Pharmacology: Local Anesthetics

• Pharmacology & Therapeutics discusses Local Anesthetics
• Fundamentals of Pharmacology (4BBY1040)

Learning Outcomes

• By the end of the lecture people should be able to name at least three clinically relevant local anesthetics
• People should be able to explain the molecular mechanism of action of these drugs and how this underlies their clinical usefulness
• Students should be able to list examples of the clinical uses of local anesthetics, including routes of administration
• Students should be able to explain how and why the effects of the drugs are altered by changes in extracellular pH
• Students should be able to list the main side effects of the drugs

Sensing Pain

• Specialized sensory nerves called nociceptors, detect tissue damage
• This triggers action potentials which propagate along the sensory nerve to the brain, via the spinal cord
• Only when that action potential reaches the brain, pain is perceived
• Local anesthetics prevent pain by stopping action potentials being triggered or propagating along sensory nerves

Local Anesthetics

• Local Anesthetics block action potentials
• Their molecular target is the voltage-dependent Na+ channel in sensory nerves involved in pain transmission
• The drugs "plug" the channel pore, preventing Na+ entry and the initiation/propagation of the action potential
• Because voltage-dependent Na+ channels are present in many tissues, the drugs have the potential to cause life-threatening side effects
• These are minimised by applying the drugs to a localised region
• The local concentration of a local anesthetic required to block the action potential in a sensory nerve is 0.1 – 1 mM
• The lethal systemic plasma concentration is 40 – 60 μM

Chemistry of Anesthetics

• Local anesthetic molecules consist of an aromatic head linked to a basic side chain by an amide or an ester bond
• Those with the ester bond are destroyed by esterase enzymes in tissues and plasma, so are shorter acting

Local Anesthetics as Weak Bases

• Local anesthetics are weak bases with pKa values around 8.0
• At physiological pH (7.4) the drugs exist in both their ionized and unionized forms

Drug Molecules

• Local anesthetics block voltage-dependent sodium channels by binding to a site deep within the ion channel pore
• The outer mouth of the pore appears too narrow to allow drug molecules through
• The inner mouth is guarded by activation and inactivation gates
• Only the basic, non-ionized form of the drug can penetrate the membrane and gain access to the channel; the ionized form is membrane impermeable
• This is called the hydrophobic pathway
• Factors which increase the degree of ionization, for example, ↓pH, will inhibit local anesthetic action

Hydrophilic Pathway

• Because the hydrophilic pathway is only available to the drug when the gates are open
• This means the more often the channel is used/opened, the more readily the drug can gain access, called use-dependence
• Nerves that fire action potential at high frequency open their voltage-dependent sodium channels more frequently, and are therefore more susceptible to block
• The hydrophobic pathway is NOT use-dependent

Other Points

• The pH of inflamed tissues can drop as low as 6.2
• Consequently, inflamed tissues do not respond well to LAs
• Small diameter nerve fibres, for example the Aδ- and C-fibres involved in pain transmission, are slightly more susceptible to LAs than larger diameter fibres, for example motor nerves
• It is impossible to selectively block transmission in pain fibers whilst leaving others untouched

Clinical Aspects

• Local anesthetics are used clinically to relieve or prevent pain, for example, during minor surgery
• They can be administered by various routes dependent upon the clinical situation
• In all cases the drugs are administered to a localized area to minimize entry of the drug into the systemic circulation and so minimize the likelihood of side effects

Types of Anesthesia

• Surface anesthesia is when the drug is applied to the surface of the body, which includes the urinary tract, bronchial tree, cornea of the eye, inside the nose
• A surface anesthetic is not very effective when applied to the skin, even the best preparations taking about 1 hour to take effect
• There is a danger of side effects if applied over a large area or to damaged skin
• Examples of surface anesthesia include catheterisation and minor eye surgery
• Infiltration anesthesia is when the local anesthetic is injected into tissues around sensory nerve terminals and branches (e.g. minor surgery such as wound stitching, dentistry)
• Nerve-block anesthesia is when the local anesthetic is injected around nerve trunks, for example in the brachial plexus in the neck to anesthetize the arm
• Nerve-blocks requires less drug than infiltration but affects a wider area
• Accurate placement of needle is important (e.g. minor surgery, dentistry, intractable pain) Spinal and epidural anesthesia involves injecting LA into (spinal) or around (epidural) the spinal cord
• Spinal and epidural anesthesia blocks nerves as they enter or rise within the spinal cord
• This spinal and epidural anesthesia has a widespread effect because all nerves entering the cord below the site of injection are blocked
• It is a highly skilled procedure used for major surgery (both) or "painless” childbirth (epidural)
• Intravenous regional anesthesia (Bier block) is when local anesthetic is injected intravenously into a limb isolated from the rest of the circulation using a pressure cuff
• An intravenous regional anesthesia is used in limb surgery e.g. to reset broken bones, repair major lacerations
• There must be caution taken to not release the cuff too quickly in order to avoid systemic side effects
• Duration of the procedure must also be limited (< 90 minutes) to avoid ischemic damage to limb

Side Effects

• All local anesthetics are inherently toxic
• If they enter the general circulation in high enough concentrations, they cause potentially life-threatening side effects
  • Confusion
  • Restlessness
  • Tremor
  • Convulsions
  • Respiratory depression (due to actions on central nervous system)
  • Vasodilation (leading to a drop in blood pressure (hypotension))
  • Myocardial depression (inhibition of heart muscle)
• Drugs are removed from their site of action either by being broken down (ester bond) or by entering into the general circulation where they become diluted
• Drugs with an amide bond get metabolized in the liver
• The duration of action when using "nerve block" or "infiltration" anesthesia can be increased by co-administration of a vasoconstrictor such as adrenaline to prevent the drug entering the general circulation
• Care must be taken if using a vasoconstrictor on fingers or toes for fear of causing ischaemic damage,