and Cl-
§ channels or channels for other ions. K+ flows to the outside down the
concentration gradient, resulting in a negative potential inside the cell.

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neurotransmission: Resting Potential

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neurotransmission: Action Potential (Depolarisation)

§ When stimulated (electrically or chemically), a depolarization of the

membrane potential in the neuron (axon) membrane opens voltage-
gated Na+ channels.
§ This leads to a burst of flow of Na+ into the cell down the
concentration gradient, causing a reverse of the membrane
potential (from negative inside to positive inside).

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neurotransmission: Action Potential (Depolarisation)

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neurotransmission: Action Potential (Repolarisation)

§ Eventually, the influx of Na+ is stopped when Na+ concentration

gradient is balanced by the reversed potential gradient.
§ Na+ channels are closed by the voltage-sensitive regulatory domain
§ Subsequently, voltage-gated K+ channels open, allowing accelerated
outflow of K+. The membrane potential returns to resting state

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neurotransmission: Action Potential (Repolarisation)

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Membrane potential and neurotransmission:

§ Action potential at one site of the neuron causes partial

depolarization of neighboring region, activates voltagegated
Na+ channels in the neighboring region and thus causes
propagation of the action potential (electrical signals) along
the axon to synapses.

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Mechanism

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Mechanism

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Mechanism

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How Local Anesthetics Work

§ Altering the basic potential of the nerve

membrane
§ Altering the threshold or firing level
§ Decrasing the rate of depolarization
§ Prolonging the rate of repolarization
§

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LOCAL ANESTHETICS CALSIFICATION

– Esters : Cocaine, Procaine , Chlore procaine

,Tetracaine .
– Amids : Lidocaine , Mepivacaine, Prilocaine , Articaine
, Popivacaine, Etidocaine
– Ketons :Dyclon.
– Quinoline: Centbucridine .

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 Differences of Esters and Amides

§ Two classes of local anesthetics are amino amides and amino esters.
 Amides: Esters:
 --Amide link b/t intermediate --Ester link b/t intermediate chain and chain
and aromatic ring aromatic ring
 --Metabolized in liver and very --Metabolized in plasma
--Cause allergic reactions


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 Differences of Esters and Amides

§ All local anesthetics are weak bases. Chemical structure of local anesthetics
have an amine group on one end connect to an aromatic ring on the other
and an amine group on the right side. The amine end is hydrophilic (soluble
in water), and the aromatic end is lipophilic (soluble in lipids)


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 Structures of Amides and Esters
§ The amine end is hydrophilic (soluble in water), anesthetic molecule dissolve in
water in which it is delivered from the dentist’s syringe into the patient’s
tissue. It’s also responsible for the solution to remain on either side of the
nerve membrane.
§ The aromatic end is lipophilic(soluble in lipids). Because nerve cell is made of
lipid bilayer it is possible for anesthetic molecule to penetrate through the
nerve membrane.

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 Structures of Amides and Esters

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 Structures of Amides and Esters

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Pharmacokinetics

§ Following injection into the area of nerve fibers to be blocked, local

anesthetics are absorbed into blood.

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Pharmacokinetics

§ Absorption of local anesthetics is affected by following factors:

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 Factors Affect the Reaction of Local
Anesthetics

 Lipid solubility
§ All local anesthetics have weak bases. Increasing the lipid solubility
leads to faster nerve penetration, block sodium channels, and speed up
the onset of action.
§ The more tightly local anesthetics bind to the protein, the longer the
duration of onset action.
§ Local anesthetics have two forms, ionized and nonionized. The
nonionizedform can cross the nerve membranes and block the sodium
channels.
§ So, the more nonionized presented, the faster the onset action.


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 Factors Affect the Reaction of Local
Anesthetics

pH influence


§ Usually at range 7.6 – 8.9

§ Decrease in pH shifts equilibrium toward the ionized form, delaying the
onset action.
§ Lower pH, solution more acidic, gives slower onset of action


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 Factors Affect the Reaction of Local
Anesthetics (cont.)
 Vasodilation
§ Vasoconstrictor is a substance used to keep the anesthetic solution in
place at a longer period and prolongs the action of the drug
§ vasoconstrictor delays the absorption which slows down the absorption
into the bloodstream
§ Lower vasodilator activity of a local anesthetic leads to a slower
absorption and longer duration of action
§ Vasoconstrictor used the naturally hormone called epinephrine
(adrenaline). Epinephrine decreases vasodilator.


 Side effects of epinephrine

§ Epinephrine circulates the heart, causes the heart beat stronger and
faster, and makes people feel nervous.


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 Toxicity
§ Toxicity is the peak circulation levels of local anesthetics
§ Levels of local anesthetic concentration administered to patients are varied
according to age, weight, and health.
§ Maximum dose for an individual is usually between 70mg to 500mg
§ The amount of dose also varied based on the type of solution used and the
presence of vasoconstrictor
Example:

---For adult whose weight is 150lbs and up, maximum dose Articaine and

lidocaine is about 500mg

---For children, the dosage reduced to about 1/3 to ½ depending on their

weight.
The doses are not considered lethal.

Some common toxic effects:

--light headedness ---shivering or twitching --seizures

--hypotension (low blood pressure) --numbness

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Drugs used in dental anesthesia

§ The most common local anesthetic used is called lidocaine.

§ Others might include mepivacaine, bupivacaine and prilocaine.
§ All of the drugs will most likely end with a caine. Procaine, which is
commonly known as novacaine is no longer used as the other drugs
mentioned here are more effective as numbing agent.

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 Drugs used in dental anesthesia

§ Bupivicaine (Marcaine®
--Produce very long acting anesthetic effect to delay the post operative pain from the surgery

for as long as possible

--0.5% solution with vasoconstrictor

--toxicity showed by the pKa is very basic

--Onset time is longer than other drugs b/c most of the radicals (about 80%) bind to sodium

channel proteins effectively

--most toxic local anesthetic drug

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 Drugs used in dental anesthesia

§ Prilocaine (Citanest®)
--Identical pKa and same conc. with lidocaine
--Almost same duration as lidocaine

--Less toxic in higher doses than lidocaine b/c small vasodilatory activity

§ Articaine (Septocaine®)
--newest local anesthetic drug approved by FDA in 2000
--Same pKa and toxicity as lidocaine, but its half life is less than about ¼ of lidocaine

--Used with vasoconstrictor.

--Enters blood barrier smoothly

--The drug is widely used in most nations today

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 Anesthetic pKa Onset Duration Max Dose
(with (with
Epinephrine Epinephrine
) in minutes )
Procaine 9.1 Slow 45 - 90 8mg/kg –
10mg/kg
Lidocaine 7.9 Rapid 120 - 240 4.5mg/kg –
7mg/kg

Bupivacaine 8.1 Slow 4 hours – 8 2.5mg/kg –

hours 3mg/kg
Prilocaine 7.9 Medium 90 - 360 5mg/kg –
7.5mg/kg
Articaine 7.8 Rapid 140 - 270 4.0mg/kg –
7mg/kg

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 The Other Drugs in a Local Anesthesia Carpule

The dentist will make a solution for the local anesthesia to be

administered prior to the surgery. Some of the other drugs in the
solution may contain an antioxidant to prevent a breakdown of the
vasoconstrictor, sodium hydroxide to adjust the acidity of the anesthetic
so it works more effectively, sodium chloride, to help the solution enter
the bloodstream more effectively and sometimes epinephrine which
also works to narrow blood vessels to help the anesthetic last longer.

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Vasoconstrictors

Vasoconstrictors, such as epinephrine and norepinephrine, are commonly

contained in local anesthetics to decrease systemic toxicity and prolong
the duration of action by retarding anesthetic absorption.

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Clinical Consideration

These catecholamines have varying degrees of α and β adrenergic effects,

resulting in cardiac and hemodynamic changes

In cardiac patients, the administration of low concentration of epinephrine

might be necessary according to the degree of severity of the disease.

These doesn`t mean the use of epinephrine free local anesthetics but to
make sure that it is not directly administrated in the blood.

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 How is it administered?

There are two local anesthesia injections a dentist will use. There is
something called an infiltration injection which numbs a small area and
there is a block injection which numbs a larger region. All of the
injections are done in the interior of the mouth.

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 Side Effects:

One possible side effect is hematoma, which is a blood filled swelling

that can form when the needle accidentally punctures a blood vessel.
You may also feel numbness outside the targeted area and this may
cause drooping in your eyelid or lips. The effects of drooping will
disappear when the anesthesia wears off. Allergic reactions are also
rare; however it is important to tell your doctor about any medication
you are taking.

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 Side Effects:

Some of the side effects include a numb mouth, which is of course

the point of the anesthetic in the first place but other effects include
dizziness and the feeling that you have a fat or swollen lip. Other
than that, side effects are very rare, which is part of the reason the
local anesthetic is so popular in dental procedures.

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 References
§ Calatayud Jesús and González Ángel. History of the Development and Evolution of
Local Anesthesia Since the Coca Leaf. © 2003 American Society of
Anesthesiologists Volume 98(6) June 2003 pp 1503-1508.
§ Peter C. Meltzer, Shanghao Liu, Heather S. Blanchette, Paul Blundell, Bertha K.
Madras. Design and Synthesis of an Irreversible Dopamine-Sparing Cocaine
Antagonist. @ Bioorganic & Medicinal Chemistry Volume 10, Issue 11 , November
2002, Pages 3583-3591
§ Shigeki Isomura, Timothy Z. Hoffman, Peter Wirsching, and Kim D. Janda. Synthesis,
Properties, and Reactivity of Cocaine BenzoylthioEster Possessing the Cocaine
Absolute Configuration. J. AM. CHEM. SOC. 2002, Issue 124, p.3661-3668
§ Mazoit, Jean-Xavier; Dalens, Bernard J. Pharmacokinetics of local anesthetics in
infants and children. Clinical Pharmacokinetics (2004), 43(1), 17-32.


§ Alejandro A. Nava-Ocampoand Angelica M. Bello-Ramirez. Lipophilicity Affects the

Pharmacokinetics and Toxicity of Local AnaestheticAgents Administered by Caudal
Block. Clinical and Experimental Pharmacology and Physiology (2004) 31, 116-118.
§ Don R Revis, Jr. Local Anesthetics. October 14,2004: (Medline)
 http://www.emedicine.com/ent/topic20.htm

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Iyad.abou.rabii@qudent.edu.sa

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