pharmacology of local anesthetics

• cocaine was the first LA, -caine is the suffix for local anaesthetics. Most LAs are amines which make them weak bases and are linked to an aromatic group. Amide links are present in drugs like lidocaine whereas procaine contains an ester link.
• PHYSIOLOGY OF LAs:

  •Prevent generation and transmission of  impulses along nerve fibres

  •More effective at smaller (Ad & C) fibres

  •Sensitivity to LAs varies among neurones: pain > sensory > autonomic > motor function

  •Other excitable tissues, e.g., heart, muscle
• point along an axon where the LA is inject is the point where the drug will interrupt the physiology of the nerve impulse, beyond here the AP will not be normal
• many different nerve axons: Large fibres have faster electrical impulse. Small fibre are more sensitive to LAs
• PHARMACOLOGY:

  TARGET = Voltage-Gated Na⁺ Channels (NaV)

  Activity = Channel blocker
• properties of LAs:

  •Use -dependence

  –Greater use = greater block

  –Anti-epileptics / anti-dysrhythmics

  –Rub where it hurts

  •pH -dependence

  –Inflamed tissue can be acidic

  –LA preparations frequently acidic (solubility)

  –Slower onset of action

  •Voltage -dependence

  –More depolarised = greater block

  –Anti-dysrhythmics
• use dependence - effectiveness is influenced by the frequency of use or the rate of neuronal activity.

  1. Repeated stimulation causes increased inhibition

  2. LAs more effective when VGNaCs open/inactivated
• used dependence: some LAs that have a higher affinity for inactivated sodium channels, which are more prevalent when neurons are firing rapidly like in chronic pain or intense stimuli which means certain LAs show increased potency. This occurs because they have a greater chance to bind to sodium channels when inactive, blocking the transmission of nerve signals more effectively.
• The pH dependence of LAS refers to the influence of the surrounding pH level on the potency and effectiveness of these anesthetics.

  LAs exist in different forms: a charged, ionized form (usually more water-soluble and inactive) and an uncharged, non-ionized form (more lipid-soluble and active). The ratio between these two forms is affected by the pH of the surrounding environment.
• pH and Ionization: The degree of ionization of a local anesthetic depends on the pH of the tissue. At lower pH (more acidic environments), the proportion of the ionized form of the LA increases. Conversely, at higher pH (more basic or alkaline environments), the non-ionized form becomes more dominant.
• Effect on Penetration and Action: The non-ionized form of local anesthetics is the active form that can penetrate cell membranes and reach the sodium channels on nerves to exert its anesthetic effect. Therefore, in tissues with a higher pH (more basic), where more of the non-ionized form is present, local anesthetics tend to be more effective because they can more readily penetrate nerve membranes.
• Clinical Considerations: In inflamed or infected tissues, which tend to be more acidic, the increased acidity can lead to a higher proportion of the ionized form of the anesthetic, potentially reducing its effectiveness due to a decreased ability to penetrate nerve cells.
• Buffering Agents: In clinical practice, adjusting the pH of the local anesthetic solution or using buffering agents can sometimes be employed to optimize the effectiveness of the anesthetic in specific situations. This adjustment helps to favor the non-ionized form, increasing its ability to penetrate cell membranes and therefore enhancing its anesthetic action.
• there are 2 ways that the blocking site in the Na channel can be reached:

  1. hydrophilic pathway: via open channel gates by charged BH+ species on the inner surface of the membrane
  2. hydrophilic pathway: through fenestrations in the channel wall while uncharged, crossing the membrane
• Voltage dependence in the context of local anesthetics (LAs) refers to the property where the binding and action of these anesthetics on sodium channels are influenced by the membrane potential or voltage across the nerve cell membrane.
• Use-Dependent Action in voltage-dependence: The voltage dependence of LAs ties in with their use-dependent action. During periods of high neuronal activity or rapid firing, sodium channels are more likely to transition to an inactivated state. LAs that preferentially target these inactivated channels are more effective in blocking nerve signals under these conditions.
• CLINICAL:

  •Local Anaesthesia

  –therapeutic

  –facilitation

  –diagnosis (veterinary medicine)

  •Anti-epileptic drugs

  •Anti-dysrhythmic drugs
• LA for Analgesia/anaesthesia (therapeutic)

  –Reduction of pain/discomfort

  •e.g., anorectal; cough; mouth ulcers; teething

  –Reduction of sensation

  •e.g., premature ejaculation
• LA for Surgical procedures (facilitative)

  –avoidance of general anaesthesia

  –dental; ophthalmology (plus vasoconstrictors/cocaine)

  Other procedures (facilitative)

  –epidural; catheterisation; intubation; endoscopy
• •Veterinary

  –Diagnosing equine lameness (diagnostic)

  –Procaine penicillin (facilitative)
• use as Anti-epileptic drugs

  •Phenytoin; carbamazepine; lamotrigine…

  •Selectivity arises because of USE-DEPENDENT properties of LAs

  –More neuronal firing = more block

  –Selectivity is strongly dose-dependent

  –ALL excitable tissues can be inhibited with LAs

  –Other factors, e.g., axon size
• Other drugs that target VGNaC

  • Pyrethroids–e.g., pyrethrin
  • tetrodotoxin (TTX) - neurotoxin

  Channelopathies (thousands of known mutations)

  •Arrhythmias–e.g., Long QT syndrome,  Brugada syndrome, heart block

  •Loss-of-function mutations–e.g., Dravet Syndrome

  •Gain-of-function mutations–e.g., Hypokalaemic Periodic Paralysis

  other pathologies: migraine, peripheral neuropathy  & chronic pain