Pharmacology of Local Anaesthetics Flashcards by Rebecca Hancorne

Define local anaesthetic

Produces a reversible blockade of the propagation of the action potential, to anaesthetize a region of the body, w/ or w/o muscle paralysis, & are applied at target site.

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What is the target site of a local anaesthetic?

Axons of A-delta and C fibres (sensory nerves)

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Aδ fibres

Axon diameter, myelination, speed (m/s), fxn

axon diameter: 2-5 micrometres
Myelination: thinly myelinated
speed: 5-30 m/s
fxn: pain, temperature

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C fibres

Axon diameter, myelination, speed (m/s), fxn

Axon diameter: 0.5-1
Myelination: Unmyelinated
Speed: 0.5-2 m/s
Fxn: pain, temperature

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Aδ is what kind of pain?

Acute

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C is what kind of pain?

Dull ache after injury

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Locals reversible block the transmission of…

AP in the neuron axon by blocking voltage-gated Na+ channels

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What is the nerve fibre’s susceptibility to local anaesthetic?

B > C = Aδ > Aγ > Aβ > Aα

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What is the basic mechanism of action of local anaesthetics?

Enters cell via membrane or Na+ channel
reversibly binds to all Na+ channels from the inside of the cell
Prevents nerve conduction
block transduction at afferent nociceptor

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The chemical structure of local anaesthetics

aromatic end = lipid solubility
Intermediate = Ester or Amide
Amine end = water solubility

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Classification of local anaesthetics is based on if they have…

an ester or amide as an intermediate chain

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What is the main ester-based local anaesthetic used in veterinary medicine? What species?

Procaine
Farm animal

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What are the main amide-based local anaesthetics used in veterinary medicine?

Lidocaine, Mepivacaine (horses), bupivacaine, ropivacaine

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lipophilicity of locals relates to the…

potency
effect on the onset of action
effect on duration

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more lipophilic =

more potent

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the pKa determines… and has an effect on…

speed of onset
Effect on the environment pH

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protein binding is associated w/

duration of action
(only the unbound drug is active)

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Extracellular pH is 7.4. This means it favours what form of local anaesthetic?

unionised form

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Locals act at the … so…

locals act at the site of injection so slow absorption is desired

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The absorption of locals is…

injection-dose-dependent

Site of injection dependent absorption depends on…

physico-chemical properties
drug-tissue binding
tissue blood flow
intrinsic drug properties

Explain the metabolism & excretion of amides.

Metabolised in liver (Cytochrome P450) –> water-soluble metabolites –> excreted by kidneys

Explain the metabolism & excretion of Esters

Metabolised in plasma (pseudocholinesterase) –> water-soluble metabolites –> excreted via kidneys

What are the three main influences of the formulation of locals on their site?

concentration/dose
adjuvants in some preparations
mixture of different locals in same syringe & injecting

How does concentration/dose of formulation influence the site of action?

* increases onset * increases efficacy * influences vol administered * has effects on epidural blocks (req high enough vol to get block level you want)

Addition of epinephrine (& other vasoconstrictors) to local...

increases duration of action thus decreasing tissue blood flow

Use of vasoconstrictors reduce...

blood perfusion by about 30%

By reducing blood perfusion, vasoconstrictors cause what effects?

* enhance conc of available drug in premises of neuronal tissue * increase duration of action * prolong analgesic effects

Vasoconstrictors + locals should not be...

* given IV --> will kill your patient * given in extremities --> necrosis risk

What locals have anti-arrhythmic effects on the heart?

Lidocaine, Procaine

What locals can CAUSE lethal arrhythmias if given in high doses?

* Bupivacaine * Ropivacaine

Explain Purkinje Fibre AP

* Phase 4: resting membrane potential * Phase 0: rapid depolarization phase: opening of the fast Na+ channels * Phase 1: repolarization "notch“: inactivation of the fast Na+ channels and movement of K+ and Cl- ions * Phase 2: "plateau" phase: inward movement of Ca2+ and outward movement of K+ * Phase 3: the "rapid repolarization“: Ca2+ channels close, K+ channels still open

Local anaesthetics used an anti-arrhythmics are what class? What does it do to the AP of the purkinje fibres?

Class I agent (membrane-stabilising agents) Interferes w/ Na channels (affects phase 0)

Lidocaine | Safety profile, Onset, Duration of action, route, Uses, Cautions

* Safety Profile: high * Onset: 5-10 mins, MM faster * Duration: 1-2 hrs * Route: IV * Uses: local infiltration, epidural, spinal anaesthesia, desensitisation larynx at intubation, class 1b anti-arrhythmic, MAC-sparing properties, prokinetic * Caution: do not use before area of FB b/c will cause more motility, lidocaine stings on injections

Mepivacaine | Safety profile, Onset, Duration of action, route, Uses, Cautions

* Safety profile: high * Onset: quick * Duration: similar to lidocaine (1-2 hrs) * Uses: local infiltration, epidural anaesthesia, Dx anaesthesia in horses * Cautions: ? * Route: ?

Bupivacaine | Safety profile, Onset, Duration of action, route, Uses, Cautions

* Safety profile: Low (know your toxic dose for P) * Onset: 10-30 mins * Duration: 4-6 hr * Route: NOT IV * Uses: local infiltration, epidural, spinal anaesthesia ## Footnote Levobupivacaine has a higher safety profile (less cardiotoxic)

Ropivacaine | Safety profile, Onset, Duration of action, route, Uses, Cautions

Onset/Duration: similar to bupivacaine (10-30 mins, 4-6 hrs) Higher safety profile than bupivacaine Use: lower motor blockade at clinical doses, similar to bupivacaine?

local anaesthetics can be found in what types of preparations?

- single use vials for injection - sprays for topical - drops for topical - creams for skin - lidocaine skin patches

What are the signs of systemic toxicity caused by locals?

1. CNS (sedation, nystagmus, lip-smacking, tonic-clonic seizures, coma) 2. CV (bradycardia, arrhythmias, hypotension, cardiac arrest) 3. Respiratory (depression)

What are signs of toxicity in a local region?

tissue irritation of neurons, skeletal muscle

What are other forms of toxicity seen with locals?

* allergic rxns * methaemoglobinaemia

What is the order of presentation of toxicity signs?

1. CNS signs, may not be observable in anaesthetized patients 2. respiratory system depression 3. cardiovascular system depression

When it comes to toxicities with Bupivacaine, what do you need to remember?

It causes cardiovascular depression 1st which can cause arrhythmias that are deadly

What are toxic doses of Lidocaine

8 -16 mg/kg 6 mg/kg in dogs, 3mg/kg in cats

What are toxic doses of bupivacaine?

5 mg/kg do not inject more than 3 mg/kg in dogs/cats

What is the toxicity level of ropivacaine in dogs/cats

3 mg/kg

local toxicities of local anaesthetics is mainly seen with...

Procaine (ester-types)

How do you treat local anaesthetic toxicity?

* symptomatic/palliative: CV &/or resp support, steroids for allergic rxn, seizure coontrol (Diazepam, Propofol) * Lipid rescue (Intralipid emulsion)