Local Anesthetics veterinary

LOCAL ANESTHETICSPharmacology IPharmacology IPharmacology I

Pharmacology I

Irene Vazquez Fuster

Local Anesthesia(Definition)

• Reversible blockade of transmission in peripheral nerves or spinal cord, usually to try to stop pain signals

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Pharmacology IPharmacology IPharmacology I

Pharmacology I


We will have reversible blockal transmission in different areas of CNS, centrally or peripherally.TO prevent pain or sensation of pain, or to treat some painful condition. Drugs will have effect as muscle relaxant agents. Will also affect motor neurons - give os indication that they are not selective at blocking nerve fibers. They will block any block fiber they come in contact with.

Local Anesthetics(Chemistry)

• An aromatic group joined to a tertiary amine group by either an amide or ester group

NH 2

CH3

CH3

CH3

CH2

CH2

CH2

CH2

CH2

CH2

CH2NH2

CH3

CH3

CH3

NH C

O

C

O

N

NO

amide link

ester link

lidocaine

procaine

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Pharmacology I


Important to know only athat there are amide local anesthetics, metabolized by the liver, and ester anesthetics which are metabolized in the plasma

Local Anesthetics(Drugs)

Amide LA

• Lidocaine

• Bupivacaine

• Mepivacaine

• Ropivacaine

• Prilocaine

• Dibucaine (Cinchocaine)

Ester LA

• Procaine

• Benzocaine

• Proparacaine

• Tetracaine

• Cocaine

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Pharmacology I


Al





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

Local Anesthetics(Mechanism of action)

• Blockade of voltage-gated sodium channels in nerve axons

Na+ Na+ Na+impulse- - - - -- - - - -

Na+ Na+ Na+ Na+ Na+

Na+ Na+ Na+ Na+ Na+5


Pharmacology I



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


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


• The sodium channels can exist in three states

resting open inactivated

Na+

out

in -70mV -50mV -20mV

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Pharmacology I


lasts very few miliseconds, the activation/desactivation


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


• Most LA (pKa = 8-9) cross the neuron cell membrane in the unionized form and get to their binding site from the inside

resting open inactivated

Na+

out

in -70mV -50mV -20mV

BH+

BH+ B + H+

B + H+

BH+

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Pharmacology I


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



takes longer, requires more concentratrion, not going to be activated by anything, does not allow entry or passage through channel of any class of on.



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

Local Anesthetics(Pharmacokinetics)

Absorption• Normally applied directly to the site of action

Distribution• The action is terminated by redistribution• Vasoconstrictors (e.g., epinephrine) decrease

distribution away from site of action

Metabolism• Ester LA are rapidly broken down by plasma

pseudocholinesterases• Amide LA are mainly metabolized in the liver

Elimination• Metabolites are excreted through the kidneys 8


Pharmacology I


Can be used as a constant infussion, not very used, a very expensive way to produce analgesia. Can be sued as an antiarrhytmic. Can be used as anticonvulsant as well but there are much better drugs nowadays.



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


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


When drug starts being absorbed by different vessels around the nerves, effect will be terminated.


Lidocaine + epi so that there is vasoconstriction and drug is not absorbed.


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

Local Anesthetics(Differential block)

• Onset of blockade follows a regular pattern- Small myelinated fibers (Aδ)- Unmyelinated fibers (C)- Large myelinated fibers (Aα)

• Pain and sympathetic transmission is blocked before motor transmission

• Difficult to achieve reliably in clinical situations

1 mV

10 ms

Lidocaine0.0625 mM

0.125 mM

0.25 mM

0.5 mM

1 mM

2 mM

C-fiberwaveform

A-fiberwaveform

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Pharmacology I


There are different tyopes of nerves, trnsmission of painful info, movement, sensations, etc. Most important is the type of fiber running throgh them



slow conduction


Adelta, C fibers, transmission of pain



myelinated - high conduction


old patients have less myelin/unmyelinated


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

Local Anesthetics(Frequency-dependent block)

• Rapidly firing nerves will be preferentially blocked

- Nerve fibers carrying pain signals

- Antiarrhythmic

- Anticonvulsant

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Pharmacology I


Help us determine where lameness come from. If we start from bottom to top. When animal stops being lame, usually the last place where you blocked is the affected area.Need to walk animal. There is going to be transmission into the CNS, drug will act faster. Helping the local anesthetic by waling the horse - frequency dependent blocl



dose dependant, we dont want to anesthesize the complete myocardium

Local Anesthetics(Clinical pharmacology)

• The dose can be increased by increasing the volume and/or the concentration- The larger the dose, the more rapid the onset of

action and the longer the duration of action (sometimes)

• Potency increases by increasing lipid and water solubility- Lipophilicity increases penetration into the cell

and therefore binding with sodium channels- Hydrophilicity increases diffusion to the site of

action 11


Pharmacology I


drugs wil come as solutions in %, depending on presentation and different uses. 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.



How much of the drug we need to give to have certain effects. If more lipid soluble, it enters easier into the cell. If more hidrophilic it can also diffue to different tissues as well. May take a little bit longer for drug to have effect because fo techincque or anatomical differences.

Local Anesthetics(Clinical pharmacology)

• Onset of action depends on placement of 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

• Duration of action depends on drug penetration into the axon (lipophilicity), binding to the sodium channel, continuous presence or absence at the site of action (vasoconstrictors)

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Pharmacology I

Local Anesthetics(Clinical uses)

• Regional anesthesia

• Operative analgesia (usually needs sedation except in ruminants)

• Postoperative analgesia

• Diagnosing lameness (usually horses)

• Ventricular arrhythmias (not with epinephrine!)

• (Convulsions)

• (Reduce intracranial pressure)13


Pharmacology I

• Topical

• Local infiltration

• Peripheral nerve block

• Intra-articular

• Epidural

• Intrathecal

• Intravenous regional anesthesia (Brier’s block)

Local Anesthetics(Routes of administration)

CRI

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Pharmacology I

Local Anesthetics(Adverse effects)

CNS stimulation

• Muscle twitching, tremors and convulsive seizures- Diazepam, midazolam

CNS depression

• Unconsciousness and respiratory arrest- Artificial respiration

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Pharmacology I


Cardiovascular depression (cocaine)

• Bradycardia, dysarrhythmias, decreased cardiac contractility

• Vasodilation, hypotension

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

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Pharmacology I


Analgesia

Muscle twitching and hypotension

Myocardial depressionand seizures

Unconsciousnessand apnea

CVS collapseand death

0 g/ml

5 g/ml

10 g/ml

15 g/ml

25 g/ml

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Pharmacology I


• Local irritation of skeletal muscles and nerves at the injection site

• Methemoglobinemia due to toxic metabolites (benzocaine, O-toluidine for prilocaine)

• Ester LA (and lidocaine preservative methylparaben) may cause histamine release due to the metabolite by-product PABA (inhibits antibacterial effect of sulfonamides)

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Pharmacology I

• 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 procaine (slows antibiotic’s absorption from muscle)

Local Anesthetics(Procaine)

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Pharmacology I

• Amide LA

• Most commonly used LA in veterinary medicine

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

• Used as 1-2% parentally, 4% topically (gels, ointments, solutions, sprays, patches)

Local Anesthetics(Lidocaine)

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Pharmacology I

• Clinical uses

- Ventricular arrhythmias (IB antiarrhythmic)

- 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

• Euthanasia in combination with embutramide

Local Anesthetics(Lidocaine)

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Pharmacology I

• Amide LA

• Similar to lidocaine, but less irritant

• Diagnostic nerve block in horses

Local Anesthetics(Mepivacaine)

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Pharmacology I

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

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Pharmacology I

• Amide LA

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

• S(-)-enantiomer of propivacaine

Local Anesthetics(Ropivacaine)

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Pharmacology I

• Amide LA

• Similar to lidocaine, but less toxic

• Used for intravenous regional anesthesia

• Methemoglobinemia may occur due to metabolic by-product O-toluidine

Local Anesthetics(Prilocaine)

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Pharmacology I

• Ester LA

• The lowest pKa (2.5)

• Unionized and low solubility

• Topical absorption only

• Metabolized to PABA

• May cause methemoglobinemia

• General anesthesia of fishes

Local Anesthetics(Benzocaine)

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Pharmacology I

• 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

Local Anesthetics(Lidocaine/Prilocaine)

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Pharmacology I

• 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

Local Anesthetics(Proparacaine)

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Pharmacology I

• Ester LA

• Topical -for corneal and conjunctival manipulation- Longer-lasting than

proparacaine

• Intrathecal

• Euthanasia in combination with embutramide

Local Anesthetics(Tetracaine)

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Pharmacology I

• 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

Local Anesthetics(Other drugs)

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Pharmacology I

• 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

Local Anesthetics(Politics)

CH3

CH3

NH2

2,6 Xylidine

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Pharmacology I

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 1.532


Pharmacology I

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Local Anesthetics veterinary