General and Local Anesthesia

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Anesthesia
Loss of sensation or state without any feeling
Types of anesthesia
General
- body wide; bigger range of surgery
- may disturb all organ systems

Local or regional (analgesia)
- minimal system disturbance
- may not be adequate
Type of General anesthetics (2)
1. Inhalable
- gasses or vapors; usually halogenated
- usually used for maintenance anesthesia
- can be used for induction pediatrics

2. IV or fixed
- usually used for induction of anesthesia and short surgical procedures
- becoming more common for maintenance
- neurosurgical cases where sensory and motor intraoperative monitoring is becoming standard of care
How does anesthesia depress spontaneous and evoked neuronal activity?
- induce neuronal hyperpolarization
- increase firing threshold (less activity)
- inhibit synaptic transmission and response to released neurotransmitters
How do anesthetics alter ion channels?
- Increases GABA(A) receptor Cl- channel activity resulting in enhanced inhibitory neurotransmission and CNS depression
-. Activate VG K+ channels resulting in hyperpolarization of neurons and reduced activation
- Inhibit glutamate NMDA receptors resulting in decreased neurotransmission
What factors determine the uptake and distribution of inhaled anesthetics?
Rate of anesthetic onset and recover

1. Anesthetic concentration in inspired air
2. Pulmonary ventilation rate
3. Solubility in blood and lipid
4. Pulmonary blood flow
5. Arteriovenous concentration gradient
6. Elimination
Anesthetic concentration in inspired air
- proportional to its partial pressure or tension: concentration of an anesthetic gas increases as the partial pressure increases
- partial pressure depends on the ability to vaporize each agent (heat of vaporization) -> use of vaporizer machine
- gas molecules move down partial pressure gradient
- higher initial concentrations of gases that are moderately soluble in blood can be given to increase the rate or rise in the brain concentration
Pulmonary ventilation rate
- better ventilation results in more rapid onset of anesthesia
- may be altered by pre-anesthetic medication or in disease
- partial pressure of anesthetics with higher solubility are affected by ventilation rate

Options:
Manual hyperventilation
Ventilator control of breathing
How is partial pressure of anesthetics with higher solubility affected by ventilation rate?
NO is not soluble in blood
- increasing ventilation rate will not show a difference in arterial ventilation

Halothane is soluble in blood
- increasing the ventilation rate will significantly increase the buildup of arterial anesthetic tension
Solubility in blood and lipid
1. blood: gas partition coefficient (Otswald Coefficient) - solubility in blood
- the lower the coefficient, the less soluble, the more rapid raise in partial pressure in blood, the faster equilibration with brain and induction
- NO, which is less soluble, reaches a higher partial pressure in the blood faster, and this is able to reach anesthetic concentrations in the brain more rapidly (more is available to reach the brain); halothane will dissolve in blood before much gets to brain, so slower induction speed

2. brain: blood partition coefficient - solubility in lipid
- based on oil/gas partition coefficient and is related to anesthetic potency (the more lipid soluble the drug is, the more potent)
- adequate for all agents, so doesn't contribute to significant differences between clinically useful anesthetics
Pulmonary blood flow / cardiac output
High blood flow -> slower rise in blood and brain -> slower onset

Low blood flow -> faster rise in blood and brain -> faster onset

Increased uptake of anesthetic into the blood, will also result in increased distribution to all tissue, not just CNS

Important for agents with moderate-to-high solubility
Arteriovenous concentration gradient
The greater the uptake of the agent, the difference between inspired and alveolar concentrations = slower rate of induction

Insoluble agents are taken up slowly -> alveolar concentration rises fast -> faster induction
Elimination
Reverse process for uptake

Dependent mainly on blood: gas partition coefficient (Otswald)
Less soluble -> faster elimination
Minimum alveolar concentration (MAC)
Measure of anesthetic potency for inhalable anesthetics

The concentration of anesthetic (%) in inspired air at equilibrium when there is no response to noxious stimulus in 50% of patients

Low MAC = more potent
High lipid solubility = more potent

Predicted by oil/gas partition coefficient

Anesthesia is produced when anesthetic potency in brain is greater than MAC

not affected by sex, height, weight
MAC values of inhaled anesthetics are additive
Ex. NO (60-70%) can be used as a carrier gas producing 40% of a MAC, thereby decreasing the anesthetic requirement of both volatile and intravenous anesthetics

(NO has fast induction, so can speed up the induction of other agents)
What can increase MAC?
young age
hyperthermia
chronic EtOH abuse
hypernatremia
cocaine
ephedrine
What can decrease MAC?
elderly
hyothermia
hyponatremia
hypercalcemia
pregnancy
CNS depressants (opioids, benzos, barbs)
chronic amphetamine use
Advantages of inhalable anesthesia
- easy to control depth of anesthesia
- readily reversible, minute-to-minute control
Disadvantages of inhalable anesthesia
- induction not as fast or smooth as with fixed agents
General properties of halogenated agents
- potent -> usually used for maintenance anesthesia
- adjuncts usually requires (poor muscle relaxation/analgesia)
- good minute-to-minute control (via inhalation)
- moderately rapid recovery (via inhalation)
- potential use for some induction
Effects of halogenating volatile agents
- Non-explosive & non-flammable
- increased potency
- increased toxicity and side effects
General adverse effects of inhalable anesthetics
Depression of cardiovascular function
- decreased blood pressure and peripheral vascular resistance
- decreased myocardium
- decreased CO
- arrythmias and/or tachycardia
- sensitization to catecholamines

Depression of respiration and response to CO2

Decreased flow to liver and kidneys

Organ toxicity

Malignant hyperthermia
- in genetically susceptible patients with inhalable anesthetics combined with paralytics (rapid increase in temperature due to increased interactions with muscles)
What are IV anesthetic agents used for?
Induction and maintenance of anesthesia
Advantages of IV anesthetics?
- quick, easy and smooth induction
- rapid and complete recovery
- absence of pain and injury upon injection
Disadvantages of IV anesthetics?
- cannot reverse the effects, except via metabolism
- slow elimination
- adverse effects on CV and respiratory system
Local Anesthesia
Loss of sensation limited to a local area or region of the body
Local anesthetic
drug that block generation and propagation of nerve impulse that results in reversible, regional loss of function (analgesia)
Advantages of local anesthesia
- drug is delivered directly to target organ
- minimal loss of function
- increased safety with less disruption of organ systems
Disadvantages of local anesthesia
- high concentration in small area may increase potential for systemic toxicity
- poor minute-to-minute control
- may not be adequate for procedure
Topical local anesthesia
- applied to surface of skin, wounds, burns or mucous membranes
- skin penetration is critical factor
Perineural infiltration local anesthesia
injection of agent at one or more sites (non-specific) around specific area where anesthesia is desired

advantage: specific area to be anesthetized, easy of delivery
disadvantage: injection of large amounts of drug into small area increases potential for systemic absorption and toxicity
Nerve block local anesthesia
injection of agent around specific nerve to block conduction of sensory and motor fibers distal to block

advantage: less drug required to block larger areas distal to injection site
disadvantage: requires more skill and knowledge of anatomy
Spinal block
Injection of agent into CSF in lumbar subarachnoid space to reach the roots of spinal nerves that supply specific region

advantage
- more reliable block, return of CSF ensures correct location of needle
- patient is conscious with minimal disruption of respiratory and cardiovascular function

disadvantage
- time limited block
- no titration of block
- not reversible if complications occur
Epidural block
Injection of agent into extradural space and blockade of nerve root as it passes through the space

Advantage
- not time limited
- may be used 4-7 days post op
- can be titrated by varying infusion rate

Disadvantage
- less reliable than spinal block
Local Anesthetics mechanism of action
Primary mechanism
- blockade of VG Na+ channels (via protonation)
- decrease in generation and conduction of action potentials
a. inhibition of Na+ (and K+) conductance
b. inhibition of depolarization
c. inhibition of repolarization

1. Increase in excitation threshold and slower impulse conduction
2. Decrease in rate of action potential generation
3. Decrease in amplitude of action potential
4. No ability to generate action potential
Local anesthetics sites of action
#1 biotoxins
#2 Lidocaine
#3 Benzocaine (uncharged)
#4 Combination #2 and #3
Properties of all local anesthetics
All are weak bases; available as salts to increase solubility and stability
- Cationic form (LAH+) -> most active form at sodium receptor
- Uncharged base (LA) -> important for lipid penetration of membranes

Absorption is more rapid in highly vascular areas

Smaller and more lipophilic LAs are more potent, have faster rate of interaction with sodium channels and have longer duration of action
Amide local anesthetics
- metabolized in liver by P450s and excreted in urine
- longer half-life and longer duration of action
- half-life can be altered in patients with liver problems
Ester local anesthetics
- rapid metabolism by hydrolysis in the plasma via butyrylcholinesterase (BChE) and excretion in urine
- short plasma half-life (<1min) -> short duration of action
Minimum anesthetic concentration (Cm)
- minimum concentration of drug for standard block
- relative standard of potency
Factors that influence LA onset and recovery
1. fiber size
2. site of deposition
3. pH
4. Nerve stimulation rate
5. Ca2+ concentration
6. addition of vasoconstrictors
Fiber size on LA onset and recovery
Bigger fiber size -> bigger Cm

LAs can block all nerves, not just nociceptors
Nerve fiber susceptibility to LAs depend on size and degree of myelination
- smallest fibers most sensitive
- myelinated nerves more sensitive than non-myelinated

Blocking effect: (in order from first to last)
B-fibers
C-fibers (carry most pain signals)
A-delta
A-gamma
A-beta
A-alpha
Site of deposition on LA onset and recovery
Anesthesia occurs first at the outer fibers as the drug moves down concentration gradient
pH on LA onset and recovery
High pH -> low Cm
more potent

Someone with lots of inflammation will have lots of H ions released, which will lower the pH in the vicinity and thus lower the potency of anesthetic
Nerve stimulation rate on LA onset and recovery
Higher frequency nerves (e.g., sensory) are more sensitive
Ca2+ concentration on LA onset and recovery
High Ca2+ -> high Cm
Addition of vasoconstrictors on LA onset and recovery
- vasoconstrictor substances reduce local blood flow and reduce systemic absorption and reduces LA toxicity
- increase in local neuronal absorption at the site of drug administration
- increased duration of action

Drugs: Epinephrine most commonly used

CAUTION
Do not inject LA with vasoconstrictor into areas with end arterioles (e.g., digits, toes, ear lobes, nose, penis)
- potential to develop gangrene or sloughing of tissue due to impaired blood flow to that region
Factors that affect reversal of LA
1. Dilution by extra-cellular fluid (ECF)
- reduces intracellular concentration of LA

2. Absorption into circulation - most important
- depends on local blood supply (vascularity), metabolism depends on this

3. Redistribution to other areas
- function of organ blood flow and plasma protein binding
- drugs with little protein binding produce less toxicity

4. Use of vasoconstrictors (eg. epinephrine)
- Decrease in blood flow -> increase in duration of action
Metabolism of Amides
Metabolized liver via P450s to inactive metabolite

Longer half-life and longer duration of action
Caution: half-life can be altered in patients with liver problems
Metabolism of Esters
Metabolized in plasma via BChE to inactive metabolite (PABA moiety)

Short plasma half-life (<1min) -> short duration of action
Caution: Metabolite para-aminobenzoid acid (PABA) is prone to allergic reaction -> Always check if patient ever reacted to LA or other drugs that metabolize into PABA
Hypersensitivity (allergic reactions) to LA
- esters are more prone due to metabolism of PABA
- No cross-reactivity between amide and ester groups
(i.e., if allergic to one group, not allergic to the other group)
- most commonly allergic not to LA itself, but to methylparaben, the preservative used in multi dose vials
Systemic toxicity with LA
- All can have systemic toxicity, but less are likely with esters due to rapid metabolims in blood
- amides circulate in blood (active drug) until metabolism in liver (more prone to systemic toxicity)

CNS effects:
- possible manifestions of stimulation or depression
- initial euphoria (as with cocaine) or twitching that may progress to coma and convulsions
- restlessness and anxiety or fear are early sings

Cardiovascular effects:
- bipuvicaine
systemic toxicity has cardiac selectivity that can lead to complete cardiac collapse and death
Treatment for local anesthetic toxicity (LAST)
Intravenous lipid emulsion or IntraLipid
- forms a "lipid sink" to absorb circulating lipophilic toxin -> reduces rebound free toxin available to bind to myocardium
- anesthesiologists incorporate this medication on all block carts that they use in all facilities
Exparel-Liposome
Encased bupivicane that provides relief for up to 72hr postop

Given as a single dose injection only - reserved for certain procedures because it is expensive
EMLA
Eutectic Mixture of Local Anesthetics

- mixture of high concentration of local anesthetics in oil-water emulsions: lidocaine + prilocaine
- use as topical anesthetic on intact skin
TAC
Tetracaine, Adrenalin (epinephrine) and Cocaine
- Use topical in pediatric emergency rooms
Topical local anesthetics general rule
Topicals too toxic for injection
Injectables do not penetrate skin to block

Lidocaine can be used for both!
Neurolytics
Agents that are not reversible
Agents achieve a permanent local anesthesia

Uses: includes permanent block in terminal cancer or some other chronic condition

Agents: Ethyl alcohol, phenol
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