Neuro: Hupka - Local Anesthetics

Front 1

1. indicate which one of the following is most likely to be cardiotoxic; which is most widely used clinically; which is most likely to cause CNS sedation; which is limited to surface or topical anesthesia only; which is most likely to produce vasoconstrictor effects.

Back 1

Cocaine:
Ester - Type LA
euphoria (unique in its ability to stimulate CNS)
Most LA cause Hypotension due to Arteriolar dilations.....but NOT cocaine
cocaine is exception: produces vasoconstriction****, blocks NE reuptake
Most LA decrease cardioexcitability and contractility....NOT cocaine --> stilumates the heart


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

Front 2

Lidocaine:

AMIDE - type LA
Most widely used LA****
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

Back 2

Benzocaine:

(pKa ~ almost 100% in nonionized form)
Topical use
ESTER - type LA
pKa ~ 3, essentially all non-ionized.... mechanism may be non-specific
Most limited to surface or topical anesthesia only!*****

Benzocaine
- 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

Front 3

Mepivacaine:

AMIDE - type LA

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)******

Back 3

Procaine:
Procaine and Lidocaine have most effect to cause Hypotension via Arteriolar dilation.

Procaine:
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

Front 4

Bupivacaine:

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

More cardiotoxic than other LA
****

Back 4

Tetracaine:
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*****

Prilocaine:
Similar clinical profile to that of lidocaine
Does cause significantly less vasodilation than lidocaine
Less vasoconstrictor need be added
Most popular clinical application is for topical anesthesia as in combo with lidocaine in a eutectic mixture***
Because of rapid systemic metabolism considered least toxic of amide LA
likely to cause Methemoglobinemia*****

Front 5

Ropivacaine:

Is structurally similar to bupivacaine (propyl group instead of butyl) and exists only as S stereoisomer

No topical effectiveness

Clinically ~ equivalent to bupivacaine

Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity****

Back 5

Most likely to cause CNS sedation:

Lidocaine - sedation even at non-toxic doses

Front 6

2. describe the nature of ‘differential nerve sensitivities’ to local anesthetics

Back 6

Most sensitive to LA block are?

Type A Delta
Type B
Type C - Dorsal root and sympathestic fibers

Front 7

What are Type A delta fibers?

Back 7

1st pain

temperature

Front 8

What are Type B fibers?

Preganglionic
autonomic
vasomotor fibers

Back 8

What are Type C dorsal root fibers?

2nd pain
temperature

Front 9

What are Type C Sympathetic fibers?

Back 9

Postganglionic

vasomotor

Front 10

3. describe the site and proposed mechanism(s) of action of local anesthetics.

Back 10

There are Both Specific and Non-specific effects

Specific:
(No effect on RMP - Resting Membrane Potential)
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 open and inactivated states and slows its reversion to the resting state.

Front 11

MOA:

**LA have low affinity for closed or resting state but have a high affinity for the open and inactivated forms.

Back 11

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 the open and inactivated states slowing return to resting form (prolonged refractory period) Increased entry into neuron through opened Na channel

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

Front 12

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

LA ACT IN CATIONIC FORM (charged)

Back 12

Non-Specific Action:

LA appear to have some non-specific actions

Appear to ‘dissolve’ in the membrane

Distorting the membrane and altering function

Ex: Benzocaine (pKa ~ almost 100% in nonionized form)
Topical use

Front 13

4. indicate the clinical significance of distinquishing between the two general chemical classes of local anesthetics in respect to elimination processes, duration of action, and allergic phenomenon.

2 classes are:

Ester linkage

Amide linkage

Back 13

Cross sensitivity (allergy):
Occurs with drugs in the same chemical class
Esters are metabolized to common metabolite PABA
Some preps have the preservative methylparaben (chemically similar to PABA)
Allergy rarely occurs with amide linkage class*****

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

Front 14

5. indicate which drug characteristics best correlates with rate of onset of local anesthesia. Indicate the relationship between local duration of anesthesia, lipid solubility, vasodilation and protein binding. Explain how local inflammation might adversely influence the effectiveness of local anesthetics.

Back 14

Rate of Onset:

FACTORS INFLUENCING LA ACTION~ Hydrogen ion concentration ~

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)*****

Front 15

The lowest pKa is fastest!

Exception is Chloroprocaine......... is given in high dose why it is fast

Back 15

FACTORS INFLUENCING LA ACTION~ LIPID SOLUBILITY ~
Potency and systemic toxicity directly correlate with LS (lipid solubility)
Ex: The more lipid soluble you are the more potent you are

Local duration positively correlated with LS and protein binding but inversely related to vasodilation
Ex: The more Vasodilation you have the Quicker the duration of the drug

Front 16

% Protein Binding:

The More Protein bound you are the LESS effect you have

Ex: 5% Protein bound is Fast duration

Ex: 94% Protein bound is Long duration

Back 16

FACTORS INFLUENCING LA ACTION~ Hydrogen ion concentration ~

INFLAMMATION

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*******

For over 100 years, LA solutions have been alkalinized to hasten onset of neural block

Front 17

6. explain the rationale for inclusion of vasoconstrictors in local anesthetic preparations and the potential risks associated with this drug combination

Back 17

ABSORPTION:
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 or alpha 2 agonists may enhance and prolong spinal anesthesia by acting on alpha 2 receptors to reduce substance P release

Front 18

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)

Back 18

7. indicate which physiological system is most sensitive to systemic effects of local anesthetics and which system is second most sensitive.

1st: CNS

2nd: Cardio

Front 19

CNS (More sensitive than cardio)
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

Back 19

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

Front 20

8. indicate in what ways cocaine differs from most local anesthetics with regards to CNS and vascular effects.

Back 20

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

Cocaine - euphoria (unique in its ability to stimulate CNS)

Front 21

9. compare procaine, lidocaine, bupivacaine, and tetracaine regarding onset and duration of action, lipid solubility, and chemical classification.

Back 21

Front 22

Procaine:

LOW lipid soluble
Low % Protein Binding
High Vasodilation
Short Duration of Action

Back 22

Lidocaine:
sort of lipid soluble
% sort of protein bound
high vasodilation

Bupivacaine
high lipid solubility
High Percent Protein binding
LOW vasodilation
Long Duration anethetic
moderate anethesthic duration

tetracaine:
High lipid solubility
high % protein bound
LOW vasofilation

Front 23

10. list two agents that are not classified as local anesthetics but have local anesthetic properties.

Back 23

A few drugs not generally used for local anesthesia have LA effects
May be substituted if patient is allergic to both esters and amide types.

propranolol
diphenhydramine
chlorpromazine
corticosteroids

Front 24

11. indicate which local anesthetic is almost 100% uncharged at physiological pH and used in many OTC preparations as a surface anesthetic.

Back 24

Benzocaine

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

Front 25

12. Lidocaine and prilocaine are quite similar in many respects, indicate two advantages that prilocaine has over lidocaine.

Does cause significantly less vasodilation than lidocaine
Less vasoconstrictor need be added
Because of rapid systemic metabolism considered least toxic of amide LA

Back 25

13. Indicate what EMLA is, local anesthetics used in this product, and some of the general uses.

EMLA = eutectic mixture of local anesthetics
Eutectic = two solid substances mixed together in equal quanitites by weight form a eutectic mixture
the melting point of the mixture is lower than the melting points of the individual components
EMLA = lidocaine and prilocaine becomes an oily mixture

Front 26

lidocaine/prilocaine combination is indicated for dermal anaesthesia

Specifically it is applied to prevent pain associated with intravenous catheter insertion, blood sampling, superficial surgical procedures; and topical anaesthesia of leg ulcers for cleansing or debridement

it can also be used to numb the skin before tattooing.

EMLA cream is also used in
the treatment of premature ejaculation
It is applied 20 minutes prior to sex

Back 26

14. Indicate the chemical relationship between bupivacaine and ropivacaine and indicate the alleged advantage of ropivacaine.

EPIDURAL AND CAUDAL ANESTHESIA
Both are Amide Linkage

Front 27

Ropivacaine
Is structurally similar to bupivacaine (propyl group instead of butyl) and exists only as S stereoisomer

Ropivacaine
Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity****

Back 27

15. indicate what methemoglobinemia is and its relationship to local anesthetic agents, which LA are most likely to produce this condition, and what agent is used to treat the condition.

Front 28

Methemoglobinemia – rare but life-threatening
Some LA metabolites have significant oxidizing properties

This may cause a significant conversion of hemoglobin to methemoglobin and compromize ability to carry oxygen

May be a problem if cardiopulmonary reserve is limited

Back 28

Treat with oxygen and methylene blue (converts methemoglobin to hemoglobin)

Prilocaine*****, benzocaine, and lidocaine have been implicated

Benzocaine most likely to cause methemoglobinemia

Front 29

16. Indicate the earliest signs of lidocaine’s CNS toxicity.

Back 29

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

Shit he said to know!

Front 30

know which are esters and which are amides

Back 30

ester has the O-C-O

Amide has the NH-C-O

Front 31

Know the groups of drugs as amides and esters

Back 31

AMIDE LINKAGE (2 EYES!!)
lidocaine (Xylocaine)
mepivacaine (Carbocaine)
bupivacaine (Marcaine)
etidocaine (Duranest)
ropivacaine (Naropin)


ESTER LINKAGE
procaine (Novocaine)
tetracaine (Pontocaine)
benzocaine
cocaine

Front 32

Know about infections and how this effects the drug

Back 32

Infection makes things more acidic
If too acidic get little drug in here and can cause toxicity because you give more drug and causes systemic effects

Front 33

Know which fibers are most susceptible to LA

Back 33

A-delta and which are most sensitive to LA block

Type C carries Pain and postganglionic SNS

EXAM!!!!

Front 34

Know Protein binding and affinity for the receptor

Back 34

Plasma protein binding may be used as an indirect measure of tissue binding tendencies

***HAS GREATER

Local duration positively correlated with LS and protein binding but inversely related to vasodilation

Front 35

Hydrogen ion concentration


rate of ONSET is related to pKa (because it determines the % of LA in a LS form)

The lowest pKa is fastest!

Back 35

Front 36

Most LAs affect the Heart:

Cardiovascular System
HYPOTENSION: Arteriolar dilation

Back 36

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

Front 37

Methemoglobinemia

Back 37

Treat with oxygen and methylene blue (converts methemoglobin to hemoglobin)
Prilocaine*** or Benzocaine*** most likley to cause this

Front 38

Tetracaine

Back 38

topical, infiltration and spinal anesthesia
Frequently used for topical ophthalomogical anesthesia

10X more toxic and more potent than procaine*****

Front 39

Mepivacaine

Back 39

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

Front 40

Bupivacaine

Back 40

Unique property of sensory and motor dissociation can provide sensory analgesia with minimal motor block
has been popular drug for analgesia during labor

More cardiotoxic than other LA******

Front 41

Ropivacaine

Back 41

Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity