Local Anesthetics veterinary

 

LOCAL LOC AL ANESTHETICS ANESTHETICS

 

Local Anesthesia We will have reversible blockal transmission in di ffer fferent ent areas of CNS, centrally or peripherally.

(Definition)

TO prevent pain o r sensation of pain, or to treat some painful condi tion. Drugs will have effect as muscle relaxant age nts. W Will ill also affect motor motor neurons - gi ve os indication that they are not selective at blocking nerve fibers. They will block any block fiber they come in contact wit with. h.

Reversible ersible blockade of transmission in • Rev

peripheral nerves or spinal cord, usually to try to stop pain signals

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Local Anesthetics (Chemistry)

Important to know on ly athat there Important are amide local ane sthetics, metabolized by the l iver, and ester anesthetics which are metabolized metabolized in the plasma

group joined to a tertiar tertiaryy amine • An aromatic group group by either an amide or ester group amide link

lidocaine CH 3

NH

C

procaine

CH3

CH2

CH3

N

O

CH3

NH NH  2 2

CH2

CH2

ester link

C

O

O

CH2

CH2

CH2

CH3

CH2

CH3

N

3

 

Local Anesthetics

Al

(Drugs)

Amide LA

Ester LA

Lidocaine

Procaine

•• Bupivacaine • Mepivacaine • Ropivacaine • Prilocaine •

Dibucaine (Cinchocaine)

•• Benzocaine • Proparacaine • Tetracaine • Cocaine

Not used because owners can use it, or personnel. Years ago, it was used as a local anesthetics

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An AP is going to be taking place i n many tissues by depolarization of membrane

blocking channels and not allowing transmission of information. Main effect by blocking sodium channels and therefore transmission of

 

Local Anesthetics (Mechanism of action)

• The sodium channels can exist in three states resting

open

inactivated

out

in

 

-70mV

-50mV

-20mV wont be able to deplarize bec they are in the inactivated state

la sts very few miliseconds, the activation/desactivation

Na+

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most at the time given di rectly into site of action, close to where we want it. Will be able to get into the inside of the neuron and bl ock the sodium channels. Needs to get into the nonionized to cross membrane,, in the inside it will get ionized and will be able to block channels.

Local Anesthetics (Mechanism of action)

• Most LA (pKa = 8-9) cross the neuron cell

membrane in the unionized form and get to their binding site from the inside +

BH

+

B+H

resting

when open, it allows entry of sodium into the inside of cell, will change membrane potential

open

inactivated

out

+

BH in

 

-7 0 m V

takes longer, requires more concen trat tratrion, rion, not going to be activated by anything, does not allow entry or passage through channel o f any class of on.

-5 0 m V

-2 0 m V

+

B+H

+ +

BH

Na 7

 

Mainly given locally. we are not completely blocking all sen sation, so we may still have some pain.

Local Anesthetics (Pharmacokinetics)

Can be used a s a constant infussion, not very u sed, a very expensive way to produce analgesia. Can be sued as an antiarrhytm antiarrhytmic. ic. Can be used as anticonvulsan t as well bu t there are much better drugs nowadays.

Absorption Normally applied directly to the site of action

•

If very high concentrations, may cause convulsions, dose dependant.

Distribution The action is terminated by redistribution Vasoconstrictors asoconstrict ors (e (e.g., .g., epinephrine) decrease When drug starts being distribution away from site of action absorbed by different v vessels essels

••

around the nerves, eff effect ect will be terminated. + epi so Metabolism Ester LA are rapidly broken down by plasma Lidocaine that there is vasoconstriction vasoconstrict ion a nd drug is not absorbed. pseudocholinesterases Amide LA are mainly metabolized in the liver

• •

liver dz, changes in the dosage, depending on techinque being used.

Elimination Metabolites are excreted through the kidneys

•

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There are d iffer ifferent ent tyopes of ne rves, tr trnsmission nsmission of p ainful i nfo, movement, sensations, etc. Most important is tthe he type of fiber running throgh them

Local Anesthetics

old patients have less myelin/unmyelinated 1 mV   A-fiber waveform

10 ms

  C-fiber waveform

(Differential block) myelinated - high conduction

• Onset of blockade follows a Adelta, C fibers,

regular pattern

0.0625 mM

!

transmission of pain

-

•

Lidocaine

Small myelinated fibers Unmyelinated fibers (C)(Aslow)conduction Large myelinated fibers (A")

Pain and sympathetic transmission is blocked before motor transmission

0.125 mM

0.25 mM

0.5 mM

•

Difficult to achieve reliably in clinical situations

For procedures in which we dont want completely anesthesize: animal wont feeltoas much pain and ani mal will be standing. If we increase, we may cause animal to not be able to st stand and

1 mM

2 mM

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Help us determine where lameness come from. If we start from bottom to top. When When animal stops being lame, usually the last place where you blocked is the a ff ffected ected area.

Local Anesthetics

Need to walk animal. There is going to be transmission in to the CNS, drug will a ct ffaster. aster. Helping the lo cal anesthetic by waling the horse frequency dependent blocl

(Frequency-dependent (Frequenc y-dependent block)

•

Rapidly blocked firing nerves will be preferentially

-

Nerve fibers carrying pain signals Antiarrhythmic Anticonvulsant

dose depen dant, we dont want tto o anesthesize the complete myocardium

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drugs wil come as solu tions in %, dep ending on presentation and different uses. We We increase drug by giving a little bit more of the solution. If giving large volumes is a concern (chihuahua), insted of increasing volume, we increase concentration of drug (%). We need to know concentration of drug.

Local Anesthetics (Clinical pharmacology)

dose can be increased by increasing the • The dose can volume and/or the concentration

-

The larger the dose, the more rapid the onset of action and the longer the duration of action How much of the drug we need to gi ve to have certain effects effects.. If more lipid soluble, it enters easier in to the cell. If more hidrophi lic it can al so diffue to (sometimes) different tissues tissues as well . May take a little bit longer for drug to ha ve effect because fo techincque or anatomical di fferences. fferences.

 increases by increasing lipid and water solubility  increases •  Potency 

-

Lipophilicity increases increases penetration into the cell and therefore binding with sodium channels

-

Hydrophilicity increa Hydrophilicity increases ses diffusion tto o the site of action

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Local Anesthetics (Clinical pharmacology)

action depends  depends on placement of •  Onset of action the drug, concentration used, molecule size, lipophilicity, protein binding, and degree of ionization of the drug

-

The lower the pKa, the more unionized drug to penetrate into the axon

action depends on drug •  Duration of action depends

penetration into the axon (lipophilicity), binding to the sodium channel, continuous presence or absence at the site of action (vasoconstrictors) 12

 

Local Anesthetics (Clinical uses)

• Regional anesthesia Operativ Operative analgesia (usually needs sedation except ineruminants)

• • Postoperative analgesia • •

Diagnosing lameness (usually horses) Ventricular arrhythmias (not with epinephrine!)

• •

(Convulsions) (Reduce intracranial pressure) 13

 

Local Anesthetics (Routes of administration)

• Topical Local infiltration • Peripheral ripheral ner nerve ve block  • Pe Intra-articular Epidural

•• CRI • Intrathecal • Intravenous regional anesthesia (Brier’s block)

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Local Anesthetics (Adverse effects)

CNS CNS  stimulation

•

Muscle twitching, tremors and convulsive seizures - Diazepam, midazolam

CNS  CNS depression  depression  Unconsciousness and respiratory arrest

•-

Artificial respiration 15

 

Local Anesthetics (Adverse effects)

Cardiovascular depression Cardiovascular  depression (cocaine)  (cocaine)

• Bradycardia, dysarrhythmias, decreased cardiac contractility

Vasodilation, hypotension

• The more potent the LA, the greater the depression on the myocardium

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Local Anesthetics (Adverse effects) 0 g/ml

Analgesia 5 g/ml

Muscle twitching and hypotension 10 g/ml

Unconsciousness and apnea 15 g/ml

Myocardial depression and seizures

25 g/ml

CVS collapse and death

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Local Anesthetics (Adverse effects)

irritation of skeletal skeletal muscles and nerves •  Local irritation of

• •

at the injection site   Methemoglobinemia due Methemoglobinemia due to toxic metabolites (benzocaine, O-toluidine for prilocaine) Ester LA (and lidocaine preservative methylparaben) may cause histamine release  release  due to the metabolite by-product PABA (inhibits antibacterial effect of sulfonamides) 18

 

Local Anesthetics (Procaine)

• Ester LA • Slow onset and short duration of action • Poor penetration of mucous membranes • Rapidly metabolized to PABA • • •

Toxic (most notably in horses, CNS stimulation) Do not use! Beware! Some penicillin G preparations contain Beware! procaine (slows antibiotic’s absorption from muscle) 19

 

Local Anesthetics (Lidocaine)

• Amide LA Most commonly used LA in veterinarr y medicine veterina

• • Rapid onset (~5 min) and medium duration (~40 min, ~60 min with epinephrine) of action

-2% parentally, parentally, 4% topically t opically • Used as 11-2% (gels, ointments, solutions, sprays, patches)

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Local Anesthetics (Lidocaine)

• Clinical uses entricular arr arrh hythmias (IB aantiarrhythmic) ntiarrhythmic) - Ventricular As a supplement to general anesthetics - Endotracheal intubation in cats -

Suppresses convulsions and decreases intracranial pressure (low dose -rarely)

• Maximum dose 7 mg/kg (sheep is the most sensitive species)

••

In combination with oxytetracycline oxytetracycline Euthanasia in combination with embutramide

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Local Anesthetics (Mepivacaine)

• •

Amide LA Similar to lidocaine, but less irritant

•

Diagnostic nerve block in horses

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Local Anesthetics (Bupivacaine)

• Amide LA • Widely used (infiltration, nerve blocks, epidural, •

intrathecal) -it does not work topically Slow onset (20 min) but long duration (up to 8 h) of action The most cardiotoxic LA Maximum dose 2 mg/kg

•• • S(-)- and R(+)-enantiomers - S(-) = levobupivacaine 23

 

Local Anesthetics (Ropivacaine)

• Amide LA • Similar to bupivacaine, but shorter duration of action and less toxic

propivacaine vacaine • S(-)-enantiomer of propi

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Local Anesthetics (Prilocaine)

• Amide LA • Similar to lidocaine, but less toxic • •

Used for intravenous regional anesthesia Methemoglobinemia may may occur due to metabolic by-product O-toluidine 25

 

Local Anesthetics (Benzocaine)

• Ester LA • •

The lowest pKa (2.5) Unionized and low solubility Topical absorption only

•• Metabolized to PABA • May cause methemoglobinemia General anesthesia of fishes •

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Local Anesthetics (Lidocaine/Prilocaine)

®

EMLA  cream 2.5% lidocaine / 2.5% prilocaine

•• • 20-30 min to full effect • Dermal analgesia (5 mm depth) • To facilitate per cutaneous vascular catheterization

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Local Anesthetics (Proparacaine)

• Ester LA Topical - for corneal and conjunctival manipulation

• • Rapid onset (within 30

sec) and short duration (10-20 min) of action

• Less irritating than tetracaine

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Local Anesthetics (Tetracaine)

• Ester LA •

Topical -for corneal and conjunctival manipulation

-

Longer-lasting than proparacaine

• Intrathecal • Euthanasia in combination with embutramide 29

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Local Anesthetics (Other drugs)

• Cocaine -

•

Topical anesthesia of the nasal passage Highly addictive (Schedule II drug) No reason to use it in veterinary medicine

Dibucaine (Cinchocaine)

-

The most potent and toxic LA Euthanasia in combination with secobarbital

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Local Anesthetics (Politics)

• 2,6 Xylidine, a metabolite of most amide LA, is probably carcinogenic

• Lidocaine is banned in Europe for use in food animals - still the most widely used LA in people

CH3

NH2

CH3

2,6 Xylidine

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Local Anesthetics (The future?) Tissue

Sodium channels

CNS

NaV 1.1, 1.2, 1.3

Dorsal root ganglia

NaV 1.8, 1.9

Peripheral neurons

NaV 1.7

Neurons and CNS glia

NaV 1.6

Skeletal muscle

NaV 1.4

Heart

NaV 1.5