Anaesthetics

Question 1

How do local anaesthetics work?

Answer 1

• Reversibly block nerve conduction, blocks nociceptors, so info detected by sensory receptors is not being consciously made aware of by brain, stops action potentials being carried to sensory neurones
• Have protein targets, in form of sodium voltage gated channels, that interferes with action potentials
• Properties: reversible, block nerve conduction, effective for time of procedure, low toxicity
• Ionised molecules can only block Na channels that are open or recently opened (local anaesthetic does not effect inactive neurones)
• Mechanism affected by:
  1. Tissue pH - affected by inflammation/infection, drive ionised molecule formation (ionised form cannot enter cell to block channel) = poor anaesthesia
  2. Neurones: size of neurone and myelination affect action of neurones (motor fibre neurones less sensitive than sensory neurones)
• Administered through:
  1. Topical anaesthesia - rub on surface (diffusion), slow process
  2. Infiltration: inject near nerve ending of target of blocking pain
  3. Nerve block: control size of area, control number of neurones it affects
  4. Epidural: enters epidural filled space that surrounds spinal cord (targets a lot of neurones)
  5. Spinal: bathe nerve endings existing spinal cord

Question 2

Chemical properties of local anaesthetics

Answer 2

• All have aromatic rings (has to be lipid soluble to cross cell membrane)
• All have amine group joined to aromatic ring through linkages (site of where drug is broken down in body, either ester or amide)
• Amine groups can be polarised (adding hydrogen)
• pH determines if amine group needs to be ionised, in solution, some molecules interact with H2O, others will not if they are strong bases
• By changing environment to more acidic, it drives reaction to a greater proportion of ionised molecules
• At physiological pH, there is imbalance, less ionised than unionised form
• Nociceptive neurones that has no stimulus triggering sensory receptors, channels are shut, no ions enter
• In a sensory neurone stimulus, neurone comes to threshold, action potential in axon depolarises membrane, opening Na voltage gated Na channels
• Local anaesthetic interferes, unionised, lipid soluble, ring-containing molecules diffuse and enter axoplasm
• New environment so new equilibrium set up between ionised and unionised molecules

Question 3

Basic principals of general anaesthetics

Answer 3

• Anaesthesia: abolition of sensation, triad of general anaesthesia include: need for unconsciousness, for analgesia, and muscle relaxation (primarily loss of reflexes)
• Action is through depressing the CNS activity
• Lipid theory of action: volume expansion of lipid membrane ↑ concentration of anaesthetic in cell, ↑ in lipid volume → ↑ pressure, anaesthesia occurs when lipid volume is expanded by 0.04%, high atmospheric pressure reverse anaesthesia
• Agents act by either volume expansion of lipid cell membrane or ↑ fluidity of cell membrane, these theories interfere with conduction of nerve impulses/action potentials
• Protein theory: protein targets, but lipid solubility is required for access to binding domain, ‘cut-off’ phenomenon for homologous series of long-chain anaesthetic compounds, ↑ chain length increases lipid solubility (not equal to ↑ anaesthetic potency)
• There is stereoselectivity so differential ability to bind to protein with different potency as general anaesthetic
• Importance of lipid solubility: access for anaesthetics to bind to hydrophobic pocket on proteins
• Molecular targets include: K+ channel activation decreases membrane excitability (hyperpolarisation), excitatory (glutamate/5-HT/Ach) or inhibitory (GABAa/glycine)
• Major effects on CNS function are through inhibition of synaptic transmission: ↓ neurotransmitter release, ↓ post-synaptic responsiveness (can depress entire CNS)

Question 4

How is anaesthetic potency measured?

Answer 4

• Minimal alveolar concentration (MAC): concentration of anaesthetic in alveoli required to produce immobility in 50% of patients when exposed to noxious stimulus
• At equilibrium: inspired concentration = alveolar concentration = brain concentration
• MAC is inversely proportional to lipid solubility (main determinant of anaesthetic potency)
• Oil: gas partition coefficient means 2 different compartments where individual agent dissolves so adding agent to mixture of oil and gas, if agent enters oil more, then it has a higher partition coefficient which would then indicate its potency

Question 5

Pharmacokinetic aspects of inhalation anaesthetics

Answer 5

• Main factors influencing rate of induction: properties of anaesthetic and physiological factors (adipose tissue)
• Access of anaesthetic to brain: equilibrium between different compartments, there is a partition coefficient between tissue and blood and another partition coefficient between blood and gas
• Need a specific sufficient concentration of anaesthetic agent in brain to produce anaesthesia
• High concentration in air breathed in or ↑ rate of depth can ↑ speed of induction
• Highly soluble gas means blood has large capacity so more molecules required to saturate blood so lower solubility is better for speed of induction (high solubility can speed up gas transfer into blood but does not speed up how quickly it enters brain - different equilibrium between compartments effects transfer)
• Relatively low soluble gas transfers to brain faster, lower blood: gas partition coefficient so gas leaves blood more quickly, increases speed of induction
• Blood: gas partition coefficient is inversely proportional to speed of induction; main factor (speed of induction and potency however are not related)
• Rate of pulmonary blood flow: higher CO = faster transfer
• Tissue blood flow is high in lean tissue so faster transfer but low blood flow in adipose tissue = slower transfer
• Elimination of inhalation anaesthetics: mainly breathe out anaesthetics, not metabolised (the ones that are can lead to toxicity), but dependent on factors involved in speed of induction in reverse