General Anesthetics and Local Anesthetics

Question 1

Which responses require the highest levels of anesthesia to block?

Answer 1

Autonomic responses

Question 2

Goals of General Anesthesia

Answer 2

1. Unconsciousness
2. Amnesia (no memory of experience)
3. Analgesia (no pain from noxious stimulus)
4. Immobility in response to noxious stimulus
5. Block ANS response to noxious stimulus

Question 3

Types of Anesthetic Agents

Answer 3

Volatile anesthetics - liquid at room temp, evaporate easily (halogenated agents)

Gaseous anesthetics 􏰖 gas at room temperature (NO)

Induction agents - bring patient to desired level of anesthesia (parenteral agents usually preferred)

Parenteral anesthetics 􏰖 -administered IV

􏰗 Maintenance agents -􏰖 maintain patients at the correct level of anesthesia (inhaled agents usually preferred)

Question 4

Mechanisms of Anesthetic Agents

Answer 4

Macroscopic Effects
􏰗- Altered electrical activity of cortex, thalamus, ascending reticular activating system (ARAS)
- 􏰚􏰎􏰑􏰒􏰑􏰐􏰇􏰏 􏰊􏰏 􏰉􏰎􏰂 􏰛􏰃􏰑􏰈􏰂􏰐􏰑􏰜􏰂􏰄􏰝􏰞 􏰈􏰅􏰋􏰉􏰄􏰅􏰒􏰏 􏰄􏰎􏰟Thalamus is the “pacemaker”, controls rhythmic firing of cortical cells􏰠activity changes with depth of anesthesia

Microscopic Effects
􏰗 - Hyperpolarization of neurons (more negative, less likely to fire action potential)

Mechanisms of neuronal hyperpolarization
􏰗- Increased inhibitory (GABAA, glycine, potassium 2-pore) neurotransmission
􏰗 - Decreased excitatory (NMDA glutamate, nicotinic ACh) neurotransmission

Question 5

Adverse effects of anesthetic agents

Answer 5

Hemodynamic : usually decreased mean arterial BP (due to vasodilation, cardiac depression, decreased sympathetic tone)􏰠–> monitor vital signs

Respiratory : nearly all general anesthetics reduce or eliminate ventilatory drive and airway reflexes (e.g., cough reflex)–> 􏰠tracheal intubation

Hypothermia 􏰖: due to exposed body cavity, cold fluids, reduced metabolic rate, increases morbidity –> 􏰠keep patients warm

PONV 􏰖: postoperative nausea / vomiting due to drug effects on brainstem vomiting center􏰠–>antiemetics

Emergence excitation 􏰖: in 5-30% of patients, delirium, crying, moaning, spasticity, thrashing, tachycardia as sympathetic responses return􏰠–> opioids, 􏰡2 agonists

Question 6

Parenteral Agents: Propofol

Answer 6

• most commonly-used parenteral anesthetic; white color due to formulation in soybean oil / egg-based emulsifier
  􏰗- Advantages: rapid onset / offset, anti-emetic (good side effect!)
  􏰗- Disadvantages: pain on injection (propofol infusion syndrome), hypotension, risk of bacterial contamination, allergic reactio

Question 7

Parenteral Agents: Midazolam

Answer 7

Midazolam
􏰗 -Advantages: reversal agent available 􏰦􏰧􏰎􏰑􏰉􏰕􏰏 􏰉􏰎􏰂 􏰄􏰂􏰙􏰂􏰄􏰏􏰑􏰒 􏰑􏰢􏰂􏰋􏰉􏰨
􏰗 -Disadvantages: slower onset / offset of effect, greater respiratory depression

Question 8

Parenteral Agent: Etomidate

Answer 8

Etomidate
􏰗-Advantages: rapid onset / offset, almost free of CV side effects
􏰗-Disadvantages: no analgesic effect

Question 9

Parenteral Agent: Thiopental (barbiturate)

Answer 9

􏰗- Advantages: rapid onset
􏰗- Disadvantages: respiratory & circulatory depressant, reduces cerebral blood,
availability may be limited due to ethical considerations (use in lethal injection)

Question 10

Parenteral Agents: Ketamine (NMDAR antagonist)

Answer 10

• a dissociative anesthetic (makes patient feel detached from pain), schedule III due to potential for abuse / misuse
  􏰗
  -Advantages: nearly free of respiratory side effects
  􏰗- Disadvantages: hallucinations, emergency reactions, CV stimulant, increases intracranial pressure

Question 11

Inhaled Agents -Potency

- Minimum alveolar concentration

Answer 11

Measures inhaled anesthetic potency; point on the dose-response curve where 50% of patients do not move in response to a painful stimulus

Higher lipophilicity = higher solubility in blood vs. air = higher partition coefficient (concentration of drug in blood vs alveoli at equilibrium) = higher potency = lower amount of drug needed to produce a given level of effect

Question 12

Inhaled Agents: Nitrous Oxide

Answer 12

Oldest anesthetic “laughing gas”
􏰅􏰒􏰆􏰂􏰏􏰉 􏰑􏰋􏰂􏰏􏰉􏰎􏰂􏰉􏰊􏰈 􏰣􏰛􏰒􏰑􏰇 􏰢􏰑- Advantages: rapid onset, pleasant sweet smell 􏰗
-Disadvantages: teratogenic

Question 13

Inhaled Agents: Sevoflurane

Answer 13

Most commonly inhaled agent; name reflects seven F atoms
􏰗 Advantages: least irritation of mucous membranes
􏰗 Disadvantages: mildly unpleasant odor, non-flammable

Question 14

Inhaled Agents: Desflurane

Answer 14

Advantages: rapid onset / offset of action, non-flammable

􏰗 Disadvantages: unpleasant pungent odor, low potency, expensive

Question 15

Inhaled Agents: Halothane

- Halothane hepatitis

Answer 15

Advantages: pleasant sweet smell, potent anesthetic 􏰗
Disadvantages: unstable in light, risk of hepatitis

􏰛Halothane hepatitis- 􏰝 􏰐􏰓􏰂 􏰐􏰊􏰒􏰆 􏰑􏰋􏰆 􏰄􏰂􏰙􏰂􏰄􏰏􏰊􏰓􏰒􏰂 􏰅􏰄 􏰣􏰄􏰑􏰄􏰂􏰒􏰟􏰪 􏰏􏰂􏰙􏰂􏰄􏰂 􏰑􏰋􏰆
Hepatic metabolism of halothane produces free radicals that damage cells,
creating antigens that cause sensitization reaction

Question 16

Local Anesthetics

Answer 16

MOA:
- All local anesthetics produce their effects by blocking the flow of Na+ through voltage-gated sodium channels on peripheral nerves
-Voltage-gated Na+ channels allow an action potential to move down an axon
- At threshold voltage, channels open and Na+ flows in 􏰖 the channels immediately close, resulting in unidirectional movement of the action potential toward the axon terminal
- Local anesthetics reversibly bind to a site in the interior of the Na+ channel, in a region of hydrophobic residues
􏰗 - Receptor affinity (and thus potency) is greater for the more hydrophobic local anesthetics

Question 17

Factors that influence Potency and Efficacy

Answer 17

1. Intrinsic responsivity of various nerve fibers: smaller diameter and myelinated nerves are more easily blocked (lower concentrations required
2. Fraction of the dose that reaches target nerve fiber, which depends on proximity to the site of action (location of administration) and the lipophilicity of the agent 􏰖 more lipophilic drugs are better able to penetrate fatty coverings on nerves
3. Ionization state :􏰖local anesthetics are weak bases; their ionization state depends on pKa and local pH
4. Nerve baseline firing rate: Recall that the binding site is inside the ion channel - local anesthetics can only gain access to the binding site when the channel is in its open (activated) state
   - Nerves that are more frequently stimulated present more opportunities for local anesthetics to bind

Question 18

Factors that influence duration of action

Answer 18

1. Rate of metabolism- amide and ester local anesthetics are metabolized by different enzymes:
   - Esters: rapidly metabolized by plasma cholinesterase’s
   - Amides: slower metabolism by liver CYP450 enzymes
2. Lipid solubility of anesthetic agent: drugs that partition more into lipid myelin sheath remain near the site of action longer
3. Vascularity of the tissue 􏰖-more tissue vascularization = more rapid clearance of drug from the site of action
4. Use of an adjunct vasoconstrictor-􏰖 a vasoconstrictor (e.g., epinephrine), is added to decrease rate of absorption from administration site into blood (localizes the drug at desired site)

Question 19

Toxicities of Local Anesthetics:

Answer 19

Dose dependent CNS and CV toxicities

• Allergic reactions :􏰖 ester local anesthetics can be metabolized to an antigenic metabolite (PABA)
• CNS toxicity - All local anesthetics can cause dose-dependent CNS stimulation (lightheadedness, numbness, etc.) 􏰖 at high doses, seizures, coma, death
• Cardiac toxicity - overdoses produce decreased contractility & conduction and hypotension*, and can cause CV collapse