Local anesthesia

DR.MAHA TALAL

LOCAL ANESTHETICS

Local anesthesia

Local anesthetics produce a transient and reversible loss of sensation (analgesia) in a circumscribed region of the body without loss of consciousness.

Normally, the process is completely reversible.

Pharmacology of Local Anesthetics
• Outline
• History
• Chemistry and Structure-Activity Relationships
• Mechanism of Action
• Pharmacological effects and toxicities
• Clinical aspects

Pharmacology of Local Anesthetics - History

1860 Albert Niemann isolated crystals from the coca leaves– and called it “cocaine” – he found that it reversibly numbed his tongue!


1884 , Koller did first eye surgery in humans using cocaine as local anesthetic

1905 German chemist Alfred Einhorn produced the first synthetic ester- type local anesthetic - novocaine (procaine) - retained the nerve blocking properties, but lacked the powerful CNS actions of cocaine

• Swedish chemist Nils Löfgren synthesized the first amide-type local anesthetic - marketed under the name of xylocaine (lidocaine)
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Pharmacology of Local Anesthetics

• Outline
• History
• Chemistry and Structure-Activity Relationships
• Mechanism of Action
• Pharmacological effects and toxicities
• Clinical aspects

Pharmacology of Local Anesthetics - Chemistry

Structure-Activity Relationships:

All local anesthetics contain 3 structural components:

an aromatic ring (usually substituted)
a connecting group which is either an ester (e.g., novocaine) or an amide (e.g. lidocaine)
an ionizable amino group

Classification, Structure and Function

ANESTHETICS

Pharmacology of Local Anesthetics – Chemistry

Chemical structures of prototypical ester- and amide-type local anesthetics – comparison with cocaine


procaine/novocaine

lidocaine/xylocaine

cocaine

Pharmacology of Local Anesthetics – Chemistry

• Structure-Activity Relationships:
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• Two important chemical properties of local anesthetic molecule that determine activity:
• Lipid solubility: increases with extent of substitution on aromatic ring and/or amino group
• Ionization constant (pK) – determines proportion of ionized and non-ionized forms of anesthetic

Pharmacology of Local Anesthetics – Chemistry

Lipid solubility: determines, potency, plasma protein binding and duration of action of local anesthetics


Lipid solubility
Relative potency
Plasma protein binding (%)
Duration
(minutes)
procaine
1
1
6
60-90
lidocaine
4
2
65
90-200
tetracaine
80
8
80
180-600


Pharmacology of Local Anesthetics – Chemistry
Local anesthetics are weak bases – proportion of free base (R-NH2) and salt (R-NH3+) forms depends on pH and pK of amino group

pH = pK + log [base]/[salt]

(Henderson-Hasselbalch equation)

Pharmacology of Local Anesthetics – Chemistry

• Both free base and ionized forms of local anesthetic are necessary for activity:
• local anesthetic enters nerve fibre as neutral free base and the cationic form blocks conduction by interacting at inner surface of the Na+ channel
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DISSOCIATION OF LOCALANESTHETICS

• Local anesthetics are available as salts (usually
hydrochlorides) for clinical use.
• The salts, both water soluble and stable, is
dissolved in either sterile water or saline.
• In this solution it exists simultaneously as
unchanged molecule (RN), also called base and
positively charged molecules (RNH+) called cations.
RNH+ ==== RN+ H+


Local anesthetics are prepared in a water soluble HCL salt with a pH of 6-7.
If epinephrine is added, in a commercial preparation, the pH is kept between 4-5 to keep epinephrine stable. This creates less free base (non-ionized) and slows the onset of action.

Some clinicians will add NaBicarb to commercially prepared solutions that contain epinephrine to increase the amount of free base (non-ionized form).
1 ml of 8.4% NaBicarb to each 10 ml of lidocaine or mepivacaine or 0.1 ml of 8.4% NaBicarb to each 10 ml of bupivacaine.
If you add more NaBicarb than suggested the solution will precipitate.

Pharmacology of Local Anesthetics

• Outline
• History
• Chemistry and Structure-Activity Relationships
• Mechanism of Action
• Pharmacological effects and toxicities
• Clinical aspects

MECHANISM OF ACTION

acetylcholin theory
calcium displacement theory
Membranes expansion theory
Surface charge or repulsion theory
Specific receptor theory


Nerve Conduction Physiology
Neural membrane voltage difference +60 mV (inner) to -90 mV (outer).
Neural membrane at rest is impermeable to Na+ ions but permeable to K+ ions.
K+ within the cell is kept at a high concentration while Na+ on the outside of the cell is high.
Gradient is kept by the Na+/K+ pump.

Mechanism of Action

• conduction of nerve impulses is mediated by action potential (AP) generation along axon
• Cationic form of anesthetic binds at inner surface of Na+ channel – preventing Na+ influx (rising phase of membrane potential) which initiates AP → blockade of nerve impulses (e.g., those mediating pain)

CONDUCTION of a NERVE IMPULSE

Conduction Blockade

LAH + LAIonized Nonionized

SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE

1. Diffusion of the base (nonionized) form across the nerve sheath and nerve membrane
2. Re-equilibration between the base and cationic forms in the axoplasm
3. Penetration of the cation into and attachment to a receptor site within the sodium channel.
4. Blockade of the sodium channel

SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE

5. Inhibition of sodium conduction
6. Decrease in the rate and degree of the depolarization phase of the action potential
7. Failure to achieve the threshold potential
8. Lack of development of a propagated action potential
9. Blockade of impulse conduction

Ionized

Mechanism of Action

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• depolarization
• Na+ channel (resting) Na+ channel (open) action potential
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• rapid Na+ channel (inactivated)
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• Na+ channel (resting) Na+ channel (open) II no depolarization
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• local anesthetic
• slow Na+ channel - local anesthetic complex (inactive)
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• local anesthetic