Introduction to Pharmacology Chapter 1 - Home

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Local Anesthetics
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
Therapeutic Rationale
• Local anesthetics work by reversibly inhibiting
nerve conduction by blocking Na+ channels
• Blockade of different peripheral nerves is dosedependent
– termed ‘differential nerve block’, a sequence of blockade of sharp pain, cold,
warmth, touch, and finally conduction in motor fibers
• Site directed injections localize the action of
the drug
– choice of local anesthetic depends on the site of
injection and the duration of action needed
Effects on Different Fibers
Fiber type
Function
Diameter (mm)
Myelination Velocity (m/s) Sensitivity
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
++
Pain, Temperature
2-5
Light
12-30
+++
Preganglionic
<3
Light
3-15
++++
Pain
0.4-1.2
None
0.5-2.3
++++
Postganglionic
0.3-1.3
None
0.7-2.3
++++
Delta
Type B
Type C
Dorsal root
Sympathetic
Pharmacokinetics
Onset
Duration
Procaine
Slow
Short
Chloroprocaine
Fast
Short
Tetracaine
Slow
Long
Lidocaine
Fast
Moderate
Mepivacaine
Fast
Moderate
Bupivacaine
Moderate
Long
Ropivacaine
Moderate
Long
Etidocaine
Fast
Long
Esters
Amides
Medicinal Chemistry
• Chemical Structure
– Most local anesthetics consist of
a lipophilic group (aromatic ring)
connected by an intermediate
chain to an ionizable group
(usually a tertiary amine)
• Optimal activity requires a
delicate balance between the
lipophilic and hydrophilic
strengths of these groups
Lidocaine
CH3
C2H5
O
NH
C
CH2
N
C2H5
CH3
Lipophillic
Group
Intermedi ate
Chain
Ami ne
Substituents
Amides Versus Esters
CH3
C2H5
O
Lidocaine (amide)
NH
C CH2 N
C2H5
CH3
Procaine (ester)
C2H5
O
H2 N
C
O
CH2
CH2
N
C2H5
Mechanism of Action
• Local anesthetics need to enter into nerve cells
– lipophilic properties allow for membrane diffusion
• Local anesthetics need to interact with the inside
of voltage gated Na+ channels
– these drugs are typically weak bases: under
physiological conditions these drugs tend to carry a
positive charge and are hydrophillic
– the cationic form of the drug is the most active inside
sodium channels
Mechanism of Action
• A characteristic blocking effect is observed with local
anesthetics
• Nearly full sized Na+ currents can be elicited during the
first depolarizing impulse in the presence of a local
anaesthetic
• Subsequent impulses elicit smaller and smaller peak
currents
•
It has been hypothesized that the drug binds
cumulatively and that this block needs open channels
• This accumulation of inhibition has been called usedependent block or phasic block
Clinical Question
Observation:
• Dentists frequently observe that local
anesthetics are less effective in infected tissues
Question:
• What might be a mechanistic explanation for this
observation?
Pharmacokinetics-Absorption
• Local anesthetics are usually administered by
localized injection
– the onset of effect is therefore typically rapid
• The systemic absorption of these drugs from the
site of injection is of considerable importance
– rate of offset of anesthesia
– CNS toxicity
– cardiac toxicity
Pharmacokinetics-Absorption
• A vasoconstrictive agent such as norepineprhine
is commonly co-administered with some local
anesthetics
– decreases blood flow to injection site
– lowers the systemic absorption of the local anesthetic
– prolongs the duration of anesthesia
• Cocaine has a unique pharmacological profile
– blocks reuptake of NE --> produces vasoconstriction
Types of Anesthesia
• Surface anesthesia
– liquid spray or drops
– lotions, creams or ointments
• Localized injection
–
–
–
–
infiltration anesthesia
nerve block anesthesia
epidural anesthesia
spinal anesthesia
Adverse Reactions and Toxicity
• Central Nervous System effects
– all local anesthetics can act on the CNS
– anxiety, paresthesias, tremors, tinnitus, convulsions
– high plasma concentrations can produce CNS
depression
• Cardiovascular effects
– most local anesthetics produce vasodilation
– cardiac depressant effects through Na+ channels
Adverse Reactions and Toxicity
• Allergic reactions (ester containing drugs)
– anaphylaxis (rare)
– contact dermatitis
• Spinal anesthetic effects
– variable hypotension
– spinal headache

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