Pharmacology I Pharmacology I LOCAL ANESTHETICS Pharmacology 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 bers. They will block any block ber they come in contact with.

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthesia
(Denition)

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

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Chemistry)

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

An aromatic group joined to a tertiary amine group by either an amide or ester group
lidocaine amide link
CH3 CH2 CH3

NH

CH2

CH3

CH2

CH3

procaine

ester link

CH2

CH3

NH NH2 2

CH2

CH2

CH2

CH3

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Al

Local Anesthetics
(Drugs)

Amide LA Lidocaine

Ester LA

Procaine

Bupivacaine

Benzocaine Tetracaine Cocaine

Mepivacaine Ropivacaine Prilocaine

Proparacaine

Dibucaine (Cinchocaine)

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

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

Pharmacology I Pharmacology I Pharmacology I - - - - - - - - Pharmacology I

Local Anesthetics
(Mechanism of action)

Blockade of voltage-gated sodium channels in nerve axons

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

Na+

Na+

Na+

Na+

Na+

impulse

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

out

in

lasts very few miliseconds, the activation/desactivation

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Mechanism of action)

The sodium channels can exist in three states

resting open inactivated

-70mV

-50mV

-20mV

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

Na+

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 nonionized to cross membrane,, in the inside it will get ionized and will be able to block channels.

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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

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

resting

open

inactivated

out

BH+

in

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.

-70mV

-50mV

-20mV

B + H+ BH+

Na+

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

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Pharmacokinetics)
Absorption Normally applied directly to the site of action Elimination Metabolites are excreted through the kidneys
liver dz, changes in the dosage, depending on techinque being used.

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.

Distribution The action is terminated by redistribution Vasoconstrictors (e.g., epinephrine) decrease When drug starts being distribution away from site of action absorbed by different vessels Metabolism + epi so Ester LA are rapidly broken down by plasma Lidocaine that there is vasoconstriction and drug is not absorbed. pseudocholinesterases Amide LA are mainly metabolized in the liver
around the nerves, effect will be terminated.

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

Adelta, C bers, transmission of pain

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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

Local Anesthetics
(Differential block)

old patients have less myelin/unmyelinated 1 mV

10 ms

A-fiber waveform

C-fiber waveform

Onset of blockade follows a regular pattern

myelinated - high conduction

Small myelinated bers (A) Unmyelinated bers (C) Large myelinated bers (A)

Lidocaine 0.0625 mM

slow conduction

0.125 mM

Pain and sympathetic transmission is blocked before motor transmission Difcult to achieve reliably in clinical situations

0.25 mM

0.5 mM

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

1 mM

2 mM

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

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Frequency-dependent block)

Rapidly ring nerves will be preferentially blocked

Nerve bers carrying pain signals Antiarrhythmic Anticonvulsant

dose dependant, we dont want to anesthesize the complete myocardium

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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.

Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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)
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.

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

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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 Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Clinical uses)

Regional anesthesia

Operative analgesia (usually needs sedation except in ruminants) Postoperative analgesia Diagnosing lameness (usually horses)
(Convulsions)

Ventricular arrhythmias (not with epinephrine!)

(Reduce intracranial pressure)

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Routes of administration)

Topical

Local inltration Intra-articular Epidural Intrathecal

Peripheral nerve block

CRI

Intravenous regional anesthesia (Briers block)

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Adverse effects)

CNS stimulation

Muscle twitching, tremors and convulsive seizures

- Diazepam, midazolam

CNS depression

Unconsciousness and respiratory arrest

- Articial respiration

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Adverse effects)

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 Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Adverse effects)
Analgesia
0 Mg/ml 5 Mg/ml

Muscle twitching and hypotension

10 Mg/ml

Unconsciousness and apnea

15 Mg/ml

Myocardial depression and seizures

25 Mg/ml

CVS collapse and death

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Adverse effects)

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 Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Procaine)

Ester LA

Slow onset and short duration of action Rapidly metabolized to PABA Do not use!

Poor penetration of mucous membranes

Toxic (most notably in horses, CNS stimulation)

Beware! Some penicillin G preparations contain procaine (slows antibiotics absorption from muscle)
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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Lidocaine)

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)

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Lidocaine)

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

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Mepivacaine)

Amide LA

Similar to lidocaine, but less irritant Diagnostic nerve block in horses

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Bupivacaine)

Amide LA

Widely used (inltration, 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(-) = levobupivacaine

S(-)- and R(+)-enantiomers

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Ropivacaine)

Amide LA

Similar to bupivacaine, but shorter duration of action and less toxic S(-)-enantiomer of propivacaine

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Pharmacology I Local Anesthetics Pharmacology I Pharmacology I Pharmacology I

(Prilocaine)

Amide LA

Similar to lidocaine, but less toxic

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

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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 shes

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(Tetracaine)

Ester LA

Topical -for corneal and conjunctival manipulation

Longer-lasting than proparacaine

Intrathecal

Euthanasia in combination with embutramide

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

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

2,6 Xylidine

CH3

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Pharmacology I Pharmacology I Pharmacology I Pharmacology I

Local Anesthetics
(The future?)
Tissue CNS Sodium channels NaV 1.1, 1.2, 1.3 NaV 1.8, 1.9 NaV 1.7 NaV 1.6 NaV 1.4 NaV 1.5 Dorsal root ganglia Peripheral neurons Neurons and CNS glia Skeletal muscle Heart

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