Pharmacology of Local Anaesthetics Flashcards
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.
What is the target site of a local anaesthetic?
Axons of A-delta and C fibres (sensory nerves)
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
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
Aδ is what kind of pain?
Acute
C is what kind of pain?
Dull ache after injury
Locals reversible block the transmission of…
AP in the neuron axon by blocking voltage-gated Na+ channels
What is the nerve fibre’s susceptibility to local anaesthetic?
B > C = Aδ > Aγ > Aβ > Aα
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
The chemical structure of local anaesthetics
aromatic end = lipid solubility
Intermediate = Ester or Amide
Amine end = water solubility
Classification of local anaesthetics is based on if they have…
an ester or amide as an intermediate chain
What is the main ester-based local anaesthetic used in veterinary medicine? What species?
Procaine
Farm animal
What are the main amide-based local anaesthetics used in veterinary medicine?
Lidocaine, Mepivacaine (horses), bupivacaine, ropivacaine
lipophilicity of locals relates to the…
potency
effect on the onset of action
effect on duration
more lipophilic =
more potent
the pKa determines… and has an effect on…
- speed of onset
- Effect on the environment pH
protein binding is associated w/
duration of action
(only the unbound drug is active)
Extracellular pH is 7.4. This means it favours what form of local anaesthetic?
unionised form
Locals act at the … so…
locals act at the site of injection so slow absorption is desired
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
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?
- CNS (sedation, nystagmus, lip-smacking, tonic-clonic seizures, coma)
- CV (bradycardia, arrhythmias, hypotension, cardiac arrest)
- 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?
- CNS signs, may not be observable in anaesthetized patients
- respiratory system depression
- 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)
