Nervous System- Local Anesthetics By Schriefer

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Nervous System- Local Anesthetics by Schriefer

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Nervous System- Local Anesthetics by Schriefer

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Drugs which

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produce a REVERSIBLE loss of sensation …
in a localized part of the body…..
when applied directly onto nerve tissues or mucous membranes

Local anesthetics are ‘local’ ONLY because of how they are administered! (Selectivity)

Desirable Characteristics:
Rapid onset of action
Brief, reversible block of nerve conduction
Low degree of systemic toxicity
Soluble in water and stable in solution
Effective on all parts of the nervous system, all types of nerve fibers and muscle fibers

NO single drugs meets all of these

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Mechanism of action...

block what type of channels?

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Block voltage-gated sodium channels:
-bind to specific receptors at the INTRACELLULAR end of the voltage gated sodium channel
-prevent axonal conduction by a functional blockade

LA have greatest affinity for sodium channel in inactivated state and interfere with its reversion to the resting state.

once a channel is activated, it has to be recycled back to the resting state before it can be activated again, and LA block this transformation.

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MoA is dependent on WHAT?

this may be due to?

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1. action is voltage dependent.

This may be due to:
Voltage changes induce changes in form of Na+ channels
LA have a higher affinity for Na+ channel in
-Some closed forms of the channel preventing them from opening
-the inactivated state; their binding slows return to resting form (prolonged refractory period)
Increased entry into neuron through opened Na channel (myocardium)

2. action is also frequency dependent:

Because high affinity forms of Na+ channel (e.g. inactivated) are more frequently presented in neurons that are firing more frequently (increased binding and effect)

This provides a degree of LA selectivity
-Frequent firing pain neurons more affected than slow firing motoneurons

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LAs are acids or bases? strong or weak? Access is dependent on what?

what form is action in?

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LA are WEAK BASES and access to receptor site is dependent on:
-pKa
-lipid solubility
-molecular size and level of neuronal activity

A LA must partition into the cell membrane, diffuse across and dissociate from it – must be moderately lipid sol.

LA ACT IN CATIONIC FORM (charged)

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FACTORS INFLUENCING LA ACTION

~ LIPID SOLUBILITY ~

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Potency and systemic toxicity directly correlate with LS

Local duration positively correlated with LS and inversely related to vasodilation

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FACTORS INFLUENCING LA ACTION

~ Hydrogen ion concentration ~

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LA are tertiary amines and WEAK BASES with pKa ~ 8-9

quaternary amine--> active form; tertiary amine--> lipid soluble

at pH 7.4 80 - 90% is ionized and can’t enter cells
-non-ionized (lipid-soluble) form needed for penetration
-cationic form required for binding to receptor

rate of ONSET is related to pKa (because it determines the % of LA in a LS form); lower the pka, the more in the lipid form that can get in so there's a faster onset.

inflammation tends to produce lower pH in tissues therefore
-LA are more ionized; don’t penetrate very well; decreased ability of LA to produce effects

RATE LIMITING FACTOR for LA onset is the time to penetrate nerve sheath and permeate cell membrane

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ESTER LINKAGE

AMIDE LINKAGE (2 EYES!!)

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Ester Linkages:
PROCAINE
procaine (Novocaine)
tetracaine (Pontocaine)
benzocaine
cocaine

Amide Linkages:
LIDOCAINE
lidocaine (Xylocaine)
mepivacaine (Carbocaine)
bupivacaine (Marcaine)
etidocaine (Duranest)
ropivacaine (Naropin)

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Clinical Significance of chemical classification:

ester vs amide and allergies

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Cross sensitivity (allergy):
-Occurs with drugs in the same chemical class
-Esters are metabolized to common metabolite PABA
-Allergy rarely occurs with amide linkage class

Biotransformation/duration of action:
-ESTERS are rapidly metabolized in the plasma by a cholinesterase
-AMIDES are more slowly destroyed by liver microsomal P450 enzymes.

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Local Anesthetics~ PHARMACOKINETICS ~

Absorption... what happens if there is systemic absorption?

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LA generally have good absorption from mucous membranes and intradermal injection sites. (into tissues)

Systemic absorption (out of tissues) terminates local action (Not local metabolism)

Factors influencing peak PLASMA concentration:
-Site of injection (vascularity)
-Total dose
-Specific drug characteristics; tendency to produce vasodilation
-Presence of vasoconstrictor (e.g., epinephrine, phenylephrine)

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Absorption and epinephrine

adverse effects with vasoconstrictors

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Effects of vasoconstrictors:
-Decrease rate of systemic absorption and decrease systemic toxicity
-Increase local drug concentration and increase neuronal uptake of LA
-Increase local duration of action (e.g. lidocaine’s duration my increase two fold with epi)

Epinephrine may enhance and prolong spinal anesthesia by acting on alpha 2 receptors to reduce substance P release

Potential adverse effects of vasoconstrictors:
DON’T use in areas of toes, fingers, ear lobes, penis (ischemia)
May produce tissue necrosis
May produce systemic toxicity (cardiovasc)

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distribution

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DISTRIBUTION
LA can be widely distributed to all parts of the body including CNS

Distribution is a means of terminating local drug action ........ not metabolism!!

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metabolism

for esters

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METABOLISM
Ester type LA
-Hydrolysis by cholinesterase in plasma to PABA derivatives
-->pseudo cholinesterase or butyrylchoinesterase
-Generally, short acting and low systemic toxicity**
-Prolonged effects seen with genetically determined deficiency or altered esterase (cholinesterase inhibitors)

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metabolism for amides

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Amide type LA:

Hydrolyzed by liver microsomal enzymes (P450)

Longer acting & more systemic toxicity than esters

Caution with severely compromised hepatic function

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What happens if they do go systemic?

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Extensions of pharmacological action
-Primarily related to blocking sodium channels

Intensity is dependent on blood levels

Toxic levels of LA in blood will not occur if absorption (into systemic blood) is slow or metabolism is rapid

CNS (More sensitive than CVS)
Dose-related spectrum of effects and All effects are due to depression of neurons:
-First an apparent CNS stimulation (convulsions most serious)
-Followed by CNS depression (death due to respir depression)
-Premonitory signs include: ringing in ears, metalic taste, numbness around lips

Cocaine - euphoria (unique in its ability to stimulate CNS)
Lidocaine - sedation even at non-toxic doses

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systemic toxicity and hypotension

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Cardiovascular System

HYPOTENSION: Arteriolar dilation is a result of:
Direct effect (procaine and lidocaine have most effect)
Block of postganglionic sympathetic fiber function
CNS depression
Avoid by adding vasoconstrictor to prep

Note: cocaine is exception: produces vasoconstriction, blocks NE reuptake

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systemic toxicities and arrhythmias

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Cardiovascular System

ARRHYTHMIAS: direct effect (More resistant than CNS)
-Decrease cardioexcitability and contractility
-Decreased conduction rate
-Increased refractory rate (bupivicaine)
Note: cocaine is exception......it stimulates heart
-ALL can cause arrhythmias if conc. is high enough

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Allergic Reactions

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ALLERGIC REACTIONS ... fairly rare
-Mostly with ester types
--esters metabolized to PABA which has allergenic properties

Cross-sensitivity within same chemical class of LA

Anaphylactic reactions are rare ..... diphenhydramine can be used to control minor reactions.

The preservative paraban in multidose vials may be responsible for some allergic phenomenon

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NEUROTOXICITY

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NEUROTOXICITY:

LA can cause concentration-dependent nerve damage to central and peripheral NS

Mechanism(s) not clear

Permanent neurological injury is rare

May account for transient neurological symptoms after spinal anesthesia
-Cauda equina syndrome

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Cocaine (Schedule II substance)

ester type LA

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Cocaine (Schedule II substance):
-Medical use limited to surface or topical anesthesia (corneal or nasopharyngeal)
-Avoid epinephrine because cocaine already has vasoconstrictor properties.
-A toxic action on heart may induce rapid and lethal cardiac failure.
-A marked pyrexia is associated with cocaine overdose.

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Ester type:

Benzocaine

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Benzocaine (Americaine)
pKa ~ 3, essentially all non-ionized.... mechanism may be non-specific
Available in many OTC preps for relief of pain and irritation
for surface anesthesia (topical) only ... ointments, sprays, etc.
Used to produce anesthesia of mucous membranes and to suppress gag reflex during endoscopy
methemoglobinemia

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Procaine

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Procaine (Novocaine)
Topically ineffective
Used for infiltration because of low potency and short duration but most commonly used for spinal anesthesia
Short local duration ......produces significant vasodilation. Epinephrine used to prolong effect
systemic toxicity negligible because rapidly destroyed in plasma

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Tetracaine

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Tetracaine (Pentocaine)
topical, infiltration and spinal anesthesia
Frequently used for topical ophthalomogical anesthesia
slow onset and more prolonged effect than procaine (longest duration of the esters)

~10X more toxic and more potent than procaine

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Amides:

Lidocaine, the most commonly used LA

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LIDOCAINE (Xylocaine)
Most widely used LA (prilocaine similar)
Effective by all routes.
Faster onset, more intense, longer lasting, than procaine.
Good alternative for those allergic to ester type
More potent than procaine but about equal toxicity
More sedative than others

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Mepivicaine

don't use it on who?

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Mepivicaine (Carbocaine)
Effective by all routes except topical

Similar onset and duration as lidocaine

More toxic to neonates so not used in obstetrical anesthesia (fetus poorly metabolizes mepivicaine)

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Bupivacaine

what is a unique property?
what is bad about it?

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Bupivacaine (Marcaine)
No topical effect
Slower onset and one of longer duration agents
Unique property of sensory and motor dissociation can provide sensory analgesia with minimal motor block
has been popular drug for analgesia during labor

Bad: More cardiotoxic than other LA

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Ropivacaine

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Ropivacaine
Enantiomer of bupivacaine (S stereoisomer)
No topical effectiveness
Clinically ~ equivalent to bupivacaine
Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity (allegedly)

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Surface anesthesia...

what do you use

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SURFACE ANESTHESIA (Topical)
Nose, mouth, bronchial tree, cornea, urinary tracts, and skin
Lidocaine, tetracaine
EMLA – mixture of lidocaine and prilocaine

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Nerve block of field block

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Interruption of nerve conduction upon injection into the region of nerve plexus or trunk.
Used for surgery, dentistry, analgesia.
Less anesthetic needed than for infiltration if you must anesthetize a large area.
Most LA’s used

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SPINAL ANESTHESIA

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SPINAL ANESTHESIA
Injection into subarachnoid space below level of L2 vertebra to produce effect in spinal roots and spinal cord.
Use hyperbaric or hypobaric solutions depending on area of blockade.
Used for surgery to abdomen, pelvis or leg when can’t use general anesthesia.

Lidocaine, tetracaine

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Spinal Anesthesia 
PROBLEMS

and advantages over epidural

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Problems:
Spinal headache due to increased CSF
Hypotension and bradycardia, respiratory depression

Advantages:
-greater predictability
-faster onset
-shorter duration

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know the pka, chemistry

and differentiate ester from amide

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ok got it.